kkkkkkBLOOD CELLS PATHOLOGY

UNIT 14
ALTERATIONS IN BLOOD VOLUME, HEMOSTASIS, ESR, ORE
Alterations of blood circulating volume
If the blood volume is normal we can estimate it as normovolemia. Normovolemia can be simple, olygocythemic and
polycythemic. It depends on the ratio of the volume of red blood cells (RBC) to the total volume of blood, which is known as
hematocrit. Normal hematocrit for males varies from 40 to 48 %, for females from 36 to 42%. Moreover, each variant of blood
volume may be:
* Simple – with normal correlation of plasma and RBC;
* Polycythemic – high hematocrit index;
* Olygocythemic – low hematocrit.
Simple normovolemia is characterized by normal hematocrit. Polycythemic normovolemia hematocrit is increased (chronic
hypoxia, RBC transfusion). Olygocythemic normovolemia (low hematocrit) is observed at depressed erythropoiesis, increased
hemolysis and in the course of acute blood loss.
The increase of the blood volume is called hypervolemia. The volume of blood can rise due to the increase of plasma and/or
blood cells amount. The following types of hypervolemia are known:
Simple hypervolemia appears rarely. It can be observed immediately after the transfusion of large doses of blood. Simple
hypervolemia can also appear during intensive physical work, because blood comes from depots into the circulation.
Olygocythemic hypervolemia develops due to the increase of plasma amount. This state appears when there is delay of water in
an organism due to diseases of the kidneys or disturbances of water-electrolyte balance. Hematocrit is decreased in this case.
Polycythemic hypervolemia develops because of the increase of RBC amount. This state can appear as a compensatory reaction
to hypoxia or in the course of Vaquez' disease. The leading symptom of Vaquez’ disease is polycythemic hypervolemia. The
number of all blood cells is increased.
Low blood volume is named hypovolemia. Simple hypovolemia develops immediately after acute blood loss.
Olygocytemic hypovolemia can be observed at the second stage of acute blood loss, when the compensatory tissue fluid outcome
to blood stream does not completely restore the volume of blood. It is also observed in the patients with severe anemias.
Polycythemic hypovolemia develops in the course of organism dehydration. Such process can be observed at diarrhoea,
vomiting, abundant sweating, burns, overheating. In addition, polycythemic hypovolemia appears after shock, when increased
vascular permeability results in fluid outflow from blood vessels.
Regenerative and degenerative forms of RBC
Regenerative forms of RBC are mainly represented by reticulocytes. Reticulocytes are young RBCs, which have extruded their
nuclei but still contain large amounts of RNA and show a basophilic reticulum under vital staining (reticulum is basically
composed of RNA). Reticulocytes normally account less than 2% of circulating erythrocytes.
The reticulocyte count is used to determine if the bone marrow responds adequately to the body’s need for RBCs, to determine
its cause and classify different types of anemia. In a healthy patient, the reticulocyte percentage is essentially stable.
An increased reticulocyte percentage usually reflects the high intensity of hemopoiesis caused by increased loss of RBC, chronic
hypoxic conditions. It may indicate such conditions:
* Bleeding. In acute hemorrhage the number of reticulocytes rises a few days later in an attempt to compensate the RBC. In
chronic blood loss, the number of reticulocytes will stay at the increased level as the marrow tries to keep up with the demand for
new RBCs.
* Hemolytic anemia. Increased hemolysis of RBC, especially in hereditary hemolytic anemias results in markedly high activity
of hemopoiesis.
* Chronic hypoxic conditions increase the production of erythropoietin by the kidney’s in order to compensate oxygen
deficiency by the increased amount of mature and immature forms of RBC.
Decreased reticulocyte percentage indicates low activity of hemopoiesis and may be seen, for example, along with:
* Iron deficiency anemia;
* Pernicious anemia or folic acid deficiency;
* Aplastic anemia;
* Radiation therapy, because ionizing radiation breaks the activity of bone marrow along with other tissues with high level of
cell division.
Degenerative forms of RBCs include variations in shape, size, colouring of erythrocytes.
Poikilocytosis is the presence of an abnormal variation in shape of erythrocytes in blood. Normally RBCs have the form of
biconcave disk. In poikilocytosis different forms and configurations of RBC are revealed in blood (as bottles, weights, mulberry
berries and etc). In iron deficiency anemias plane RBC – planocytes are found out; in some inherited hemolytic anemias little
spherical RBC are named microspherocytes, oval form of RBC - ovalocytes, In thalassemia there are RBCs with the decreased
thickness and dark-painted area in the centre (target type RBC).
Anisocytosis is the change of RBC size. Normally, about 80% RBC have a size of 7 – 7,5 µm. Microcyte is 4 – 6 µm, schistocyte
or schizocyte – 2 – 3 µm, macrocyte – 8 – 12 µm. Schistocyte is an erythrocyte of irregular asymmetrical shape which was
fragmented under hemolytic conditions. It has not central pallor zone in comparison with normal RBC.
 Megalocytes are associated with pernicious anemia. They result from irregular type of erythropoiesis which starts from
megaloblasts. Megaloblasts look like embryonic erythroblasts. Megaloblasts transform to megalocytes – large, sometimes
changed form RBC; size > 12 µm.
FIGURE 12 Degenerative forms of erythrocytes
The colouring of erythrocyte is determined by its hemoglobin content and described by color index. Normal color index for
erythrocytes is 0,85 – 1. Erythrocytes which are normally colored are called normochromic.
Hypochromic erythrocytes are poorly colored RBCs containing the decreased quantity of hemoglobin which are attributed to the
degenerative forms. Their color index is lower than normal. When color index is more than 1 such erythrocytes are named as
hyperchromic erythrocytes.
RBCs containing different pathological inclusions:
Howell-Jolly Bodies are remains of nucleus, saved in RBC as a result of pathologic process of nucleus extrusion. It appears in
severe anemias (pernicious and after splenectomy).
The Cabot’s Rings are remains of nucleus membrane that look like ovals or eights. It appears as a result of pathological
destruction of normocyte nucleus in megaloblastic and pernicious anemia.
Heinz Bodies are round inclusions of different sizes that are revealed in mature RBC at poisoning by hemolytic poisons. They
are seen only at the special supravital colouring.
Siderocytes contain granules of iron that are not bounded with hemoglobin. Their presence in blood smear indicates the
problems with iron junction to hemoglobin (iron refractory anemia).
Erythrocytes with basophilic stippling (accumulations of rRNA or aggregated ribosomes) are always pathological and may
indicate: poisoning (lead, arsenic), sideroblastic anemia, hemolytic anemia.
Pappenheimer bodies are abnormal granules of iron found inside RBC. They are formed by phagosomes that have engulfed
excessive amounts of iron. They appear as dense, blue-purple granules within the red blood cell and there are usually only one or
two, located in the cell periphery. They are seen in diseases such as sideroblastic anemia, hemolytic anemia, and sickle cell
disease.
Accelerated erythropoiesis – increased input of stem cells and a shortened precursor generation time. The rate of erythropoiesis
may increase as much as 8 fold if RBCs are destroyed (hemolytic anemia), or lost (bleeding). The number of regenerative RBC
forms will increase.
Ineffective erythropoiesis is a term used to describe the destruction of developing erythroid cells in marrow. Normally, few of
them die within the marrow. Disorders of nucleic acid, heme, or globin synthesis caused by folate deficiency, iron deficiency,
vitamin B12 deficiency, lead poisoning, and thalassemia will result in ineffective erythropoieis. Ineffective erythropoiesis also
occurs in association with myeloproliferative (Vaquez disease) and myelodysplastic (hematological malignancies) disorders.
Osmotic resistance of erythrocytes
Osmotic resistance of erythrocytes (ORE) is a stability (susceptibility) of certain RBC to hemolysis in increasingly hypotonic
solutions. This test is also known as erythrocyte fragility test.
When erythrocyte is placed in the hypotonic NaCl solution, a net influx of solvent (water) into the cell will occur and the cell
will swell. If the cell reaches a certain point, its membrane will become leaky and hemoglobin will diffuse out (hemolysis). If the
NaCl solution is hypotonic enough, the cell will rupture.
Minimal and maximal osmotic resistance of RBC are determined. ORE min is such NaCl concentration at which the beginning
of hemolysis is noted (single RBCs are hemolysed). In a healthy person hemolysis starts in 0,45–0,4% NaCl solution. ORE max
is such concentration of NaCl at which complete hemolysis of RBCs is observed (0,33 – 0,28% solution NaCl).
The ORE increase (erythrocytes are less fragile) is observed:
* in mechanical jaundice and atherosclerosis – due to the absorption of cholesterol on RBC membrane, it makes it more resistant
to hemolysis;
* in tumors and amyloidosis – because of the proteins absorption on RBC that decrease RBC membrane permeability;
* when young RBC prevail which are more resistant to hemolysis are output from marrow (after blood loss, hypoxic influence);
* in anemias with abnormally shaped RBC (sickle cell, thalassemia).
The ORE decrease is observed in:
* hereditary microshperocytosis (RBC membrane defect);
* intoxication with hemolytic poisons due to violation of RBC membrane structure;
* cardiovascular insufficiency due to absorption of the products of metabolism and swelling of RBC;
* the case of increase of old, low resistant RBC number;
* in mechanical trauma to RBCs (prosthetic heart valves, disseminated intravascular clotting, parasites).
Erythrocyte sedimentation rate (ESR)
The ESR measures the rate at which RBCs in anticoagulated blood settle to the bottom of a calibrated tube in a period of 1 hour.
It is a relatively nonspecific test that is frequently ordered during the diagnosis and monitoring of disease. The ESR may be used
to evaluate patients with unexplained symptoms or deterioration of health when an inflammatory, neoplastic, or infectious disease
is suspected.
Sedimentation of RBC is affected by forces both for and against sedimentation. The forces resisting sedimentation are the
negative electric charge on the erythrocyte surface (causing them to repel each other), the up flow of plasma displaced by falling
erythrocytes, and the rigidity of red cells. The forces accelerating sedimentation are plasma proteins, as well as cholesterol,
phospholipids, and some medications.
 Plasma proteins bind to red cell membranes thereby reducing the negative electric charge on RBC membrane thus allowing
rouleaux formation to occur. Rouleaux is the stacking up of red blood cells, caused by extra or abnormal proteins in blood that
decrease the normal distance which red cells maintain between each other. The most common promoter of rouleaux is increased
plasma fibrinogen. The degree to which proteins reduce the negative electric charge on RBC membrane can be rated on a scale of
1-10: fibrinogen -10, beta-globulin - 5, alpha globulin - 2, gamma globulin - 2, and albumin - 1.
Any condition that elevates fibrinogen or globulin content (e.g., inflammation, pregnancy, diabetes mellitus, malignancy) may
also elevate the ESR. Anemia and macrocytosis increase the ESR. In anemia, with reduced hematocrit, the velocity of the upward
flow of plasma is altered so that red blood cell aggregates fall faster. Macrocytic red cells with a smaller surface-to-volume ratio
also settle more rapidly.
A decreased ESR is associated with a number of blood diseases in which red blood cells have an irregular or smaller shape that
causes slower settling. In patients with polycythemia, too many red blood cells decrease the compactness of the rouleaux network
and artificially lower the ESR. Rouleaux formation is hindered by spherocytosis, sickle cell disease, microcytosis, marked
variation in RBC size (anisocytosis), and some drugs. Hypofibrinogenemia associated with dysproteinemia, and hyperviscosity
may cause a marked decrease in the ESR.
Factors influencing ESR
categoryIncreased ESRDecreased ESRBlood substancesHigh level of cholesterol, fibrinogen, immunoglobulin; low level of
albumens.High level of albumens, glucose, bile salts, lipidsBlood cellsAnemia, leukemiaErythrocytosis, polycythemia, sickle
cells, spherocytosis, microcytosisClinical conditionsInflammation, acute bacterial infections, diabetes mellitus, pregnancy, tumor,
myocardial infarctionCachexia, newborn, congestive heart failureDrugsHeparin, theophylline, penicillamin, vitamin AACTH,
cortisone, salicylates, quinine
Vascular-thrombocytic hemostasis in norm
The system of hemostasis provides structural integrity of blood vessels walls, stops bleeding at the damage of vessel wall and
maintain blood liquid state.
The process of hemostasis is divided into two stages:
Primary (vascular-thrombocytic) hemostasis can stop bleeding from small vessels. It consists of following successive processes:
* Spasm of vessels at the cite of damage due to local reflex mechanisms, and vasoconstrictor substances (serotonin, adrenalin,
thromboxane)
* Adhesion of platelets to the site of the damage on subendothelial layer of vessel – due to vascular factor (uncovered fibres of
collagen at the primary damage, which help to stick negatively charged platelets); and plasma factor - synthesized by
endothelium of vessels (Willebrand’s factor).
* Aggregation of platelets at the site of damage is provided due to "agglutination" of platelets with each other and their adhesion
on the vessel wall. This process causes the excretion of platelets’ hemostatic factors. The basic stimulus of platelets aggregation is
thrombin. Thrombin is synthesized by the system of coagulation hemostasis at the same time (5-10 seconds after vessel damage).
This stage is completed by formation of primary blood clot (formed from platelets).
* Retraction of primary blood clot. Destroyed platelets release thrombostenin which acts like actomyosin of skeletal muscles, it
shortens and retracts blood clot.
Primary thrombus is usually successful in blocking the blood loss if the vascular opening is small. However it can’t stand high
BP and can be washed. Therefore, a natural thrombus is formed in the coagulative hemostasis.
The first phase of coagulative hemostasis is the formation of prothrombinase either by extrinsic or intrinsic mechanism.
Extrinsic mechanism. The first step for the formation of active prothrombinase is cell injury and tissue thromboplastin (III
factor) release. There is a successive activation in the beginning of VII factor, then X factor, and then prothrombin. Ions Na2+
and V factor also take part in tissue prothrombinase formation. Traumatized tissue releases a complex of several factors called
tissue thromboplastin, including phospholipids and lipoprotein complex. It plays the role of matrix for prothrombinase synthesis.
Formation of tissue prothrombinase lasts 5-10 seconds, but that of blood prothrombinase -5-10 minutes after damage.
Intrinsic mechanism. It is carried out without the participation of III factor (thromboplastin). The contact of factor XII with
collagen of the damaged vascular wall or other foreign surface is a starting mechanism. As a result of this contact, the factor XII
transforms to the active form. The activation of factor XII promotes the formation of complexes that includes factors XI, IX, VIII
and the ions Na2+. These complexes activate X factor which is necessary for the transformation of prothrombin to thrombin.
Blood prothrombinase is synthesized on the basis of membrane phospholipids of damaged blood cells (platelets, RBC). The
fibres of collagen, that are uncovered at the vessel damage, are the initiators of this process. The contact of collagen with factor
OII starts the cascade of processes with participation of Na2+ on a phospholipid matrix to form blood prothrombinase:
The second phase is the formation of thrombin from prothrombin under prothrombinase influence. Previously formed blood
prothrombinase after 2-5 sec adsorbs on prothrombin and converts it into thrombin.
The third phase. Plasma fibrinogen turns into fibrin under the influence of thrombin in the presence of Na2+ ions. Thrombin
appearing at the second phase chips off fibrinopeptides A and B from the molecule of fibrinogen, forming a fibrin-monomer
(soluble). A fibrin-monomer, spontaneously polymerising, forms a fibrin-polymer (insoluble). For the transformation of soluble
fibrin into insoluble one, OII factor (fibrin stabilising) is activated.
Insoluble fibrin forms fibre network, in which all blood cells are tangled. This process completes the thrombus formation.
Tangled blood cells are destroyed and membranes phospholipids are released. This promotes a further activation of coagulation
and thrombus formation.
Retraction of blood clot. Damaged platelets release thrombostenin. Under its influence, fibrin filaments are drawn together and
shortened. Because of retraction thrombus becomes compact, it compresses almost in 2 times. Retraction lasts for 2-3 hours.
Later platelets’ growth factor activates the proliferation of fibroblasts, smooth muscle and endothelial cells so that vessels’
damaged area is restored.
At the same time, fibrinolysis (lysis of fibrin) begins. It is carried out by proteolytic enzyme – plasmin, which is activated from
plasminogen under the influence of kininogene and precallicreine (plasma kinine system). Besides, leukocytes can release
enzymes from their granules to support a non-plasmic way of fibrinolysis. The lysis of fibrin is needed for unblocking of vessels
(intravascular blood coagulation).
When the vessel is damaged, blood must be coagulated only at the site of damage. This process is controlled by the
anticoagulants:
* primary (anthitrombin III, heparin) are synthesized independently of blood coagulation and fibrinolysis;
* secondary (XIa(XII(Va) which appear during blood coagulation as products of fibrinolysis.
Pathology of hemostasis
Pathology of vascular-thrombocytic hemostasis includes:
Thrombocytopenia (platelets number <100*109/L) resulting from:
* Increased destruction and consumption of platelets in the presence of anti-platelets antibodies. Thus the term of platelets life
shortens from 7-10 days to several hours, and their production in marrow greatly increases (for example: thrombocytopenic
purpura);
* If there is a mechanical damage to platelets which may occur in splenomegaly and when artificial cardiac valves and vessels
are present;
* In a DIC-syndrome (disseminated intravascular coagulation) because of the increased use of platelets.
* Decreased marrow production of platelets caused by leukemic metaplasia, metastases of tumor in marrow, vitamin A12 and
thrombopoietines deficiency.
Thrombocytopathias are qualitative violations of platelets in combination with their normal or lowered amount. These forms of
pathology include structural, functional, and biochemical violations of platelets.
Blood vessels pathology (vasopathias) leads to hemorrhagic syndrome due to primary disorders of the vascular link of
hemostasis. Primary vasopathies are a consequence of structural abnormalities of blood vessels, violations of the chemical
composition of the vascular wall, as well as vasculitis of various etiologies. Secondary vasopathies develop with severe chronic
thrombocytopenia. The indices of platelet function and fibrin system are normal in primary vasopathies. Petechiae and
ecchymoses arise spontaneously or from minor influences; there may be positive endothelial tests.
Henoch-Sch?nlein purpura is an acute disorder characterized by a generalized vasculitis involving the small vessels of the skin,
GIT, kidneys, joints, and, rarely, the lungs and the CNS. It is the most frequent vasculitis in childhood, the incidence decreasing
with age. The etiology of the disease is associated with streptococcal infection. The inflammation of blood vessels develops as a
result of post-streptococcal immunocomplex injury mediated by IgA autoantibodies.
Disturbances of blood coagulation
Hypercoagulation is the acceleration of blood coagulation. It is observed under stress conditions, when time of blood coagulation
goes down from 5-10 min to 3-4 min. The basis of this process is the influence of catecholamines. Adrenalin promotes
prothrombinase release from vessel walls. Besides, high concentration of adrenalin is able to activate factor OII directly in
bloodstream. Adrenalin also activates lipid catabolism. Free fatty acids appear in blood, which increase prothrombinase activity.
The excitation of the parasympathetic nervous system results in the release of substances from vessels walls, which are similar to
those, released at adrenalin action that causes hypercoagulation.
Thrombocytemia is another reason of hypercoagulation. Transient thrombocytosis is a normal physiologic response to stress,
infection, trauma, exercise and ovulation (intravascular clot formation can occur).
Hypocoagulation may result from coagulopathies.
The deficiency of any of plasma clotting factors or kallikrein-kinin system complexes determine inherited coagulopathias. Two
common inherited disorders are hemophilias and Willebrand disease. They are caused by the deficiency of clotting factors.
Hemophilias lack factors VIII and IX; Willebrand disease has low levels of factor VII and impaired platelet’s function.
Acquired coagulopathies result from:
* The violation of K-dependent factors of blood coagulation ((((, (, (((, (() synthesis in the liver; lack of vitamin K (inflammatory
or degenerative diseases of liver);
* DIC-syndrome;
* Organism production of specific immune inhibitors and immunoglobulins that cause inhibition of separate clotting factors
(more frequent (((((( and the Willebrand factor);
* Adsorption or outcome with urine of separate factors of blood coagulation (more frequent (((, (().
* The inhibition of blood coagulation always occurs after the previous coagulation. It is determined, on the one hand, by
intensive use of clotting factors in the process of thrombus formation, and on the other hand by the activation of anticoagulating
mechanisms. It must be taken into account in postoperative and post-delivery states.
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) occurs when coagulation cascade is activated at a system-wide level by circulating
thromboplastic substances, which usually leads to bleeding complications. This disorder is another termed as consumptive
thrombohemorrhagic disorder. This consumptive coagulopathy results from a disseminated coagulation that depletes clotting
factors and platelets and stimulates endogenous fibrinolysis. Thrombosis in microcirculation stimulates increased fibrinolysis.
This fibrinolytic response, combined with the depleted clotting factors and thrombocytopenia, results in clinical bleeding.
 Etiology of DIC is generally associated with pathologic processes that include endothelial damage, the release of tissue
thromboplastin and direct activation of factor X. Gram-negative sepsis, septic shock, hypoxia, uremia, and low flow states
associated with cardiopulmonary insufficiency can result in vessels endothelium damage and cause DIC by activating intrinsic
way of blood coagulation. The release of tissue thromboplastin is associated with burns, traumatic injury, myocardial infarction,
surgeries, obstetrics accidents, and malignancies. Pancreatic and hepatic enzymes, snake venom stimulate the activation of factor
X. The obstruction of blood vessels with thrombus causes widespread organ hypoperfusion that can lead to ischemia, infarction,
and necrosis with manifestation of multisystem organ dysfunction.
Pathogenesis. The activation of coagulation system leads to formation of thrombin and plasmin. Thrombin, on one hand,
facilitates the formation of a stable fibrin clot. This disseminated fibrin clot travels to microcirculation/capillaries or smaller
vessels, obstructing the flow of blood to the tissue. Lack of blood supply due to obstruction of bloodflow results in decreased
tissue oxygenation, organ infarction and necrosis. The release of tissue factor from the organ contributes to continued
uncontrolled intravascular fibrin formation as well as plasmin activation. Plasmin, on the other hand, degrades the cross-linked
fibrin clot.
DIC is a paradoxical condition in which clotting and hemorrhage occur within vascular system simultaneously. This combination
of uncontrolled coagulation and fibrinolysis leads to consumption of coagulation factors and platelets. As the rate of clot
formation exceeds the rate of synthesis of coagulation factors and platelets, a bleeding tendency develops along with shock and
vascular occlusion. In addition, the patient's liver is overworked by the need to produce more coagulation factors as well as
remove the fibrin degradation products.
The clinical symptoms and laboratory presentation of the syndrome are influenced by various parameters and also affected by
the underlying disease conditions. The classical clinical symptoms of DIC depend upon:
* Functional ability of the liver to produce coagulation factors and remove fibrin degradation products;
* Bone marrow ability to replace platelets which were consumed
The initial pathological event of acute DIC syndrome leads to a thrombotic tendency but later acute DIC syndrome presents itself
with hemorrhagic symptoms associated with ecchymoses, bleeding from needle puncture sites. The symptoms may develop from
a few hours to a few days after the stimulus activates uncontrolled clot formation.
The occurrence of a hemorrhagic condition arises in acute DIC, as the patient's liver and bone marrow cannot produce
coagulation factors and platelets fast enough to compensate for their increase uncontrolled consumption. Patients with acute
uncompensated DIC have the highest mortality risk due to the hemorrhagic state.
UNIT 15
RBC PATHOLOGY:ANEMIA AND ERYTHROCYTOSIS
Anemia definition and classifications
Anemia is the most common disorder of blood. Anemia refers to the deficiency of red blood cells (RBCs) and/or hemoglobin.
This results in a reduced ability of blood to transfer oxygen to the tissues, causing hypoxia; since all human cells depend on
oxygen for survival, varying degrees of anemia can have a wide range of clinical consequences.
Anemia can be classified in a variety of ways.
1. Classification due to pathogenesis of anemia.
Anemias related to blood loss are posthemorrhagic.
Anemias due to increased RBC destruction are hemolytic.
Anemias caused by disturbances of hemopoiesis may result from:
* deficiency of plastic substances (iron, proteins; vitamin A12, folic acid);
* depression of RBC maturation in marrow (inherited and acquired hypoplastic and aplastic anemias);
* depression of erythropoiesis by quickly proliferating tumor tissue (metaplastic anemia in leukemia patients);
* lack of erythropoietin (chronic kidney diseases).
2. Classification due to hemoglobin content in RBC
Hemoglobin content in erythrocyte may be described by the following parameters. In our country we previously used color index
mainly. Normally color index of erythrocyte is 0,8 – 1. It is calculated by the formula:
CI = (content of Hb in g/L x 0,03) / three first figures of RBC quantity
Mean cell hemoglobin (MCH) refers to the average weight of hemoglobin in the erythrocytes. The reference interval for adults is
typically 26 - 32 pg (one picogram is 10 -12 grams).
Mean cell hemoglobin concentration (MCHC) refers to the average concentration of hemoglobin in the RBCs contained within
the sample. Reference interval for adults is typically 32 - 36 g/dL.
In hyperchromic anemias – hemoglobin content is higher than normal (vitamin A12 deficiency), hypochromic – are characterised
with hemoglobin content lower than normal (iron deficiency anemia), normochromic – hemoglobin content is not changed
(chronic hemolytic inherited anemias).
3. Classification based on the degree of regeneration
The regeneration processes in the bone marrow can be virtually measured with the reticulocytes quantity. Normally reticulocytes
constitute 0,5 to 2% of the RBC. The majority of anemias are normally regenerative (normal reticulocytes count). Regenerative
processes in bone marrow accompany them. Factors, which strengthen the regeneration are: hypoxia, some hormones
(androgens), and the products of RBC decomposition.
The reticulocyte count lower 0,5% means that anemia is hyporegenerative. The total absence of reticulocytes verifies
aregenerative anemia. Anemia accompanied by low level of regeneration occur when the activity of bone marrow is considerably
depressed by physical factor (radiation sickness), chemical factor (benzol intoxication, myelotoxic drugs), severe avitaminosis,
primary or secondary tumor nodes.
Inherited hemolytic anemia is accompanied with high reticulocytes count, therefore it is hyperregenerative.
4. Classification based on the type of RBC maturation
There are anemias with erythroblastic or normal type of blood maturation (most of anemias) and megaloblastic or embryonic
type of blood maturation (B12 vitamin and folic acid deficiency).
5. Classification based on the size of RBC
The size of RBC refers to mean corpuscular (cell) volume, or MCV. MCV can be calculated by dividing the hematocrit by the
red blood cell count and multiplying by ten. The result is typically reported in femtolitres. If the cells are smaller than normal
(MCV is under 80 fl), anemia is said to be microcytic; if they are of normal size (80-100 fl) – normocytic; and if they are larger
than normal (over 100 fl), anemia is classified as macrocytic.
General symptoms and signs of anemia
The amount of blood in anemias is usually not decreased. Blood volume is maintained at the normal level due to the
compensatory fluid outflow from tissues into a bloodstream. This fact means that anemic patients usually have olygocythemic
normovolemia. But the volume of blood can be decreased in acute posthemorrhagic anemia, or in pernicious anemia manifesting
in olygocythemic hypovolemia.
One of the symptoms of any anemia is the paleness of skin and visible mucous membranes. Severe anemia reduces the nutrition
of all organs and systems, and as a result the functions of many organs are violated, and physical capacity decreases. Both
nutrients and oxygen delivery to the body tissues are disturbed. The leading mechanism of general symptoms of anemia
manifestation is the development of hypoxia condition. Hemic hypoxia of anemic type results in the alterations of various organs
and organs systems functioning.
The changes in CNS activity include the lowering of mental ability to work, the decline of memory, insomnia, fatigueability,
dizziness, noise in ears, headaches, episodes of fainting. The manifestation of these symptoms is usually observed in older
people.
The functional changes in endocrine organs involve practically all endocrine glands, the function is especially decreased in
thyroid gland. Therefore the level of basic metabolism falls down, and other signs of hypothyroidism can appear. They are
sensitivity to cold, apathy, dry skin, fragility and shedding of hair, edema.
The changes in gastrointestinal tract are manifested with the decrease of stomach and intestinal secretory function. Decreased
level of digestive enzymes in the intestines, pepsin and hydrochloric acid in the stomach may result in malabsorption of important
nutrients. Anorexia, flatulence, nausea, constipation and weight loss may also occur.
CVS and the lung evidence adaptation to hypoxia. There are tachycardia, dyspnea in exertion. In some patients systolic murmur
is auscultated over the heart. In older people heart failure can develop.
Anemia goes undetected in many people, and symptoms can be vague. That is due to the following fact: in most cases of anemia
the fall in RBCs oxygen transport capacity develops slowly, so there is enough time for physiological adaptation to minimize
symptoms and signs of anemia. The falling RBC count reduces the oxygen delivery but also leads to falling viscosity of the
blood. The reduced viscosity can reduce the total peripheral vascular resistance (TPVR) to less than half of the resting value. It
makes the cardiac work easier and improves the bloodflow. A slight fall in systemic arterial pressure reduces the stimulus of the
arterial baroreceptors, and causes a rise in heart rate and cardiac output. The low oxygen capacity of hemoglobin is compensated
by an increased coronary bloodflow at rest.
The important role for diagnostics of anemias belongs to specific manifestation of certain anemias. The following examples can
be given:
* in posthemorrhagic anemia – the clinical manifestation of basic disease, which is the reason of blood loss (GIT ulcer, piles,
menstrual bleeding, etc);
* in iron deficiency anemias – perversion of taste, trophic disorders of skin, often gastric achylia;
* drumstick fingers with spoon-shaped nails (are seen in chronic anemia with hypoxia such as in chronic iron deficiency);
* in hemolytic anemia – hemolytic jaundice.
Acute and chronic posthemorrhagic anemia
Anemia of blood loss may be of 2 types: acute posthemorrhagic anemia and anemia of chronic blood loss.
The main reasons of blood loss are:
* blood vessels or heart walls safety loss (incision, rupture, tumor growth, aneurysm);
* increased vessel permeability (radiation sickness, leukemia, sepsis, vitamin C deficiency);
* decreased blood coagulation (coagulation factor deficiency).
The consequence of acute blood loss is hypovolemic shock. If a patient survives and body iron stores are adequate, blood count
will be normalized. When chronic blood loss occurs, iron stores are gradually depleted resulting in iron deficiency anemia.
Acute post-hemorrhagic anemia develops after single massive blood loss. The prognosis in acute post hemorrhagic anemia
depends not only on volume but also on the speed of bleeding. Rapid blood loss of 1/4 general blood volume can result in the
development of shock and the rapid loss of half of blood volume usually results in death. At the same time, slow blood loss of
even up to 3/4 of mass of blood cured by the modern methods of treatment often has a positive outcome. Healthy persons can
restore normal blood count even at considerable blood loss in 4-5 weeks.
Acute hemorrhage develops in three stages.
The 1st stage – reflexive – develops immediately after blood loss and is characterized by heart and vessels compensatory
reactions. Heart rate and blood vessel tone are increased. Bloodflow is “centralized”, that is the vessels of the heart and brain are
dilated; the vessels of skin, muscles, and organs of abdominal cavity are constricted. Blood volume is decreased, hematocrit is
normal (simple hypovolemia).
The 2nd stage is called hydremic. It develops since the first hours after acute blood loss till 2-3 days and is characterized by the
increased tissue fluid outflow to blood vessels. Blood volume changes from olygocythemic hypovolemia to olygocythemic
normovolemia.
The 3rd stage is characterized by activated erythropoiesis and liver function. It helps to compensate RBCs number and blood
protein content. It develops in 5-7 day after acute blood loss and is characterized by increased reticulocyte count in peripheral
blood. Blood volume at this stage is olygocythemic normovolemia.
Chronic posthemorrhagic anemia develops when the loss of blood is slow and insidious. The signs of anemia in this case will
become apparent only when rate of blood loss is more than the rate of RBCs production and the iron stores are depleted. More
frequently anemia develops after repeated bleedings from GIT (piles, cancer, ulcer, cirrhosis of liver and etc), uterine, kidney, etc.
The RBC count as well as hemoglobin content decreases in this anemia. This anemia is hypochromic, the color index is 0,6-0,4.
The number of reticulocytes is low (hyporegenerative anemia), degenerative forms prevail: hypochromic erythrocytes,
poikilocytosis, anisocytosis with predominance of microcytes. WBC count may show leukopenia, neutropenia and relative
lymphocytosis, the amount of platelets is normal or a little lower.
In bone marrow the decrease of erythroblasts maturation with the prevalence of basophilic and polychromatophilic forms is
observed. Because of the lack of iron, the process of RBCs saturation with hemoglobin is violated and hypochromic RBC appear
in peripheral blood.
There are 3 stages in the pathogenesis of this anemia development.
At regenerative stage RBC and hemoglobin count, color index are lower that normal. Hypochromic RBC and regenerative forms
of RBC (reticulocytes) are found in blood smear. It lasts from several months to several years depending on the intensity of blood
loss and regenerative ability of the bone marrow.
When the body iron stores and compensatory ability of the organism are exhausted, anemia transforms to the hyporegenerative
stage. The contents of hemoglobin and RBC are lower than at the first stage. Color index is even less than 0,5. Microcytes form
the majority of RBC, poikilocytosis is observed too. The level of serum iron is decreased. Reticulocyte count is lower than
normal. The signs of iron deficiency will be observed in the patient.
If blood loss proceeds, this anemia turns from hyporegenerative to the non-regenerative (aregenerative) stage (marrow
exhaustion). Reticulocytes are not found in a blood smear. This sign testifies profound disturbances of hemopoiesis.
Acute hemolytic anemia
Normally, at the end of their life span (about 120 days), RBCs are removed from the circulation. Hemolysis of increased
intensity involves premature destruction and hence shortened RBC life span. Anemia symptoms occur when bone marrow
production can no longer compensate for the shortened RBC survival; this condition is termed hemolytic anemia. Compensatory
bone marrow hyperplasia may cause 6-8 fold increase in RBC production. Hemolytic anemia is characterized by increased
osmotic fragility of RBC, high reticulocytosis, increased serum bilirubin, and hyperplasia of the bone marrow erythroid stem.
FIGURE 13 Types of hemolysis
*Shear stress (e.g., defective mechanical heart valves)
*Haptoglobin binds to free hemoglobin for removal by spleen and liver macrophages
The premature destruction of RBC may occur via 2 mechanisms: intravascular and extravascular hemolysis. Hemolysis is mainly
extravascular and occurs in phagocytic cells of the spleen, liver, and bone marrow. An enlarged spleen may sequester even
normal RBCs. Intravascular hemolysis is uncommon: RBCs undergo lysis in the circulation and release their content into plasma.
It results in a rise of free plasma hemoglobin and its appearance in urine (hemoglobinuria).
Hemolytic anemias are classified into 2 main categories: acute and chronic hemolytic anemias. Acute hemolytic anemias are
usually caused by the influence of various extrinsic to RBC pathogenic factors.
Increased hemolysis caused by immune abnormalities occurs due to the production of antibodies against RBC in the following
cases:
* against own undamaged RBC (autoimmune hemolytic anemia);
* against RBC whose membrane structure was changed as a result of drug intake (sulfonamides, penicilline);
* when antibodies are acquired by blood transfusions, pregnancies and hemolytic disease of the newborns (isoimmune hemolytic
anemia).
Mechanical injury of RBC is possible in the patients with abnormalities of microcirculation. In this case intravascular hemolysis
of RBC occurs. It may occur as a result of direct external trauma to RBC when they pass through microcirculation over the bones
during high physical activity on hard surface – prolonged marchers, joggers, marathon runners. These patients are known to
develop hemoglobinemia and hemoglobinuria (march hemoglobinuria).
Some people with prosthetic cardiac valves or artificial grafts develop hemolysis as a result of direct trauma of RBC from
turbulent bloodflow.
Hemolysis may result from direct toxic effect of infectious and non-infectious agents. Infectious agents may produce hemolytic
anemia through the direct action of toxins (e.g., from Clostridium perfringens, ?- or ?-hemolytic streptococci, or meningococci)
or by invasion and destruction of the RBC by the organism (e.g., Plasmodium and Bartonella spp). Non-infectious agents causing
RBC hemolysis are copper, lead, snakes and spiders venoms, extensive burns.
Increased reticuloendothelial activity is observed in any case of spleen enlargement. A normal spleen poses no risk to normal
blood cells. Besides hemolytic anemia splenomegaly (enlarged spleen) is usually associated with pancytopenia (decreased
number of all blood cells).
Chronic hemolytic anemia
Chronic hemolytic anemias can be inherited or acquired. The reasons of chronic hemolysis due to acquired extrinsic influences
are the same as in acute hemolytic anemia.
Hereditary hemolytic anemias are usually the result of intracellular RBC defects. They are divided due to the location of the
defects which may occur in RBC membrane, enzymes and hemoglobin.
The abnormalities of RBC membranes are identified during blood smear examination. There are 3 important types of inherited
RBC membrane defects: spherocytosis, elliptocytosis (ovalocytosis) and stomatocytosis. These defects result in the decrease of
RBC’s osmotic and mechanical resistance.
Hereditary spherocytosis may be autosomal dominant or recessive disease. Sometimes it is named Minkowski–Chauffard
disease/syndrome. It can be caused by molecular defects in the genes that code for spectrin, ankyrin and other erythrocyte
membrane proteins. These proteins are necessary to maintain the normal shape of erythrocyte, which is a biconcave disk. As the
spleen normally targets abnormally shaped red cells (which are typically older), it also destroys spherocytes.
The most common defect of RBC enzyme is glucose-6-phosphate dehydrogenase deficiency (G6PD) – an X-linked recessive
hereditary disease. G6PD is the key enzyme of pentosophosphate cycle, which provides the synthesis of NADF*I, that is
necessary for the synthesis of reduced glutathione. Glutathione carries out RBC antioxidant defence, destroying peroxides and
preventing oxidative stress. Oxidative stress of RBC can occur in severe infection, some medicines (sulfonamides, primaquine,
glibenclamide) and certain foods. Individuals with inherited deficiency of G6PD fail to develop adequate levels of reduced
glutathione. This results in oxidation and precipitation of Hb within erythrocytes forming Heinz bodies.
Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin
molecule. Normally RBC of adults contains hemoglobin A which consists of 2 alfa and 2 beta chains (?2?2). Hemoglobinopathies
include sickle-cell disease and thalassemia. Sickle cell disease is a qualitative disorder of Hb, whereas thalassemia is a
quantitative disorder.
Sickle-cell disease is a general term for a group of genetic disorders caused by sickle hemoglobin – HbS. In HbS the genetic
defect is the single point mutation of one aminoacid – there is a substitution of valine for glutamic acid. During deoxygenation
RBC containing HbS changes its shape (sickle cell) because of polymerization of the abnormal sickle hemoglobin. This process
damages the red blood cell membrane, and can cause the cells to become stuck in blood vessels. This deprives the downstream
tissues of oxygen and causes ischemia and infarction. There can be different sites of infarctions: abdomen, spleen, bone marrow,
kidneys, joints etc. The consequences of infarction are determined by their location and can vary from skin ulcers to osteomyelitis
and CNS strokes.
Thalassemia is an inherited disease; the genetic defect results in reduced rate of synthesis of normal globin chains. The
thalassemias are classified according to which chain of the globin molecule is affected: in ? thalassemia, the production of ?
globin is deficient, while in ? thalassemia the production of ? globin is defective.
The heterozygous form manifests as thalassemia minor and may be asymptomatic or mildly symptomatic. The homozygous form
– thalassemia major is associated with severe hemolytic anemia. Beta thalassemia major is also known as Cooley's anemia.
A deficiency in the production of one of the globin chains type results in excessive production of other globin chains in the
developing RBC. Excessive globin chains are precipitated within the RBC (target-type erythrocytes). Such erythrocytes are
damaged during their passage through the splenic vessels and further phagocyted by the macrophages of the liver and spleen
causing anemia, enlargement of the liver and spleen and excess of tissue iron stores.
Anemias caused by disturbed erythropoiesis
Iron deficiency anemia is one of the most widespread diseases in the world. The reasons of iron deficiency are:
* chronic blood losses;
* increased iron requirements (pregnancy, lactation, spurts of growth in infancy, childhood and adolescence);
* inadequate dietary intake;
* insufficient absorption (achlorhydria, partial or total gastrectomy, intestinal malabsorption).
The onset of iron deficiency anemia is generally slow. Clinical features include usual common symptoms of anemia - weakness,
fatigue, dyspnea, palpitation and other symptoms. Long standing iron deficiency causes epithelial tissue changes. The changes
occur in the nails (koilonychia or spoon-shaped nails, brittle nails), tongue (atrophic glossitis), mouth (angular stomatitis). The
perversion of taste in the patients with iron deficiency manifests as unusual cravings for non-nutritive substances (clay, chalk, ice,
dirt or starch). The appetite is usually decreased in these patient due to low functional activity of GIT organs. Severe and
prolonged iron deficiency also may cause dysfunction of iron-containing cellular enzymes taking part in DNA synthesis and
electron transport chain.
Blood count is characterized by the low color index and RBC number. Microcytes and poikylocytes are found in blood smear.
The decreased level of blood serum iron is common in all cases of iron deficiency anemia. The treatment with iron medicines
gives a good result.
Syderoblastic anemia (refractory to iron) develops in patients with defect of enzymes that include iron to hemoglobin. This
defect can be inherited and acquired (lead intoxication). In these patients, the level of plasma iron is higher than normal. In the
bone marrow erythroblasts with increased iron content (in the form of granules) – syderoblasts are found. RBC containing non-
hemoglobin iron is named siderocyte.
Megaloblastic anemia is anemia resulting from a deficiency of vitamin B12 and folic acid. This anemia is characterized by
impaired nucleic acids metabolism, DNA synthesis and abnormalities in hemopoiesis. Lack of vitamin B12 in the bone marrow
turns the normal erythroblasts into abnormal megaloblasts. The RBC maturation is inhibited, and the cells synthesize much more
RNA than normal and much less DNA. Ineffective hematopoiesis affects all cell lines that results in leukopenia and
thrombocytopenia. Instead of normal RBC, the megaloblasts deliver megalocytes to the circulation. Megalocytes are fragile and
only have an average life of 40 days (normal erythrocytes – 120 days).
The reasons of B12 deficiency are:
* inadequate dietary intake (strict vegetarians);
* inadequate production of intrinsic factor (autoantibodies to intrinsic factor, atrophic gastritis, congenital lack);
* disorders of the terminal ileum resulting in malabsorption.
The reasons of folate’s deficiency are:
* inadequate dietary intake (teenagers, infants, old age, alcoholics);
* malabsorption (celiac disease, partial gastrectomy, jejunal resection);
* excessive demand (pregnancy, lactation, infancy, malignant tumors).
Vitamin B12 normally enters organism with food, in the stomach it combines with the intrinsic factor (glycoprotein, produced by
the parietal cells of the stomach). The complex of B12+intrinsic factor is absorbed in the ileum. Intrinsic factor acts as cell
directed carrier protein (like transferrin). In blood it is destroyed and B12 with the help of another carrier protein transcobalamin
is taken by the liver, bone marrow and other cells. Vitamin B12 participates in hemopoiesis, myelination of nervous fibres and
regeneration of GIT epithelium.
This anemia is hyperchromic, macrocytic, hyporegenerative. RBC degenerative forms can be observed in a blood smear -
poikilocytosis, anisocytosis (schistocytes and megalocytes, megaloblasts), RBC with the Kebot rings and Howell-Jolly bodies.
Other disturbances of hemopoiesis are also seen in this anemia. Hypersegmented neutrophils can be present in megaloblastic
anemias. Their nucleus has more than usual 3 or 4 lobes. Neutropenia and thrombocytopenia are often present in severe cases.
Clinical features of megaloblastic anemia include both common and specific anemia symptoms. Specific symptoms of B12 and
folate deficiency anemia are: glossitis (inflammation of the tongue; smooth, beefy, red tongue), jaundice, symptoms of
malabsorption, weight loss and anorexia.
B12 deficiency is also associated with neurological signs, which include demyelination of the nervous fibres and irreversible
nerve cell death. Symptoms include peripheral neuropathy, pain, numbness or tingling of the fingers or extremities and an ataxic
gait.
Pernicious anemia (Addyson-Biermer anemia) refers to a type of megaloblastic autoimmune anemia. This disease is
characterized with the presence of antibodies directed against intrinsic factor or parietal cells of the stomach, which produce
intrinsic factor. This will result in development of chronic autoimmune atrophic gastritis and parietal cell loss.
Hypoplastic and aplastic anemias
The term ‘hypoplastic' means that bone marrow suffers from an hypoplasia (decreased cell count), ‘aplastic” refers to the
inability marrow to form blood cells. Typically, anemia refers to low RBC counts, but aplastic anemia patients have lower counts
of all blood cell types. The following factors may suppress hemopoiesis:
* medicines with myelotoxic effect (antineoplastics, amidopyrine, sulfanilamides, cytostatic chemicals, antibiotics);
* autoimmune reactions in bone marrow;
* chemical substances: benzol, petrol, arsenic, mercury etc.;
* ionizing radiation;
* severe infections (sepsis).
The blood count is characterized by acute decrease of all blood cells – pancytopenia. The indices of hemoglobin and RBC are
reduced, but anemia is normochromic. Regenerative forms of blood cells are absent. Common symptoms of anemia are present.
Thrombocytopenia may cause petechiae, ecchymosis, and bleeding (gums, conjunctivae, or other tissues); agranulocytosis
commonly causes life-threatening infections.
Metaplastic anemia develops when there is an alteration of bone marrow cellular count:
* in the course of leukemia, when normal bone marrow turns into metaplastic (and it consists of leukemic cells mainly);
* if the cancer metastases into bone marrow;
* in the case of diffuse osteosclerosis with marrow obliteration.
Blood count: normochromic anemia with low reticulocyte count.
Disregulatory anemia appears due to the lack of erythropoiesis regulatory factors. Such anemia appears in the patient with
chronic kidney disease due to the decreased synthesis of erythropoietin.
Erythrocytosis
Erythrocytosis or polycythemia is characterized with high RBC count: more than 4,7*1012//L in women and more than
5,0*1012//L in men.
Erythrocytoses are classified into two groups: primary and secondary ones. Primary erythrocytoses include polycythemia vera
(Vaquez disease) and different congenital forms. Secondary erythrocytoses are divided into absolute and relative forms.
Vaquez disease – Polycythemia vera is an idiopathic chronic myeloproliferative disorder (benign tumor) characterized by an
increase in RBC mass. But not only RBC production is increased. Vaquez disease involves increased production of all cell lines,
including RBCs, WBCs, and platelets. The reason of polycythemia is increased number of the hematopoietic stem cells in the
bone marrow, which does not depend on the level of erythropoietin and refers to transformation of the normal stem cell to tumor
cell. Moreover, extramedullary hematopoiesis occurs in the spleen and liver which are potential for blood cell maturation.
Blood count: increased number of RBC, reticulocytes, WBC and platelets. Blood volume – polycythemic hypervolemia,
hematocrit is increased > 52%. Hemoglobin content is increased too up to 180-200 g/L. Usually polycytemia is also accompanied
with the increase of blood viscosity that impairs blood circulation and often increases risk of thrombosis development.
The clinical signs of Vaquez disease are the following:
 * arterial hypertension (due to hypervolemia);
* plethora (an excess of blood) with congested mucous membranes conjunctiva and retinal veins;
* CNS disturbances (headache, dizziness, visual disturbances, paresthesias, strokelike symptoms);
* cardiovascular symptoms (myocardial ischemia, vessels thrombosis) – due to increased blood viscosity, low speed of
bloodflow;
* enlargement of the spleen and liver (due to extramedullary sites of hematopoiesis and high activity of reticulo-endothelial
system function;
* frequent bleedings (due to the changes of RBC and platelets structure as a result of tumor anaplasia).
Primary congenital erythrocytoses are not of tumor nature. Their etiology and pathogenesis are not completely studied.
Secondary erythrocytoses are developed as a result of other diseases or pathological states.
Secondary absolute erythrocytosis is an increased red cell mass due to stimulation of erythropoiesis by either physiological or
pathological influences.
The main reason for erythropoiesis stimulation is hypoxia. We can observe secondary erythrocytosis in the following situations,
accompanied by different types of hypoxia:
* Chronic lung diseases;
* Carbon monoxide poisoning;
* Smoker's erythrocytosis;
* High-altitude natives.
Local renal hypoxia also results in increased erythropoietin production. Its causes are: renal artery stenosis, final stages of renal
diseases.
Erythropoietin can also be synthesized by the some tumors (hepatocellular carcinoma, renal cell cancer).
Blood count in secondary absolute erythrocytosis: increased number of RBC, reticulocytes, high indices of hematocrit and
hemoglobin. Polycythemic hypervolemia and increased blood viscosity are observed too. The number of WBC and platelets is
normal.
Secondary relative erythrocytosis is characterized by increased RBC number in the unit of blood volume, meanwhile
erythropoiesis is not activated and absolute RBC count is normal.
It may be observed as a result of organism dehydration (at diarrhea, vomiting, abundant sweating, burns, overheating) or as a
result of blood redistribution from blood depot to peripheral flow (stress reaction, acute hypoxia, high level of catecholamines).
Clinical signs: increased hematocrit, polycythemic normovolemia or hypovolemia, increased blood viscosity.
UNIT 16
WBC PATHOLOGY: LEUKOCYTOSIS AND LEUKOPENIA
Leukocytic formula
Regenerative and degenerative forms of WBC
All the leukocytes originate from the pluripotent hematopoietic stem cells which give rise to several cell lines. Under the
influences of specific factors first two progenitors are formed: myeloid and lymphoid stem cells.
* Mature myeloid cells
FIGURE 14 Stages of hematopoiesis
Lymphoid stem cells divide and differentiate to lymphocytes. Myeloid progenitors give rise to committed cells: monoblasts and
myeloblasts. The latter ones differentiate to eosinophils, neutrophils and basophils. Each of these cells develops through the same
stages: promyelocyte, myelocyte, band cell and segmented cell. Monoblast differentiate to promonocyte and than to mature
monocyte. An average lifespan of WBC is about few days. When the organism fights against infection the lifespan may shorten to
few hours. Normal WBC count for a healthy person is 4 – 9 *109/L.
Those cells which are less differentiated (younger) than mature cell are named regenerative forms of leukocytes. Juvenile and
band forms of neutrophils are normally present in blood smear. Younger forms of leukocytes usually appear in peripheral blood
smear when the process of leukopoiesis is intensified. The presence of poorly-differentiated myelocytes and blast cells is the sign
of high regeneration process. It can be observed in the course of leukemoid reactions and leukemia.
If we want to know the percentage of each type of white blood cell differential WBC count or leukocytic formula is made. The
sum of all leukocytes in formula always comprises 100%. To make an accurate conclusion about patients WBC state you should
also take into account not only percentage of each type of leukocyte but also their absolute number, one should consider both
relative and absolute values.
Normal differential WBC count or leukocytic formula
Eosino-Baso-NeutrophilsLympho Mono-philsphilsmyelocytesjuvenile
cellsband
cellssegmented cellscytescytes2-4%0-1%0%0-1%2-6%50-70%20-40%3-10% It is important to mention that indices of normal
leukocyte count and leukocyte formula may differ depending on the country, region of residence, life style, etc. It is explained by
the fact that WBCs, as a part of immune system, are very sensitive to environmental influences, especially those which have
depressive influence on immune system.
Degenerative forms of leukocytes are the following:
* neutrophils with hypersegmented nucleus - five or more lobes indicate hypersegmentation – an aging change, which occurs
with prolonged exposure to glucocorticoid therapy, hyperadrenocorticism or neutrophilia associated with chronic infections, B12
deficiency.
 * neutrophils with foamy vacuolation of the cytoplasm – an irregular clearing in the cytoplasm produces vacuolation (sepsis,
especially anaerobic, abscesses, liver dystrophy).
* Dohle bodies — one or more, irregular sites in cytoplasm that don’t include specific granularity. D?hle bodies are found in
infections, poisoning, burns, and following chemotherapy.
* toxic granulation in cytoplasm – indicates the disturbances of neutrophils maturation, or it may be the result of accumulation of
toxic substances (septic and purulent infections, tumor necrosis, measles)
* Gumprecht’s cells (shadows) –immature leukocytes that have undergone partial breakdown during preparation of a stained
smear or tissue section, because of their greater fragility; smudge cells are seen in largest numbers in chronic lymphocytic
leukemia. Synonyms: smudge cells, basket cell, Gumprecht's shadows, shadow cells.
Decreased WBC count: leukopenia
Leukopenia occurs when the WBC count falls below 4*109 per L. In the patients with leukopenia immune system can’t work
properly so they become more susceptible to bacterial infections; the course of these bacterial infections may become life-
threatening without medical attention.
Leukopenia may be one the symptoms of pancytopenia - abnormal decrease of all blood cells: RBC, WBC and thrombocytes.
Pancytopenia generally develops due to:
* tumor growth in the bone marrow (leukemia or tumor metastases);
* aplastic state of bone marrow (irradiation, myelotoxic drugs);
* in megaloblastic states (B12 deficiency);
* peripheral destruction of blood cells in overactive spleen.
Leukopenias are termed due to the type of leukocytes decreased. The term basopenia is not used, because basophils can normally
be absent in the blood smear.
Eosinopenia is a decrease in eosinophils number; it occurs after anaphylactic attacks, in the cases of severe stress and in all the
cases of increased glucocorticoids level (when they are prescribed for treatment or when hypersecretion of glucocorticoids takes
place in the organism). The granules of eosinophils contain enzyme which is necessary for histamine degradation (histaminase);
in anaphylactic attacks when big amount of histamine is released from must cells, eosinophils migrate to the tissues to inactivate
histamine. The process of eosinophils migration to the tissues is activated by glucocorticoids, so when their content increases the
amount of eosinophils in peripheral blood will be decreased.
Lymphopenia is characterized by the decrease of lymphocytes number in peripheral blood. It may occur as a result of impaired
lymphocytes maturation and migration or acceleration of their destruction.
Chronic disturbance of lymphocytes maturation is a characteristic feature of primary immune deficiencies such as DiGeorges or
Wiskott-Aldrich syndromes, Bruton’s agammaglobulinemia, the combined syndrome of immunodeficiency. Other cases of
disturbed lymphocytes maturation include: protein starvation, irradiation of bone marrow, immunosuppressive drugs, metaplasia
of a bone marrow due to metastases of malignant tumors or leukemic infiltration. Increased destruction of lymphocytes is typical
for diseases in which infectious agent is directly affecting lymphocytes (measles, poliomyelitis, AIDS).
Monocytopenia is not thought to be an isolated/distinct disorder. It may result from pancytopenia, severe infections, stress and
other cases of increased glucocorticoids level.
Neutropenia is characterized by an abnormally low number of neutrophil granulocytes. Normal lower limit of the neutrophil
count – their absolute value (total WBC ? % neutrophils and bands) is 1500-1200/?L.
Severe neutropenia (regardless of its etiology) is manifested with typical signs, determined by the lowering of resistance to
bacterial and fungal infection: sore throat, quinsy, fever, inflammation of the mucous covering of the mouth, nose and eyes. It
occurs due to activation of endogenous microbial flora (e.g., in the mouth, skin or gut). Acute, severe neutropenia, can lead to
rapidly fatal infections which may manifest as pneumonia or septicemia.
Neutropenia can result from use of certain drugs which may act as toxins on bone marrow leukopoiesis (e.g. phenothiazines) and
produce dose-related neutropenia. In some cases reactions are unpredictable and not dependent on the dose of drugs.
Infections can cause neutropenia by impairing neutrophil production or by inducing immune destruction or rapid use of
neutrophils. Infections may be caused by viruses (infectious mononucleosis, hepatitis, HIV, rubella) and bacteria (staphylococci,
tuberculosis, typhoid fever). Sepsis is a particularly serious cause.
Bone marrow infiltration by leukemia, myeloma, lymphoma, or metastatic tumors (e.g., breast, prostate) can impair neutrophils
production and also result in pancytopenia.
Autoimmune destruction of neutrophils is thought to arise from drugs that act as haptens which bind to neutrophil membrane and
stimulate antibody formation. These antibodies are directed against circulating neutrophils or neutrophil precursor cells (type 2
allergic reaction). Some cytokines when produced in big amounts (? interferon, TNF) can cause neutrophil apoptosis.
Critical decrease of neutrophils along with other granulocytes (mainly eosinophils) is named agranulocytosis. Agranulocytosis is
usually diagnosed when total WBC count falls to 1-3*109/L and absolute granulocytes value is less than 750 cell in 1 microliter.
Myelotoxic agranulocytosis occurs due to suppression of the myelopoiesis progenitor cells in the bone marrow. This type of
agranulocytosis can develop with exposure to the body of ionizing radiation, cytostatic drugs and other pharmacological agents
(levomycetin, streptomycin, gentamicin, penicillin, colchicine, aminazine), etc.
Autoimmune agranulocytosis is associated with the formation of antibodies against own granulocytes. Some drugs
(sulfonamides, amidopyrine, analgin, aspirin, butadione, etc), act as haptens fixing on the membrane of granulocyte thereby
altering the structure of its antigens.
Increased WBC count: leukocytosis
 Leukocytosis is WBC count greater than 9 *109 per L. The number of leukocytes is not constant even in healthy persons: it
increases in the second half of the day and decreases in the early morning. It is also dependent on body pose: in vertical position
leukocytes number becomes higher, in horizontal position it becomes lower.
Leukocytosis can be absolute, that is caused by activation of normal or tumor-induced leukopoiesis or as a result of increased
release of leukocytes from bone marrow storage pools.
Relative leukocytosis is determined by the redistribution of leukocytes in the vessels. It is known that leukocytes in the blood
vessels may be present in two compartments: a circulating pool and a marginal pool. Leukocytes from the circulating pool are
measured in the complete blood count. The marginal pool consists of leukocytes (predominantly neutrophils) that are
intermittently adhered to endothelium, especially in small veins and capillaries.
Leukocytosis may be of physiological or pathological origin.
Physiological leukocytosis, which is usually neutrophilic, is caused both by stimulation of bone marrow and by stress-dependent
redistribution. It is observed:
* In newborns, - within the 1st week of life – protective value.
* In pregnant women, developing in 2nd half of pregnancy.
* On the 2nd week after delivery.
Corticosteroids release during stress-reaction causes increased bone marrow release of mature neutrophils, demargination into
the circulating pool, and decreased tissue migration. The named processes result in physiological short-term (1-2 hours)
leukocytosis, such as related to:
* physical overload (myogenic);
* psychical overload (emotional);
* flight over the time zones (acclimatization);
* in 1-2 hours after food intake (alimentary).
Stress leukocytosis reverses within hours of elimination of the inciting factor. No increase in nonsegmented forms occurs
because no change occurs in the inflow of neutrophils from the marrow. WBC differential count (leukocytic formula) is usually
normal in physiological leukocytosis.
Other causes of leukocytosis include drug intake, splenectomy, hemolytic anemia and malignancy. Drugs commonly associated
with leukocytosis include low doses of corticosteroids, lithium and beta blockers. Splenectomy causes a transient leukocytosis
that lasts for weeks to months. It is caused by the decrease of WBC destruction in the spleen. In hemolytic anemia, nonspecific
increases in leukocyte production and release occur in association with increased red blood cell production; because marrow
growth factors are likely contributors.
In most cases, increased WBC count is the result of normal bone marrow response to inflammation or infection. Malignancy is
another recognized cause of leukocytosis; the tumor nonspecifically stimulates bone marrow to produce leukocytes. Leukocytosis
can be subcategorized according the type of white blood cell that is increased in number.
Eosinophilia and basophilia
Most common cause for eosinophilia are parasitic infections (such as hookworm, schistosomiasis), allergic conditions (such as
asthma and hay fever) and certain types of drug reactions. Eosinophils enzymes and cationic proteins are toxic to helminthes, and
eosinophilia commonly accompanies helminthic infestations. Eosinophils may modulate immediate hypersensitivity reactions by
degrading or inactivating mediators released by mast cells, such as histamine, leukotrienes and others, thereby reducing the
intensity of allergic inflammation.
Dermatologists frequently find eosinophilia in patients with skin rashes, and pulmonologists often see elevated numbers of
eosinophils in conjunction with pulmonary infiltrates and bronchoallergic reactions. Other causes of eosinophilia include
malignancies, especially those affecting the immune system (Hodgkin's disease and non-Hodgkin's lymphoma), and immunologic
disorders such as rheumatoid arthritis and periarteritis.
Basophilia is the uncommon cause of leukocytosis. Basophils contain inflammatory mediators (histamine and heparin). These
cells, along with similar tissue-based cells (mast cells), have receptors for IgE and participate in the degranulation that occurs
during allergic reactions, including anaphylaxis. The possible causes of basophilia are:
* Anaphylactic allergic reactions;
* Autoimmune diseases (ulcerative colitis, autoimmune thyroiditis, type 1 diabetes mellitus);
* Inflammatory conditions: inflammatory bowel disease, chronic airway inflammation, chronic dermatitis, viral infections
(varicella);
* Myeloproliferative disorders: chronic myelogenous leukemia, polycythemia vera, myelofibrosis;
* Chronic hemolytic anemia, Hodgkin's disease, splenectomy.
Lymphocytosis and monocytosis
As it is known lymphocytes are immune active cells, their number will increase in immune and allergic reactions. Increased
numbers of lymphocytes occur with certain acute and chronic infections.
Physiological lymphocytosis is usually observed in children from the 4-5 day of life up to 4-5 years. In this period of life
lymphocytes prevail in leukocytic formula of children, because immune system have to produce memory cells against the
antigens of the surrounding (mainly viruses).
Lymphocytosis can be relative and absolute.
Absolute lymphocytosis is caused by the activation of lymphocyte maturation which accompanies infectious inflammation cases.
It may also be the result of tumor development in the bone marrow.
* Acute infections: cytomegalovirus infection, Epstein-Barr virus, pertussis, hepatitis, toxoplasmosis;
 * Chronic infections: tuberculosis, brucellosis;
* Bronchial asthma;
* Lymphoid malignancies: chronic lymphocytic leukemia.
Relative lymphocytosis is a state when the total WBC count is normal or even lower than normal and lymphocytes % is higher
than normal. This situation usually occurs due to increased neutrophils migration to the site of inflammation or in other cases of
decreased neutrophils count:
* Acute phase of several viral illnesses;
* Connective tissue diseases;
* Thyrotoxicosis;
* Addison's disease;
* Splenomegaly with splenic sequestration of granulocytes.
Monocytosis is characterized by the increased quantities of monocytes in blood count over 10 %. Some common causes of
monocytosis are:
* certain bacterial infections (tuberculosis, syphilis, subacute bacterial endocarditis);
* viral infections, protozoal, rickettsial infections (malaria, typhus);
* convalescence from acute infection;
* hematopoietic disorders (leukemia, myeloma);
* malignancies (cancer of the ovary, stomach, breast);
* granulomatous diseases and collagen vascular diseases.
Neutrophilia
Neutrophilia is characterized by the increased quantity of neutrophils in blood count over 75%. As it is known, the basic function
of neutrophils is phagocytosis. Therefore the most common reason of neutrophilia is inflammation of infectious and non-
infectious (aseptic) origin. Aseptic neutrophilia etiology include:
* massive burns, myocardial infarction, postoperative state, intestinal impassability, acute attacks of gout, acute
glomerulonephritis, rheumatic fever, collagen vascular diseases, immunocomplex diseases which are accompanied with the cells
damage and aseptic inflammation;
* uremia, diabetic ketoacidosis, thyrotoxicosis, poisoning with the venom of some snakes, excessive histamine synthesis, acute
hemorrhage (especially into the peritoneal cavity, pleural cavity, joint cavity, and intracranial);
Neutrophilia can occur in association with rapidly growing neoplasms when the tumor outgrows its blood supply. This is thought
to be due to tumor necrosis factor-alpha. Some tumor types produce neutrophilic growth factors (e.g., squamous cell cancers of
the head and neck). Increased number of neutrophils is also observed in the cases of marrow tumors (myelogenous leukemia,
Vaquez disease).
More commonly neutrophilia accompanies acute bacterial infections, caused by pyogenic bacteria (Pneumococcus,
Streptococcus, staphylococcus and others).
During early infection, the neutrophil count may actually decrease due to margination of cells from blood. During the first 1-3
hours, neutrophilia occurs because of a shift from the marginal pool to the circulating pool. After 3-6 hours, neutrophils are
released from the marrow.
Neutrophilia combined with total leukocytes number increase as a rule testifies to high resistance of an organism.
Neutrophilia combined with the reduced total number of leukocytes is a sign of weak resistance of the organism that can be the
consequence of severe infections and long current inflammatory diseases.
Types of neutrophil nuclear shift
The important practical value for neutrophilia diagnosing has the definition of the degree of neutrophil nuclear shift (NNS). The
term “left shift” means that in patient’s blood smear more immature neutrophils are present than there it would be normally.
“Right shift” and “left shift” are currently used to describe opposite directions in myeloid maturation. A “shift to the right” is
observed in megaloblastic anemia when the amount of mature neutrophils is decreased and degenerative forms appear
(hypersegmented cells with 5 or more segment).
The types of neutrophil nuclear shift to the left are:
1. Hyporegenerative NNS to the left – the increase of band neutrophils % (>5 %). It is observed in easy course of infectious and
inflammatory diseases;
2. Regenerative NNS to the left – the increase of band neutrophils percentage, appearance of juvenile cells. It is characteristic of
purulent and septic diseases;
3. Hyperregenerative NNS to the left – the appearance of juvenile cells, myelocytes, promyelocytes and even single myeloblasts.
It is observed at myelogenous type of leukemoid reaction. It is also observed in very severe course of infectious and purulent -
septic diseases. It is frequently considered to be an unfavorable sign;
4. Regenerative- degenerative NNS – the increase of band neutrophils %, presence of juvenile neutrophils and myelocytes, the
decrease of segmented neutrophils, the appearance of a significant amount of degenerative forms of neutrophils. It is observed in
a severe course of infectious diseases, endogenous intoxications and is a parameter of suppression of functional activity of bone
marrow.
UNIT 17
WBC PATHOLOGY: LEUKEMOID REACTION AND LEUKEMIA
Leukemoid reaction: definition, causes and types
 Leukemoid reaction is an excessive white blood cell response (more than 30*109/L WBC). Leukemoid reaction is caused by
changes in blood and organs of hemopoiesis, which look like leukemia, because immature leukocytes up to blasts cells are found
in peripheral blood, but its character is always reversible and it does not transform in the tumor. The mechanism of leukemoid
reaction can be different: in some cases, there is output of immature cellular elements in blood, in the other increased production
of WBC.
Leukemoid reaction is termed due to activated leukocyte type:
* myelogenous type – production of granulocytes is increased;.
* lymphocytic and monocytic type.
The majority of leukemoid reactions involve granulocytes. It may occur in association with a wide variety of diseases:
* Infectious diseases (e.g. pyogenic infection, meningitis, diphtheria, sepsis, edocarditis, infected abortions etc.). It is usually
accompanied with the presence of other signs of inflammation.
* Intoxication – mercury poisoning, severe burns, eclampsia (toxemia of pregnancy)
* Malignant diseases – multiple myeloma, bone marrow metastases, tumor decay
* Acute hemolysis, hemorrhagic shock.
* Metabolism disorders – uremia, endocrine pathology.
Neutrophilic leukocytosis with the hyperregenerative neutrophils nuclear shift is registered in blood count. Despite myeloid
hyperplasia of the bone marrow, infiltration of organs and tissues with immature blast cells (which is typical for leukemia
pathogenesis) is absent.
The leukemoid reactions of lymphatic type more often are the result of viral infection (infectious mononucleosis, measles,
hepatitis, tuberculosis).
Leukemia: definition, etiology, pathogenesis
Leukemia is a malignant neoplasm of cells originally derived from hematopoietic stem cells. They are characterized by diffuse
replacement of bone marrow with unregulated, proliferating, immature neoplastic cells.
Malignant transformation may occur at the pluripotent stem cell level, or committed stem cell with more limited capacity for
differentiation. Leukemia development is characterized by abnormal proliferation, clonal expansion, and diminished apoptosis of
leukemic cells. All these events lead to suppression of normal blood cell formation and organs infiltration by leukemic cells.
The etiology of leukemia is not known in most patients, but a number of factors have been implicated. They are:
* natural or artificial ionizing radiation;
* chemicals (benzene and other aromatic hydrocarbons);
* some viruses (human T-lymphotrophic virus, Epstein-Barr virus);
* genetic predisposition, association with other hereditary diseases (Down’s, Klinefelter’s and Wiskott-Aldrich’s syndromes).
Leukemia, like other cancers, result from somatic mutations in the DNA, which activate oncogenes or deactivate tumor
suppressor genes, and disrupt the regulation of blood cell death, differentiation or division.
The stages of leukemia pathogenesis are:
* malignant transformation of a single hematopoietic cell (initiation stage);
* monoclonal proliferation of the transformed cell (promotion) results in primary leukemia of some hematopoietic stem. The
tumor at this stage consists of similar cells descendants of mutated cell and is less malignant;
* polyclonal proliferation (corresponds to tumor progression stage). Tumor tissue under additional mutations obtains
polymorphism (consists of different cellular clones that differ from each other), increases the speed of its growth, and obtains its
malignant character.
Common symptoms and signs of leukemia
The early signs of leukemia are often non-specific, and may be similar to those of common illnesses. Some generalized
symptoms include fever, fatigue, weight loss or loss of appetite, shortness of breath with exertion, anemia, easy bruising or
bleeding, petechiae (flat, pin-head sized spots under the skin caused by bleeding), bone and joint pain and persistent or frequent
infections. Other presenting symptoms and signs are usually nonspecific (e.g., pallor, tachycardia, chest pain) and are determined
by anemia and a catabolic state typical for malignancies.
Manifestations of leukemia result from suppression of normal hemopoiesis and organ infiltration by leukemic cells.
Suppression of normal hemopoiesis occurs not simply due to overcrowding of marrow by leukemic cells. They produce humoral
and cell-derived factors that may suppress normal hematopoiesis. Some patients with acute leukemia have a hypocellular marrow.
Nevertheless, some normal hematopoietic stem cells remain in the marrow which are capable of proliferating and restoring
normal hemopoiesis after effective treatment. Blood count in leukemia reveals anemia, thrombocytopenia. WBC count in these
diseases may vary; blast cells are found in peripheral blood smear.
Disrupted hematopoiesis leads to the most common leukemia syndromes:
* metaplastic anemia (due the metaplasia of the bone marrow);
* immunodeficiency (due to decreased number of normal WBCs) with high susceptibility to infections;
* easy bruising and bleeding (due to low thrombocytes count).
Leukemic infiltration results from the growth of the secondary tumor nodes outside the bone marrow (metastasis). The leukemic
hyperplasia (unlimited proliferation of leukemia cells) at the beginning of disease is observed in those organs and tissues which
normally take part in hemopoiesis (bone marrow in myelogenous leukemia, spleen and other sites of lymphoid tissue in
lymphogenous leukemia). Then, leukemic hyperplasia is spread over those organs which were hematopoietic in the embryonic
state (liver, thymus).
 Extramedullary infiltration by leukemic cells may cause lymphadenopathy, splenomegaly, hepatomegaly, and leukemia cutis (a
raised, nonpruritic skin rash).At the terminal stages of disease leukemic infiltration theoretically may involve all organs: bones,
lung, nervous system, kidneys, etc.
Principles of leukemia classification
Leukemia is divided into acute and chronic forms according to the level of leukemic cells differentiation.
Acute leukemia is characterized by the rapid growth of immature poorly differentiated cells, usually blast forms of blood cells.
Blast cells are found in the peripheral blood up to 30-90%. Leukocytic formula is characterized with "hiatus leukemicus." This
term means a lack of cell stages of maturation between blasts and mature cells. The majority of the cells are blasts and mature
cells. This type of leukemia has poor prognosis due to the rapid progression, early metastasis, high level of autonomy, severe
depression of normal hemopoiesis. If left untreated, the patient will die within months or even weeks. Acute leukemia never
transforms to chronic form.
Chronic leukemias produce more differentiated cells, but they are still abnormal. Typically lasting for months to years to
progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal WBC in blood. Chronic
leukemia sometimes can loose the ability to differentiate and neoplastic progression can manifest as ‘blast crisis” when blast cells
number significantly increases in peripheral blood.
Leukemias are classified according to the type of abnormal cell which is mostly found in blood. The type of abnormal cell is
usually determined morphologically and by a series of biochemical reactions detecting the markers and enzymes typical for
different blasts. In the course of Pathophysiology we should study 3 forms of acute leukemia: myeloid (myeloblastic),
lymphoblastic and undifferentiated; and 2 forms of chronic leukemia: myelocytic and lymphocytic.
Due to the total WBC count leukemias are divided into such forms:
* leukemic form – more than 50*109/L, blasts prevalence in peripheral blood;
* subleukemic form – 10-50 *109/L, less blasts in peripheral blood;
* aleukemic form – WBC count lower than 10*109/L, blasts are few or absent in peripheral blood;
* leukopenic form – total WBC count lower than 4*109/L.
In other words leukemia is not generally accompanied by increased WBC number: in acute forms WBC number is usually lower
than in chronic ones.
Acute leukemia
Acute myeloid leukemia (AML) is the group of cancers of the myeloid line of WBC, the most common acute leukemia affecting
adults, and its incidence increases with age. The malignant cell in AML is the myeloid stem cell or myeloblast blast that gives a
positive reaction to myeloperoxidase, lipids, chloroacetate esterase. AML progresses rapidly and is typically fatal in weeks to
months if left untreated.
The AML diagnosis can be verified with the following signs:
* myeloblasts in a peripheral blood and their prevalence in marrow;
* enlargement of the spleen and liver (indicates leukemic infiltration);
* later AML blasts may occupy gums, inner organs and meninges;
* hiatus leukemicus – lack of cell stages of maturation between myeloblasts and mature neutrophils;
* absence of eosinophils and basophils in the leukocytic formula;
* anemia and thrombocytopenia which indicate leukemia severity;
* high susceptibility to severe bacterial and fungal infections (due to decreased number of granulocytes and monocytes).
Other symptoms of AML may include:
* DIC syndrome arising as a result both of thrombocytopenia and neoplastic procoagulants secretion;
* leukostasis – aggregation of WBC in the vessels of different organs with their subsequent occlusion, it usually accompanies
leukemic forms;
* hyperuricemia – which is caused by increased breakdown of purine nucleotides due to non-effective hemopoiesis and blood
cell destruction.
Acute lymphoblastic leukemia (ALL) more frequently affects children of 2-4 years old. The majority of ALL cases are presented
with pre-B-clones (75%). 25% of cases are presented with pre-T clones. Cytochemically, lymphoblast is detected with the
positive PAS reaction (Periodic acid–Schiff staining for glycogen) and negative reaction to peroxidase, lipids, chloroacetate
esterase, cationic proteins. Immunophenotyping of leukemia cells reveals the CD markers typical for T- or B-lymphocytes.
The main feature of ALL in children is the affection of lymphatic nodes and spleen. Clinical symptoms are determined by the
place of enlarged lymphatic nodes localization. If they are localized in mediastinum there are dry cough, shortness of breath;
enlarged mesoperitoneal nodes can cause stomachaches. Pains in bones (more often in shins) are the other feature of ALL. Other
clinical signs are similar to AML: fatigue, pallor, infection, and easy bruising and bleeding. They occur due to suppression of
normal hemopoiesis resulting in anemia, granulocytopenia and thrombocytopenia. Immunodeficiency in ALL is characterized by
the absence of specific immunity (humoral or cellular). Complete blood count reveals the presence of lymphoblasts in peripheral
blood smear.
Acute undifferentiated leukemia (leukemia of uncertain lineage)
Rare cases of acute leukemia remain difficult to classify even after extensive morphologic and biochemical studies. Such
leukemias are designated acute undifferentiated or stem cell leukemia (AUL). Morphologically, the blasts of AUL may resemble
ALL and AML, but other markers identifying the lineage are absent. The lack of lineage-associated markers in AUL may be due
to immaturity of the leukemic cells (affection of hemopoietic stem cell) or disorders of genes regulating these markers presence.
 This is one of the most malignant forms of acute leukemia, which is characterised by fast progress, and severe course of the
disease due to marked pancytopenia. Immunodeficiency in AUL is especially severe because both innate and adaptive immunity
are not functioning properly due to decrease of granulocytes, lymphocytes and monocytes.
Chronic leukemia
Chronic myelogenous leukemia (CML) is a form of chronic leukemia characterized by increased and unregulated clonal
production of predominantly myeloid cells in the bone marrow. CML occurs in all age groups, but most commonly in the middle-
aged and elderly. CML is a myeloproliferative disease associated with a characteristic chromosomal translocation called the
Philadelphia chromosome. The appearance of Ph’-chromosome is registered in 86-88 % of CML cells. Ph’-chromosome is
present in granulocytes, cells of RBC stem, in megakaryocytes and monocytes. The presence of Ph’ chromosome is the evidence
of leukemia development from single affected cell.
Symptoms of CML may include: malaise, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia.
The enlargement of spleen (up to 10 kg) is observed in the patients with CML. Spleen is enlarged due to growth of myeloid tissue
in it. The same process is observed in liver, which is sometimes enlarged more, than spleen. The fat marrow of long bones is
replaced with myeloid tissue. Many sites of hemopoiesis are developed outside bone marrow (in lymphatic nodes, kidneys, lungs,
intestine, etc.). CML usually manifests in leukemic form.
CML is often suspected according to the complete blood count, which shows increased count of all granulocytes types.
Basophils and eosinophils are almost universally increased. This sign is called eosinophil-basophil association and helps to
differentiate CML from a leukemoid reaction of myelogenous type. CML diagnose is verified by detecting the Philadelphia
chromosome.
CML is often divided into three phases based on clinical characteristics and laboratory findings. In the absence of intervention,
CML typically begins at the chronic phase, and progresses over of several years to an accelerated phase and ultimately to a blast
crisis. One of the drivers of the progression from chronic phase through acceleration and blast crisis is the acquisition of new
chromosomal abnormalities (in addition to the Philadelphia chromosome).
Chronic phase: patients are usually asymptomatic or have only mild symptoms of fatigue or abdominal fullness.
Accelerated phase is characterized by the further increase in granulocytes count, decrease of RBC and platelets, increasing
splenomegaly.
Blast crisis is the final phase in the evolution of CML, and manifests like an acute leukemia, with rapid progression and short
survival, >20% myeloblasts in peripheral blood.
Chronic lymphogenous leukemia (CLL)
In about 98% of cases, B cells undergo malignant transformation, with lymphocytes initially accumulating in bone marrow and
then spreading to lymph nodes and other lymphoid tissues, eventually inducing splenomegaly and hepatomegaly. Leukemic
infiltration are also founds in bone, skin (shins), lung and other organs. As the disease progresses, abnormal hemopoiesis results
in anemia, neutropenia, thrombocytopenia, and decreased immunoglobulin production. Many patients develop
hypogammaglobulinemia and impaired antibody response. Patients have increased susceptibility to autoimmune disease and a
modest increase in risk of developing other cancers. Mainly mature lymphocytes form the bulk of CLL which have lost the ability
to transform to plasmocytes.
The onset is usually insidious; CLL is often diagnosed incidentally during routine blood tests or through evaluation of
asymptomatic lymphadenopathy. The patient usually has nonspecific complaints of fatigue, anorexia, weight loss, dyspnea on
exertion, or a sense of abdominal fullness (secondary to an enlarged spleen). Initial findings include generalized
lymphadenopathy and minimal-to-moderate hepatomegaly and splenomegaly. With progressive disease, there may be pallor due
to anemia. Hypogammaglobulinemia and granulocytopenia in late CLL may predispose to bacterial, viral, and fungal infection,
especially pneumonia.
Blood count in CLL is characterized by the considerable increase of leukocytes quantity, mainly due to mature lymphocytes,
among which there are young forms - prolymphocytes and lymphoblasts. The so-called Gumprekht’s shadows (cells) are seen in
peripheral blood smear. At the late stages of CLL anemia and thrombocytopenia develop.
5 CARDIOVASCULAR AND LUNG SYSTEM PATHOLOGY
UNIT 18
HEART PATHOLOGY: ARRHYTHMIA, MYOCARDITIS
Functions of the heart
There are several functions that determine the work of heart.
Automatism is an ability of the heart to produce electric impulses with no external irritation. The cells of sinus node and cells of
the heart conducting system have this ability.
Conductivity is an ability to conduct excitation in the conducting system of the heart and myocardium. Excitation is conducted
from sinus node to all parts of the heart.
Excitability is an ability of the conducting system of the heart and myocardium to respond to electric impulses by depolarisation.
This ability is different in different phases of heart contraction.
Contractility is an ability of the heart to contract under the influence of impulses of internal and external origin.
Arrhythmia is any cardiac rhythm that is different from the normal sinus rhythm. It is classified due to disturbed function of the
heart:
Disturbed functionArrhythmia typeautomatismchronotropic (chronos – time)conductivitydromotropic (dromos –
running)excitabilitybathmotropic (bathmos – degree of excitation)contractilityinotropic arrhythmia (inos – force, strength) These
terms are also used in reference to drugs that affect the functions named above.
The increased concentration of noradrenaline and adrenaline causes increased contractility, increased frequency, increased
conduction velocity, and increased excitability of the heart (positive inotropic, chronotropic, dromotropic and bathmotropic
effects).
The neurotransmitter acetylcholine (which activates muscarinic receptors) and vagal stimulation cause reduced contractility,
reduced frequency, reduced conduction velocity, and reduced excitability (negative inotropic, chronotropic, dromotropic and
bathmotropic effects). .
The conducting system of the heart consists of the: sinoatrial (SA) node, atrioventricular (AV) node, bundle of His, bundle
branches, Purkinje fibres. Contractions in the heart begin when electrical impulses are sent from the SA node (also known as the
natural pacemaker) which is located in the right atrium.
The signal leaves the SA node and travels through the atria, stimulating them to contract. Then the signal passes through the AV
node, and finally, through the ventricles, stimulating them to contract. The sinus node depolarizes spontaneously with a frequency
between 60 and 100 beats per min (bpm) at rest. In the norm the only driver of rhythm is the sinus node, which suppresses the
other drivers of rhythm. When SA is damaged, cells of the AV node and His bundle become rhythm drivers; they produce 40-50
bpm. When both SA and AV node are unable to produce impulses the branches of His bundle and Purkinje fibers become rhythm
drivers; they possess the lowest ability of automatism and produce about 25 – 40 bpm.
Normal ECG features
* normal sinus rhythm : each P wave is followed by a QRS;
* P wave rate 60 - 100 bpm with <10% variation;
* normal PR interval is from 0.12 to 0.20 seconds;
* normal QRS complex is < 0.12 s
* normal QT interval ? 0.44 s;
* normal ST segment should be without elevation or depression.
Pathology of automatism (chronotropic arrhythmia)
Sinus tachycardia (heart rate above 100 bpm) is caused by psychological (panic, anxiety) or physical stress (anemia, hypoxia,
exercise, fever, intoxication, shock etc). Any condition with increased sympathetic tone results in tachycardia.
Sinus bradycardia (heart rate below 60 bpm) is a normal phenomenon in well-trained people and in elderly persons. Athletes at
rest have a high stroke volume and a low pulse, because they are dominated by vagal tone under this condition. All people react
with sinus bradycardia during hypothermia, hypothyroidism, jaundice, increased intracranial pressure, increased vagal activity,
and in sinus node disease.
Sinus arrhythmia is a normal phenomenon. There is a rise in heart rate during inspiration followed by a fall during expiration.
During inspiration the low intrathoracic pressure improves the venous return, which (with a delay through the pulmonary
circulation) increases the stroke volume of the left ventricle. The resulting increase in aortic intravascular pressure causes strong
stimulation of the aortic baroreceptors. That is why the vagal tone falls and the sinus node discharge quickens. The reflex and
circulation delay explains why the fall in heart rate manifests itself during expiration and not during inspiration.
Pathology of conduction (dromotropic arrhythmia)
Abnormality of conduction in electrical system of the heart is termed block. Blocks can occur at any part of conduction system.
ECG signs will depend on the site of block occurrence.
Sino-atrial block is characterized by long intervals between consecutive P-waves. It is caused by inability of SA node to generate
impulse (ischemia or infarction of the SA node) or by block of the impulse conduction from the SA node to the atrial tissue. It
may occur in healthy patients with increased vagal tone. This type of block usually occurs transiently and produces no symptoms.
Intra-atrial block is defined as delayed conduction between the right and left atrium, manifested by widened and often notched P
waves. Intra-atrial block has strong associations with multiple medical conditions including atrial fibrillation, myocardial
ischemia, left atrium enlargement.
Atrioventricular block is the blockage of the conduction from the atria to the AV-node. Three degrees of AV block are known.
The first-degree AV block manifest as a prolongation of the PQ (PR)-interval (above 0.2 s) implying a delay of the conduction.
All beats are conducted, i.e. each P-wave is followed by a QRS-complex.
The second-degree AV block occurs when some signals are not conducted to the AV-node, so some of the P-waves are not
followed by QRS-complexes. The ventricles actually drop some beats. A typical example is Mobitz type I block or Wenckebach
block, which is characterized by a predictive loss of a QRS-complex. The PQ-interval is progressively increased until a P-wave is
not followed by a QRS-complex (Wenckebach phenomenon). Following the drop beat PQ interval is again normal. Then the
cycle repeats.
Mobitz type II block occurs without warning. The PQ interval is constant, but some P waves are not followed by QRS- complex.
The third degree AV block (complete AV-block) is a total block of the conduction between the sinoatrial node and the ventricles.
The atria and ventricles beat independently. The atria are driven by SA node. The ventricles are driven by His bundle or Purkinje
fibers. The ventricular rate may be 45-60 bpm, if upper part of His bundle produces impulses, or lower than 40 when pacemaker
is situated lower in the system. In the latter case the survival of the patient is uncertain. Discoordination of atrial and ventricle
contractions results in low cardiac output and sudden loss of consciousness (Stokes-Adams syndrome).
 Bundle branch block is a block of the right or the left His bundle branches. The signal is conducted first through the healthy
branch and then it is distributed to the damaged side. This distribution takes more time than usually, so that the QRS-complex
becomes wider than normal (>0.12 s).
Pathology of excitability (bathmotropic arrhythmia)
Pathology of excitability is manifested with ectopic and premature beats (extrasystole), paroxysmal tachycardia and fibrillation.
Ectopic beats originate in pacemaker cells outside the sinus node. The abnormal pacemaker tissue can be triggered by ischemia,
mechanical or chemical stimuli. Ectopic beats can be of atrial, AV, or ventricular origin.
Sinus extrasystole (premature beat) originates in the normal pacemaker – SA node. ECG recording is normal, there is no
compensatory pause after it.
Atrial ectopic beats appear as early (premature extrasystoles) and abnormal P-waves in the ECG. They are usually followed by
normal QRS-complexes. There is often a short compensatory pause after it.
Premature junctional contraction or atrioventricular extrasystole occurs when the ectopic beat originates in the AV node. P-wave
in premature junctional contraction is negative, compensatory pause is longer than after premature atrial contraction.
Ventricular ectopic beats (extrasystoles) are recognized on the ECG by their wide and bizarre QRS-complex (above 0.12 s), since
they originate in the ventricular tissue and slowly spread throughout the two ventricles without passing the Purkinje system. P-
wave is usually absent in ventricular extrasystole because electrical impulse can’t pass the AV node in a retrograde direction.
Such extrasystole is sometimes recognized by a double R-wave and full compensatory pause (2RR). A premature beat in the left
ventricle is weak because of low venous return, but after the long compensatory pause, the post-extrasystolic contraction
(following a long venous return period) is strong due the Starling?s law of the heart.
Ectopic tachycardia occurs in paroxysms and is either of atrial or ventricular origin. Paroxysmal atrial tachycardia
(supraventricular) is elicited in the atrial tissue outside the SA node. Heart rate is characterized by a regular tachycardia 160 to
200 bpm, that begins and ends suddenly. Paroxysmal ventricular tachycardia is elicited from one focus in the ventricular tissue
with a frequency at least 120 bpm. It is characterized by abnormal intraventricular impulse conduction (disturbed QRS
complexes). There are no P-waves in the ECG, QRS-complexes are wide and irregular. Ventricular tachycardia may be thought to
be a sequence of consecutive ventricular premature beats.
The influence of extrasystole on blood circulation
Paroxysmal tachycardia of atrial or ventricular origin reduces stroke volume and cardiac output particularly when the ventricular
rate is > than 160 bpm. The stroke volume becomes reduced because of decreased ventricular filling time and decreased time of
ventricular filling at high rates of contraction. Furthermore, if tachyarrhythmia is associated with abnormal ventricular
conduction, the synchrony and therefore effectiveness of ventricular contraction will be impaired leading to reduced stroke
volume. Another consequence of tachycardia is increased myocardial oxygen demand. This can cause angina (chest pain),
particularly in patients having underlying coronary artery disease.
Single extrasystole doesn’t cause serious disorders of hemodynamic function of the heart and clinically manifests in the feeling
of «interruption» of cardiac activity. Plural extrasystoles can seriously violate the functioning of cardiac muscle. It occurs due to
the following features of extrasystole:
* Extrasystoles are ineffective in hemodynamic because the stroke volume of premature contraction is lower due to shortened
time of ventricular filling. It is shown that even a single extrasystole can result in reduced brain blood supply, and plural
extrasystoles lead to the considerable decrease of the heart stroke volume.
* Compensatory pause following extrasystole is the lengthened diastole. Myocardium can’t react to the nomotopic impulse and
its reaction to the ectopic impulsion is acutely increased during compensatory pause. If ectopic impulse arises during
compensatory pause, there can be fibrillation of heart ventricles.
Pathology of excitability: flutter and fibrillation
Atrial ?utter is characterized by an atrial rate around 250 - 350 bpm. Because the AV node cannot usually conduct at this rate,
typically half of the impulses get through (2:1 block), resulting in a regular ventricular rate of 150 beats/min (recorded as QRS-
complexes). Atrial flutter is recognized in the ECG as sawtooth-like P-waves. It is less common than fibrillation.
Atrial fibrillation is a common arrhythmia that may occur in paroxysmal and persistent forms. It may be seen in normal
individuals, particularly during emotional stress or following surgery, exercise, acute alcoholic intoxication, or a prominent surge
of vagal tone (i.e., vaso-vagal response). It may also occur in patients with heart or lung disease who develop acute hypoxia,
hypercapnia, or metabolic or hemodynamic derangements. Persistent atrial fibrillation usually occurs in patients with
cardiovascular disease.
Under this condition SA node can’t control the rhythm and the atrial muscle fibres undergo a tumultuous rapid twitching. An
excitation wave with 350-600 cycles per min courses continuously through the atrial wall over a circular pathway. It is difficult to
observe and count the P-waves of the ECG. Because of the refractoriness of the AV node only some of the excitation waves result
in ventricular beats. The pulse of the patient is therefore irregular as the occurrence of QRS-complexes in the ECG. Many P-
waves (also called f-waves for fluctuations) are characteristic for atrial fibrillation.
During atrial fibrillation or flutter, the contractions of the atria are so fast that the atrial walls quiver. As a result, blood is not
pumped effectively to the ventricles. Atrial fibrillation decreases the contribution of atrial contraction to ventricular filling.
Normally, under low, resting heart rates, atrial contractions account for about 10% of ventricular filling. However, during exercise
when heart rate is elevated and ventricular filling time is reduced, atrial contraction can contribute up to 40% of ventricular
filling. Therefore, atrial fibrillation generally has relatively minor hemodynamic consequence at rest, but can significantly limit
normal increases in ventricular stroke volume and cardiac output on exertion. This may cause shortness of breath (exertional
dyspnea) and impaired perfusion of active muscles, which will limit exercise capacity. When the heart pumps inefficiently, blood
pressure may fall, and heart failure may occur.
Other important result of atrial fibrillation is the increased risk of thrombus formation within the atria and the release of these
thrombi into the pulmonary or systemic circulation, which can lead to pulmonary embolism or cerebral stroke.
Atrial fibrillation or flutter are caused by “re-entry” phenomenon. Normally, when the cardiac impulse has travelled throughout
the entire extent of the heart, it has nowhere to go and therefore it simply dies. Then the heart remains still until a new signal
begins in SA node. However, under certain conditions this normal sequence of events does not occur. The cardiac impulse
sometimes travels around and around in cardiac muscle without stopping. This phenomenon is called re-entry or the circus
movement.
The reasons of such phenomenon are:
* Dilatation of the heart that makes the length of the impulse pathway in cardiac muscle too long so that originally stimulated
muscle will no longer be refractory and the impulse can stimulate the muscle again.
* Ischemia of the heart, high blood potassium level that decrease the velocity of impulse conduction.
* Epinephrine injection or following repetitive electrical stimulation that shorten the refractory period of the muscle greatly.
Ventricular flutter and fibrillation are characterized by irregular twitching of ventricular muscle fibers, which are ineffectual in
expelling blood. The condition is lethal without effective resuscitation. Ventricular ?utter usually appears as a sine wave with a
rate between 150 and 300 bpm. The rate of ventricular fibrillation may rise up to 600 twitches/min. Actually, heart stops its
pumping activity, cardiac output is decreased to zero. It leads to unconsciousness within 5 seconds, because of lack of blood in
the brain. In patients with coronary artery disease, ventricular fibrillation is a cause of sudden death. The trigger of ventricular
fibrillation is anoxia and the impulses arise from several foci in the ventricular tissue. There is no regular pattern in the ECG.
Ventricular fibrillation is initiated when a premature signal arrives during the downslope of the T-wave (vulnerable period).
Ventricular fibrillation is the most serious cardiac arrhythmia due to the fact that cardiac output significantly decreases that
manifests as a heart failure. It should be converted to sinus rhythm by the application of an electrical shock to the heart
(ventricular defibrillation).
Defibrillation is defined as the termination of fibrillation or, the absence of ventricular fibrillation 5 sec after electric shock
delivery. Ventricular fibrillation is a state of unorganized electrical activity within the myocardium. The goal of defibrillation is to
stop all electrical activity within the myocardium. A maximum greater number of cardiomyocytes are simultaneously depolarized
by electric shock and brought to one stable state – the phase of absolute refractivity. It will provide a subsequent renewal of the
organized cardiac rhythm, if SA node normally functions. Defibrillation is the only treatment available to terminate ventricular
fibrillation.
Pathology of contractility (inotropic arrhythmia)
An alternating pulse (pulsus alternans) belongs to arrhythmias caused by the violation of heart’s contractility. Pulsus alternans is
a cardio-vascular phenomenon characterized by alternating strong and weak pulse pressures during a sinus rhythm. Pulsus
alternans occurs in aortic and mitral valve stenosis, hypertrophic, congestive or metabolic cardiomyopathy, effusive pericarditis.
Pulsus alternans may be a sign of severe ventricular failure.
The mechanism of pulsus alternans is an alteration in the stroke volume with every other cardiac cycle. In left ventricular
dysfunction, the ejection fraction will decrease significantly, causing reduction in stroke volume, hence causing an increase in
end-diastolic volume. There may initially be a tachycardia as a compensatory mechanism to try to keep the cardiac output
constant. As a result, during the next cycle of systolic phase, the myocardial muscle will be stretched more than usual and as a
result there will be an increase in myocardial contraction, related to the Frank–Starling law of the heart. This results, in turn, in a
stronger systolic pulse.
Myocarditis
Myocarditis is an inflammatory disease of cardiac muscle. It can be acute, subacute, or chronic, and there may be either focal or
diffuse involvement of the myocardium. It is rather common form of heart disease that can occur at any age.
Myocarditis can be caused by a variety of infectious and noninfectious causes.
Infectious causes: viral (coxsackie, Epstein-Barr, cytomegalovirus, herpes), bacterial (diphtheria, tuberculosis, salmonellosis,
tetanus, pyogenic bacteria), spirochetal (syphilis, leptospirosis), fungal (candidiasis, aspergillosis), protozoal (toxoplasmosis,
malaria), helminthic (trichomonosis, filariasis).
The most frequent cause of infectious myocarditis in Europe is viral myocarditis; coxsackie virus infection accounts for 50% of
cases. However in Central and South Africa the most frequent cause of myocarditis is the protozoa Trypanosoma cruzi.
Non-infectious causes include:
Physical and chemical agents (alcohol, CO, As, copper, lead, iron) and some drugs (catecholamines, cocaine) that may cause
focal areas of degeneration and necrosis of myocardium and following inflammation.
Inflammatory involvement of myocardium occurs in a number of connective tissue diseases (rheumatoid arthritis, lupus
erythematosus, dermatomyositis) and systemic disorders (sarcoidosis, thyrotoxicosis).
Hypersensitivity reactions in response to sulfonamides, penicillins, methyldopa, insect and animal venoms may result in
myocarditis too.
Idiopathic or Fiedler’s myocarditis is an isolated myocarditis, which occurs without the usual apparent causes.
Pathogenesis of myocarditis includes necrosis caused by direct invasion of the microorganism, toxic effects of exogenous toxins
or endotoxins produced by a systemic pathogen (diphtheria myocarditis), or destruction of cardiac tissue by immunologic
mechanisms initiated by the infectious agent. The immune response may be directed at foreign antigens of the infectious agent
that are similar with those of the host myocardiocytes (as in the case of streptococcal myocarditis). This leads to a continuous
stimulus for the immune response even after the infectious agent has been cleared from the body.
The manifestations of myocarditis vary from the absence of symptoms to profound heart failure, cardiogenic shock or sudden
death. When viral myocarditis occurs in children or young adults, it is often asymptomatic. Acute symptomatic myocarditis
typically manifests as a ?u-like syndrome with malaise, low-grade fever, and tachycardia that is more pronounced than could be
expected for the level of fever present. There commonly is a history of the upper respiratory tract or GIT infection, followed by a
latent period of several days.
The diagnosis of myocarditis can be suggested by clinical manifestations of the disturbed heart functions. The ECG changes of
acute myocarditis include conduction disturbances such as ventricular arrhythmias, low voltage QRS complexes, AV-junctional
block, ST-segment elevation, T-wave inversion, and transient Q waves. Serum creatinine kinase is often elevated. Either troponin
T or troponin I, or both, may be elevated, providing evidence of myocardial cell damage.
UNIT 19
HEART PATHOLOGY: HEART FAILURE, ISCHEMIC HEART DISEASE
Heart failure: definition, classification.
Heart failure or cardiac insufficiency is a disorder, when the heart cannot pump enough blood to satisfy the nutritive needs of the
body.
The main characteristic of heart work is cardiac output: the volume of blood ejected from the left ventricle each minute. It is
calculated by the formula:
Cardiac Output = Heart Rate x Stroke Volume
Average cardiac output is 5 L/min at rest and can increase 5-6 times during exercise. Cardiac output is also influenced by venous
return, peripheral vascular tone, and neurohumoral factors. In most cases heart failure is manifested by a consequential decrease
in cardiac output (lower output failure). In some cases an increase in cardiac output is observed (higher output failure) as it
happens in a patient with high level of thyroid hormones (thyrotoxicosis).
There are several classifications of cardiac failure.
1. Due to the pathogenesis of failure, such forms are distinguished:
Myocardial – develops as a result of the direct injury of myocardium (myocarditis, myocardial infarction, myocardiopathy, etc.).
Overload – develops as a result of heart overload. Overload may occur due to increased pressure load or volume load.
Mixed – develops as a result of the combination of myocardium direct injury and its overload.
The following types of heart overload are known:
Increased pressure load leads to the increased force resisting myocardial fiber contraction at the start of systole (afterload) and is
determined by heart chamber pressure and volume, and heart wall thickness. Increased pressure load is observed at systemic and
pulmonary arterial hypertension, valvular stenosis (mitral, aortic, pulmonary), chronic lungs diseases.
Increased volume load occurs when a ventricle is required to eject more than normal volume of the blood. It leads to the
increased workload of the heart at the end of its relaxation phase (diastole) just before contraction (systole) – preload. This is
found under the following conditions: valvular insufficiency, severe anemia, thyrotoxicosis.
FIGURE 17 The difference between preload and afterload
2. According to the speed of heart failure development, heart failure is divided into acute and chronic forms. Acute heart failure
is caused by acute myocardial infarction, acute intoxications, ruptures of the ventricle walls or valves. In acute heart failure there
is a sudden reduction in cardiac output resulting in systemic hypotension, and then a state of cardiogenic shock and cerebral
hypoxia develops.
Chronic or congestive heart failure occurs in such conditions as ischemic heart disease, systemic arterial hypertension, chronic
lungs diseases. In chronic cardiac failure compensatory mechanisms try to maintain the cardiac output.
3. Due to the localization of the heart affection, one can define the failure of the left ventricle – left-sided failure, right ventricle
failure – right - sided failure and mixed forms.
4. Due to disturbed phase of heart cycle: systolic dysfunction – inability to pump during systole (ischemic heart disease, arterial
hypertension, dilated cardiomyopathy, valvular stenosis) and diastolic dysfunction – inability to fill properly during diastole
(hypertrophic and restrictive cardiomyopathy)
5. Due to the sequence of events, we can name primary heart failure (cardiogenic form) which occurs in direct affection of the
heart (ischemic heart disease, myocarditis) and secondary (non-cardiogenic form). Secondary heart failure can occur in the cases
of acute profound blood loss, collapse; when the heart is squeezed with exudate (exudative inflammation of the pericardium).
Clinical manifestation of heart failure
The manifestations of heart failure depend on the degree and type of heart dysfunction, as well on the rate of its development.
The manifestations of heart failure re?ect the signs of adaptation to the impaired pumping ability of the heart, decreased renal
blood ?ow, and activation of the sympathetic mechanisms. The severity and progression of symptoms depend on the degree and
type of dysfunction that is present.
Fluid retention and edema. Many of the manifestations of congestive heart failure result from the increased capillary pressures
that develop in the peripheral circulation in right-sided heart failure and in the pulmonary circulation in left-sided heart failure.
The increased capillary pressure re?ects an over?lling of the vascular system because of increased salt and water retention and
venous congestion resulting from the impaired pumping ability of the heart.
Respiratory manifestations. Shortness of breath due to congestion of the pulmonary circulation is one of the major
manifestations of left-sided heart failure. Perceived shortness of breath (breathlessness) is called dyspnea. Orthopnea is shortness
of breath that is relieved by sitting or standing in an erect position. It is explained by the following fact. The gravitational forces,
that cause ?uid to become sequestered in the lower legs and feet when the person is standing or sitting, are removed when a
person with congestive heart failure assumes the supine position; ?uid from the legs and dependent parts of the body is mobilized
and redistributed to an already distended pulmonary circulation. This phenomenon also explains the mechanism of paroxysmal
nocturnal dyspnea – sudden attack of dyspnea that occurs during sleep. It disrupts sleep, and the person awakens with a feeling of
extreme suffocation that resolves when he or she sits up.
A subtle and often overlooked symptom of heart failure is a chronic dry, nonproductive cough, which becomes worse when the
person lies down. Bronchospasm due to congestion of the bronchial mucosa may cause wheezing and difficulty in breathing. This
condition is sometimes referred to cardiac asthma.
Fatigue and limited exercise tolerance. Fatigue and limb weakness often accompany diminished output from the left ventricle.
Cardiac fatigue is different from general fatigue in that it is usually not present in the morning but appears and progresses as
activity increases during the day.
Cachexia and malnutrition. Cardiac cachexia is a condition of malnutrition and tissue wasting that occurs in persons with end-
stage heart failure. A number of factors probably contribute to its development, including the fatigue and depression that interfere
with food intake, the congestion of the liver and gastrointestinal structures that impairs digestion and absorption and produces
feelings of fullness, and the circulating toxins and mediators released from poorly perfused tissues that impair appetite and
contribute to tissue wasting.
Cyanosis is the bluish discoloration of the skin and mucous membranes; it is often a late sign of heart failure. Cyanosis may be
central, or peripheral. Central cyanosis is caused by conditions that impair oxygenation of the arterial blood, such as pulmonary
edema, left heart failure. Peripheral cyanosis is caused by conditions such as low-output failure that cause delivery of poorly
oxygenated blood to the peripheral tissues, or by conditions such as peripheral vasoconstriction that cause excessive removal of
oxygen from the blood. Central cyanosis is best monitored on the lips and mucous membranes.
The clinical manifestations of the left-sided failure result from accumulation of fluid upstream in the lungs and from decreased
left ventricular output. They are:
* pulmonary congestion and edema causing dyspnea and orthopnoea due to increased pulmonary venous pressure;
* low perfusion and decreased oxygen supply of all the tissues due to decreased left ventricular output.
The mechanism of pulmonary edema is the following. As pulmonary capillary pressure exceeds the oncotic pressure of plasma
proteins (about 24 mm Hg), fluid extravasates from the capillaries into the interstitial space and alveoli, increasing the work of
breathing. Marked fluid accumulation in alveoli (pulmonary edema) significantly alters ventilation-perfusion relationships:
deoxygenated pulmonary arterial blood passes through poorly ventilated alveoli, decreasing systemic arterial oxygenation
(hypoxia of respiratory type) and causing dyspnea.
The most common causes of left-sided heart failure are acute myocardial infarction and cardiomyopathy. Decreased left ventricle
output may cause disorders in any organs and tissues due to low perfusion and decreased oxygen supply. It can cause ischemic
necrosis in the kidney, hypoxic encephalopathy, weakness and fatigue in skeletal muscles.
A major effect of right-sided heart failure is the development of peripheral edema. Because of the effects of gravity, the edema is
most pronounced in the lower extremities when the person is in the upright position and in the area over the sacrum when the
person is supine.
Right-sided heart failure also produces congestion of the viscera. As venous distention progresses, blood backs up in the hepatic
veins that drain into the inferior vena cava, and the liver overfills with blood. This may cause hepatomegaly and pain. In severe
and prolonged right-sided failure, liver function is impaired and hepatic cells may die. Congestion of the portal circulation also
may lead to enlargement of the spleen and ascites development. Congestion of the GIT may interfere with digestion and
absorption of nutrients, causing anorexia and abdominal discomfort.
The jugular veins, which are above the level of the heart, are normally collapsed in the standing position or when sitting. In
severe right-sided failure, the external jugular veins become distended and can be visualized at these positions.
The causes of right-sided heart failure include conditions that restrict blood ?ow into the lungs. Stenosis or regurgitation of the
tricuspid or pulmonic valves, right ventricular infarction, cardiomyopathy, and persistent left-sided failure are common causes.
Acute or chronic pulmonary disease, such as severe pneumonia, pulmonary embolism, or pulmonary hypertension, can cause
right-sided heart failure, referred to cor pulmonale.
Urgent mechanisms of heart failure compensation
It is known that cardiac output is determined by heart rate and stroke volume. So in order to increase cardiac output, heart rate or
stroke volume should be increased by the means of compensatory mechanisms which include urgent reactions and long-term
mechanisms.
Urgent reactions include the following mechanisms:
1. Dilatation of the heart results in an increase of heart stroke volume due to Frank-Starling mechanism. This form of
compensation (tonogenic dilatation) may be helpful in the case of increased preload (heterometric mechanism of heart
autoregulation).
In the normally functioning heart, the Frank-Starling mechanism serves to match the outputs of the two ventricles. With
increased diastolic ?lling (due to increased venous return), there is an increased stretching of the myocardial ?bers, more optimal
approximation of the actin and myosin ?laments, and a resultant increase in the force of the next contraction. In heart failure, the
Frank-Starling mechanism helps to maintain the cardiac output. But such stretching of myocardial fibers is helpful to a certain
point. When the heart gets bigger, there is more tension on its walls. This increases the strain on the heart, worsening its function
(myogenic dilatation).
 2. Homeometric mechanism of heart autoregulation increases contractility and maintain stroke volume when afterload increases.
This mechanism develops with stenosis of heart valves, arterial hypertension, etc. Homeometric autoregulation is not dependent
on cardiomyocyte fiber length, via Anrep effect (increased contractility due to increased intraventricular pressure). If we compare
the two mechanisms of autoregulation, then the heterometric mechanism is more effective, since less oxygen and energy are
consumed.
3. Bainbridge reflex (atrial reflex) is the development of tachycardia due to increased pressure in the vena cava, the right atrium
and their further stretching which occurs when heart pumps inefficiently.
4. The low cardiac output and BP cause an increased sympathetic tone, which cause the constriction of blood vessels and
speeding up of the heart rate (tachycardia).
5. Constriction of the afferent renal arterioles results in decrease of renal bloodflow and GFR. The renin-angiotensin-aldosterone
cascade is activated, which enhances salt and water retention. Angiotensin II is a strong vasoconstrictor, which further decreases
the renal bloodflow, and aldosterone promotes the reabsorption of NaCl and water from the distal renal system. A certain salt-
water retention is beneficial at the early stages of cardiac failure, due to improved venous return and thus improved cardiac output
according to Frank-Starling law of the heart.
The prolonged activation of the renin-angiotensin-aldosterone cascade and the sympathetic nervous system damage the heart
muscle further and reduce its contractility. This is because of circulating vasoconstrictors, such as catecholamines, vasopressin
and angiotensin II, which imply an extra workload on the damaged myocardium.
Other mechanism of brain and heart blood supply maintenance is centralization of bloodflow. If the brain and vital organs do not
receive enough blood, peripheral arteries constrict and arteries supplying the brain and vital organs widen to carry the increased
blood flow.
Long-term mechanism of heart failure compensation
Long-term mechanism of compensation results in the thickening of heart muscle. This is called hypertrophy, and it can help heart
to pump more forcefully and increase stroke volume. However, hypertrophy of the heart muscle increases the heart's
requirements for oxygen and other nutrients, and these requirements can eventually get ahead the blood supply to the heart,
leading to further weakening of the heart muscle. In addition, hypertrophy of the heart walls can worsen diastolic function by
impairing the ability of the heart to relax properly, which limits its ability to fill with blood, which can also further diminish
cardiac output.
Myocardial hypertrophy can be physiological or pathological. Physiological hypertrophy usually develops in persons which have
a high muscular activity (sportsmen, dancers, workers). Physiological hypertrophy of the heart provides for high stroke volume
and is characterized with adequate innervation and vascularisation of hypertrophied heart. Physiological hypertrophy with high
stroke volume explains the fact of bradycardia in sportsmen.
The heart with pathological hypertrophy is weak, because the number of nervous fibers and blood vessels doesn’t corresponds to
increased mass of myocardium. It may be caused by a variety of disorders:
* Heart diseases: myocardial disorders, pericarditis, valvular disorders, congenital heart disease.
* Vascular disorders: atherosclerosis, systemic hypertension, aortic stenosis, renal disorders, arteriovenous shunts, and
aneurysms.
* Thoracic diseases: diseases of the lung and pleura, kyphoscoliosis.
* Pumping of increased blood volume: acromegaly, anemia, obesity and excessive alcohol intake, thyrotoxicosis.
In the most cases left ventricle hypertrophy develops. Right ventricle hypertrophy is usually caused by high blood pressure in the
lungs (pulmonary hypertension) in the cases of chronic obstructive pulmonary diseases, pulmonary embolism, sarcoidosis,
pneumosclerosis.
Ischemic heart disease
Ischemic heart disease is defined as acute or chronic form of imbalance between the myocardial oxygen supply and its demands
in oxygenated blood. The alternative term is used coronary artery disease, because the most common cause of this disease results
from narrowing or obstruction of the coronary arteries.
The reasons of increased oxygen demand are: exercises, mental stress, exposure to cold, infectious diseases, pregnancy,
increased basal metabolic rate in hyperthyroidism, hypertrophy of cardiac muscle.
The reasons of low oxygen supply are: atherosclerosis, spasm of arteries, thrombosis and embolism, shock, severe anemia, CO
poisoning, lung disease (lower oxygen diffusion into blood).
Risk factors for IHD include high blood cholesterol, high blood pressure (hypertension), physical inactivity, smoking, obesity.
The main reason of IHD is atherosclerosis of the coronary arteries. The main event in atherosclerosis is formation of
atherosclerotic plaques in arterial vessels. These plaques narrow the lumen of coronary arteries and produce myocardial ischemia,
which initially manifests during intensive loading on the heart (due to increase in oxygen demands) and later even in the state of
rest when artery is critically narrowed.
Myocardial ischemia diminishes delivery of oxygen and nutrients that significantly alter cell’s energy metabolism and may result
in myocardial necrosis (see Hypoxic cell injury).
Clinical manifestations of IHD can be acute (myocardial infarction, cardiogenic shock) or chronic (angina pectoris).
Stenocardia (angina pectoris)
Angina pectoris is chest pain or discomfort due to ischemia of the heart muscle. An imbalance between oxygen delivery and
oxygen demand, results in myocardial hypoxia. Accumulation of lactic acid and other products of incomplete oxidation
stimulates pain receptors within the heart and produces anginal pain which is accompanied by generalized sympathetic activation,
leading to elevated BP, tachycardia and sweating. Most patients with angina complain of chest discomfort rather than actual pain:
the discomfort is usually described as a pressure, heaviness, tightness, squeezing, or burning sensation. Apart from chest
discomfort, anginal pains may also be experienced in the epigastrium (upper central abdomen), back, neck, jaw, or shoulders.
Typical locations for radiation of pain are arms (often inner left arm), shoulders, and neck into the jaw.
Irritation of the heart muscle with hypoxia is transmitted by subendocardially situated nerve fibres through the afferent
sympathetic nociceptive pathways to the spinal cord. where they synapse with somatic and visceral afferent pathways (cardiac
sympathetic plexi, sympathetic ganglion chain and spinal cord). Because of the extensive connections angina may be expressed
over such a large area of the upper body.
As the myocardium becomes ischemic, coronary sinus blood pH falls, cellular K is lost, lactate accumulates, ECG abnormalities
appear, and ventricular function deteriorates. The typical ECG sign of angina pectoris is elevation of ST segment, which indicates
the disturbances of ventricles repolarisation phase.
Angina chest pain is usually relieved within a few minutes by resting or by taking prescribed cardiac medications. Organic
nitrates (nitroglycerine) dilate constricted coronary vessels, improve the bloodflow to the subendocardial (pain sensitive) part of
the myocardium, and dilate coronary vessels. This dilatation reduces the venous return to the heart and the arterial pressure.
Myocardial infarction and cardiogenic shock
Acute myocardial infarction (AMI) is defined as death or necrosis of myocardial cells. Myocardial infarction occurs when
myocardial ischemia exceeds a critical threshold and results in irreversible myocardial cell damage (necrosis).
Critical myocardial ischemia may occur as a result of increased myocardial metabolic demand and/or decreased delivery of
oxygen and nutrients to the myocardium via the coronary circulation. The reasons are thrombus coronary occlusion, fixed
(atherosclerosis) or a dynamic coronary artery stenosis. Conditions associated with increased myocardial metabolic demand
include extremes of physical exertion, severe hypertension, and severe aortic valve stenosis.
The severity of an AMI is dependent on three factors: the level of the occlusion in the coronary artery, the length of time of the
occlusion, and the presence or absence of collateral circulation. Generally speaking, the more proximal the coronary occlusion,
the more extensive is the amount of myocardium at risk of necrosis. The larger is the AMI, the greater is the chance of death due
to a mechanical complication or pump failure. The longer is the time period of vessel occlusion, the greater are the chances of
irreversible myocardial damage distal to the occlusion.
The death of myocardial cells first occurs in the area of myocardium that is most distal to the arterial blood supply — that is, the
endocardium. As the duration of the occlusion increases, the area of myocardial cell death enlarges, extending from the
endocardium to the myocardium and ultimately to the epicardium. The area of myocardial cell death then spreads laterally to
areas of collateral perfusion. Generally, after a 6- to 8-hour period of coronary occlusion, most of the distal myocardium has died.
The extent of myocardial cell death defines the magnitude of the AMI. If blood flow can be restored to myocardium, more heart
muscle can be saved from irreversible damage or death.
The onset of AMI usually is abrupt, with pain as a significant symptom. The pain typically is severe and crushing, often
described as constricting, suffocating. The pain usually is substernal, radiating to the left arm, neck, or jaw, although it may be
experienced in other areas of the chest. Unlike that of angina, the pain associated with AMI is more prolonged and not relieved by
rest or nitroglycerin.
Gastrointestinal complaints are common. There may be a sensation of epigastric distress; nausea and vomiting may occur. These
symptoms are thought to be related to the severity of the pain and vagal stimulation. The epigastric distress may be mistaken for
indigestion, and the patient delays medical attention. Complaints of fatigue and weakness, especially of the arms and legs, are
common. Pain and sympathetic stimulation combine to give rise to tachycardia, anxiety, restlessness, and fear of death. The skin
is often pale, cool, and moist. Impairment of myocardial function may lead to hypotension and shock.
Cardiogenic shock is a disorder caused by decreased systemic cardiac output in the presence of adequate intravascular volume,
resulting in tissue hypoxia. The shock state is present when a systolic BP is lower than 90mm Hg in the absence of hypovolemia
or other potential causes of hypotension. The reduction in systolic blood pressure leads to systemic signs of hypoperfusion,
including paleness of skin, tachycardia, altered mental state, cold clammy skin and oliguria.
The diagnosis of AMI is based on ECG signs and serum markers study. The classic ECG changes that occur with AMI involve T-
wave inversion, ST-segment elevation, and development of an abnormal Q wave. These changes vary considerably depending on
the duration of the ischemic event, its extent (subendocardial versus transmural), and its location (anterior versus inferior
posterior).
The repolarization phase of the action potential (T wave and ST segment on the ECG) is usually the first to be involved during
myocardial ischemia and injury. As the involved area becomes ischemic, myocardial repolarization is altered, causing changes in
the T wave. This is usually represented by T-wave inversion, although a hyperacute T-wave elevation may occur as the earliest
sign of infarction.
ST-segment changes occur with ischemia that produces myocardial injury. Normally, the ST segment of the ECG is nearly
isoelectric (?at along the baseline) because healthy myocardial cells attain the same potential during early repolarization.
Subendocardial injury results in ST depression, while transmural infarction results in ST-segment elevation.
With actual infarction, depolarization (QRS) changes often follow the T-wave and ST-segment abnormalities. With Q-wave
infarction, abnormal Q waves develop because there is no depolarizing current conduction from the necrotic tissue.
As the myocardial cells become necrotic, their intracellular molecules begin to diffuse into the surrounding interstitium and then
into the blood. The concentration of these markers in the patient’s serum correlates with extent of cardiac muscle necrosis.
The serum markers for acute myocardial infarction include myoglobin, troponins T and I, myocardial muscle creatine kinase
(CK-MB). Myoglobine is released more rapidly from infarcted myocardium than troponin and CK-MB and may be detected as
early as two hours after an acute myocardial infarction. Myoglobine has high sensitivity but poor specificity in comparison with
troponin. Troponin is highly specific to cardiac tissue and accurately diagnoses myocardial infarction with a history of ischemic
pain or ECG changes reflecting ischemia. Cardiac troponin level is dependent on infarct size, thus providing an indicator for the
prognosis following an infarction. Creatine kinase sensitivity and specificity are not as high as for troponin levels but it is also
used in diagnostics.
Other laboratory findings in the patient with AMI are explained by the development of aseptic inflammation in myocardial
tissue:
* Leukocytosis may be seen within several hours after an acute myocardial infarction. It peaks in 2-4 days and returns to normal
levels within one week;
* Erythrocyte sedimentation rate rises above reference range values within three days and may remain elevated for weeks.
UNIT 20
BLOOD VESSELS PATHOLOGY
Mechanisms of arterial pressure regulation
Rapid pressure control is provided with nervous reflexes and hormonal mechanisms. The reflex regulation system of
baroreceptors in the aortic arch and carotid sinuses is able to control sudden changes in BP under conditions of posture change,
exercise, and moderate temperature changes. Sympathetic and parasympathetic nerves also take part in BP regulation. Increased
sympathetic activity will result in an increased heart rate and cardiac contractility, it will also cause a widespread
vasoconstriction. This effect may be provided by direct stimulation of the peripheral arterioles by nervous fibers and by indirect
stimulation through the release of epinephrine and norepinephrine. Increased parasympathetic activity produces the opposite
motor responses.
Other reflex mechanisms involved in the regulation of BP are the cardiopulmonary receptors and chemoreceptors. The
cardiopulmonary receptors are located in the walls of the cardiac chambers and the pulmonary artery. Their activation can
produce a global vasoconstriction, and stretching the atria may also produce tachycardia.
The chemoreceptors are located close to the arterial baroreceptors and within the CNS. These receptors are sensitive to pH, blood
gases, or changes in plasma composition. Low oxygen blood level will cause severe vasoconstriction and bradycardia. Increased
plasma CO2, or H+ concentration, can cause a marked vasoconstriction too.
There are three main hormonal mechanisms in rapid control of BP:
* Norepinephrine-epinephrine system provides systemic vasoconstriction and increases heart rate.
* The vasopressin has a direct vasoconstrictor effect on the blood vessels. It also takes part in long-term control of arterial
pressure by influencing water resorption at the distal tubule of the nephron.
* The renin-angiotensin-aldosterone mechanism plays a central role in BP regulation.
Renin is an enzyme that is synthesized, and released by the kidneys in response to an increase in sympathetic nervous system
activity or a decrease in BP or Na+ in renal arteries. Most of the renin that is released acts enzymatically to convert an inactive
circulating plasma protein called angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by the
angiotensin-converting enzyme that is present in the endothelium of the lung vessels.
Angiotensin II functions in both the short-term and long-term regulation of BP. It is a strong vasoconstrictor, particularly of
arterioles and to a lesser extent of veins. The vasoconstrictor response produces an increase in peripheral vascular resistance (and
BP) and functions in the short-term regulation of blood pressure. A second major function of angiotensin II, stimulation of
aldosterone secretion from the adrenal gland, contributes to the long-term regulation of BP by increasing salt and water retention
by the kidney. It also acts directly on the kidney to decrease the elimination of salt and water.
Aldosterone causes the kidneys to retain Na+ and excrete K+. Sodium causes water to be retained, thus increasing blood volume
and BP.
Long-term regulation of BP is primarily accomplished with the help of the kidneys. The kidneys control BP through the retention
and excretion of extracellular fluid. This function of the kidney in the long-term regulation of blood pressure can be influenced by
a number of factors. Water resorption in the kidney is controlled by aldosterone and vasopressin.
When the body contains an excess of extracellular fluid and BP rises, the rate at which water and salt are excreted by the kidney
is increased. The increase in renal output will decrease the extracellular volume, decreasing venous return and subsequently
cardiac output and BP.
There are several ways in which extracellular fluid volume regulates BP. One is through a direct effect on cardiac output, and
another is indirect, resulting from autoregulation of blood flow and its effect on peripheral vascular resistance. Autoregulatory
mechanisms function in distributing blood flow to the various tissues of the body according to their metabolic needs. When the
blood flow to a specific tissue is excessive, local blood vessels constrict, and when the flow is deficient, the local vessels dilate.
In situations of increased blood volume and cardiac output, all the tissues of the body are exposed to the same increase in flow.
This results in a generalized constriction of arterioles and an increase in the peripheral vascular resistance (and BP).
Atrial natriuretic factor (ANF) has also been shown to increase glomerular filtration rate and sodium excretion. ANF may play an
important indirect role in regulating intravascular volume and decreasing blood pressure. An increased intravascular volume (i.e.
extracellular fluid) will stretch the atria and stimulate the release of ANF. ANF is also known to inhibit the release of vasopressin.
Arterial hypertension: classification and causes
The optimal BP for minimizing the risk of cardiovascular problems and stroke is equal or below 120/80 mm Hg. Hypertension is
sustained elevation of resting systolic BP (? 140 mm Hg), diastolic BP (? 90 mm Hg), or both. While measuring the BP, the
higher index (systolic or diastolic) should be taken into account. There are two forms of hypertension: primary or essential, and
secondary hypertension.
 Approximately 90% of all cases are classified as primary or essential hypertension, because the causative factors are not clarified
in detail. Increased peripheral vessels resistance is responsible for most cases of primary hypertension. It always has a diastolic
element reflecting involvement of the resistance vessels (e.g., muscular arterioles), i.e. diastolic BP is increased.
A number of factors are related to essential hypertension occurrence:
* The role of heredity is evidenced by familiar cases of hypertension, occurrence of hypertension in twins;
* Racial factors: black race has higher incidence of essential hypertension than white;
* Increased salt intake has long been suspected as an etiologic factor in the development of hypertension. It may be that salt
causes an elevation in blood volume, increases the sensitivity of cardiovascular or renal mechanisms to adrenergic influences, or
exerts its effects through the renin-angiotensin-aldosterone mechanism. Regardless of the mechanism, numerous studies have
shown that a reduction in salt intake can lower BP.
* More than half of the incidence of hypertension is related directly to obesity and stresses.
* Insulin resistance and/or hyperinsulinemia have been suggested as being responsible for the increased BP in some patients with
hypertension. This feature is now widely recognized as part of syndrome X, or the metabolic syndrome marked also by central
obesity, dyslipidemia (especially elevated triglycerides), and high BP. Insulin resistance is common in patients with diabetes
mellitus type 2 and in obesity; both of these conditions are more common in hypertensive than in normotensive persons. It was
also found that hyperinsulinemia and insulin resistance are present even in lean hypertensive patients without type 2 diabetes,
suggesting that this relationship is more than a coincidence.
Hyperinsulinemia can increase BP by the following mechanisms:
* hyperinsulinemia produces renal sodium retention (at least acutely) and increases sympathetic activity. Either or both of these
effects could lead to an increase in arterial pressure;
* mitogenic action of insulin promotes is vascular smooth-muscle hypertrophy increasing total peripheral vascular resistance
(TPVR).
In about 10% of all cases, the cause of the hypertension is clarified, and these cases are classified as secondary hypertension.
Renal disorders account for more than 80% of all cases of secondary hypertension. The initial event in secondary renal
hypertension is the decrease of GFR. The disorders are chronic cases of glomerulonephritis, pyelonephritis, renal artery stenosis
(due to atherosclerosis or fibromuscular hyperplasia) which reduce the GFR and activate renin-angiotensin-aldosterone system
with subsequent increase of salt-water retention and TPVR. The hypertension caused by renal artery stenosis is also named –
renovascular hypertension.
Endocrine disorders as a cause of secondary hypertension (5–10% of cases) include hypersecretion of aldosterone, cortisol,
adrenaline, noradrenaline and thyroid hormones.
Increased primary secretion of aldosterone – Conn’s syndrome leads to hypertension development through sodium retention in
kidneys and further increase of blood circulating volume. Renin level is usually low.
Cushing’s syndrome or disease describes clinical conditions with increased glucocorticoid concentration in blood plasma.
Cortisol increases BP by the following mechanisms: potentiates vasoconstrictor effect of catecholamines, causes sodium
retention, increases synthesis of angiotensinogen in the liver, causing suppression of the vasodilatory systems (prostaglandins and
nitric oxide)
Phaeochromocytoma. This is a tumor of the sympathetic nervous system which releases both noradrenaline and adrenaline. The
signs are intermittent or constant systemic hypertension, tachycardia with other arrhythmias, orthostatic hypertension and
flushing.
Hyperthyroidism is also accompanied by hypertension with high stroke volume and cardiac output, high systolic BP, low
diastolic BP and TPVR. Thyroid hormones also increase synthesis of angiotensinogen.
Drugs such as steroids or oral contraceptives with high oestrogen, sympatomimetics, aldosterone, and vasopressin cause severe
systemic hypertension. Monoamineoxidase-inhibitors combined with tyramine (cheese) or wines sometimes cause hypertension.
Cardiovascular disorder (as coarctation of the aorta) is the cause of hypertension in some young patients. These hypertonics have
a low pressure distal to the coarctation.
Atherosclerosis is characterized by a special systolic hypertension frequently found in the elderly without any diastolic
hypertension.
Pathogenesis of hypertension
It is known that arterial BP can be described by the following formula:
BP = cardiac output * total peripheral vascular resistance.
Therefore, pathogenic mechanisms must involve increased cardiac output, increased TPVR or both of them. The following
alterations in hemodynamics may be observed in the course of hypertension:
In most patients TPVR rises while cardiac output remains normal or slightly increased – eukinetic type of hypertension. This
pattern is typical of primary hypertension and hypertension due to primary aldosteronism, pheochromocytoma, and renal
parenchymal or vascular disease.
In other patients, cardiac output is increased (possibly because of venoconstriction in large veins), and TPVR is inappropriately
normal. Such type of hypertension is named as hyperkinetic. Some disorders that increase cardiac output and stroke volume
(thyrotoxicosis, aortic regurgitation), cause isolated systolic hypertension.
In long-standing hypertension TPVR significantly increases and cardiac output may be even decreased – hypokinetic type of
hypertension.
The modern lifestyle pattern including psychological stress in career and family life, eating fast food, smoking, alcohol and low
exercises frequently implies a serious sympathetic overactivity. At the early stages of hypertension, the arterial BP is oscillating
between hypertensive episodes and normal periods. The hypertensive episodes are typically dominated by sympathetic
overactivity with increased cardiac output and almost unchanged TPVR.
Exposure to stress increases sympathetic outflow, and repeated stress-induced vasoconstriction may result in progressive
increase in TPVR. Eventually, the pressure changes the distensibility of the arteriolar walls and thus leads to reduced
distensibility of the resistance system. The rising TPVR implies a rising workload for the left ventricle and thus creates left
ventricular hypertrophy.
In some cases of hypertension there is a clear relation to the renin-angiotensin-aldosterone cascade. Over months and years, the
walls of arteries and arterioles thicken and atherosclerosis is spread in the arterial tree. Such changes reduce the driving pressure
in the renal arteries, which leads to a fall in GFR and increased NaCl/water retention. The falling pressure in the renal artery
triggers b-receptors on the JG-cells of the juxtaglomerular apparatus. Renin is released from these cells. It leads to activation of
renin-angiotensin-aldosterone cascade which further contributes to the salt and water retention.
Hypertension leads to more hypertension. This process is known as vicious circle. Smooth muscle cell hypertrophy and
hyperplasia in the arterioles resulting from prolonged hypertension reduce the caliber of the lumen, thus increasing TPVR. In
addition, trivial shortening of hypertrophied smooth muscle in the thickened wall of an arteriole will reduce the radius of an
already narrowed lumen to a much greater extent than if the muscle and lumen are normal.
Deficiency of vasodilator substances may also cause hypertension. The kallikrein system which produces the potent vasodilator
bradykinin is known. The tissue of kidneys contains vasodilators including a neutral lipids and prostaglandins. Absence of these
vasodilators due to renal parenchymal disease or bilateral nephrectomy would permit BP to rise. Moderate hypertension sensitive
to Na and water balance is characteristic in anephric persons (renoprival hypertension).
Endothelial cells produce potent vasodilators (NO, prostacyclin) and the most potent vasoconstrictor – endothelin. Therefore,
dysfunction of the endothelium could have a profound effect on BP. There is a preliminary evidence that hypertensive persons
have decreased activity of NO. Vascular effects of NO include the following:
* Direct vasodilation (flow dependent and receptor mediated);
* Indirect vasodilation by inhibiting vasoconstrictor influences (e.g., inhibits angiotensin II and sympathetic vasoconstriction);
* Anti-thrombotic effect – inhibits platelet adhesion to the vascular endothelium;
* Anti-inflammatory effect – inhibits leukocyte adhesion to vascular endothelium; scavenges superoxide anion;
* Anti-proliferative effect – inhibits smooth muscle hyperplasia.
Because of the above listed actions of NO, the impairment of its production due to endothelial dysfunction or when its
bioavailability is reduced, the following can result:
* Vasoconstriction (e.g., coronary vasospasm, elevated systemic vascular resistance, hypertension);
* Thrombosis due to platelet aggregation and adhesion to vascular endothelium;
* Inflammation due to upregulation of leukocyte and endothelial adhesion molecules;
* Vascular hypertrophy and stenosis.
Manifestation of hypertension
Primary hypertension is asymptomatic until complications develop in target organs. The term target-organ damage is used to
describe the heart, brain, kidney, and retinal complications associated with hypertension.
Cardiac compensation for the excessive workload determined by increased systemic pressure is at first compensated by left
ventricular hypertrophy, characterized by the increase in wall thickness. Along with duration of hypertension, the function of this
chamber deteriorates, the cavity dilates, and the symptoms and signs of heart failure appear.
Angina pectoris may also occur because of the combination of accelerated coronary arterial disease and increased myocardial
oxygen requirements as a consequence of the increased myocardial mass. Evidence of ischemia or infarction may be observed
late in the disease. Most deaths due to hypertension result from myocardial infarction or congestive heart failure.
Hypertensive retinopathy may include arteriolar narrowing, retinal hemorrhages, exudates, papilledema (swelling of the optic
disc), and vascular accidents.
Hypertensive encephalopathy can manifest by dizziness, flushed faces, headache, fatigue, epistaxis (hemorrhage from the nose)
and nervousness. Long standing hypertension may also cause two types of brain strokes:
* Cerebral infarction is secondary to the increased atherosclerosis observed in hypertensive patients,
* Cerebral hemorrhage is the result of both the elevated arterial pressure and the development of cerebral vascular
microaneurysms.
Chronically elevated BP causes renal vascular lesions which result in a decreased glomerular filtration rate and tubular
dysfunction. This state is named hypertensive nephropathy which results from arteriolar nephrosclerosis. It can lead to chronic
renal failure with polyuria, nocturia, diminished renal concentrating ability, proteinuria, microhematuria, cylindruria, and nitrogen
retention. Hypertension also plays an important role in accelerating the course of other types of kidney disease.
Arterial hypotension
Arterial hypotension is characterised by clinical depression of arterial pressure below 100/60 mm Hg for persons aged till 25
years and below 105/65 mm hg for persons more than 30 years.
The physiological arterial hypotension may be caused by individual constitutional and hereditary factors. This type of
hypotension is quite often observed in absolutely healthy persons and is not accompanied by any complaints and pathological
changes in the organism. The physiological hypotension of the sportsmen is known too.
Pathological arterial hypotension is subdivided into acute and chronic forms. The general mechanisms of arterial hypotension
development are:
* decreased cardiac output;
 * decreased blood circulating volume;
* decreased tonus of resistant blood vessels (arterioles, arteries).
Acute arterial hypotension is manifested with collapse. Collapse (circulatory collapse) is an acute vascular insufficiency that is
characterized by a rapid and significant drop in vascular (arterial and venous) tone, circulatory failure, primary circulatory
hypoxia that impairs function of tissues and organs. The direct cause of the collapse is the rapid development of the significant
excess of the vascular bed volume compared with the blood circulating volume.
The main reasons of collapse development are:
* hypovolemia (hemorrhage, plasmorrhage, dehydration, burn, intoxication, infection);
* vasodilation (pancreatitis, hyperthermia, toxic-infectious, orthostatic drop of pressure);
* myocardial disorders (all cases of cardiac output and stroke volume decrease).
The main links of pathogenesis and manifestation of collapse are.
Dysfunction of CVS is the initial and main pathogenetic link in collapse and is characterized by inadequate blood supply to
organs and tissues. Stroke volume, cardiac output of blood and BP are decreased. Redistribution of blood is obsereved: blood is
deposited in the vessels of the abdominal cavity, lungs, spleen while brain, heart and muscles are hypoperfused.
Disorders of the nervous system (due to significant hypoperfusion and brain hypoxia) manifest as retardation, apathy,
indifference to what is happening, tremor of fingers, sometimes cramps, hyporeflexia and fainting.
Violations of lung function are evidenced by frequent and shallow breathing, hypoxemia and hypercapnia.
Disorders of kidney function are caused by renal hypoperfusion: decreased amount of urine, increase of urine specific gravity
and hyperazotemia.
Disorders of blood and hemostasis include hypovolemia, increase in blood viscosity, aggregation of platelets and RBC, the
formation of blood clots, the development of the sludge phenomenon.
Chronic arterial hypotension may be of primary and secondary pathogenesis. Secondary (symptomatic) arterial hypotension
arises as a result of various problems in: heart (myocardial infarction, myocarditis, heart valves defects), lung (pneumonia), liver
(hepatitis, obstructive jaundice), blood (anemia), endocrine system (decreased synthesis of catecholamines, vasopressin, ACTH,
aldosterone, thyroid hormones), also in chronic intoxications, chronic infections, starvation, hypohydration.
Primary arterial hypotension results from the disturbance of neural control upon the BP. Neurogenic causes of hypotension
include autonomic dysfunction or failure, which results in increase of parasympathetic influence on the cardiovascular system. It
can occur in association with other CNS abnormalities, such as Parkinson’s disease, or may be secondary to systemic diseases
that can damage the autonomic nerves, such as diabetes or amyloidosis; vasovagal hyperactivity; and drugs with sympathetic
stimulating or blocking properties.
Clinical manifestation of arterial hypotension is variable and involves the following symptoms: weakness, fatigability, lowered
working capacity, habitual headaches, dizziness, dyspnea at moderate physical work and in extreme cases even fainting.
Orthostatic or postural hypotension is an abnormal drop in BP on assumption of the standing position. In the absence of normal
circulatory reflexes or blood volume, blood pools in the lower part of the body when the standing position is assumed, venous
return decreases, cardiac output and BP fall, and blood flow to the brain is inadequate. Dizziness, fainting or both may occur.
Weakness and dizziness on standing are common complaints of elderly persons.
Normally, this decrease in BP is transient, lasting through several cardiac cycles, because the baroreceptors located in the carotid
sinus area and aortic arch sense the decreased pressure and initiate reflex constriction of the veins and arterioles and an increase
in heart rate, which brings BP back to normal. The initial adjustment to orthostatic stress is mediated exclusively by the
autonomic nervous system, so ANS dysfunction plays an important role in postural hypotension. Within a few minutes of
standing, blood levels of antidiuretic hormone and sympathetic neuromediators increase as a secondary means of ensuring
maintenance of normal BP in the standing position. Orthostatic hypotension is often an early sign of reduced blood volume or
fluid deficit – dehydration which may occur as a result of excessive use of diuretics, excessive diaphoresis, loss of gastrointesinal
fluids through vomiting and diarrhea.
Atherosclerosis etiology and pathogenesis
Atherosclerosis is a process of progressive lipid accumulation (atheromatosis) and calcification of the inner arterial walls in the
abdominal aorta, lower extremities and the arteries of the heart, brain and kidneys. It is caused by the formation of multiple
plaques within the arteries.
The hallmark of atherosclerosis is an atherosclerotic plaque, which contains lipids (cholesterol and phospholipids), inflammatory
cells (macrophages, T cells), smooth muscle cells, connective tissue (collagen, glycosaminoglycans, elastic fibers), thrombi, and
Ca deposits. All stages of atherosclerosis—from initiation and growth to complication of the plaque—are considered to be an
inflammatory response to blood vessels injury.
Atherosclerosis risk factors
Positive risk factors
(increase the risk)Negative risk factors
(decrease the risk)hyperlipidemia (high cholesterol)high levels of circulating high density lipoproteinscigarette
smokinghypertensionmoderate alcohol consumptiondiabetes mellituscardiovascular fitnessadvancing agefamily history
(polygenic inheritance)male genderhigh saturated fat diet and obesitystressful and sedentary lifestylesexcess alcohol consumption
Two main hypotheses of atherosclerosis pathogenesis have been proposed: lipid hypothesis and chronic endothelial injury
hypothesis.
The lipid hypothesis postulates that an elevation in plasma LDL levels results in penetration of LDL into the arterial wall, leading
to lipid accumulation in smooth muscle cells and in macrophages (which will further transform into foam cells). LDL also causes
smooth muscle cell hyperplasia and migration into the subintimal and intimal region in response to growth factors. LDL is
modified or oxidized in this environment and is rendered more atherogenic. Small dense LDL cholesterol particles are also more
susceptible to modification and oxidation. The modified or oxidized LDL is chemotactic to monocytes, promoting their migration
into the intima, and retention in the subintimal compartment as macrophages. The entry of oxidized LDL into macrophages turn
them into foam cells. Oxidized LDL is also cytotoxic to endothelial cells and may be responsible for their dysfunction or loss
from the more advanced lesion.
The chronic endothelial injury hypothesis postulates that endothelial injury by various mechanisms produces the loss of
endothelium, adhesion of platelets to subendothelium, aggregation of platelets, chemotaxis of monocytes and T-lymphocytes, and
the release of platelet-derived and monocyte-derived growth factors that induce migration of smooth muscle cells from the media
into the intima, where they replicate, synthesize connective tissue and proteoglycans, and form a fibrous plaque. Other cells (e.g.,
macrophages, endothelial cells, arterial smooth muscle cells) also produce growth factors that can contribute to smooth muscle
hyperplasia and extracellular matrix production.
These two hypotheses are closely linked and not mutually exclusive. Modified LDL is cytotoxic to endothelial cells and may
induce endothelial injury, attract monocytes and macrophages, and stimulate smooth muscle growth. Modified LDL also inhibits
macrophage mobility, so that once macrophages transform into foam cells in the subendothelial space, they may become trapped.
In addition, endothelial cells after injury are functionally impaired and increase the uptake of LDL from plasma.
Early in the atherosclerosis process, the endothelial cells become dysfunctional. Endothelial dysfunction is also seen in a variety
of pathological conditions in addition to atherosclerosis, including hypercholesterolemia, diabetes, hypertension, heart failure,
cigarette smoking, and aging. Normally the endothelium modulates vascular tone, blood coagulation, cell growth, and
inflammation in the circulatory system.
Endothelial dysfunction may result in misbalanced concentrations of vasodilating and vasoconstricting factors and lead to
vasospasm, impaired relaxation, and formation of blood clots inside the vessel. The most important vasodilating substance is NO.
Clinical manifestation of atherosclerosis
The atherosclerotic plaque may grow slowly and in some years may produce a severe stenosis or may progress to total arterial
occlusion. With time, the plaque becomes calcified. Some plaques are stable, but others, especially those rich in lipids and
macrophages and covered by a thin fibrous cap, may undergo spontaneous rupture, exposing the plaque contents to flowing
blood. These plaques are considered to be unstable; they are more closely associated to the onset of an acute ischemic event. The
ruptured plaque stimulates thrombosis; the thrombi may embolize, rapidly occlude the lumen to precipitate a heart attack or an
acute ischemic syndrome, or gradually become incorporated into the plaque, contributing to its stepwise growth.
Usually, atherosclerosis does not produce symptoms until it narrows the interior of an artery by more than 70%. At this point
tissues supplied by the artery may not receive enough blood and oxygen, and local ischemia occurs. Typically, symptoms develop
gradually as the plaque slowly narrows an artery. However, sometimes the first symptoms occur suddenly because the blockage
occurs suddenly—for example, when a blood clot sticks in a narrowed artery, causing a heart attack or stroke.
Clinical symptoms depend on where the narrowing or blockage of artery occurs. Such narrowing can occur almost anywhere in
the body and may produce chronic or acute vascular diseases:
* Carotid arteries – cerebrovascular disease, transient ischemic attacks and stroke;
* Arteries of the lower limbs – chronic peripheral vascular disease, leg cramps (intermittent claudication) or acute limb ischemia;
* Kidney arteries – renovascular disease, which may result in kidney failure or secondary arterial hypertension.
In coronary arteries:
* stable atherosclerotic plaques produce ?xed obstruction of coronary blood flow with myocardial ischemia occurring during
periods of increased metabolic need, such as in stable angina
* unstable atherosclerotic plaques tend to ?ssure or rupture, causing platelet aggregation and potential for thrombus formation
which clinically manifest as unstable angina or myocardial infarction.
UNIT 21
LUNG PATHOLOGY
Respiratory failure classification
Respiratory failure is a condition in which the lungs fail to oxygenate the blood adequately and prevent carbon dioxide retention.
Normally, in arterial blood: pO2 - 95-100 mm Hg, pCO2 - 43-46 mm Hg. Respiratory failure can be indicated by observing a
drop in pO2 (hypoxemia) and/or a rise in pCO2 (hypercapnia).
Respiratory failure can be classified according to the speed of its development and correlation of blood oxygen and carbon
dioxide levels.
Acute respiratory failure develops during minutes, hours (e.g. the attack of bronchial asthma (minutes), acute pneumonia
(hours)). Subacute respiratory failure develops during days, weeks (e.g. pneumonias, bronchitis). Chronic respiratory failure
develops during months and years (e.g. chronic obstructive lung emphysema, disseminated lung fibrosis).
Type 1 respiratory failure is defined as hypoxia without hypercapnia (normal or low pCO2). Hypoxemic type of respiratory
failure usually accompanies the diseases of lungs parenchyma (lung edema, pneumonia), disturbances of gases diffusion,
ventilation/perfusion mismatch.
Type 2 respiratory failure is defined as hypoxia with hypercapnia. It occurs due to inadequate air flow in the alveoli of the lungs
that causes a build up of CO2 that has been generated by the body. The underlying causes are: reduced breathing effort (in the
fatigued patient), increased resistance to breathing (such as in asthma) or an increase in the area of the lung that is not available
for gas exchange (such as in emphysema).
Respiratory failure causes can be divided into disturbances of lungs function and extra-lungs disturbances.
 The disturbances of the following lungs function can result in respiratory failure development: alveolar ventilation, lung blood
perfusion, correlation between alveolar ventilation and perfusion, diffusion of gases through alveolar-capillary membrane.
Extra-lungs disturbances:
* disturbances of nervous regulation of respiration (brain stroke or trauma, tumor affecting respiratory centre);
* disturbances of respiratory muscles function (myasthenia, poliomyelitis, muscles dystrophy);
* disturbance of the chest respiratory movements (fracture of ribs or spinal column, chest wall deformities);
* impaired blood circulation in lungs (cardiac failure, severe anemia).
Alveolar ventilation disturbance
Alveolar hypoventilation occurs when the volume of “fresh” air moving into and out of the lung is significantly reduced.
Hypoventilation may be commonly caused either by conditions outside the lung (listed previously), or by violations of
respiration. There are obstructive and restrictive lungs disorders that can result in hypoventilation development.
Obstructive disorders are characterized by low expiratory airflow due to narrowing of the airways with the increase of airflow
resistance. This leads to the overload of the respiratory muscular system. The causes and mechanisms of the obstructive
violations are:
* Violations of the upper respiratory ways permeability because of their embolism (e.g. with foreign substance), compression by
tumor, spasm of larynx etc. In these situations inspiratory dyspnoea develops, when inspiration is disturbed.
* Violations of the lower respiratory ways permeability because of the increased bronchial muscles tonus (bronchospasm),
embolism of bronchi with the edema of bronchi mucous tunic and hypersecretion of mucus by bronchial glands (inflammation,
asthma). In such cases expiratory dyspnea with the difficulty of exhalation develops.
* Violation of bronchi flexibility which is observed in lungs emphysema, obstruction of bronchi.
Restrictive lung diseases result in problems with lung expansion.
Pulmonary reasons that restrict expansion of the lung include:
* Decreased area of lung (due to resection or destruction in tuberculosis);
* Decreased elasticity of lung tissue due to excessive connective tissue growth (pneumonia, diffuse fibrosis caused by various
reasons, alveolitis, granulomatosis, pulmonary tuberculosis, collagenosis etc.);
* Alveolar or interstitial edema, which will stiffen the lung and make it hard to expand. The most common reasons are: bacterial
pneumonia, aspiration of gastric contents, sepsis, severe trauma with shock;
* Acute respiratory distress syndrome (ARDS);
* Deficiency of surfactant (premature infants) Surfactant is a complex of lipids proteins that is produced in the lungs. It reduces
the surface tension of fluid in the lungs and helps to make the alveoli more stable. This keeps them from collapsing when an
individual exhales.
ARDS may result from a number of conditions, including aspiration of gastric contents, major trauma (with or without fat
emboli), sepsis, acute pancreatitis, hematologic disorders, metabolic events, and reactions to drugs and toxins.
The pathogenesis of ARDS includes diffuse alveolar epithelial cell injury with increased permeability of the alveolar-capillary
membrane. The increased permeability permits fluid, plasma protein, and blood cells to move out of the vascular compartment
into the interstitium and alveoli of the lung. Alveolar cell damage leads to accumulation of edema fluid, surfactant inactivation,
and formation of a hyaline membrane that is impervious to gas exchange. Neutrophils accumulate early in the lung in the course
of the disorder. Activated neutrophils synthesize and release a variety of products, including proteolytic enzymes, ROS, and
phospholipid products that increase the inflammatory response and cause injury to the capillary endothelium and alveolar
epithelium.
As the disease progresses, the work of breathing becomes greatly increased as the lung stiffens and becomes more difficult to
inflate. There is an increased intrapulmonary shunting of blood, impaired gas exchange, and profound hypoxia. Gas exchange is
further compromised by alveolar collapse resulting from abnormalities in surfactant production. When injury of the alveolar
epithelium is severe, disorganized epithelial repair may lead to fibrosis.
Extrapulmonary reasons that restrict expansion of the lung are:
* Changes in pleura and mediastinum (exudative pleurisy, pneumothorax, tumors of pleura and mediastinum, heart enlargement);
* Changes of the thorax and respiratory muscles (deformation of thorax, limitation of backbone mobility, costal joints, affection
of diaphragm and respiratory muscles, including affection of their innervation);
* Changes of abdominal cavity organs (hepatomegaly, ascites, obesity, cachexia, inflammatory diseases of abdominal cavity
organs).
Mixed violations of ventilation of the lungs are more common because obstructive and restrictive violations are combined
usually. Flow rate and lung volume measurements can be used to differentiate obstructive from restrictive pulmonary disorders
(see Module 2 manual).
Disorders of lung perfusion and diffusion
Disorders of perfusion can manifest as hypoperfusion or hyperperfusion. Hyperpefusion may be local – increased perfusion in
the lungs (e.g. in the case of pneumonia). Total hyperperfusion is observed during stress reaction or in asphyxia. The mechanism
of respiratory failure development in this case is explained by the following fact. For normal oxygen exchange erythrocytes need
some time (from 0,3 to 0,5 seconds) for moving through alveolar capillary. If the blood flow speed is increased, erythrocytes have
less time for normal gas exchange. As a result, hypoxemia develops. The diffusion of CO2 in this case is not impaired, because its
diffusion is easier. Type 1 respiratory failure develops.
 Hypoperfusion may be either a result of heart pathology (heart failure, valvular disorders) or blood vessels pathology
(atherosclerosis, thromboembolism). The pathogenesis of respiratory failure development in this case may have the following
variants:
* hypoperfusion may occur due to heart failure (low cardiac output);
* opening of shunts between arteries and veins of pulmonary circulation. In this case blood comes more quickly to the left
ventricle and maintain normal stroke volume, but this impairs blood oxygenation;
* if vessels of pulmonary circulation are obstructed by the sclerotic processes or embolism, pulmonary hypertension develops.
All the cases of lungs hypoperfusion result in respiratory failure type 1 development (hypoxemia without hypercapnia).
The mismatching of ventilation and perfusion ratio occurs when areas of the lung are ventilated but not perfused well or when
areas are perfused but not ventilated properly.
Ventilation-perfusion ratio is different in different areas of lungs: lower parts of lungs are better perfused; upper parts are better
ventilated. In lung diseases pathological mismatch is added to physiological one.
Severe mismatching of ventilation and perfusion often is seen in persons with chronic obstructive pulmonary disease. It is a
group of respiratory disorders characterized by chronic and recurrent obstruction of airflow in the pulmonary airways. These
disorders contribute to the retention of CO2 by reducing the effective alveolar ventilation, even when total ventilation is
maintained. This occurs because a region of the lung is not perfused and gas exchange cannot take place or because an area of the
lung is not being ventilated. In this situation also hypoxic pulmonary vasoconstriction occurs. It is a paradoxical, physiological
phenomenon in which pulmonary arteries constrict in the presence of hypoxia without hypercapnia, redirecting blood flow to
alveoli with higher oxygen content. The process might at first seem illogical, as low oxygen levels should theoretically lead to
increased blood flow to the lungs to receive increased gaseous exchange. However, it is explained by the fact that constriction
leads to redistribution of bloodflow to better-ventilated areas of the lung, which increases the total area involved in gaseous
exchange.
Maintaining a high ventilation rate effectively prevents hypercapnia but also increases the work of breathing.
The hypoxemia associated with ventilation-perfusion disorders often is exaggerated by conditions such as hypoventilation and
decreased cardiac output. For example, a decrease in cardiac output because of myocardial infarction can exaggerate the
ventilation-perfusion impairment in a person with mild pulmonary edema.
Diffusion of gases impairment describes a condition in which gas exchange between the alveoli and the red blood cells is
impeded. It may be because of an increase in the distance for diffusion. Normally thickness of alveolar-capillary barrier is less
then 0,5 mkm in the norm. The distance of diffusion can enlarge because of alveolar and/or interstitial edema, inflammation,
lymphostasis, fibrous changes in the lung.
Decrease in the permeability of the alveolar capillary membrane to movement of gases also impairs diffusion (interstitial lung
disease, ARDS, pulmonary edema, emphysema).
Hypoxemia resulting from impaired diffusion is not accompanied by hypercapnia, because the elimination of CO2, which has a
diffusion capacity about 20 times that of oxygen, is generally unaffected by diffusion abnormalities.
Clinical manifestation of respiratory failure
Respiratory failure is manifested by varying degrees of hypoxemia and hypercapnia. As a general rule, respiratory failure refers
to a pO2 level of 50 mm Hg or less and a pCO2 level greater than 50 mm Hg.
Hypoxemia produces its effects through tissue hypoxia and the compensatory mechanisms that the body uses to adapt to the
lowered oxygen level. Body tissues vary considerably in their vulnerability to hypoxia; those with the greatest need are the
nervous system and heart. Cessation of blood flow to the cerebral cortex results in loss of consciousness within 10 to 20 seconds.
If pO2 of the tissues falls below the critical level, aerobic metabolism ceases, and anaerobic metabolism takes over, with
formation and release of lactic acid.
The signs and symptoms of hypoxia can be grouped into two categories: those resulting from impaired function of vital centers
and those resulting from activation of compensatory mechanisms. Mild hypoxemia produces few manifestations. There may be
slight impairment of mental performance and visual acuity and sometimes hyperventilation. More pronounced hypoxemia may
produce personality changes, restlessness, agitated behavior, uncoordinated muscle movements, euphoria, impaired judgment,
delirium, and eventually, stupor and coma. Recruitment of sympathetic nervous system compensatory mechanisms produces an
increase in heart rate, peripheral vasoconstriction, diaphoresis, and a mild increase in BP. Profound acute hypoxemia can cause
convulsions, retinal hemorrhages, and permanent brain damage. Hypotension and bradycardia often are preterminal events in
persons with hypoxemia, indicating the failure of compensatory mechanisms.
Cyanosis refers to the bluish discoloration of the skin and mucous membranes that result from an excessive concentration of
reduced or deoxygenated hemoglobin in the small blood vessels. It is usually mostly marked in the lips, nail beds, ears, and
cheeks. Although cyanosis may be evident in persons with respiratory failure, it is often a late sign.
Cyanosis can be divided into two types: central or peripheral. Central cyanosis is evident o the tongue and lips. It is caused by an
increased amount of deoxygenated hemoglobin or an abnormal hemoglobin derivative in the arterial blood.
Peripheral cyanosis occurs in the extremities and on the tip of the nose or ears. It is caused by slowing of blood flow to an area of
the body, with increased extraction of oxygen from blood. It results from vasoconstriction and diminished peripheral blood flow,
as occurs with cold exposure, shock, congestive heart failure, and peripheral vascular disease.
Hypercapnia affects a number of body functions, including renal function, neural function, cardiovascular function, and acid-
base balance. Elevated levels of pCO2 produce a decrease in pH and respiratory acidosis. The body normally compensates for an
increase in pCO2 by increasing renal bicarbonate retention. As long as pH is in an acceptable range, the main complications of
hypercapnia are those resulting from the accompanying hypoxia. Because the body adapts to chronic increases in blood levels of
CO2, persons with chronic hypercapnia may not have symptoms until pCO2 becomes markedly elevated.
CO2 has a direct vasodilating effect on many blood vessels and a sedative effect on the nervous system. Raised levels of pCO2
greatly increase cerebral blood flow, causing headache, increased cerebral spinal fluid pressure, and sometimes papilledema.
There is a headache due to dilation of the cerebral vessels; the conjunctivae are hyperemic; and the skin is warm and flushed.
Hypercapnia has nervous system effects similar to those of an anesthetic (hence the term carbon dioxide narcosis). There is
progressive somnolence, disorientation, and, if untreated, coma.
Pulmonary edema
There are two ways in which edema occurs in the lung. The most common is the elevation of hydrostatic pressure in the
capillaries above the force exerted by osmotic pressure, so that fluid is pushed out of the distended capillaries. This happens in
left ventricle failure, in which the left heart cannot handle all the blood coming into it. Blood backs up into the lung filling up
capillaries, which are normally empty. When the capillaries are all full, as blood continues to back up and pressure rises, fluid
eventually leaks through the endothelium into the interstitium. It goes from there into lymphatics, but if the lymphatics cannot
handle it fast enough, the interstitial space fills up, and the fluid breaks through the alveolar epithelial cells into the alveolar
spaces.
A second way in which pulmonary edema can occur does not involve heart failure; the edema is non-cardiogenic. In this case,
the alveolar walls are damaged directly by some agent. Damaged capillaries leak into the interstitium, and the interstitial fluid
leaks out through damaged epithelial cells into the airspaces. The harmful agents can come in from the alveolar space (e.g. toxic
fumes or bacterial toxins from pneumonia) or via the bloodstream (e.g. bacterial toxins in sepsis, proteolytic pancreatic enzymes
in acute pancreatitis).
Edema of the lungs can appear at quick intravenous infusion of big amount of fluid (physiological solution, blood substitutes).
This results in «dilution» of plasma proteins, decrease of oncotic pressure and increase of hydrostatic pressure.
At the microbial affection of the lungs, the development of edema is connected with the affection of surfactant system by
microbial agents. This is accompanied by the increase of alveolar-capillary membrane permeability, diffusion of oxygen
decreases. This is seen not only at the inflammatory site, but diffusely in the lungs on the whole.
Allergic edema of the lungs develops because of anaphylactic allergic reaction development. Its mechanism is the rapid increase
of capillaries permeability as the result of biologically active substances release from mast cells and thrombocytes.
The infusion of big amounts of catecholamines (adrenalin), and stressful situations, that are accompanied by excretion of big
amount of noradrenaline, cause the constriction of arterioles in many parts of the body and the increase of lungs blood supply
(redistribution of blood). This process forms the basis of lungs edema development because of lung hypertension and congestion
of blood in the pulmonary circulation.
The most common symptom of pulmonary edema is dyspnea, or breathlessness. This may be of gradual onset if the process
slowly develops, or it can have a sudden onset in the case of acute pulmonary edema. Moist rales or crackles (discontinuous short
bubbling sounds corresponding to the splashing of the fluid in the alveoli during breathing) are auscultated over the lungs. Patient
has a cough with frothy and blood-tinged sputum. If pulmonary edema has been developing gradually, symptoms of fluid
overload may be elicited: nocturia, ankle edema, orthopnea and paroxysmal nocturnal dyspnea.
Hypoxia symptoms are usually observed in patients with pulmonary edema: easy fatigue, more rapidly developing shortness of
breath than normal with usual activity (dyspnea on exertion), rapid breathing (tachypnea), dizziness, or weakness. Without
effective treatment progressive hypercapnia, respiratory acidosis and respiratory arrest ensue.
Dyspnea
Dyspnea (shortness of breath, breathlessness) is a shortness of breath, a subjective difficulty or distress in breathing. It is
characterised by the alteration of the frequency, depth, rhythm of breath that is accompanied by feeling of “air hunger”. Dyspnea
occurs normally during intense physical exertion or at high altitude.
Several classifications of dyspnea are known:
1. Classification of dyspnea according to its pathogenesis
* Cerebral dyspnoea (central) – is observed at the violations of respiratory centre activity due to the diseases of CNS or
psychogenic causes;
* Pulmonary dyspnea – occurs at the diseases of the lungs, bronchi, and pleura;
* Cardiac dyspnoea – accompanies diseases of the heart complicated by the cardiac failure development, the decrease of BP can
also stimulate respiration;
* Hematic dyspnoea – manifests when blood oxygen capacity is significantly decreased (anemia).
2. The classification based on the character the dyspnoea:
* Hyperpnea – abnormally frequent, deep respiration;
* Tachypnea – very rapid respirations (more than 20 breaths/min), the rate is fast and the depth is shallow;
* Bradypnea – low rate of breathing (lower than 12 breaths/min);
* Apnea – respiratory arrest, temporary absence of breathing;
3. The classification based on the prevalence of the inhalation or exhalation disturbances:
* Inspiratory dyspnea – prior difficulty of inhalation caused by an obstruction in the larynx, trachea, or bronchi and sometimes
disorders of the pleura. The patient attempts to compensate for this deficiency with prolonged, deep inspirations;
* Expiratory dyspnea – prior difficulty of exhalation (associated with lower airway obstruction and the decrease of lung elasticity
– bronchial asthma, emphysema; as the expiration process is less active than the inspiration, it needs an additional effort to exhale
against resistance that occurs in constricted bronchioles);
 * Mixed dyspnoea – difficulty both of inhalation and exhalation, respiratory frequency increases and respiration is superficial (it
is caused by decrease of ventilation and gas exchange capacity of the lung in severe pneumonia, pulmonary fibrosis, massive
atelectasis).
The pathogenesis of dyspnoea is multifactorial and involves the following important components:
The sense of respiratory effort increases when the muscle load is increased (e.g., breathing against increased resistance in chronic
obstructive pulmonary diseases) or when the muscles are weakened by fatigue, paralysis, or an increase in lung volume.
Chemoreceptors activation:
Hypercapnia has long been known to cause dyspnea independently of any associated reflex increase in respiratory-muscle
activity. It seems likely that the effects of carbon dioxide on dyspnea are mediated through changes in pH at the level of the
central (medullary) chemoreceptors.
Hypoxia. There is a widely held belief that breathlessness arises primarily from lack of oxygen. Despite that, hypoxia may play a
limited part in the breathlessness. Normally moderate hypoxemia is needed to trigger the peripheral chemoreceptors. Some
patients with hypoxia do not have dyspnea; many patients with dyspnea are not hypoxic.
Mechanoreceptors activation:
Upper-airway receptors and facial receptors modify the sensation of dyspnea. Patients sometimes notice a decrease in the
intensity of their dyspnea when sitting by a fan or open window. Conversely, the dyspnea of some patients worsens when they
breathe through a mouthpiece during pulmonary-function tests.
Lung Receptors. The lung contains a variety of receptors that transmit afferent information to the CNS by way of the vagus
nerve. Stimulation of vagal irritant receptors appears to intensify the sensation of dyspnea and may impart a sense of chest
tightness or constriction, whereas stimulation of pulmonary stretch receptors probably decreases the sensation of dyspnea.
Chest-Wall Receptors. Afferent information from a variety of receptors in the joints, tendons, and muscles of the chest wall
modifies the intensity of dyspnea.
Afferent Mismatch. Normally, the brain “expects” a certain pattern of ventilation and associated afferent feedback. Dyspnea
arises from a mismatch between outgoing motor signals to the respiratory muscles and incoming afferent information.
Periodic and terminal breathing
Periodic breathing is abnormal respiration in which there is an alteration of the periods of shallow, deep breathing and pauses.
Cheyne-Stokes respiration is an abnormal pattern of breathing characterized by periods of breathing with gradually increasing
and decreasing tidal volume interspersed with periods of apnea.
This type of respiration is caused by the failure of the respiratory center in the brain to compensate quickly for changing serum
partial pressure of O2 and CO2. It is supposed, that low excitable respiratory
center cannot react at the normal concentration of CO2 and I+ ions in blood. It demands big concentrations of these substances
for the excitation of respiratory centre. The duration of pause determines the time of these irritants accumulation to the necessary
level. The engaging of respiratory movements leads to increased ventilation of the lungs, at which NI2 is washed out of blood,
and respiratory movements stop again.
This abnormal pattern of breathing can be seen in patients with strokes, head injuries or brain tumors, and in patients with
congestive heart failure. In some instances, it can occur in otherwise normal people during sleep, at high altitudes, where it is an
important sign of altitude sickness. It is a symptom of carbon monoxide poisoning, along with syncope or coma. This type of
respiration is often seen after morphine administration, too.
Bioth's respirations, sometimes also called cluster respiration, is an abnormal pattern of breathing characterized by groups of
quick, shallow inspirations followed by regular or irregular periods of apnea.
It is caused by damage to the medulla oblongata due to strokes or trauma or by pressure on the medulla due to uncal or tentorial
herniation. It generally indicates a poor prognosis.
Kussmaul breathing and agonal breathing belong to terminal types of respiration.
Kussmaul breathing is the very deep and labored breathing with normal or reduced frequency. The cause of Kussmaul breathing
is a respiratory compensation for a metabolic acidosis (diabetic ketoacidosis, uremia). Blood gases in a patient with Kussmaul
breathing will show a low pCO2 because of a forced increased respiration (blowing off the CO2). The patient feels an urge to
breathe deeply, and it appears almost involuntary.
A metabolic acidosis produces hyperventilation, but at first it will tend to be rapid and shallow. Kussmaul breathing develops as
the acidosis grows more severe. Indeed, Kussmaul originally identified this type of breathing as a sign of coma and imminent
death in diabetic patients.
Agonal respiration is an abnormal pattern of breathing characterized by shallow, slow (3-4 per minute), irregular inspirations
followed by irregular pauses. They may also be characterized as gasping, labored breathing, accompanied by strange
vocalizations and myoclonus. The cause is due to cerebral ischemia, due to extreme hypoxia or even anoxia. Agonal breathing is
an extremely serious medical sign requiring immediate medical attention, as the condition generally progresses to complete apnea
and foretell death.
Agonal respirations are also commonly seen in cases of cardiac arrest, and may persist for several minutes after cessation of
heartbeat. The presence of agonal respirations in these cases indicates a more favorable prognosis than in cases of cardiac arrest
without agonal respirations.
Asphyxia: etiology and pathogenesis
Asphyxia is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. It
manifests by severe syndrome of disorders of vitally important functions of the organism, mainly of nervous system, respiration
and circulation of the blood.
 There are several groups of reasons resulting in asphyxia:
Insufficient environmental oxygen:
* Breathing a hypoxic breathing gas mixture while diving;
* Inhalation of overwhelming amounts of non-oxygen gases such as helium or CO2 fire;
* Loss of aircraft cabin pressure;
* Exposure to vacuum (decompression of a spacecraft or space suit).
Physical obstruction of air flow:
* Crushing or constriction of the chest or abdomen (compressive asphyxia);
* Drowning caused by water or other liquids;
* Choking due to object in the airway;
* Strangling where the airway is constricted;
* Hanging or ligature strangulation may lead to asphyxia;
* Reduction of the airways due to anaphylaxis or asthma;
* Inhalation of vomit.
Chemical or physiological interference with respiration:
Various chemical and physiological situations can interfere with the body ability to absorb and use oxygen or regulate blood
oxygen levels:
* Carbon monoxide inhalation;
* Contact with certain chemicals, including pulmonary agents (such as phosgene) and blood agents (such as hydrogen cyanide);
* Sleep apnea;
* Drug overdose.
There are four stages of asphyxia:
The 1st stage is characterized by the increased activity of respiratory centre which manifests as increased frequency of breathing;
BP and heart rate are increased too. The phase of inspiration is prolonged; it is provided with the visible effort. Because of these
factors this phase is called the phase of inspiratory dyspnea. Sympathetic effects prevail.
The 2nd stage is characterized by more rare respiration with enforced expiration, slowing-down of heart rate, ABP gradually
reduces. This phase is a phase of expiratory dyspnea.
The 3rd stage is characterized by the increase of parasympathetic nervous system influence. There is a temporary (from several
seconds to several minutes) stopping of rhythmic activity of respiratory centre – preterminal pause. ABP greatly reduces, spinal,
eye and other reflexes become extinct. The loss of consciousness develops.
The 4th stage is terminal or agonal breathing (rare deep convulsive «sighs» during several minutes). Strong convulsions,
involuntary urination and dejection develop. The death comes because of respiratory centre paralysis; heart work lasts several
minutes more.
6 GIT, KIDNEY, ENDOCRINE AND NERVOUS SYSTEM PATHOLOGY
UNIT 22
GASTROINTESTINAL PATHOLOGY
The violation of digestion in the stomach
The violations of stomach functions manifest as quantitative violations (hyposecretion, hypersecretion or increased fasting
secretion (“spontaneous” secretion) and qualitative changes (increased acidity, reduced acidity or absence of INl). The main
components of gastric juice are: hydrochloric acid, pepsin, intrinsic factor, and mucus.
The types of gastric secretion are: Normal type of secretion – the amount of secreted juice and its acidity (free and general)
increase according to the two used irritants – mechanical and chemical stimuli, ?I of contents of fasting stomach is from 1,7 to 5.
Asthenic type of gastric secretion is characterized by the increase of excitability of the gastric glands at the mechanical irritation
and the decrease at the chemical stimulation. This type of secretion occurs at the increased excitability and quick exhausting of
the gastric glands. Inhibitory type – the decrease of secretion both on mechanical and on chemical stimuli. Excitable type – the
increase of secretion both on mechanical and on chemical stimuli. Inert type – more expressed secretion to chemical stimuli and
decreased to mechanical stimuli.
Hypersecretion of the gastric juice is characterized by: increased amount of gastric juice both after meals and at fasting, high
amount of total acidity and free HCL, increased digestive ability. It has the following consequences for the digestion:
* gastric content passes to duodenum slower than usually, because more time is needed to neutralize the increased acidity of the
gastric juice;
* the amount of chymus in intestines is decreased, that leads to decreased peristalsis and constipation;
* the motility of the stomach is increased, the processes of fermentation and gases formation are overactivated that leads to
eructation and heatburn development;
* the risk of peptic ulcer occurrence is highly increased.
Hyposecretion of the gastric juice is accompanied by decreased amount of gastric juice both after meals and at fasting, low
amount or even absence of total acidity and free HCL, decreased digestive ability. It is also termed achylia. Achylia may be
partial or total. In this case the following disturbances of digestion will occur:
* chymus quickly passes to duodenum, the process of digestion is disturbed;
* undigested food components irritate the receptors of intestines that results in diarrhoea development;
* the low amount of HCL leads to excessive growth of pathogenic bacteria in GIT.
Gastritis
 The stomach lining usually is impermeable to the acid it secretes, a property that allows the stomach to contain acid and pepsin
without having its wall digested. Several protective mechanisms are collectively referred to as the gastric mucosal barrier:
* tight junctions between gastric epithelial cells;
* presence of protective mucus layer;
* secretion of bicarbonate ions against hydrogen ions;
* synthesis of prostaglandins.
The gastric epithelial cells are connected by tight junctions that prevent acid penetration, and they are covered with an
impermeable hydrophobic lipid layer that prevents diffusion of ionized water-soluble molecules. Aspirin, which is nonionized
and lipid soluble in acid solutions, rapidly diffuses across this lipid layer, increasing mucosal permeability and damaging
epithelial cells. Gastric irritation and occult bleeding due to gastric irritation occur in a significant number of persons who take
aspirin on a regular basis. Alcohol, which is also lipid soluble, disrupts the mucosal barrier. Bile acids also attack the lipid
components of the mucosal barrier and afford the potential for gastric irritation when there is reflux of duodenal contents into the
stomach. Normally, the secretion of hydrochloric acid by the parietal cells of the stomach is accompanied by secretion of
bicarbonate ions (HCO3?). For every hydrogen ion (H+) that is secreted, an HCO3? ion is produced, and as long as HCO3?
production is equal to H+ secretion, mucosal injury does not occur. Changes in gastric blood flow, as in shock, tend to decrease
HCO3? production. This is particularly true in situations in which decreased blood flow is accompanied by acidosis. Aspirin and
other NSAIDs, such as indomethacin and ibuprofen, also impair HCO3? secretion.
Prostaglandins, chemical messengers derived from cell membrane lipids, play an important role in protecting the gastrointestinal
mucosa from injury. The prostaglandins probably exert their effect through improved blood flow, increased HCO3? secretion, and
enhanced mucus production. The fact that drugs such as aspirin and the NSAIDs inhibit prostaglandin synthesis may contribute to
their ability to produce gastric irritation.
Chronic or acute gastric irritation may result in the inflammation development. The inflammation of the gastric mucosa is called
gastritis.
Acute gastritis is a transient acute inflammatory involvement of the stomach, mainly mucosa.
A variety of etiologic agents have been implicated in the pathogenesis of acute gastritis. These are following:
* Diet and personal habits (highly spiced food, excessive alcohol consumption, malnutrition, heavy smoking).
* Infections (bacterial - Helicobacter pylori, diphtheria, salmonellosis, staphylococcal food poisoning; viral infections – viral
hepatitis, influenza).
* Drugs (non-steroidal anti-inflammatory drugs, aspirin, cortisone).
* Chemical and physical agents (intake of corrosive chemicals such as caustic soda, phenol, lysol; gastric irradiation or freezing).
* Severe stress (emotional factors like shock, anger, resentment etc; extensive burns, trauma, surgery).
The complaints of persons with acute gastritis vary. Persons with aspirin-related gastritis can be totally unaware of the condition
or may complain only of heartburn or sour stomach. Gastritis associated with excessive alcohol consumption often causes
transient gastric distress, which may lead to vomiting and, in more severe situations, to bleeding and hematemesis (vomiting with
blood).
Gastritis caused by the toxins of infectious organisms, such as the staphylococcal enterotoxins, usually has an abrupt and violent
onset, with gastric distress and vomiting ensuing approximately 5 hours after the ingestion of a contaminated food source. Acute
gastritis is usually a self-limiting disorder, with complete regeneration and healing occurring within several days.
The mucosal injury and subsequent acute inflammation in acute gastritis occurs by one of the following mechanisms:
* Reduced blood flow, resulting in mucosal hypo-perfusion due to ischemia.
* Increased acid secretion and its accumulation due to H.pylori infection resulting in damage to epithelial barrier.
* Decreased production of bicarbonate buffer.
Chronic gastritis is characterized by chronic inflammatory changes leading eventually to atrophy of the glandular epithelium of
the stomach.
Classification of chronic gastritis includes the following forms:
* Type A – autoimmune;
* Type B – Helicobacter pylori-related;
* Type AB – environmental;
* Type C – chemical (reflux);
* Uncommon forms of gastritis.
Type A Gastritis (Autoimmune gastritis). Type A gastritis is also called autoimmune gastritis due to the presence of circulating
antibodies and is sometimes associated with other autoimmune diseases such as Hashimoto's thyroiditis and Addison's disease. As
a result of the antibodies influence against parietal cells and intrinsic factor, there is a depletion of parietal cells and impaired
secretion of intrinsic factor. These changes may lead to significant gastric atrophy where intestinal metaplasia may occur, and
some of these patients may develop pernicious anemia. Due to depletion of gastric acid-producing mucosal area, there is hypo- or
achlorhydria.
Type B Gastritis (H. pylori-related). It is also called hypersecretory gastritis due to excessive secretion of acid, commonly due to
infection with H. pylori. These patients may have associated peptic ulcer. Unlike type A gastritis, this form of gastritis has
association with autoimmunity activation.
Type AB Gastritis (environmental gastritis, chronic atrophic gastritis). This is the most common type of gastritis in all age
groups. It is also called environmental gastritis because a number of environmental factors have been implicated in its
pathogenesis.
 Type C Gastritis (chemical or reflux) is a chronic gastric injury resulting from reflux of alkaline duodenal contents, pancreatic
secretions, and bile into the stomach. It is most commonly seen in persons who have had gastroduodenostomy or
gastrojejunostomy surgery. A milder form may occur in persons with gastric ulcer, gallbladder disease, or various motility
disorders of the distal stomach.
Peptic ulcer disease (PUD)
Peptic ulcer is a term used to describe a group of ulcerative disorders that occur in areas of the upper gastrointestinal tract that
are exposed to acid-pepsin secretions. The most common forms of peptic ulcer are duodenal and gastric ulcers. Duodenal ulcers
occur five times more commonly than gastric ulcers. Ulcers in the duodenum occur at any age. Gastric ulcers tend to affect the
older age group. Both types of ulcer affect men three to four times more frequently than women.
The etiology of peptic ulcer disease includes the following:
• H pylori infection;
• Drugs (NSAID);
• Lifestyle factors (alcohol, smoking, spices, malnutrition);
• Severe physiologic and psychological stress;
• Genetic factors (PUD is a polygenic disease with hereditary predisposition).
H pylori infection and NSAID are responsible for most cases of PUD. Ulcer development in NSAID users is dose dependent.
Aspirin appears to be the most ulcerogenic of the NSAIDs. The pathogenesis of NSAID-induced ulcers is thought to involve
mucosal injury and inhibition of prostaglandin synthesis. In contrast to peptic ulcer from other causes, NSAID-induced gastric
injury is often without symptoms, and life-threatening complications can occur without warning.
Cigarette smoking is a risk factor for the development of ulcers and their complications. Also, smoking impairs ulcer healing and
increases the incidence of recurrence. The risk correlates with the number of cigarettes smoked per day. Smoking may accelerate
gastric emptying and decrease pancreatic bicarbonate production.
Stressful conditions that may cause PUD include burns, CNS trauma, surgery, and severe medical illness. Serious systemic
illness, sepsis, hypotension, respiratory failure, and multiple traumatic injuries increase the risk for secondary (stress) ulceration
due to increased synthesis of stress hormones glucocorticoids and adrenaline. Glucocorticoids decrease mucus secretion in gastric
mucosa and regeneration of gastric epithelial cells. Both glucocorticoids and adrenaline decrease microcirculation in the stomach,
causing ischemia of its mucosal lining. Ischemia may also result from collapse, shock, acute blood loss and spasm of blood
vessels. It results in decrease of prostaglandins synthesis and bicarbonate secretion which greatly impair the protective function
of gastric mucosa. Stress is also known to increase the tonus of the vagal nerve that provides increased secretion of HCl and
pepsin.
A peptic ulcer can affect one or all layers of the stomach or duodenum. The ulcer may penetrate only the mucosal surface, or it
may extend into the smooth muscle layers. Occasionally, an ulcer penetrates the outer wall of the stomach or duodenum.
Spontaneous remissions and exacerbations are common. Healing of the muscular layer involves replacement with scar tissue;
although the mucosal layers that cover the scarred muscle layer regenerate, the regeneration often is less than perfect, which
contributes to repeated episodes of ulceration.
Manifestations. Symptoms depend on ulcer location and patient age; many patients, particularly elderly patients, have few or no
symptoms. Pain is most common, often localized to the epigastrium. The pain is described as burning or gnawing, or sometimes
as a sensation of hunger. An additional characteristic of ulcer pain is periodicity. The pain tends to recur at intervals of weeks or
months. During an exacerbation, it occurs daily for a period of several weeks and then remits until the next recurrence.
Characteristically, the pain is relieved by food or antacids.
Gastric ulcer symptoms often do not follow a consistent pattern (e.g., eating sometimes exacerbates rather than relieves pain).
This is especially true for pyloric channel ulcers, which are often associated with symptoms of obstruction (e.g., bloating, nausea,
vomiting) caused by edema and scarring. Duodenal ulcers tend to produce more consistent pain. Pain is absent when a patient
awakens but appears in mid-morning, is relieved by food, but recurs 2 to 3 h after a meal. Pain that awakens the patient at night is
common and is highly suggestive of duodenal ulcer.
Complications. The complications of peptic ulcer include hemorrhage, penetration, perforation, and obstruction.
Mild to severe hemorrhage is the most common complication of peptic ulcer disease. It is caused by bleeding from granulation
tissue or from erosion of an ulcer into an artery or vein. Symptoms include hematemesis (vomiting of fresh blood or “coffee
ground” material) and passage of black tarry stools (melena). Bleeding may be sudden, severe, without warning, or it may be
without clinical symptoms of pain, the only sign will be blood in the stool (this is particularly true in persons receiving NSAIDs).
Acute hemorrhage is evidenced by the sudden onset of weakness, dizziness, thirst, cold and moist skin, the desire to defecate, and
the passage of loose, tarry, or even red stools and coffee-ground emesis. Signs of circulatory shock develop depending on the
amount of blood lost.
A peptic ulcer may penetrate the wall of the stomach. If adhesions prevent leakage into the peritoneal cavity, free penetration is
avoided and confined perforation occurs. Still, the ulcer may penetrate into the duodenum and enter the adjacent confined space
(lesser sac) or another organ (e.g., pancreas, liver). Pain may be intensive, persistent, referred to sites other than the abdomen
(usually the back when caused by penetration of a posterior duodenal ulcer into the pancreas), and modified by body position.
Ulcers that perforate into the peritoneal cavity unchecked by adhesions are usually located in the anterior wall of the duodenum
or, less commonly, in the stomach. With perforation, gastrointestinal contents enter the peritoneum and cause peritonitis, or
penetrate adjacent structures such as the pancreas. The patient presents with an acute abdomen. There is sudden, intense,
continuous epigastric pain that spreads rapidly throughout the abdomen, often becoming prominent in the right lower quadrant
and at times referred to one or both shoulders. The patient usually lies still because even deep breathing worsens the pain.
Palpation of the abdomen is painful, rebound tenderness is prominent, abdominal muscles are rigid (boardlike), and bowel sounds
are diminished or absent. Shock may ensue, heralded by increased pulse rate and decreased BP and urine output.
Obstruction is caused by inflammatory edema, spasm, or contraction of scar tissue and it disturbs free passage of gastric contents
through the pylorus or adjacent areas. Symptoms include recurrent, large-volume vomiting, occurring more frequently at the end
of the day and often as late as 6 hours after last meals. Loss of appetite with persistent bloating or fullness after eating also
suggests gastric outlet obstruction. Prolonged vomiting may cause weight loss, dehydration, and alkalosis.
Disorders of the exocrine pancreas
The pancreatic enzymes are secreted in the inactive form and become activated in the intestine. This is important because the
enzymes would digest the tissue of the pancreas itself if they were secreted in the active form. In order to prevent this
autodigestion the acinar cells secrete a trypsin inhibitor, which prevents trypsin activation. Because trypsin activates other
proteolytic enzymes, the trypsin inhibitor prevents subsequent activation of other enzymes.
Inflammation of the pancreas can be acute and chronic. The most common causes of pancreatitis are gallstones (stones in the
common biliary duct) or alcohol abuse. Acute pancreatitis also is associated with hyperlipidemia, hyperparathyroidism, infections
(particularly viral), abdominal and surgical trauma, and some drugs (steroids and thiazide diuretics).
Acute pancreatitis like any other inflammation is associated with the tissue injury. The injury of the pancreatic tissue causes the
escape of activated pancreatic enzymes into the pancreas and surrounding tissues. These enzymes cause fat necrosis,
(autodigestion) of the pancreas and produce fatty deposits in the abdominal cavity with hemorrhage from the necrotic vessels.
The mechanism of pancreatitis development is the following. In the case of biliary tract obstruction due to gallstones, pancreatic
duct obstruction increases intra-duct pressure and activates the enzymes in the pancreatic duct system. Alcohol is known to be a
potent stimulator of pancreatic secretions, and it causes partial obstruction of the sphincter of the pancreatic duct that causes the
activation of the enzymes. The onset of acute pancreatitis usually is sudden it may follow a heavy meal or alcohol intake. The
initial event in acute pancreatitis pathogenesis is a premature activation of the enzyme trypsin. Once trypsin is activated, it
activates other pancreatic digestive enzymes which start the process of self digestion of the pancreatic cells. Later the process of
self digestion is spread outside the pancreas to other tissues and organs. The intensity of inflammation may vary from mild cases
to severe forms with features of pancreatic necrosis, injury to extrapancreatic organs and shock development.
The most common initial symptom is severe epigastric and abdominal pain that radiates to the back. The other manifestations of
pancreatitis include:
• hypovolemia – tachycardia, hypotension (loss of fluid from due to increased capillary permeability from the abdominal
vessels to the retroperitoneal and peripancreatic spaces and the abdominal cavity)
• acute respiratory distress syndrome (due to the damage of alveolo-capillary membrane with activated pancreatic
enzymes),
• disseminated intravascular coagulations and gastrointestinal hemorrhage (caused by increased activity of clotting
factors and their subsequent deficiency, increased vessels permeability),
• paralytic intestinal impassability – obstruction (due to acute peritonitis development there is a disturbance of neural
control upon the bowels motility)
• renal failure (presence of the products of autodigestion which also cause intoxication),
• cardiovascular failure (due to low blood circulating volume and toxins in the bloodstream)
Laboratory indices show increased total serum amylase and lipase level, increased amylase level in the urine, increase of the
WBC count and fever, the increase of bilirubin level with the signs of jaundice (decreased bile flow to the intestines due to edema
of the pancreas).
Chronic pancreatitis is manifested in episodes that are similar, or of lesser severity, to those of acute pancreatitis. Patients have
persistent, recurring episodes of epigastric and upper left quadrant pain; the attacks often are precipitated by alcohol abuse or
overeating. Anorexia, nausea, vomiting, constipation, and ?atulence are common. Eventually, the disease progresses to the extent
that exocrine and endocrine pancreatic functions become de?cient. At this point, signs of secondary diabetes mellitus and the
malabsorption syndrome (e.g., weight loss, fatty stools - steatorrhea) become apparent.
The violations of intestines motility
The violations of digestion in the intestines are presented with the disorders of intestinal digestion and alterations in intestinal
motility.
Diarrhea is excessively frequent passage of stools.
The complaint of diarrhea is a general one and can be related to a number of pathologic and nonpathologic factors. Diarrhea can
be acute or chronic and can be caused by infectious organisms, food intolerance, drugs, or intestinal disease. Acute diarrheas that
last less than 4 days are predominantly caused by infectious agents and follow a self-limited course.
Chronic diarrheas are those that persist for longer than 3 to 4 weeks. They are often caused by conditions such as in?ammatory
bowel disease, irritable bowel syndrome, malabsorption syndrome, endocrine disorders (hyperthyroidism, diabetic autonomic
neuropathy), or radiation colitis.
Several mechanisms are responsible for the most clinically significant diarrheas. In many disorders, more than one mechanism is
active.
Osmotic load. Diarrhea occurs when unabsorbable, water-soluble solutes remain in the bowel and retain water. Osmotic diarrhea
occurs with sugar intolerance (e.g., lactose intolerance caused by lactase deficiency)
Increased secretions. Diarrhea occurs when the bowels secrete more electrolytes and water than they absorb. Causes of increased
secretions include infections, unabsorbed fats, certain drugs, and various intrinsic and extrinsic secretagogues (substances that
promote secretion).
 Reduced contact time/surface area. Rapid intestinal transit and diminished surface area impair fluid absorption and cause
diarrhea. Common causes include small-bowel or large-bowel resection or bypass, gastric resection, and inflammatory bowel
disease. Stimulation of intestinal smooth muscle by drugs (e.g., Mg-containing antacids, cholinesterase inhibitors)or humoral
agents (e.g., prostaglandins, serotonin) can also speed transit.
Complications manifest as fluid loss with consequent dehydration, electrolyte loss (Na, K, Mg, Cl), and even vascular collapse
sometimes occur. Collapse can develop rapidly in patients who have severe diarrhea (e.g., patients with cholera) or are very
young, very old, or weakened. HCO3- loss can cause metabolic acidosis. Hypokalemia can occur in severe or chronic diarrhea or
if the stool contains excess mucus. Hypomagnesemia after prolonged diarrhea can cause tetany.
Intestinal obstruction is defined as a significant mechanical impairment or complete arrest of the passage of contents through the
intestine. The causes of intestinal obstruction can be categorized as mechanical or paralytic obstruction. Strangulation with
necrosis of the bowel may occur and lead to perforation, peritonitis, and sepsis.
Mechanical obstruction can result from intrinsic or extrinsic conditions. Major causes include external hernia and postoperative
adhesions. Less common causes are strictures, tumor, foreign bodies, intussusception, and volvulus. Intussusception involves the
telescoping of bowel into the adjacent segment. It is the most common cause of intestinal obstruction in children younger than 2
years of age. Volvulus refers to a complete twisting of the bowel on an axis formed by its mesentery.
Paralytic, or adynamic, obstruction results from neurogenic or muscular impairment of peristalsis. Paralytic ileus is most
commonly seen after abdominal surgery. It also accompanies inflammatory conditions of the abdomen, intestinal ischemia, pelvic
fractures, and back injuries. It occurs early in the course of peritonitis and can result from chemical irritation caused by bile,
bacterial toxins, electrolyte imbalances as in hypokalemia, and vascular insufficiency.
The cardinal symptoms of intestinal obstruction are pain, absolute constipation, abdominal distention, vomiting and fluid and
electrolyte disorders.
The major effects of both types of intestinal obstruction are abdominal distention and loss of fluids and electrolytes. In simple
obstruction, blockage occurs without vascular compromise. Ingested fluid and food, digestive secretions, and gas accumulate
above the site of obstruction. The proximal bowel distends, and the distal segment collapses. The normal secretory and absorptive
functions of the mucosa are depressed, and the bowel wall becomes edematous and congested. Severe intestinal distention is self-
perpetuating and progressive, intensifying the peristaltic and secretory derangements and increasing the risks of dehydration.
Either form of obstruction eventually may lead to strangulation (i.e., interruption of blood flow), gangrenous changes, and,
ultimately, perforation of the bowel. Strangulating obstruction is more frequently observed in the patients with small-bowel
obstruction. In large-bowel obstruction, strangulation is rare. The increased pressure in the intestine tends to disturb mucosal
blood flow, leading to necrosis and movement of blood into the luminal fluids. This promotes rapid growth of bacteria in the
obstructed bowel. Anaerobes grow rapidly in this favorable environment and produce a lethal endotoxin.
The manifestations of intestinal obstruction depend on the degree of obstruction and its duration. With acute obstruction, the
onset usually is sudden. With chronic conditions, the onset often is more gradual. The cardinal symptoms of intestinal obstruction
are pain, absolute constipation, abdominal distention, and vomiting. With mechanical obstruction, the pain is severe and acute, in
contrast to the continuous pain and silent abdomen of paralytic obstruction. Vomiting and fluid and electrolyte disorders occur
with both types of obstruction.
Slowing of the intestinal motility, which is observed in constipation and intestinal obstruction results in the body’s intoxications
with the substances that are normally excreted with the feces. This process is known as intestinal autointoxication.
There is a rich microflora in the bowels of a healthy man. The normal microflora of the bowels provides the processes of
zymosis and putrefaction that lead to the end remaking of the intestinal chyme and the formation of the fecal masses. Appearing
toxic substances absorb in blood and come in the liver, where they are neutralized.
The causes and mechanisms of intoxication:
* Increased formation of the toxic substances (hydrogen sulphide, skatole, cresol, indole, phenol, etc) in the bowels that appears
at the decrease of secretion and motility (constipations).
* The increase of the intestinal wall permeability, which accompanies inflammation (enteritis, colitis) and stretching (meteorism)
of bowels.
* Hepatic failure is accompanied by the decrease of the detoxication function of the liver.
Toxic substances, besides reflex influences from the chemoreceptors and mechanoreceptors of the bowels, influence the
receptors of the vessels and brain centres. The decrease of the ABP, the decrease of the pain sensitivity, the decrease of glycogen
amount in the liver and hyperglycemia, weakening of the cardiac contractions, respiratory depression, deep inhibition of the
cerebral cortex belong to the typical development of intestinal intoxication. This may lead to coma. Headaches, anemias,
dystrophic changes in the myocardium are typical for the chronic intestinal intoxication. The appetite decreases, the digestion is
violated because of the suppression of glands of the digestive tract. The failure of digestion develops.
The malabsorption syndrome
Digestion and absorption occur in three phases: 1) intraluminal hydrolysis of fats, proteins, and carbohydrates by enzymes—bile
salts enhance the solubilization of fat in this phase; 2) digestion by brush border enzymes and uptake of end-products; and 3)
lymphatic transport of nutrients. Malabsorption occurs when any of these phases is impaired.
Malabsorption syndrome (MAS) is subdivided into two groups:
* Primary MAS – which is due to primary deficiency of the absorptive mucosal surface and of the associated enzymes
(pancreatic or intestinal).
* Secondary MAS – in which mucosal changes result secondary to other factors such as diseases, surgery, trauma and drugs.
 Persons with intestinal malabsorption usually have symptoms directly referable to the GIT that include diarrhea, steatorrhea,
flatulence, bloating, abdominal pain, and cramps. Weakness, muscle wasting, weight loss, and abdominal distention are often
present. Neuropathy, atrophy of the skin, and peripheral edema may be present. Peripheral neuropathy occurs due to deficiency of
vitamins B1, B6, B12. Peripheral edema is usually a result of hypoproteinemia, caused by insufficient absorption of proteins.
The reasons of MAS
MechanismCauseInadequate gastric mixing, rapid emptying, or bothBillroth II gastrectomy, gastrocolic fistula,
gastroenterostomyInsufficient digestive agentsBiliary obstruction , chronic liver failure
Chronic pancreatitis, pancreatic cancer, pancreatic resection
Lactase deficiency, sucrase deficiencyImproper environmentAbnormal motility secondary to diabetes, scleroderma,
hyperthyroidism
Bacterial overgrowth (deconjugation of bile salts)Epithelium injury Acute intestinal infections, alcohol, antibiotics, ischemia,
radiation influenceShort bowelIntestinal resection Impaired transport of nutrients
Abetalipoproteinemia
Addison's disease
Block of lymphatic vessels
Weight loss often occurs despite normal or excessive caloric intake. Steatorrhea – fatty stool, the hallmark of malabsorption –
occurs when > 7 g/day of fat are excreted. Steatorrhea causes foul-smelling, pale, bulky, and greasy stools. Along with the loss of
fat in stools, there is a failure to absorb the fat-soluble vitamins. This can lead to easy bruising and bleeding (i.e., vitamin K
deficiency), bone pain, a predisposition to the development of fractures and tetany (i.e., vitamin D and calcium deficiency),
macrocytic anemia, and glossitis (i.e., folic acid deficiency). Vitamin A deficiency may result in night blindness.
One of the MAS important types is celiac disease. Celiac disease (celiac sprue, gluten-sensitive enteropathy) is an immune-
mediated disorder triggered by ingestion of gluten-containing grains (including wheat, barley, rye). The classic form of celiac
disease presents in infancy and manifests as failure to thrive, diarrhea, abdominal distention, and occasionally, severe
malnutrition. In adults, gastrointestinal symptoms may manifest as diarrhea, constipation, or other symptoms of malabsorption
such as bloating, flatus, or belching. The primary treatment of celiac disease consists of removal of gluten and related proteins
from the diet.
UNIT 23
LIVER PATHOLOGY
Normal bilirubin metabolism
Most of bilirubin comes from erythrocytes (85%), which are removed by the phagocytosis in the spleen, bone marrow and liver.
The other 15% derives from premature breakdown of hemoglobin in developing red cells in the bone marrow. In the process of
degradation, hemoglobin from the red blood cell is broken down to form biliverdin, which is further converted to free bilirubin.
Free bilirubin, which is insoluble in plasma, is transported in blood attached to plasma albumin. Even when it is bound to
albumin, this bilirubin is still called free bilirubin. As it passes through the liver, free bilirubin is released from its albumin carrier
molecule and moved into the hepatocytes. Inside the hepatocytes, free bilirubin is transferred to the smooth endoplasmic
reticulum, where it is conjugated with glucuronic acid. The result is water soluble bilirubin diglucuronide and a small amount of
monoglucuronide.
Conjugated bilirubin is secreted as a constituent of bile, and in this form it passes through the bile ducts into the small intestine.
In the intestine, approximately one half of the bilirubin is converted into a highly soluble substance called urobilinogen by the
intestinal flora.
Urobilinogen is either absorbed into the portal circulation or excreted in the feces. Most of the urobilinogen that is absorbed is
returned to the liver to be re-excreted into the bile. A small amount of urobilinogen, approximately 5%, is absorbed into the
general circulation and then excreted by the kidneys. Usually, only a small amount of bilirubin is found in blood; the normal level
of total serum bilirubin is 0.1 to 1.2 mg/dL. Laboratory measurements of bilirubin usually measure the free and the conjugated
bilirubin as well as the total bilirubin. These are reported as the direct (conjugated) bilirubin and the indirect (unconjugated or
free) bilirubin.
Jaundice
The abnormally high accumulation of bilirubin in blood results in a yellowish discoloration to the skin and deep tissues which is
called jaundice (i.e., icterus). Jaundice becomes evident when the serum bilirubin levels rise above 2-2.5 mg/dL.
The four major causes of jaundice are excessive destruction of red blood cells, impaired uptake of bilirubin by the liver cells,
decreased conjugation of bilirubin, and obstruction of bile flow in the canaliculi of the hepatic lobules or in the intrahepatic or
extrahepatic bile ducts. From an anatomic standpoint, jaundice can be categorized as prehepatic, intrahepatic, and posthepatic.
Prehepatic or hemolytic (hemolysis, neonatal jaundice)
The major cause of prehepatic jaundice is excessive hemolysis of red blood cells. Hemolytic jaundice occurs when red blood
cells are destroyed at a rate in excess of the liver’s ability to remove the bilirubin from blood. It includes all the cases of
hereditary and acquired hemolytic anemias, hemolytic blood transfusion reaction and neonatal jaundice (physiologic jaundice).
Neonatal hyperbilirubinemia results from an increased production of bilirubin in newborn infants and their limited ability to
excrete it. Premature infants are at particular risk because their red cells have a shorter life span and higher turnover rate. In
prehepatic jaundice, there is a mild jaundice, the unconjugated bilirubin is elevated, the stools are of normal color or darkly
colored, and there is no bilirubin in urine.
Hepatic jaundice or hepatocellular jaundice is caused by disorders that directly affect the ability of the liver to remove bilirubin
from blood or to conjugate it, so that it can be eliminated in bile. Conjugation of bilirubin is impaired whenever liver cells are
damaged, when transport of bilirubin into liver cells becomes deficient, or when the enzymes needed to conjugate the bile are
lacking. Liver diseases such as hepatitis and cirrhosis are the most common causes of intrahepatic jaundice. Drugs such as the
halothane, oral contraceptives, estrogen, anabolic steroids, isoniazid, and chlorpromazine may also be implicated in this type of
jaundice.
Intrahepatic or hepatocellular jaundice usually interferes with all phases of bilirubin metabolism—uptake, conjugation, and
excretion. Both the conjugated and unconjugated bilirubin are elevated, urine is often dark because of bilirubin in it. Faeces
contain less stercobilin than normally.
Hepatocellular jaundice may also be a result of hereditary disorders resulting in:
• disturbance of bilirubin uptake due to pathology of liver receptors (Gilbert’s syndrome);
• disturbance of bilirubin conjugation with glucuronic acid due to deficiency of necessary enzyme (Crigler-Najjar
syndrome, neonatal jaundice in premature born children);
• disturbance of bilirubin excretion due to deficiency of transport system (Dubin-Johnson syndrome).
Posthepatic (mechanical, obstructive, cholestatic) jaundice occurs when bile flow is obstructed between the liver and the
intestine. The obstruction may be located at any point between the junction of the right or left hepatic duct and the point where
the bile duct opens into the intestine.
Among the causes are strictures of the bile duct, gallstones, and tumors of the bile duct or the pancreas. Conjugated bilirubin
levels are usually elevated; stools are clay colored because of the lack of bilirubin in bile; urine is dark. Blood levels of bile acids
are often elevated in obstructive jaundice. As the bile acids accumulate in blood, pruritus develops.
Cholemia and acholia syndromes
Posthepatic jaundice is usually accompanied with cholemia and acholia. The term “cholemia” describes the presence of bile
pigments in blood, either because of intra or extrahepatic biliary obstruction; normal bile flow is decreased. Bile constituents are
transferred to blood, resulting in elevated levels of cholesterol, bile acids and bilirubin – this reflects regurgitation from the
hepatocyte to the bloodstream.
Clinical signs of cholemia:
* High amount of conjugated bilirubin and bile acids in blood and subsequently in urine. Urine gets dark color;
* High blood cholesterol level. The excess of cholesterol is ingested by the tissue phagocytes and yield in xanthomas formation
(see lipid metabolism pathology);
* Skin itching – pruritis (due to the nerve ending irritation by bile salts);
* Arterial hypotension – due to the decreased tonus of arterioles and increased vagal tone;
* Bradycardia – due to the direct inhibitory influence of bile acids on the SA node cells;
* Increased irritability and excitability of the patient – due to the decreased activity of brain cortex inhibitory neurons;
* Depression, insomnia, increased fatigueability – as a result of nervous system inhibition by bile components;
* Multiply subcutaneous hemorrhages – due to decreased absorption of lipid-soluble vitamin K (disturbance of blood
coagulation).
Acholia is a decrease in or an absence of bile secretion into the intestines which is accompanied by the digestion disturbances.
The signs of acholia are:
* steatorrhea – fat and clay colored stools – due to disturbances of lipids digestion in the absence of bile;
* intestinal autointoxication and disbacteriosis development – bile is bacteriostatic and bactericidic to pathogenic intestinal
microflora;
* clinical symptoms of fat soluble vitamins (A,D,E,K) deficiency.
Hepatic failure
Hepatic failure is a clinical syndrome caused by severe impairment of the liver cells, which can not maintain the vital metabolic,
detoxifying and synthetic functions of the liver. Hepatic failure may result from sudden and massive liver destruction, as in
fulminant hepatitis, or be the result of progressive damage to the liver, as occurs in alcoholic cirrhosis. Whatever is the cause,
80% to 90% of hepatic functional capacity must be lost before liver failure occurs.
The manifestations of liver failure reflect the various synthesis, storage, metabolic, and elimination functions of the liver. Fetor
hepaticus refers to a characteristic musty, sweetish odor of the breath in a patient with advanced liver failure, resulting from the
metabolic byproducts of the intestinal bacteria.
Hematologic disorders. Liver failure can cause anemia, thrombocytopenia, coagulation defects, and leukopenia. Anemia may be
caused by blood loss, excessive red blood cell destruction, and impaired formation of red blood cells. A folic acid deficiency may
lead to severe megaloblastic anemia. Changes in the lipid composition of the red cell membrane increase hemolysis. Because
factors V, VII, IX, X, prothrombin and fibrinogen are synthesized by the liver, their decline in liver disease contributes to
bleeding disorders. Malabsorption of the fat-soluble vitamin K contributes further to the impaired synthesis of these clotting
factors. Thrombocytopenia often occurs as the result of splenomegaly. The person with liver failure is a subject to purpura, easy
bruising, hematuria, and abnormal menstrual bleeding, and is vulnerable to bleeding from the esophagus and other GIT segments.
Endocrine disorders. The liver metabolizes the steroid hormones. Endocrine disorders, particularly disturbances in gonadal (sex
hormone) function, are common accompaniments of cirrhosis and liver failure. Women may have menstrual irregularities
(usually amenorrhea) and sterility. In men, testosterone levels usually fall, the testes atrophy and gynecomastia occur. A decrease
in aldosterone metabolism may contribute to salt and water retention by the kidney, along with a lowering of serum potassium
resulting from increased elimination of potassium.
Skin disorders. Liver failure brings on numerous skin disorders. These lesions, called variously vascular spiders, telangiectases,
spider angiomas, and spider nevi, are most often seen in the upper half of the body. They consist of a central pulsating arteriole
from which smaller vessels radiate. Palmar erythema is the redness of the palms, probably caused by increased blood flow from
higher cardiac output. Clubbing of the fingers may be seen in persons with cirrhosis. Jaundice is usually a late manifestation of
liver failure.
Hepatic encephalopathy refers to the CNS manifestations of liver failure. It is characterized by neural disturbances ranging from
a lack of mental alertness to confusion, coma, and convulsions. There are four stages of encephalopathy:
Stage I: Sleep disturbance, irritability, personality changes
Stage II: Lethargy and disorientation
Stage III: Deep somnolence
Stage IV: Coma
A very early sign of hepatic encephalopathy is a flapping tremor called asterixis. Various degrees of memory loss may occur,
coupled with personality changes such as euphoria, irritability, anxiety, and lack of concern about personal appearance. Speech
may be impaired, and the patient may be unable to perform certain purposeful movements. The encephalopathy may progress to
decerebrate rigidity and then to a terminal deep coma. The reason of such changes is the accumulation of neurotoxins, which
appear in blood because the liver has lost its detoxifying capacity.
One of the suspected neurotoxins is ammonia. A particularly important function of the liver is the conversion of ammonia, a
byproduct of protein and amino acid metabolism, to urea. The ammonium ion is produced in abundance in the intestinal tract,
particularly in the colon, by the bacterial degradation of luminal proteins and aminoacids. Normally, these ammonium ions
diffuse into the portal blood and are transported to the liver, where they are converted to urea before entering the general
circulation. When blood from the intestine bypasses the liver, or the liver is unable to convert ammonia to urea, ammonia moves
directly into the general circulation and from there to the cerebral circulation. Hepatic encephalopathy may become worse after a
large protein meal or gastrointestinal tract bleeding.
Hepatorenal syndrome. Patients with acute liver failure may develop kidney failure as a complication; it manifests by severely
decreased urine output (oliguria) with rising blood urea nitrogen and creatinine levels. It is thought to be secondary to kidneys
hypoperfusion. Hypoperfusion causes a reduction in glomerular filtration rate; patients with hepatorenal syndrome have high
levels of renin, a potent vasoconstrictor and decreased levels of prostaglandins, vasodilatory agents that play a role in renal
hemodynamics.
Portal hypertension
Portal hypertension is characterized by increased resistance to flow in the portal venous system and sustained portal vein
pressure above 12 mm Hg (normal, 5 to 10 mm Hg). Normally, venous blood returning to the heart from the abdominal organs
collects in the portal vein and travels through the liver before entering the vena cava for detoxification. Portal hypertension can
be caused by a variety of conditions that increase resistance to hepatic blood flow, including prehepatic, posthepatic, and
intrahepatic obstructions.
Prehepatic portal hypertension:
Prehepatic obstruction in the portal circulation may be caused by portal vein thrombosis (e.g. in hypercoagulable states, tumors,
pancreatitis, and sepsis) and external compression due to cancer, metastases or enlarged lymph nodes.
Intrahepatic portal hypertension:
It is the most frequent clinical type, mainly secondary to cirrhosis. The cirrhotic nodules impinge and deform the hepatic veins,
obstructing blood flow distal to the lobules. Fibrosis in the portal tracts obliterates branches of the portal veins. In addition there
is an increased arterial blood flow. Central vein sclerosis and sinusoidal fibrosis also increase portal pressure. Other causes of
intrahepatic portal hypertension are infestation of the liver with schistosomes, idiopathic portal hypertension polycystic liver and
hepatic tumors.
Post hepatic portal hypertension:
Posthepatic obstruction refers to any obstruction to blood flow through the hepatic veins beyond the liver lobules, either within
or distal to the liver. It is caused by conditions such as thrombosis of the hepatic veins, venoocclusive disease, and severe right-
sided heart failure that impede the outflow of venous blood from the liver. The most common entity is the Budd-Chiari syndrome.
It refers to congestive disease of the liver caused by occlusion of the portal veins and their tributaries. The principal cause of the
Budd-Chiari syndrome is thrombosis of the hepatic veins, in association with diverse conditions such as polycythemia vera,
hypercoagulability states associated with malignant tumors, pregnancy, bacterial infection, metastatic disease of the liver, and
trauma.
Complications of portal hypertension arise from the increased pressure and dilatation of the venous channels behind the
obstruction. In addition, collateral channels open that connect the portal circulation with the systemic circulation. The major
complications of the increased portal vein pressure and the opening of collateral channels are ascites, splenomegaly, and the
formation of portosystemic shunts.
Ascites occurs when the amount of fluid in the peritoneal cavity is increased, and is a late-stage manifestation of cirrhosis and
portal hypertension. Those who gain much fluid often experience abdominal discomfort, dyspnea, and insomnia. Several factors
contribute to fluid accumulation, including: 1) increase in capillary pressure due to portal hypertension and obstruction of venous
flow through the liver, 2) salt and water retention by the kidney, and 3) decreased colloidal osmotic pressure due to impaired
synthesis of albumin by the liver.
Splenomegaly. The spleen enlarges progressively in portal hypertension because of shunting of blood into the splenic vein. The
enlarged spleen often gives rise to sequestering of significant numbers of blood elements and development of a syndrome known
as hypersplenism. Hypersplenism is characterized by a decrease in the life span and a subsequent decrease in all the blood cells
count, leading to anemia, thrombocytopenia, and leukopenia. The decreased life span of the blood elements is thought to result
from an increased rate of removal because of the prolonged transit time through the enlarged spleen.
Portosystemic shunts. With the gradual obstruction of venous blood flow in the liver, the pressure in the portal vein increases,
and collateral circulation develops between the portal and systemic veins. The main areas of collaterals are situated in the lower
rectum and esophagus and the umbilical veins of the falciform ligament that attaches to the anterior wall of the abdomen. The
collaterals between the inferior and internal iliac veins may give rise to hemorrhoids. In some persons, the fetal umbilical vein is
not totally obliterated; it forms a channel on the anterior abdominal wall. Dilated veins around the umbilicus are called caput
medusae. Portopulmonary shunts also may develop and cause blood to bypass the pulmonary capillaries, interfering with blood
oxygenation and producing cyanosis.
Clinically, the most important collateral channels are those connecting the portal and coronary veins that lead to reversal of flow
and formation of thin-walled varicosities in the submucosa of the esophagus. These thinwalled esophageal varices are a subject to
rupture, producing massive and sometimes fatal hemorrhage. Impaired hepatic synthesis of coagulation factors and decreased
platelet levels (i.e., thrombocytopenia) due to splenomegaly may further complicate the control of esophageal bleeding.
Hepatolienal syndrome. Enlargement of the liver is usually combined with the enlargement of the spleen. Combination of the
lesions of these organs is explained by their close connection with the portal vein, commonness of innervation and ways of
outflow of lymph, belonging to reticuloendothelial system. Hepatolienal syndrome is observed at the acute and chronic diffuse
affections of the liver; inherited and acquired defects of vessels of the portal system; some violations of metabolism; system
diseases of blood, chronic infections. Diseases of the liver have the main role in the development of hepatolienal syndrome.
Clinically it can manifest with hypersplenism, which is accompanied by decreased blood cell count and increase of ESR
UNIT 24
KIDNEY PATHOLOGY
Quantitative and qualitative violations of uropoiesis
Polyuria is the increase of amount of excreted urine for 24 hours. Different reasons can cause polyuria. Extra-kidney’s factors
include:
* excessive intravenous injection of fluid, which decrease blood colloid and osmotic pressure;
* low temperature of surrounding – narrowing of peripheral and kidney vessels results in the increase of hydrostatic pressure;
* increased amount of osmotically active substances in blood (glucose) which are filtered to urine (as it develops in diabetes
mellitus);
* decrease of secretion of ADH (vasopressin) – due to decreased water reabsorption.
Renal factors: the trauma of the kidneys, thrombosis and embolism of kidney arteries, acute glomerulonephritis, poisoning by
nephrotic toxins (salts of heavy metals, potassium dichromate, NNl4 etc.), toxic or allergic influence of medicines (sulfonamides,
antibiotics), in the terminal stage of chronic renal failure.
Oliguria and anuria are the decrease of daily excreted urine. Oliguria is defined as a urine output that is less than 400-500 ml/day
in adults; anuria less than 100-50 ml/day or complete stop of urine excretion.
The pathophysiological mechanisms of oliguria and anuria include:
* hypoperfusion of the kidney (e.g. as a result of dehydration by poor oral intake, diarrhea, massive bleeding, shock conditions);
* kidney damage (severe hypoperfusion, medications);
* obstruction of urine flow (e.g. enlarged prostate, tumor compression of urinary outflow, expanding hematoma or fluid
collection, urolithiasis).
Qualitative changes of urine
Isosthenuria is the excretion of urine that has not been concentrated by the kidneys and has the same osmolality as that of plasma
in different portions of urine – around 1,010, irrespective of the fluid intake. Normal urine specific gravity – 1,010-1,025.
Hyposthenuria is the excretion of urine with low specific gravity due to an inability of the tubules of the kidneys to produce
concentrated urine.
Hypersthenuria is the excretion of urine with unusually high specific gravity and concentration of solutes, resulting usually from
dehydration or deprivation of water, increased concentration of osmotically active substances (glucose, high content of salts).
Nocturia is the need to get up during the night in order to urinate, thus interrupting sleep. Its occurrence is more frequent in the
elderly. Nocturia could result simply from too much liquid intake before going to bed, or it could be a symptom of urinary
incontinence, diabetes.
Pathological components of urine
Proteinuria is the presence of an excess of serum proteins in urine. The protein in urine often causes urine to become foamy.
A small amount of protein (20 to 150 mg/day) normally passes through the glomerular filtration barrier and is reabsorbed by the
tubules. Daily excretion of proteins with urine is 30 -50 mg, maximum 100 mg.
The excretion of proteins with urine may occur both as a result of kidney pathology and in healthy people. So called functional
proteinuria develops in the following states: physical overload (march proteinuria), hypothermia, stress. Orthostatic proteinuria
(nonpathological proteinuria) usually occurs between the ages of 10 and 20, and manifests when the person stands erectly but
disappears when the person lies down. This type of proteinuria is diagnosed by comparing urine analysis after night and after 1- 2
hours of walking.
Proteinuria can be divided into glomerular and tubular types. Glomerular proteinuria is caused by increased glomerular
permeability to plasma proteins due to its affection in different diseases (acute and chronic glomerulonephritis, diabetic
nephropathy, systemic collagenous diseases). In this case excess of protein is filtered out exceeding the capacity of tubules for
reabsorption and, therefore, appears in urine. Tubular proteinuria occurs when distal tubules are affected that impairs proteins
reabsorption (pyelonephritis, hereditary tubules pathology). In some cases mixed forms of proteinuria occur.
Urine may contain both low and high molecular weight proteins. A highly-selective proteinuria consists mostly of loss of low
molecular weight proteins, while a poorly-selective proteinuria is the loss of high molecular weight proteins in urine.
Hematuria is the presence of blood in urine. Urine analysis may reveals microscopic hematuria (small amounts of blood, can be
seen only on urinalysis or light microscopy) or macroscopic ("frank" or "gross") hematuria – when urine gets red coloring.
The following types of hematuria exist:
Renal hematuria occurs when RBC get in the primary urine through the damaged wall of glomerular capillaries or nephron
tubules. RBC in this case are damaged – leached (lost hemoglobin) have the form of colorless one - or two-circuit rings.
Post renal hematuria is diagnosed when undamaged RBC are found in urinary sediment, that proves the affection of ureter,
urinary bladder or urethra.
Cylinderuria – the presence of renal casts in urine. Urine casts are small cylinder-shaped formations of cells and debris from
inside the tubules of the kidneys. The various types of casts that can be found in urine sediment may be classified as cellular and
acellular casts.
Acellular casts
The most common type of cast is hyaline cast. Low urine flow, concentrated urine, or an acidic environment can contribute to the
formation of hyaline casts. They may be seen in normal individuals in dehydration or excessive exercise. The 2nd most common
type of cast, granular casts can result either from the breakdown of cellular casts, or the inclusion of aggregates of plasma
proteins (e.g., albumin) or immunoglobulin light chains.
Waxy casts suggest the very low urine flow associated with severe, longstanding kidney disease. Fatty casts are hyaline casts
with fat globule inclusions, and are yellowish-tan in appearance. They can be present in various disorders, including the high
urinary protein nephrotic syndrome, diabetic or lupus nephropathy. Pigment casts are so named due to their discoloration. They
contain hemoglobin in hemolytic anemia, bilirubin in liver disease. Crystal casts are crystallized urinary solutes, such as oxalates,
urates, or sulfonamides, which are enmeshed within a hyaline cast during its formation.
Cellular casts
Red blood cell casts is an index of glomerular damage, which can occur in glomerulonephritis from various causes, vasculitis,
systemic lupus erythematosis. White blood cell casts are indicative of inflammation or infection (pyelonephritis, nephrotic
syndrome, post-streptococcal acute glomerulonephritis). Epithelial cell casts are formed via inclusion or adhering of desquamated
epithelial cells of the tubule lining. These can be seen in acute tubular necrosis and toxic ingestion (mercury, salicylate).
Cytomegalovirus and viral hepatitis are organisms that can cause epithelial cell death as well.
Leukocyturia is leukocytes presence in urine. Single leukocytes are observed in urine of healthy people. The presence of big
amount of leukocytes in urine is seen at pyelonephritis, tuberculosis of kidney, inflammatory diseases of urinary tracts.
Glycosuria is the presence of glucose in blood. Normally glucose is completely reabsorbed by kidney tubules. High blood
glucose level (more than 9 mmol/L) “overloads” glucose transporting mechanisms that results in glucosuria. Inherited defect of
enzymes that take part in glucose reabsorption also results in glucosuria.
Glomerular diseases
Glomerulonephritis (GN) is a primary or secondary autoimmune renal disease characterized by inflammation of the glomeruli.
Primary glomerulonephritis – the glomeruli are the predominant site of involvement (acute GN, membranous GN, membrano-
proliferative GN and other forms). Secondary glomerular diseases include certain systemic and hereditary diseases which
secondarily affect the glomeruli (lupus erythematosus, diabetes mellitus, amyloidosis etc.)
Glomerulonephritis is characterized by hematuria with red cell casts, a diminished glomerular ?ltration rate (GFR), azotemia
(presence of waste nitrogen products in blood), oliguria, and hypertension. The in?ammatory process in the kidney damages the
capillary wall, permitting red blood cells to escape into urine and producing hemodynamic changes that decrease the GFR.
Pathogenesis of glomerular injury involves immunologic and non-immunologic mechanisms.
Immunologic mechanisms underlying glomerular injury are primarily antibody-mediated (immune-complex disease). The
majority of cases of glomerular disease results from deposits of immune complexes (antigen-antibody complexes) in the kidney
tissue. The immune complexes are represented by glomerular deposits of immunoglobulins (IgG, IgM) and complement (mainly
C3). The other immunologic mechanism is the injury resulting from antibodies reaction with ?xed glomerular antigens.
The mediators of immunologic injury are neutrophils, mononuclear phagocytes, platelets, complement and coagulation system.
Biologically active substances produced by these cellular elements and proteins systems damage glomeruli causing inflammation
development.
Non-immunologic mechanisms include:
* metabolic glomerular injury (due to hyperglycemia in diabetes mellitus);
* hemodynamic glomerular injury (systemic hypertension);
* deposition diseases (amyloidosis) and other mechanisms.
Acute GN is known to follow acute infection. The most common form is acute post-streptococcal GN. The onset of disease is
generally sudden after 1-2 weeks of streptococcal infection, most frequently of the throat (e.g. streptococcal pharyngitis, acute
tonsillitis,) and sometimes of the skin (e.g. streptococcal impetigo, erysipelas).
The relationship between streptococcal infection and this form of GN is now well established. The glomerular lesions appear to
result from deposition of immune complexes in the glomeruli. The evidences are following:
* There is an epidemiological evidence of preceding streptococcal sore throat or skin infection about 1-2 weeks prior to the
attack.
 * The latent period between streptococcal infection and the onset of clinical manifestations of the disease is compatible with the
period required for building up of antibodies.
* Streptococcal infection may be identified by culture or may be inferred from elevated titres of antibodies against streptococcal
antigens.
* There is usually hypocomplementemia indicating the involvement of complement in the glomerular deposits.
A number of clinical syndromes are recognized in glomerular diseases. The most important of them are: nephritic syndrome,
nephrotic syndrome and acute or chronic renal failure.
Nephritic and nephrotic syndrome
Nephritic syndrome is the acute onset of hematuria, proteinuria, hypertension, edema and oliguria following an infectious
disease about 10 to 20 days earlier.
* The hematuria is detectable by microscopy or by chemical testing for hemoglobin. RBC casts are also present.
* The proteinuria is less than 3 gm per 24 hrs.
* Hypertension is variable depending upon the severity of the glomerular disease but is generally mild.
* Edema in nephritic syndrome is usually mild and results from sodium and water retention.
* Oliguria is variable and reflects the severity of glomerular involvement.
Nephrotic syndrome is not a specific glomerular disease but a combination of clinical ?ndings that result from increased
glomerular permeability to the plasma proteins. It is characterized by:
Severe proteinuria (protein loss of more than 3 gm per 24 hrs) is the chief characteristic of nephrotic syndrome. In nephrotic
syndrome, proteinuria mostly consists of loss of albumin in urine.
Hypoalbuminemia is produced primarily consequent to urinary loss of albumin, and partly due to increased renal catabolism and
inadequate hepatic synthesis of albumin. The concentration of other proteins in plasma such as immunoglobulins, clotting factors
and antithrombin may fall rendering these patients more vulnerable to infections and thrombotic and thromboembolic
complications.
Edema in nephrotic syndrome appears due to the fall in oncotic pressure consequent upon hypoalbuminemia. Sodium and water
retention further contribute to edema. Nephrotic edema is usually peripheral.
Hyperlipidemia is a frequent accompaniment of nephrotic syndrome. The exact mechanism of its genesis is not clear. It is
hypothesized that the liver faced with the stress of massive protein synthesis in response to heavy urinary protein loss, also causes
the increased synthesis of lipoproteins. There are increased blood levels of total lipids, cholesterol, triglycerides, VLDL and LDL
but decrease in HDL. Low blood level of HDL is partly due to its loss in urine.
Lipiduria occurs following hyperlipidemia due to excessive leakiness of glomerular filtration barrier.
Hypercoagulability occurs due to increased urinary loss of antithrombin, hyperfibrinogenemia – due to increased synthesis in the
liver, decreased fibrinolysis, increased platelet aggregation.
Acute renal failure
Renal failure is a syndrome caused by severe violations of kidneys functions. Acute renal failure is a rapid loss of renal function
due to damage to the kidneys, resulting in diuresis disturbances and retention of nitrogenous (urea and creatinine) and non-
nitrogenous waste products that are normally excreted by the kidney.
The causes of renal failure may be classified as:
Prerenal (decrease in the blood supply):
* hypotension, usually from shock (cardiac failure, myocardial infarction) or dehydration and fluid loss (bleeding, vomiting,
diarrhea, uncontrolled reception of diuretics);
* hepatorenal syndrome in which renal perfusion is compromised in liver failure;
* increased blood hemolysis (transfusion of incompatible blood, sickle cell crisis) in addition the hemoglobin may damage the
tubules;
* massive necrosis of tissue (gangrene, crush syndrome).
Renal (damage to the kidney itself):
* infection, usually sepsis (systemic inflammation due to infection), rarely of the kidney itself, termed pyelonephritis;
* toxins or medication (e.g. some NSAIDs, aminoglycoside antibiotics, iodinated contrast, lithium);
* acute glomerulonephritis;
* severe hypoperfusion or pathology of renal vessels (thrombosis and embolism), resulting in kidney ischemia and necrosis.
Post-renal (obstructive causes) due to obstruction in:
* ureter (i.e., calculi and strictures);
* bladder (i.e., tumors);
* urethra (i.e., prostatic hypertrophy);
* due to abdominal malignancy (e.g. ovarian cancer, colorectal cancer) which also may impair urine flow.
Acute renal failure typically progresses through 3 stages or phases.
1. Oliguric phase. The initial oliguric phase lasting on an average from 7 to 10 days is characterized by urinary output of less
than 400 ml per day. The decline in formation of urine leads to accumulation of waste products of protein metabolism in blood
and resultant azotemia, metabolic acidosis, hyperkalemia, hypernatremia and hypervolemia due to secondary effects of
circulatory overload and pulmonary edema. The specific gravity of urine is low but the concentration of sodium in urine tends to
be elevated.
 2. Diuretic phase. With the onset of healing of tubules, there is an improvement in urinary output. This is believed to occur due
to drawing of water and sodium by preceding high levels of creatinine and urea as they move through the nephron so as to be
excreted. Since tubular cells have not regained normal functional na?anity, urine is of low or fixed specific gravity.
3. Phase of recovery. Full recovery with healing of tubular epithelial cells occurs in about half the cases, while others terminate
in death. The process of healing may take up to one year with restoration of normal tubular function.
Chronic renal failure
Chronic renal failure is a slowly progressive loss of renal function over a period of months or years and defined as an abnormally
low glomerular filtration rate, which is usually determined indirectly by the creatinine level in blood serum. Creatinine, a by-
product of muscle metabolism, is freely filtered in the glomerulus and is not reabsorbed in the renal tubules. Creatinine is
produced at a relatively constant rate, and any creatinine that is filtered in the glomerulus is lost in urine rather than being
reabsorbed into blood. Thus, serum creatinine can be used as an indirect method for assessing the GFR and the extent of renal
damage that has occurred in renal failure
The diseases leading to chronic renal failure can generally be classified into two major groups:
1. Those causing glomerular pathology:
Primary glomerular pathology – chronic glomerulonephritis,
Secondary glomerular pathology – resulting from systemic lupus erythematosus, serum sickness nephritis, diabetic nephropathy,
etc.
2. Those causing tubulointerstitial pathology:
* Vascular causes: long-standing primary or essential hypertension produces characteristic changes in renal arteries and arterioles
referred to as nephrosclerosis.
* Infectious causes - chronic pyelonephritis.
* Toxic causes: intake of high doses of analgesics such as analgin, aspirin and other (chronic analgesic nephritis). Other
substances that can cause CRF after prolonged exposure are lead, cadmium and uranium.
* Obstructive causes: chronic obstruction in the urinary tract leads to progressive damage to the nephron due to fluid back-
pressure (kidney stones, blood clots, tumors, strictures and enlarged prostate).
Chronic renal failure progressively passes through 4 stages:
1. Decreased renal reserve. At this stage damage to renal parenchyma is marginal and the kidneys remain functional. The normal
level of GFR varies with age, sex, and body size. The normal GFR for young healthy adults is approximately 120 to 130
ml/minute. When renal reserve is diminished, GFR decreases about 50% of normal, blood urea nitrogen (BUN) and creatinine
level are normal.
2. Renal insufficiency represents a reduction in the GFR to 20% to 50% of normal. It is observed when more than 50% of
functional renal parenchyma has been destroyed. As nephrons are destroyed, the remaining nephrons undergo changes to
compensate for those that are lost. In this process, each of the remaining nephrons must ?lter more solute particles from blood.
Because the solute particles are osmotically active, they cause additional water to be lost in urine. One of the earliest symptoms
of renal insufficiency is isosthenuria, or polyuria with urine that is almost isotonic with plasma. During this stage azotemia,
anemia, and hypertension also begin to appear.
3. Renal failure. Renal failure develops when the GFR is less than 20% of normal. At this point, the kidneys cannot regulate
volume and solute composition, and edema, metabolic acidosis, and hyperkalemia develop. Overt uremia may ensue with
neurologic, gastrointestinal, and cardiovascular manifestations.
4. End-stage kidney. GFR is less than 5%. Complex clinical picture of uremic syndrome is observed in a patient.
Uremia syndrome
Primary uraemic (renal) manifestations
Uremia, which literally means “urine in blood,” is the term used to describe the clinical manifestations of renal failure. Few
symptoms of uremia appear until at least two thirds of the nephrons have been destroyed. The signs of intoxication by urea
appear as its concentration rises 200-300 mg/100 ml. Uremia differs from azotemia, which simply indicates the accumulation of
nitrogenous wastes in blood and can occur without symptoms. The uremic state includes signs and symptoms of altered body
metabolism and alterations in virtually every organ and structure in the body. The symptoms at the onset of uremia
(e.g.,weakness, fatigue, nausea, apathy) often are subtle. More severe symptoms include extreme weakness, frequent vomiting,
fatigability, headache, skin itch, violation of sleep, hypothermia, decrease of tolerance to glucose, bleeding sickness etc. Without
treatment, coma and death follow.
The accumulation of nitrogenous wastes is an early sign of renal failure, usually occurring before other symptoms become
evident. Urea is one of the ?rst nitrogenous wastes to accumulate in blood, and the BUN level becomes increasingly elevated as
renal failure progresses.
Metabolic acidosis. As a result of renal dysfunction, acid-base balance is progressively lost. Excess of hydrogen ions occurs,
while bicarbonate level declines in blood, resulting in metabolic acidosis. The clinical symptoms of metabolic acidosis include
compensatory Kussmaul breathing, hyperkalemia and hypercalcemia.
Hyperkalemia. A decreased GFR results in excessive accumulation of potassium in blood since potassium is normally excreted
mainly in urine. Hyperkalemia is further worsened by metabolic acidosis. Excess of K ions in blood plasma impairs the function
of muscles and neuro-muscular transmission. The clinical features of hyperkalemia are cardiac arrhythmias, weakness, nausea,
intestinal colic, diarrhea, muscular irritability and flaccid paralysis.
 Sodium and water imbalance. As GFR declines, Na and water cannot pass sufficiently into Bowman's capsule leading to their
retention. Release of renin from juxtaglomerular cells further aggravates this process. The main symptoms referable to Na and
water retention are hypervolemia and circulatory overload with congestive heart failure.
Hyperuricemia. Decreased GFR results in excessive accumulation of uric acid in blood. Uric acid crystals may be deposited in
joints and soft tissues resulting in gout.
Extra-renal manifestations
Uremia results in many different compounds being retained by the body. With the failure of the kidneys, these compounds can
build up to dangerous levels. The most toxic compounds are urea, creatinine, cyanate, polyols and phenols. Circulating toxins
may impair function practically of all body tissues and organs.
Chronic anemia is the most profound hematologic alteration that accompanies renal failure. Anemia ?rst appears when the GFR
falls below 40 ml/minute, and is present in most persons with end stage renal disease. It develops due to the following causes:
* Decrease of erythropoietin production in the kidneys;
* Shortened period of erythrocytes’ life;
* Depression of hemopoiesis due to waste products retention;
* Disturbance of platelets’ function leads to intestinal bleeding;
* Systematic bleeding during hemodialysis.
Particular features of renal disease anemia: it is normocytic and hyporegenerative (reticulocytes are decreased). WBC count may
be normal.
Bleeding disorders are manifested by epistaxis, menorrhagia, bleedings from GIT and bruising of the skin and subcutaneous
tissues. Although platelet production is often normal, platelet function is impaired.
Hypertension is commonly an early manifestation of chronic renal failure. The mechanisms that produce hypertension are
multifactorial; they include an increased vascular volume, elevation of peripheral vascular resistance, decreased levels of renal
vasodilator prostaglandins, and increased activity of the renin-angiotensin system.
Heart disease. Fluid retention and hypervolemia result in increased workload on the heart which secondarily causes
cardiovascular symptoms. The spectrum of cardiovascular disease in CRF includes left ventricular hypertrophy and ischemic
heart disease. Congestive heart failure and pulmonary edema tend to occur at the late stages of renal failure.
Respiratory system. Hypervolemia and heart failure cause pulmonary congestion and pulmonary edema due to back pressure.
Radiologically, uraemic lung shows a characteristic central, butterfly-pattern of edema and congestion in the chest radiograph.
Gastrointestinal disorders. Anorexia, nausea, and vomiting are common in patients with uremia, along with a metallic taste in the
mouth that further depresses the appetite. A possible cause of nausea and vomiting is the decomposition of urea by intestinal ?ora,
resulting in a high concentration of ammonia. Azotemia directly induces mucosal ulcerations in the lining of the stomach and
intestines. Subsequent bleeding can aggravate the existing anemia.
Skeletal disorders. The term renal osteodystrophy is used to describe the skeletal complications of the end stage of renal disease.
Several factors are thought to contribute to the development of renal osteodystrophy, including elevated serum phosphate levels,
decreased serum calcium levels, impaired renal activation of vitamin D, and hyperparathyroidism. Secondary
hyperparathyroidism of variable severity is observed in the majority of the patient with CRF.
Uremic encephalopathy may accompany any form of severe acute or chronic renal failure. In many cases, impairment of the
nervous system provides the first indication of metabolic derangements. The clinical features include loss of memory, impaired
concentration, depression, delusions, lethargy, irritability, fatigue, insomnia, psychosis, stupor, catatonia, and coma. Patients may
complain of slurred speech, pruritus, muscle twitches, or restless legs.
Peripheral neuropathy affects the lower limbs more frequently than the upper limbs. It is symmetric and affects both sensory and
motor function. Neuropathy is caused by atrophy and demyelination of nerve ?bers, possibly caused by uremic toxins.
Disorders of immune system. Infection is a common complication and cause of hospitalization and death of patients with chronic
renal failure. Immunologic abnormalities decrease the ef?ciency of the immune response to infection. All aspects of in?ammation
and immune function may be affected adversely by the high levels of urea and metabolic wastes, including a decrease in
granulocyte count, impaired humoral and cell-mediated immunity, and defective phagocyte function.
Skin manifestations are common in persons with renal failure. The skin often is pale owing to anemia and may have a sallow,
yellow-brown hue. The skin and mucous membranes often are dry, and subcutaneous bruising is common. Skin dryness is caused
by a reduction in perspiration owing to the decreased size of sweat glands and the diminished activity of oil glands. Pruritus is
common; it results from the high serum phosphate levels and the development of phosphate crystals that occur with
hyperparathyroidism. At advanced stages of untreated renal failure, urea crystals may precipitate on the skin as a result of the
high urea concentration in body fluids.
UNIT 25
ENDOCRINE SYSTEM PATHOLOGY
General mechanisms of endocrine system functions disturbances
Disturbances of endocrine function can be divided into two categories: hypofunction and hyperfunction.
Hypofunction of an endocrine gland can occur for a variety of reasons. Congenital defects can result in the absence or impaired
development of the gland or in the absence of an enzyme needed for hormone synthesis.
The example of congenital endocrine disorder is cretinism. It is usually caused by failure of embryonic development of the
thyroid gland, but in some cases it may result from inborn enzymatic defects in the synthesis of thyroxine. The severity of the
disorder depends on the amount of thyroid tissue present. There are no sign of disorder in newborns due to the presence of
thyroid hormone supplied by the maternal circulation. Mental retardation and delayed growth can be observed after 3-6 month of
life.
The gland may be destroyed by a
* disruption in blood flow – acute ischemia of the adrenals due to thromboembolism, trauma or bilateral adrenal hemorrhage
results in acute adrenal insufficiency;
* infection with the subsequent inflammation (tuberculosis of the adrenals can cause Addison disease – deficiency of
glucocorticoids and mineralocorticoids;
* autoimmune destruction (80-90% cases of DM type 1 development). Viral infection can cause the alteration of self-antigens on
the beta cells of the pancreas that will initiate synthesis of IgM and IgG against pancreatic beta cell. The mechanism of
destruction is provided with the type 2 allergic reaction (cytotoxic);
* neoplastic growth (non-endocrine tumors or growth of leukemia metastases) Tumor or its metastases will damage normal
endocrine tissue and displace it.
There may be also a decline in function with aging, or the gland may atrophy as a result of drug therapy or for unknown reasons.
Other group of endocrine gland hypofunction includes the reasons arising outside the gland:
* understimulation by the pituitary gland. which normally stimulates the function of thyroid gland, adrenals and genital glands;
* deficiency of substances needed for hormone synthesis (hypofunction of thyroid gland which occurs in alimentary lack of
iodine and clinically manifests as goiter);
* depression of hormones secretion by drugs or alimentary components (rodanides and cyanides of some vegetables - marrows,
manioc and tapioca can cause anti-thyroids influence);
* the antibodies to circulating hormones may be also present (antibodies to vasopressin in diabetes insipidus). In this case
vasopressin is secreted in normal amounts, but it is destroyed with the antibodies;
* several hormones require conversion to an active form after secretion from the peripheral endocrine gland. Certain disorders
can block this step (e.g., renal disease can inhibit production of the active form of vitamin D).
Some endocrine-deficient states are associated with receptor defects:
* hormone receptors may be absent or defective due to congenital reasons (congenital resistance to cortisol);
* defect of hormone receptors may be acquired – type 2 diabetes mellitus – insulin amount is normal but insulin resistance is
present (the structure of insulin receptor is damaged in the presence of high level of triglycerides and lipids in circulation);
* antibodies to hormone receptor;
* cellular responsiveness to the hormone may be impaired (if target cells are atrophied or damaged – glucagon which normally
increases blood glucose level in the case of severe liver failure will not produce this effect).
A decrease in hormone production by the peripheral endocrine gland with a resulting increase in production of pituitary
regulating hormone can lead to peripheral endocrine gland hyperplasia due to physiological negative feedback. For example, if
synthesis of thyroid hormone is inadequate, thyroid-stimulating hormone (TSH) is produced in excessive amounts, causing goiter.
Hyperfunction of endocrine glands may result from:
* overstimulation by the pituitary;
* hyperplasia or neoplasia of the gland itself (acromegaly – pituitary somatotrope adenoma, Cushing disease – neoplastic growth
of ACTH-producing cells;
* antibodies can stimulate peripheral endocrine glands, as occurs in hyperthyroidism of Graves' disease;
* destruction of a peripheral endocrine gland can rapidly release stored hormone (e.g., thyroid hormones in acute thyroiditis) but
this increase is transient and later the level of hormone will decrease.
* an ectopic tumor can produce hormones – certain bronchogenic tumors produce hormones ADH and ACTH – this effect is
explain by the anaplasia of malignant tumor cells;
* hormone excess can result from exogenous hormone administration. In some cases, patients take hormones without telling the
physician (factitious disease).
General principles of treatment
Hypofunction disorders are usually treated by replacement of the peripheral endocrine hormone regardless of whether the defect
is primary or secondary. If resistance to the hormone exists, drugs that reduce resistance can be used. Occasionally, a hormone-
stimulating drug is used.
Radiation therapy, surgery, and drugs that suppress hormone production are used to treat hyperfunction disorders. In some cases,
a receptor antagonist is used.
From another point of view, endocrine disorders in general can be divided into primary, secondary, and tertiary groups. Primary
defects in endocrine function originate in the target gland responsible for producing the hormone. In secondary disorders of
endocrine function, the target gland is essentially normal, but its function is altered by defective levels of stimulating hormones or
releasing factors from the pituitary system. For example, adrenalectomy produces a primary deficiency of adrenal corticosteroid
hormones. Removal or destruction of the pituitary gland eliminates ACTH stimulation of the adrenal cortex and brings about a
secondary deficiency. A tertiary disorder results from hypothalamic dysfunction (as may occur with craniopharyngiomas or
cerebral irradiation); thus, both the pituitary and target organ are understimulated.
Anterior pituitary lobe disorders
Hyposecretion of anterior pituitary may be generalized (panhypopituitarism) or caused by the selective loss of one or more
pituitary hormones. It occurs as a result of pituitary gland affection by the tumor, hemorrhage or trauma which reduces or
destroys its function.
* Tumors and mass lesions – pituitary adenomas, metastatic cancer;
 * Pituitary surgery or irradiation;
* Pituitary infarction – infarction of the pituitary gland after substantial blood loss during childbirth (Sheehan’s syndrome);
* Pituitary apoplexy—sudden hemorrhage into the pituitary gland.
The loss of hormones production is usually gradual. Clinical presentation of hypopituitarism depends on certain hormone
deficiency:
Thyrotropin deficiency leads to secondary hypothyroidism. Corticotropin deficiency causes adrenal insufficiency; symptoms of
weakness, hypoglycemia, weight loss, suggest the diagnosis. Gonadotropin deficiency: luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) leads to different symptoms in men and women. Women experience oligo- or amenorrhea
(infrequent/light or absent menstrual periods respectively) and infertility. Men lose facial and trunk hair, they may have decreased
muscle mass and anemia. Both sexes may experience a decrease in libido and loss of sexual function, and have an increased risk
of osteoporosis (bone fragility). Lack of LH/FSH in children is associated with delayed puberty. Prolactin deficiency may result
in the inability of lactation after delivery.
Growth hormone (GH) deficiency causes growth retardation and short stature in children – pituitary dwarfism. Persons with
classic GH deficiency have normal intelligence, short stature, obesity with immature facial features and some delay in skeletal
maturation. Puberty often is delayed. GH level normally decreases with aging. The symptoms of GH deficiency may be absent. In
some cases its deficiency in adults may result in the altered body composition due to loss of GH lipolytic and homeostatic
activity. This results in central obesity and reduced muscle mass. Exercise capacity is reduced, and quality of life is impaired. The
plasma lipid profile is unfavorable (hypertriglyceridemia and low levels of high density lipoprotein) cardiovascular morbidity
may be increased.
Panhypopituitarism is a condition of inadequate or absent production of the most of anterior pituitary hormones. Clinical
manifestation includes the symptoms of different hormones deficiencies. Typically, 70 to 90% of the anterior pituitary must be
destroyed before hypopituitarism becomes clinically evident. It may vary from minimal clinical manifestation including fasting
hypoglycemia and decreased stress resistance (due to low levels of ACTH) to severe form with affection of many endocrine
glands. Simmonds’ syndrome and Sheehan’s syndrome are the clinical forms of panhypopituitarism.
Sheehan's Syndrome, also known as postpartum pituitary necrosis, is a rare syndrome that occurs most commonly in the third
trimester of pregnancy when the anterior pituitary suffers ischemic necrosis precipitated by obstetrical hemorrhage or shock. The
syndrome can occur in men and non-pregnant women associated with DIC or trauma. Pregnant women are more susceptible due
to the pituitary enlargement that occurs in pregnancy. Disease usually manifests early with inability to lactate but it can also
present years later with multiple hormone deficiencies.
Hypersecretion of anterior pituitary (hyperpituitarism)
The anterior pituitary hormones that are most commonly secreted in excess are GH (as in acromegaly, gigantism), ACTH and
prolactin (which clinically manifests with galactorrhea),
Gigantism and Acromegaly are the syndromes of excessive secretion of GH nearly always due to a pituitary adenoma.
Rarely, GH hypersecretion begins in childhood, before closure of the epiphyses, and leads to the exaggerated skeletal growth
termed pituitary gigantism. In children, growth velocity is increased but with little bony deformity. However, soft tissue swelling
occurs and the peripheral nerves are enlarged. Sometimes tall stature in children may be not a result of GH hypersecretion, but a
result of prolongated growth period. Therefore many causes of delayed puberty or hypogonadotropic hypogonadism are
accompanied with tall stature. When GH hypersecretion begins after epiphyseal closure, the earliest clinical manifestation is
coarsening of the facial features and soft tissue swelling of the hands and feet. The patient's appearance changes, and larger rings,
gloves, and shoes are needed. Previous photos of the patient may help you to define disease. The increase in proportions of the
acral parts (belonging to the extremities or peripheral body parts) has led to the term acromegaly. The most common reason of
acromegaly is somatotrope adenoma. It affects men as frequently as women.
In adults with acromegaly, other changes also occur. Coarse body hair increases, and the skin thickens and frequently darkens.
The size and function of sebaceous and sweat glands increase, such that patients frequently complain of excessive perspiration
and an offensive body odor. Overgrowth of the mandible leads to protrusion of the jaw (prognathism) and malocclusion of teeth.
Cartilaginous proliferation of the larynx leads to a deep, husky voice. The tongue is frequently enlarged. In long-standing
acromegaly, costal growth leads to a barrel chest. Articular cartilaginous proliferation occurs early in response to GH excess, with
the articular cartilage possibly undergoing necrosis and erosion. Joint symptoms are common, and degenerative arthritis may
occur. The heart, liver, kidneys, spleen, thyroid, parathyroid glands, and pancreas are also larger than normal. GH increases
tubular reabsorption of phosphate and leads to mild hyperphosphatemia.
Acromegaly is also associated with the metabolic disturbances. The level of GH and its main mediator insulin-like growth (IGF-
1) is increased. IGF-1 is synthesized by many body cells, mainly by liver macrophages – it mediates all metabolic and growth
effects of GH. GH itself causes acute contrinsular effects: decrease synthesis of lipids in adipocytes, increase lipolysis and free
fatty acids level in blood plasma, decrease synthesis of glycogen in hepatocytes, and increase blood glucose level. Increased
blood glucose level, decreased tolerance to carbohydrates is observed in about half of the patients, resistance to insulin and
diabetes mellitus in about 10 -25% of cases.
IGF-1 may cause the hyperplasia of thyroid gland with the clinics of hyperthyroidism. Cardiovascular system is also affected:
hypertension, cardiomegaly and congestive type of left-sided heart failure is observed
Galactorrhea is lactation in men, or in women who are not breastfeeding an infant. Amenorrhea is commonly associated with
galactorrhea in women. Men with prolactin-secreting pituitary tumors typically complain of headaches or visual difficulties.
Increased prolactin level leads to lowered LH and FSH levels and to hypogonadism.
 ACTH excess results in Cushing's disease. Cushing's disease occurs due to an ACTH-secreting pituitary adenoma. High ACTH
levels cause overproduction of cortisol and subsequent bilateral adrenal hyperplasia. Clinically, the patients have all the features
of Cushing’s syndrome, which includes: central obesity, moon face, buffalo hump, muscle weakness and glucose intolerance.
Cushing's disease also causes skin hyperpigmentation due to melanocyte stimulation by ACTH (a close relative of melanocyte-
stimulating hormone).
The difference between Cushing’s disease and Cushing’s syndrome
Cushing’s diseaseCushing’s syndromeCortisol levelhighhighACTH levelhighlowAdrenal glandsbilateral hyperplasiaadrenal
tumorAnterior pituitaryadenoma, increased size of sella turcicanormal appearing
Posterior pituitary lobe disorders
Hormones secreted by the posterior pituitary are antidiuretic hormone (ADH) and oxytocin. Clinical manifestation of oxytocin
excess or hyposecretion is not described.
ADH deficiency causes diabetes insipidus and ADH excess causes syndrome of inappropriate ADH.
Diabetes insipidus (DI) is a disease characterized by excretion of large amounts of severely diluted urine, which cannot be
reduced when fluid intake is reduced. It denotes inability of the kidney to concentrate urine. DI is divided into: central DI which
is caused by a deficiency of ADH secretion due to pituitary trauma, stroke or infection, and nephrogenic DI due to the inability of
the kidney to respond normally to ADH which may occur as a hereditary or acquired defect (medications effect, polycystic
kidney). The only symptoms in primary DI are polydipsia and polyuria. Enormous quantities of fluid may be ingested, and large
volumes (3 to 30 L/day) of very diluted urine are excreted. Nocturia is almost always present in DI. Dehydration and
hypovolemia may develop rapidly if urinary losses are not continuously replaced. Symptoms of diabetes insipidus are quite
similar to those of untreated diabetes mellitus, with the distinction that urine is free of glucose and there is no hyperglycemia.
Syndrome of inappropriate ADH or ADH excess results in decreased excretion of free water. The most common cause is
production of ectopic ADH or ADH-like substance by neoplasms, particularly lung cancers. Clinical manifestation consists of
hyponatremia, inappropriately elevated urine osmolarity, excessive urine sodium concentration, and decreased serum osmolarity.
Blood circulating volume in such patient is usually normal, signs of edema are absent. Blood sodium level is decreased: this case
of hyponatremia is a result of water excess (not a serum sodium deficiency).
Disturbances of thyroid gland function
Thyroid hormone (TH) interacts with nuclei of cells by binding to nuclear receptors and mitochondrial receptors with resulting
increase of ATP. TH is essential for adequate fetal growth and development of neural and skeletal systems. TH level determines
BMR regulation and O2 consumption. TH is known to separate processes of oxidation and phosporilation which results in
increased heat production. TH causes sympathetic effect on myocardium and marked chrono- and inotropic effects. TH also
causes drive of CNS respiratory centers and increased erythropoiesis.
Goiter is an increase in the size of the thyroid gland. It can occur in hypothyroid, euthyroid, and hyperthyroid states. Goiters may
be diffuse, involving the entire gland without evidence of nodularity, or they may contain nodules. Goiters may be toxic,
producing signs of extreme hyperthyroidism, or thyrotoxicosis, or they may be nontoxic. Diffuse nontoxic and multinodular
goiters are the result of compensatory hypertrophy and hyperplasia of follicular epithelium from some derangement that impairs
thyroid hormone output. The degree of thyroid enlargement usually is proportional to the extent and duration of thyroid
deficiency. When sufficiently enlarged, they may compress the esophagus and trachea, causing difficulty in swallowing, a
choking sensation, and inspiratory stridor. Such lesions also may compress the superior vena cava, producing distention of the
veins of the neck and upper extremities, edema of the eyelids and conjunctiva, and syncope with coughing.
Hypothyroidism
Congenital hypothyroidism. Hypothyroidism in a infant may result from a congenital lack of the thyroid gland or from abnormal
biosynthesis of thyroid hormone or deficient TSH secretion. With congenital lack of the thyroid gland, the infant usually appears
normal and functions normally at birth because hormones have been supplied in utero by the mother. The manifestations of
untreated congenital hypothyroidism are referred to as cretinism. Thyroid hormone is essential for normal brain development and
growth, almost half of which occurs during the first 6 months of life. If untreated, congenital hypothyroidism causes mental
retardation and impairs growth.
Hypothyroidism in older children and adults causes a general slowing down of metabolic processes and myxedema. Myxedema
implies the presence of an edema caused by an accumulation of a hydrophilic mucopolysaccharide substance in the connective
tissues throughout the body. The hypothyroid state can result from destruction or dysfunction of the thyroid gland (i.e., primary
hypothyroidism), or it can be a secondary disorder caused by impaired pituitary function or a tertiary disorder caused by a
hypothalamic dysfunction.
Primary hypothyroidism is much more common than secondary and tertiary hypothyroidism. It may result from thyroidectomy
(i.e., surgical removal) or ablation of the gland with radiation. Iodine deficiency can cause goiter and hypothyroidism, too. The
most common cause of hypothyroidism is Hashimoto’s thyroiditis, an autoimmune disorder in which the thyroid gland may be
totally destroyed by an immunologic process.
Hypothyroidism affects almost all organ systems in the body. The manifestations of the disorder are related largely to two
factors: the hypometabolic state resulting from thyroid hormone deficiency, and myxedematous involvement of body tissues.
Although the myxedema is most obvious on the face and other superficial parts, it also affects many of the body organs and is
responsible for many of the manifestations of the hypothyroid state. The hypometabolic state associated with hypothyroidism is
characterized by a gradual onset of weakness and fatigue, a tendency to gain weight despite a loss of appetite, and cold
intolerance. As the condition progresses, the skin becomes dry and rough and acquires a pale yellowish cast, which primarily
results from carotene deposition, and the hair becomes coarse and brittle. Gastrointestinal motility is decreased, producing
constipation, flatulence, and abdominal distention. Nervous system involvement is manifested in mental dullness, lethargy, and
impaired memory.
As a result of myxedematous fluid accumulation, the face takes on a characteristic puffy look, especially around the eyes. The
tongue is enlarged, and the voice is hoarse and husky. Myxedematous fluid can collect in the interstitial spaces of almost any
organ system. Pericardial or pleural effusion may develop. Mucopolysaccharide deposits in the heart cause generalized cardiac
dilatation, bradycardia, and other signs of altered cardiac function.
Hyperthyroidism
Thyrotoxicosis is the clinical syndrome that occurs when tissues are exposed to high levels of circulating thyroid hormone. In
most instances, thyrotoxicosis is due to hyperactivity of the thyroid gland, or hyperthyroidism. The most common cause of
hyperthyroidism is Graves’ disease.
Graves’ disease is a state of hyperthyroidism, goiter, and ophthalmopathy (or, less commonly, dermopathy). The onset usually is
between the ages of 20 and 40 years, and women are five times more likely to develop the disease than men. Graves’ disease is an
autoimmune disorder characterized by abnormal stimulation of the thyroid gland by thyroid-stimulating antibodies (thyroid-
stimulating immunoglobulins) that act through the normal TSH receptors. It may be associated with other autoimmune disorders
such as myasthenia gravis and pernicious anemia.
Manifestations of hyperthyroidism are associated with increased tissue metabolic activity – hypermetabolic state and apparent
increased tissue sensitivity to catecholamines.
BMR in these patients is increased. Along with this thyroid hormones separate the processes of oxidation and phosphorilation in
mitochondria that results in increased aerobic glycolysis and heat production. Such alteration results in heat intolerance.
Excess of thyroid hormones alters the equilibrium between the sympathetic and parasympathetic regulation: sympathetic
influences prevail. It explains the exophthalmia – muscles moving eyes are constricted under the sympathetic influences and eye
is “pushed out” from orbital tissues. If the patient remains untreated for a long time retrobulbar fat tissue undergoes hyperplasia
and the eye can’t return to its normal position. Prevailing of sympathetic effects can also explain such symptoms as warm and
moist skin due to increased perspiration, increased gases turnover in the lungs and dyspnea, increased GIT motility and diarrhea.
The excess of thyroid hormones causes alterations in adrenal function – cortisol metabolism is increased and ACTH production
is increased too. In the early stages it results in high function of the adrenal gland later their exhaustion develops.
The influence of thyroid hormones on the heart increases its sensitivity to catecholamines and produces positive chronotropic
effect (tachycardia) and increase of stroke volume that determines hypertension. This hypertension is accompanied by widening
of the pulse pressure due to constriction of arterioles and decrease of microcirculatory blood volume. Increased myocardial
demand for the oxygen and disturbed energy metabolism in cardiomyocytes results in heart failure. This type of heart failure is
characterized by increased minute blood volume.
Increased glycogenolysis and lypolysis lead to significant weight loss in these patients despite increased appetite.
CNS affection manifests as high excitability, nervousness, agitation, emotional lability and insomnia. The typical symptom of
thyroid hormones excess is tremor of the muscles, their weakness and low resistance to physical loading.
Pathology of parathyroid glands
Parathyroid hormone (PTH) acts to increase the concentration of calcium in the blood by acting upon its receptor in three parts
of the body:
* it enhances the release of calcium from the bones;
* it enhances reabsorption of calcium from distal tubules of kidneys;
* it enhances the absorption of calcium in the intestine by increasing the production of vitamin D in intestines.
Hypoparathyroidism is an inadequate secretion of PTH or ineffective hormone influence, resulting in hypocalcemia and
hyperphosphatemia. There are such reasons of hypoparathyroidism:
* Postsurgical (thyroid or parathyroid surgery) up to 10%;
* Autoimmune – antibodies production to the parathyroid gland can be isolated or associated with a variety of polyglandular
syndromes;
* DiGeorge syndrome – a primary congenital defect resulting in thymus and parathyroid gland hypoplasia.
Increased neuromuscular irritability, arising from hypocalcemia, is the hallmark of the condition. These features can range from
mild-to-moderate paresthesias (unpleasant tingling sensation) of the extremities or lips to painful muscle cramps and twitching or
tetany (involuntary muscle contraction). In severe cases, tetany can result in carpopedal spasm, laryngospasm, or generalized
seizures.
Additionally, severe hypocalcemia can result in neurologic symptoms which include mental depression, s fatigue, headaches, and
insomnia. Cardiovascular abnormalities manifest as Q-T and S-T prolonged intervals because hypocalcemia disturbs the
processes of myocardial repolarization.
Hyperparathyroidism is caused by excess secretion of PTH.
Primary hyperparathyroidism is usually a result of adenoma development in a single parathyroid gland.
Secondary hyperparathyroidism occurs when the parathyroid glands are chronically stimulated to release parathyroid hormone. A
decrease in circulating calcium is the stimulus for this release. The following clinical conditions are involved:
* Chronic renal failure (main cause). Failing kidneys do not convert enough vitamin D to its active form, and they do not
adequately excrete phosphate. In the absence of vitamin D the processes of bones calfication are disturbed. When this happens,
insoluble calcium phosphate forms in the body and removes calcium from the circulation. Both processes lead to hypocalcemia
and hence secondary hyperparathyroidism;
* Other causes of vitamin D deficiency (rickets, intestinal malabsorption, lack of UV rays).
 In these cases, the elevation of PTH is the appropriate response. Hyperplasia of chief parathyroid cells ensues. If the cause of
hyperparathyroidism is removed, tissues may revert to normal state.
In cases of hyperparathyroidism increased PTH consequently leads to increased serum calcium (hypercalcemia) due to:
* increased bone resorption, allowing flow of Ca from bone to blood;
* reduced renal clearance of calcium and decreased renal tubular phosphorus reabsorption;
* increased intestinal calcium absorption.
First of all the presence of high level of PTH results in osteodystrophy due to increased activity of osteoclasts and decreased
activity of osteoblasts. Clinically it manifests with pain in bones and joint, softening of the bones (osteomalacia) and bones
deformities development.
Since calcium is responsible for the electrical conduction within our nervous system, high blood calcium levels have a direct
effect on the nervous system. Thus, most of the symptoms of parathyroid disease are "neurologic" in origin. The most common
symptom is fatigue and tiredness. Other very common symptoms are lack of energy, memory problems, depression, problems
with concentration, and problems with sleeping. Other manifestations of hyperparathyroidism usually involve nephrolitiasis,
headaches, gastroesophageal reflux, thinning hair, hypertension, and heart palpitations which are often due to attacks of atrial
fibrilation.
Metastatic calcification of soft tissues is also observed. Laboratory analysis reveal elevated PTH, hypercalcemia,
hypophosphatemia, hypercalciuria.
Hypofunction of adrenal cortex
The adrenal cortex produces corticosteroids, which are produce in distinct zones of adrenal cortex and are classified according to
their effects:
* mineralocorticoids produced in zona glomerulosa (aldosteron, deoxycorticosterone) regulate BP and electrolyte balance;
* glucocorticoids produced in zona fasciculate (mainly cortisol, less corticosteron, cortisone) regulate carbohydrate and lipid
metabolism, suppress immune system;
* androgens produced in zona reticularis (dehydroepiandrosterone) are converted to fully functional sex hormones in the gonads.
Adrenal cortical hypofunction may be partial (deficiency of a single hormone) or total; primary (Addison's disease) or secondary
(due to damage of ACTH-producing cells or when durable treatment with corticosteroids is stopped.
The majority of Addison's disease cases are due to idiopathic atrophy of the adrenal cortex probably caused by autoimmune
processes. The other reasons are tuberculosis of adrenals, tumors, amyloidosis, sarcoidosis, metastatic disease, surgical ablation
or inflammatory necrosis. Symptoms of Addison's disease usually appear when there are less than 10% of functioning cells, and
tends to become clinically apparent during metabolic stress or trauma.
Mineralocorticoid (aldosteron) deficiency results in increased excretion of Na and chlorides accompanied by retention of K.
Hyperkalemia results in severe arrhythmias. Inability to concentrate urine produces severe dehydration, plasma hypertonicity,
acidosis, decreased circulatory volume, hypotension.
Cortisol deficiency contributes to hypotension which is observed in 90% of the patients by decreasing the sensitivity of blood
vessels to catecholamines. Orthostatic collapse is often observed in these patients.
Carbohydrate metabolism is characterized with frequent spontaneous hypoglycemic states. The amount of glycogen in liver and
in muscles is significantly decreased – it explains muscular weakness in the patients. Cortisol deficiency results in decrease of
protein synthesis in the liver with subsequent hypoproteinemia. The decrease of anabolic processes in the muscles which may be
also caused by androgens deficiency results in the muscle hypothrophy. Such decrease in mass is also observed in fat tissue:
lipogenesis is decreased and lipolysis is increased. As a result patients loose weight. Deficiency of androgens and glucocorticoids
leads to hyporegenerarive anemia.
Decreased cortisol blood levels result in hyperpigmentation of skin and mucous membranes which is a characteristic of
Addison's disease. Increased pigmentation is characterized by diffuse tanning of both exposed and unexposed portions of the
body.
This occurs because melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) share the same
precursor molecule, pro-opiomelanocortin (POMC). After production in the anterior pituitary gland, POMC gets cleaved into
gamma-MSH, ACTH and beta-lipotropin. The subunit ACTH undergoes further cleavage to produce alpha-MSH, the most
important MSH for skin pigmentation. In secondary and tertiary forms of adrenal insufficiency, skin darkening does not occur, as
ACTH is not overproduced.
In some cases, Addison's symptoms may present rapidly. This "acute adrenal failure" is known as an Addisonian or adrenal crisis
– severe health state in which patient may die due to acute failure of blood circulation. The reasons of it are trauma of both
adrenal glands, acute or fulminant sepsis, adrenal bilateral hemorrhage (Waterhouse–Friderichsen syndrome). An adrenal crisis is
characterized by:
* acute hypotension – due to low cardiac output, low vascular tone and decreased blood circulating volume;
* dehydration of the organism – the lack of aldosterone results in water and sodium loss, plus vomiting (especially in acute
infections);
* insufficiency of bloodflow on all the levels – central circulation, tissues and organs circulation and microcirculation. The
causes of it are acute cardiac failure, decrease of the arterioles tone, decrease of blood circulating volume.
Secondary adrenal insufficiency is characterized with adrenal hypofunction due to the lack of ACTH. The difference between
primary and secondary forms of adrenal insufficiency is the following. ACTH blood level is high in patients with primary disease
of the adrenals; patients with secondary adrenal insufficiency have low ACTH level. Most instances of secondary
hypoadrenocorticism are caused by destruction of the pituitary. It also can be caused with long term steroid administration, which
suppresses ACTH synthesis.
Patients with secondary adrenal insufficiency are not hyperpigmented, as are those with Addison's disease. They have relatively
normal electrolyte levels. Hyperkalemia and elevated blood urea nitrogen generally are not present because of the near-normal
secretion of aldosterone in these patients.
Hyperfunction of adrenal cortex
Partial hypersecretion of one or more adrenocortical hormones produces distinct clinical syndromes. Excessive production of
androgens results in adrenal virilism; hypersecretion of glucocorticoids produces Cushing's syndrome; and excess aldosterone
output results in hyperaldosteronism. In the case of secondary disorder due to increased ACTH production total hypercorticism
appear which include symptoms of above mentioned diseases because ACTH stimulates cells from all zones of adrenal cortex.
Adrenal virilism (adrenogenital syndrome) is either congenital or acquired syndrome, in which excessive output of adrenal
androgens causes virilization.
The effects depend on the sex and age of the patient at disease onset and are more marked in women than in men. In adult
women, adrenal virilism is caused by adrenal hyperplasia or an adrenal tumor. In either case, symptoms and signs include
hirsutism, baldness, acne, deepening of the voice, amenorrhea, atrophy of the uterus, decreased breast size, and increased
muscularity. Hirsutism may be the only sign in mild cases.
Cushing’s syndrome is a complex of clinical abnormalities due to chronic exposure to excesses of cortisol (the major
adrenocorticoid) or related corticosteroids.
Clinical manifestations include rounded "moon" face with a plethoric appearance. There is central obesity with prominent
supraclavicular and dorsal cervical fat pads ("buffalo hump"); the distal extremities and fingers are usually quite slender. The
central type of obesity is explained by the fact that the adipocytes of visceral fat tissue bear the receptors for cortisol.
Muscle wasting and weakness are present. The main reason of it is hypokalemia (loss of K) and low glucose level in the muscles
(due to contrinsular effect of cortisol).
The skin is thin and atrophic, with poor wound healing. Purple striae may appear on the abdomen. The mechanism of it is
activation of protein catabolism and inhibition of proteins synthesis in the skin. It leads to the deficiency of collagen, elastin and
other proteins which form skin structures. The purple color of the striae is due to venous congestion in the microcirculation.
Hypertension is observed in 75% of the patients. It is caused by cortisol and aldosterone effect (Na and water retention,
hypervolemia, increased vessels tone due to high level of angiotensin).
Osteoporosis is the result of increased catabolism in the bone, inhibition of bone proteins synthesis and calcium fixation by the
protein matrix of the bone. Blood level of calcium is increased, that leads to renal calculi formation.
Hyperglycemia, glucose intolerance and secondary diabetes mellitus (in 10% of the patients) are explained by contrinsular effect
of cortisol.
Reduced resistance to infection and secondary immune deficiency are caused by suppression of immune cells activity by excess
of glucocorticoids and decreased anabolism.
In adrenal tumors, an increased production of androgens, in addition to cortisol, may lead to hirsutism, temporal balding and
other signs of virilism in the females.
Hyperaldosteronism is the clinical syndrome resulting from excess aldosterone secretion.
Aldosterone is the most potent mineralocorticoid produced by the adrenals. It causes Na retention and K loss. In the kidney,
aldosterone causes the transfer of Na from the lumen of the distal tubule into the tubular cells in exchange for K and hydrogen.
The same effect occurs in the salivary glands, sweat glands, and cells of the intestinal mucosa and in exchanges between intra-
and extracellular fluids. Aldosterone secretion is regulated by the renin-angiotensin mechanism and to a lesser extent by ACTH.
Primary hyperaldosteronism (Conn's Syndrome) is due to a tumor of the adrenal cortex or, more rarely, to adrenal hyperplasia.
Hypersecretion of aldosterone may result in the following clinical findings:
Blood analysis show hypernatremia, hyperchlorhydria, hypervolemia, and hypokalemia due to activation of sodium and water
retention and excessive loss of potassium.
Low blood potassium level results in the disturbances of neuromuscular excitability manifested by muscular weakness,
paresthesias, transient paralysis, and tetany.
Hypertension develops due to sodium and water retention, hypervolemia and increased cardiac output.
Hypokalemic nephropathy with polyuria and polydipsia are common. The mechanism of it lies in dystrophic changes of the
tubules and their insensitivity to antidiuretic hormone.
Hyperglycemia, and glycosuria occasionally occur. In many cases, the only manifestation is mild to moderate hypertension.
Plasma renin activity in Conn’s syndrome is low or normal because secretion of renin is suppressed by excess of aldosterone and
hypervolemia.
Secondary hyperaldosteronism usually arises as the compensatory increase of aldosterone synthesis in all situations when there
is a decrease in blood circulating volume and/or low BP. This occurs in cardiac failure, liver cirrhosis with ascites, the nephrotic
syndrome, other cases of polyuria and hypoproteinemia.
Secondary aldosteronism is also caused by reduced renal blood flow, which stimulates the renin-angiotensin mechanism with
resultant hypersecretion of aldosterone. Causes of reduced renal blood flow include obstructive renal artery disease (e.g.,
atheroma, stenosis), renal vasoconstriction (as occurs in accelerated hypertension). The clinical manifestations were listed before.
Pathology of adrenal medulla
Pheochromocytoma is a tumor of chromaffin cells that secrete catecholamines, causing hypertension.
 The most prominent feature is hypertension, which may be paroxysmal or persistent. The hypertension is due to secretion of one
or more of the catecholamine hormones or precursors: norepinephrine, epinephrine, dopamine, or dopa. Common symptoms and
signs are tachycardia, diaphoresis, postural hypotension, tachypnea, flushing, cold and clammy skin, severe headache, angina,
palpitation, nausea, vomiting, epigastric pain, visual disturbances, dyspnea, paresthesias, constipation. Paroxysmal attacks may
be provoked by palpation of the tumor, postural changes, abdominal compression or massage, induction of anesthesia, emotional
trauma.
General adaptation syndrome and stress
The term stress was defined by Dr. Hans Selye, a Canadian endocrinologist who won the Nobel Prize for his studies on stress. It
refers to the consequence of the failure of an organism – human or animal – to respond appropriately to emotional or physical
threats, whether actual or imagined. Any case of body’s overload with excessive physical, emotional or physical irritants will
result in typical tension of non-specific adaptive mechanisms and stress reaction development.
Stress is divided into eustress and distress. Where stress enhances function (physical or mental, such as through strength training
or challenging work), it may be considered eustress. Persistent stress that is not resolved through coping or adaptation, named
distress, may lead to anxiety or withdrawal (depression) behavior.
The difference between experiences which result in eustress or distress is determined by the disparity between an experience
(real or imagined), personal expectations, and resources to cope with the stress. Alarming experiences, either real or imagined,
can trigger a stress response.
General Adaptation Syndrome (GAS) is a clinical manifestation of body’s reaction to stress. This reaction occurs in three phases:
1st phase: Alarm reaction. In the case of stress the pituitary influences the work of all endocrine glands. ACTH stimulates the
adrenals to secrete adrenaline, noradrenaline, cortisone, cortisol. The adrenal gland is also stimulated by the sympathetic nervous
system, which arouses reaction immediately. Adrenaline and noradrenaline cause rise in heart rate, blood pressure and respiration
rise in order to supply muscles and brain with more oxygen. More blood is sent to the skeletal muscles and the brain, while blood
flow decreases to the stomach, kidneys, skin and liver. Adrenal hormones mobilize the physical energy needed to combat the
stress.
It should be noted however that some people tend to respond in just the opposite way in a stressful situation. In their organisms
the parasympathetic system is stimulated, hence the symptoms are opposite - low blood pressure, slower respiration rate, muscles
are relaxed. However the majority of people respond to stressors with activation of the sympathetic system.
Cortisol and cortisone suppress the immune system. The corticoids have significant effect on emotions, for instance, adrenaline
injected into a person who is not under stress will cause him to feel fear, even though he will not be able to explain the reason for
that fear.
The thyroid gland is stimulated by the TSH to secrete thyroxine. At the same time the production of sex hormones is decreased.
The secretion of endorphins usually increases. Endorphins are produced by the brain and act as natural opiates - they have robust
effect on relieving pain and cause positive emotions. Sport activities are a natural means for stimulating secretion of endorphins.
The beginning of the alarm stage is characterized with the decreased resistance of the organism but later resistance is normalized
and further increased.
2nd phase: The phase of adaptation or resistance. If stress is not overcome, the second phase commences. The organism tries to
deal with stress by producing and activating corticosteroid hormones in the adrenal gland that work as anti-inflammatory agents.
This mechanism creates hypertrophy of the adrenal glands. Nevertheless this process of adaptation results in a consumption of
the organism’s energy reserves. The second phase can continue for a long period of time, gradually weakening the organism. The
resistance to stress factor and other factors is increased.
3rd phase: Phase of exhaustion. This is the G.A.S. phase where depletion is so high that the patient loses the ability to adapt to
the stress. It is the phase when medical intervention is requested for a number of symptoms, which are sometimes difficult to
define. The organism has exhausted its energy reserves trying to contain the stress and starts to self-destruct. The typical
symptom of the exhaustion phase is chronic fatigue which is probably the most widespread symptom in our society.
Morphological signs of GAS include the following:
* hypertrophy of adrenal cortex;
* involution of thymus and lymphatic nodes;
* erosions and ulcers formation in GIT.
If an individual is subjected to frequent and strong stressors, this may cause severe endocrine disorders. The humoral feedback
does not influence directly the pituitary, but other parts of the brain first. Oversecretion of hormones may adversely affect brain
tissue, which in turn will fail to send proper signals to the pituitary. The whole process turns into a vicious cycle, which can
become a reason for severe endocrine (and mental) disorders. Once the organism is subjected to endocrine disorders, the stress
reaction does not take its normal course and may lead to life-threatening conditions.
UNIT 26
NERVOUS SYSTEM PATHOLOGY
EXTREME STATE: SHOCK, COMA
The disturbances of nervous system motor function
The neurons that control motor function are referred to as motoneurons or sometimes as alpha motoneurons. A motor unit
consists of one motoneuron and the group of muscle ?bers it innervates in a muscle. The motoneurons supplying a motor unit are
located in the ventral horn of the spinal cord and are called lower motoneurons (LMNs). The synapse between a LMN and the
muscle ?bers of a motor unit is called the neuromuscular junction. Upper motoneurons (UMNs), which exert control over LMNs,
project from the motor strip in the cerebral cortex to the ventral horn and are fully contained within the CNS
 Paralysis is the loss or impairment of motoneuron function. Paresis is a slight or incomplete paralysis.
Paralysis due to localization is divided into:
* monoplegia – paralysis affecting a single limb;
* diplegia – paralysis of corresponding parts on both sides of the body;
* paraplegia – paralysis of the legs and lower part of the body;
* hemiplegia – paralysis of one side of the body;
* triplegia – paralysis of an upper and a lower extremity and of the face, or of both extremities on one side and of one on the
other;
* tetraplegia or quadriplegia – paralysis of all four limbs.
Clinical manifestation of paralysis depends on which motoneuron is affected. An UMN lesion can involve the motor cortex, the
internal capsule, or other brain structures through which the corticospinal or corticobulbar tracts descend, or the spinal cord.
When the lesion is at or above the level of the pyramids, paralysis affects the structures on the opposite side of the body. In UMN
disorders involving injury to the L1 level or above, there is an immediate, profound weakness and loss of ?ne, skilled voluntary
lower limb movement, reduced bowel and bladder control, followed by an exaggeration of muscle tone. With UMN damage
above C5, upper limb movement is also affected.
With UMN lesions, the LMN spinal re?exes remain intact, but communication and control from higher brain centers are lost.
Descending excitatory in?uences from the pyramidal system and some descending inhibitory in?uences from other cortical
regions are lost after injury, resulting in immediate weakness accompanied by the loss of control of delicate, skilled movements.
After several weeks, this weakness becomes converted to hypertonicity or spasticity, which is manifested by an initial increased
resistance (stiffness) to the passive movement of a joint at the extremes of range of motion followed by a sudden or gradual
release of resistance. The spasticity is often the greatest in the ?exor muscles of the upper limbs and extensor muscles of the
lower limbs. The tendon and other spinal reflexes are increased, and the extensory (Barbinsky) reflex appears. That is why this
type of paralysis is called the spastic type.
In contrast to UMN lesions, in which the spinal re?exes remain intact, LMN disorders disrupt communication between the
muscle and all neural input from spinal cord re?exes, including the stretch re?ex, which maintains muscle tone.
With complete LMN lesions, the muscles of the affected limbs, bowel, bladder, and genital areas become atonic, and it is
impossible to elicit contraction by stretching the tendons. One of the outstanding features of LMN lesions is the profound
development of muscle atrophy. This disorder is named ?accid paralysis.
Brown-Sequard paralysis or Brown-Sequard syndrome is an incomplete spinal cord lesion characterized by a clinical picture
reflecting hemisection of the spinal cord, often in the cervical cord region. It is a rare syndrome, consisting of ipsilateral
hemiplegia with contralateral pain and temperature sensation deficits because of the crossing of the fibers of the spinothalamic
tract. Pure Brown-S?quard syndrome is associated with:
Interruption of the lateral corticospinal tracts that manifest as:
1. Hypotonic (flaccid) paralysis at the level of the lesion (injury of LMN);
2. Ipsilateral spastic paralysis below the level of the lesion (injury of UMN) with Babinsky sign ipsilateral to lesion.
At the same zone there’ll be ipsilateral loss of fine touch, vibratory, and proprioception (position sensation) below the level of the
lesion due to interruption of posterior white column
3. Contralateral loss of pain and temperature sensation. This usually occurs 2-3 segments below the level of the lesion and results
from interruption of lateral spinothalamic tracts.
Pain
Pain stimuli are received by nociceptors in the skin and the viscera which are excited by high-intensity, non-noxious stimuli
(distension, temperature) as well as by tissue lesions. Necrotic cells release K+ and intracellular proteins. An increase in
extracellular K+ concentration depolarizes the nociceptors, while the proteins and, in some circumstances, infiltrating
microorganisms may cause an inflammation. As a result, pain-producing mediators are released. Leukotrienes, prostaglandin E2,
and histamine sensitize the nociceptors so that even otherwise subthreshold noxious and harmless stimuli can produce pain
(hyperalgesia or allodynia). Tissue lesions also activate blood clotting and thus the release of bradykinin and serotonin. If there is
vascular occlusion, ischemia occurs and the resulting extracellular accumulation of K+ and H+ further activates the sensitized
nociceptors. The mediators histamine, bradykinin, and prostaglandin E2 have a vasodilator effect and increase vascular
permeability. This results in local edemas; the tissue pressure rises and this also stimulates the nociceptors. Their stimulation
releases the peptide substance P and the calcitonin gene-related peptide, which promote the inflammatory response and also
produce vasodilatation and increase vascular permeability.
Afferents from organs and the surface of the skin are intertwined in parts of the spinal cord, i.e., the afferent nerves converge
upon the same neurons in the spinal cord. Excitation of the nociceptors in an organ then triggers pain sensations in those areas of
the skin whose afferents make connections in the same spinal cord segment (referred pain). In myocardial infarction, for example,
pain radiates into the left shoulder and left arm (Head’s zones). Projected pain is produced by stimulation of a nerve (e.g., of the
ulnar nerve in the ulnar sulcus). The perception of pain is projected to the innervation area of the nerve. A special form of
projected pain is phantom pain of an amputated limb or a part of it. In neuralgia, continued abnormal stimulation of a nerve or
posterior root results in chronic pain in the area of innervation.
The impulses along the afferent nerves synapse in the spinal cord and pass via the anterolateral tracts to the thalamus and from
there to the somatosensory cortex, the cingular gyrus, and the insular cortex. Appropriate connections produce various
components of pain sensation: sensory (e.g., perception of localization and intensity), affective (ailment), motor (protective
reflex, muscle tone, mimicry), and autonomic (changes in blood pressure, tachycardia, pupillary dilatation, sweating, nausea).
The connections in the thalamus and spinal cord are inhibited by the descending tracts from the cortex, midbrain periaqueductal
gray matter, and raphe nucleus, these tracts employing norepinephrine, serotonin, and especially endorphines. Lesions of the
thalamus, for example, can produce pain through an absence of these inhibitions (thalamus syndrome).
To counteract pain, the activation of pain receptors can be inhibited, for example, by cooling of the damaged area and by
prostaglandin synthesis inhibitors. The transmission of pain can be inhibited by cooling and by Na+ channel blockers (local
anesthetics). Transmission in the thalamus can be inhibited by anesthesia and alcohol. Attempts have now and again been made to
interrupt pain transmission by means of surgical nerve transection. Electroacupuncture and transcutaneous nerve stimulation act
via activation of the descending, pain-inhibiting tracts. The endorphine receptors are activated by morphine and related drugs.
Endogenous pain-inhibiting mechanisms can be aided by psychological methods of treatment.
The absence of pain brought about by pharmacological means or the very rare congenital condition of congenital analgesia
interrupt these warning functions. If the cause of the pain is not removed, the consequences can be life-threatening.
Disorders of neuromuscular junction
Myasthenia gravis is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired
immunological abnormality (autoantibodies to acetylcholine muscle receptors), but some cases result from genetic abnormalities
at the neuromuscular junction.
Patients with myasthenia gravis complain of specific muscle weakness but not of general fatigue. Ocular motor disturbances,
ptosis or diplopia, are the initial symptoms of myasthenia gravis in two-thirds of patients. Oropharyngeal muscle weakness,
difficulty in chewing, swallowing, or talking, are the initial symptoms in one-sixth of patients, and limb weakness in 10% only.
Initial weakness is rarely limited to single muscle groups such as neck or finger extensors or hip flexors. The severity of
weakness fluctuates during the day, usually being the least in the morning and it becomes worse during the day, especially after
prolonged use of affected muscles.
The normal neuromuscular junction releases acetylcholine from the motor nerve terminal in discrete packages (quanta). The
acetylcholine quanta diffuse across the synaptic cleft and bind to receptors on the folded muscle end-plate membrane. Stimulation
of the motor nerve releases many acetylcholine quanta that depolarize the muscle end-plate region and then the muscle membrane
causes muscle to contract. In acquired myasthenia gravis, the post-synaptic muscle membrane is distorted and simplified, having
lost its normal folded shape. The concentration of acetylcholine receptors on the motor end plate of the neuromuscular junction is
reduced, and antibodies are attached to the membrane. Acetylcholine is released normally, but its effect on the post-synaptic
membrane is reduced. The post-junctional membrane is less sensitive to acetylcholine, and the probability that any nerve impulse
will cause a muscle action potential is reduced.
Disorders of neuromediatiors’ metabolism. Drugs addiction
Among the wide list of chemicals there is a group of substances which can cause addictive disorders when they are chronically
used because they alter normal metabolism of neuromediators.
Commonly abused drugs include:
• narcotic analgesic agents (morphine, codeine, heroin);
• benzodiazepines (phenazepamum, sibasonum, mesapamum);
• cocaine (psychostimulant that acts to increase extraneuronal dopamine in midbrain by binding to the dopamine uptake
transporter and hence inhibiting dopamine reuptake at the plasma membrane);
• amphetamines (sympathomimetic and CNS stimulators causing excitation, vasopression, bronchodilation, and to
varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation);
• barbiturates (sedatives and hypnotics (sedatives, barbiturate);
• marijuana (used to heighten perception, cause mood swings and relax the mind and body) ;
• LSD (lysergic acid diethylamide) is centrally acting agent with hallucinogenic properties, may precipitate psychosis.
Other substances that cause dependence are alcohol and nicotine that are widely used in different societies.
The initial stage (mental dependence) of drug addiction is characterized by increased tolerance to higher doses of substance and
invincible pathological addiction to the substance. The person feels uncomfortable without drug intake: depression, irritability,
high physical and mental fatigue, disturbances of memory and sensitivity, insomnia.
The physical dependence stage is characterized by the development of withdrawal (abstinence syndrome).
The mechanism of drugs dependence development is complicated, but some pathways of it are now understandable. When
abused drugs reach the brain, they can attach to receptors, transporters, or even structural elements of the neurons. For example,
opiates such as heroin bind to mu-opioid receptors, which are on the surfaces of opiate-sensitive neurons. The linkage of heroin
with the receptors imitates the linkage of endogenous opioids such as beta-endorphin with the same receptors and triggers the
same biochemical brain processes that reward people with the feelings of pleasure when they are engaged in activities promoting
basic life functions, such as eating and sex. Opioids are prescribed therapeutically to relieve pain, but when these exogenous
opioids activate the reward processes in the absence of significant pain, they can motivate repeated use of the drug simply for
pleasure.
One of the brain circuits activated by opioids and most, if not all, abused drugs is the mesolimbic (midbrain) reward system. This
system generates signals in the ventral tegmental area part of the brain that result in the release of the dopamine in the nucleus
accumbens. This release of causes the feelings of pleasure. Other abused drugs activate the same brain pathway, but via different
mechanisms and by stimulating or inhibiting different neurons in this pathway.
Repeated exposure to escalating dosages of most drugs alters the brain, so that it functions more or less normally when the drugs
are present and abnormally when they are not. Two clinically important results of this alteration are drug tolerance (the need to
take higher and higher dosages of drugs to achieve the same effect) and drug dependence (susceptibility to withdrawal
symptoms). Withdrawal symptoms occur only in patients who have developed tolerance.
Tolerance occurs because the brain cells that have receptors or transporters on them gradually become less responsive to the
stimulation by the exogenous substances. Therefore, more substance is needed to produce pleasure comparable to that provided in
previous drug-taking episodes. The mechanism of withdrawal symptoms appearance is explained by the changes in locus
coeruleus (LC) brain system. Neurons in the LC produce noradrenaline (NA) and widely distribute it to other parts of the brain
including the cerebral cortex, brainstem, and various subcortical regions, where it stimulates wakefulness, breathing, blood
pressure, and general alertness, along with other functions. When opioid molecules link to mu-receptors on brain cells in the LC,
they suppress the neurons’ release of NA, resulting in drowsiness, slowed respiration, and low blood pressure—familiar effects of
opioid intoxication. With repeated exposure to opioids, however, LC neurons adjust by increasing their level of activity. Now,
when opioids are present, their suppressive impact is offset by this heightened activity, with the result that roughly normal
amounts of NA are released and the patient feels more or less normal. When opioids are not present to suppress the LC brain
cells’ enhanced activity, however, the neurons release excessive amounts of NA, triggering jitters, anxiety, muscle cramps, and
diarrhea (withdrawal symptoms).
The mechanism of drug dependence development is that drug abuse alters a physiological setting or baseline of brain function.
Abused drugs cause addiction by initiating a vicious cycle of changing this set point, such that the release of dopamine is reduced
when normally pleasurable activities occur and abused drugs are not present. Similarly, a change in set point occurs in the LC,
but in the opposite direction, such that NA release is increased during withdrawal, thus accounting for both the positive (drug
liking) and negative (drug withdrawal) aspects of drug addiction.
The exhaustion stage is characterized by an absence of pleasure feeling which was achieved in the earlier stages of addiction,
decreased tolerance to the substance, decreased general reactivity of the organism, long-term abstinence, severe disturbances of
central and peripheral nervous system activity, multiply injury and failure of inner organs.
Alcoholism
Alcoholism is a disease characterized by pathological pattern of alcohol use that causes a serious impairment in social or
occupational functioning. It is also termed alcohol abuse or, if tolerance or withdrawal is present, alcohol dependence.
Alcohol is absorbed from the stomach and the proximal part of the small bowel. Ninety-five percent of alcohol is metabolized in
the liver by alcohol dehydrogenase (ADH), which converts alcohol to the toxic substance acetaldehyde. Acetaldehyde is further
broken down to acetic acid via the enzyme aldehyde dehydrogenase (ALDH), and subsequently goes through the citric acid cycle
to become carbon dioxide and water.
Alcohol intoxication is a reversible syndrome characterized by slurred speech, impaired judgment, disinhibition, mood lability,
motor incoordination, cognitive impairment, and impaired social or occupational functioning. These effects are a result of a direct
stimulant effect of alcohol on norepinephrine and dopamine systems, combined with inhibition of the stimulating effect of the
glutamate-mediated receptor and facilitation of the inhibiting function of the GABA system.
A blood alcohol level of 30 mg% will produce a euphoric effect in most individuals who are not tolerant. At 50 mg%, the CNS
depressant effects of alcohol become prominent, with associated motor coordination problems and some cognitive deficits. At
levels > 250 mg%, a significant confusion and a decreased state of consciousness may occur. Alcoholic coma may occur at this
level, and at greater than 400 mg%, death may result. Because of tolerance, some heavy drinkers may not show these effects even
at high blood levels.
With prolonged exposure to ethanol, when alcohol use is discontinued, there is a relative decrease in inhibiting (GABA)
mechanisms and a relative increase in excitatory (NMDA) mechanisms. The symptoms of alcohol withdrawal then emerge and
commonly include tremor, sweating, anxiety or agitation, elevated blood pressure, increased pulse, increased respiration,
headaches, nausea, vomiting, and light and sound sensitivity.
Pathogenesis of alcoholism includes the following stages.
The initial stage is characterized by the syndrome of altered reactivity to alcohol (invincible attraction to alcoholic beverages and
loss of quantitative control over their using) and increased tolerance to alcohol.
The middle stage is characterized by:
* clinical manifestation of abstinence/withdrawal syndrome. The most severe form of withdrawal is called "delirium tremens".
The presence of withdrawal symptoms strongly indicates an alcohol addiction;
* formation of maximum tolerance to alcohol;
* social problems (the involvement in crime, accidents, poor job performance, relationship problems, broken families).
The final stage is characterized by the loss of tolerance to alcohol, severe disturbances of brain and internal organs, progress of
social misadaptation.
Chronic alcohol use can damage any organ systems. Besides the well known liver cirrhosis, there can be enlargement and
weakening of the heart (cardiomyopathy) and subsequent heart failure. There is also an increased risk of mouth, throat, stomach,
colon, liver, breast cancers.
Chronic intake is associated with brain shrinkage, cognitive defects and declines measured by neuropsychological testing. Along
with the brain atrophy, the nerves may be damaged, with loss of sensation in the hands and feet, and difficulty walking. There can
be depressed sexual response, disordered sugar metabolism, and premature aging.
Mechanisms of general toxic effect of alcohol are:
* membranotropic effect (the disruption of the phospholipid molecular chain in the cell membrane, the increase of membrane
permeability, the change of membrane enzymes activity, the disturbance of trans-membranous ion transport);
 * alteration of carbohydrate metabolism (the decrease of gluconeogenesis, the disturbance of glucose oxidation and its utilization
by tissues because of inhibition of Krebs’s cycle, the activation of glycolysis);
* alteration of protein metabolism (the inhibition of protein synthesis, accumulation of ammonia in blood);
* alteration of lipid metabolism (the increase of lipogenesis and cholesterol synthesis, the activation of peroxide lipid oxidation
and development of ketonic acidosis);
* alteration of electrolyte metabolism (the decrease of sodium and potassium blood level);
* alteration of vitamin metabolism (the development of avitaminosis B, C, PP, K, etc);
* accumulation of acetaldehyde (the main toxic substance).
Ethanol damages the CNS and peripheral nervous system by altering both neurotransmitter levels and cell membrane fluidity and
function. The main effects on neuromediator’s systems of the brain are:
GABA (gamma-aminobutyric acid) system: The brain GABA A receptors are the targets for alcohol, benzodiazepines,
barbiturates. Stimulation of the GABA receptor by the binding of these compounds causes sedative and anxiolytic effects.
Chronic use of alcohol down-regulates the GABA system, and the neuron eventually becomes dependent on alcohol to enable
GABA to function. If alcohol is withdrawn, GABA is no longer capable to perform the task secondary to the cell, having adapted
to the role of alcohol. Thus, the cell becomes hyperexcitable, leading to irritability, insomnia, hypertension, tachycardia, and
possibly hallucinations and seizures.
Glutamate system: Ethanol is a potent inhibitor of the NMDA glutamate receptor and most likely blocks NMDA-stimulated
calcium uptake. The NMDA receptor is involved in memory formation, neuronal excitability, and seizures. Alcohol’s acute action
on this receptor leads to sedative, amnestic, and anxiolytic effects. However, when alcohol is withdrawn, the NMDA receptor
becomes abnormally excited, and seizure activity and hypoxic damage may result.
Norepinephrine and dophamine: Low doses of alcohol activate the norepinephrine system via the activating reticular system in
the brain stem. This action stimulates behavior and arousal, and as the concentration of alcohol in the brain increases, the
dopamine pathways in the mesolimbic system assume importance as a reward center. Long-term consumption of alcohol leads to
the deficiency of these catecholamines.
Endorphines and serotonin: It has been demonstrated that individuals with family histories of alcoholism show increased beta-
endorphin release and increased euphoria after drinking alcohol. Similarly, serotonin function might predispose to alcoholism, as
evidenced by the fact that some alcoholics have been found to have reduced serotoninergic function and, although inconsistent,
some serotonin medications have attenuated drinking behavior.
Pathogenesis of extreme state
Extreme state/condition – severe life-threatening state of the body, that develops under the influence of extreme factors of the
external or internal environment which is characterized by significant disturbance of vital functions and may result in death.
Extreme states require emergency medical care. The most common extreme conditions include collapse (see Blood vessels
pathology), shock and coma.
Terminal state is usually the result of an unfavorable course of an extreme state that is observed in the last stages of the
organism’s life and the borderline state between life and death.
Shock is a life threatening condition characterized by critical state of organ hypoperfusion with resultant cellular dysfunction and
death.
The main mechanisms of shock development are: decrease of blood circulating volume, decrease of cardiac output and
disturbance in the fluid distribution in the body.
Hypovolemic shock results from loss of about 15-20% or more of intravascular fluid volume. Fluid may be lost by external and
internal hemorrhages, diarrhea, vomiting, surgical drainage, burns, adrenal insufficiency, osmotic/drug-induced diuresis, etc.
Cardiogenic shock results from severe reduction in cardiac output due to a primary cardiac disorder: myocardial infarction,
arrhythmias (especially ventricle fibrillation). Cardiogenic shock also occurs when there is a mechanical interference with
ventricular filling (tension pneumothorax, cardiac tamponade, constrictive pericarditis, restrictive cardiomyopathy, atrial tumor or
clot) – obstructive shock.
Distributive shock results from a relative inadequacy of intravascular fluid volume caused by arterial or venous vasodilation;
circulating blood volume is normal. It may be caused by anaphylaxis, bacterial infection with endotoxin release, loss of
sympathetic vascular tone (neurogenic shock).
The most common type of distributive shock is septic shock. It is characterized by toxemia and abnormal systemic inflammatory
host response to infection which result in capillary leakage and systemic vasodilation.
Anaphylactic shock develops due to multitude degranulation of mast cells and massive histamine release resulting in systemic
vasodilation and increased capillary leakage. Anaphylactic shock and septic shock often have a component of hypovolemia as
well.
Neurogenic shock develops due to the loss of sympathetic vascular tone that causes peripheral vasodilation with subsequent
pooling of peripheral blood. Etiology of neurogenic shock include: spinal cord injury, traumatic brain injury, cerebral hemorrhage
and severe pain (trauma, burns, myocardial infarction, etc.).
Common symptoms of shock include: altered mental status (lethargy, confusion, somnolence), tachycardia, weak pulse,
hypotension (< 90 mm Hg systolic), and oliguria. Tachypnea (>22) and hyperventilation may be present.
The links of shock pathogenesis include:
Neuroendocrine link – excessive (inadequate) pain and non-pain stimuli from various reflexogenic zones (extero-, inter- and
proprioreceptors; nociceptors, thermo-, mechano-, baro-, volumo-, chemo- and other receptors), but especially from the zones of
damaged and paranecrotic structures that greatly alters body organs function.
 After a short-term excitation of different parts of the CNC, accompanied by a significant activation of body’s systems and
organs, sooner or later, deficiency of their energy, plastic and functional reserves occurs. As a result of this, the tissues, organs
and systems of the body lose their normal innervation and function improperly.
Toxemia – accumulation of endo- and exogenous toxic substances: lysosomal enzymes, denatured proteins, protein complexes,
their degradation products, products of degradation of damaged cells, toxins of intestinal and microbial origin, an excess of the
biologically active substances: catecholamines, histamine, serotonin, acetylcholine, kinins, prostaglandins, adenosine, potassium
ions, etc.)
Acidosis – firstly compensated, then decompensated (due to the progressive accumulation of suboxidized metabolites, especially
lactate, pyruvate, ketoacids, peroxides, free radicals, etc.).
Circulatory hypoxia – rapidly and progressing decrease in oxygen content and use. Later may be accompanied by tissue type of
hypoxia.
Metabolic disorders – especially important in the liver, kidneys, heart, brain. They are caused by disturbances in the water-
electrolyte, acid-base, osmotic and oncotic balance in the intracellular and extracellular spaces, as well as disorders of protein,
lipid, carbohydrate, vitamin, neurotransmitter, hormonal, etc. metabolism. Blood composition disorders are also important in the
development of metabolic disorders: hypo- and dysproteinemia, hypoalbuminemia, hyperglobulinemia, hyper- and then
hypoglycemia, dyslipoproteinemia, hyperfermentemia, accumulation of acidic products, bicarbonate deficiency, etc.
Disorders of systemic, regional bloodflow and microcirculation determine the progress of shock development. Increase in the
shock severity is also accompanied by pulmonary, renal, liver, and multiple organ failure.
Shock (especially caused by a major trauma) usually passes two stages: erectile stage and torpid stage.
The erectile stage is characterized by a pronounced activation of the somatic and autonomic nervous system, especially the
sympathetic and sympatho-adrenal systems, increased pain sensitivity, general motor and speech agitation, euphoria, often
inappropriate behavior, elevated blood pressure, tachycardia, peripheral vascular spasm (especially skin).
The torpid stage is characterized by manifestations of circulatory and respiratory disorders, decompensation of vital functions,
structural and metabolic disorders, progressive hypoxia, intoxication, irreversible changes in organs and systems. The torpid stage
is also characterized by inhibition of all types of sensitivity, including pain, as well as the function of the regulatory systems and
other organs (nervous, endocrine, CVS, respiratory, kidney, liver, GIT). It is important to note that consciousness with shock is
violated, but not absent.
A coma is a pathological state that is characterized with serios depression of the CNS functions that manifests with prolonged
unconsciousness, absence of reflexes on external irritators and disorders of the vital functions regulation of an organism. Coma
can be caused by either a direct (primary) damage to the CNS or indirect (secondary) damage to the brain as a result of
intoxication, metabolic disorders and others. The development of coma can be very fast, almost instantaneous, or phased – during
several days.
Rapid development is possible with a coma of any etiology, but more often it is observed with epilepsy, traumatic brain injury,
cerebral hemorrhage. The patient suddenly loses consciousness and in the next few minutes and hours he develops all signs of
deep coma: noisy deep breathing (Kussmaul type), BP fluctuates and gradually decreases, heart rhythm disturbances, disorders of
the uination and defecation develop, the pupils are narrowed and do not respond to light, cyanosis of the skin and mucous
membranes is observed, body temperature decreases.
Pathogenesis of coma depends on its type and etiology:
neurogenic coma – cerebral hemorrhage or mechanical, electrical, toxic, infectious and tumor damage to the brain;
toxic coma – endogenous intoxication: hepatic coma, uremic coma, pancreatic coma;
toxic coma – exogenous intoxication (barbiturates, alcohol);
endocrine coma due to hormones deficiency – diabetic coma (hyperglycemic), hypothyroid (myxedema) coma, hypocorticoid
coma;
endocrine coma due to hormones excess – hypoglycemic coma, hyperthyroid coma;
hypoxic coma – due to severe rapidly developing hypoxia;
metabolic coma – hypochloremic coma, hyperosmolar coma.
LIST OF ABBREVIATIONS
ABB – acid-base balance
AV – atrioventricular
BMR – basal metabolic rate
BP – blood pressure
bpm – beats per minute
BUN – blood urea nitrogen
CNS – central nervous system
CVS –cardio-vascular system
ECG – electrocardiogram
GFR – glomerular filtration rate
GIT –gastro-intestinal tract
Ig – immunoglobulin
IHD – ischemic heart disease
LDL – low density lipoproteins
MHC – major histocompatibility complex
NSAID – non-steroid antiinflammatory drug
RBC – red blood cell
ROS – reactive oxygene species
SA – sino-atrial
TNF – tumor necrosis factor
TPVR – total peripheral vascular resistance
WBC – white blood cells