PBL 2 Failure to thrive

CASE HISTORY

A three year-old girl, with Turkish parentage, presented to her GP with fatigue, shortness of
breath, pallor and excessive sweating. Her mother explained, through an interpreter, that
symptoms had manifested several months after birth when she noticed a prominent pallor. The
infant had failed to gain weight. Her development was retarded; she was unable to sit at the
expected time, and was yet to walk. She had a poor appetite. Her GP suspected severe anaemia
and was extremely concerned for her well-being. He referred the girl to the haematology clinic
at her local hospital. He explained the seriousness of the illness to the interpreter and asked this
be impressed on the mother.
Physical Examination
Physical examination revealed an underdeveloped infant with skeletal abnormalities. Her
weight was 10.3 Kg (1st 9lbs); height, 86 cm (2ft 10in); and head circumference 50 cm (19.5 in).
She was easily fatigued and had retained the noticeable pallor and had sclera icterus. The
extremities, chest, back, and femoral head were tender. She had an apex beat of 124/min with
signs of arrhythmia. Her liver was 1.5 cm below the right costal margin. Abdominal palpation
revealed tenderness and hepatosplenomegaly. Her haemoglobin concentration was 49 g/l.
Because of the severe anaemia, haemoglobin electrophoresis was performed on the patient and
both her parents. The mother and the father were relatives.
Laboratory tests

 Peripheral blood test results were as follows:

She presented with both a decreased haematocrit; and total red blood cell count (normal value
3.9-5.6 x 1012/l), which exhibited decreased osmotic fragility and increased haemolysis. She had
marked hypochromic, microcytic anaemia with depressed (all types) haemoglobin levels 49g/l
(normal 115-160 g/l); HbA2 level 8% and HbF; a small increase in reticulocytes, (normal 0.8-2%);
an apparent decreased white blood cell count, (normal 4-11 x 10 9/l) with occasional immature
granulocytes.

Other haematologies were decreased MCV, 62fl (normal 82-98fl) and MCHC (normal 310-
370g/l); increased RDW, (11.5-14.5%); and ESR, 12 mm/h

Serum iron and related haematology test results were:

Increased serum iron and ferritin; decreased Total Iron Binding Capacity; increased total
bilirubin; increased unconjugated bilirubin. She was Coomb’s test negative.

Enzymology was:

Mildly increased LDH 350 U/l (normal < 200 U/l); increased AST , 57 U/l (<35 U/l); increased
ALT 72 (normal <55 U/l); increased alkaline phosphatase: 165 U/l (normal <120 U/l).

Blood chemistries were:

Blood urea, 2.98 mmol/l (normal 2.5-6.7 mmol/l); increased uric acid; increased creatinine
(normal 70-150 mmol/l). She had decreased serum folate
.
Blood was taken for haemoglobin protein and DNA analysis.

Define clinical/biological terms

Pallor is a reduced amount of oxyhemoglobin in skin or mucous membrane, a pale color

which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to
sunlight, anemia or genetics. It is more evident on the face and palms. It can develop
suddenly or gradually, depending on the cause.

3 year old girl - average height 33 inches (2 ft 9 inches);

Average weight - 30.8 lbs.

Scleral icterus is a yellowing of the whites of the eyes that most classically occurs in patients
with liver disease. People with scleral icterus may experience a change in color in the sclera
that ranges from a muddying of the sclera to a bright yellow or orange discoloration. This
phenomenon is a symptom, rather than an underlying condition, and it is resolved when the
cause of the liver problems is treated.

The offspring of consanguinous relationships are at greater risk of certain genetic disorders.
Autosomal recessive disorders occur in individuals who are homozygous for a particular
recessive gene mutation.

Costal margin: The lower edge of the chest (thorax) formed by the bottom edge of the rib
cage.

palpation /pal·pa·tion/ (pal-pa´shun) the act of feeling with the hand; the application of the
fingers with light pressure to the surface of the body for the purpose of determining the
condition of the parts beneath in physical diagnosis.

Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of

both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can
occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of
a serious and life threatening lysosomal storage disease.

Hemoglobin electrophoresis is a blood test that can detect different types of hemoglobin. It
uses the principles of gel electrophoresis to separate out the various types of hemoglobin.
The test can detect abnormal levels of HbS, the form associated with sickle-cell disease, as
well as other abnormal hemoglobin-related blood disorders, such as hemoglobin C. It can
also be used to determine whether there is a deficiency of any normal form of hemoglobin,
as in the group of diseases known as thalassemias. Different hemoglobins have different
charges, and according to those charges and the amount, hemoglobins move at different
speeds in the gel whether in alkaline gel or acid gel.The hemoglobin electrophoresis is also
known to be thalessemia screening, this also can be helpful for the patient who is frequently
need of fresh blood transfusion. The patient need blood transfusion because the body is
unable to produce the enough Hemoglobin required for the body.(See Migration Patterns) .
Thalassemia major Hb F level and Hb A2 levels increase

Haematocrit : The hematocrit (Ht or HCT) or packed cell volume (PCV) or erythrocyte
volume fraction (EVF) is the proportion of blood volume that is occupied by red blood cells.
It is normally about 48% for men and 38% for women.[1] It is considered an integral part of a
person's complete blood count results, along with hemoglobin concentration, white blood
cell count, and platelet count.

Hypochromic microcytic anemias, characterized by the presence in the circulating blood of

red cells that are smaller than normal and poorly filled with hemoglobin, fall into two main
categories. The first is a result of a deficiency of iron, and the second is a result of impaired
production of hemoglobin;

Normal HbA2 level- below 3.5 percent

Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in
the human body. Reticulocytes develop and mature in the red bone marrow and then
circulate for about a day in the blood stream before developing into mature red blood cells.

MCV - Mean corpuscular volume (MCV) is a measurement of the average size of your
RBCs.

MCHC - Mean corpuscular haemoglobin concentration (MCHC) is a calculation of the

concentration of haemoglobin inside the RBCs. Decreased MCHC values (hypochromia) are
seen in conditions where the haemoglobin is abnormally diluted inside the red cells, such as
in iron deficiency anaemia and in thalassaemia. Increased MCHC values (hyperchromia) are
seen in conditions where the haemoglobin is abnormally concentrated inside the red cells,
such as in hereditary spherocytosis, a relatively rare congenital disorder.

RDW - Red cell distribution width (RDW) is a calculation of the variation in the size of your
RBCs. In some anaemias, such as pernicious anaemia, the amount of variation (anisocytosis)
in RBC size (along with variation in shape – poikilocytosis) causes an increase in the RDW.
Increased RDW indicates mixed population of RBCs; immature RBCs tend to be larger

ESR- The erythrocyte sedimentation rate (ESR), also called a sedimentation rate or
Biernacki Reaction, is the rate at which red blood cells precipitate in a period of 1 hour. It is
a common hematology test that is a non-specific measure of inflammation. To perform the
test, anticoagulated blood is placed in an upright tube, known as a Westergren tube, and the
rate at which the red blood cells fall is measured and reported in mm/h. The ESR is
governed by the balance between pro-sedimentation factors, mainly fibrinogen, and those
factors resisting sedimentation, namely the negative charge of the erythrocytes (zeta
potential). When an inflammatory process is present, the high proportion of fibrinogen in
the blood causes red blood cells to stick to each other. The red cells form stacks called
'rouleaux,' which settle faster. Rouleaux formation can also occur in association with some
lymphoproliferative disorders in which one or more immunoglobulin/s is/are secreted in
high amounts. Rouleaux formation can, however, be a normal physiological finding in
horses, cats, and pigs.

The ESR is increased by any cause or focus of inflammation. The ESR is increased in
pregnancy or rheumatoid arthritis, and decreased in polycythemia, sickle cell anemia,
hereditary spherocytosis, and congestive heart failure. The basal ESR is slightly higher in
females.

serum iron and ferritin : Ferritin is a protein found inside cells that stores iron so your body
can use it later. A ferritin test indirectly measures the amount of iron in your blood. The
amount of ferritin in your blood (serum ferritin level) is directly related to the amount of
iron stored in your body.
Normal results:
Male: 12-300 ng/mL
Female: 12-150 ng/mL
Ferritin is an indicator of stored iron in the body. Ferritin is the main protein that stores iron
for areas that need it, especially the liver and the bone marrow where red blood cells are
made. The iron ferritin level is the first in line to drop if the individual suffers any iron
insufficiency from diet, malabsorption or loss during heavy or menstruation lasting more
than 5 days. A drop in the iron ferritin level occurs before any depletion in serum iron (as
seen in iron-deficient anemia) and may decrease significantly without any obvious
symptoms whatsoever. While the serum ferritin level at which a deficiency can be claimed is
hotly argued by different schools of doctors, an excess of serum ferritin is generally agreed
to be a bad thing. Iron stored at high levels is toxic. The body can only metabolize so much
iron in a day. If it receives too much, the body is overwhelmed and toxic effects develop. It is
possible to overdose on iron supplements. For this reason, taking large supplement doses of
iron is not recommended. If, in response to a low iron and ferritin test result, you start to
take iron supplements and feel ill, it probably means you are taking too much for your body
to cope with. Take a lower dose.

Total Iron Binding Capacity (TIBC) - TIBC measures the amount of transferrin you have.
Transferrin is a blood protein that transports iron from the gut, where the iron is absorbed
from food, to the cells that use it. When iron stores are low, the body will make more
transferrin so that it can collect more iron absorbed from food and make more efficient use
of it. If there is too much iron coming from the gut, the body will reduce production of
transferrin so that less of the iron is taken up and transported around the body. On average
about one third of the transferrin in the body is being used to transport iron. Because of this,
the blood serum of healthy individuals has an excess iron-binding capacity. This is called the
Unsaturated Iron Biding Capacity (UIBC). The TIBC equals UIBC plus the serum iron
measurement. Some laboratories measure UIBC, some measure TIBC, and some measure
transferrin. These tests are usually done together and analyzed in relation to each other. On
their own the values do not mean much, but together the test results are helpful in defining
several iron problems.
Normal range:
Adult men : 240 to 450 µg/dL
Adult women: 240 to 450 µg/dL

total bilirubin: When bilirubin levels are high, in a condition called jaundice (a yellowing of
the skin and the whites of the eyes), and further testing is needed to find out what is the
cause. Too much bilirubin may mean that too many red cells are being destroyed, or that the
liver cannot remove all of the bilirubin from the blood.

It is not uncommon to see high bilirubin levels in newborn babies who are typically 1–3 days
old, and then this conditions is called neonatal bilirubinaemia.  Withing the first 24 hours of
life, up to 50% of full-term newborns, and an even greater percentage of pre-term babies,
may have a high a bilirubin level. At birth, the newborn lacks the intestinal bacteria that help
process bilirubin. This is not abnormal and resolves itself within a few days. In other
instances, newborns’ red blood cells may have been destroyed because of blood typing
incompatibilities. In adults or older children, bilirubin is measured to diagnose and/or
monitor liver diseases (such as cirrhosis, hepatitis, or gallstones).
Newborns: Excessive bilirubin damages developing brain cells in infants and may cause
mental retardation, physical abnormalities, or blindness. It is important that bilirubin in
newborns does not get too high. When the level of bilirubin is above a critical threshold,
special treatment is used to reduce it. An excessive bilirubin level may result from the
breakdown of red blood cells (RBCs) due to Rhesus blood typing incompatibility. (if the
mother is Rhesus negative [Rh-], the father is Rhesus positive [Rh+], and the fetus is Rh+,
then the mother develops antibodies against the newborn baby's RBCs, which are
destroyed.)

unconjugated bilirubin: Erythrocytes (red blood cells) generated in the bone marrow are
disposed of in the spleen when they get old or damaged. This releases hemoglobin, which is
broken down to heme as the globin parts are turned into amino acids. The heme is then
turned into unconjugated bilirubin in the reticuloendothelial cells of the spleen. This
unconjugated bilirubin is not soluble in water. It is then bound to albumin and sent to the
liver

Coomb’s test: The Coombs' test looks for antibodies that may bind to your red blood cells
and cause premature red blood cell destruction (hemolysis). There are two forms of the
Coombs' test: direct and indirect.

The direct Coombs' test is used to detect antibodies that are already bound to the surface of
red blood cells. Many diseases and drugs (quinidine, methyldopa, and procainamide) can
lead to production of these antibodies. These antibodies sometimes destroy red blood cells
and cause anemia. This test is sometimes performed to diagnose the cause of anemia or
jaundice.

The indirect Coombs' test looks for unbound circulating antibodies against a series of
standardized red blood cells. The indirect Coombs' test is only rarely used to diagnose a
medical condition. More often, it is used to determine whether a person might have a
reaction to a blood transfusion.

No clumping of cells (agglutination), indicating that there are no antibodies to red blood
cells, is normal. An abnormal (positive) direct Coombs' test means you have antibodies that
act against your red blood cells.

LDH: Lactate dehydrogenase (LDH or LD) is an enzyme (EC 1.1.1.27) present in a wide
variety of organisms, including plants and animals.
Lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate with
concomitant interconversion of NADH and NAD+. It converts pyruvate, the final product of
glycolysis to lactate when oxygen is absent or in short supply, and it performs the reverse
reaction during the Cori cycle in the liver. At high concentrations of lactate, the enzyme
exhibits feedback inhibition and the rate of conversion of pyruvate to lactate is decreased.
It also catalyzes the dehydrogenation of 2-Hydroxybutyrate, but it is a much poorer
substrate than lactate. There is little to no activity with beta-hydroxybutyrate.
Currently, the main use for LDH is as a general indicator of the existence and severity of
acute (short-term) or chronic (long-term) tissue damage and, sometimes, as a monitor of
progressive conditions. LDH isoenzymes may also be used to help determine which organs
are likely to be involved.

The overall use of LDH and LDH isoenzymes has decreased. Traditionally, they were most
frequently used, along with other tests such as CK and CK-MB, to help diagnose and
monitor myocardial infarctions (heart attacks). This use of LDH, however, has been almost
entirely replaced by troponin measurements in recent years because troponin is more
specific and sensitive to heart tissue injury than LDH. Elevated levels of LDH and changes in
the ratio of the LDH isoenzymes usually indicate some type of tissue damage. Usually LDH
levels will rise as the cellular destruction begins, peak after some time period, and then
begin to fall. For instance, when someone has a heart attack, blood levels of total LDH will
rise within 24 to 48 hours, peak in 2 to 3 days, and return to normal in 10 to 14 days. LDH
levels are elevated in many other conditions reflecting its widespread tissue distribution.

AST:An aspartate aminotransferase (AST) test measures the amount of this enzyme in the
blood. AST is normally found in red blood cells, liver, heart, muscle tissue, pancreas, and
kidneys. AST formerly was called serum glutamic oxaloacetic transaminase (SGOT).

Low levels of AST are normally found in the blood. When body tissue or an organ such as
the heart or liver is diseased or damaged, additional AST is released into the bloodstream.
The amount of AST in the blood is directly related to the extent of the tissue damage. After
severe damage, AST levels rise in 6 to 10 hours and remain high for about 4 days.

The AST test may be done at the same time as a test for alanine aminotransferase, or ALT.
The ratio of AST to ALT sometimes can help determine whether the liver or another organ
has been damaged. Both ALT and AST levels can test for liver damage.
ALT : An alanine aminotransferase (ALT) test measures the amount of this enzyme in the
blood. ALT is found mainly in the liver, but also in smaller amounts in the kidneys, heart,
muscles, and pancreas. ALT was formerly called serum glutamic pyruvic transaminase
(SGPT).

ALT is measured to see if the liver is damaged or diseased. Low levels of ALT are normally
found in the blood. But when the liver is damaged or diseased, it releases ALT into the
bloodstream, which makes ALT levels go up. Most increases in ALT levels are caused by
liver damage.

The ALT test is often done along with other tests that check for liver damage, including
aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and
bilirubin. Both ALT and AST levels are reliable tests for liver damage.

alkaline phosphatise: Alkaline phosphatase (ALP, ALKP) (EC 3.1.3.1) is a hydrolase

enzyme responsible for removing phosphate groups from many types of molecules,
including nucleotides, proteins, and alkaloids. The process of removing the phosphate
group is called dephosphorylation. As the name suggests, alkaline phosphatases are most
effective in an alkaline environment. It is sometimes used synonymously as basic
phosphatase. An alkaline phosphatase (ALP) test measures the amount of the enzyme ALP
in the blood. ALP is made mostly in the liver and in bone with some made in the intestines
and kidneys. It also is made by the placenta of a pregnant woman.

The liver makes more ALP than the other organs or the bones. Some conditions cause large
amounts of ALP in the blood. These conditions include rapid bone growth (during puberty),
bone disease (osteomalacia or Paget's disease), or a disease that affects how much calcium is
in the blood (hyperparathyroidism), or damaged liver cells.

If the ALP level is high, more tests may be done to find the cause.

Creatinine (from the Greek κρέας, flesh) is a break-down product of creatine phosphate in
muscle, and is usually produced at a fairly constant rate by the body (depending on muscle
mass). In chemical terms, creatinine is a spontaneously formed cyclic derivative of creatine.
Creatinine is chiefly filtered out of the blood by the kidneys (glomerular filtration and
proximal tubular secretion). There is little-to-no tubular reabsorption of creatinine. If the
filtering of the kidney is deficient, creatinine blood levels rise. Therefore, creatinine levels in
blood and urine may be used to calculate the creatinine clearance (CrCl), which reflects the
glomerular filtration rate (GFR). The GFR is clinically important because it is a measurement
of renal function. However, in cases of severe renal dysfunction, the creatinine clearance rate
will be "overestimated" because the active secretion of creatinine will account for a larger
fraction of the total creatinine cleared[clarification needed]. Ketoacids, cimetidine and trimethoprim
reduce creatinine tubular secretion and therefore increase the accuracy of the GFR estimate,
particularly in severe renal dysfunction. (In the absence of secretion, creatinine behaves like
inulin.)
Vitamin B12 and folate are primarily requested to help diagnose the cause of macrocytic
anaemia. They can be requested as follow-up tests when large red cells and a decreased
haemoglobin concentration are found during a FBC test. Folate and vitamin B12 may be
used to help evaluate the nutritional status of a patient with signs of significant malnutrition
or malabsorption. This may include those with alcoholism and those with disorders
associated with malabsorption such as coeliac disease, Crohn's disease, and cystic
fibrosis. B12 and folate may also be used to help diagnose the cause of mental or behavioural
changes, especially in the elderly.

In patients with known vitamin B12 and folate deficiencies, these tests may be used
occasionally to help monitor the effectiveness of treatment. This is especially true in patients
who cannot absorb vitamin B12 and/or folate and must have lifelong treatment. Either a
serum or RBC folate test may be used to help detect a deficiency. Some doctors feel that the
RBC folate test is more clinically relevant than serum folate but there is no widespread
agreement on this.

The doctor is looking for vitamin B12 and/or folate deficiency. If a symptomatic patient has
decreased concentrations of vitamin B12 and/or folate, then it is likely that he has some
degree of deficiency. The test results indicate the presence of deficiency, but do not
necessarily reflect the severity of the anaemia or neuropathy associated with the deficiency.

If a patient with a vitamin B12 or folate deficiency is being treated with supplements (or
with B12 injections), then normal or elevated results indicate a response to treatment.

High levels of B12 and folate are not usually monitored. Increased B12 may be seen in
conditions such as leukemia or liver dysfunction. Increased folate may be seen with
pernicious anaemia, vegetarian diets, or with a condition called bacterial overgrowth
syndrome where bacteria multiply in the upper bowels.

Moderate and severe thalassemias usually are diagnosed in early childhood. This is because
signs and symptoms, including severe anemia, occur within the first 2 years of life.

People who have milder forms of thalassemia may be diagnosed after a routine blood test
shows they have anemia. Doctors may suspect thalassemia if a child has anemia and is a
member of an ethnic group that's at increased risk for thalassemias.

Thalassemia (also spelled thalassaemia) is an inherited autosomal recessive blood disease.

In thalassemia the genetic defect, which could be either mutation or deletion, results in
reduced rate of synthesis or no synthesis of one of the globin chains that make up
hemoglobin. This can cause the formation of abnormal hemoglobin molecules, thus causing
anemia, the characteristic presenting symptom of the thalassemias.

Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell

anemia (a hemoglobinopathy) is a qualitative problem of synthesis of an incorrectly
functioning globin. Thalassemias usually result in underproduction of normal globin proteins,
often through mutations in regulatory genes. Hemoglobinopathies imply structural
abnormalities in the globin proteins themselves.[1] The two conditions may overlap, however,
since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also
affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but
most are not. Either or both of these conditions may cause anemia.

The two major forms of the disease, alpha- and beta- (see below), are prevalent in discrete
geographical clusters around the world - probably associated with malarial endemicity in
ancient times.

The thalassemia trait may confer a degree of protection against malaria, which is or was
prevalent in the regions where the trait is common, thus conferring a selective survival
advantage on carriers, and perpetuating the mutation. In that respect the various thalassemias
resemble another genetic disorder affecting hemoglobin, sickle-cell disease