1.

All about jaundice membrane transport and bound to proteins in the cytosol
• Prehepatic (the problem occurs “before the liver”), or to decrease the efflux of bilirubin back into the plasma.
hemolytic, jaundice arises from excessive breakdown • Conjugation of bilirubin - This unconjugated bilirubin then
(hemolysis) of red blood cells, which results in the liver proceeds to the endoplasmic reticulum, where it
being presented with more bilirubin than it is capable of undergoes conjugation to glucuronic acid resulting in the
excreting. formation of conjugated bilirubin, which is soluble in the
• Hepatic (the problem is the “liver”) jaundice occurs when bile. This is rendered by the action of UDP-glucuronosyl
the liver is diseased and cannot deal with even the normal transferase.
load of bilirubin. POSTHEPATIC
• Posthepatic (the problem occurs “after the liver”), or • Bile secretion from hepatocytes- Conjugated bilirubin is
obstructive, jaundice occurs when the bile duct is now released into the bile canaliculi into the bile ducts,
obstructed, such as by a gallstone, so that bilirubin cannot stored in the gallbladder, reaching the small bowel
be eliminated in the feces. through the ampulla of Vater and finally enters the colon.
Etiology • Intestinal metabolism and Renal transport- The intestinal
CONJUGATED HYPERBILIRUBINEMIA mucosa does not reabsorb conjugated bilirubin due to its
• Defect of canalicular organic anion transport: Dubin- hydrophilicity and large molecular size. The colonic
Johnson syndrome bacteria deconjugate and metabolize bilirubin into
• Defect of sinusoidal reuptake of conjugated bilirubin: urobilinogen's, 80% of which gets excreted into the feces
Rotor syndrome and stercobilin and the remaining (10 to 20%) undergoes
• Decreased intrahepatic excretion of bilirubin: enterohepatic circulation. Some of these urobilin's are
o Hepatocellular disease - Viral hepatitis A, B, D; alcoholic excreted through the kidneys imparting the yellow
hepatitis; cirrhosis, nonalcoholic steatohepatitis, EBV, pigment of urine.
CMV, HSV, Wilson, autoimmune • Dysfunction in prehepatic phase results in elevated serum
o Cholestatic liver disease-Primary biliary cholangitis, levels of unconjugated bilirubin while insult in post hepatic
primary sclerosing cholangitis phase marks elevated conjugated bilirubin. Hepatic phase
o Infiltrative diseases (e.g., amyloidosis, lymphoma, impairment can elevate both unconjugated and
sarcoidosis, tuberculosis) conjugated bilirubin.
o Sepsis and hypoperfusion states, • Increased urinary excretion of urobilinogen can be due to
o Total parenteral nutrition increased production of bilirubin, increased reabsorption
o Drugs & Toxins - oral contraceptives, rifampin, of urobilinogen from the colon, or decreased hepatic
probenecid, steroids, chlorpromazine, herbal clearance of urobilinogen.
medications (e.g., Jamaican bush tea, kava kava), Complication
arsenic Portal hypertension
o Hepatic crisis in sickle cell disease • abnormally high blood pressure in the portal vein (the
o Pregnancy large vein that brings blood from the intestine to the liver)
• Extrahepatic cholestasis (biliary obstruction) and its branches.
o Choledocholithiasis • The portal vein receives blood from the entire intestine
o Tumors (e.g., cholangiocarcinoma, head of pancreas and from the spleen, pancreas, and gallbladder and carries
cancer) that blood to the liver. After entering the liver, the vein
o Extrahepatic biliary atresia divides into right and left branches and then into tiny
o Acute and chronic pancreatitis channels that run through the liver. When blood leaves
o Strictures the liver, it flows back into the general circulation through
o Parasitic infections (e.g., Ascaris lumbricoides, liver the hepatic vein.
flukes) • Factors can increase blood pressure in the portal blood
UNCONJUGATED HYPERBILIRUBINEMIA vessels:
• Excess production of bilirubin: Hemolytic anemias, o An increased volume of blood flowing through the
extravasation of blood in tissues, dyserythropoiesis vessels
• Reduced hepatic uptake of bilirubin: Gilbert syndrome o Increased resistance to the blood flow through the liver
• Impaired conjugation • In Western countries, the most common cause of portal
o Crigler–Najjar syndrome type 1 and 2 hypertension is increased resistance to blood flow caused
o Hyperthyroid by extensive scarring of the liver in cirrhosis. Cirrhosis is
o Estrogen most often caused by
Mechanism o Chronic hepatitis C (hepatitis that has lasted at least 6
PREHEPATIC months)
• Production - Bilirubin is the end product of heme, which is o Drinking large amounts of alcohol over a long period of
released by senescent or defective RBCs. In the time
reticuloendothelial cells of spleen, liver and bone marrow, o Nonalcoholic fatty liver disease
heme released from the RBC undergoes a series of • Portal hypertension leads to the development of new
reactions to form the final product bilirubin: veins (called collateral vessels) that bypass the liver. These
• Heme-->Biliverdin-->Bilirubin (insoluble due to tight veins directly connect the portal blood vessels to veins
hydrogen bonding) that take blood away from the liver into the general
HEPATIC circulation. Because of this bypass, substances (such as
• Hepatocellular uptake - The bilirubin released from the toxins) that are normally removed from the blood by the
reticuloendothelial system is in an unconjugated form (i.e., liver can pass into the general circulation. Collateral
non-soluble) and gets transported to the hepatocytes vessels develop at specific places. The most important are
bound to albumin which accomplishes solubility in blood. located at the lower end of the esophagus and at the
The albumin-bilirubin bond is broken, and the bilirubin upper part of the stomach. Here, the vessels enlarge and
alone is then taken into the hepatocytes through a carrier- become full of twists and turns—that is, they become
varicose veins in the esophagus (esophageal varices) or
 stomach (gastric varices). These enlarged vessels are and lightheadedness. If bleeding is severe, the person may
fragile and prone to bleeding, sometimes seriously and lose consciousness.
occasionally with fatal results (see Gastrointestinal • Esophageal varices are dilated collateral blood vessels that
Bleeding). Other collateral vessels may develop on the develop as a complication of portal hypertension, usually
abdominal wall and at the rectum. in the setting of cirrhosis. Once cirrhosis has developed,
• Portal hypertension often causes the spleen to enlarge increasing hepatic vein pressure gradient and
because the pressure interferes with blood flow from the deteriorating liver function may result in the formation of
spleen into the portal blood vessels. When the spleen esophageal varices.
enlarges, the number (count) of white blood cells can Hemorrhoid
decrease (increasing the risk of infections), and the • Rectal varices are enlarged portal-systemic collateral veins
number (count) of platelets can decrease (increasing the that may develop in patients with portal hypertension;
risk of bleeding). thus, they represent another pathway for portal venous
• Increased pressure in the portal blood vessels may cause flow from the superior hemor- rhoidal veins (portal) to
protein-containing (ascitic) fluid to leak from the surface and through the middle and inferior hemorrhoidal veins
of the liver and intestine and to accumulate within the (systemic). Massive rec- tal hemorrhage in this
abdomen. This condition is called ascites. circumstance has been re- ported, albeit infrequently (9-
• If a large amount of fluid accumulates in the abdomen, the 11). Hemorrhoids, on the other hand, are a frequent cause
abdomen swells (distends), sometimes noticeably and of annoyance and rectal bleeding in the general
sometimes enough to make the abdomen greatly enlarged population, and their presence in patients with portal
and taut. This distention can be uncomfortable or painful. hypertension has not been observed with increased
An enlarged spleen may cause a vague sense of discomfort prevalence
in the upper left part of the abdomen. • Increased pressure in the veins of the anorectal area leads
• The varicose veins in the esophagus and stomach bleed to hemorrhoids. This pressure may result from pregnancy,
easily and sometimes massively. Then, people may vomit frequent heavy lifting, or repeated straining during
blood or dark material that resembles coffee grounds. defecation (eg, due to constipation).
Stools may be dark and tarry. Much less commonly, • External hemorrhoids are located below the dentate line
varicose veins in the rectum bleed. Then, stools may and are covered by squamous epithelium.
contain blood. Bleeding from these veins may result in • Internal hemorrhoids are located above the dentate line
death. and are lined by rectal mucosa. Hemorrhoids typically
• Collateral blood vessels may be visible on the skin of the occur in the right anterior, right posterior, and left lateral
abdomen or around the rectum. zones. They occur in adults and children.
• When substances that are normally removed from the • External hemorrhoids may become thrombosed, resulting
liver pass into the general circulation and reach the brain, in a painful, purplish swelling. Rarely, they ulcerate and
they may cause confusion or drowsiness (hepatic cause minor bleeding. Cleansing the anal region may be
encephalopathy). Because most people with portal difficult.
hypertension also have severe liver malfunction, they may • Internal hemorrhoids typically manifest with bleeding
have symptoms of liver failure, such as a tendency to after defecation; blood is noted on toilet tissue and
bleed. sometimes in the toilet bowl. Internal hemorrhoids may
• Etiology be uncomfortable but are not as painful as thrombosed
o Prehepatic: splenic or portal vein thrombosis external hemorrhoids. Internal hemorrhoids sometimes
(obstruction), arteriovenous fistula, massive cause mucus discharge and a sensation of incomplete
splenomegaly caused by a primary hematologic evacuation.
disorder (increased portal flow) • Strangulated hemorrhoids occur when protrusion and
o Hepatic: idiopathic portal hypertension, primary biliaru constriction occlude the blood supply. They cause pain
cholangitis, sarcoidosis, congenital hepatic fibrosis, that is occasionally followed by necrosis and ulceration.
schistosomiasis (presinusoidal), cirrhosis (sinusoidal), Melena
hepatic sinusoidal obstruction syndrome • black, tarry stool and typically indicates upper GI bleeding,
(postsinusoidal) but bleeding from a source in the small bowel or right
o Posthepatic: hepatic vein thrombosis, obstruction IVC colon may also be the cause.
(obstruction), constrictive pericarditis, restrictive • Bleeding of any cause is more likely, and potentially more
cardiomyopathy (resistance to right heart filling) severe, in patients with chronic liver disease (eg, alcoholic
Varices esophagus liver disease, chronic hepatitis), in those with hereditary
• Varices are expanded blood vessels that develop most coagulation disorders, or in those taking certain drugs.
commonly in the esophagus and stomach. In people with Drugs associated with GI bleeding include anticoagulants
cirrhosis, varices develop when blood flow through the (eg, heparin, warfarin), those affecting platelet function
liver is obstructed (blocked) by scarring, increasing the (eg, aspirin and certain other nonsteroidal anti-
pressure inside the portal vein, which carries blood from inflammatory drugs [NSAIDs], clopidogrel, selective
the intestines to the liver; this condition is called portal serotonin reuptake inhibitors [SSRIs]), and those affecting
hypertension. mucosal defenses (eg, NSAIDs).
• Portal hypertension leads to an increase in the blood Hematemesis
pressure inside the veins in the lower esophagus and • vomiting of red blood and indicates upper GI bleeding,
stomach. These veins were not designed for the higher usually from a peptic ulcer, vascular lesion, or varix
pressure, and thus they begin to expand, resulting in Pre-hepatic Hepatic Post-hepatic
varices. Once varices develop, they can remain stable, • Hemolytic anemia • Alcoholic liver • Intra-luminal causes
increase in size (if the liver disease worsens), or decrease • Gilbert’s syndrome disease (gallstone)
in size (if the liver disease improves). • Criggler-Najjar • Viral hepatitis • Cholangiocarcinoma,
• Varices do not cause symptoms until they leak or rupture, syndrome • Medications strictures, or drug
leading to massive bleeding. Signs of bleeding from varices • Hereditary induced cholestasis
can include vomiting blood, dark-colored or black stools, hemochromatosis
 • Autoimmune • Pancreatic cancer or enter the liver at the porta hepatis and follow the course
hepatitis abdominal mass of branches of the hepatic artery and portal vein.
• Primary biliary (lymphoma) • Glisson’s capsule, the fibrous covering of the liver, is
cirrhosis or • Cholecystitis or innervated by branches of the lower intercostal nerves.
primary sclerosing cholelithiasis Distension of the capsule results in a sharp, well localised
cholangitis pain.
• Hepatocellular
carcinoma
• Unconjugated • Conjugated & • Conjugated
bilirubin ­ unconjugated ­ bilirubin
• Indirect bilirubin + • Biphasic • Direct bilirubin +
• Urobilinogen +++ • Conjugated ++ • Conjugated +++
• Conjugated • Urobilinogen + • Urobilinogen –
bilirubin & bile salt • Bile salt + • Bile salt ++
absent in urine • Urine: dark • Urine: dark
• Urine color: (choluric) (choluric)
normal (acholuric) • Stool: normal • Stool: clay colored
• Stool: dark brown • AST, ALT very high • AST, ALT increased
• AST, ALT, ALP • ALP 2-3x increased • ALP 10-12x
normal • Clotting time, PT ­ increased
• Clotting time, PT, • Plasma protein ¯ • Clotting time, PT ­
plasma protein • Plasma protein ¯
normal

2. Anatomy of hepatobiliary system

Gallbladder
3. Association between alcohol and liver failure
• Vasculature:
• Alcohol is chiefly metabolized in hepatocytes using alcohol
o cystic artery – a branch of the right hepatic artery
dehydrogenase (ADH) with the help of catalase enzyme in
(which itself is derived from the common hepatic
peroxisome
artery, one of the three major branches of the coeliac
• Catalase: detoxify H2O2 to water and oxygen® in ethanol
trunk).
metabolism ® oxidize ethanol to acetaldehyde
o cystic veins, which drain directly into the portal vein.
Venous drainage of the fundus and body of the • Heavy ethanol consumption produces a wide spectrum of
gallbladder flows into the hepatic sinusoids. hepatic lesions, the most characteristic being fatty liver
(i.e., steatosis), hepatitis, and fibrosis/cirrhosis
• Innervation:
o Coeliac plexus carries sympathetic and sensory fibres • Steatosis was formerly considered a benign consequence
o Vagus nerve delivers parasympathetic innervation of alcohol abuse. It is characterized by the deposition of
fat, seen microscopically as lipid droplets, initially in the
• Bile is initially secreted from hepatocytes and drains from
both lobes of the liver via canaliculi, intralobular ducts and hepatocytes that surround the liver’s central vein (i.e.,
perivenular hepatocytes), then progressing to mid-lobular
collecting ducts into the left and right hepatic ducts. These
hepatocytes, and finally to the hepatocytes that surround
ducts amalgamate to form the common hepatic duct,
the hepatic portal vein (i.e., periportal hepatocytes). If the
which runs alongside the hepatic vein.
affected individual ceases drinking, steatosis is a reversible
• As the common hepatic duct descends, it is joined by the
condition with a good prognosis
cystic duct – which allows bile to flow in and out of the
• the presence of fat likely represents a greater risk for lipid
gallbladder for storage and release. At this point, the
peroxidation and oxidative damage.
common hepatic duct and cystic duct combine to form the
common bile duct. • Alcoholic hepatitis is a more severe, inflammatory type of
• The common bile duct descends and passes posteriorly to liver injury characterized by swollen, dying hepatocytes
the first part of the duodenum and head of the pancreas. (i.e., ballooning degeneration), neutrophilic infiltration,
Here, it is joined by the main pancreatic duct, forming the and the development of tangled aggregates of insoluble
hepatopancreatic ampulla (commonly known as the proteins called Mallory-Denk bodies within hepatocytes.
Central to hepatitis development is the activation of KCs,
ampulla of Vater) – which then empties into the
the resident liver macrophages.
duodenum via the major duodenal papilla. This papilla is
regulated by a muscular valve, the sphincter of Oddi. • Fibrosis and its terminal or late stage, cirrhosis, refer to
Liver the deposition of abnormal amounts of extracellular
• Vasculature: matrix proteins, principally by activated HSCs. Patients
o Hepatic artery proper (25%) - supplies the non- initially exhibit active pericellular fibrosis, which may
progress to cirrhosis, the late stage of hepatic scarring.
parenchymal structures of the liver with arterial blood.
However, some degree of hepatitis likely is always present
It is derived from the coeliac trunk.
in cirrhotic patients, whereas hepatic fat usually is not
o Hepatic portal vein (75%) - supplies the liver with
partially deoxygenated blood, carrying nutrients prominent in these individuals.
absorbed from the small intestine. This is the dominant Steatosis
Alcohol accelerate hepatic lipogenesis
blood supply to the liver parenchyma, and allows the
liver to perform its gut-related functions, such as • Enhanced lipid synthesis results from a higher expression
detoxification. of lipogenic enzymes and cytokines
• The parenchyma of the liver is innervated by the hepatic • Adipose tissue normally is an important energy depot,
plexus, which contains sympathetic (coeliac plexus) and storing excess calories derived from food consumption as
parasympathetic (vagus nerve) nerve fibres. These fibres fat. When necessary, high-energy fat then can be used to
 fulfill energy requirements during times of low nutrition • Hepatic fibrosis is a transient and reversible wound-
(e.g., fasting) or high calorie utilization (e.g., exercise). healing response, which may be restored to normal in
• Ethanol consumption reduces adipose tissue mass by some patients if alcohol intake ceases. However, if
enhancing fat breakdown (i.e., lipolysis) in adipose tissue drinking continues, chronic inflammation and sustained
® free fatty acids released from adipose tissue are taken fibrogenesis progress, resulting in the substitution of liver
up by the liver and esterified into triglycerides, thereby parenchyma by scar tissue that severely compromises the
exacerbating fat accumulation in the liver liver’s vascular architecture. The main pathological feature
Decelerates hepatic lipid breakdown of cirrhosis is the formation of regenerative nodules of
• Because most lipids in hepatocytes are stored in lipid hepatic parenchyma surrounded by fibrous septa.
droplets, these organelles must first be degraded to Cirrhosis development progresses from a compensated
extract the lipids for their subsequent oxidation. phase, in which part of the liver remains undamaged and
Breakdown of lipid droplets is accomplished by lipophagy, functionally compensates for the damaged regions, to a
a specialized form of the intracellular process that decompensated phase, in which scar tissue fully envelops
degrades cytoplasmic components (i.e., autophagy). the organ. The latter is characterized by development of
During lipophagy, lipid droplets are engulfed within portal hypertension and/or liver failure.
double- membrane–bound vacuoles called
autophagosomes. These vacuoles transport the lipid-
droplet cargo to lysosomes, where they are degraded by
lipid-digesting enzymes (i.e., lipases), releasing free fatty
acids that then undergo β-oxidation inside mitochondria.
The rates of autophagy reportedly are retarded by chronic
ethanol consumption, at least in part because ethanol is
thought to cause faulty lysosome biogenesis. This results
in fewer, more defective lysosomes (Kharbanda et al.
1995, 1996), thereby slowing the breakdown of lipid
droplets in the steatotic liver.
• Heavy alcohol consumption reduces their rates of β-
oxidation.
Causes defective hepatic lipid export
• liver exports triglycerides and cholesterol only as
constituents of very low density lipoprotein (VLDL)
particles; any impairment in either the synthesis or export
of VLDL particles therefore contributes to fat accumulation
within hepatocytes
Hepatitis
• Ballooning degeneration of hepatocytes containing
Mallory-Denk bodies, infiltrating neutrophils, and fibrosis
are characteristic pathologic findings indicative of hepatitis
• Because the liver is exposed to countless antigens,
pathogens, and toxic substances that come from the
intestine via the portal circulation, it must be protected
from developing an immune response to such exposure.
As a result, KCs usually have tolerogenic properties,
meaning that they do not respond to all antigens with an
immune response.
• However, excessive alcohol exposure can switch KCs to a
proinflammatory M1 phenotype. Usually, ALD progression
from liver steatosis to inflammation requires a second
insult in addition to the alcohol exposure, such as another
toxic insult, nutritional factor, or viral infection
• excess ethanol intake induces endotoxemia through two
main mechanisms—by stimulating bacterial overgrowth
and by increasing intestinal permeability
Fibrosis or cirrhosis
• HSCs are the key players in the development of fibrosis.
These cells normally reside in the space of Disse as
quiescent, lipid (retinyl-ester)-storing cells.
• Following hepatic injury, HSCs undergo a complex
activation process and become the principal source for the
increased and irregular deposition of extracellular-matrix
components that characterize fibrosis. Activated HSCs also
contribute to the inflammatory response, coordinating the
recruitment and stimulation of leukocytes by releasing
chemokines and proinflammatory cytokines as well as 4. Physiology of hepatobiliary system
expressing adhesion molecules. The leukocytes, in turn, Pancreas
not only attack and destroy hepatocytes, but also activate Exocrine
quiescent and activated HSCs, thereby exacerbating the • Consist of acini (secretory cells) which connect to duct ®
fibrogenic response empty into duodenum
 • Pancreatic juices: pancreatic enzymes actively secreted by o Synthesizing plasma proteins
acinar cells, aqueous alkaline solution actively secreted by o Storing glycogen, fats, iron, copper, vitamins
duct cells rich in sodium bicarbonate (NaHCO3) o Activating vitamin D
• Pancreatic enzymes ® within zymogen granules o Secreting the hormones thrombopoietin (stimulates
(secretory vesicles) ® exocytosis as needed platelet production), hepcidin (inhibit iron uptake from
• Acinar cells secretes: proteolytic enzymes for protein intestine), insulin-like growth factor I (stimulates
digestion, pancreatic amylase for carbohydrate digestion, growth)
pancreatic lipase for fat digestion o Producing acute phase proteins in inflammation
• Proteolytic enzymes o Excreting cholesterol and bilirubin
o Trypsinogen, chymotrypsinogen, procarboxypeptidase o Removing bacteria and worn out RBC (macrophage)
secreted in inactive form • Resident macrophage: Kupffer cells
o Trypsinogen ® secreted into duodenum ® • Opening of bile duct is guarded by sphincter of Oddi
enteropeptidase ® activated ® trypsin ® (prevents bile from entering the duodenum except during
autocatalytically activates more trypsinogen digestion of meals)
o Pancreas also produce trypsin inhibitor to block its • When the sphincter is closed ® bile diverted back to
action if spontaneous activation inadvertently occurs gallbladder
o Chymotrypsinogen & procarboxypeptidase ® • After a meal ® relaxation of sphincter Oddi, gallbladder
converted by trypsin ® active form ® chymotrypsin, contraction, increased bile secretion by liver ® bile enters
carboxypeptidase within duodenal lumen the duodenum
o End product: small peptide chains, amino acids • Bile contains bile salt, cholesterol, lecithin (phospholipid),
• Pancreatic amylase and bilirubin in aqueous alkaline fluid
o Converting dietary starches (amylose, amylopectin) Bile salt
into disaccharide maltose and branched polysaccharide • Derivatives of cholesterol
o Secreted in active form • After fat digestion and absorption ® reabsorbed into
• Pancreatic lipase blood by special active transport mechanism in terminal
o The only enzyme that can digest fat ileum ® return by hepatic portal system ® to liver ®
o Hydrolyzes dietary triglycerides into monoglycerides & recreates bile ® recycling called enterohepatic circulation
free fatty acids (absorbable units) • Aid fat digestion through detergent action (emulsification)
o Secreted in active form & facilitate fat absorption by participating in formation of
• Aqueous alkaline micelles
o Pancreatic enzymes function best in neutral or slightly • Detergent action: bile salt ability to convert large fat
alkaline environment globules into lipid emulsion consisting of many small fat
o The acidic chyme entering the duodenum must be droplets suspended in aqueous chyme ® stabilizes
neutralized quickly to allow functioning of pancreatic droplets ® increase surface area for lipase to work (bind
enzymes and prevent damage to duodenal mucosa to triglyceride)
o HCO3- is secreted into duct lumen from: • Lipase cannot penetrate the layer of bile salt adsorbed on
§ CO2 from diffusion or cellular metabolism ® the surface of small emulsified fat droplets ® pancreas
carbonic anhydrase ® CO2 + OH- ® HCO3- secrets colipase (has both lipid and water-soluble part)
§ HCO3- exits across luminal membrane enters the • In micelle: bile salts & lecithin aggregate in small clusters
cell from the plasma via Na/HCO3 symporter at with their fat-soluble part in the middle forming
basolateral membrane hydrophobic core, while the water-soluble part form outer
o HCO3 exits the pancreatic duct cell to enter duct lumen: hydrophilic shell ® provide vehicle for carrying water
§ CL/HCO3 antiporter insoluble substances through the watery luminal contents
§ Diffusing through a cystic fibrosis transmembrane • The most important lipid-soluble substances carried within
conductance regulator (CFTR) channel micelles are the products of fat diges- tion
o Na diffuse down an electrochemical gradient via (monoglycerides and free fatty acids), and fat-soluble vita-
paracellular transport through the leaky tight junctions mins, which are all transported to their sites of absorption
between duct cells into lumen by this means. If they did not hitch a ride in the water-
Endocrine soluble micelles, these nutrients would float on the
• The islets of Langerhans ® secrete insulin & glucagon surface of the aque- ous chyme (just as oil floats on top of
• Regulated by secretin and CCK in response to chyme in the water), never reaching the absorptive surfaces of the small
duodenum (fat, acid, hypertonicity, distension) intestine. In addition, choles- terol, a highly water-
• Acid in duodenal lumen ® secretin release from duodenal insoluble substance, dissolves in the micelle’s hydrophobic
mucosa ® carried by blood ® stimulates duct cells ® core.
increase secretion of NaHCO3 rich aqueous fluid into • Choleretic: any substance that increase bile secretion
duodenum ® neutralizes the acid • Bile salt return by enterohepatic circulation to liver ® act
• CCK: regulate pancreatic digestive enzyme secretion as potent choleretics ® stimulate further bile secretion
• Fat, protein products in duodenal lumen ® CCK release • Vagal stimulation plays minor role in bile secretion during
from duodenal mucosa into blood ® CCK transported by cephalic phase
blood to pancreas ® stimulate acinar cells ® increase • When chyme reaches the small intestine ® fat presence
digestive enzyme secretion (lipase, proteolytic enzymes) ® trigger release of CCK ® stimulate contraction of
Liver gallbladder and relaxation of sphincter Oddi ® bile
• Biliary system: liver, gallbladder, ducts discharged into duodenum
• Liver functions: Bilirubin
o Secretion of bile salts ® aid fat digestion & absorption • A waste product excreted in bile
o Metabolic processing of major nutrients after their • Primary bile pigment derived from the breakdown of
absorption from digestive tract worn-out RBC which are removed from the blood by
o Detoxifying or degrading body waste and hormones macrophages that line the liver sinusoids
 • Is the end product from degradation of heme between hepatocytes and plasma facilitates most key
• Hepatocytes takes up bilirubin from plasma ® slightly hepatocyte functions that involve uptake and release of
modify it to increase its solubility ® actively excreted into nutrients, proteins, and potential toxins.
bile • Two other functionally important cells are found with the
• Within intestinal tract ® it is modified by bacterial sinusoids of hepatic lobules:
enzymes ® brown color of feces o Numerous specialized stellate macrophages, usually
• When bile secretion does not occur (gallstone) ® feces called Kupffer cells, are found within the sinusoid lining.
grayish white These cells recognize and phagocytose aged
• Small amount of bilirubin is reabsorbed into blood ® erythrocytes, freeing heme and iron for reuse or
excreted in urine storage in ferritin complexes. Kupffer cells are also
antigen-presenting cells and remove any bacteria or
debris present in the portal blood.
o In the perisinusoidal space are hepatic stellate cells (or
Ito cells) with small lipid droplets that store vitamin A
and other fat-soluble vitamins. These mesenchymal
cells, which are difficult to see in routine preparations,
also produce extracellular matrix (ECM) components
(becoming myofibroblasts after liver injury) and
cytokines that help regulate Kupffer cell activity.
• The classic hepatic lobule (Figure 16–18a), with blood
flowing past hepatocytes from the portal areas to a cen-
tral venule, emphasizes the endocrine function of the
structure producing factors for uptake by plasma.
• The concept of portal lobules of hepatocytes is more
useful when considering the exocrine function of these
cells, that is, bile secretion. The portal area has the bile
ductule at the center, and bile, moving in the opposite
direction as the blood, flows toward it from all the sur-
rounding hepatocytes. The tissue draining bile into each
portal area duct is roughly triangular in shape, with the
central veins of three classic lobules at its angles
• The hepatic acinus, a third way of viewing liver cells,
emphasizes the nature of the blood supply to the hepa-
tocytes and the oxygen gradient from the hepatic artery
branch to the central vein. In a liver acinus hepatocyte
make up an irregular oval or diamond-shaped area
extending from two portal triads to the two closest cen-
tral veins. Periportal hepatocytes nearest the hepatic
5. Histology of liver, bile duct, bile sac arteriole, comprising zone I in the acinus, get the most
Liver oxygen and nutrients and can most readily carry out
• Hepatocytes are large cuboidal or polyhedral epithelial functions requiring oxidative metabolism such as protein
cells, with large, round central nuclei and eosinophilic synthesis. Hepatocytes in zone III, near the central vein,
cytoplasm rich in mitochondria. get the least oxygen and nutrients. They are the
• The liver parenchyma is organized as thousands of small preferential sites of glycolysis, lipid formation, and drug
(~0.7 × 2 mm) hepatic lobules in which hepatocytes form biotransformations and are the first hepatocytes to
hundreds of irregular plates arranged radially around a undergo fatty accumulation and ischemic necrosis. In the
small central vein intervening zone II, hepatocytes have an intermediate
• The hepatocyte plates are supported by a delicate stroma range of metabolic functions between those in zones I and
of reticulin fibers III. The major activities in any given hepatocyte result from
• Peripherally each lobule has three to six portal areas with the cell adapting to the microenvironment produced by
more fibrous connective tissue, each of which contains the contents of the blood to which it is exposed.
three interlobular structures that comprise the portal triad
• A venule branch of the portal vein, with blood rich in
nutrients but low in O2,
• An arteriole branch of the hepatic artery that supplies O2,
• One or two small bile ductules of cuboidal epithelium,
branches of the bile conducting system.
• Between all of the anastomosing plates of hepatocytes of
a hepatic lobule are important vascular sinusoids that
emerge from the peripheral branches of the portal vein
and hepatic artery and converge on the lobule's central
vein. The venous and arterial blood mixes in these
irregular hepatic sinusoids. The anastomosing sinusoids
have thin, discontinuous linings of fenestrated endothelial
cells surrounded by sparse basal lamina and reticular
fibers. The discontinuities and fenestrations allow plasma
to fill a narrow perisinusoidal space (or space of Disse) and
directly bathe the many irregular microvilli projecting from
the hepatocytes into this space. This direct contact
 insoluble and therefore doesn’t affect the colour of the patient’s
urine. Conjugated bilirubin, however, can pass into the urine as
urobilinogen, causing the urine to become darker. 1
In a similar fashion, the colour of the stools can be used to
differentiate the causes of jaundice. If bile and pancreatic lipase’s
are unable to reach the bowel because of a blockage (e.g. in
obstructive post-hepatic pathology), fat is not able to be absorbed,
resulting in stools appearing pale, bulky and more difficult to flush.
The combination of the colour of urine and stools can give an
indication as to the cause of jaundice:
Normal urine + normal stools = pre-hepatic cause
Dark urine + normal stools = hepatic cause
Dark urine + pale stools = post-hepatic cause (obstructive)

Gallbladder Albumin
Albumin is synthesised in the liver and helps to bind water, cations,
fatty acids and bilirubin. It also plays a key role in maintaining the
oncotic pressure of blood.
Albumin levels can fall due to:
Liver disease resulting in a decreased production of albumin (e.g.
cirrhosis)
Inflammation triggering an acute phase response which temporarily
decreases the liver’s production of albumin
Excessive loss of albumin due to protein-losing enteropathies or
nephrotic syndrome

Prothrombin time
Prothrombin time (PT) is a measure of the blood’s coagulation
6. How splenomegaly occurs in this case tendency, specifically assessing the extrinsic pathway. In the
7. All about the lab (sgot, sgpt, gamma gt, ap, albumin, globulin, absence of other secondary causes such as anticoagulant drug use
pt, apt) and vitamin K deficiency, an increased PT can indicate liver disease
• ALT is found in high concentrations within hepatocytes and dysfunction. The liver is responsible for the synthesis of clotting
and enters the blood following hepatocellular injury. It is, factors, therefore hepatic pathology can impair this process
therefore, a useful marker of hepatocellular injury. resulting in an increased prothrombin time.
• ALP is particularly concentrated in the liver, bile duct and
bone tissues. ALP is often raised in liver pathology due to ALT/AST ratio
increased synthesis in response to cholestasis. As a result, The ALT/AST ratio can be used to determine the likely cause of LFT
ALP is a useful indirect marker of cholestasis. derangement:
• A greater than 10-fold increase in ALT and a less than 3- ALT > AST is seen in chronic liver disease
fold increase in ALP suggests a predominantly AST > ALT is seen in cirrhosis and acute alcoholic hepatitis
hepatocellular injury
• A less than 10-fold increase in ALT and a more than 3-fold Gluconeogenesis
increase in ALP suggests cholestasis Gluconeogenesis is a metabolic pathway that results in the
• It is possible to have a mixed picture involving generation of glucose from certain non-carbohydrate carbon
hepatocellular injury and cholestasis substrates. The liver plays a significant role in gluconeogenesis and
• If there is a rise in ALP, it important to review the level of therefore assessment of serum blood glucose can provide an
gamma-glutamyl transferase (GGT). A raised GGT can be indirect assessment of the liver’s synthetic function.
suggestive of biliary epithelial damage and bile flow Gluconeogenesis tends to be one of the last functions to become
obstruction. It can also be raised in response to alcohol impaired in the context of liver failure.
and drugs such as phenytoin. A markedly raised ALP with a
raised GGT is highly suggestive of cholestasis. Hepatocellular Labs
• A raised ALP in the absence of a raised GGT should raise Aminotransferase includes AST and ALT. They are markers of
your suspicion of non-hepatobiliary pathology. Alkaline hepatocellular injury. They participate in gluconeogenesis by
phosphatase is also present in bone and therefore catalyzing the transfer of amino groups from aspartic acid or alanine
anything that leads to increased bone breakdown can to ketoglutaric acid to produce oxaloacetic acid and pyruvic acid
elevate ALP. respectively. AST is present in cytosolic and mitochondrial
• Causes of an isolated rise in ALP include: isoenzymes and is found in the liver, cardiac muscle skeletal muscle,
o Bony metastases / primary bone tumours (e.g. kidneys, brain, pancreas, lungs, leucocytes, and red cells. It is not as
sarcoma) sensitive or specific for the liver. ALT is a cytosolic enzyme that is
o Vitamin D deficiency found in high concentrations in the liver. Hepatocellular injury and
o Recent bone fractures not necessarily cell death is the trigger for the release of these
o Renal osteodystrophy enzymes into the circulation.
Bilirubin
Bilirubin is a breakdown product of haemoglobin. Unconjugated Cholestasis Labs
bilirubin is taken up by the liver and then conjugated. Alkaline phosphatase is part of a family zinc metalloenzymes that
Hyperbilirubinaemia may not always cause clinically-apparent are highly concentrated in the microvilli of the bile canaliculus as
jaundice (usually visible >60 umol/l). The patient’s symptoms and well as several other tissues (e.g., bone, intestines). Glycoprotein
clinical signs can help differentiate between conjugated and gamma-glutamyltransferase (GGT) is located on membranes of cells
unconjugated hyperbilirubinaemia. Unconjugated bilirubin is water- with high secretory or absorptive activities. Its main function is to
catalyze the transfer of a gamma-glutamyl group from peptides to
other amino acids. It is also abundant in many other sources of the
body (kidney, pancreas, intestine, and prostate) but is more specific If ALP is elevated in isolation, measurement of GGT (see below) can
for biliary disease when compared to alkaline phosphatase because help to provide some indication as to whether or not the origin is
it is not present in bone. hepatic, and, if doubt remains, electrophoresis can be used to
differentiate hepatic from non-hepatic ALP.3
Bilirubin is formed from the lysis of red cells within the
reticuloendothelial system. Unconjugated bilirubin is transported to Aspartate aminotransferase and alanine aminotransferase
the liver loosely bound to albumin. Bilirubin is water-insoluble and
cannot be excreted in urine. Bilirubin that is conjugated is water Elevated levels of aspartate aminotransferase (AST) and alanine
soluble and appears in the urine. It is conjugated in the liver to aminotransferase (ALT) are the most common abnormalities seen in
bilirubin glucuronide and subsequently secreted into bile and the liver blood tests. Both AST and ALT are enzymes present in
gut respectively. hepatocytes that are released into the blood following hepatocyte
injury or death.3 Alanine aminotransferase is present at low
Synthetic Function Tests concentrations in non-hepatic tissue and elevations that are not
Albumin is synthesized in the liver, producing approximately 10 liver-related are uncommon. In contrast, AST is present in cardiac,
grams per day. With any liver disease, there is a fall in serum smooth, and skeletal muscle and may be elevated in myocardial
albumin, reflecting decreased synthesis. If liver function is normal infarction or myositis. Although AST is not as liver-specific as ALT, it
and serum albumin is low, this may reflect on poor intake of protein may be a more sensitive indicator of liver cell injury.3
(malnutrition) or loss of protein (nephrotic syndrome,
malabsorption, or protein-losing enteropathy) In children, creatine kinase measurement may help to determine
whether an isolated rise in either of these two enzymes is due to an
Prothrombin time (PT) measures the rate of conversion of underlying skeletal muscle disorder, such as muscular dystrophy.3
prothrombin to thrombin. Except for factor VIII, all other
coagulation factors are synthesized by the liver. This requires factors Gamma-glutamyltransferase
II, V, VII, and X and, as these are made in the liver, the liver's
function is important. If the synthetic function of the liver is normal Abundant in the liver and also present in the intestines, kidneys,
and prothrombin time is delayed this may indicate treatment with pancreas, and prostate, but not in bone, GGT can be useful in
warfarin, consumptive coagulopathy (e.g., disseminated determining whether elevated ALP is of bone or liver origin. Levels
intravascular coagulopathy), or deficiency of vitamin K. of GGT may be elevated by factors that are not liver-related,
including obesity, excess alcohol consumption, and certain drugs. In
Bilirubin spite of this low specificity, GGT is one of the best predictors of
mortality in liver disease.3
Most laboratories report total bilirubin, which will be raised by an
elevation of either the conjugated or the unconjugated form. In As ALP is not a reliable indicator in children, GGT can be used to
adults, the most likely cause of an isolated raised unconjugated establish the likelihood of biliary disease, for example congenital
bilirubin, once haemolysis has been excluded, is Gilbert’s abnormalities of the biliary tract and genetic disorders of bile
syndrome—an inherited metabolic disorder characterised by metabolism.3
impaired conjugation, which is not associated with liver disease.3
Raised conjugated bilirubin is seen in obstruction of the Coagulation tests
hepatobiliary system or in parenchymal liver disease, such as
hepatitis from any cause or advanced cirrhosis.3 Prothrombin time (PT) and international normalised ratio (INR) are
measures of blood clotting. Clotting factors are synthesised in the
Interpretation of hyperbilirubinaemia in neonates and infants liver and, when there is significant liver damage (usually >70% loss
requires specialist support because of the risk of kernicterus and the of synthetic function), their production is reduced, which may be
need to diagnose with urgency conditions such as biliary atresia.8 demonstrated by prolonged PT or INR. Prolonged PT or INR can,
therefore, indicate acute or chronic liver dysfunction, but can also
Albumin be caused by vitamin K deficiency in fat malabsorption and chronic
cholestasis.3
Albumin is a protein synthesised by the liver that can serve as a
marker of synthetic liver function. Albumin concentration may, Platelets
however, be reduced in other clinical situations, including sepsis,
systemic inflammatory disorders, nephrotic syndrome, Platelet reduction is an indicator of advanced liver disease, although
malabsorption, and gastrointestinal protein loss.3 platelets may be reduced in a wide variety of medical conditions. In
liver morbidity, platelet reduction is associated with splenic
Alkaline phosphatase enlargement secondary to portal hypertension with consequent
platelet sequestration; a reduction in thrombopoietin levels; and
Alkaline phosphatase (ALP) is predominantly a liver enzyme but is reduced platelet production.3
also found in bone and in smaller quantities in the intestines,
kidneys, and white blood cells. Levels of ALP are higher in childhood
and in pregnancy, where it is associated with bone growth and
placental production, respectively.3 Consequently, pathologically
increased levels of ALP may be found not only in cholestatic liver
disease (e.g. common bile duct obstruction, intrahepatic duct
obstruction [including by metastases], primary biliary cholangitis,
primary sclerosing cholangitis, and drug-induced cholestasis) but
also in bone disease (metastatic bone disease, vitamin D deficiency,
Paget’s disease, and bone fractures). Raised ALP may also result
from cholestasis caused by hepatic congestion due to right-sided
heart failure.3
1. Hepatitis A • Antigen expressed on the surface of nucleocapsid core ®
• Hepatovirus genus of the picornavirus family, RNA virus hepatitis B core antigen (HBcAg) ® antibody ® anti-HBc
• Hepatitis A has an incubation period of ~4 weeks. • Hepatitis B e antigen (HBeAg) ® soluble, nucleocapsid
• Its replication is limited to the liver, but the virus is present protein that is immunologically distinct from intact HBcAg
in the liver, bile, stools, and blood during the late • HBsAg (+) serum containing HBeAg ® highly infectious ®
incubation period and acute preicteric/ presymptomatic associated with presence of hepatitis B virion
phase of illness. • Persistent HBeAg in serum beyong 3 months of acute
• Despite slightly longer persistence of virus in the liver, infection ® predictive of chronic infection development
fecal shedding, viremia, and infectivity diminish rapidly • Presence of HBeAg during chronic hepatitis ® ongoing
once jaundice becomes apparent. viral replication, infectivity, inflammatory liver injury
• Transmitted by fecal-oral route • Serologic & virologic markers:
• Incubation: 15-45 days (4 weeks) o HBsAg: within 1-12 weeks (usually 8-12 weeks) ®
• Antibodies to HAV (anti-HAV) can be detected during precedes elevation of serum aminotransferase &
acute illness when serum aminotransferase activity is symptoms by 2-6 weeks ® remain detectable during
elevated and fecal HAV shedding is still occurring. entire icteric or symptomatic phase of acute infection
• This early antibody response is predominantly of the IgM ® undetectable 1-2 months after onset of jaundice,
class and persists for several (~3) months, rarely for 6–12 rarely persist beyond 6 months
months. o After HBsAg disappears ® anti-HBs detectable and
• During convalescence, however, anti-HAV of the IgG class remain indefinitely
becomes the predominant antibody. o HBcAg is intracellular and sequestered within HBsAg
• Diagnosis of hepatitis A is made during acute illness by coat ® HBcAg not detectable
demonstrating anti- HAV of the IgM class. After acute o Anti-HBc detectable within 1-2 weeks after the
illness, anti-HAV of the IgG class remains detectable appearance of HBsAg ® preceding anti-HBs by weeks
indefinitely, and patients with serum anti-HAV are to months
immune to reinfection. Neutralizing antibody activity o Window (gap) period: absence of HBsAg and anti-HBs,
parallels the appearance of anti-HAV, and the IgG anti- only contain anti-HBc
HAV present in immune globulin accounts for the o Isolated anti-HBc: hepB infection on remote past
protection it affords against HAV infection. o IgM anti-HBc predominates during first 6 months after
• Diagnosis: acute infection (recent or current), IgG anti-HBc
o Serum or fecal HAV not routinely available predominates beyond 6 months (chronic, remote past)
o Detection of IgM anti-HAV during acute illness o HBeAg: concurrent or shortly after HBsAg ® high level
of virus replication, reflects the presence of circulating
intact virion and detectable HBV DNA ® undetectable
shortly after peak elevations of aminotransferase
o Anti-HBe detectable before the disappearance of HBsAg
® lower infectivity
o Chronic infection: HBsAg remains beyond 6 months,
anti-HBc IgG, anti-HBs undetectable
o HBV DNA: quantitative marker of replicative phase
o HBeAg: qualitative marker of replicative phase
• Hepatitis B antigens & HBV DNA have been identified in
lymph nodes, bone marrow, circulating lymphocytes,
spleen, pancreas
Pathogenesis
• Nucleocapsid proteins (HBcAg & HBeAg) on cell membrane
2. Hepatitis B
® invite cytolytic T cells ® destroy HBV-infected
• Hepadnavirus (hepatotropic DNA virus)
hepatocytes
• Transmission: percutaneous inoculation, body fluids
• Innate immune system, inflammatory cytokines ® early
(saliva, semen), intimate (sexual) contact, perinatal
immune response to HBV ® elimination of HBV
• High risk population: born in high or intermediate
replication intermediates from cytoplasm and covalently
prevalence of HBV, household & sexual contacts with hepB
closed circular viral DNA from nucleus of infected
+ person, babies born to HBsAg + mother, injection drugs
hepatocytes
user, multiple sexual contact or history of std, person with
• Innate immune response: mediated by NK cell activated by
HCV or HIV infection, blood/plasma/organ/tissue/semen
cytokines ® increased signals from activating receptor
donor, hemodialysis patient, immunocompromised
expression on infected hepatocytes ® reduce THelper
• Incubation: 30-180 days (8-12 weeks)
cells ® reduce CD8 T cell
• HBV replicate in liver but exist in extrahepatic sites ®
• HBV-HLA specific cytolytic T cell responses of adaptive
associated with acute and chronic hepatitis, hepatocellular
immune system responsible for recovery from HBV
carcinoma
• Vertical transmission from mother with highly replicative
• Contain its own endogenous DNA polymerase
(HBeAg +) to baby ® develop chronic infection ® because
• Morphology form:
o Double-shelled virion (surface & core spherical) exposure to HBeAg induce T cell tolerance ® immunologic
o Nucleocapsid core clearance doesn’t occur ® infection persist ® prevention:
o Spherical & filamentous, represent excess virus coat immunization
material • Immune complex (HBsAg-anti-HBsAg) may deposit in
• Envelope protein expressed on the outer surface of virion tissue ® prodromal serum sickness, glomerulonephritis
& on smaller spherical tubular structure ® hepatitis B Diagnosis
surface antigen (HBsAg) • Detection of HBsAg in serum
 • If levels of HBsAg too low during acute HBV infection ® • Acute infection yg recover: immune response more robust
test for IgM anti-HBc ® high in number, more diverse in viral antigen
• HBeAg ® indicator of relative infectivity ® indicated in specificity, more functionally effective, more long lasting
chronic infection Diagnosis
• If patients receiving blood donor yg HBsAg + ® test IgM • Episodic pattern of aminotransferase elevation
anti-HBc to distinguish between acute or recent infection • Specific: anti-HCV during initial phase of elevated
(IgM anti-HBc +), or chronic (IgM anti-HBc -, IgG anti-HBc+) aminotransferase activity and remains after recovery
• Anti-HBs rarely detectable in acute infection (rare) or during chronic infection (common)
• After immunization: anti-HBs • HCV RNA: detectable before acute elevation of
• HBV DNA: indicator of HBV replication ® 103-104 IU/mL aminotransferase ® not reliable marker of disease
threshold for infectivity and liver injury ® important in severity or prognosis, helpful in predicting relative
chronic infection receiving antiviral responsiveness to antiviral therapy
4. Hepatitis D
• Deltavirus, RNA virus ® co-infects with and require helper
function of HBV for its replication & expression
• Transmission: nonpercutaneous, close personal contact ®
blood-blood products, injection drug users, hemophiliacs
• Incubation: 30-180 days (8-12 weeks)
• HDV core is encapsidated by outer envelope of HBsAg
• HDV can infect a person simultaneously with HBV (co-
infection) or superinfect a person already infected with
HBV (super-infection
• Duration of HDV infection determined by duration of HBV
infection
• HDV replication tend to suppress HBV replication ® in
HepD, HBV lower level
• Acute infection: IgM anti-HDV predominates 30-40 days
after symptoms appear ® anti-HDV
• Self-limited infection: anti-HDV low-titer, transient
• Chronic infection: anti HDV high titer IgM & IgG
• HDV antigen in liver, HDV RNA in serum & liver ® during
HDV replication
• Diagnosis:
o Anti-HDV: presence 30-40 days
o Often undetectable once HBsAg disappears
o If HBsAg & anti-HDV presence in serum ® anti HBc
helpful in establishing relationship between infection
with HBV & HDV ® anti-HBc (+): recent infection. (-):
infection in remote past
o Co-infection: IgM anti-HBc
o Superinfection: IgG anti-HBc
o HDV RNA: ongoing HDV replication, relative infectivity
5. Hepatitis E
• Enterically transmitted virus ® primarily in India, Asia,
3. Hepatitis C Africa, Central America
• Hepacivirus in family Flaviviridae, RNA • Resemble hepatitis A
• Anti HCV during acute infection • ssRNA virus, Hepevirus within family Hepeviridae
• HCV RNA detected within few days of exposure to HCV ® • Transmission: contaminated water supplies
tend to persist for the duration of HCV infection • Incubation: 14-60 days (5-6 weeks)
• Transmission: blood transfusion, percutaneous routes, • Animal reservoirs: swine
injection drug use, occupational exposure to blood, • Detected in stool, bile, liver ® excreted in stool during
hemodialysis late incubation period
• High risk: injection drugs users, HIV infection, • IgM anti-HEV: early acute infection, IgG anti-HEV: after 3
hemophiliacs treated with clotting factor, long-term months
hemodialysis, unexplained elevations of aminotransferase • Diagnosis:
levels, transfusion, recipients of blood or organs yg +hepC, o IgM anti-HEV: first 3 months
perinatal, healthcare medical personnel following needle o IgG anti-HEV
injury or mucosal exposure to HCV contaminated blood, Lab test
sexual partners • Patient with acute hepatitis: HBsAg, IgM anti-HAV, IgM
• Incubation: 15-160 days (7weeks) anti-HBc, anti HCV
Pathogenesis o HBsAg (+), IgM anti-HBc (+/-): HBV infection
• Exposure to HCV ® host cell identifies viral product § IgM anti-HBc (+): acute
(pattern recognition receptors) ® distinguish virus from § IgM anti-HBc (-): chronic
self ® elaboration of interferon & cytokines ® activation o IgM anti-HAV (+): HAV infection
of innate and adaptive immune response o Anti-HCV (+): HCV infection
• Chronic infection: CD4 proliferative defect ® response o If chronic hepatitis B ® test HBeAg and anti HBe
turun ® mutation in CD8 ® HCV escape immune- § HBeAg (-): inactive
mediated clearance 6. Sign & symptoms of acute hepatitis
 • Prodromal: anorexia, nausea, vomiting, fatigue, malaise, Cirrhosis due to chronic viral hepatitis B or C
arthralgias, myalgia, headache, photophobia, pharyngitis, • Of patients exposed to the hepatitis C virus (HCV),
cough, coryza precede jaundice by 1-2 weeks approximately 80% develop chronic hepatitis C, and of
• Low grade fever (38-39) in hep A & E those, about 20–30% will develop cirrhosis over 20–30
• Jaundice years.
• Liver enlarges & tender ® RUQ pain, discomfort • Progression of liver disease due to chronic hepatitis C is
• Cholestatic ® extrahepatic biliary obstruction characterized by portal-based fibrosis with bridging
7. Interpretasi pg 3 &4 fibrosis and nodularity developing, ultimately culminating
8. Spider naevi, palmar erythema, caput medusa in the development of cirrhosis
9. Liver cirrhosis (pathogenesis, komplikasi hepatic • In cirrhosis due to chronic hepatitis C, the liver is small and
encephalopathy, initial treatment hematemesis and melena, shrunken with characteristic features of a mixed micro-
klo ada ascites cara drainage gmn knp, cara periksanya and macronodular cirrhosis seen on liver biopsy. In
• Pathologic features: development of fibrosis ® addition to the increased fibrosis that is seen in cirrhosis
architectural distortion ® formation of regenerative due to hepatitis C, an inflammatory infiltrate is found in
nodules ® hepatocellular mass ® alter blood flow portal areas with interface hepatitis and occasionally some
• Activation of hepatic stellate cells ® formation of collagen lobular hepatocellular injury and inflammation. In patients
& other ECM component increased ® fibrosis with HCV genotype 3, steatosis is often present.
• Etiology: alcoholism, chronic viral hepatitis (B&C), • Of adult patients exposed to hepatitis B, about 5% develop
autoimmune hepatitis, nonalcoholic steatohepatitis, chronic hepatitis B, and about 20% of those
biliary cirrhosis (primary biliary cirrhosis, primary • patients will go on to develop cirrhosis. Special stains for
sclerosing cholangitis, autoimmune cholangiopathy), hepatitis B core (HBc) and hepatitis B surface (HBs) antigen
cardiac cirrhosis, inherited metabolic liver disease will be positive, and ground-glass hepatocytes signifying
(hemochromatosis, Wilson’s disease, alpha1 antitrypsin hepatitis B surface antigen (HBsAg) may be present.
deficiency, cystic fibrosis), cryptogenic cirrhosis • Symptoms: fatigue, malaise, vague RUQ pain
Alcoholic cirrhosis • Diagnosis: quantitative HCV RNA testing and analysis for
• Excessive chronic alcohol use can cause different types of HCV genotype, or hepatitis B serologies to include HBsAg,
chronic liver disease ® fatty liver, hepatitis, cirrhosis anti-HBs, HBeAg (hepatitis B e antigen), anti-HBe, and
• Can produce fibrosis in the absence of accompanying quantitative HBV DNA levels.
inflammation or necrosis Complication
• Fibrosis: centrilobular, pericellular, or periportal ® reach Portal hypertension
certain degree ® disrupt normal liver architecture ® • Elevation of hepatic venous pressure gradient to >5 mmHg
replacement of liver cells by regenerative nodule • Caused by increased intrahepatic resistance to the passage
• Nodule usually <3 mm in diameter (micronodular) ® of blood flow through the liver due to cirrhosis &
cessation of alcohol use ® larger nodules may form ® regenerative nodules, increased splanchnic blood flow
mixed micronodular & macronodular cirrhosis secondary to vasodilation within splanchnic vascular bed
Pathogenesis • gastroesophageal varices, portal hypertensive
• Ethanol mainly absorbed in small intestine gastropathy, splenomegaly, hypersplenism, ascites
(spontaneous bacterial peritonitis)
• Intake of ethanol ® increase intracellular accumulation of
triglycerides by increasing fatty acid uptake and by • Hepatorenal syndrome
reducing fatty acid oxidation & lipoprotein secretion • Hepatic encephalopathy
• Oxidative damage to hepatocyte membrane due to • Hepatopulmonary syndrome
formation of reactive oxygen species ® Kupffer cell • Portopulmonary hypertension
activation ® profibrogenic cytokines produced ® initiate • Malnutrition
& perpetuate stellate cell activation ® production of • Coagulopathy (factor deficiency, fibrinolysis,
excess collagen & ECM ® regenerative nodules ® thrombocytopenia)
hepatocyte loss, increased collagen production & • Bone disease (osteopenia, osteoporosis, osteomalacia)
deposition ® continue hepatocyte destruction ® liver •
contracts & shrinks in size
Clinical features
• Nonspecific: RUQ abdominal pain, fever, nausea, vomit,
diarrhea, anorexia, malaise
• Complications: ascites, edema, upper GI hemorrhage
• Jaundice or encephalopathy abrupt onset
• PE: liver and spleen may be enlarged, liver edge being firm
& nodular, sclera icterus, palmar erythema, spider
angiomas, parotid gland enlargement, digital clubbing,
muscle wasting, or development of edema & ascites
• Laboratory test:
o Anemic: GI blood loss, nutritional deficiencies, or
hypersplenism related to portal hypertension, or as
direct suppressive effect of alcohol on bone marrow
o Platelet counts reduced: portal hypertension with
hypersplenism
o Serum bilirubin may be elevated
o PT: prolonged, don’t respond to administration of
parenteral vit K
o Serum sodium: normal unless have ascites ® turun
o ALT, AST: elevated ® AST>ALT 2:1