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THE LIVER • Blood traverses the sinusoids and exits into the terminal

Normal hepatic vein through innumerable orifices in the vein
• The liver and biliary tree and the gallbladder occupy the wall.
right upper quadrant of the abdomen. • Hepatocytes are thus bathed on two sides by well-mixed
• The liver resides between the digestive tract and the rest portal venous and hepatic arterial blood, placing
of the body and functions as a way station between the hepatocytes among the most richly perfused cells in the
splanchnic and systemic circulation body.
• The liver has the critical job of maintaining the body's • The sinusoids are lined by fenestrated and
metabolic homeostasis. This includes: discontinuous endothelial cells, which demarcate an
a. the processing of dietary amino acids, extrasinusoidal space of Disse, into which protrude
carbohydrates, lipids, and vitamins; abundant microvilli of hepatocytes.
b. removal of microbes and toxins in splanchnic blood • Scattered Kupffer cells of the mononuclear phagocyte
en route to the systemic circulation; system are attached to the luminal face of endothelial
c. synthesis of many plasma proteins; and cells, and scattered fat-containing perisinusoidal stellate
detoxification and excretion into bile of endogenous cells are found in the space of Disse.
waste products and pollutant xenobiotics.
• The mature liver lies in the right hypochondrium under • These stellate cells play a role in the storage and
the rib cage and extends from the right fifth intercostal metabolism of vitamin A and are transformed into
space at the midclavicular line to just below the costal collagen-producing myofibroblasts when there is
margin. inflammation of the liver.
• It projects slightly below the costal margin at the right • Between abutting hepatocytes are bile canaliculi, which
intercostal line and under the xyphoid process in the are channels 1 to 2 μm in diameter, formed by grooves
midline. in the plasma membranes of the facing cells and
• The physiologic or functional right and left lobes are delineated from the vascular space by tight junctions.
defined by the distribution of the right and left portal vein • Numerous microvilli extend into these intercellular
systems. spaces, which constitute the outermost reaches of the
• The watershed between these two vascular beds biliary tree.
corresponds to a plane that passes superiorly through • Hepatocellular actin and myosin microfilaments
the left side of the sulcus of the inferior vena cava to the surrounding the canaliculus help propel secreted biliary
middle of the gallbladder fossa inferiorly. fluid along the canaliculi.
• The quadrate lobe and the greater part of the caudate • These channels drain into the canals of Hering in the
lobe on the posterior aspect of the liver belong periportal region.
functionally to the left hemiliver. • These canals are troughlike extensions of biliary
epithelium into the periportal parenchyma, abutting with
Microarchitecture hepatocytes to form efficient channels for draining bile.
• The liver has been divided into 1- to 2-mm diameter • Biliary fluid is conveyed through their lumina to bile
hexagonal lobules oriented around the terminal ductules, which traverse the portal mesenchyme to
tributaries of the hepatic vein (terminal hepatic veins), empty into the terminal bile ducts within the portal tracts.
with portal tracts at the periphery of the lobule.
• Accordingly, the hepatocytes in the vicinity of the Pathology
terminal hepatic vein are called "centrilobular" (or • The dominant primary diseases of the liver are viral
centrolobular); those near the portal tract are hepatitis, alcoholic liver disease, and hepatocellular
"periportal." carcinoma.
• However, since hepatocytes near the terminal hepatic • More often, hepatic damage is secondary, to some of
veins are most remote from the blood supply, it has the most common diseases in humans, such as cardiac
been argued that they are at the distal apices of roughly decompensation, disseminated cancer, and extrahepatic
triangular acini, with the bases formed by penetrating infections.
septal venules from the portal vein extending out from • With the rare exception of fulminant hepatic failure, liver
the portal tracts. disease is an insidious process in which symptoms of
• In the "acinus," the parenchyma is divided into three hepatic decompensation may occur weeks, months, or
zones, zone 1 being closest to the vascular supply, zone even years after the onset of injury.
3 abutting the terminal hepatic venule, and zone 2 being • There is often a long time interval between disease
intermediate. onset (or initiation) and detection. Conversely, the liver
• The hepatic parenchyma is organized into cribiform, may be injured and heal without clinical detection.
anastomosing sheets or "plates" of hepatocytes, seen in • Three general aspects of liver disease
microscopic sections as cords of cells. (1) patterns of hepatic injury,
• Hepatocytes immediately abutting the portal tract are (2) hepatic failure and cirrhosis, and
referred to as the limiting plate, forming a discontinuous (3) jaundice and cholestasis.
rim around the mesenchyme of the portal tract.
• There is a radial orientation of the hepatocyte cords 1. PATTERNS OF HEPATIC INJURY
around the terminal hepatic vein. • The liver is an inherently simple organ with a limited
• Hepatocytes exhibit minimal variation in overall size, but repertoire of responses to injurious events.
nuclei may vary in size, number, and ploidy, particularly • Regardless of cause, five general responses are seen.
with advancing age.
• Uninucleate, diploid cells tend to be the rule, but with a. Degeneration and Intracellular Accumulation.
increasing age, a significant fraction are binucleate, and - Damage from toxic or immunologic insult may cause
the karyotype may range up to octaploidy. swelling of hepatocytes.
• Between the cords of hepatocytes are vascular - Moderate cell swelling is reversible.
sinusoids. - With more severe damage (ballooning degeneration),
swollen hepatocytes have irregularly clumped
cytoplasmic organelles and large clear spaces.

- In cholestatic liver injury, retained biliary material may - Destruction of antigen-expressing liver cells by cytotoxic
impart a diffuse, foamy appearance to the swollen lymphocytes is a common mechanism of liver damage,
hepatocyte (feathery degeneration). especially during viral infection.
- This lesion can be difficult to distinguish from ballooning - In viral hepatitis, quiescent lymphocytes may collect in
degeneration, except for the variable yellow the portal tracts as a reflection of mild smoldering
discoloration of the cytoplasm. inflammation, spill over into the periportal parenchyma
- Substances may accumulate in viable hepatocytes, as activated lymphocytes (interface hepatitis) causing
including iron and copper. a moderately active hepatitis, or suffuse the entire
- Accumulation of triglyceride fat droplets within parenchyma in severe hepatitis.
hepatocytes is known as steatosis - Once killed, apoptotic hepatocytes do not incite an
inflammatory reaction per se.
- Multiple tiny droplets that do not displace the nucleus
- However, scavenger macrophages (Kupffer cells and
are known as microvesicular steatosis, and appear in
circulating monocytes recruited to the liver) engulf the
such conditions as acute fatty liver of pregnancy and
apoptotic cell fragments within a few hours, generating
valproic acid toxicity.
clumps of inflammatory cells.
- A single large droplet that displaces the nucleus, - Hence, identification of apoptotic hepatocytes is a sign
macrovesicular steatosis, may be seen in hepatocytes of very recent hepatocyte destruction.
throughout the livers of obese or diabetic individuals - Foreign bodies, organisms, and a variety of drugs may
and, interestingly, in scattered hepatocytes in patients incite a granulomatous reaction.
with hepatitis C viral infection.
d. Regeneration.
b. Necrosis and Apoptosis. - Hepatocytes have long life spans, and they proliferate in
- Any significant insult to the liver can cause hepatocyte response to tissue resection or cell death
necrosis. - Regeneration occurs in all but the most fulminant
- In ischemic coagulative necrosis, the liver cells are hepatic diseases.
- Hepatocellular proliferation is marked by mitoses,
poorly stained and "mummified" and often have lysed
thickening of the hepatocyte cords, and some
nuclei.
disorganization of the parenchymal structure.
- In apoptotic cell death, isolated hepatocytes round up
- The canal of Hering-bile ductule unit constitutes a
to form shrunken, pyknotic, and intensely eosinophilic
reserve compartment for restitution of severe
cellscontaining fragmented nuclei.
parenchymal injury; when it is activated, innumerable
- Hepatocytes may also osmotically swell and rupture, so- serpentine profiles resembling bile ductules appear-so-
called lytic necrosis, the outcome of ballooning called ductular reaction.
degeneration. - This compartment also proliferates during large bile duct
- Lytic necrosis leaves neither mummified hepatocytes nor obstruction.
pyknotic cells but rather shards of cellular debris. - When hepatocellular necrosis occurs and leaves the
- Necrosis frequently exhibits a zonal distribution. connective tissue framework intact, almost perfect
- The most obvious is necrosis of hepatocytes restitution of liver structure can occur, even when the
immediately around the terminal hepatic vein (so-called necrosis is submassive or massive.
centrilobular necrosis, using the historical
terminology), an injury that is characteristic of ischemic e. Fibrosis.
injury and a number of drug and toxic reactions. - Fibrous tissue is formed in response to inflammation or
- Pure midzonal and periportal necrosis are rare; the direct toxic insult to the liver.
latter may be seen in eclampsia. - Unlike other responses, which are reversible, fibrosis
- With most other causes of hepatic injury, a variable points toward generally irreversible hepatic damage.
- However, there is now considerable debate about the
mixture of hepatocellular death through the parenchyma
irreversibility of liver fibrosis and even cirrhosis
is encountered.
- Deposition of collagen has lasting consequences on
- The hepatocyte necrosis may be limited to scattered patterns of hepatic blood flow and perfusion of
cells within hepatic lobules (focal or spotty necrosis) or hepatocytes.
to the interface between the periportal parenchyma and - In the initial stages, fibrosis may develop around portal
inflamed portal tracts (interface hepatitis). tracts or the terminal hepatic vein or may be deposited
- With more severe inflammatory injury, necrosis of directly within the space of Disse.
contiguous hepatocytes may span adjacent lobules in a - With continuing fibrosis, the liver is subdivided into
portal-to-portal, portal-to-central, or central-to-central nodules of proliferating hepatocytes surrounded by
fashion (bridging necrosis). scar tissue, termed "cirrhosis."
- Necrosis of entire lobules (submassive necrosis) or of - This end-stage form of liver disease is discussed later in
most of the liver (massive necrosis) is usually this section.
accompanied by hepatic failure.
- With disseminated candidal or bacterial infection, 2.A HEPATIC FAILURE
macroscopic abscesses may occur. • The most severe clinical consequence of liver disease is
hepatic failure.
c. Inflammation. • More often, it is the end point of progressive damage to
the liver as part of chronic liver disease, either by
- Injury to the liver associated with an influx of acute or insidious destruction of hepatocytes or by repetitive
chronic inflammatory cells is termed hepatitis. discrete waves of parenchymal damage.
- Direct toxic or ischemic hepatocyte necrosis incites an • These include gastrointestinal bleeding, systemic
inflammatory reaction.
infection, electrolyte disturbances, and severe stress
- With toxic damage, inflammation may also precede the
such as major surgery or heart failure.
onset of inflammation.
• In most cases of severe hepatic dysfunction, liver
transplantation is the only hope for survival

carbon days in fulminant hepatic failure or more tetrachloride. and perform normal metabolic function. and mushroom poisoning consciousness. inflammation with immune-mediated . consideration. gastrointestinal hemorrhage. .or toxin-induced. dilated arteriole necrosis). including a decreased renal perfusion pressure • Fetor hepaticus is a characteristic body odor that is due to systemic vasodilation. hepatic necrosis. circulatory physiology. which may play a role in functional abnormalities. Hepatocytes may be viable but unable to such as edema and an astrocytic reaction.Hepatic encephalopathy is regarded as a disorder of neurotransmission in the central b. to deep coma and death. industrial chemicals such as carbon . tetracycline toxicity. Sodium retention. which predisposes to peripheral glomerular filtration rate are the main renal edema. 2. and decreased renal perfusion and Hypoalbuminemia. and angiomas of the skin.g. function and promote generalized brain edema.In the great majority of instances. This is the most common route to hepatic and appears to be associated with elevated failure and is the endpoint of relentless chronic blood ammonia levels. hepatic failure: isoniazid). hyperestrogenemia are the putative causes of palmar producing a hyperosmolar urine devoid of erythema (a reflection of local vasodilatation) and spider proteins and abnormal sediment. as • Alternatively. Hepatic dysfunction without overt necrosis only minor morphologic changes in the brain. VII. from which small vessels radiate. blood urea nitrogen and creatinine.Onset of this syndrome is typically heralded by from the portal into the systemic circulation a drop in urine output. and hyperammonemia. . In the male.The ability to concentrate urine is retained. excretion. with a median survival of X. . from acetaminophen (38% of massive hepatic • Two particular complications merit separate necrosis cases in the United States). amino acid methionine and shunting of splanchnic blood . Chronic liver disease. antituberculosis drugs (rifampin. These changes may progress over hours or hepatocytes (e. fatty liver of pregnancy. are extremely worrisome . hepatic synthesis of blood clotting factors II. only 2 weeks in the rapid-onset form and 6 • The resultant bleeding tendency can lead to massive months with the insidious-onset form. patients are highly susceptible to result of progressive destabilization of failure of multiple organ systems. activation of the variously described as "musty" or "sweet and sour" and renal sympathetic nervous system with occurs occasionally. • Hepatic failure is life-threatening because with severely or a major surgical procedure. . . and . Rapid development of renal failure is usually hyperestrogenemia also leads to hypogonadism and associated with a precipitating stress factor gynecomastia. impaired free-water • Jaundice is an almost invariable finding. which further decrease glomerular of gastrointestinal bacteria on the sulfur-containing filtration. pulsating. Hepatorenal syndrome refers to the appearance of renal failure in patients with severe chronic liver Clinical Features disease. and increased synthesis of renal vasoactive • It is related to the formation of mercaptans by the action mediators. is manifested by a spectrum of disturbances in tetrachloride. . antidepressant monoamine oxidase a. nervous system and neuromuscular system5 . . Insidious development of renal failure is the impaired liver function.Associated fluctuating neurologic signs include hepatocyte destruction. nonrhythmic. collectively accounting for abnormalities to marked confusion and stupor an additional 14% of cases. associated with rising (portosystemic shunting). • Impaired estrogen metabolism and consequent . in whom there are no intrinsic morphologic • Regardless of cause. surprisingly low in sodium (unlike renal tubular • Each angioma is a central. IX.This is most often drug. Hepatic encephalopathy inhibitors. Massive hepatic necrosis. ranging from subtle behavioral (Amanita phalloides). hyperreflexia. which impair neuronal hepatitis ending in cirrhosis. b. function. . best causes (including unknown) account for 37%. acetaminophen. which worsens the extent of hepatic failure.• The morphologic alterations that cause liver failure fall • A fortunate few can endure an acute episode until into three categories: hepatocellular regeneration restores adequate hepatic a. and other movements of the head and extremities. gastrointestinal bleeding as well as petechial bleeding elsewhere. and particularly asterixis: . . cerebral dysfunction. rigidity. Hepatitis A infection accounts for 4% of cases. developments. vasoconstriction of the afferent renal arteriolae. are much the same. mushroom toxins) but more often insidiously in a patient with marginal hepatic is a variable combination of toxicity and function from chronic liver disease. such as infection. Western world.The mechanism may be direct toxic damage to . as with the encephalopathy is reversible if the Reye syndrome. and acute underlying hepatic condition can be corrected. frequently in the setting • A coagulopathy develops. The prognosis is poor. liver transplantation might save the patient. as they herald the most grave stages of halothane. attributable to impaired of severe refractory ascites. there are c. the clinical signs of hepatic failure or functional causes for the renal failure. Several factors are involved in its development.. rapid extension-flexion hepatitis B infection accounts for 8%.B CIRRHOSIS • Intestinal absorption of blood places a metabolic load on • Cirrhosis is among the top 10 causes of death in the the liver. seen when the arms are held in extension with Hepatitis C infection does not cause massive dorsiflexed wrists.

The parenchymal injury and consequent fibrosis are (3) increased capacity for synthesis and secretion of diffuse. the magnitude of also increases vascular resistance within the liver this "wastebasket" category speaks eloquently to the parenchyma. Fibrosis is the key feature of progressive damage to (TNF). and a. with the formation come from several sources: of abnormal interconnections between vascular inflow a. • In the normal liver. usually • The central pathogenetic processes in cirrhosis are precipitated by a superimposed metabolic load on the progressive fibrosis and reorganization of the vascular liver. hepatocytes. weakness. in advanced disease. have been excluded. • An example of the progression to cirrhosis is given • In particular. between hepatocytes and plasma. Disruption of the extracellular matrix. • All forms of cirrhosis may be clinically silent. interstitial collagens (types I and III) • Imbalances of pulmonary blood flow. • It is predominantly the cytokines secreted by activated nor does diffuse nodular transformation without Kupffer cells and other inflammatory cells that stimulate fibrosis. weight loss. since tonic contraction of these difficulties in discerning the many origins of cirrhosis. (PDGF). and.• The chief worldwide contributors are alcohol abuse and • In the process. osteoporosis. remain. extending throughout the liver."). lipoproteins) is greatly • Cirrhosis as the end-stage of chronic liver disease is impaired. with occasional bundles in the space of Disse. areas of severe hepatocellular necrosis and d. . and drug-induced cirrhosis. hepatocellular secretion of proteins (e. with production of and hepatic vein outflow channels. • Once cirrhosis is established. the greatest activation of stellate cells is in scarring. "myofibroblasts" constricts the sinusoidal vascular channels. with diameters activated. frank debilitation. defined by three characteristics: • The major source of excess collagen in cirrhosis is the a. a process that includes: varying from very small (<3 mm. and lipid peroxidation products. • Acquisition of myofibers by perisinusoidal stellate cells • Referred to as cryptogenic cirrhosis. including transforming growth tyrosinosis. creating delicate or broad septal tracts. and interleukin-1 (IL-1). factor-β (TGF-β). prehepatic. Parenchymal nodules containing proliferating cells. alone. to be Clinical Features discussed. the liver. balance between regenerative activity and constrictive • Moreover. b. inflammatory cytokines such as tumor necrosis factor e. (hepatopulmonary syndrome). intrahepatic. and bile developing in infants and children with galactosemia and duct epithelial cells). as with α.. endothelial cells. during the development of cirrhosis they become hepatocytes encircled by fibrosis. c.7 hemorrhage. types I and III collagen are deposited in the (2) a complication related to portal hypertension. Chronic inflammation. platelet-derived growth factor methyldopa.Vascular architecture is reorganized by the inflammation. macronodules) parenchymal fibrosis. which can be divided into loss of fenestrations in the sinusoidal endothelial cells. as from systemic infection or a gastrointestinal microarchitecture of the liver. albumin. which are poorly are concentrated in portal tracts and around central understood. Cytokine production by activated endogenous cells • Infrequent types of cirrhosis also include the cirrhosis (Kupffer cells. extracellular matrix. Focal injury with scarring does not constitute cirrhosis.g. • New vascular channels in the septae connect the vascular structures in the portal region (hepatic arteries and portal veins) and terminal hepatic veins. under the subsequent discussion on alcohol. Bridging fibrous septae in the form of delicate bands perisinusoidal stellate cells. is composed of delicate strands of type IV collagen in • The ultimate mechanism of most cirrhotic deaths is: the space of Disse. it is usually impossible to • When symptomatic they lead to nonspecific clinical establish an etiologic diagnosis on morphologic grounds manifestations: anorexia. Pathogenesis • Incipient or overt hepatic failure may develop. Nodularity is part of the diagnosis and reflects the large amounts of extracellular matrix. • In cirrhosis. clotting factors. and posthepatic causes. and iron overload. a substantial number of cases d. b. are extraordinarily responsive to the status of their • After all the categories of cirrhosis of known causation substrate. as stellate cells disease (sometimes called "cardiac cirrhosis. a capillary rather than a channel for exchange of solutes • Other causes include biliary disease. the sinusoidal space comes to resemble viral hepatitis. • Continued deposition of collagen in the space of Disse • Increased resistance to portal blood flow may develop in within preserved parenchyma is accompanied by the a variety of circumstances. or lobule. and portal tracts with terminal hepatic veins • Although normally functioning as vitamin A fat-storing b. The stimuli for stellate cell activation may parenchymal damage and scarring. • A growing concern is that many of these cases are due to undiagnosed nonalcoholic fatty liver disease. shunting PORTAL HYPERTENSION blood around the parenchyma. which lie in the space of or broad scars linking portal tracts with one another Disse. may lead to severely impaired oxygenation veins. Direct stimulation of stellate cells by toxins. perisinusoidal stellate cells to divide and to produce c. further stressing the • The collagen (reticulin) coursing alongside hepatocytes patient. (3) the development of hepatocellular carcinoma. (1) progressive liver failure (discussed earlier). lymphotoxin. micronodules) to (1) robust mitotic activity in areas developing new large (several centimeters. • Severe fibrosis can occur in the setting of cardiac c. Disruption of the architecture of the entire liver (2) a shift from the resting-state lipocyte phenotype to a • Several features of cirrhosis should be underscored: transitional myofibroblast phenotype.

portal hypertension. for most cases of portal hypertension. the cardioesophageal • The major posthepatic causes are severe right-sided junction (producing esophagogastric varices). diffuse fibrosing granulomatous disease such that appear in about 65% of patients with advanced as sarcoidosis and miliary tuberculosis. concentrations of solutes such as glucose. Percolation of hepatic lymph into the peritoneal 450 cytochromes) and from premature destruction of cavity: Normal thoracic duct lymph flow approximates newly formed erythrocytes in the bone marrow. ascitic fluid promotes movement of additional fluid out of intestinal capillaries into the abdomen. and xenobiotics that are protein (largely albumin) as well as the same insufficiently water-soluble to be excreted into urine. especially in the a. and bone marrow. constrictive pericarditis. hydrothorax. Ascites 3. characterized by • Influx of neutrophils suggests secondary infection. respectively) due to retention of pigmented bilirubin. nodular regenerative hyperplasia. With cirrhosis. constitutes the primary pathway for elimination of • It is generally a serous fluid having less than 3 gm/dL of bilirubin. and Because bile formation requires well-functioning potassium as in the blood. seepage of peritoneal fluid Bilirubin and Bile Formation through transdiaphragmatic lymphatics may produce • Bilirubin is the end product of heme degradation. but many liters may collect (2) the elimination of systemic waste products. involving the derived from breakdown of senescent erythrocytes by following mechanisms: the mononuclear phagocytic system. systemic retention of not only bilirubin but also other solutes whereas red cells point to possible disseminated intra- eliminated in bile. exceeding thoracic duct associated with excessive intramedullary hemolysis of capacity. and hepatic vein retroperitoneum.g. hepatic venous system. heme oxygenase oxidizes heme ascitic fluid. altering Starling's forces spleen. • Anastomoses between the arterial and portal systems in Splenomegaly the fibrous septa also contribute to portal hypertension • Long-standing congestion may cause congestive by imposing arterial pressure on the low-pressure splenomegaly. and diseases cirrhosis of the liver and cause massive hematemesis affecting the portal microcirculation.2 to 0. and as cholestasis. and driving fluid into the space of Disse. sclerae (jaundice and icterus. The osmotic action of the protein-rich bound to serum albumin. the heart failure. (1) the emulsification of dietary fat in the lumen of the • It usually becomes clinically detectable when at least gut through the detergent action of bile salts and 500 mL has accumulated.• The major prehepatic conditions are obstructive • With the rise in portal system pressure. turnover of hepatic heme or hemoproteins (e. • With long-standing ascites. • Albumin binding is necessary. Sinusoidal hypertension. • The majority of daily production (0. the P- b. scarring and expansile parenchymal nodules. bypasses thrombosis and narrowing of the portal vein before it develop wherever the systemic and portal circulation ramifies within the liver. Hepatic lymph is rich in proteins and low in defective erythrocytes (ineffective erythropoiesis.. and towards the rib margins (caput medusae) and constitute compression of terminal hepatic veins by perivenular an important clinical hallmark of portal hypertension. causes increased perfusion pressure in intestinal • Bilirubin thus formed outside the liver is released and capillaries. (manifest as hemorrhoids). triglycerides.3 gm) is • The pathogenesis of ascites is complex. The fluid may contain a scant hepatocytes. and of hematologic abnormalities attributable to (4) hepatic encephalopathy (discussed earlier). massive fatty • Much more important are the esophagogastric varices change. share common capillary beds. liver. which is reflected in the protein-rich • Whatever the source. . • The very small fraction of unbound bilirubin in plasma may increase in severe hemolytic disease or when Portosystemic Shunts protein-binding drugs displace bilirubin from albumin. Bile and cause massive abdominal distention. JAUNDICE AND CHOLESTASIS • Ascites refers to the collection of excess fluid in the • Hepatic bile formation serves two major functions: peritoneal cavity. • Abdominal wall collaterals appear as dilated • Portal hypertension in cirrhosis results from increased subcutaneous veins extending from the umbilicus resistance to portal flow at the level of the sinusoids. excess cholesterol. Such disruption becomes number of mesothelial cells and mononuclear clinically evident as yellow discoloration of the skin and leukocytes. sodium. secondary hyperaldosteronism. Renal retention of sodium and water due to insoluble in aqueous solutions at physiologic pH. and the falciform ligament of the liver outflow obstruction. hypersplenism. 800 to 1000 mL/day. it is rarely • The dominant intrahepatic cause is cirrhosis. (involving periumbilical and abdominal wall collaterals). it is readily disrupted. • Massive splenomegaly may also shunt excessive blood • Principal sites are veins around and within the rectum into the splenic vein. abdominal cancer. more often on the right side. • The degree of enlargement varies widely up to 1000 gm • The four major clinical consequences are and is not necessarily correlated with other features of (1) ascites. Intestinal fluid leakage: Portal hypertension also biliverdin reductase. to biliverdin (which is then reduced to bilirubin by c. accounting massive or life-threatening. hepatic lymphatic • The latter pathway is important in hematologic disorders flow may approach 20 L/day. • Far less frequent are schistosomiasis. which is then removed by hepatic lymphatics. (2) the formation of portosystemic venous shunts. exemplified by and death in about half of them. • Although hemorrhoidal bleeding may occur. since bilirubin is virtually d. • Massive splenomegaly may secondarily induce a variety (3) congestive splenomegaly. this movement of fluid • Most of the remainder of bilirubin is derived from the is also promoted by hypoalbuminemia.

5 mg/dL. bacterial β-glucuronidases and degraded to colorless • Ten percent to 20% of secreted bile salts are urobilinogens. unconjugated bilirubin in the brain. Following translation into a polypeptide. undergoes differential splicing to four common exons • This is particularly evident in the yellowing of the sclerae (exons 2 through 5). levels rise above 2. • This obligatory fecal loss of sterols in the form of bile olfactory epithelium. • In the normal adult. are reabsorbed. production and clearance is disturbed by one or more of the following mechanisms: . kidney. • In humans. interaction with the common donor substrate. conjugated or largely excreted in feces. between the two forms of bilirubin. UGT1A1. one isoform is physiologically relevant in vivo. and are a family of water-soluble sterols with carboxylated side chains. these insoluble amphiphiles enhance the uptake at the sinusoidal membrane. is a product • The enterohepatic circulation of bile acids provides an of the UGT1 gene located on chromosome 2q37. • Because of its solubility and weak association with albumin.2 to 0. and drugs.or glycine-conjugated salts 0. deconjugated in the intestines by bacterial action. conjugation. • In contrast. increased several million-fold by the presence of bile • Most bilirubin glucuronides are deconjugated by salts and lecithin. conjugation with limited cholesterol-solubilizing capacity of bile salts in one or two molecules of glucuronic acid by bilirubin bile. nontoxic a single polar hydroxyl group. UDP- glucuronic acid. displace bilirubin from albumin. physiologic pH and is tightly complexed to serum and the common carboxy terminus specifies the enzyme albumin. referred to as kernicterus by weight about 3% organic solutes. • The urobilinogens and the residue of intact pigment are • Ninety-five percent of secreted bile acids. • This differential splicing leads to the generation of • There are two important pathophysiologic differences different mRNAs that encode the different UGT isoforms. • With prolonged conjugated hyperbilirubinemia.0 to 2. which are very hydrophobic and • Jaundice occurs when the equilibrium between bilirubin have no appreciable aqueous solubility of their own. and biliary excretion. levels as high as 30 • The principal secreted lipids (>95%) are lecithins to 40 mg/dL can occur with severe disease. skin. locus. taurine or glycine. • This form cannot be excreted in the urine even when blood levels are high. glucuronidation of an array of substrates such as steroid • Fecal loss of bile acids (0. conjugated bilirubin is water soluble. lung. serum bilirubin levels vary between • Bile acids and their taurine. hemolytic disease of the newborn minor cogs in the hepatic machinery that secretes (erythroblastosis fetalis) may lead to accumulation of approximately 0. primarily through the urobilinogens formed are reabsorbed in the ileum and action of a sodium-bile acid cotransporter in the apical colon. and resecretion. insoluble lipids secreted by hepatocytes into bile.• Hepatic processing of bilirubin involves carrier-mediated • However. and promptly re-excreted into membrane of ileal enterocytes and are returned to the bile. • The unbound plasma fraction may increase in severe • The brilliant yellow color of bilirubin makes it an easily hemolytic disease or when protein-binding drugs identified component of hepatic bile formation. (phosphatidylcholine). excess conjugated bilirubin in plasma can be • Bile acids are the major catabolic products of cholesterol excreted in urine. and testis. efficient mechanism for maintaining a large endogenous • It is a member of a family of UGTs that catalyze the pool of bile acids for digestive and excretory purposes. tissues. Approximately 20% of the unconjugated. chenodeoxycholic acid. • The hepatic conjugating enzyme. which can cause • Newly secreted bile is a bicarbonate-rich fluid containing severe neurologic damage. reconjugation with circulation is excreted in urine. a portion • The primary human bile acids are cholic acid and of circulating pigment may become covalently bound to albumin (the delta fraction). The small amount that escapes this enterohepatic liver via portal blood for uptake.0 L of bile daily. and only loosely bound to albumin. production is equal to the rates of hepatic uptake. but only is present as an albumin-free anion in plasma. two members of the UGT1 family possess • Normally. • However. • Two thirds of the organic material in bile are bile salts: nontoxic. tissues. and • Jaundice becomes evident when the serum bilirubin solubilizing dietary lipids within the gut lumen. glucuronidation of bilirubin to its monoglucuronidated and diglucuronidated forms.3 and 1. UGT1A1 is located salts and residual free cholesterol constitutes the only primarily in the smooth and rough endoplasmic reticulum effective mechanism for elimination of excess of hepatocytes. including the liver. intestine. (icterus).6 gm per day) is hormones. and excretion of the water-soluble. the unique • Unconjugated bilirubin is virtually insoluble in water at amino terminus specifies acceptor-substrate selection. bilirubin metabolism and excretion are but • Hence.5 to 1. and the rate of systemic bilirubin act as highly effective detergents. each of which possesses a unique promoter and giving rise to the yellow discoloration of jaundice. particularly the brain in infants. carcinogens. • This fraction of unbound bilirubin may diffuse into • This bilirubin glucuronidating isoform is termed UGT1A1. Pathophysiology of Jaundice • The sequence of the human UGT1 gene shows that • Both unconjugated bilirubin and bilirubin glucuronides there are 13 isoform sequences in a tandem array for may accumulate systemically and deposit in tissues. as a single isoform that catalyzes the cholesterol from the body. returned to the liver. whose solubility in bile is bilirubin glucuronides into bile. a very small amount of unconjugated bilirubin the capability to glucuronidate bilirubin in vitro.2 mg/dL. UDP-glucuronyltransferase in the endoplasmic • Cholesterol is a negligibly soluble steroid molecule with reticulum. bile acids conjugated with taurine or glycine to form bile salts. • Their primary physiologic role is solubilizing water. matched by their daily de novo hepatic synthesis from • The various UGTs are distributed in a wide range of cholesterol. and produce as it is generated from the exon 1A of the UGT1 gene toxic injury. exon 1.

strenuous exercise. related disorder in which UGT1A1 enzyme activity is greatly to the elevation in plasma bile acids and their deposition reduced. so knowledge of the major form of some 6% of the population. (2) reduced hepatocyte uptake. • Because the hepatic machinery for conjugating and • Dubin-Johnson syndrome results from a hereditary excreting bilirubin does not fully mature until about 2 defect in hepatocellular excretion of bilirubin weeks of age. two extra bases (TA) are found in hyperbilirubinemia. also may present with jaundice. increasing intestinal reabsorption of hepatocytes unconjugated bilirubin. or fasting. jaundice but otherwise live normal lives. Affecting predominates. the multidrug resistance protein 2 (MRP2. this condition is invariably • Cholestatic conditions. amounts of unconjugated bilirubin. fluctuating hyperbilirubinemia. hepatocytes that is released into the circulation because o Mutations either reduce the affinity of UGT1A1 of the detergent action of retained bile salts on toward bilirubin or reduce enzyme activity. serum unconjugated bilirubin reaches very high levels. completely absent. and it appears to be later under neonatal hepatitis. (1) excessive production of bilirubin. most patients are • In Crigler-Najjar syndrome type I. Hereditary Hyperbilirubinemias o The liver is otherwise normal. o The liver is darkly pigmented owing to coarse • These enzymes deconjugate bilirubin glucuronides in pigmented granules within the cytoplasm of the gut. (creating an A(TA)7TAA element rather than the • More than one mechanism may operate to produce normal A(TA)6TAA. there may be a genetic lack of o Apart from chronic or recurrent jaundice of UGT1A1 fluctuating intensity. conjugated hyperbilirubinemia with multiple defects in • The liver is incapable of synthesizing a functional hepatocellular uptake and excretion of bilirubin enzyme. except for the anxiety that a jaundiced sufferer might justifiably experience with this otherwise Neonatal Jaundice innocuous condition. with mild. almost every newborn develops transient glucuronides across the canalicular membrane. (4) decreased hepatocellular excretion. intercurrent illness. Sustained jaundice in the o Electron microscopy reveals that the pigment is newborn is indicative of a disease condition. • Skin xanthomas (focal accumulations of cholesterol) o Unlike Crigler-Najjar syndrome type I. • Crigler-Najjar syndrome type II is a less severe. present in maternal milk. causing death within 18 months of birth secondary dysfunction or intrahepatic or extrahepatic biliary to kernicterus. it is due to bilirubin overproduction (as from hemolytic typically in association with stress. hepatitis. the mild plasma bilirubin is of value in evaluating possible causes hyperbilirubinemia may go undiscovered for years of hyperbilirubinemia. patients may be heterozygous for • Generally speaking. and o The primary cause is reduction in hepatic bilirubin (5) impaired bile flow (both intrahepatic and glucuronidating activity to about 30% of normal extrahepatic). protein. particularly skin. pruritus is a presenting symptom. resulting in reduced expression jaundice. patients with Rotor syndrome exhibit microscopy. but there is a • An isozyme derived from posttranscriptional changes is risk for some neurologic damage from kernicterus. so the increased levels must be verified as being hepatic in origin. and mild unconjugated hyperbilirubinemia. • Gilbert syndrome is a relatively common. and the enzyme is capable of forming only in peripheral tissues. the enzyme is asymptomatic and have a normal life expectancy. and is not associated with functional derangements. producing severe jaundice and icterus. o Alternatively. an enzyme present in bile duct hypertrophy of the hepatocellular endoplasmic epithelium and in the canalicular membrane of reticulum. unconjugated and conjugated hyperbilirubinemia. nonfatal • Alternatively. . somewhat heterogeneous inherited condition presenting (3) impaired conjugation. • However. from moderate to high levels of circulating unconjugated bilirubin. possibly the result of β-glucuronidases organic anions into bile. • Of the various causes of jaundice the most common are o When detected in adolescence or adult life. located on chromosome 10q24). Cholestasis • Without liver transplantation. the result of hyperlipidemia and major consequence is extraordinarily yellow skin impaired excretion of cholesterol. that is responsible • Breast-fed infants tend to exhibit jaundice with greater for transport of bilirubin glucuronides and related frequency. termed neonatal jaundice or physiologic jaundice of the o The defect is due to absence of the canalicular newborn. which result from hepatocellular fatal. and the latter two produce the TATAA element of the 5' promoter region predominantly conjugated hyperbilirubinemia. As with Dubin-Johnson • The liver is morphologically normal by light and electron syndrome. the only sometimes appear. composed of polymers of epinephrine metabolites. however. such as an anemias and resorption of major hemorrhages). one mechanism missense mutations in the UGT1A1 gene. levels. and the colorless bile contains only trace pigments. normally present in many other tissues such as bone. and obstruction to the flow of bile (considered o Gilbert syndrome has no clinical consequence later in this chapter). discussed located in lysosomes. monoglucuronidated bilirubin. which can produce of UGT1A1. especially hepatitis. benign. Multiple genetic defects in the locus • Rotor syndrome is a rare form of asymptomatic coding for UGT1A1 may give rise to this disorder. phenobarbital treatment can • A characteristic laboratory finding is elevated serum improve bilirubin glucuronidation by inducing alkaline phosphatase. o Almost all patients develop normally. • In rare instances. o The liver is not pigmented. • The first three mechanisms produce unconjugated o In most patients. obstruction. hepatocyte membranes. not bilirubin pigment.

encoded by the ABCB11 gene on chromosome 2q24). with solubilization of these membrane ectoenzymes.1-1. None include r carcinoma above HBV but unlikely 1) Infectious mononucleosis (Epstein-Barr virus) virtual absence of bile salts within the canalicular lumen . the absence of secreted transplantation). and U.may cause a mild hepatitis during the acute phase between hepatocytes means that serum γ-glutamyl 2) Cytomegalovirus infection transpeptidase (GGT) levels are low for the degree of . imperative. candidiasis. MDR3. Familial Intrahepatic Cholestasis • Children with severe cholestasis but with absence of elevated serum GGT and absence of pruritus may also have inherited defects in bile acid synthesis. Hepatitis A Virus . progressive familial intrahepatic cholestasis 1 (PFIC-1). malaria. the term “viral hepatitis” is • The first major characterized family with the latter reserved for infection of the liver caused by a group of viruses having a particular affinity for the liver syndrome are descendants of Jacob Byler. cholestasis begins in infancy with severe pruritus due to adenovirus. and Western Western amebiasis world world • Foremost hepatic infections are viral in origin Chronic None 5-10% of >50% <5% None None hepatitis acute coinfection. .S. destruction of these epithelia and release of GGT into the circulation. the Hepatitis A Hepatitis Hepatitis Hepatitis D Hepatitis E Hepatitis • Any insult to the liver can kill hepatocytes and recruit Virus B Virus C Virus Virus Virus G Virus* inflammatory cells that’s why inflammatory disorders Agent Icosahedral Enveloped Enveloped Enveloped Unenveloped ssRNA of the liver are frequently long-term chronic capsid. an enzyme located early in the pathway for bile acid synthesis from cholesterol.a major and serious cause of hepatitis in tropical there are intermittent attacks of cholestasis over life countries without progression to chronic liver disease. herpesvirus. In • Not frequently in children and immunosuppressed pts. or enterovirus infections high serum bile acid levels and relentlessly progresses to liver failure before adulthood. • The encoded protein. an Amish patient. due to mutations in the ABCB4 surgical alleviation.• Another canalicular ectoenzyme. uncertain function. • Mention should be made of a striking but heterogeneous group of autosomal-recessively inherited cholestatic • The most common condition is a deficiency of 3β- conditions. membranes of hepatocytes and bile duct epithelial cells. and U. is also released into the circulation.2-1. are the cause of progressive familial intrahepatic • Other manifestations of reduced bile flow relate to cholestasis 2 (PFIC-2). whether they be systemic or arise within period the abdomen Carrier state None 0. • Unless otherwise specified. D. salmonelloses. serum GGT is progressive familial intrahepatic • Extrahepatic biliary obstruction is frequently amenable to cholestasis 3 (PFIC-3). • These conditions encompass a spectrum arising usually from mutations in the ATP8B1 gene on chromosome 18q21. reflects the detergent action of bile salts retained in the luminal space of the bile canaliculus on the apical • Mutations in the canalicular bile salt export pump (BSEP. intestinal malabsorption. • Affected members of this particular family are designated as having Byler syndrome. staphylococcal U. possibly playing a role in secretion of bile salts indirectly through maintenance of • The elevated levels of these enzymes in the circulation aminophospholipid polarity in the canalicular membrane. with resultant toxic diagnosis of the cause of jaundice and cholestasis. or K.S.0% 0.particularly in the newborn or immunosuppressed pt hyperbilirubinemia. including nutritional • An autosomal-recessive cholestatic disorder with high deficiencies of the fat-soluble vitamins A. γ-glutamyl • The encoded protein is a canalicular P-type ATPase of transpeptidase. Parenteral. bacteremia. infections 80% upon superinfection • Systemic viral infections that can involve the liver Hepatocellula No Yes Yes No increase Unknown. Viral Hepatitis INFECTIOUS DISORDERS • However. hydroxysteroid dehydrogenase.0% 1-10% in drug Unknown 1-2% of • Conditions in which hepatic lesion is prominent of blood of blood addicts and blood donors in donors in hemophiliacs donors in include miliary tuberculosis. Parenteral. unlike many other cholestatic conditions. Waterborne Parenteral close close close contact supreme contact contact • The liver is inevitably involved in blood-borne Incubation 2-6 wk 4-26 wk 2-26 wk 4-7 wk 2-8 wk Unknown infections. unrelated * At present. individuals with different mutations have Byler disease. the liver is affected in the course of rubella virus.S. cannot be benefited by surgery (short of • In patients with this disorder. is a canalicular transport • In contrast. infection ranks Transmission Fecal-oral Parenteral. correct and prompt diagnosis is gene on chromosome 7q21. dsDNA ssRNA ssRNA ssRNA virus conditions that must be managed medically ssRNA • Among inflammatory disorders. cholestasis due to diseases of the protein that is responsible for flipping intrahepatic biliary tree or hepatocellular secretory phosphatidylcholine from the internal to the external failure (collectively termed intrahepatic cholestasis) hemileaflet of the canalicular membrane. 3) Yellow fever • In benign recurrent intrahepatic cholestasis (BRIC). and the patient's condition may be phosphatidylcholine in bile leaves the apical surfaces of worsened by an operative procedure. the biliary tree epithelia subject to the full detergent • There is thus some urgency in making a correct action of secreted bile salts. hepatitis G virus is not considered pathogenic.

infectivity ends Hepatocellular carcinoma and liver damage subsides. urine. 5) An asymptomatic carrier state. the long asymptomatic 4 to • Also present in all physiologic and pathologic body fluids 26 week incubation period (mean 6-8 weeks) is with the exception of stool followed by acute dse. However. mussels. virus may also be spread by contact undetectable levels in 3 to 6 mos . it is an icosahedral capsid 27 nm in diameter • The mature HBV virion is a spherical double-layered • Spread by ingestion of contaminated water and foods “Dane particle” that has an outer surface envelope of • Shed in the stool for 2 to 3 weeks before and 1 week protein. • Whereas blood and body fluids are the primary vehicles peaks during overt dse. and genomic replication not specifically screened for this virus occurs through an intermediate RNA template • Serologic Dx o A protein from the X region (HBX). sweat. HBX is also o Fecal shedding of the virus ends as the IgM titer thought to play a key role in the causation of rises hepatocellular carcinoma o IgM response usually begins to decline in a few • HBV infections pass through 2 phases: mos. Infected contracted by consumption of raw or steamed shellfish hepatocytes are capable of synthesizing and (oysters. designated HBeAg (hepatitis B e antigen) • Among developed countries. breast milk. • Long known as infectious hepatitis and the scourge of tears. and regions of the viral genome encode protein sequences: water-borne epidemics under overcrowded. . tends to be mild or asymptomatic and rare • In endemic regions such as Africa and Southeast Asia. and followed by the appearance of IgG anti. Cell surface expression of viral HBsAg and HBcAg • Can produce: in association with the MHC class I molecules leads 1) Acute hepatitis to activation of cytotoxic CD8+ T lymphocytes and 2) Nonprogressive chronic hepatitis hepatocytes destruction 3) Progressive chronic hepatitis ending in cirrhosis 2) Integrative phase 4) Fulminant hepatitis with massive liver necrosis . and pathologic effusions military campaigns since antiquity • Primary risk categories of HBV infection: • A benign self-limited disease with an incubation period o Transfusion of 2 to 6 weeks o Blood products • Does not cause chronic hepatitis or a carrier state and o Dialysis only rarely causes fulminant hepatitis so the fatality rate o Needle-stick accidents among health workers associated with this is about 0. lasting many wks. Viral DNA is incorporated into the host genome. a family of DNA- • A small.1% o Intravenous drug abuse • Occurs throughout the world and endemic in countries o Homosexual activity constitute the primary risk with substandard hygiene and sanitation. • A hardy virus and can withstand extremes of o Most pts experience a self-limited illness temperature and humidity  HBsAg appears before the onset of symptoms. to mos. HBV remains in blood during the last stages hepatocellular carcinoma persists of a prolonged incubation period (4 to 26 weeks) and • Serologic Dx during active episodes of acute and chronic hepatitis o After exposure to HBV. carbohydrate enclosing a slightly hexagonal core after the onset of jaundice • The genome is a partially double stranded circular DNA • Thus. so that most categories for HBV infection native populations have detectable anti-HAV by the age • The source of infection in one-third of pts is unknown of 10 y/o • Clinical dse. HAV accounts for about 25% of clinically the carrier state for live evident acute hepatitis worldwide • A member of the Hepadnaviridae. lipid. HBV DNA is present in episomal form. while providing immunity against reinfection by all strains formation of complete virions and all associated of HAV antigens Hepatitis B Virus • The cause of “serum hepatitis” . with or without may occur in hepatocytes not destroyed by the progressive subclinical dse immune response 6) The backdrop for hepatitis D virus . and then declines to of transmission. sporadic infections may be o Envelope glycoprotein (HBsAg). or semen with a precore and core region. HBcAg) and a longer polypeptide transcript • It is not shed in saliva. 1) Proliferative phase HAV which persists fore years. perhaps for life. Hepatovirus animal species • Ultrastructurally. after childhood spread from an infected mother to a neonate during birth (vertical transmission) is common which often lead to • Overall. nurseries. close personal contact with an infected individual molecule or fecal-oral contamination during this period accounts for most cases which explains the outbreaks in • The organization of HBV genome is unique in that all institutional settings such as schools. which is o Specific antibody against HAV of IgM type appears necessary for virus replication and acts as a in blood at onset of symptoms which constitutes a transcriptional transactivator of the viral genes and reliable marker of acute infection a wide variety of host gene promoters. saliva. unsanitary o A nucleocapsid “core” protein (Hepatitis B core conditions antigen. with body secretions such as semen. With cessation of viral replication and the • Also plays an important role in the development of appearance of antiviral antibodies. single-stranded RNA picornavirus containing viruses that cause hepatitis in a multiple that occupies its own genus. the risk of • Unlike HAV. clams) which concentrate the virus secreting massive quantities of noninfective surface from seawater contaminated with human sewage protein (HBsAg) • HAV viremia is transient so blood-borne transmission of o A DNA polymerase that exhibits reverse HAV occurs only rarely and therefore donated blood is transcriptase activity. unenveloped.

• HDV infection is uncommon in the large population of newly mutated strain HBsAg carriers in Southeast Asia and China • Hallmarks of HCV infection despite the generally • A 35-nm. homosexuals. During the months. double-shelled particle that by electron asymptomatic nature of the acute illness: microscopy resembles the Dane particle of HBV o Progressive infection • The external coat antigen of HBsAg surrounds as o Chronic hepatitis internal polypeptide assembly. The presence of HBsAg alone does not necessarily Hepatitis D Virus indicate replication of complete virions. transaminases. is less than 0. being responsible for 90% to 95% the HBsAg necessary for development of of all cases complete HDV virions • Sexual transmission and vertical transmission are o Superinfection infrequent  a chronic carrier of HBV with a new inoculum of • 40% of cases are accounted for sporadic hepatitis of HDV (and HBV) results in dse about 30-50 days later unknown cause  carrier may be previously “healthy” or may • Seroprevalence in the US pop. HBeAg.2% but is have had underlying chronic hepatitis higher in house contacts. and pts may be asymptomatic and without liver damage • Also called the delta agent and hepatitis delta virus o In contrast. HCV may in fact be the leading infectious cause 1) Mild HBV hepatitis may be converted into fulminant of chronic liver dse in the Western world dse • HCV and closely related HGV occupy a genius in the 2) Acute. designated delta antigen (HDAg) . Anti-HBs may persist for live. and all develop during a period of 5 to 10 yrs signifiy active viral replication • Serologic Dx:  IgM anti-HBc becomes detectable in serum o Incubation period: from 2 10 26 weeks (mean shortly before the onset of symptoms. HCV has a high rate of progression • 3 possibilities may arise when HDV is superimposed on to chronic dse or eventual cirrhosis. but prevalence • Inherently unstable. severe hepatitis may erupt in a previously Flaviviridae healthy HBV carrier • A small. giving rise to multiple types and varies subtypes seriously hampering efforts to develop an HCV • 20-40% of HBsAg carriers have anti-HDV vaccine • In the US. implying that the than 90% of pts with chronic dse acute infection has peaked and the dse is on o Clinical course is milder than that of HBV but the wane individual cases may be severe and  IgG anti-HBs does not rise until the acute dse indistinguishable from HAV or HBV hepatitis is over and is usually not detectable for a few o A characteristic clinical feature of chronic HCV wks to several mos after the disappearance of infection is episodic elevations in serum HBsAg. HBV DNA. with fulminant • Pts with unexplained cirrhosis and hepatocellular dse more likely (3-4%) than with HBV alone carcinoma have anti-HCV prevalence rates exceeding • Chronicity rarely develops 50% • In contrast to HBV. exceeding 50% chronic HBV infection: • Thus. This peptide pts) often culminating in cirrhosis is subsequently processed into functional proteins • Infection by delta agent is worldwide. more disappearance of HBeAg. chronic replication of HBV virions is • A unique RNA virus that is replication defective causing characterized by persistence of circulating HBsAg. between 6 and 12 weeks) concurrent with the onset of elevated serum o HCV RNA is detectable in blood for 1 to 6 and 12 transaminase levels. HDV infection is uncommon and largely • Elevated titers of anti-HCV IgG occuriing after an active restricted to drug addicts and hemophiliacs with infection do not confer effective immunity prevalence rates of 1-10% • Characteristic feature of HCV infection: repeated bouts • Homosexual men and health care workers are at low of hepatic damage as a result of reactivation of a risk for HDV infection for unclear reasons preexisting infection or emergence of an endogenous. the wks IgM antibody is replaced by IgG anti-HBc o Circulating RNA persists in many pts despite the  Anti-HBe is detectable shortly after the presence of neutralizing antibodies. hemodialysis • Simultaneous coinfection with HBV and HDV results in pts. hemophiliacs.  HBV must become established first to provide associated hepatitis. and IV drug abusers hepatitis ranging from mild to fulminant. with intervening normal or near- conferring protection. progressive dse may develop (in 80% of genome that codes for a single polyprotein. incldg. enveloped. transaminases may be persistently noninfectious HBsAg elevated or may remain normal o Carrier state is defined by the presence of HBsAg in serum for 6 mos or longer after initial detection. HDV is damage may occur in these pts absolutely dependent on the genetic information provided by HBV for multiplication and causes hepatitis Hepatitis C Virus only in the presence of HBV • Delta hepatitis arises in two settings: • A major cause of liver dse worldwide o Acute coinfection • Main routes of transmission are inoculations and blood  Occurs after exposure to serum containing both transfusions HDV or HBV • Believed to be the most important cause of transfusion. and DNA polymerase • Cirrhosis can be present at the time of dx or may appear in the serum soon after HBsAg. and HBV DNA usually with anti-HBc and infection only when it is encapsulated by HBsAg occasionally with anti-HBs. single-stranded RNA virus with a 3) Chronic. this is the basis for normal periods current vaccination strategies using o Alternatively.  HBeAg. Progressive liver • Although taxonomically distinct from HBV.

by the presence of • An enterically transmitted water-borne infection antiviral antibodies. rash. virions are shed in the stool during the acute illness (2) a symptomatic preicteric phase • Serologic Dx (3) a symptomatic icteric phase o HEV RNA and HEV virions can be detected in the (4) convalescence stool and liver before the onset of clinical illness o Incubation period o The onset of rising serum transaminases. and loss of appetite according to epidemiologic studies  Inconstant symptoms that can also manifest • A viral agent bearing similiarities to HCV has been are weight loss. o Acute symptomatic hepatitis with recovery: anicteric o Icteric phase or icteric  If this appears. is caused mainly by conjugated o Chronic hepatitis: without or with progression to hyperbilirubinemia cirrhosis  Usual in adults with acute HAV infection but not o Fulminant hepatitis: with massive to submassive in children. although this is • An unenveloped single-stranded RNA virus structurally uncommon for acute HCV infection similar to Calciviridae • A specific antigen (HEV Ag) can be identified in the o Regardless of the agent. headaches. can lead to essentially identical clinical o Acute coinfection by HDV and HBV is best indicated syndromes by detection of IgM against both HDAg and HBcAg • Thus serologic and molecular studies are essential for (denoting new infection with hepatitis B) the diagnosis of viral hepatitis and the distinction o With chronic delta hepatitis arising from HDV between the various types. and elevated IgM anti-HEV titers are  Peak infectivity occurs during the last virtually simultaneous asymptomatic days of incubation period and o Symptoms resolve in 2-4 wks. arthralgias • That’s why designation of HGV as a “hepatitis” virus is due to circulating immune complexes) may be premature  True origin of these symptoms is suggested by elevated serum aminotransferase levels CLINOCOPATHOLOGIC SYNDROMES  PE reveals a mildly enlarged.• Serologic Dx: • HCV is notorious for chronic infection o HDV RNA is detectable in the blood and liver just • HAV and HEV do not cause chronic hepatitis in rare before and in the early days of acute symptomatic exceptions dse • Fulminant hepatitis is unusual. after the fact. clinical  Differs in the various viruses illness. HBsAg is present in serum and IgM anti-HDV persists for mos or longer 1. low-grade fever. and headache. Acute Asymptomatic Infection with Recovery o Pts in this group are identified only incidentally on Hepatitis E Virus the basis of minimally elevated serum transaminases or. tender liver  In some patients. HGV appears to be nonpathogenic causing those with hepatitis B. Acute Symptomatic Infection with Recovery o Any of the hepatotropic viruses can cause • Average incubation period after exposure is 6 wks symptomatic acute viral hepatitis. the nonspecific symptoms • Clinical syndromes may develop after exposure to are more severe. nausea. • Occurring primarily in young to middle-aged adults o HAV and HBV infection worldwide are frequently • Sporadic infection and overt illness in children are rare subclinical events in childhood. and pains and diarrhea • Transfusion related transmission has been documented  10% of patients with acute hepatitis. superinfection. with higher fever. verified only in • Sporadic infection seems to be uncommon and is seen adulthood by the presence of anti-HAV or anti-HBV mainly in travelers antibodies • Characteristic feature of this infection: o Though asymptomatic acute infection is most often o High mortality rate among pregnant women the case for HCV-infected patients for whom the approaching 20% exposure event is not known. most often • However. sometimes accompanied o Acute asymptomatic infection with recovery: by right upper quadrant pain and tender liver serologic evidence only enlargement. and almost unheard of o IgM anti-HDV is the most reliable indicator of recent with HCV HDV exposure. develop a serum neither liver dse nor exacerbation of liver dse sickness-like syndrome (fever. cloned and designated hepatitis G virus (HGV) muscle and joint aches. constitutional Other Hepatitis Viruses symptoms  Malaise is followed in a few days by general • Some cases of hepatitis are caused by infectious agents fatigability. particularly frequently short-lived drugs and toxins. but is absent in about half the cases hepatic necrosis of HBV & majority of HCV cases • Each of the hepatotropic viruses can cause acute  As jaundice appears. recovery and • Disease is self-limited in most cases eradication of the virus are not common • It is not associated with chronic liver dse or persistent viremia 2. though appearance is late and • Other infectious or noninfectious causes. during which time early days of acute symptoms IgM is replaced with a persistent IgG anti-HEv titer o Preicteric phase  Marked by nonspecific. shaking hepatitis virus: chills. the disease is more or less the same and can be divided into four phases: cytoplasm of hepatocytes during active infection and (1) an incubation period. these pts enter the icteric asymptomatic or symptomatic infection phase • A small number of HBV-infected patients develop  Other symptoms begin to abate and the pt feels chronic hepatitis better .

in the form of vasculitis  Recovery is heralded by the generation of (subcutaneous or visceral) & strong T cell responses against viral antigens glomerulonephritis expressed on infected liver cells  Cryoglobulinemia is found in 35% of pts with o Chronic Hepatitis chronic HCV hepatitis  Defined as symptomatic. with Acute Hepatitis histologically documented inflammation and Enlarged. early infection particularly via vertical Fibrosis: transmission during childbirth produces a Portal deposition. disease. and mild elevations in . although there is a well-defined low risk of posttransfusion hepatitis D. loss of conjugated hyperbilirubinemia and not a result appetite. biochemical. some instances: hyperglobulinemia. mild hepatomegaly to retention of bile acids . or carrier state of 90-95% of the time Portal and periportal deposition. and occasional bouts of mild of biliary obstruction jaundice  Accompanied by a dark-colored urine related to  Physical findings: the presence of conjugated bilirubin . reddened liver. hyperglobulinemia hyperbilirubinemia. etiology is Sinusoidal cell reactive changes: the single most important indicator of likelihood Accumulation of phagocytosed cellular debris in Kupffer to progress to cirrhosis cells  Chronic viral hepatitis constitutes a "carrier" Influx of mononuclear cells into sinusoids state wherein these individuals harbor Portal tracts: replicating virus and can transmit an organism Inflammation: predominantly mononuclear Inflammatory spillover into adjacent parenchyma.g. indicative of a Morphology of Acute and Chronic Hepatitis carrier state in conjunction with HBV  HCV can clearly induce a carrier state given its ACUTE HEPATITIS high rate of chronicity  Clinical features are extremely variable and are • Hepatocyte injury takes the form of diffuse swelling not predictive of outcome ("ballooning degeneration"). or  In contrast. drugs (e. "sanded" nuclei  Individuals with impaired immunity are likely to HCV: bile duct epithelial cell proliferation. only 1-10% of adult HBV infections Formation of bridging fibrous septa yields a carrier state HBV: "ground-glass" hepatocytes. hepatic tenderness  Liver may be mildly enlarged and moderately . spider angiomas  Stools may become lighter owing to cholestasis . lymphoid become HBV carriers because the protective T aggregate formation cell response does not develop Cirrhosis: The end-stage outcome  This situation is less clear with HDV. prolonged prothrombin time . or  All constitute reservoirs of infection Bridging inflammation and necrosis  In HBV. HCV. α-methyldopa. occasionally immune  Jaundice and most of other systemic symptoms complex disease may develop secondary to the abates in a few weeks to several mos as presence of circulating antibody-antigen convalescence begins complexes. α1-antitrypsin deficiency. some only manifest with persistent empty and contains only scattered eosinophilic elevations of serum transaminases remnants of cytoplasmic organelles . and HBV Cholestasis: canalicular bile plugs + HDV) are responsible for most cases of HCV: mild focal fatty change of hepatocytes chronic hepatitis. mild splenomegaly tender to percussion  Lab studies:  Lab findings . there hepatocyte necrosis are: Chronic Hepatitis 1) those who harbor one or more of the viruses Changes shared with acute hepatitis: but are suffering little or no adverse clinical Hepatocyte injury. necrosis. methotrexate). or 3) those who have clinically symptomatic Spillover into adjacent parenchyma. mild elevation of serum alkaline alkaline phosphatase levels phosphatase  In HBV and HCV. most common symptom: fatigue .  The jaundice is caused predominantly by . central-central. so cytoplasm looks . and Lobular disarray: loss of normal architecture autoimmunity Regenerative changes: hepatocyte proliferation  In all instances of chronic hepatitis. and regeneration or histologic effects Sinusoidal cell reactive changes 2) those who have chronic disease by Portal tracts: laboratory or histologic findings but are Inflammation: essentially free of symptoms or disability Confined to portal tracts. . prolongation of prothrombin time . greenish if cholestatic necrosis Parenchymal changes: Hepatocyte injury: swelling (ballooning degeneration)  Though hepatitis viruses (HBV. less common symptoms: malaise. with necrosis of chronic disease hepatocytes ("interface hepatitis"). with  With “carriers” of hepatotropic viruses. palmar erythema  A distressing pruritus can be experienced due . Wilson If severe: bridging necrosis (portal-portal. portal-central) isoniazid. there are many other causes Hepatocyte necrosis: isolated cells or clusters of chronic hepatitis Cytolysis (rupture) or apoptosis (shrinkage)  Other causes: chronic alcoholism. or Key Morphologic Features of Viral Hepatitis serologic evidence of continuing or relapsing hepatic disease for more than 6 months..

parenchyma to cause necrosis of periportal hepatocytes. with bile plugs in linking of fibrous septa between lobules (bridging fibrosis) canaliculi and brown pigmentation of hepatocytes • Continued loss of hepatocytes and fibrosis results • Canalicular bile plugs result from cessation of the in cirrhosis. leishmaniasis. amebic. Apoptotic cells also are phagocytosed within of the so-called postnecrotic cirrhosis cannot be hours by macrophages and hence might be determined at all ("cryptogenic cirrhosis") difficult to find despite a brisk rate of hepatocyte injury • Morphology of the end-stage cirrhotic liver is neither helpful in determining the basis of the liver injury. and the • Even in mild chronic hepatitis due to HCV infection. regardless of etiology 2) Apoptosis . cryptosporidiosis. periportal septal fibrosis occurs. some have rapidly progressive disease and • A characteristic and usually prominent feature of acute develop cirrhosis within a few year hepatitis: Inflammation • Major causes of death: • Kupffer cells undergo hypertrophy and hyperplasia o cirrhosis. and Helminthic Infections chronic hepatitis • Finally. but smoldering • Bacteria may also proliferate in the biliary tree hepatocyte necrosis throughout the lobule may occur in compromised by partial or complete obstruction all forms of chronic hepatitis • Bacterial composition reflects the gut flora. • The latter is due to effects of proinflammatory cytokines released by kupffer cells and endothelial cells in CHRONIC HEPATITIS response to circulating endotoxin • Histo features range from exceedingly mild to severe • Bacteria that can affect the liver directly: • Mildest forms: significant inflammation is limited to portal o Staphylococcus aureus – in toxic shock syndrome tracts and consists of lymphocytes. hepatotoxins (carbon . only portal tracts exhibit increased fibrosis. but and mostly represent parasitic infections (e. confluent circumstances. with fibrous septae and hepatocyte contractile activity of the hepatocyte pericanalicular actin regenerative nodules microfilament web • This pattern of cirrhosis characterized by irregularly • Two patterns of hepatocyte cell death are seen sized nodules separated by variable but mostly broad 1) Rupture of cell membranes leads to cytolysis and scars focal loss of hepatocytes . macrophages. followed by . nor can it be easily related to any specific set of clinical . become drugs (acetaminophen. Apoptotic hepatocytes shrink. Parasitic. o Salmonella typhi – typhoid fever occasional plasma cells. and rare neutrophils or eosinophils o 20 or 30 syphilis • Liver architecture usually well preserved. and infections by liver flukes Fasciola hepatica. or portal-to-central regions of adjacent lobules • Unpredictable course . caused by anti-viral cytotoxic T cells tetrachloride. • However.• Cholestasis. the inciting cause . the more or less radial array of the indolent disease without progression for many years parenchyma is lost. Clonorchis • The hallmark of irreversible liver damage is the sinensis and Opisthorchis viverrini deposition of fibrous • Liver abscesses are common in developing countries • At first. more conspicuous • Autoimmune hepatitis. this "interface hepatitis" can occur in both acute and Bacterial. schistosomiasis. severe acute inflammatory response within the common findings are lymphoid aggregates and bile intrahepatic biliary tree is called ascending cholangitis duct damage in the portal tracts and focally mild to • Major causes of morbidity worldwide wherein the liver is moderate macrovesicular steatosis frequently involved are parasitic and helminthic • In all forms of chronic hepatitis: continued interface infections • Diseases include malaria. an inconstant findings. Hepatocyte swelling and regeneration compress sinusoids • Pts experience spontaneous remission or may have . central-to-central. irregular-sized nodules with mark sites of hepatocyte loss broad scars. and have fragmented may give rise to a cirrhotic liver with irregular-sized large nuclei. hepatitis and bridging necrosis are harbingers of progressive liver damage strongyloidiasis. necrosis of hepatocytes may lead to bridging necrosis connecting portal-to.g. with liver failure and are often laden with lipofuscin pigment due to o hepatic encephalopathy phagocytosis of hepatocellular debris • Portal tracts are usually infiltrated with a mixture of o massive hematemesis from esophageal varices inflammatory cells o hepatocellular carcinoma in those with long- standing HBV (particularly neonatal) or HCV • Inflammatory infiltrate may spill over into the adjacent infection. bile duct epithelia may become reactive and • Extrahepatic bacterial infections particularly sepsis can even proliferate to form poorly defined ductular induce mild hepatic inflammation and varying degrees of structures (ductular reaction). and even alcohol intensely eosinophilic. particularly in cases of hepatocellular cholestasis HCV hepatitis. with time. pharmaceutical . In severe cases of acute hepatitis. α-methyldopa). Clinical course of Viral hepatitis portal. mushroom poisoning). this term has been applied to all forms of cirrhosis in and scavenger macrophage aggregates which the liver shows large. effector T cells may still be present in nodules the immediate vicinity • In some cases that come to autopsy.sinusoidal collagen reticulin framework • Historically. this pattern of cirrhosis has been termed postnecrotic cirrhosis (but it should be noted that the collapses where the cells have disappeared.

anti-smooth muscle. chlorpromazine thoracic cavity producing empyema or a lung . usually multiple. appendicitis. • Idiosyncratic reactions are caused by: incldg antinuclear. may contain sufficient dose purulent material from adjacent bile ducts o unpredictable (idiosyncratic) reactions o Gross and microscopic features are those to be  depend on idiosyncrasies of the host. • Drug reactions may be classified as: whereas direct extension and trauma usually cause o predictable (intrinsic) reactions solitary large abscesses  may occur in anyone who accumulates a o Biliary abscesses. representing a distinction from primary biliary cirrhosis or primary complication of a bacterial infection elsewhere sclerosing cholangitis • Organisms reach the liver by: 1) the portal vein DRUG. brain and elsewhere. AUTOIMMUNE HEPATITIS cholestasis. ranging in size metabolite acting as hapten to convert a cellular o Bacterimic spread thru the arterial or portal system protein to an immunogen) tends to produce multiple small abscesses. to while antibiotic therapy may control smaller lesions develop which may present only after severe liver • Pts may survive with early recognition and Mx damage has developed o Injury may take the form of hepatocytes necrosis.can cause a fatal immune-mediated instances. may burrow into the 1.AND TOXIN-INDUCED LIVER DISEASE 2) arterial supply 3) ascending infection in the biliary tract (ascending • The liver is subject to potential damage from an array of cholangitis) pharmaceutical and environmental chemicals because it 4) direct invasion of the liver from a nearby source is the major drug metabolizing and detoxifying organ in 5) a penetrating injury the body • Majority of hepatic abscesses used to result from portal • Injury may result: spread of intra-abdominal infections (e. occurs predominantly • A subgroup of pts exhibits antibodies either to in children given acetylsalicylic acid (aspirin) for the liver/kidney microsomes or “soluble liver antigen” relief of virus-induced fever (cytokeratins 8 and 18). seen in any abscess particularly the host’s propensity to mount an o Causative organism occasionally can be identified immune response to antigenic stimulus and the in fungal or parasitic abscesses rate of which the host metabolizes the agent o Rarely.5 gm/dl) o Alcohol (certain extent) o High serum titers of autoantibodies in 80% of cases. thyroiditis. halothane • Liver abscesses are associated with fever and in most . is • Clinical presentation is similar to other forms of chronic rare hepatitis • Drug-induced liver dse is followed usually by recovery • Autoimmune hepatitis may present in an atypical fashion on removal of drug with associated dse involving other organ systems. and o Sulfonamides antimitochondrial antibodies o Methyldopa o An increased frequency of HLA-B8 or HLA-DRw3 o Allopurinol • Other forms of autoimmune dses present in pts are • Reye syndrome Rheumatoid arthritis.g. Dx of liver dse . particularly young to o Amanita phalloides toxin perimenopausal women o Absence of viral serologic markers o Carbon tetrachloride o Elevated serum IgG levels (>2.agent that causes cholestasis in those pts abscess who are slow to metabolize it to an o Rupture of subcapsular liver abscess can lead to innoculous by product peritonitis or localized peritoneal abscesses 2. right upper quadrant pain and tender hepatitis in some pts exposed to this hepatomegaly anesthetic on multiple occasions • Jaundice may result from extrahepatic biliary obstruction • It should be noted that: • Surgical drainage is often necessary for larger lesions o Injury may be immediate or take weeks to mos. • Exposureto a toxin or therapeutic agent should always hampering diagnostic efforts be included in the diff. Sjogren syndrome. or insidious onset of liver dysfunction o Drug-induced chronic hepatitis is clinically and • A syndrome of chronic hepatitis in pts with a histologically indistinguishable from chronic viral hepatitis heterogenous set of immunologic abnormalities o Histologic markers of viral infection are critical for • Histo features are indistinguishable from chronic viral making the distinction hepatitis • Predictable rxns are ascribed to: • Dse may run an indolent or severe course and typically o Acetaminophen responds dramatically to immunosuppressive therapy o Tetracycline • Salient features include: o Antineoplastic agents o Female predominance (70%). colitis) 2) by hepatic conversion of a xenobiotic to an active • Morphology toxin o Pyogenic hepatic abscesses may occur as solitary 3) through immune mechanisms (usually by a drug or or multiple lesions. particulary amebic. echinococcal and (less commonly) other protozoal and • Clinical autoimmune hepatitis exhibiting destruction of helminthic organisms bile ducts (“autoimmune cholangitis”) may make • Most abscesses are pyogenic. 1) from direct toxicity diverticulitis. abscesses located in the subdiaphragmatic  major examples: region. suggesting 3 types of o features extensive accumulation of fat droplets autoimmune hepatitis exist within hepatocytes (microvesicular steatosis). & o a potentially fatal syndrome of mitochondrial dysfxn ulcerative colitis in liver..

such as fatty liver filaments and other proteins. often contains visible nodules and • Adverse effects of chronic alcohol consumption lead to fibrosis indicative of evolution to development of overlapping forms of liver dse: cirrhosis 1) Hepatic steatosis 2) Alcoholic hepatitis o Alcoholic Cirrhosis 3) Cirrhosis (collectively referred to as alcoholic liver  Final and irreversible form of alcoholic liver dse dse) usually evolves slowly and insidiously • Morphology  At first.cholestasis and mild deposition of pathogenic factors influencing liver damage. develop seen in primary biliary cirrhosis. readily fractured  As fibrous septa dissect and surround nodules. and o Hepatic Steatosis (Fatty liver) enlarged. soft organ that is yellow  Scattered larger nodules create a “hobnail” .swelling results from accumulation of fat cirrhosis developing from viral hepatitis and and water and proteins that normally are other causes exported • Pathogenesis 2. liver is mottled red with bile-stained areas • The leading cause of liver dse in most western countries . visible as o Daily intake of 80 gm or more of ethanol generates eosinophilic cytomplasmic inclusions in significant risk of severe hepatic injury degenerating hepatocytes o Daily ingestion of 160 gm or more for 10-20 years is . part. fatty converted to a mixed micronodular and change is completely reversible if there is macronodular pattern abstention from further intake of alcohol  Ischemic necrosis and fibrous obliteration of nodules eventually create broad expanses of o Alcoholic Hepatitis tough. Hepatocyte swelling and necrosis  Mallory bodies are rarely evident at this stage . it is transformed into accumulate in hepatocytes after even moderate a brown. the cirrhotic liver is yellow-tan. the . pale scar tissue (Laennec cirrhosis)  Characterized by:  Bile statis often develops 1. shrunken. greasy appearance on liver surface .scattered hepatocytes accumulate tangled beers or 7 oz of 80-proof liquor) generally produces skeins of cytokeratin intermediate mild. those having Mallory than are men bodies  Genetic susceptibility may exist but no reliable . Neutrophilic reaction  Decreased gastric metabolism of ethanol . developing fibrous septa are delicate displacing the nucleus to the periphery of the and extend through sinusoids from central vein hepatocytes to portal regions as well as from portal tract to  Transformation is initially centrilobular. and outset. chronic cholestatic syndromes. however. reversible hepatic changes.almost always accompanied by a brisk alcoholic hepatitis as precursors to cirrhosis both sinusoidal and periventricular fibrosis causally and temporally is not yet clear . Alcoholic Liver Disease .single or scattered foci of cells undergo  Thus. fibrous tissue develops around the shrinks progressively in size central veins & extends into the adjacent  Parenchymal islands are engulfed by ever sinusoids with continued alcohol intake wider bands of fibrous tissue and liver is  Up to the time that fibrosis appears. . lipid the setting of alcoholic hepatitis within 1-2 accumulates to the point of creating large clear years macrovesicular globules. though there is little or no fibrosis at the liver becomes more fibrotic loses fat.neutrophils permeate the lobule and  Differences in body composition accumulate around degenerating  Women are more susceptible to hepatic injury hepatocytes.periportal fibrosis may occasionally o Cirrhosis may develop without antecedent evidence predominate. less than 1 kg in weight intake of alcohol  Arguably.inclusions are characteristic of but not associated more consistently with severe injury specific feature because they are also o Only 10-15% if alcoholics. both micro and macroscopically. usually weighing more than 2 kg  Small (microvesicular) lipid droplets  During the span of years. fatty. o Reasons are: hepatocellular tumors 3. but may portal tract involve the entire lobule in severe cases  Regenerative activity of entrapped  Macroscopic appearance of fatty liver of parenchymal hepatocytes regenerates fairly chronic alcoholism: uniformly sized “micronodules” . large (up to 4-6 kg)  The nodularity becomes more prominent . end-stage alcoholic cirrhosis comes to swelling (ballooning) and necrosis resemble. Mallory bodies o Short-term ingestion of up to 80 gm of ethanol (8 . particulary with repeated of steatosis or alcoholic hepatitis bouts of heavy alcohol intake o In the absence of a clear understanding of the . cirrhosis may develop more rapidly in  With chronic intake of alcohol.lymphocytes & macrophages also enter genetic markers of susceptibility have been portal tracts and spill into the parenchyma identified 4. liver may be of normal or increased size is excessive alcohol consumption . Wilson cirrhosis dse. compressing and  Initially. Fibrosis o Relationship between hepatic steatosis and . no hemosiderin (iron) in hepatocytes and “safe” upper limit for alcohol consumption can be Kupffer cells may develop in some cases proposed (despite the current popularity of red  Macroscopic appearance: wines for amelioration of CVD) .

IL-1 and 6. a  in some instances. albumin.B12) stigmata (e. generated during microsomal  Lab findings ethanol-oxidizing system oxidation of alcohol. decreasing sinusoidal 1) hepatic coma perfusion and causing regional hypoxia 2) massive GI hemorrhage o Net effect: chronic d/o featuring: 3) intercurrent infection  Steatosis 4) hepatorenal syndrome after a bout of  Hepatitis alcoholic hepatitis  Progressive fibrosis 5) hepatocellular carcinoma  Marked derangement of vascular perfusion o Nonalcoholic steatohepatitis o In essence. elevated alkaline phosphatase levels  alcohol directly affects microtubular & . hyperbilirubinemia react with cellular membranes and proteins . anorexia.  Tends to appear relatively acutely. ascites. neutrophilic leukocytosis mitochondrial function and membrane fluidity  acute cholestatic syndrome may appear. with infection or trauma tips the balance toward release of their noxious substances hepatic insufficiency o These events are exerted by local toxic effects of alcohol and by alcohol-induced release of bacterial o Long-term outlook for alcoholics with liver dse is endotoxin into portal circulation form a variable compromised gut o 5-year survival approaches to 90% in abstainers o Alcohol also induces a vasoconstricting endothelins free of jaundice. tender metabolites hepatomegaly  free radicals. .  acetaldehyde (major intermediate metabolite of resembling large bile duct obstxn alcohol en route to acetate prod’n) induces lipid  may be superimposed on established cirrhosis peroxidation and acetaldehyde-protein adduct  with proper nutrition and total cessation of formation. it may clear slowly membrane fxn  in some pts. drops to from sinusoidal endothelial cells 50% .. with release of phosphatase proinflammatory cytokines (TNF-α. liver biopsy may be lecithin-related lipid released by endothelial indicated cells and kupffer cells  cirrhosis may be clinically silent discovered  Influx of neutrophils into parenchyma in only at autopsy or when stress such as response to proinflammatory cytokines. possibly the result of alcohol- induced or acetaldehyde-induced alteration in o Alcohol cirrhosis hepatic proteins  Manifestations are similar to other forms of o alcohol is food and can become a major calorie cirrhosis source in the diet of an alcoholic.60% to those who continue to imbibe o Endothelins induce the myofibrolast-like hepatic o Causes of death in end-stage alcoholic: stellate cells to contract. Hypoproteinemia (globulins. anemia  Amplication of cytokine stimuli by PAF. further disrupting cytoskeletal and alcohol consumption. sinusoidal fibrosis  may become evident as hepatomegaly with  Pts are largely asymptomatic with mild elevation of serum bilirubin and alkaline abnormalities in biochemical lab test results phosphatase levels  Nonspecific constitutional symptoms may be present . hepatitis persists despite  alcohol induces immunologic attack on hepatic abstinence and progresses to cirrhosis neoantigens. o Hepatic steatosis Mallory hyaline. caput medusae) chronic gastric and intestinal mucosal damage and  Lab findings reflect developing hepatic pancreatitis compromise: o collagen deposition by perisinusoidal hepatic . o compounded by impaired digestive fxn related to wasted extremities. and TGF-β) clotting factors) . • Clinical course mixed inflammatory infiltrate of parenchyma. o Detrimental effects of alcohol and its byproducts on  There may be no clinical or biochemical hepatocellular function: evidence of liver dse alternatively  Hepatocellular steatosis results from  Alcohol withdrawal and provision of an 1) shunting of normal substrates away from adequate diet are sufficient Tx catabolism and toward lipid biosynthesis owing to generation of excess NADH by 2 o Alcoholic hepatitis major enzymes of alcohol metabolism. Elevated serum transaminase levels stellate cells is a response to many converging . . Variable elevation of serum alkaline  Kupffer cell activation. weight loss. jaundice. other deficiency (Vit. usually after alcohol dehydrogenase a bout of heavy drinking 2) impaired assembly and secretion of  Symptoms & lab manifestations may be lipoproteins minimal or those of fulminant hepatic failure 3) increases peripheral catabolism of fat  Between these 2 extremes are nonspecific  induction of CP450 leads to augmented symptoms of malaise. or hematemesis. grossly distended abdomen. ascites.g. transformation of other drugs to toxic upper abdominal discomfort. Hyperbilirubinemia events . displacing other  Include those of portal Htn (with life-threatening nutrients and leading to malnutrition and vitamin variceal hemorrhage). alcoholic liver dse can be regarded as a  An uncommon condition resembling alcoholic maladaptive state in w/c cells in liver respond in hepatitis occurring in pts who do not drink increasingly pathologic manner to a stimulus alcohol (alcohol) that originally was marginally harmful  Features liver biopsy findings of steatosis.

epithelium and Kupffer cell pigmentation tyrosine substitution at amino acid 282 • Iron is a direct hepatotoxin • Inflammation is absent . hepatocyte death. in 75 to 80% of patients myocardium. or scarring  Small intestinal crypt cells are • STEATOHEPATITIS (aka non-alcoholic steatohepatitis) preprogrammed to absorb dietary iron regardless of the systemic iron overload – intermediate form of liver damage o Excessive iron appears to be directly toxic to host • CIRRHOSIS – result of years of subclinical progression tissues by the ff mechanisms: of the inflammatory and fibrotic processes. occurs in patients who are accumulated not heavy drinkers • Critical site for HFE expression is on the basolateral • Men and women equally affected surface of the small intestinal crypt epithelial cell • Strong associations with obesity. along with bile duct  Most common HFE mutation: cysteine-to. and skin o Cirrhosis  Symptoms first appear in 5th to 6th decades o Pancreatic fibrosis of life o Hemochromatosis gene located on the short arm • In the liver. multifocal parenchymal  This is a sensing mechanism for the inflammation. Mallory hyaline. there is progressive absorption of dietary iron. enabling the binding of plasma transferring • Patients are largely asymptomatic. glutamyl transpeptidase values TfR. • Nonalcoholic fatty liver disease (NAFL) – resembles • Disease manifests after 20 gm of storage iron have alcohol-induced liver disease. iron becomes evident first as golden-yellow of chromosome 6 at 6p21.  Lipid peroxidation via iron-catalyzed free radical reactions Hemachromatosis  Stimulation of collagen formation  Interactions of reactive oxygen species • Excessive accumulation of body iron – most are and of iron itself. hepatocyte death. although ako di ko pa din diabetes naintindihan haha) • Elevated serum aminotransferases and/or gamma o HFE complexes with the transferring receptor. • (see Figure 18-27 pg 909 sa Robbins 7th edition para hyperinsulinemia and insulin resistane.  Obesity is the most important risk factor (called C282Y). joints. thus accumulation within hepatocytes decreasing the regulatory iron pool in the crypt • Clinically benign end: no appreciable hepatic cell. dyslipidemia.0 gm/year. and overt type 2 mas maintindihan. pituitary gland. but also from increased inherited disorder absorption • Secondary hemachromatosis – acquired forms of  Transfusions alone (aplastic anemias) lead hemochromatosis with known sources of excess iron to systemic hemosiderosis -> parenchymal • Total body iron pool: 2-6gm in normal adults organ injury tends to occur in extreme o 0. abnormalities only in and its bound iron biochemical lab tests o The TfR-Tf-iron complex is endocytosed into the • Most common cause of “cryptogenic” cirrhosis crypt enterocyte o Acidification of the endosome releases iron into Morphology the regulatory iron pool of the crypt cell • Liver biopsy findings: steatosis. systemic iron balance sinusoidal fibrosis o Crypt cells with mutant HFE lack the facilitating • Large and small vesicles of fat (triglycerides) effect on TfR-dependent iron uptake. common antecedent conditions o Males predominate with slightly earlier clinical  Chief risk is the dev’t of cirrhosis occurring in a presentation minority of pts  Because physiologic iron loss delays iron accumulation in women METABOLIC LIVER DISEASE Pathogenesis • In HH. and (3) skin pigmentation (in decreasing order of severity): liver. (2) diabetes mellitus in o Deposition of hemosiderin in the following organs 75% to 80% of patients. leading to net iron accumulation of 0. over modest increase in stainable iron within liver cells 1/3 accumulates in liver • Ff features characterize this disease: Morphology o Fully developed cases exhibit: (1)micronodular • Characterized principally by: cirrhosis in all patients. inflammation.5 to 1. which inactivates this 343-  Type II DM and hypertriglyceridemia are less amino-acid-protein. leading to lethal injury or deposited in parenchymal organs such as liver and predisposition to hepatocellular carcinoma pancreas o Most common cause of secondary • Results from a genetic defect causing excessive iron hemochromatosis: haemolytic anemias absorption or as a consequence of parenteral associated with ineffective erythropoeisis administration of iron  Excess iron may result not only from • Hereditary hemochromatosis – homozygous-recessive transfusions.5 gram stored in Liver cases  98% in hepatocytes o Alcoholic cirrhosis – often associated with a • In HH: total iron accumulation may exceed 50 gm. involvement of the rest of the lobule.3 close to the HLA hemosiderin granules in the cytoplasm of periportal gene locus hepatocytes o Stains blue with the Prussian blue stain  HFE gene – encodes an HLA class I-like molecule that regulates intestinal • With increasing iron load. adrenal gland. pancreas. regulation of intestinal absorption of dietary iron Nonalcoholic Fatty Liver Disease and Steatohepatitis is lost. o Iron accumulation is lifelong thyroid and parathyroid glands.

the presenting complaint is • Fatty change: mild to moderate. encodes a 7.000 o Homozygotes may be identified before onset of ug per gram – associated with fibrosis and clinical disease cirrhosis • Identification of HFE gene opens the way for genetic • Pancreas screening. vacuolated hepatocellular o A significant cause of death is hepatocellular nuclei. and diabetes mellitus hepatitis. o Deranged glucose homeostasis or frank diabetes • Once hepatic capacity for incorporationg copper into mellitus due to destruction of pancreatic islets ceruloplasmin is exceeded  sudden onset of critical o Cardiac dysfunction (arrhythmias. focal hepatocyte necrosis • Classic triad: pigment cirrhosis with hepatomegaly. • Principal manifestations • Defective biliary excretion leads to copper accumulation o Hepatomegaly in the liver in excess of the metallothionein-binding o Abdominal pain capacity. with • Death: may result from cirrhosis or cardiac disease macrovesicular steatosis. the myocardium and eye o Delicate interstitial fibrosis may appear • Normal: 40% to 60% of daily ingested copper (2 to 5 • Skin pigmentation mg) is absorbed in the stomach and duodenum and o Attributable to hemosiderin deposition in dermal transported to the liver loosely complexed with albumin macrophages and fibroblasts o Free copper dissociates and is taken up into o Most results from increased epidermal melanin hepatocytes. located on the hepatocyte canalicular membrane Clinical Features • Majority of patients are compound heterozygotes • More often a disease of males containing different mutations of the Wilson disease • Rarely becomes evident before age 40 gene on each allele. except for the fatty change o May not develop until late in the course of the • Chronic hepatitis exhibits moderate to severe disease inflammation and hepatocyte necrosis. cardiomyopathy) o Atypical arthritis Morphology • Some patients. causing toxic liver injury through copper- o Skin pigmentation (particularly in exposed areas) catalyzed formation of reactive oxygen species. dense. but not to the degree required to cause weightr significant tissue damage o Hepatic iron concentrations in excess of 22. with vacuolated nuclei hypogonadism and occasionally. carcinoma o With progression.5 kB the hypothalamic-pituitary axis transcript for a transmembrane copper-transporting o Not usually significantly pigmented ATPase. and its copper damages the articular cartilage  produces disabling is excreted into bile polyarthritis referred to as PSEUDO-GOUT  This is the primary route for copper • Testes elimation o Small and atrophic o Estimated total body copper: 50 to 150 mg  Atrophy secondary to a derangement in • Gene: ATP7B. skin • Acute hepatitis can exhibit features mimicking acute viral pigmentation.000 ug iron per gram dry iron. illness. where it is incorporated into an a2- production globulin synthesized in the endoplasmic reticulum o Combination of these pigments imparts a to form ceruloplasmin and resecreted into plasma characteristic slate-gray color to the skin • Ceruloplasmin accounts for 90% to 95% of plasma • Joint synovial linings copper o Acute synovitis may develop due to hemosiderin • Circulating ceruloplasmin is desialylted as part of normal deposition plasma protein aging o Desialylated ceruloplasmin is endocytosed by the • Excessive deposition of calcium pyrophosphate liver. limited by the heterogeneity of mutations in o Intensely pigmented this disease o Diffuse interstitial fibrosis • Patients with HH diagnosed in the subclinical. principally in the liver. • HH can be diagnosed long before irreversible tissue and chocolate brown damage has occurred • Fibrous septa develop slowly  leading to micronodular • Screening: pattern of cirrhosis in an intensely pigmented liver o Demonstration of very high levels of serum iron • Biochemical determination of hepatic iron concentration and ferritin in unfixed tissue – standard for quantitating hepatic iron o Exclusion of secondary causes of iron overload content o Liver biopsy. brain. cirrhosis will develop o Treatment for iron overload does not remove the • Massive liver necrosis risk for this aggressive neoplasm o Rare manifestation . liver is slightly larger than normal. degraded within lysosomes.• At this stage. on chromosome 13. o May exhibit some parenchymal atrophy precirrhotic stage and treated by regular phlebotomy o Hemosiderin is found in both acinar and the islet have a normal life expectancy cells and sometimes in the interstitial fibrous stroma Wilson Disease • Heart o Often enlarged • Autosomal-recessive o Has hemosiderin granules within the myocardial • Marked by the accumulation of toxic levels of copper in fibers  producing a striking brown coloration to many tissues and organs. if indicated o In normal individuals: iron content of unfixed liver • Screening of family members of probands is important is less than 1000 ug per gram dry weight of liver o Heterozygotes for HH also accumulate excessive o Adults with HH: over 10.

mainly in neonates and • Major conditions causing it: young adults o Cholangiopathies. and polymerizes. orcein stain for disease copper-associated protein) o They exhibit lags in the ER protein degradation • Demonstration of hepatic copper content in excess of pathway  designed to degrade abnormally 250 ug per gram dry weight is most helpful for making a folded or unassembled polypeptidees diagnosis • The intense autophagocytic response stimulated within • Brain hepatocytes: chief cause of liver injury. or Parkinson present disease-like syndrome.AT-Z in the ER of hepatocytes • Excess copper deposition – can be demonstrated by • Only 10% of PiZZ individuals develop clinical liver special stains (rhodanine for copper. very • Idiopathic neonatal hepatitis represents up to 50% of polymorphic cases. are the initial features in most of • Diagnostic a1-antitrypsin globules may be absent in the remaining cases. such as mild • Infrequently. and hepatomegaly • Gene is located on human chromosome 14. young infant • Biochemical diagnosis: based on a decrease in serum ceruloplasmin. proteases. light of acholic predominantly by hepatocytes stools. causing its retention in the ER Secondary Biliary Cirrhosis . and proteinase 3 Neonatal Cholestasis • Leads to the development of pulmonary emphysema  lack of this protein permits tissue-destructive enzymes to • Prolonged conjugated hyperbilirubinemia in neonate run amok • Affects approx 1 in 2500 live births • Can also cause liver disease. fatty change and Mallory bodies are behavioural changes. particularly elastase. possibly by o Toxic injury primarily affects the basal ganglia (the autophagocytosis of mitochondria. biliary atresia another 20%. dark urine. and a1-antitrypsin • General notation: Pi for protease inhibitor and an deficiency represents 15% alphabetic letter for the position on the gel. Morphology o Most common genotype: PiMM (occurs in 90% of • Morphologic features of neonatal hepatitis: individuals) o Lobular disarray with focal liver cell necrosis o Most common clinically significant mutation: PiZ o Panlobular giant cell transformation of  individuals have high risk for developing hepatocytes and formation of hepatocyte clinical disease “rosettes”: radially arrayed hepatocytes o Prominent hepatocellular and canalicular Pathogenesis (di ko nagets wahahaha!) cholestasis • Normal: The mRNA is translated and the protein is o Mild mononuclear infiltration of the portal areas synthesized and secreted o Reactive changes in the Kupffer cells • Deficiency variants: selective defect in migration of this o Extramedullary hematopoiesis secretory protein from the ER to Golgi apparatus o Most marked for the PiZ polypeptide INTRAHEPATIC BILIARY TRACT DISEASE o Mutant polypeptide is abnormally folded. two letters denote the genotype of the two alleles. an increase in hepatic copper content. Clinical Features and increased urinary excretion of copper • Neonatal hepatitis with cholestatic jaundice appears in • Early recognition and long-term copper chelation 10-20% of newborns with the deficiency therapy (as with D-penicillamine) can dramatically alter • Adolescence: presenting symptoms may be related to the usual progressive downhill course hepatitis or cirrhosis • Fulminant hepatitis or unmanageable cirrhosis – liver • The disease may remain silent until cirrhosis appears in transplant middle to later life • Hepatocellular CA may develop in 2-3% of PiZZ adults a1-Antitrypsin Deficiency • Treatment and cure for severe hepatic disease: orthotopic liver transplantation • Autosomal recessive disorder • In patients with pulmonary disease: avoid cigarette • Abnormally low serum levels of a1-antitrypsin smoking  can accelerate the destructive lung disease o Major function of this protein: inhibition of associated with a1-antitrypsin deficiency. primarily biliary atresia • Most commonly diagnosed genetic liver disease in o A variety of disorders causing conjugated infants and children hyperbilirubinemia in the neonate (collectively called neonatal hepatitis) a1-Antitrypsin o Table 18-10 pg 912 • Small. o Indistinguishable from that caused by viruses or • All individuals with the PiZZ genotype accumulate drugs a1. 394-amino acid plasma glycoprotein synthesized • Affected infants: jaundice. frank psychosis. cathepsin G. putamen)  atrophy and cavitation o Develop eye lesions called Kayser-Fleishcer rings Morphology  green to brown deposits of copper in • Characterized by the presence of round-to-oval Descemet’s membrane in the limbus of the cytoplasmic globular inclusions in hepatocytes cornea o In routine H and E stains – acidophilic and indistinctly demarcated from the surrounding Clinical Features cytoplasm • Rarely manifests before 6 years of age • Globules are also present in diminished size and • Most common presentation: acute or chronic liver number in intermediate deficiency states disease • Distinctive feature: the PAS-positive globules • Neuropsychiatric manifestations.

with finely granular o Celiac disease appearance • Etiology and inciting triggers of primary biliary cirrhosis • Histology: are not clear o Coarse fibrous septae that subdivide the liver in a jigsaw-like pattern Morphology o Embedded in the septa are distended small and • Prototype of conditions leading to small-duct biliary large bile ducts. • Most common cause of obstruction in adults: dihydrolipoamide acetyltransferase extrahepatic cholelithiasis. including portal hypertension with secondary biliary cirrhosis or the cirrhosis that follows variceal bleeding and hepatic encephalopathy chronic hepatitis from other causes • Serum alkaline phosphatase and cholesterol: elevated • Hyperbilirubinemia: late development. inflammatory o Parenchyma develops generalized cholestasis destruction of medium-sized intrahepatic bile ducts • Relentless portal tract scarring and bridging fibrosis lead • Primarily. characterized by the destruction of intrahepatic exhibit bile ductular proliferation. often fatal cholestatic liver o Portal tracts upstream from damaged bile ducts disease. peak incidence: 40-50 years o As disease progresses. • Ascending bacterial infection incites a robust plasma cells. and occasional eosinophils neutrophilic infiltration of bile ducts o Terminal and conducting bile ducts are infiltrated • Severe pylephlebitis and cholangitic abscesses may by lymphocytes. bile ducts. o These antibodies are against the E2 subunit of • Prolonged obstruction of the extrahepatic biliary tree the pyruvate dehydrogenase complex (PDC-E2). contain inspissated pigmented fibrosis and cirrhosis material • Focal and variable disease • Cholestatic feature in the parenchyma may be severe. portal inflammation and scarring. centomeric proteins. accumulation of autoreactive T cells around bile which eventually leads to hepatic scarring and nodule ducts formation. progressive. liver weight is slightly • Late features: stigmata of chronic liver disease decreased • Over a period of two or more decades: develop hepatic • Most cases. bile stasis stains the liver green • Onset is insidious. inflammation. may be symptom free for • 90% of patients: presence of circulating many years “antimitochondiral antibodies” • Pruritis. jaundice develops later o Capsule remains smooth and glistening until a • Hepatomegaly is typical fine granularity appears  culminates in a well- developed. normal to increased (due to retention inflammation). signifies incipient Clinical Features hepatic decompensation • Onset is extremely insidious. presents with pruritus. o Different degrees of severity in different portions with extensive feathery degeneration and formation of of the liver bile lakes • Precirrhotic Stage • Once regenerative nodules have formed. followed by secondary features: xanthomas and . a disease of middle-aged women to cirrhosis • Female:male predominance in excess of 6:1 • Macroscopically: • Age of onset: 20-80 years. fatigue. and abdominal discomfort develop. macrophages. bile stasis may o Portal tracts are infiltrated by a dense become less conspicuous. ultimately. accumulation of lymphocytes. etc) are also produced infection of the biliary tree  aggravates the • Has extrahepatic manifestations of autoimmunity inflammatory injury • Enteric organisms (colifroms and enterococci) – o Sicca complex of dry eyes and mouth (Sjogren common culprits syndrome. and the and necrosis of the adjacent periportal hepatic eventual development of cirrhosis and liver failure parenchyma • Primary feature: nonsuppurative. Latin sicca meaning dryness) o Scleroderma Morphology o Thyroiditis • End-stage obstructed liver: extraordinary yellow-green o Rheumatoid arthritis pigmentation and is accompanied by marked icteric o Raynaud phenomenon discoloration of body tissues and fluids o Membranous glomerulonephritis • On cut surface: liver is hard. end-stage picture is indistinguishable from decompensation. generating secondary biliary cirrhosis • Antibodies against other cellular components (nuclear • Subtotal obstruction may promote secondary bacterial pore proteins. uniform micronodularity • Xanthomas and xanthelasmas arise owing to cholesterol o Liver weight: first. followed by malignancies of o Enzyme complex is located on the inner face of the biliary tree or head of the pancreas and strictures the inner mitochondrial membrane  well- resulting from previous surgeries shileded from circulating antibodies in • Obstructive conditions in children: undamaged hepatocytes o Biliary atresia o Cystic fibrosis Pathogenesis o Choledochal cysts • Auto-immune etiology o Syndromes in which there are insufficient o Includes aberrant expression of MHC class II intrahepatic blie ducts molecules on bile duct epithelial cells and • Secondary inflammation initiates periportal fibrosis. may exhibit noncaseating develop granulomatous inflammation and undergo progressive destruction Primary Biliary Cirrhosis • The obstruction to intrahepatic bile flow leads to progressive secondary hepatic damage • Chronic.

also • There is persistent elevation of serum alkaline portal hypertension phosphatase o Has an increased risk of cholangiocarcinoma • Progressive fatigue. particularly bleeding varices • Caroli disease is frequently complicated by intrahepatic Clinical Features cholelithiasis. liver becomes markedly o May still face complications of portal cholestatic  culminates in biliary cirrhosis hypertension. a cell-surface protein that modestly dilated bile ducts embedded in a fibrous. cholangitis. particularly chronic ulcerative colitis o Sometimes. with a lymphocytic • Von Meyenburg Complexes are common and usually infiltrate. curved bile duct profiles are arranged • Prevalence of primary sclerosing cholangitis in in a concentric circle around portal tracts ulcerative colitis patients: 4% • The increased number of bile ducts profiles are in • Tends to occur in third through fifth decades of life continuity with the biliary tree • Males predominate. and hepatic abscesses. triangular bile duct hamartoma may lie • Entry into end-stage of disease: general features of under Glisson’s capsule jaundice and hepatic decompensation. • (fig 18-33 pg 916) Well-documented association of variceal bleeding. liver cysts of biliary origin are identified. bile ducts o Presentation common during pregnancy become ecstatic and inflamed • Patients with congenital hepatic fibrosis rarely develop o Result of downstream obstruction cirrhosis • As disease progresses. steatorrhea. pruritus. more commonly in women • Characterized by inflammation and obliterative fibrosis Congenital Hepatic Fibrosis of intrahepatic and extrahepatic bile ducts. ascites. but portal tract bile ducts Morphology are completely absent Von Meyenburg Complexes o Cause by mutations in the gene Jagged1 on • Close to or within portal tracts: small clusters of chromosome 20p. and malabsorption-related • Arise from residual embryonic bile duct remnants osteomalacia and/or osteoporosis • Occasionally. and encephalopathy autosomal-dominant polycystic kidney disease with • Has increased risk for cholangiocarcinoma polycystic liver disease • Definitive treatment: liver transplantation o Liver cyst in isolation or in abundance represent the most frequent extra-renal manifestation of Anomalies Of The Biliary Tree (Including Liver Cysts) autosomal-dominant polycystic kidney disease and occur in most patients • Lesions may be found during radiographic studies or at • Congenital hepatic fibrosis is strongly associated with autopsy or may become manifest as the autosomal-recessive form of polycystic kidney hepatosplenomegaly and portal hypertension in the disease absence of hepatic dysfunction • Alagille syndrome – syndromatic paucity of bile ducts • Four distinct lesions have been described o Uncommon autosomal-dominant condition o Liver is almost normal. progressive atrophy of the bile duct epithelium. functions as a ligand for the Notch sometimes hyalinized stroma transmembrane receptors • Free of pigmented material . with dilation • Portal tracts are enlarged by irregular and broad bands of preserved segments of collagenous tissue. without clinical significance and obliteration of the lumen • Polycystic liver disease may develop abdominal • Onion-skin fibrosis – concentric periductal fibrosis tenderness or pain in stooping around affected ducts o Occasionally. cordlike fibrous scar o Slight female predilection • In between areas of progressive stricture. and jaundice may develop • Each of these 4 conditions appears to arise from • Autoantibodies are present in less than 10% of patients intrinsic anomalies in the development of the smaller to • Severely afflicted patients: symptoms associated with larger portions of the intrahepatic biliary tree chronic liver disease such as weight loss. forming septa and dividing the • There is “beading” of a barium column in radiographs of liver into irregular islands the intrahepatic and extrahepatic biliary tree • Variable numbers of abnormally shaped bile ducts are o Due to irregular strictures and dilations of affected embedded in the fibrous tissue bile ducts • Bile duct remnants are distributed along the septal • Commonly seen in association with inflammatory bowel margin disease. including portal Polycystic Liver Disease hypertension and variceal bleeding • Liver contains multiple diffuse cystic lesions • Major cause of death: liver failure • Cysts are lined by cuboidal or flattened biliary epithelium o Followed by massive variceal hemorrhage and and contain straw-colored fluid intercurrent infection • Do not contain pigmented material • Detached from the biliary tree Primary Sclerosing Cholangitis • Occasionally. requires surgical intervention o Followed by solid. xanthelasmas. 2:1 • Anomaly arises because of persistence of a malformed embryonic form of the biliary tree Pathogenesis Caroli Disease • Cause is unknown • Larger ducts of the intrahepatic biliary tree are • Key events: segmentally dilated and may contain insipissated bile o Secretion of proinflammatory cytokines by • Pure forms are rare activated hepatic macrophages • Usually associated with portal tract fibrosis of the o Followed by infiltration of T cells into the stroma congenital hepatic fibrosis type immediately around bile ducts Morphology Clinical Features • Fibrosing cholangitis of bile ducts.

eye. both free within the vascular space and phagocytosed by Kupffer cells o Leads to panlobular parenchymal necrosis • Obstruction of a single main hepatic vein by thrombosis • DIC: may occlude sinusoids is clinically silent o Periportal sinusoidal occlusion and parenchymal • Obstruction of 2 or more major hepatic vein produces necrosis may arise in pregnancy as part of liver enlargement. skeleton. oral contraceptives and danazol chronic exposure to arsenicals o Pathogenesis is unknown o Histologic manifestation: hepatoportal sclerosis • Clinical signs are generally absent  dense fibrosis of intrahepatic portal tracts with • Potentially fatal intra-abdominal hemorrhage or hepatic obliteration of portal vein channels failure may occur • Lesions usually disappear after cessation of drug IMPAIRED BLOOD FLOW THROUGH THE LIVER treatment • Most common cause: cirrhosis • Physical occlusion of the sinusoids occur in a small but HEPATIC VENOUS OUTFLOW OBSTRUCTION striking group of diseases • Sickle cell disease: hepatic sinusoids may become Hepatic Vein Thrombosis and Inferior Vena Cava Thrombosis packed with sickled erythrocytes. or sepsis may result in a localized infarct that is Morphology usually anemic and pale-tan or sometimes hemorrhagic • Right-sided cardiac decompensation leads to passive • Hepatic artery thrombosis in a transplanted liver leads to congestion of the liver infarction of the major ducts of the biliary tree and loss of o Liver is slightly enlarged. and ascites  called the Budd- eclampsia Chiari syndrome • Metastatic tumor cells may fill the hepatic sinusoids in o Caused by increased intrahepatic blood pressure the absence of a mass lesion and an inability of the massive hepatic blood flow to shunt around the blocked outflow tract . generally bland condition of impaired portal vein inflow and noncirrhotic portal hypertension • Rare condition in which sinusoidal dilation is primary o May be associated with hypercoagulability of the • Most commonly associated with exposure to anabolic blood. vertebral anomalies. o Jagged1:Notch signalling pathway – regulates • The obstruction to blood flow and massive necrosis of cell fate and involved in the development of liver. neoplasia. pain. but at risk for hepatic • Considered together because they represent a failure and hepatocellular CA morphologic continuum o Both changes are commonly seen at autopsy CIRCULATORY DISORDERS because there is an element of pretermed circulatory failure with every death IMPAIRED BLOOD FLOW INTO THE LIVER • The only clinical evidence of centrilobular necrosis or its variants is mild to moderate transient elevation of serum Hepatic Artery Compromise aminotransferases • Parenchymal damage: can induce mild to moderate • Thrombosis or compression of an intrahepatic branch of jaundice the hepatic artery by embolism. peritonitis. and CV defects o Can survive into adulthood. myeloproliferative disorders. face. mostly discoloration (infarct of Zahn) o No necrosis. and kidney o Patients exhibit extrahepatic features: peculiar Passive Congestion and Centrolobular Necrosis facies. ascites. or steroids. and rarely. tense. and cyanotic with the organ rounded edges o Microscopically: congestion of centrolobular Portal Vein Obstruction and Thrombosis sinusoids o With time: centrolobular hepatocytes become • Occlusive disease of the portal vein or its major radicles atrophic  results in markedly attenuated liver produces abdominal pain. o Pancreatitis that initiates vein thrombosis which with suffusion of blood through the centrilobular region propagates into the portal vein • Uncommon complication of severe congestive heart • Acute thrombosis of an intrahepatic portal vein radicle failure: cardiac sclerosis results in a sharply demarcated area of red-blue o Pattern of liver fibrosis is distinctive. and other cell cords manifestations of portal hypertension (principally • Left-sided cardiac failure or shock esophageal varices which are prone to rupture) o Ascites is often massive and intractable o May lead to hepatic hypoperfusion and hypoxia • Acute impairment of visceral blood flow leads to • Hepatocytes in the central region of the profound congestion and bowel infarction lobule undergo ischemic coagulative necrosis (centrolobular necrosis) • Extrahepatic portal vein obstruction may arise from: • Hypoperfusion + retrograde congestion = centrolobular o Banti Syndrome – subclinical occlusion of the hemorrhagic necrosis portal vein presents as variceal bleeding and ascites o Liver has mottled appearance reflecting o Intra-abdominal sepsis leading to pylephlebitis in hemorrhage and necrosis in the centrilobular the splanchnic circulation regions  known as nutmeg liver o Thrombogenic disorders o Microscopically: sharp demarcation of viable o Trauma periportal and necrotic pericentral hepatocytes. with severe hepatocellular atrophy centrilobular and marked hemostasis in distended sinusoids Peliosis Hepatis • Idiopathic portal hypertension is a chronic. polyarteritis nodosa. hepatocytes can lead to fulminant hepatic failure heat.

and HBV+HDV) • Prompt surgical creation of a portosystemic venous o Pregnancy does not specifically alter the course shunt: revese flow through the portal vein. and varying degrees of DIC subtotal occlusion. reticulated collagen jaundice. firm. HBV. weight gain. organized • Eclampsia adherent thrombi o When hyperreflexia and convulsions occur • Thrombosis of obliterative hepatocavopathy may heal to o May be life threatening leave only an incomplete membranous web protruding • Subclinical hepatic disease may be the primary into the lumen of the inferior vena cava manifestation of preeclampsia. and low platelets  Veno-Occlusive Disease (Sinusoidal Obstruction HELLP syndrome Syndrome) • Patients with hepatic involvement in preeclampsia may exhibit modest to severe elevation of serum • Occurs primarily in the immediate weeks following bone aminotrasnferases and mild elevation of serum bilirubin marrow transplantation • Definitive treatment in severe cases: termination of • Incidence: 25% in recipients of allogeneic marrow pregnancy transplants. peripheral edema. there is striking centrolobular congestion • Can progress within days to hepatic failure and death with hepatocellular necrosis and accumulation o • Primary treatment: termination of pregnancy hemosiderin-laden macrophages . acute fatty liver of pregnancy. with small red patches due to hemorrhage sinusoidal blood flow • Occasionally. and jaundice) without sequelae o High risk of liver biopsy in these patients • Arises from toxic injury to the sinusoidal epithelium Morphology o Cells round up and slough off the sinusoidal wall. improves of the liver disease. and intrahepatic cholestasis of pregnancy Morphology o Extreme cases of the first 2 conditions is fatal • Liver is swollen and red-purple and has a tense capsule • Microscopically: Preeclampsia and Eclampsia o The affected hepatic parenchyma reveals severe • Preeclampsia centrilobular congestion and necrosis o Affects 7-10% of pregnancies • Centrilobular fibrosis: develops when thrombosis is o Characterized by maternal hypertension. including bleeding. inherited disorders of the venule is easily identified by using special stains for coagulation. frequently with total obliteration of thrombogenic disorder the venule • 10% of cases: idiopathic in origin o Hemosiderin deposition is evident in the scar • Separate distinction is made for inferior vena cave tissue thrombosis at its hepatic portion (obliterative o Congestion is minimal heptocavopathy) o Frequently idiopathic HEPATIC DISEASE ASSOCIATED WITH PREGNANCY o Nepal: endemic • Most common cause of jaundice in pregnancy: viral • Mortality if untreated: high hepatitis (HAV. slowly developing proteinuria. • Affected liver in preeclampsia is normal in size. with deposition of • Blood under pressure may coalesce and expand to form extracellular matrix a hepatic hematoma • Obliterative changes in the terminal hepatic vein are o Dissection of blood under Glisson’s capsule: may secondary to sinusoidal damage  alternative name: lead to hepatic rupture sinusoidal obstructive syndrome • 70-85% of patients recover spontaneously Acute Fatty Liver of Pregnancy • Treatment: largely supportive • Present in later half of pregnancy. abnormalities. ascites. fatality rates of 10-20% caval obstruction may be possible during angiography • Unique and very small subgroup develop hepatic • Chronic forms are far less lethal. yellow or white patches of ischemic o Accompanied by passage of erythrocytes into the infarction can be seen space of Disse and downstream accumulation of • Microscopically: cellular debris in the terminal hepatic vein o Periportal sinusoids contain fibrin deposits with o It is followed by proliferatin of perisinusoidal hemorrhage into the space of Disse  leads to stellate cells and subendothelial fibroblasts in the periportal hepatocellular coagulative nerosis terminal hepatic vein. direct dilation of pregnant patients. mortality: over 30% o Mild cases: managed conservatively • Diagnosis: made on clinical grounds only (tender • Those who survived severe preeclampsia recover hepatomegaly. over 2/3 of patients are complications directly attributable to pregnancy: alive after 5 years preeclampsia. antiphospholipid syndrome. as part of a syndrome of hemolysis. elevated liver enzymes. and intra-abdominal cancers • Chronic or healed veno-occlusive disease: • Occurance in pregnant women or those taking OCPs is o Dense perivenular fibrosis radiating out into the usually through interaction with an underlying parenchyma. HCV. or in chronic cases. paroxysmal connective tissue nocturnal hemoglobinuria. usually in the 3rd Morphology trimester • Characterized by obliteration of hepatic vein radicles by • Symptoms are directly attributable to incipient hepatic varying amouns of subendothelial swelling and fine failure. and embolizing downstream and obstructing pale. coagulation • Major veins may contain totally occlusive fresh thrombi. nausea and vomiting. obliteration of the lumen of myeloproliferative disorders. except hepatitis E viral prognosis infection  runs a more severe course in • In the case of vena caval thrombosis.• Hepatic vein thrombosis is associated with primary • As the disease progresses. and coma • Acute disease.

and aggregation. with variable degrees of centrilobular necrosis HEPATIC COMPLICATIONS OF ORGAN OR BONE MARROW TRANSPLANTATION • Severe injury: portal tracts are damaged  cause inflammation. and/or 2. and a fall in urinary sodium excretion TUMORS AND TUMOR-LIKE CONDITIONS • Onset: days immediately following the transplantation • The most common hepatic neoplasms are metastatic • A spectrum of centrolobular necrosis and inflammatory carcinomas changes is encountered  culminates in veno-occlusive • Important in the differential diagnosis of hepatic masses disease are • Clinical outcome is directly related to the severity of liver 1. and local cytokine release prematurity is modestly increased • Hepatocyte ballooning and cholestasis follow. hepatocellular carcinoma succumbs to septicemia. platelet o Incidence of fetal distress. soft nodules. stillbirth. These well-circumscribed lesions consist of many donor lymphocytes. often. and portal tract inflammation endothelitis  subendothelial lympocytic infiltrate lifts • Diagnosis depends on: the endothelium from its basement membrane o High index of suspicion • Cholestasis seen in both acute and chronic o Confirmation of microvesicular steatosis using • Acute cellular rejection special stains for fat (oil-red-O or Sudan black) on o Characterized by infiltration of a mixed population frozen tissue sections of inflammatory cells into portal tracts. pneumonia. neutrophil adhesion. followed by o Bile ducts are progressively occluded  due to darkening of urine and occasionally light stools and direct attack or obliteration of their arterial supply jaundice heralds the development of this syndrome • Both may lead to loss of the graft • Serum bilirubin (conjugated mostly) rarely exceeds 5mg/dl Nonimmunologic Damage to Liver Allografts • Alkaline phosphatase may be slightly elevated • Liver biopsy: mild cholestasis without necrosis • Revascularization and prefusion of the donor liver may o Altered hormonal state of pregnancy appears to result in preservation injury combine with biliary secretion defects to o Attributable to generation of oxygen radicals in a engender cholestasis hypoxic organ with insufficient reserves of oxygen • Generally a benign condition scavengers to prevent damage o But mother is at risk for gallstones and o Leads to sinusoidal endothelial injury and Kuppfer malabsorption cell activation. whether there is underlying liver disease. establishing a state of endothelial cell-lined vascular channels and chimerism in the recipient intervening stroma  Prevents the recipient’s immune system . whether the mass is solitary or multiple multiorgan failure Benign Tumors Graft-Versus-Host Disease and Liver Rejection • Liver transplants are reasonable tolerated by recipients • The most common benign lesions are cavernous o This is because the transplanted liver carries hemangiomas . bile duct proliferation. in which there is a greater risk for primary • Persistent severe liver dysfunction: fatal outcome. • Chronic graft-versus-host disease (more than 100 days Morphology after) • Diagnosis rests on biopsy identification of the o Portal tract inflammation characteristic microvesicular fatty transformation of o Selective bile duct destruction hepatocytes o Eventual fibrosis • In severe cases: lobular disarray with hepatocyte • Portal vein and hepatic vein radicles may exhibit dropout. hyperbilirubinemia. especially toxicity cirrhosis. in diameter donor lymphocytes on epithelial cells and inflammation of the parenchyma and portal tracts . bile duct  Electron microscopy can ale be used for and hepatocyte injury. from reacting against donor alloantigens usually less than 2 cm in diameter. tender hepatomegaly. directly beneath the capsule Morphology • Acute graft-versus-host disease (10-50 days after • Focal nodular hyperplasia – a well-demarcated but transplant) poorly encapsulated nodule with a central fibrous scar o Liver damage is dominated by direct attack of ranging up to many cm. reticulin collapse. and endothelitis steatosis • Chronic rejection Intrahepatic Cholestasis of Pregnancy o Severe obliterative arteritis of small and large arterial vessels results in ischemic changes in the liver parenchyma • Onset of pruritus in the 3rd trimester. bleeding. ascites. with the native common bile duct edema. They appear as discrete red-blue. and fibrosis Drug Toxicity After Bone Marrow Transplantation • Hepatic artery thrombosis – sufficiently severe vascular insult to cause severe compromise in the transplanted • Describes a syndrome of hepatic dysfunction following liver the cytotoxic therapy administered to patients just prior • Portal vein thrombosis may be insidious and present to bone marrow transplantation only as variceal hemorrhage weeks to months later • Affects up to one half of patients • Bile duct obstruction – from stricture at the anastomosis • Characterized by weight gain.

Significant for 2 reasons: Morphology 1.Repeated cycles of cell death and regeneration. chronic . Believed to represent nodular regeneration in disruption of cell cycle control. the HBV X-protein disrupts normal growth control by activation of host cell protooncogenes and . viruses. punctuated sometimes by bile staining and areas of • Most arise from hepatocytes and are termed hemorrhage or necrosis hepatocellular carcinoma (HCC) • All patterns of HCC have a strong propensity for • Much less common are carcinomas of bile duct origin invasion of vascular channels (cholangiocarcinomas) or tumors that are a mixture of • Snakelike masses of tumor invade the portal vein (with the 2 cell types occlusion of the portal circulation) or inferior vena cava • Two rare forms are: extending to the right side of the heart 1. translocations. infection with HBV • Fibrolamellar carcinoma – single. Genomic instability is more ascites likely in the presence of integrated HBV DNA. and duplications • Elevated serum levels of a-fetoprotein = lacks specificity . Bind covalently with cellular DNA and cause capsule mutations in protooncogenes or tumor suppressor . • Aflatoxins – derived from the fungus Aspergillus flavus stained. hepatocarcinogens in food (aflatoxin) . neoplasm per se . as the cells occurs in chronic hepatitis from any cause. • Cholangiocarcinomas – well-differentiated • Rare hereditary tyrosinemia most likely give rise to HCC adenocarcinomas with abundant fibrous stroma • Cirrhosis appears to be an important but not requisite (desmoplasia) explaining their firm. • Fever giving rise to chromosomal aberrations such as • Pain deletions. • Primary liver carcinomas appear grossly as: particularly during pregnancy (under estrogenic 1. o Rupture of the tumor with fatal hemorrhage the HBV X-protein that is a transacting transcriptional activator of many genes and is present in most tumors with integrated HBV DNA. chemicals. diffusely infiltrative – permeating widely and sometimes involving the entire liver Primary Carcinoma of the Liver • Discrete tumor masses are usually yellow-white. prominent arterial infection of the biliary tract by the liver fluke Opisthorchis vessels and draining veins are distributed through sinensis and previous exposure to Thorotrast the substance of the tumor . particularly TP53 resemble normal hepatocytes or have some • Cholangiocarcinoma – only recognizes causal variation in cell and nuclear size influences are primary sclerosing cholangitis. and nutrition. some studies • Liver cell adenoma – occur in women of childbearing suggest that certain HBV proteins bind to and inactivate the tumor suppressor gene TP53 age who have used OCPs . are important in the pathogenesis of liver cancers Clinical Features .an aggressive hepatocellular • Histologically. The HBV genome encodes a regulatory element. HCCs range from well-differentiated tumor of childhood lesions with hepatocytes arranged in cords or small 2. It appears that in liver cells infected with HBV. Molecular analysis of tumor cells in HBV-infected • Complications: individuals reveals that each case is clonal with o Profound cachexia respect to HBV DNA integration pattern suggesting that viral integration precedes or accompanies a o GI or esophageal variceal bleeding transforming event o Liver failure with hepatic coma . Clearly defined glandular and tubular structures • Extensive epidemiologic evidence links chronic HBV lined by somewhat anaplastic cuboidal-to-low infection with liver cancer. instead. or Thorotrast multinucleated anaplastic tumor giant cells • Globules of bile may be found within the cytoplasm of Pathogenesis cells and pseudocanaliculi between cells • Three major etiologic associations have been • Acidophilic hyaline inclusions may be present established: resembling Mallory bodies 1. arsenic. Composed of sheets and cords of cells that may genes. gritty consistency contributor to HCC . subcapsular adenomas are at risk for rupture. when they present as an intrahepatic mass 2. The accumulation of mutations during continuous • Rapid increase in liver size cycles of cell division may eventually transform • Sudden worsening of ascites or appearance of bloody some hepatocytes. causing life-threatening 2. large. Liver angiosarcoma – associated with exposure to nests to poorly differentiated lesions made up of large vinyl chloride. separated by parallel lamellae of dense collagen hormones. hard “scirrhous” 2. sex. yellow-tan or bile. chronic liver disease (including HCV and alcohol) tumor with fibrous bands coursing through it 3. and there is a strong evidence columnar epithelial cells implicating HCV infection . It also exerts anti response to local vascular injury and is not a apoptotic effects. interact in the bundles development of HCC. alcohol. Hepatoblastoma . Bile pigment and hyaline inclusions not found within . Portal tract are absent. . These tumors may be pale. well-demarcated nodules found anywhere found in “moldy” grains and peanuts in the hepatic substance but often beneath the . unifocal – massive tumor stimulation). Well-differentiated polygonal cells in nests or cords • Many factors including age. As with human papillomaviruses. multifocal – widely distributed nodules of variable intraabdominal hemorrhage size 3.