IUHS Student-2-Student USMLE Step 1 Recall

                                                    Liver

Bilirubin and Bile Formation

bilirubin is the end product of heme degradation...the majority of daily production is derived form breakdown of senescent erythrocytes by the mononuclear phagocyte system, especially in the spleen, liver, and bone marrow...most of the remainder of bilirubin is derived from the turnover of hepatic hemoproteins (P-450 cytochromes) and from premature destruction of newly formed erythrocytes in the bone marrow...the lattter pathway is important in hematologic disorders associated with excessive intramedullary hemolysis of defective erythrocytes...

whatever the source, heme oxygenase oxidized heme to biliverdin, which is then reduced to bilirubin by biliverdin reductase...

 bilirubin thus formed outside the liver is released and bound to serum albumin...albumin binding is necessary since bilirubin is virtually insoluble in aqueous solutions at physiologic pH...the small fraction of unbound bilirubin in plasma may increase in severe hemolytic diseae or when protein-binding drugs displace bilirubin from albumin...

hepatic processing of bilirubin involves carrier-mediated uptake at the sinusoidal membrane, conjugation with one or two molecules of glucuronic acid by bilirubin uridine diphosphate glucuronosyltransferase (UGT) in the endoplasmic reticulum, and excretion of the water soluble, nontoxic bilirubin glucuronides into bile...

most bilirubin glucuronides are deconjugated by bacterial beta-glucuronidases and degraded to colorlesss urobilinogens...

the urobilinogens, and the residue of intact pigment, are largely excreted in feces...

approximatelyt 20% of the urobilinogens formed are reabsorbed in the illeum and colon, returned to the liver, and promptly re-excreted into bile...the small amount that escaped this enterohepatic circulation is excreted in urine...

Enterohepatic Circulation of Bile Acids

the brillant yellow color of bilirubin makes it an easily identified component of hepatic bile formation....

however, bilirubin metabolism and excretions is but a minor cog in the hepatic machinery that secretes 12-36gm of bile acids into bile per day...

bile acids are carboxylated steroid molecules derived from cholesterol and are the detergent molecules primarily responsible for promoting bile flow and the secretion of phospholipid and cholesterol...

the primary human bile acids are cholic acid and chenodeoxycholic acid, which are secreted as taurine and glycine conjugates...

10-20% of excreted bile acids is deconjugated in the intestines by bacertial action....

virtually all conjugated and deconjugated bile acids are reabsorbed, primarily through the action of a sodium-bile acid cotransporter in the apical membrane of ileal enterocytes, and are returned to the liver for uptake, reconjugation, and resecretion...

fecal loss of bile acids is matched by de novo hepatic synthesis of bile acids from cholesterol...the enterohepatic circulation of bile acids provides an efficient mechanism for maintaining a large endogenous pool of bile acids for digestive and excretory purposes...

Excess Unconjugated Bilirubin in the circulation

unconjugated bilirubin is virtually insoluble in water at physiologic pH and is tightly complexed to serum albumin...

this form cannot be excreted in the urine even when blood levels are high...a small amount of unconjugated bilirubin is normally present as an albumin-free anion in plasma...

this fraction of unbound bilirubin may diffuse into tissues, particularly the brain in infants, and produces toxic injury...

the unbound plasma fraction may increase in severe hemolytic disease or when protein binding drugs displace bilirubin from albumin...

hence, hemolytic diseae of the newborn (erythroblastosis fetalis) may lead to accumulation of unconjugated bilirubin in the brain, which can cause severe neurologic damage, referered to as kenricterus)...

damage to basal ganglia and extra pyramidal damage...

Excess of Conjugated Bilirubin in the circulation

conjugated bilirubin is water soluble, nontoxic, and only loosely bound to albumin...

b/c of its solubility and weak association with albumin, excess conjugated bilirubin is plasma can be excreted in urine...

with prolonged conjugated hyperbilirubinemia, a portion of circulating pigment may become covalently bound to albumin...

Neonatal Jaundice

b/c the hepatic machinery for conjugation and excretion of bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia, termed neonatal or physiologic jaundice of the newborn...

deficiency of enzymes regulating bilirubin solubility...

breast fed infants tend to exhibit jaundice with greater frequency, possibly the result of beta-glucuronidases present in maternal milk...

these enzymes deconjugate bilirubin glucuronides in the gut, increasing intestinal reabsorption of unconjugated bilirubin...

deficiency of UDP-glucuronate or glucoranyltransferases...

Crigler Najjar Syndrome Type I

unconjugated hyperbilirubinemia...

the enzyme UDP glucuronate is completely absent, is invariably fatal, causing death within 18 months of birth secondary to kernicterus...

multiple genetic defects in the locus coding for the bilirubin UDP-glucuronosyltransferae enzyme, UGT1, may give rise to this disorder...

the liver is incapable of synthesizing a functional enzyme, and the colorless bile contains only trace amounts of unconjugated bilirubin...

the liver is morphologically normal by light and electron microscopy...

autosomal recessive...normal liver pathology...fatal in neonatal period...

Crigler Najjar Syndrome Type II

its a less severe, nonfatal disorder exhibiting  a partial defect in bilirubin conjugation; the major consequence is extraordinarily yellow skin....

a mutation that disrupts the hydrophobic core of the signal peptide for bilirubin UGT has been reported for this syndrome...

almost all patients develop normally, but there is a risk for some neurologic damage from kernicterus...

autosomal dominant with variable penetrance...generally mild, occasional kernicterus...

Gilbert Syndrome

relatively common, benign, somewhat heterogenous inherited condition presenting with mild, fluctuating Unconjugated hyperbilirubinemia...

the primary cause is reduction in hepatic bilirubin glucuronidating activity to about 30% of normal levels...

missense mutations and molecular anomalies in the promoter regions of the UGT1 gene result in reduced expression of the enzyme...

affecting some 6% of the population, the mild hyperbilirubinemia may go undiscovered for years and is not associated with functional derangements....

when detected in adolescence or adult life, it is typically in association with stress, such as an intercurrent illness, strenuous illness. strenuous exercise, or fasting...

there is no clinical consequence for Gilbert syndrome except for anxiety that a jaundiced sufferer might justifiably experience with this otherwise innocuous condition...

2nd most common cause of jaundice...

Dubin-Johnson Syndrome

Conjugated Hyperbilirubinemia...

results from a hereditary defect in hepatocellular excretion of bilirubin glucuronides across the canlicular membrane...

the defect is attributable to an absence of the canlicular transport protein for bilirubin glucuronides and related organic anions...

the liver is darkly pigmented owing to coarse pigmented granules within the cytoplasm of hepatocytes...

electron microsopy reveals coarse granules in hepatocellular lysosomes, which appear to be polymers of adrenaline (epinephrine) metabolites....

the liver is otherwise normal...apart from chronic or recurrent jaundice of fluctuating intensity, most patients are symptomatic and have a normal life expectancy....

Dirty Johnson = dirty liver...

Rotor Syndrome

rare, separate form of asymptomatic Conjugated hyperbilirubinemia with multiple defects in hepatocellular uptake and excretion of bilirubin pigments...

the liver is not pigmented...

as with Dubin-Johnson Syndrome, patients with Rotor Syndrome exhibit jaundice but otherwise live normal lives...

Cholestasis

cholestatic conditions, which result from hepatocellular dysfunction or intrahepatic or extrahepatic biliary obstruction, may also present with jaundice...

alternatively, pruritus is a common presenting symptom, presumably related to the elevation in plasma bile acids and deposition in peripheral tissues, particularly skin...

skin xanthomas (focal accumulations of cholesterol) sometimes appear, the result of hyperlipidemia and impaired excretion of cholesterol...

a characteristic laboratory finding is elevated serum alkaline phosphatase, an enzyme present in bile duct epithelium and in the canalicular membrane of hepatocytes....

common to both obstructive and hepatocellular cholestasis is the accumulation of bile pigment within the hepatic parenchyma...

elongated green-brown plugs of bile are visible in dilated bile canaliculi...rupture of canliculi leads to extravasation of bile, which is phagocytosed by kupffer cells...droplets of bile pigment also accumulate within hepatocytes, which can take on a wispy appearance (feathery or foamy degeneration)...

obstruction to the biliary tree, either intrahepatic or extrahepatic, induces distention of upstream bile ducts by bile...the bile stasis and back pressure induced proliferation of the duct epithelia cells and looping and reduplication of ducts, termed bile duct proliferation...

ultimately, end stage, bile stained, cirrhotic liver is created (biliary cirrhosis)...

Hepatic Failure

whatever the sequence, 80-90% of hepatic functional capacity must be eroded before hepatic failure ensues...in many cases, the balance is tipped toward decompensation by intercurrent conditions that place demands on the liver...

regardless of cause, the clincial signs of hepatic failure are much the same...jaundice is an almost invariable finding..hypoalbuminemia, which predisposes to peripheral edema, and hyperammonemia, which may play a role in cerebral compromise, are extremly worrisome developments...

fatel hepaticus, a characteristic body odor variously described as "musty" or "sweet and sour", occurs occasionally...it is related to the formation of mercaptans by the action of GI bacteria on the sulfur containing amino acid methionine and shunting of splanchnic blood from the portal into the systemic circulation (portosystemic shunting)...impaired estrogen metabolism and consequent hyperestrogenemia are the putative causes of palmar erythema and spider angiomas of the skin...each angioma is a central, pulsating, dilated arteriole from which small vessels radiate...in the male, hyperestrogenemia also leads to hypogonadism and gynecomastia...

hepatic failure is life threatening, for a number of reasons...first, with severly impaired liver function, patients are highly susceptible to failure of multiple organ systems...

thus, respiratory failure with pneumonia and sepsis combine with renal failure to claim the lives of many patients with hepatic failure...

a coagulopathy develops, attributable to impaired hepatic synthesis of blood clotting factors II, VII, IX, and X...the resultant bleeding tendency may lead to massive GI bleeding as well as petechial bleeding elsewhere...intestinal absoption of blood places a metabolic load on the liver, which worsens the extent of hepatic failure...the outlook of full blown hepatic failure is grave: a rapid downhill course is usual, with death occuring within weeks to a few months in about 80%...

Hepatic Encephalopathy and Hepatorenal Syndrome

Hepatic Encepalopathy - manifested by a spectrum of disturbances in consciousness, ranging from subtle behavioral abnormalities to marked confusion and stupor to deep coma and death...associated fluctuating neurologic signs include rigidity, hyperreflexia, and particulary asterixis: nonrhythmic, rapid extension-flexion movements of the head and extermities, best seen when the arms are held in extension with dorsiflexed wrists...

hepatic encephalopathy is caused by abnormal neurotransmission in the central nervous and neuromuscular systems and appears to be associated with elevated blood ammonia levels, which impair neuronal function and promote generalized brain edema...

also, GI bleeding is the most important preceipitating event of hepatic encephalopathy...other factors that can precipitate hepatic encephalopathy include hyperkalemia, hypernatremia, and constipation...

lactulose decreases amonia absorption...so does tetracycline, ampicllin, and metronidazole...

Hepatorenal Syndrome - refers to the appearance of acute renal failure in patients with severe liver disease, in whom there are no intrinsic morphologic or functional causes for the renal failure...kidney function promplty improves if hepatic renal failure is reversed....onset of this syndrome is typically heralded by a drop in urine output (oliguria) associated with rising blood urea nitrogen and creatinine concentration...the prognosis is poor with a mortality of 90-95%...alternatively, borderline renal insufficiency (serum creatinine concentration 2-3 mg/dl) may persist for weeks to months, as in cirrhotic patients whose ascites is refractory to diuretic therapy...

Cirrhosis of the Liver

cirrhosis is among the top ten causes of death in the western world...although it is largely the result of alcohol abuse, other major contributors include chronic hepatitis, biliary disease, and iron overload...this end stage of chronic liver diseae is defined by three characteristics...

(1) bridging fibrous septa in the form of delicate bands or broad scars replacing mutiple adjacent lobules...

(2) parenchymal nodules created by regeneration of encircled hepatocytes, varying from small (<3mm in diameter, micronodules) to large (several centimeters in diameter, macronodules)...

(3) disruption of the architecture of the entire liver...

the cental pathogenetic process in cirrhosis is progressive fibrosis deposited by the Ito cell (hepatic stellate cells)...in the normal liver, interstitial collagens (type I and III) are connected in portal tracts and around cental veins, with occasional bundles in the space of Disse...

the collagen (reticulin) coursing alongside hepatocytes is composed of delicate strands of type IV collagen in the space of Disse...in cirrhosis, type I and III collagen are deposited in the lobule, creating delicate or broad septal tracts...

new vascular channels in the septa connect the vascular structrues in the portal region (hepatic arteries and portal veins) and terminal hepatic veins, shunting blood around the parenchyma...

continued deposition of collagen in the space of Disse within preserved parenchyma is accompanied by the loss of fenestrations in the sinusoidal endothelial cells... in the process, the sinusoidal space comes to resemble a capillar rather than a channel for exchange of solutes between hepatocytes and plasma...

in particular, hepatocellular secretion of proteins (albumin, clotting factors, lipoproteins) is greatly impaired...

throughout the process of liver damage and fibrosis, remaining hepatocytes are stimulated to regenerate, and they proliferate as spherical nodules within the confines of the fibrous septa...the net outcome is a fibrotic, nodular liver in which delivery of blood to hepatocytes is severly compromised, as is the ability of hepatocytes to secrete substances into plasma...disruption of the interface between the parenchyma and portal tracts obliterates biliary channels as wel...thus, the cirrhotic patient may develop jaundice and even hepatic failure, despite having a liver of normal mass...

all forms of cirrhosis may be clinically silent...when symptomatic, they lead to nonspecific clinical manifestations: anorexia, weight loss, weakness, osteoporosis, and, in advanced disease, frank debilitation...

incipient or overt hepatic failure may develop, usually precipitated by superimposition of a metabolic load on the liver, as from systemic infection or a GI hemmorrhage...

imbalances of pulmonary blood flow, which are poorly understood, may lead to severly impaired oxygenation (hepatopulmonary syndrome), further stressing the patient...

the ultimate mechanism of most cirrhotic death is (1) progressive liver failure, (2) a complication related to portal hypertension, or (3) the development of hepatocellular carcinoma...

Portal Hypertension in the Liver

increased resistance to portal blood flow may develop in a variety of circumstances, which can be divided into prehepatic, intrahepatic, and posthepatic causes...

the major prehepatic conditions are obstructive thrombosis and narrowing of the portal vein before it ramifies within the liver...massive splenomegaly may also shunt excessive blood into the splenic vein...

the major posthepatic causes are severe right sided heart failure, constrictive pericarditis, and hepatic vein outflow obstruction...

the dominant intraheptic cause is cirrhosis (60%), accounting for most cases of portal hypertension...far less frequent are schistosomiasis, masssive fatty change, diffuse fibrosing granulomatous disease such as sarcoidosis and miliary tuberculosis, and diseases affecting the portal microcirculation exemplified by nodular regenerative hyperplasia...

portal hypertension in cirrhosis results from increased resistance to portal flow at the level of the sinusoids, and compression of central veins by perivenular fibrosis and expansile parenchymal nodules...anastomoses between the arterial and portal systems in the fibrous bands also contribute to portal hypertension by imposing arterial pressure on the low-pressure portal venous system...

the four major clinical consequences are (1) ascites, (2) the formation of portosystemic venous shunts, (3) congestive splenomegaly, and (4) hepatic encephalopathy...

ascites forms in perons with cirrhosis who suffer from both portal hypertension and hypoalbuminemia...hepatic lymph flow is increased in cirrhosis and contributes to the ascites...aldosterone also increases ascites...

Ascites in Cirrhosis of the Liver

ascites refers to the colletion of excess fluid in the peritoneal cavity...it usually becomes clinically detectable when atleast 500ml has accumulated, but many liters may collect and cause massive abdominal distention...

it is generally a serous fluid having less than 3 gm/dl of protein (largely albumin) as well as the same concentration as in the blood of solutes such as glucose, sodium and potassium...

influx of neutrophils suggests secondary infection, whereas red cells point to possible disseminated intraabdominal cancer...

with long standing ascites, peritoneal fluid through transdiaphragmatic lymphatics may produce hydrothorax, more often on the right side...

the pathogenesis of ascites is complex, involving the following mechanisms...

sinusoidal hypertension, altering starling focres and driving fluid into the space of disse, which is then removed by hepatic lymphatics; this movement of fluid is also promoted by hypoalbuminemia...

percolation of hepatic lymph into the peritoneal cavity...normal thoracic duct lymph flow approximates 800 to 1000 ml/day...with cirrhosis, hepatic lymphatic flow may appraoch 20L/day, exceeding thoracic duct capacity...hepatic lymph is rich in proteins and low in triglycerides, which is reflected in the protein-rich ascitic fluid...

intestinal fluid leakage...portal hypertension also engenders increased perfusion pressure in intestinal capillaries...the osmotic action of the protein rich ascitic fluid promotes movement of additional fluid out of intestinal capillaries into the abdomen...

renal retention of sodium and water due to secondary hyperaldosteronism...

Portosystemic Shunts in Cirrhosis of the Liver

with the rise in potal system pressure, bypasses develop wherever the systemic and portal circulation share common capillary beds...

principal sites are veins around and within the rectum (manifest as hemorrhoids); the cardioesophageal junction (producing esophagogastric varices); the retroperitoneam; and the falciform ligament of the liver (involving periumbilical and abdominal wall collaterals)...

although hemorrhoidal bleeding may occur, it is rarely massive or life threatening...

much more important are the esophagogastric varices that appear in about 65% of patients with advanced cirrhosis of the liver and cause massive hematemesis and death in about half of them...

abdominal wall collaterals appear as dialated subcutaneous veins extending from the umbilicus toward the rib margins and constiture an important clinical hallmark of portal hypertension...

Splenomegaly in Cirrhosis of the Liver

long-standing congestion may cause congestive splenomegaly...

the degree of enlargement varies widely up to 1000gm and is not necessarily correlated with other features of portal hypertension...

massive splenomegaly  may secondarily induce a variety of hematologic abnormalities attributable to hypersplenism...

Alcoholic Liver Disease

three distinctive, albeit overlapping, forms of liver diseae:

(1) hepatic steatosis...

(2) alcoholic hepatitis...

(3) cirrhosis, collectively refered to as alcholic liver disease...

b/c the first two conditions may develop independently, they do not necessarily represent a continuum of changes...

the morphology of the three forms of alcholic liver disease is presented first, b/c this facilitates consideration of their pathogenesis...

excess production of NADH changes the normal hepatic metabolism away from catabolism of fats and toward anabolism of fats (lipid synthesis), resulting in decreased mitochondrial oxidation of fatty acids and increased hepatic production of triglyceride...

Hepatic Steatosis (Fatty Liver)

after even moderate intake of alcohol, small (microvesicular) lipid droplets accumulate in hepatocytes...with chronic intake of alcohol, lipid accumulates to the point of creating large clear macrovesicular globules, compressing and displacing the nucleus to the periphery of the hepatocyte...

this transformation is initially centrilobular, but it may involve the entire lobule in severe cases...

in macroscopic appearance, the fatty liver of chronic alcoholism is a large (up to 4-6 kg) soft organ that is yellow, greasy, and readily fractured...

although there is little or no fibrosis at the outset, fibrous tissue develops around the central veins and extends into the adjacent sinusoids with continued alcohol intake...

up to the time that fibrosis appears , the fatty change is completely reversible if there is abstention from further intake of alcohol...

Alcoholic Hepatitis

AST is higher than ALT...ALT is higher in viral hepatitis...

hepatocyte swelling and necrosis...single or scattered foci of cells undergo swelling (balloning) and necrosis...the swelling results from the accumulation of fat and water as well as proteins that normally are exported...

ubiquinated filaments...

mallory bodies...scattered hepatocytes accumulate tangled skins of cytokeratin intermediate filaments and other proteins, visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes...these inclusions are a characteristic but not specific feature of alcoholic liver disease, as they are also seen in primary biliary cirrhosis, Wilson disease, chronic cholestatic syndromes, and hepatocellualr tumors...

neutrophilic reaction...neutrophils permeate the lobule and accumulate around degenerating hepatocytes, particularly those having mallory bodies...lymphocytes and macrophages also enter portal tracts and spill into the parenchyma...

acetylaldehyde protein complex stimulates ito cell to produce fibrosis...

fibrosis...alcoholic hepatitis is almost always accompanied by a brisk sinusoidal and perivenular fibrosis; periportal fibrosis may occasionally predominate, particularly with repeated bouts of heavy alcohol intake...in some cases, there is cholestasis and mild deposition of hemosiderin (iron) in hepatocytes and kupffer cells...

in macroscopic appearance, the liver is mottled red with bile stained areas...although the liver may be of normal or increased size, it often contains visible nodules and fibrosis indicative of evolution to cirrhosis...

liver will revert to normal if patient stops drinking...

Alcoholic Cirrhosis

the final and irreversible form of alcoholic liver diseaes usually evolves slowly and insidously...at first the cirrhotic liver is yellow tan, fatty, and enlarged, usually weighing more than 2 kg...

during the span of years, it is transformed into a brown, shrunken, nonfatty organ, sometimes less than 1 kg in weight...

arguably, cirrhosis may develop more rapidly in the setting of alcoholic hepatitis, within 1-2 years...initially, the developing fibrous septa are delicate and extend through sinusoids from central vein to portal regions as well as from potal tract to portal tract...

regenerative activity of entrapped parenchymal hepatocytes generates fairly uniformly sized "micronodules"...with time, the nodularity becomes more prominent; scattered larger nodules create a "hobnail" appearance on the surface of the liver...as fibrous septa dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks progressively in size...

parenchymal islands are engulfed by ever wider bands of fibrous tissue, and the liver is converted into a mixed micronodular pattern and macronodular pattern...

ischemic necrosis and fibrous obliteration of nodules  eventually create broad expanses of tough, pale scar tissue...

bile stasis often develops; mallory bodies are only rarely evident at this stage...thus, end-stage alcohlic cirrhosis come to resemble, both macroscopically and microscopically, the cirrhosis developing from viral hepatitis and other causes...

Hemochromatosis

hemochromatosis is characteized by the excessive accumulation of body iron, most of which is deposited in parenchymal organs such as the liver and pancreas...

bronze diabetes...iron overload...

b/c humans do not have a major excretory pathway for iron, hemochromatosis results either from a genetic defect causing excessive iron absorption or as a consequence of parenteral administration of iron (usually in the form of transfusions)...

genetic hemochromatosis, also called hereditary hemochromatosis, is a homozygous recessive heritable disorder...acquired forms of hemochromatosis with known sources of excess iron are called secondary hemochromatosis...

total iron pool ranges from 2-6 gm in normal adults; about .5gm is stored in the liver, 98% of which is in hepatocytes...in genetic hemochromatosis, total iron accumulation may exceed 50gm, more than one  third of which accumulates in the liver...

(1) micronodular cirrhosis - all cases...

(2) diabetes mellitus - 75-80% of cases...

(3) skin pigmentation 75-80% of cases...

iron accumulation is lifelong; symptoms usually first appear in the fifth to sixth decades of life...

the hemochromatosis gene is located on the short arm of chromosome 6, close to the HLA gene locus...this gene, called HLA-H, encodes a novel HLA class I - like molecule that in some uncharacterize manner influences iron absorption...the most common mutation is a cysteine to tyrosine substitution at amino acid 282, which inactivated this 343 amino acid protein; other alleles have also been identified...HLA-H is in linkage disequilibrium with HLA-A3, thus accounting for the association of this haplotype with genetic hemochromatosis...

it may be recalled that the total body content of iron is tightly regulated, whereby the limited daily loses of iron are matched by GI absorption...in genetic hemochromatosis, there is a primary defect in the intestinal absorption of dietary iron, leading to net iron accumulation of .5 to 1.0 gm/year...

the disease manifests itself typically after 20gm of storage iron has accumulated...the exact mechanism by which a defect in HLA-H engenders excessive iron absorption is not yet known...

regulated transfer of iron from intesintal mucosal cells to plasma may be involved, since HLA-H is expressed on the mucosal cell surface an interacts with circulating beta2 microglobulin...

excessive iron appears to be directly toxic to host tissues by the following mechanisms: (1) lipid peroxidation through iron catalyzed free radical reactions; (2) stimulation of collagen formation; (3) direct interactions of iron with DNA, leading to lethal injury or predisposition to hepatocellular carcinoma..

genetic hemochromatosis is more often a disease of male and rarely becomes evident before age 40 years...the principal manifestation include hepatomegaly, abdominal pain, skin pigmentation (particulary in sun-exposed areas), deranged glucose homeostasis or frank diabetes mellitus due to destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis...

in some patients, the presenting complaint is hypogonadism (amenorrhea in the female, and loss of libido and impotence in the male)...

the classic triad of pigment cirrhosis with hepatomegaly, skin pigmentation, and diabetes mellitus may not develop until late in the course of the disease...death may result from cirrhosis or cardiac disease...a significant cause of death is hepatocellular carcinomas; the risk is 200 fold greater than in the general population, and treatment for iron overload does not remove the risk for this aggressive neoplasm....

fortunately, genetic hemochromatosis can be diagnosed long before irreversible tissue damage has occurred...screening involves demonstration of high levels of serum iron and ferritin, exclusion of secondary causes of iron overload, HLA gene molecular analysis, and liver biopsy if indicated...screening of family members of probands is important...heterozygotes for genetic hemochromatosis also accumulate excessive iron, but not to the degree required to cause significant tissue damage...

decreased total iron binding capacity (TIBC)...

Wilson Disease (hepatolenticular degeneration)

this autosomal recesive disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye...normally, 40-60% of daily ingested copper (2-5mg) is absorbed in the stomach and duodenum and transported to the liver loosely complexed with albumin...

free copper dissociates and is transferred into hepatocytes, where it is incorporated into an alpha2-globulin to form ceruloplasmin (a metallothionein) and resecreted into plasma...ceruloplasmin accounts for 90-95% of plasma copper, although its biologic role is unknown since the contained six to seven atoms of copper per molecule are not readily exchangeable...

desialylated, senescent ceruloplasmin is endocytosed by the liver, degraded within lysosomes, and excreted into bile; this is the primary route for copper elimination...estimated total body copper is only 50-150mg...

the gene for wilson disease, disignated ATP7B is on chromosome 13 and encodes a transmembrane copper transporting ATPase, located on the hepatocyte canalicular membrane...

the liver often bears the brunt of injury in wilson disease; hepatic changes range from relatively minor to massive damage...fatty change may be mild to moderate, with vacuolated nuclei (glycogen or water) and occasional hepatocyte focal necrosis...

an acute hepatitis can exhibit features mimicking acute viral hepatitis, save possibly for the accompanying fatty change...a chronic hepatitis resembles chronic hepatitis or viral, drug, or alcoholic origin but may exhibit such distinguishing features as fatty change, vacuolated nuclei, and mallory bodies...

with progression of chronic hepatitis, cirrhosis will develop...massive liver necrosis is rare manifestation that is indistinguishable from that caused by viruses or drugs...excess copper deposition can often be demonstrated by special stains (rhodamine stain for copper, orcein stain for copper associated protein)...

b/c copper also accumulates in chronic abstructive cholestasis, and b/c histology cannot reliably distinguish wilson disease from viral and drug induced hepatitis (and vice versa), demonstration of hepatic copper content in excess of 250ug per gram dry weight is most helpful for making a diagnosis...

in the brain, toxic injury primarily affects the basal ganglia, particularly the putamen, which demonstrates atrophy and even cavitation...nearly all patients with neurologic involvemnt develop eye lesions called kayser fleischer rings (green to brown deposits of copper in descemet membrane in the limbus of the cornea) hence the alternative designation of hepatolenticular degeneration...

the age at onset and the clinical presentation of Wilson disease are extermely variable, but the disorder rarely manifests before age 6 years...the most comon presentation is acute or chronic liver disease...

neuropsychiatric manifestations, including mild behavioral changes, frank psychosis, or a parkinson disease like syndrome, are the initial features in most of the remaining cases...

the biochemical diagnosis of wilson disease is based on a  decrease in serum ceruloplasmin, increase in hepatic copper content, and increased urinary excretion of copper...

serum coppper levels are of no diagnositc value, since they may be low, normal, or elevated, depending on the stage of evolution of the disease...

demonstration of kayser fleischer rings further favors the diagnosis...

early recognition and long term copper chelation therapy (as with D-pencillamine) have dramatically altered the usual progressive downhill course...

Alpha1-Antitrypsin Deficiency

Alpha1-antitrypsin is an autosomal recessive disorder marked by abnormally low serum levels of this major protease inhibitor (Pi)...

the major function of this protein is the inhibition of proteases, particularly neutrophil elastase released at site of inflammation...

the deficiency leads to the development of pulmonary emphysema, b/c a relative lack of this protein permits tissue destructive enzymes to run amok...

the most common genotype is PiMM, occurring in 90% of individuals...

with most allelic genes, the mRNA is translated and the protein is synthesized and secreted normally...

deficiency variants exhibit a selective defect in movement of this secretory protein

from the endoplasmic reticulum to golgi apparatus; this is most marked for the PiZZ polypeptide, attributable to a single amino acid substitution of Glu to Lys...

the mutant polypeptide (alpha1-antitrypsin Z) is abnormally folded, blocking its movement along the raminder of the secretory pathway...

alpha-1 antitrypsin deficiency is characterized by the presence of round to oval cytoplasmic globular inclusions in hepatocytes, which in routine hematoxylin and eosin stains are acidophilic and indistinctly demarcated from the surrounding cytoplasm...

they are strongly periodic acid schiff (PAS) positive and diastase resistant...

the globules are also present in diminshed size and number in intermediate deficiency states...

the hepatic syndromes associated with PiZZ homozygosity are extremely varied, ranging from neonatal hepatitis without or with cholestasis and fibrosis, to childhood cirrhosis, to a smoldering chronic inflammatory hepatitis or cirrhosis that becomes apparent only later in life...

for the most part, the only distinctive feature of the hepatic disease is the periportal PAS positive globules; infrequently, fatty change and mallory bodies are present...

neonatal hepatitis with cholestatic jaundice appears in 10-20% of newborns with the deficiency...

in adolescence, presenting symptoms may be related to hepatitis or cirrhosis...

attacks of hepatitis may subside with apparent complete recovery, or they may become chronic and lead progressively to cirrhosis...

finally, the disease may remain silent until cirrhosis appears in middle to later life...

hepatocellular carcinoma develops in 2-3% of PiZZ adults, usually but not always in the setting of severe cirrhosis...

the treatment, and cure, for severe hepatic disease is orthotopic liver transplantation...

in patients with pulmonary disease, the single most important treatment is avoidance of cigarette smoking, since this behavior markedly acceleates the destructive lung disease associated wih alpha1-antitrypsin deficiency... 

Neonatal Hepatitis

lobular disarray with focal liver cell necrosis...

panlobular giant cell transformation of hepatocytes...

prominent hepatocellular and canalicular cholestasis...

mild mononuclear infiltration of the potal areas...

reactive changes in the kupffer cells....

extramedullary hematopoiesis...

this predominantly parenchymal pattern of injury may blend imperceptibley into a ductal pattern of injury, with bile duct proliferation and fibrosis of portal tracts...clear distinction from an obstructive cholangiopathy may thus be impossible...

specific features that permit diagnosis of a particular cause include the inclusions of alpha1-antitrypsin or cytomegalovirus, and fatty change wih cirrhosis in galactosemia and tyrosinemia...

Secondary Biliary Cirrhosis

prolonged obstruction to the extrahepatic biliary tree results in profound alteration of the liver itself...the most common cause of obstruction in adults is extrahepatic cholelithiasis (gallstones), followed by malignant neoplasms of the biliary tree or head of the pancreas and strictures resulting from previous surgical procedures...

obstructive conditions in children include biliary atresia, choledochal cysts (a cystic anomaly of the extrahepatic biliary tree), cystic fibrosis, and syndromes in which there  are insufficient intrahepatic bile ducts (paucity of bile duct syndromes)...

the initial morphologic features of cholestasis, are entirely reversible with correction of the obstruction...however, seconday inflammation resulting from biliary obstruction initiates periportal fibrosis, which eventually leads to scarring and nodule formation, resulting in secondary biliary cirrhosis...

the end-stage obstructed liver exhibits extraordinary yellow green pigmentation and is accompanied by marked icteric discoloration of body tissue and fluids...

on cut surface, the liver is hard, with a finely granular appearance...the histology is characterized by coarse fibrous septa that subdivide the liver in a jigsaw like pattern...embedded in the septa are distended small and large bile ducts, which frequently contain inspissated pigmented material...

there is extensive proliferation of smaller bile ductules and edema, particulaly at the interface between septa (formerly portal tracts) and the parenchyma...

Primary Biliary Cirrhosis

primary biliary cirrhosis is a chronic, progressive, and often fatal cholestatic liver disease characterized by the destruction of intrahepatic bile ducts, portal inflammation and scarring, and the eventual development of cirrhosis and liver failure...

the primary feature of this disease is a non suppurative, granulomatous destruction of medium sized intrahepatic bile ducts...cirrhosis develops only after many years...

this is primarily a disease of middle age women, with a female to male predominance in excess of 6:1...age at onset is between 20-80 years, with peak incidence bwetween 40-50 years of age...

serum alkaline phosphatase and cholesterol are almost always elevated; hyperbilirubinemia is a late development and usually signifies incipient hepatic decompensation....a striking feature of the disease is the presence of serum autoantibodies, especially antimitochondrial antibodies in more than 90% of patients...

particularly characteristic of primary biliary cirrhosis are circulating "antimitochondiral antibodies" against the E2 subunit of the pyruvate dehydrogenase complex, dihydrolipoamide acetlytransferase, located on the inner face of the inner mitochondrail membrane...however, 5-10% of patients with granulomatous destruction of bile ducts do not exhibit antimitochondrial antibodies...

many lines of evidence indicate an autoimmune etiology for primary biliary cirrhosis, including aberrant neoexpression of MHC class II molecules on bile duct epithelial cells and accumulation of autoreactive T cells around bile ducts...

the disease features a systemic polyclonal hypergammaglobulinemia, failure to convert IgM to IgG antibodies, and hypocomplementemia from complement activation and formation of immune complexes...

morever, patients may develop extrahepatic autoimmune associations including Sjogren syndrome, scleroderma, thyroiditis, rheumatoid arthritis, raynaud phenomen, membranous glomerulonephritis, and celiac disease...

however, the initiating events in primary biliary cirrhosis are not clear, nor is it undertood how the antimitochondrial antibodies result in the formation granulomas...

the onset is insidous, usually presenting with pruritus...jaundice develops late in the course...

hepatomegaly is typical...xanthomas and xanthelasmas arise b/c of cholesterol retention...

Primary Sclerosing Cholangitis

primary sclerosing cholangitis is characterized by inflammation, obliterative fibrosis, and

segmental constriction of the intrahepatic and extrahepatic bile ducts...

characteristic "beading" of a barium column in radiographs of the intrahepatic and extrahepatic biliary tree is attributable to the irregular strictures and secondary dilations of affected bile ducts...

primary sclerosing cholangitis is commonly seen in association with inflammatory bowel disease, particulaly chronic ulcerative colitis, which coexists in approximately 70% of primary sclerosing cholangitis patients...

the cause of primary scleroisng cholangitis is unknown, despite its clear association with inflammmatory bowel disease...

primary sclerosing cholangitis is a fibrosing cholangitis of bile ducts, with a lymphocytic infiltrate, progressive atrophy of the bile duct epithelium, and obliteration of the lumen...

the concentric periductal fibrosis around affected ducts ("onion skin fibrosis") is followed by their disapearance, leaving behind a solid, cordlike fibrous scar...

asymptomatic patients may come to attention only on the basis of persistent elevation of serum alkaline phosphatase...

alternatively, progressive fatigue, pruritus, and jaundice may develop...

unlike in primary biliary cirrhosis, autoantiboides are present in less than 10% of patients...

severely affected patients exhibit symptoms associated with chronic liver diseae, including weight loss, ascites, variceal bleeding, and encephalopathy...

this disease also follows a protracted course for many years...there is an increased risk for the development of cholangiocarcinoma...as with primary biliary cirrhosis, liver transplantation is the definitive treatment...

p-ANCA antibodies are characteristic for primary sclerosing cholangitis...

Passive Congestion of the Liver

develops cor pulmonale with ascites and peripheral edema...

right sided cardiac decompensation leads to passive congestion of the liver...the liver is slightly enlarged, tense, and cyanotic with rounded edges...

on microscopic examination, there is congestion of centrilobular sinusoids...with time, centrilobular hepatocytes become atrophic, resulting in markedly attenuated liver cell cords...

left sided cardiac failure or shock may lead to hepatic hypoperfusion and hypoxia...in this instance, hepatocytes in the central region of the lobule undergo ischemic necrosis (centrilobular necrosis)...

the combination of hypoperfusion and retrograde congestion acts synergistically to generate centrilobular hemorrhagic necrosis...the liver takes on a variegated mottled appearance reflecting hemorrhage and necrosis in the centrilobular regions, known traditionally as the nutmeg liver...

Centrilobular Necrosis of the Liver

often occurs in acetaminophen overdose...

right sided cardiac decompensation leads to passive congestion of the liver...the liver is slightly enlarged, tense, and cyanotic with rounded edges...

on microscopic examination, there is congestion of centrilobular sinusoids...with time, centrilobular hepatocytes become atrophic, resulting in markedly attenuated liver cell cords...

left sided cardiac failure or shock may lead to hepatic hypoperfusion and hypoxia...in this instance, hepatocytes in the central region of the lobule undergo ischemic necrosis (centrilobular necrosis)...

the combination of hypoperfusion and retrograde congestion acts synergistically to generate centrilobular hemorrhagic necrosis...the liver takes on a variegated mottled appearance reflecting hemorrhage and necrosis in the centrilobular regions, known traditionally as the nutmeg liver...

by microscopy, there is a sharp demarcation of viable periportal and necrotic pericentral hepatocytes, with suffusion of blood through the centrilobular region...

an uncommon complication of sustained chronic severe congestive heart fialure is so called cardiac sclerosis..the pattern of liver fibrosis is distinctive, inasmuch as it is mostly centrilobular...the damage rarely fulfills the accepted criteria for the diagnosis of cirrhosis, but the historically sanctified term cardiac cirrhosis cannot easily be dislodged...

in most instances, the only clinical evidence of centrilobular necrosis is mild to moderate transient elevation of serum aminotransaminases...the parenchymal damage may be suficient to induce mild to moderate jaundice...

Peliosis Hepatis

sinusoidal dilation occurs in any condition in which efflux of hepatic blood is impeded...peliosis hepatitis is a rare condition in which the dilation is primary...it is most commonly associated with exposure ot anabolic steroids, and rarely oral contraceptives and danazol, although the pathogenesisis not known...

in patients infected with HIV, pelioitic liver lesions can develop as a result of hepatic infection by bartonella hensela, as a component of bacillary agiomatosis...

although clinical signs are generally absent even in advanced peliosis, potentially fatal intra-abdominal hemorrhage or hepatic failure may occur...in the case of drug induced peliosis, the lesions usually disappear after cessation of drug treatment...

Heptic Vein Thrombosis (Budd-Chiari Syndrome)

the Budd-Chiari syndrome was originally described for acute and usually fatal thrombotic occlusion of the hepatic veins...

the definition has now been expanded to include subacute and chronic occlusive syndromes, characterized by hepatomegaly, weight gain, ascites, and abdominal pain...

hepatic vein thrombosis is associated with (in order of frequency) polycythemia vera, pregnancy, the postpartum state, the use of oral contraceptives, paroxysmal nocturnal hemoglobinuria, and intra-abdominal cancers, particularly hepatocellualr carcinoma...

all these conditions produce thrombotic tendencies or, in the case of liver cancers, sluggish blood flow...about 30% of cases are idiopathic in origin...

with acutely developing thrombosis of the major hepatic viens or inferior vena cava, the liver is swollen and red purple and has a tense capsule...

on microscopic examination, the affected hepatic parenchyma reveals severe centrilobular congestion and necrosis...

centrilobular fibrosis develops in instances in which the thrombosis is more slowly developing...

Veno-Occlusive Disease

originally described in jamaican drinkers of pyrrolizidine alkaloid containing bush tea, veno-occlusive diseae now occurs primarily in the weeks immediately after bone marrow transplantation...

the incidence approaches 25% in recepients of allogeneic marrow tranplants, with mortality rates of more than 30%...

a diagnosis of veno-occlusive disease is frequently made on clinical grounds only (tender hepatomegaly, ascites, weight gain, and jaundice) b/c of the high risk of liver biopsy in these patients...

veno-occlusive disease is characterized by obliteration of hepatic vein radicles by varying amounts of subendothelial swelling and fine reticulated collagen....

in acute disease, there is striking centrilobular congestion with hepatocellular necrosis and accumulation of hemosiderin laden macrophages....

as the disease progresses, obliteration of the lumen of the venule is easily identified with use of special stains for connective tissue...with chronic or healed veno-oclusive disease, dense perivenular fibrosis radiating out into the parenchyma may be present, frequently with total obliteration of the venule; hemosiderin deposition is evident in the scar tissue, and congestion is minimal...

the pathogenesis of veno-occlusive diseae has been attributed (without rigorous proof) to toxic damage of the sinusoidal endothelium allowing erythrocyte extravasation into the space of disse, activation of the coagulation cascade, and downstream accumulation of debris into the central vein...

Liver changes seen in Pre-eclampsia

preeclampsia is a complication of pregnancy and is characterized by maternal hypertension, proteinuria, peripheral edema, coagulation abnormalities, and varying degrees of dissemianted intravascular coagulation....

when hyperreflexia and convulsions occur, the condition is called eclampsia...hepatic disease is distressingly common in preeclampsia, usually as part of a syndrome of hemolysis, elevated liver enzymes, and low patelets, dubbed the HELLP syndrome...

patients with hepatic involvement in preeclampsia my exhibit modest to severe elevation of serum transaminases and mild elevation of serum bilirubin...

the affected liver in preeclampsia is normal in size, firm, and pale with small red patches due to hemorrhage....

yellow or white patches of ischemic infarction can be seen occasionally...

on microscopic examination, the periportal sinusoids contain fibrin deposits with hemorrhage into the space of disse, leading to periportal hepatocellular coagulative necrosis...

Acute Fatty Liver of Pregnancy

this disease exhibits a spectrum ranging from modest or even subclinical hepatic dysfunction (evidenced by elevated transaminase serum levels) to hepatic failure, coma, and death...

affected women present in the latter half of pregnancy, usually in the third trimester...symptoms are directly attributable to incipient hepatic failure, including bleeding, nausea and vomiting, jaundice, and coma...

in 20-40% of cases, the presenting symptoms may be those of coexistent preeclampsia...

while this condition most commonly runs a mild course, patients with acute fatty liver of pregnancy can progress within days to hepatic failure and death...the primary treatment of acute fatty liver of pregnancy is termination of the pregnancy...

a defect in intramitochondrial fatty acid oxidation has been identified: a substantial portion of mothers exhibit a heterozygous deficiency in long chain 3-hydroxyacyl-coenzyme A dehydrogenase, and their fetuses are homozygously affected (with a heterozygous state in the father as well)...

the diagnosis of acute fatty liver rests on biopsy confirmation of characteristic microvesicular fatty transformation of hepatocytes...

in severe cases, there may be lobular disarray with hepatocyte dropout, reticulin collapse, and portal tract inflammation, making distinction from viral hepatitis difficult...

diagnosis depends on (1) a high index of suspicion and (2) confirmation of microvesicular steatosis with use of special stains (oil red O or Sudan black)...

Intrahepatic Cholestasis of Pregnancy

the onset of pruritus in the third trimester, followed by darkening of the urine and occasionally light stools and jaundice, heralds the development of this enigmatic syndrome...

serum bilirubin concentration (mostly conjugated) rarely exceeds 5 mg/dl; alkaline phosphatase may be slightly elevated...

liver biopsy reveals mild cholestasis without necrosis...estrogenic hormones appear to play a causal role by inhibiting hepatocellular bile secretory function....

although this is generally a benign condition, the mother is at risk for gallstones and malabsorption, and the incidence of fetal distress, still births, and prematurity is modestly increased...

Focal Nodular Hyperplasia of the Liver

often due to women taking contraceptives...

presents as a spontaneous mass lesion, most frequently in young to middle aged women, and has an excellent prognosis...

focal nodular hyperplasia appears as a well-demarcated but poorly encapsulate nodule, ranging up to many centimeters in diameter...

the lesion is generally lighter in color than the surrounding liver and is sometimes yellow...there is typically a central gray white, depressed stellate scar from which radiate fibrous septa to the periphery...

the central scar contains large vessels, usually arterial, that typically exhibit fibromuscular hyperplasia with eccentric or concentric narrowing of the lumen...the radiating septa exhibit foci of intense lymphocytic infiltrates and exuberant bile duct proliferation along septal margins...the parenchyma between the septa is composed largely of normal hepatocytes...

Adenomas of the Liver

hepatocellular adenomas are benign tumors that occur predominantly in women and are influenced by hormones, mainly oral contraceptives...they occur mostly in the right lobe of the liver...multiple adenoams in the liver have been associated with glycogen storage disease type I...

benign neoplasms developing form hepatocytes are called liver cell adenomas...these tend to occur in young women who have used oral contraceptives, and they regress on discontinuance of use...liver cell adenomas have clinical significance for three reasons...

Hepatocellular Carcinoma

hepatocellular carcinoma arises from the hepatocytes...accounts for more than 90% of all primary liver cancers...

Hepatocellular carcinoma occurs most often in the setting of cirrhosis

which is most often from chronic alcoholism

in the U.S., but from viral hepatitis in the rest of the world).

most common primary malignant tumor of the liver...

aflatoxins, produced by food spoilage molds, are encountered in certain areas endemic for hepatocellular carcinoma...they are the most potent environmental factor implicated in hepatocellular carcinogenesis...

aflotoxins are activated in hepatocytes, and their products intercalate into DNA to form mutagenic adducts with guanosine...

a particular susceptibility site for aflatoxin action is the guanosine base in codon 249 of the p53 gene, leading to G to T transversion at this site...this specific p53 mutation is found frequently in hepatocellular carcinomas from sub-Saharan africa and china...

it is these same world regions in which there are inherited susceptibilities to aflatoxin...hepatocellular microsomal epoxide hydrolase and glutathione S-transferase are responsible for detoxifying aflatoxin, and in sub-saharan africa and china, patients with hepatocellular carcinoma exhibit mutant hepatic enzymes with little or no activity towards aflatoxin...it appears that HBV infection, aflatoxin exposure, and genetic variation act synergistically in some world regions to increase risk for hepatocellular carcinoma...