9189574 Liver Robbins

8/8/2019 9189574 Liver Robbins

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THE LIVERNormal• The liver and biliary tree and the gallbladder occupy the

right upper quadrant of the abdomen.• The liver resides between the digestive tract and the rest

of the body and functions as a way station between thesplanchnic and systemic circulation

• The liver has the critical job of maintaining the body'smetabolic homeostasis. This includes:a. the processing of dietary amino acids ,

carbohydrates, lipids, and vitamins;b. removal of microbes and toxins in splanchnic blood

en route to the systemic circulation;c. synthesis of many plasma proteins; and

detoxification and excretion into bile of endogenouswaste products and pollutant xenobiotics.

• The mature liver lies in the right hypochondrium under the rib cage and extends from the right fifth intercostalspace at the midclavicular line to just below the costalmargin.

• It projects slightly below the costal margin at the rightintercostal line and under the xyphoid process in themidline.

• The physiologic or functional right and left lobes aredefined by the distribution of the right and left portal veinsystems.

• The watershed between these two vascular bedscorresponds to a plane that passes superiorly throughthe left side of the sulcus of the inferior vena cava to themiddle of the gallbladder fossa inferiorly.

• The quadrate lobe and the greater part of the caudatelobe on the posterior aspect of the liver belongfunctionally to the left hemiliver.

Microarchitecture• The liver has been divided into 1- to 2-mm diameter

hexagonal lobules oriented around the terminal

tributaries of the hepatic vein ( terminal hepatic veins ),with portal tracts at the periphery of the lobule.• Accordingly, the hepatocytes in the vicinity of the

terminal hepatic vein are called "centrilobular" (or centrolobular); those near the portal tract are"periportal."

• However, since hepatocytes near the terminal hepaticveins are most remote from the blood supply, it hasbeen argued that they are at the distal apices of roughlytriangular acini, with the bases formed by penetratingseptal venules from the portal vein extending out fromthe portal tracts.

• In the "acinus," the parenchyma is divided into threezones, zone 1 being closest to the vascular supply, zone

3 abutting the terminal hepatic venule, and zone 2 beingintermediate.

• The hepatic parenchyma is organized into cribiform,anastomosing sheets or "plates" of hepatocytes, seen inmicroscopic sections as cords of cells.

• Hepatocytes immediately abutting the portal tract arereferred to as the limiting plate , forming a discontinuousrim around the mesenchyme of the portal tract.

• There is a radial orientation of the hepatocyte cordsaround the terminal hepatic vein.

• Hepatocytes exhibit minimal variation in overall size, butnuclei may vary in size, number, and ploidy, particularlywith advancing age.

• Uninucleate, diploid cells tend to be the rule, but withincreasing age, a significant fraction are binucleate, andthe karyotype may range up to octaploidy.

• Between the cords of hepatocytes are vascular sinusoids.

• Blood traverses the sinusoids and exits into the terminalhepatic vein through innumerable orifices in the veinwall.

• Hepatocytes are thus bathed on two sides by well-mixedportal venous and hepatic arterial blood, placinghepatocytes among the most richly perfused cells in thebody.

• The sinusoids are l ined by fenestrated anddiscontinuous endothelial cells, which demarcate anextrasinusoidal space of Disse , into which protrudeabundant microvilli of hepatocytes.

• Scattered Kupffer cells of the mononuclear phagocytesystem are attached to the luminal face of endothelialcells, and scattered fat-containing perisinusoidal stellatecells are found in the space of Disse.

• These stellate cells play a role in the storage andmetabolism of vitamin A and are transformed intocollagen-producing myofibroblasts when there isinflammation of the liver.

• Between abutting hepatocytes are bile canaliculi , whichare channels 1 to 2 μm in diameter, formed by groovesin the plasma membranes of the facing cells anddelineated from the vascular space by tight junctions.

• Numerous microvilli extend into these intercellular spaces, which constitute the outermost reaches of thebiliary tree.

• Hepatocellular actin and myosin microfilamentssurrounding the canaliculus help propel secreted biliaryfluid along the canaliculi.

• These channels drain into the canals of Hering in theperiportal region.

• These canals are troughlike extensions of biliaryepithelium into the periportal parenchyma, abutting withhepatocytes to form efficient channels for draining bile.

• Biliary fluid is conveyed through their lumina to bileductules, which traverse the portal mesenchyme to

empty into the terminal bile ducts within the portal tracts.

Pathology• The dominant primary diseases of the liver are viral

hepatitis, alcoholic liver disease, and hepatocellular carcinoma.

• More often, hepatic damage is secondary, to some of the most common diseases in humans, such as cardiacdecompensation, disseminated cancer, and extrahepaticinfections.

• With the rare exception of fulminant hepatic failure, liver disease is an insidious process in which symptoms of hepatic decompensation may occur weeks, months, or even years after the onset of injury.

• There is often a long time interval between diseaseonset (or initiation) and detection. Conversely, the liver may be injured and heal without clinical detection.

• Three general aspects of liver disease(1) patterns of hepatic injury,(2) hepatic failure and cirrhosis, and(3) jaundice and cholestasis.

1. PATTERNS OF HEPATIC INJURY • The liver is an inherently simple organ with a limited

repertoire of responses to injurious events.• Regardless of cause, five general responses are seen.

a. Degeneration and Intracellular Accumulation.- Damage from toxic or immunologic insult may cause

swelling of hepatocytes.- Moderate cell swelling is reversible.- With more severe damage ( ballooning degeneration ),

swollen hepatocytes have irregularly clumpedcytoplasmic organelles and large clear spaces.

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- In cholestatic liver injury, retained biliary material mayimpart a diffuse, foamy appearance to the swollenhepatocyte ( feathery degeneration ).

- This lesion can be difficult to distinguish from ballooningdegeneration, except for the variable yellowdiscoloration of the cytoplasm.

- Substances may accumulate in viable hepatocytes,including iron and copper .

- Accumulation of triglyceride fat droplets withinhepatocytes is known as steatosis

- Multiple tiny droplets that do not displace the nucleusare known as microvesicular steatosis , and appear insuch conditions as acute fatty liver of pregnancy andvalproic acid toxicity.

- A single large droplet that displaces the nucleus,macrovesicular steatosis , may be seen in hepatocytesthroughout the livers of obese or diabetic individualsand, interestingly, in scattered hepatocytes in patientswith hepatitis C viral infection.

b. Necrosis and Apoptosis.- Any significant insult to the liver can cause hepatocyte

necrosis .

- In ischemic coagulative necrosis , the liver cells arepoorly stained and "mummified" and often have lysednuclei.

- In apoptotic cell death , isolated hepatocytes round upto form shrunken, pyknotic, and intensely eosinophiliccellscontaining fragmented nuclei.

- Hepatocytes may also osmotically swell and rupture, so-called lytic necrosis, the outcome of ballooningdegeneration.

- Lytic necrosis leaves neither mummified hepatocytes nor pyknotic cells but rather shards of cellular debris.

- Necrosis frequently exhibits a zonal distribution.- The most obvious is necrosis of hepatocytes

immediately around the terminal hepatic vein (so-calledcentrilobular necrosis, using the historicalterminology), an injury that is characteristic of ischemicinjury and a number of drug and toxic reactions.

- Pure midzonal and periportal necrosis are rare; thelatter may be seen in eclampsia.

- With most other causes of hepatic injury, a variablemixture of hepatocellular death through the parenchymais encountered.

- The hepatocyte necrosis may be limited to scatteredcells within hepatic lobules ( focal or spotty necrosis ) or to the interface between the periportal parenchyma andinflamed portal tracts ( interface hepatitis ).

- With more severe inflammatory injury, necrosis of contiguous hepatocytes may span adjacent lobules in aportal-to-portal, portal-to-central, or central-to-centralfashion ( bridging necrosis ).

- Necrosis of entire lobules ( submassive necrosis ) or of most of the liver ( massive necrosis ) is usuallyaccompanied by hepatic failure.

- With disseminated candidal or bacterial infection,macroscopic abscesses may occur.

c. Inflammation.- Injury to the liver associated with an influx of acute or

chronic inflammatory cells is termed hepatitis .- Direct toxic or ischemic hepatocyte necrosis incites an

inflammatory reaction.- With toxic damage, inflammation may also precede the

onset of inflammation.

- Destruction of antigen-expressing liver cells by cytotoxiclymphocytes is a common mechanism of liver damage,especially during viral infection.

- In viral hepatitis, quiescent lymphocytes may collect inthe portal tracts as a reflection of mild smolderinginflammation, spill over into the periportal parenchymaas activated lymphocytes ( interface hepatitis ) causinga moderately active hepatitis, or suffuse the entireparenchyma in severe hepatitis.

- Once killed, apoptotic hepatocytes do not incite an

inflammatory reaction per se.- However, scavenger macrophages (Kupffer cells and

circulating monocytes recruited to the liver) engulf theapoptotic cell fragments within a few hours, generatingclumps of inflammatory cells.

- Hence, identification of apoptotic hepatocytes is a signof very recent hepatocyte destruction.

- Foreign bodies, organisms, and a variety of drugs mayincite a granulomatous reaction.

d. Regeneration.- Hepatocytes have long life spans, and they proliferate in

response to tissue resection or cell death- Regeneration occurs in all but the most fulminant

hepatic diseases.- Hepatocellular proliferation is marked by mitoses,

thickening of the hepatocyte cords, and somedisorganization of the parenchymal structure.

- The canal of Hering-bile ductule unit constitutes areserve compartment for restitution of severeparenchymal injury; when it is activated, innumerableserpentine profiles resembling bile ductules appear-so-called ductular reaction .

- This compartment also proliferates during large bile ductobstruction.

- When hepatocellular necrosis occurs and leaves theconnective tissue framework intact, almost perfectrestitution of liver structure can occur, even when the

necrosis is submassive or massive.

e. Fibrosis.- Fibrous tissue is formed in response to inflammation or

direct toxic insult to the liver.- Unlike other responses, which are reversible, fibrosis

points toward generally irreversible hepatic damage .- However, there is now considerable debate about the

irreversibility of liver fibrosis and even cirrhosis- Deposition of collagen has lasting consequences on

patterns of hepatic blood flow and perfusion of hepatocytes.

- In the initial stages, fibrosis may develop around portaltracts or the terminal hepatic vein or may be deposited

directly within the space of Disse.- With continuing fibrosis, the liver is subdivided into

nodules of proliferating hepatocytes surrounded byscar tissue, termed "cirrhosis ."

- This end-stage form of liver disease is discussed later inthis section.

2.A HEPATIC FAILURE • The most severe clinical consequence of liver disease is

hepatic failure .• More often, it is the end point of progressive damage to

the liver as part of chronic liver disease, either byinsidious destruction of hepatocytes or by repetitivediscrete waves of parenchymal damage.

• These include gastrointestinal bleeding, systemicinfection, electrolyte disturbances, and severe stresssuch as major surgery or heart failure.

• In most cases of severe hepatic dysfunction, liver transplantation is the only hope for survival

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• The morphologic alterations that cause liver failure fallinto three categories:

a. Massive hepatic necrosis .- This is most often drug- or toxin-induced, as

from acetaminophen (38% of massive hepaticnecrosis cases in the United States),halothane , antituberculosis drugs ( rifampin , isoniazid ), antidepressant monoamine oxidaseinhibitors, industrial chemicals such as carbontetrachloride, and mushroom poisoning

( Amanita phalloides ), collectively accounting for an additional 14% of cases.

- The mechanism may be direct toxic damage tohepatocytes (e.g., acetaminophen , carbontetrachloride, mushroom toxins) but more oftenis a variable combination of toxicity andinflammation with immune-mediatedhepatocyte destruction.

- Hepatitis A infection accounts for 4% of cases,hepatitis B infection accounts for 8%, and other causes (including unknown) account for 37%.Hepatitis C infection does not cause massivehepatic necrosis.

b. Chronic liver disease .- This is the most common route to hepaticfailure and is the endpoint of relentless chronichepatitis ending in cirrhosis.

c. Hepatic dysfunction without overt necrosis- Hepatocytes may be viable but unable to

perform normal metabolic function, as withReye syndrome, tetracycline toxicity, and acutefatty liver of pregnancy.

Clinical Features• Regardless of cause, the clinical signs of hepatic failure

are much the same.• Jaundice is an almost invariable finding.

Hypoalbuminemia , which predisposes to peripheraledema, and hyperammonemia , which may play a role incerebral dysfunction, are extremely worrisomedevelopments.

• Fetor hepaticus is a characteristic body odor that isvariously described as "musty" or "sweet and sour" andoccurs occasionally.

• It is related to the formation of mercaptans by the actionof gastrointestinal bacteria on the sulfur-containingamino acid methionine and shunting of splanchnic bloodfrom the portal into the systemic circulation(portosystemic shunting).

•

Impaired estrogen metabolism and consequenthyperestrogenemia are the putative causes of palmar erythema (a reflection of local vasodilatation) and spider angiomas of the skin.

• Each angioma is a central, pulsating, dilated arteriolefrom which small vessels radiate. In the male,hyperestrogenemia also leads to hypogonadism andgynecomastia .

• Hepatic failure is life-threatening because with severely impaired liver function, patients are highly susceptible tofailure of multiple organ systems .

• A coagulopathy develops, attributable to impairedhepatic synthesis of blood clotting factors II, VII, IX, and

X.• The resultant bleeding tendency can lead to massivegastrointestinal bleeding as well as petechial bleedingelsewhere.

• Intestinal absorption of blood places a metabolic load onthe liver, which worsens the extent of hepatic failure.

• A fortunate few can endure an acute episode untilhepatocellular regeneration restores adequate hepaticfunction.

• Alternatively, liver transplantation might save the patient.• Two particular complications merit separate

consideration, as they herald the most grave stages of hepatic failure:

a. Hepatic encephalopathy - is manifested by a spectrum of disturbances in

consciousness, ranging from subtle behavioralabnormalities to marked confusion and stupor to deep coma and death.

- These changes may progress over hours or days in fulminant hepatic failure or moreinsidiously in a patient with marginal hepaticfunction from chronic liver disease.

- Associated fluctuating neurologic signs includerigidity, hyperreflexia, and particularly asterixis :nonrhythmic, rapid extension-flexionmovements of the head and extremities, bestseen when the arms are held in extension withdorsiflexed wrists.

- Hepatic encephalopathy is regarded as adisorder of neurotransmission in the central nervous system and neuromuscular system 5

and appears to be associated with elevatedblood ammonia levels, which impair neuronalfunction and promote generalized brain edema.

- In the great majority of instances, there areonly minor morphologic changes in the brain,such as edema and an astrocytic reaction , andthe encephalopathy is reversible if theunderlying hepatic condition can be corrected.

b. Hepatorenal syndrome refers to the appearance of renal failure in patients with severe chronic liver disease , in whom there are no intrinsic morphologicor functional causes for the renal failure.- Sodium retention, impaired free-water

excretion, and decreased renal perfusion andglomerular filtration rate are the main renalfunctional abnormalities.

- Several factors are involved in its development,including a decreased renal perfusion pressuredue to systemic vasodilation, activation of therenal sympathetic nervous system withvasoconstriction of the afferent renal arteriolae,and increased synthesis of renal vasoactivemediators, which further decrease glomerular filtration.

- Onset of this syndrome is typically heralded bya drop in urine output, associated with risingblood urea nitrogen and creatinine.

- The ability to concentrate urine is retained, producing a hyperosmolar urine devoid of proteins and abnormal sediment, and surprisingly low in sodium (unlike renal tubular necrosis).

- Rapid development of renal failure is usuallyassociated with a precipitating stress factor such as infection, gastrointestinal hemorrhage,or a major surgical procedure.

- Insidious development of renal failure is theresult of progressive destabilization of circulatory physiology, frequently in the settingof severe refractory ascites.

- The prognosis is poor, with a median survival of

only 2 weeks in the rapid-onset form and 6months with the insidious-onset form.

2.B CIRRHOSIS • Cirrhosis is among the top 10 causes of death in the

Western world.












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• The chief worldwide contributors are alcohol abuse andviral hepatitis.

• Other causes include biliary disease, and iron overload.• An example of the progression to cirrhosis is given

under the subsequent discussion on alcohol.• Cirrhosis as the end-stage of chronic liver disease is

defined by three characteristics:a. Bridging fibrous septae in the form of delicate bands

or broad scars linking portal tracts with one another and portal tracts with terminal hepatic veins

b. Parenchymal nodules containing proliferatinghepatocytes encircled by fibrosis, with diametersvarying from very small (<3 mm, micronodules) tolarge (several centimeters, macronodules)

c. Disruption of the architecture of the entire liver • Several features of cirrhosis should be underscored:

a. The parenchymal injury and consequent fibrosis arediffuse , extending throughout the liver.

b. Focal injury with scarring does not constitute cirrhosis,nor does diffuse nodular transformation withoutfibrosis.

c. Nodularity is part of the diagnosis and reflects thebalance between regenerative activity and constrictivescarring.

d.Vascular architecture is reorganized by theparenchymal damage and scarring, with the formationof abnormal interconnections between vascular inflowand hepatic vein outflow channels.

e. Fibrosis is the key feature of progressive damage tothe liver.

• Infrequent types of cirrhosis also include the cirrhosisdeveloping in infants and children with galactosemia andtyrosinosis, and drug-induced cirrhosis, as with α-methyldopa.

• Severe fibrosis can occur in the setting of cardiacdisease (sometimes called "cardiac cirrhosis,").

• After all the categories of cirrhosis of known causationhave been excluded, a substantial number of casesremain.

• Referred to as cryptogenic cirrhosis , the magnitude of this "wastebasket" category speaks eloquently to thedifficulties in discerning the many origins of cirrhosis.

• A growing concern is that many of these cases are dueto undiagnosed nonalcoholic fatty liver disease , to bediscussed.

• Once cirrhosis is established, it is usually impossible toestablish an etiologic diagnosis on morphologic groundsalone .

Pathogenesis• The central pathogenetic processes in cirrhosis are

progressive fibrosis and reorganization of the vascular microarchitecture of the liver. 7

• In the normal liver, interstitial collagens (types I and III)are concentrated in portal tracts and around centralveins, with occasional bundles in the space of Disse.

• The collagen (reticulin) coursing alongside hepatocytesis composed of delicate strands of type IV collagen inthe space of Disse.

• In cirrhosis, types I and III collagen are deposited in thelobule, creating delicate or broad septal tracts.

• New vascular channels in the septae connect thevascular structures in the portal region (hepatic arteriesand portal veins) and terminal hepatic veins, shunting

blood around the parenchyma.• Continued deposition of collagen in the space of Dissewithin preserved parenchyma is accompanied by theloss of fenestrations in the sinusoidal endothelial cells.

• In the process, the sinusoidal space comes to resemblea capillary rather than a channel for exchange of solutesbetween hepatocytes and plasma.

• In particular, hepatocellular secretion of proteins (e.g.,albumin, clotting factors, lipoproteins) is greatlyimpaired.

• The major source of excess collagen in cirrhosis is theperisinusoidal stellate cells, which lie in the space of Disse.

• Although normally functioning as vitamin A fat-storingcells, during the development of cirrhosis they becomeactivated, a process that includes:(1) robust mitotic activity in areas developing new

parenchymal fibrosis,(2) a shift from the resting-state lipocyte phenotype to a

transitional myofibroblast phenotype, and(3) increased capacity for synthesis and secretion of

extracellular matrix.• It is predominantly the cytokines secreted by activated

Kupffer cells and other inflammatory cells that stimulateperisinusoidal stellate cells to divide and to producelarge amounts of extracellular matrix.

• Moreover, the greatest activation of stellate cells is inareas of severe hepatocellular necrosis andinflammation. The stimuli for stellate cell activation maycome from several sources:a. Chronic inflammation, with production of

inflammatory cytokines such as tumor necrosis factor (TNF), lymphotoxin, and interleukin-1 (IL-1).

b. Cytokine production by activated endogenous cells(Kupffer cells, endothelial cells, hepatocytes, and bileduct epithelial cells), including transforming growthfactor-β (TGF-β), platelet-derived growth factor (PDGF), and lipid peroxidation products.

c. Disruption of the extracellular matrix, as stellate cellsare extraordinarily responsive to the status of their substrate.

d. Direct stimulation of stellate cells by toxins.• Acquisition of myofibers by perisinusoidal stellate cells

also increases vascular resistance within the liver parenchyma, since tonic contraction of these"myofibroblasts" constricts the sinusoidal vascular channels.

Clinical Features• 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, frankdebilitation.

• Incipient or overt hepatic failure may develop, usuallyprecipitated by a superimposed metabolic load on theliver, as from systemic infection or a gastrointestinalhemorrhage.

• Imbalances of pulmonary blood flow, which are poorlyunderstood, may lead to severely impaired oxygenation(hepatopulmonary syndrome ), further stressing thepatient.

• The ultimate mechanism of most cirrhotic deaths is:(1) progressive liver failure (discussed earlier),(2) a complication related to portal hypertension, or

(3) the development of hepatocellular carcinoma.

PORTAL HYPERTENSION

• Increased resistance to portal blood flow may develop ina variety of circumstances, which can be divided into

prehepatic, intrahepatic, and posthepatic causes .









• The major prehepatic conditions are obstructivethrombosis and narrowing of the portal vein before itramifies within the liver.

• Massive splenomegaly may also shunt excessive bloodinto the splenic vein.

• The major posthepatic causes are severe right-sidedheart failure, constrictive pericarditis, and hepatic veinoutflow obstruction.

• The dominant intrahepatic cause is cirrhosis, accounting

for most cases of portal hypertension .• Far less frequent are schistosomiasis, massive fatty

change, diffuse fibrosing granulomatous disease suchas sarcoidosis and miliary tuberculosis, and diseasesaffecting the portal microcirculation, exemplified bynodular regenerative hyperplasia.

• Portal hypertension in cirrhosis results from increasedresistance to portal flow at the level of the sinusoids, andcompression of terminal hepatic veins by perivenular scarring and expansile parenchymal nodules.

• Anastomoses between the arterial and portal systems inthe fibrous septa also contribute to portal hypertensionby imposing arterial pressure on the low-pressurehepatic venous system.

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

Ascites• Ascites refers to the collection of excess fluid in the

peritoneal cavity .• It usually becomes clinically detectable when at least

500 mL has accumulated, but many liters may collectand cause massive abdominal distention.

• It is generally a serous fluid having less than 3 gm/dL of

protein (largely albumin) as well as the sameconcentrations of solutes such as glucose , sodium, andpotassium as in the blood. The fluid may contain a scantnumber of mesothelial cells and mononuclear leukocytes.

• Influx of neutrophils suggests secondary infection,whereas red cells point to possible disseminated intra-abdominal cancer.

• With long-standing ascites, seepage of peritoneal fluidthrough transdiaphragmatic lymphatics may producehydrothorax, more often on the right side.

• The pathogenesis of ascites is complex, involving thefollowing mechanisms:a. Sinusoidal hypertension , altering Starling's forces

and driving fluid into the space of Disse, which is thenremoved by hepatic lymphatics; this movement of fluidis also promoted by hypoalbuminemia .

b. Percolation of hepatic lymph into the peritoneal cavity : Normal thoracic duct lymph flow approximates800 to 1000 mL/day. With cirrhosis, hepatic lymphaticflow may approach 20 L/day, exceeding thoracic ductcapacity. Hepatic lymph is rich in proteins and low intriglycerides, which is reflected in the protein-richascitic fluid.

c. Intestinal fluid leakage : Portal hypertension alsocauses increased perfusion pressure in intestinalcapillaries. The osmotic action of the protein-richascitic fluid promotes movement of additional fluid out

of intestinal capillaries into the abdomen.d. Renal retention of sodium and water due tosecondary hyperaldosteronism.

Portosystemic Shunts

• With the rise in portal system pressure, bypassesdevelop wherever the systemic and portal circulationshare common capillary beds.

• Principal sites are veins around and within the rectum(manifest as hemorrhoids), the cardioesophageal

junction (producing esophagogastric varices), theretroperitoneum, and the falciform ligament of the liver (involving periumbilical and abdominal wall collaterals).

• Although hemorrhoidal bleeding may occur, it is rarelymassive or life-threatening.

• Much more important are the esophagogastric varicesthat appear in about 65% of patients with advanced cirrhosis of the liver and cause massive hematemesisand death in about half of them .

• Abdominal wall collaterals appear as dilatedsubcutaneous veins extending from the umbilicustowards the rib margins ( caput medusae ) and constitutean important clinical hallmark of portal hypertension.

Splenomegaly• Long-standing congestion may cause congestive

splenomegaly.• The degree of enlargement varies widely up to 1000 gm

and is not necessarily correlated with other features of portal hypertension.

• Massive splenomegaly may secondarily induce a varietyof hematologic abnormalities attributable tohypersplenism.

3. JAUNDICE AND CHOLESTASIS • Hepatic bile formation serves two major functions:

(1) the emulsification of dietary fat in the lumen of thegut through the detergent action of bile salts and

(2) the elimination of systemic waste products. Bileconstitutes the primary pathway for elimination of bilirubin, excess cholesterol, and xenobiotics that areinsufficiently water-soluble to be excreted into urine.

Because bile formation requires well-functioninghepatocytes, it is readily disrupted. Such disruption becomesclinically evident as yellow discoloration of the skin andsclerae ( jaundice and icterus , respectively) due to retentionof pigmented bilirubin, and as cholestasis , characterized bysystemic retention of not only bilirubin but also other soluteseliminated in bile.

Bilirubin and Bile Formation• Bilirubin is the end product of heme degradation.• The majority of daily production (0.2 to 0.3 gm) is

derived from breakdown of senescent erythrocytes bythe mononuclear phagocytic system, especially in thespleen, liver, and bone marrow.

• Most of the remainder of bilirubin is derived from theturnover of hepatic heme or hemoproteins (e.g., the P-450 cytochromes) and from premature destruction of newly formed erythrocytes in the bone marrow.

• The latter pathway is important in hematologic disordersassociated with excessive intramedullary hemolysis of defective erythrocytes (ineffective erythropoiesis.

• Whatever the source, heme oxygenase oxidizes hemeto biliverdin (which is then reduced to bilirubin bybiliverdin reductase.

• Bilirubin thus formed outside the liver is released andbound to serum albumin.

• Albumin binding is necessary, since bilirubin is virtuallyinsoluble in aqueous solutions at physiologic pH.

• The very small fraction of unbound bilirubin in plasmamay increase in severe hemolytic disease or whenprotein-binding drugs displace bilirubin from albumin.







• Hepatic processing of bilirubin involves carrier-mediateduptake at the sinusoidal membrane, conjugation withone or two molecules of glucuronic acid by bilirubinUDP-glucuronyltransferase in the endoplasmicreticulum, and excretion of the water-soluble, nontoxicbilirubin glucuronides into bile.

• Most bilirubin glucuronides are deconjugated bybacterial β-glucuronidases and degraded to colorlessurobilinogens.

• The urobilinogens and the residue of intact pigment arelargely excreted in feces. Approximately 20% of theurobilinogens formed are reabsorbed in the ileum andcolon, returned to the l iver, and promptly re-excreted intobile. The small amount that escapes this enterohepaticcirculation is excreted in urine.

• The hepatic conjugating enzyme, UGT1A1, is a productof the UGT1 gene located on chromosome 2q37.

• It is a member of a family of UGTs that catalyze theglucuronidation of an array of substrates such as steroidhormones, carcinogens, and drugs.

• The various UGTs are distributed in a wide range of tissues, including the liver, kidney, intestine, skin, lung,olfactory epithelium, and testis. UGT1A1 is located

primarily in the smooth and rough endoplasmic reticulumof hepatocytes, as a single isoform that catalyzes theglucuronidation of bilirubin to its monoglucuronidatedand diglucuronidated forms.

• The sequence of the human UGT1 gene shows thatthere are 13 isoform sequences in a tandem array for exon 1, each of which possesses a unique promoter andundergoes differential splicing to four common exons(exons 2 through 5).

• This differential splicing leads to the generation of different mRNAs that encode the different UGT isoforms.Following translation into a polypeptide, the uniqueamino terminus specifies acceptor-substrate selection,and the common carboxy terminus specifies the enzymeinteraction with the common donor substrate, UDP-glucuronic acid.

• In humans, two members of the UGT1 family possessthe capability to glucuronidate bilirubin in vitro, but onlyone isoform is physiologically relevant in vivo.

• This bilirubin glucuronidating isoform is termed UGT1A1,as it is generated from the exon 1A of the UGT1 genelocus.

• The brilliant yellow color of bilirubin makes it an easilyidentified component of hepatic bile formation.

• However, bilirubin metabolism and excretion are butminor cogs in the hepatic machinery that secretesapproximately 0.5 to 1.0 L of bile daily.

• Newly secreted bile is a bicarbonate-rich fluid containingby weight about 3% organic solutes.

• Two thirds of the organic material in bile are bile salts:bile acids conjugated with taurine or glycine to form bilesalts.

• Bile acids are the major catabolic products of cholesteroland are a family of water-soluble sterols withcarboxylated side chains.

• The primary human bile acids are cholic acid andchenodeoxycholic acid.

• Bile acids and their taurine- or glycine-conjugated saltsact as highly effective detergents.

• Their primary physiologic role is solubilizing water-

insoluble lipids secreted by hepatocytes into bile, and solubilizing dietary lipids within the gut lumen.

• The principal secreted lipids (>95%) are lecithins(phosphatidylcholine), which are very hydrophobic andhave no appreciable aqueous solubility of their own.

• However, these insoluble amphiphiles enhance thelimited cholesterol-solubilizing capacity of bile salts inbile.

• Cholesterol is a negligibly soluble steroid molecule witha single polar hydroxyl group, whose solubility in bile isincreased several million-fold by the presence of bilesalts and lecithin .

• Ten percent to 20% of secreted bile salts aredeconjugated in the intestines by bacterial action.

•

Ninety-five percent of secreted bile acids, conjugated or unconjugated, are reabsorbed, primarily through theaction of a sodium-bile acid cotransporter in the apicalmembrane of ileal enterocytes and are returned to theliver via portal blood for uptake, reconjugation withtaurine or glycine , and resecretion.

• The enterohepatic circulation of bile acids provides anefficient mechanism for maintaining a large endogenouspool of bile acids for digestive and excretory purposes.

• Fecal loss of bile acids (0.2 to 0.6 gm per day) ismatched by their daily de novo hepatic synthesis fromcholesterol.

• This obligatory fecal loss of sterols in the form of bilesalts and residual free cholesterol constitutes the onlyeffective mechanism for elimination of excesscholesterol from the body.

Pathophysiology of Jaundice• Both unconjugated bilirubin and bilirubin glucuronides

may accumulate systemically and deposit in tissues,giving rise to the yellow discoloration of jaundice.

• This is particularly evident in the yellowing of the sclerae(icterus).

• There are two important pathophysiologic differencesbetween the two forms of bilirubin.

• Unconjugated bilirubin is virtually insoluble in water at physiologic pH and is tightly complexed to serumalbumin.

• This form cannot be excreted in the urine even whenblood levels are high .

• Normally, a very small amount of unconjugated bilirubinis present as an albumin-free anion in plasma.

• This fraction of unbound bilirubin may diffuse intotissues, particularly the brain in infants, and producetoxic injury.

• The unbound plasma fraction may increase in severehemolytic disease or when protein-binding drugsdisplace bilirubin from albumin.

• Hence, hemolytic disease of the newborn(erythroblastosis fetalis) may lead to accumulation of unconjugated bilirubin in the brain, which can causesevere neurologic damage, referred to as kernicterus

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

• Because of its solubility and weak association withalbumin, excess conjugated bilirubin in plasma can beexcreted in urine.

• With prolonged conjugated hyperbilirubinemia, a portionof circulating pigment may become covalently bound toalbumin (the delta fraction).

• In the normal adult, serum bilirubin levels vary between0.3 and 1.2 mg/dL, and the rate of systemic bilirubinproduction is equal to the rates of hepatic uptake,conjugation, and biliary excretion.

• Jaundice becomes evident when the serum bilirubinlevels rise above 2.0 to 2.5 mg/dL; levels as high as 30to 40 mg/dL can occur with severe disease.

• Jaundice occurs when the equilibrium between bilirubin production and clearance is disturbed by one or more of the following mechanisms:







(1) excessive production of bilirubin,(2) reduced hepatocyte uptake,(3) impaired conjugation,(4) decreased hepatocellular excretion, and (5) impaired bile flow (both intrahepatic and

extrahepatic). • The first three mechanisms produce unconjugated

hyperbilirubinemia, and the latter two producepredominantly conjugated hyperbilirubinemia.

• More than one mechanism may operate to produce

jaundice, especially hepatitis, which can produceunconjugated and conjugated hyperbilirubinemia.

• Generally speaking, however, one mechanismpredominates, so knowledge of the major form of plasma bilirubin is of value in evaluating possible causesof hyperbilirubinemia.

• Of the various causes of jaundice the most common aredue to bilirubin overproduction (as from hemolyticanemias and resorption of major hemorrhages),hepatitis, and obstruction to the flow of bile (consideredlater in this chapter).

Neonatal Jaundice• Because the hepatic machinery for conjugating and

excreting bilirubin does not fully mature until about 2weeks of age, almost every newborn develops transientand mild unconjugated hyperbilirubinemia, termedneonatal jaundice or physiologic jaundice of thenewborn .

• Breast-fed infants tend to exhibit jaundice with greater frequency, possibly the result of β-glucuronidasespresent in maternal milk.

• These enzymes deconjugate bilirubin glucuronides inthe gut, increasing intestinal reabsorption of unconjugated bilirubin. Sustained jaundice in thenewborn is indicative of a disease condition, discussedlater under neonatal hepatitis.

Hereditary Hyperbilirubinemias• In rare instances, there may be a genetic lack of

UGT1A1• In Crigler-Najjar syndrome type I, the enzyme is

completely absent. Multiple genetic defects in the locuscoding for UGT1A1 may give rise to this disorder.

• The liver is incapable of synthesizing a functionalenzyme, and the colorless bile contains only traceamounts of unconjugated bilirubin.

• The liver is morphologically normal by light and electronmicroscopy.

• However, serum unconjugated bilirubin reaches veryhigh levels, producing severe jaundice and icterus.

• Without liver transplantation, this condition is invariablyfatal, causing death within 18 months of birth secondaryto kernicterus.

• Crigler-Najjar syndrome type II is a less severe, nonfataldisorder in which UGT1A1 enzyme activity is greatlyreduced, and the enzyme is capable of forming onlymonoglucuronidated bilirubin.o Unlike Crigler-Najjar syndrome type I, the only

major consequence is extraordinarily yellow skinfrom moderate to high levels of circulatingunconjugated bilirubin; phenobarbital treatment canimprove bilirubin glucuronidation by inducinghypertrophy of the hepatocellular endoplasmicreticulum.

o Mutations either reduce the affinity of UGT1A1toward bilirubin or reduce enzyme activity.

o Almost all patients develop normally, but there is arisk for some neurologic damage from kernicterus.

• Gilbert syndrome is a relatively common, benign,somewhat heterogeneous inherited condition presentingwith mild, fluctuating hyperbilirubinemia.o The primary cause is reduction in hepatic bilirubin

glucuronidating activity to about 30% of normallevels.

o In most patients, two extra bases (TA) are found inthe TATAA element of the 5' promoter region(creating an A(TA) 7TAA element rather than thenormal A(TA) 6TAA, resulting in reduced expressionof UGT1A1.

o Alternatively, patients may be heterozygous for missense mutations in the UGT1A1 gene. Affectingsome 6% of the population, the mildhyperbilirubinemia may go undiscovered for yearsand is not associated with functional derangements.

o When detected in adolescence or adult life, it istypically in association with stress, such as anintercurrent illness, strenuous exercise, or fasting.

o Gilbert syndrome has no clinical consequenceexcept for the anxiety that a jaundiced sufferer might justifiably experience with this otherwiseinnocuous condition.

•

Dubin-Johnson syndrome results from a hereditary defect in hepatocellular excretion of bilirubinglucuronides across the canalicular membrane .o The defect is due to absence of the canalicular

protein, the multidrug resistance protein 2 (MRP2;located on chromosome 10q24), that is responsiblefor transport of bilirubin glucuronides and relatedorganic anions into bile.

o The liver is darkly pigmented owing to coarsepigmented granules within the cytoplasm of hepatocytes

o Electron microscopy reveals that the pigment islocated in lysosomes, and it appears to becomposed of polymers of epinephrine metabolites,

not bilirubin pigment.o The liver is otherwise normal.o Apart from chronic or recurrent jaundice of

fluctuating intensity, most patients areasymptomatic and have a normal life expectancy.

• Rotor syndrome is a rare form of asymptomaticconjugated hyperbilirubinemia with multiple defects inhepatocellular uptake and excretion of bilirubinpigments.o 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 biliaryobstruction, also may present with jaundice.

• Alternatively, pruritus is a presenting symptom, relatedto the elevation in plasma bile acids and their depositionin peripheral tissues, particularly skin.

• Skin xanthomas (focal accumulations of cholesterol)sometimes appear, the result of hyperlipidemia andimpaired excretion of cholesterol.

• A characteristic laboratory finding is elevated serumalkaline phosphatase , an enzyme present in bile ductepithelium and in the canalicular membrane of hepatocytes that is released into the circulation becauseof the detergent action of retained bile salts onhepatocyte membranes.

• An isozyme derived from posttranscriptional changes isnormally present in many other tissues such as bone, sothe increased levels must be verified as being hepatic inorigin.








• Another canalicular ectoenzyme, γ -glutamyl transpeptidase , is also released into the circulation.

• The elevated levels of these enzymes in the circulationreflects the detergent action of bile salts retained in theluminal space of the bile canaliculus on the apicalmembranes of hepatocytes and bile duct epithelial cells,with solubilization of these membrane ectoenzymes.

• Other manifestations of reduced bile flow relate tointestinal malabsorption, including nutritional

deficiencies of the fat-soluble vitamins A, D, or K.• Extrahepatic biliary obstruction is frequently amenable tosurgical alleviation; correct and prompt diagnosis isimperative.

• In contrast, cholestasis due to diseases of theintrahepatic biliary tree or hepatocellular secretoryfailure (collectively termed intrahepatic cholestasis )cannot be benefited by surgery (short of transplantation), and the patient's condition may beworsened by an operative procedure.

• There is thus some urgency in making a correct diagnosis of the cause of jaundice and cholestasis.

Familial Intrahepatic Cholestasis

• Mention should be made of a striking but heterogeneousgroup of autosomal-recessively inherited cholestaticconditions.

• However, unlike many other cholestatic conditions, the

virtual absence of bile salts within the canalicular lumenbetween hepatocytes means that serum γ-glutamyltranspeptidase (GGT) levels are low for the degree of hyperbilirubinemia.

• In benign recurrent intrahepatic cholestasis (BRIC) ,there are intermittent attacks of cholestasis over lifewithout progression to chronic liver disease. In

progressive familial intrahepatic cholestasis 1 (PFIC-1) ,cholestasis begins in infancy with severe pruritus due tohigh serum bile acid levels and relentlessly progressesto liver failure before adulthood.

• The first major characterized family with the latter syndrome are descendants of Jacob Byler, an Amishpatient.

• Affected members of this particular family aredesignated as having Byler syndrome ; unrelatedindividuals with different mutations have Byler disease .

• These conditions encompass a spectrum arising usuallyfrom mutations in the ATP8B1 gene on chromosome18q21.

• The encoded protein is a canalicular P-type ATPase of uncertain function, possibly playing a role in secretion of bile salts indirectly through maintenance of aminophospholipid polarity in the canalicular membrane.

• Mutations in the canalicular bile salt export pump (BSEP,encoded by the ABCB11 gene on chromosome 2q24),are the cause of progressive familial intrahepatic cholestasis 2 (PFIC-2) .

• An autosomal-recessive cholestatic disorder with high

serum GGT is progressive familial intrahepatic cholestasis 3 (PFIC-3) , due to mutations in the ABCB4gene on chromosome 7q21.

• The encoded protein, MDR3, is a canalicular transportprotein that is responsible for flippingphosphatidylcholine from the internal to the externalhemileaflet of the canalicular membrane.

• In patients with this disorder, the absence of secretedphosphatidylcholine in bile leaves the apical surfaces of the biliary tree epithelia subject to the full detergentaction of secreted bile salts, with resultant toxicdestruction of these epithelia and release of GGT intothe circulation.

• Children with severe cholestasis but with absence of

elevated serum GGT and absence of pruritus may alsohave inherited defects in bile acid synthesis.• The most common condition is a deficiency of 3β-

hydroxysteroid dehydrogenase, an enzyme located earlyin the pathway for bile acid synthesis from cholesterol.

INFECTIOUS DISORDERS

• Any insult to the liver can kill hepatocytes and recruitinflammatory cells that’s why inflammatory disordersof the liver are frequently long-term chronicconditions that must be managed medically

• Among inflammatory disorders, infection ranks

supreme• The liver is inevitably involved in blood-borneinfections, whether they be systemic or arise withinthe abdomen

• Conditions in which hepatic lesion is prominentinclude miliary tuberculosis, malaria, staphylococcalbacteremia, salmonelloses, candidiasis, andamebiasis

• Foremost hepatic infections are viral in origin

• Systemic viral infections that can involve the liver include

1) Infectious mononucleosis (Epstein-Barr virus)

- may cause a mild hepatitis during the acute phase2) Cytomegalovirus infection

- particularly in the newborn or immunosuppressed pt3) Yellow fever

- a major and serious cause of hepatitis in tropicalcountries

• Not frequently in children and immunosuppressed pts,the liver is affected in the course of rubella virus,adenovirus, herpesvirus, or enterovirus infections

• Unless otherwise specified, the term “ viral hepatitis ” isreserved for infection of the liver caused by a group of viruses having a particular affinity for the liver

* At present, hepatitis G virus is not considered pathogenic.

Hepatitis A Virus

Hepatitis AVirus

HepatitisB Virus

HepatitisC Virus

Hepatitis DVirus

Hepatitis EVirus

HepatitisG Virus *

Agent Icosahedralcapsid,ssRNA

EnvelopeddsDNA

EnvelopedssRNA

EnvelopedssRNA

UnenvelopedssRNA

ssRNAvirus

Transmission Fecal-oral Parenteral;closecontact

Parenteral;closecontact

Parenteral;close contact

Waterborne Parenteral

Incubationperiod

2-6 wk 4-26 wk 2-26 wk 4-7 wk 2-8 wk Unknown

Carrier state None 0.1-1.0%of blooddonors inU.S. andWesternworld

0.2-1.0%of blooddonors inU.S. andWesternworld

1-10% in drugaddicts andhemophiliacs

Unknown 1-2% of blooddonors inU.S.

Chronichepatitis

None 5-10% of acuteinfections

>50% <5%coinfection,80% uponsuperinfection

None None

Hepatocellular carcinoma

No Yes Yes No increaseabove HBV

Unknown,but unlikely

None

Viral Hepatitis



• Long known as infectious hepatitis and the scourge of military campaigns since antiquity

• A benign self-limited disease with an incubation periodof 2 to 6 weeks

• Does not cause chronic hepatitis or a carrier state andonly rarely causes fulminant hepatitis so the fatality rateassociated with this is about 0.1%

• Occurs throughout the world and endemic in countrieswith substandard hygiene and sanitation, so that mostnative populations have detectable anti-HAV by the ageof 10 y/o

• Clinical dse. tends to be mild or asymptomatic and rareafter childhood

• Overall, HAV accounts for about 25% of clinicallyevident acute hepatitis worldwide

• A small, unenveloped, single-stranded RNA picornavirusthat occupies its own genus, Hepatovirus

• Ultrastructurally, it is an icosahedral capsid 27 nm indiameter

• Spread by ingestion of contaminated water and foods• Shed in the stool for 2 to 3 weeks before and 1 week

after the onset of jaundice•

Thus, close personal contact with an infected individualor fecal-oral contamination during this period accountsfor most cases which explains the outbreaks ininstitutional settings such as schools, nurseries, andwater-borne epidemics under overcrowded, unsanitaryconditions

• It is not shed in saliva, urine, or semen• Among developed countries, sporadic infections may be

contracted by consumption of raw or steamed shellfish(oysters, mussels, clams) which concentrate the virusfrom seawater contaminated with human sewage

• HAV viremia is transient so blood-borne transmission of HAV occurs only rarely and therefore donated blood isnot specifically screened for this virus

• Serologic Dxo Specific antibody against HAV of IgM type appears

in blood at onset of symptoms which constitutes areliable marker of acute infection

o Fecal shedding of the virus ends as the IgM titer rises

o IgM response usually begins to decline in a fewmos. and followed by the appearance of IgG anti-HAV which persists fore years, perhaps for life,providing immunity against reinfection by all strainsof HAV

• The cause of “ serum hepatitis ”• Can produce:

1) Acute hepatitis2) Nonprogressive chronic hepatitis3) Progressive chronic hepatitis ending in cirrhosis4) Fulminant hepatitis with massive liver necrosis5) An asymptomatic carrier state, with or without

progressive subclinical dse6) The backdrop for hepatitis D virus

• Also plays an important role in the development of Hepatocellular carcinoma

• Unlike HAV, HBV remains in blood during the last stagesof a prolonged incubation period (4 to 26 weeks) andduring active episodes of acute and chronic hepatitis

• Also present in all physiologic and pathologic body fluidswith the exception of stool

• A hardy virus and can withstand extremes of temperature and humidity

• Whereas blood and body fluids are the primary vehiclesof transmission, virus may also be spread by contact

with body secretions such as semen, saliva, sweat,tears, breast milk, and pathologic effusions

• Primary risk categories of HBV infection:o Transfusiono Blood productso Dialysiso Needle-stick accidents among health workerso Intravenous drug abuseo Homosexual activity constitute the primary risk

categories for HBV infection• The source of infection in one-third of pts is unknown• In endemic regions such as Africa and Southeast Asia,

spread from an infected mother to a neonate during birth(vertical transmission ) is common which often lead tothe carrier state for live

• A member of the Hepadnaviridae, a family of DNA-containing viruses that cause hepatitis in a multipleanimal species

• The mature HBV virion is a spherical double-layered“Dane particle ” that has an outer surface envelope of protein, lipid, carbohydrate enclosing a slightlyhexagonal core

• The genome is a partially double stranded circular DNAmolecule

• The organization of HBV genome is unique in that allregions of the viral genome encode protein sequences:o A nucleocapsid “core” protein (Hepatitis B core

antigen, HBcAg) and a longer polypeptide transcriptwith a precore and core region, designated HBeAg(hepatitis B e antigen)

o Envelope glycoprotein (HBsAg). Infectedhepatocytes are capable of synthesizing andsecreting massive quantities of noninfective surfaceprotein (HBsAg)

o A DNA polymerase that exhibits reversetranscriptase activity, and genomic replicationoccurs through an intermediate RNA template

o A protein from the X region (HBX), which isnecessary for virus replication and acts as atranscriptional transactivator of the viral genes anda wide variety of host gene promoters. HBX is alsothought to play a key role in the causation of hepatocellular carcinoma

• HBV infections pass through 2 phases:1) Proliferative phase

- HBV DNA is present in episomal form, whileformation of complete virions and all associatedantigens

- Cell surface expression of viral HBsAg and HBcAgin association with the MHC class I molecules leadsto activation of cytotoxic CD8+ T lymphocytes andhepatocytes destruction

2) Integrative phase- Viral DNA is incorporated into the host genome,

may occur in hepatocytes not destroyed by theimmune response

- With cessation of viral replication and theappearance of antiviral antibodies, infectivity endsand liver damage subsides. However, the risk of hepatocellular carcinoma persists

• Serologic Dxo After exposure to HBV, the long asymptomatic 4 to

26 week incubation period (mean 6-8 weeks) is

followed by acute dse. lasting many wks. to mos.o Most pts experience a self-limited illness

HBsAg appears before the onset of symptoms,peaks during overt dse, and then declines toundetectable levels in 3 to 6 mos

Hepatitis B Virus



HBeAg, HBV DNA, and DNA polymeraseappear in the serum soon after HBsAg, and allsignifiy active viral replicationIgM anti-HBc becomes detectable in serumshortly before the onset of symptoms,concurrent with the onset of elevated serumtransaminase levels. During the months, theIgM antibody is replaced by IgG anti-HBcAnti-HBe is detectable shortly after thedisappearance of HBeAg, implying that the

acute infection has peaked and the dse is onthe waneIgG anti-HBs does not rise until the acute dseis over and is usually not detectable for a fewwks to several mos after the disappearance of HBsAg. Anti-HBs may persist for live,conferring protection; this is the basis for current vaccination strategies usingnoninfectious HBsAg

o Carrier state is defined by the presence of HBsAg inserum for 6 mos or longer after initial detection. Thepresence of HBsAg alone does not necessarilyindicate replication of complete virions, and pts maybe asymptomatic and without liver damage

o

In contrast, chronic replication of HBV virions ischaracterized by persistence of circulating HBsAg,HBeAg, and HBV DNA usually with anti-HBc andoccasionally with anti-HBs. Progressive liver damage may occur in these pts

Hepatitis C Virus

• A major cause of liver dse worldwide• Main routes of transmission are inoculations and blood

transfusions• Believed to be the most important cause of transfusion-

associated hepatitis, being responsible for 90% to 95%of all cases

• Sexual transmission and vertical transmission areinfrequent

• 40% of cases are accounted for sporadic hepatitis of unknown cause

• Seroprevalence in the US pop. is less than 0.2% but ishigher in house contacts, homosexuals, hemodialysispts, hemophiliacs, and IV drug abusers

• Pts with unexplained cirrhosis and hepatocellular carcinoma have anti-HCV prevalence rates exceeding50%

• In contrast to HBV, HCV has a high rate of progressionto chronic dse or eventual cirrhosis, exceeding 50%

• Thus, HCV may in fact be the leading infectious causeof chronic liver dse in the Western world

• HCV and closely related HGV occupy a genius in theFlaviviridae

• A small, enveloped, single-stranded RNA virus with agenome that codes for a single polyprotein. This peptideis subsequently processed into functional proteins

• Inherently unstable, giving rise to multiple types andsubtypes seriously hampering efforts to develop an HCVvaccine

• Elevated titers of anti-HCV IgG occuriing after an activeinfection do not confer effective immunity

• Characteristic feature of HCV infection: repeated boutsof hepatic damage as a result of reactivation of apreexisting infection or emergence of an endogenous,

newly mutated strain• Hallmarks of HCV infection despite the generallyasymptomatic nature of the acute illness:o Progressive infectiono Chronic hepatitis

• Cirrhosis can be present at the time of dx or maydevelop during a period of 5 to 10 yrs

• Serologic Dx:o Incubation period: from 2 10 26 weeks (mean

between 6 and 12 weeks)o HCV RNA is detectable in blood for 1 to 6 and 12

wkso Circulating RNA persists in many pts despite the

presence of neutralizing antibodies, incldg. morethan 90% of pts with chronic dse

o Clinical course is milder than that of HBV butindividual cases may be severe andindistinguishable from HAV or HBV hepatitis

o A characteristic clinical feature of chronic HCVinfection is episodic elevations in serumtransaminases, with intervening normal or near-normal periods

o Alternatively, transaminases may be persistentlyelevated or may remain normal

Hepatitis D Virus

• Also called the delta agent and hepatitis delta virus• A unique RNA virus that is replication defective causing

infection only when it is encapsulated by HBsAg• Although taxonomically distinct from HBV, HDV is

absolutely dependent on the genetic informationprovided by HBV for multiplication and causes hepatitisonly in the presence of HBV

• Delta hepatitis arises in two settings:o Acute coinfection

Occurs after exposure to serum containing bothHDV or HBVHBV must become established first to providethe HBsAg necessary for development of complete HDV virions

o

Superinfectiona chronic carrier of HBV with a new inoculum of HDV (and HBV) results in dse about 30-50days later carrier may be previously “healthy” or mayhave had underlying chronic hepatitis

• Simultaneous coinfection with HBV and HDV results inhepatitis ranging from mild to fulminant, with fulminantdse more likely (3-4%) than with HBV alone

• Chronicity rarely develops• 3 possibilities may arise when HDV is superimposed on

chronic HBV infection:1) Mild HBV hepatitis may be converted into fulminant

dse

2) Acute, severe hepatitis may erupt in a previouslyhealthy HBV carrier

3) Chronic, progressive dse may develop (in 80% of pts) often culminating in cirrhosis

• Infection by delta agent is worldwide, but prevalencevaries

• 20-40% of HBsAg carriers have anti-HDV• In the US, HDV infection is uncommon and largely

restricted to drug addicts and hemophiliacs withprevalence rates of 1-10%

• Homosexual men and health care workers are at lowrisk for HDV infection for unclear reasons

• HDV infection is uncommon in the large population of HBsAg carriers in Southeast Asia and China

• A 35-nm, double-shelled particle that by electronmicroscopy resembles the Dane particle of HBV

• The external coat antigen of HBsAg surrounds asinternal polypeptide assembly, designated delta antigen(HDAg)



• Serologic Dx:o HDV RNA is detectable in the blood and liver just

before and in the early days of acute symptomaticdse

o IgM anti-HDV is the most reliable indicator of recentHDV exposure, though appearance is late andfrequently short-lived

o Acute coinfection by HDV and HBV is best indicatedby detection of IgM against both HDAg and HBcAg(denoting new infection with hepatitis B)

o With chronic delta hepatitis arising from HDVsuperinfection, HBsAg is present in serum and IgManti-HDV persists for mos or longer

Hepatitis E Virus

• An enterically transmitted water-borne infection• Occurring primarily in young to middle-aged adults• Sporadic infection and overt illness in children are rare• Sporadic infection seems to be uncommon and is seen

mainly in travelers• Characteristic feature of this infection:

o High mortality rate among pregnant women

approaching 20%• Disease is self-limited in most cases• It is not associated with chronic liver dse or persistent

viremia• Average incubation period after exposure is 6 wks• An unenveloped single-stranded RNA virus structurally

similar to Calciviridae• A specific antigen (HEV Ag) can be identified in the

cytoplasm of hepatocytes during active infection andvirions are shed in the stool during the acute illness

• Serologic Dxo HEV RNA and HEV virions can be detected in the

stool and liver before the onset of clinical illnesso The onset of rising serum transaminases, clinical

illness, and elevated IgM anti-HEV titers arevirtually simultaneous

o Symptoms resolve in 2-4 wks, during which timeIgM is replaced with a persistent IgG anti-HEv titer

Other Hepatitis Viruses

• Some cases of hepatitis are caused by infectious agentsaccording to epidemiologic studies

• A viral agent bearing similiarities to HCV has beencloned and designated hepatitis G virus (HGV)

• Transfusion related transmission has been documented• However, HGV appears to be nonpathogenic causing

neither liver dse nor exacerbation of liver dse• That’s why designation of HGV as a “hepatitis” virus ismay be premature

CLINOCOPATHOLOGIC SYNDROMES

• Clinical syndromes may develop after exposure tohepatitis virus:o Acute asymptomatic infection with recovery:

serologic evidence onlyo Acute symptomatic hepatitis with recovery: anicteric

or icterico Chronic hepatitis: without or with progression to

cirrhosiso Fulminant hepatitis: with massive to submassive

hepatic necrosis• Each of the hepatotropic viruses can cause acute

asymptomatic or symptomatic infection• A small number of HBV-infected patients develop

chronic hepatitis

• HCV is notorious for chronic infection• HAV and HEV do not cause chronic hepatitis in rare

exceptions• Fulminant hepatitis is unusual, and almost unheard of

with HCV• Other infectious or noninfectious causes, particularly

drugs and toxins, can lead to essentially identical clinical syndromes

• Thus serologic and molecular studies are essential for the diagnosis of viral hepatitis and the distinctionbetween the various types.

1. Acute Asymptomatic Infection with Recoveryo Pts in this group are identified only incidentally on

the basis of minimally elevated serumtransaminases or, after the fact, by the presence of antiviral antibodies.

o HAV and HBV infection worldwide are frequentlysubclinical events in childhood, verified only inadulthood by the presence of anti-HAV or anti-HBVantibodies

o Though asymptomatic acute infection is most oftenthe case for HCV-infected patients for whom theexposure event is not known, recovery anderadication of the virus are not common

2. Acute Symptomatic Infection with Recoveryo Any of the hepatotropic viruses can cause

symptomatic acute viral hepatitis, although this isuncommon for acute HCV infection

o Regardless of the agent, the disease is more or lessthe same and can be divided into four phases:

(1) an incubation period,(2) a symptomatic preicteric phase(3) a symptomatic icteric phase(4) convalescence

o Incubation period

Differs in the various virusesPeak infectivity occurs during the lastasymptomatic days of incubation period andearly days of acute symptoms

o Preicteric phaseMarked by nonspecific, constitutionalsymptomsMalaise is followed in a few days by generalfatigability, nausea, and loss of appetiteInconstant symptoms that can also manifestare weight loss, low-grade fever, headaches,muscle and joint aches, and pains and diarrhea10% of patients with acute hepatitis, most oftenthose with hepatitis B, develop a serum

sickness-like syndrome (fever, rash, arthralgiasdue to circulating immune complexes)True origin of these symptoms is suggested byelevated serum aminotransferase levelsPE reveals a mildly enlarged, tender liver In some patients, the nonspecific symptomsare more severe, with higher fever, shakingchills, and headache, sometimes accompaniedby right upper quadrant pain and tender liver enlargement.

o Icteric phaseIf this appears, is caused mainly by conjugatedhyperbilirubinemiaUsual in adults with acute HAV infection but not

in children, but is absent in about half the casesof HBV & majority of HCV casesAs jaundice appears, these pts enter the ictericphaseOther symptoms begin to abate and the pt feelsbetter



The jaundice is caused predominantly byconjugated hyperbilirubinemia and not a resultof biliary obstructionAccompanied by a dark-colored urine related tothe presence of conjugated bilirubinStools may become lighter owing to cholestasisA distressing pruritus can be experienced dueto retention of bile acidsLiver may be mildly enlarged and moderatelytender to percussionLab findings- prolonged prothrombin time- hyperglobulinemia- mild elevation of serum alkaline

phosphataseJaundice and most of other systemic symptomsabates in a few weeks to several mos asconvalescence beginsRecovery is heralded by the generation of strong T cell responses against viral antigensexpressed on infected liver cells

o Chronic HepatitisDefined as symptomatic, biochemical, or serologic evidence of continuing or relapsinghepatic disease for more than 6 months, withhistologically documented inflammation andnecrosisThough hepatitis viruses (HBV, HCV, and HBV+ HDV) are responsible for most cases of chronic hepatitis, there are many other causesof chronic hepatitis

Other causes: chronic alcoholism, Wilsondisease, α 1-antitrypsin deficiency, drugs (e.g.,isoniazid, α-methyldopa, methotrexate), andautoimmunityIn all instances of chronic hepatitis, etiology isthe single most important indicator of likelihood to progress to cirrhosis

Chronic viral hepatitis constitutes a "carrier"state wherein these individuals harbor replicating virus and can transmit an organismWith “carriers” of hepatotropic viruses, thereare:1) those who harbor one or more of the viruses

but are suffering little or no adverse clinicalor histologic effects

2) those who have chronic disease bylaboratory or histologic findings but areessentially free of symptoms or disability

3) those who have clinically symptomaticchronic disease

All constitute reservoirs of infectionIn HBV, early infection particularly via verticaltransmission during childbirth produces acarrier state of 90-95% of the timeIn contrast, only 1-10% of adult HBV infectionsyields a carrier state

Individuals with impaired immunity are likely tobecome HBV carriers because the protective Tcell response does not developThis situation is less clear with HDV, althoughthere is a well-defined low risk of posttransfusion hepatitis D, indicative of acarrier state in conjunction with HBVHCV can clearly induce a carrier state given its

high rate of chronicityClinical features are extremely variable and arenot predictive of outcome- some only manifest with persistent

elevations of serum transaminases- most common symptom: fatigue

- less common symptoms: malaise, loss of appetite, and occasional bouts of mild

jaundicePhysical findings:- spider angiomas- palmar erythema- mild hepatomegaly- hepatic tenderness- mild splenomegalyLab studies:

- prolongation of prothrombin time- some instances: hyperglobulinemia,hyperbilirubinemia, and mild elevations inalkaline phosphatase levels

In HBV and HCV, occasionally immunecomplex disease may develop secondary to thepresence of circulating antibody-antigencomplexes, in the form of vasculitis(subcutaneous or visceral) &glomerulonephritisCryoglobulinemia is found in 35% of pts withchronic HCV hepatitis

Key Morphologic Features of Viral Hepatitis

Acute HepatitisEnlarged, reddened liver; greenish if cholestaticParenchymal changes:

Hepatocyte injury: swelling (ballooning degeneration)Cholestasis: canalicular bile plugsHCV: mild focal fatty change of hepatocytes

Hepatocyte necrosis: isolated cells or clustersCytolysis (rupture) or apoptosis (shrinkage)If severe: bridging necrosis (portal-portal, central-central,portal-central)Lobular disarray: loss of normal architecture

Regenerative changes: hepatocyte proliferationSinusoidal cell reactive changes:

Accumulation of phagocytosed cellular debris in Kupffer cells

Influx of mononuclear cells into sinusoidsPortal tracts:

Inflammation: predominantly mononuclear Inflammatory spillover into adjacent parenchyma, withhepatocyte necrosis

Chronic HepatitisChanges shared with acute hepatitis:

Hepatocyte injury, necrosis, and regenerationSinusoidal cell reactive changes

Portal tracts:Inflammation:

Confined to portal tracts, or Spillover into adjacent parenchyma, with necrosis of hepatocytes ("interface hepatitis"), or

Bridging inflammation and necrosisFibrosis:

Portal deposition, or Portal and periportal deposition, or Formation of bridging fibrous septa

HBV: "ground-glass" hepatocytes, "sanded" nucleiHCV: bile duct epithelial cell proliferation, lymphoidaggregate formationCirrhosis: The end-stage outcome

Morphology of Acute and Chronic Hepatitis

ACUTE HEPATITIS• Hepatocyte injury takes the form of diffuse swelling

("ballooning degeneration" ), so cytoplasm looksempty and contains only scattered eosinophilicremnants of cytoplasmic organelles



• Cholestasis , an inconstant findings, with bile plugs incanaliculi and brown pigmentation of hepatocytes

• Canalicular bile plugs result from cessation of thecontractile activity of the hepatocyte pericanalicular actinmicrofilament web

• Two patterns of hepatocyte cell death are seen1) Rupture of cell membranes leads to cytolysis and

focal loss of hepatocytes- sinusoidal collagen reticulin framework

collapses where the cells have disappeared,and scavenger macrophage aggregatesmark sites of hepatocyte loss

2) Apoptosis- more conspicuous- caused by anti-viral cytotoxic T cells- Apoptotic hepatocytes shrink, become

intensely eosinophilic, and have fragmentednuclei; effector T cells may still be present inthe immediate vicinity

- Apoptotic cells also are phagocytosed withinhours by macrophages and hence might bedifficult to find despite a brisk rate of hepatocyte injury

- In severe cases of acute hepatitis, confluentnecrosis of hepatocytes may lead tobridging necrosis connecting portal-to-portal, central-to-central, or portal-to-centralregions of adjacent lobules

- Hepatocyte swelling and regenerationcompress sinusoids

- the more or less radial array of theparenchyma is lost.

• A characteristic and usually prominent feature of acutehepatitis: Inflammation

• Kupffer cells undergo hypertrophy and hyperplasiaand are often laden with lipofuscin pigment due tophagocytosis of hepatocellular debris

• Portal tracts are usually infiltrated with a mixture of inflammatory cells

• Inflammatory infiltrate may spill over into the adjacentparenchyma to cause necrosis of periportal hepatocytes;this "interface hepatitis" can occur in both acute andchronic hepatitis

• Finally, bile duct epithelia may become reactive andeven proliferate to form poorly defined ductular structures (ductular reaction), particularly in cases of HCV hepatitis.

CHRONIC HEPATITIS•

Histo features range from exceedingly mild to severe• Mildest forms: significant inflammation is limited to portal

tracts and consists of lymphocytes, macrophages,occasional plasma cells, and rare neutrophils or eosinophils

• Liver architecture usually well preserved, but smolderinghepatocyte necrosis throughout the lobule may occur inall forms of chronic hepatitis

• Even in mild chronic hepatitis due to HCV infection,common findings are lymphoid aggregates and bileduct damage in the portal tracts and focally mild tomoderate macrovesicular steatosis

• In all forms of chronic hepatitis: continued interface

hepatitis and bridging necrosis are harbingers of progressive liver damage• The hallmark of irreversible liver damage is the

deposition of fibrous• At first, only portal tracts exhibit increased fibrosis, but

with time, periportal septal fibrosis occurs, followed by

linking of fibrous septa between lobules ( bridgingfibrosis )

• Continued loss of hepatocytes and fibrosis resultsin cirrhosis, with fibrous septae and hepatocyteregenerative nodules

• This pattern of cirrhosis characterized by irregularlysized nodules separated by variable but mostly broadscars

• Historically, this pattern of cirrhosis has been termedpostnecrotic cirrhosis (but it should be noted that thethis term has been applied to all forms of cirrhosis inwhich the liver shows large, irregular-sized nodules withbroad scars, regardless of etiology

• Autoimmune hepatitis, hepatotoxins (carbontetrachloride, mushroom poisoning), pharmaceuticaldrugs (acetaminophen, α-methyldopa), and even alcoholmay give rise to a cirrhotic liver with irregular-sized largenodules

• In some cases that come to autopsy, the inciting causeof the so-called postnecrotic cirrhosis cannot bedetermined at all ("cryptogenic cirrhosis")

• Morphology of the end-stage cirrhotic liver is neither helpful in determining the basis of the liver injury, nor can it be easily related to any specific set of clinicalcircumstances.

Clinical course of Viral hepatitis

• Unpredictable course• Pts experience spontaneous remission or may have

indolent disease without progression for many years• However, some have rapidly progressive disease and

develop cirrhosis within a few year • Major causes of death:

o cirrhosis, with liver failureo

hepatic encephalopathyo massive hematemesis from esophageal variceso hepatocellular carcinoma in those with long-

standing HBV (particularly neonatal) or HCVinfection.

Bacterial, Parasitic, and Helminthic Infections

• Extrahepatic bacterial infections particularly sepsis caninduce mild hepatic inflammation and varying degrees of hepatocellular cholestasis

• The latter is due to effects of proinflammatory cytokinesreleased by kupffer cells and endothelial cells inresponse to circulating endotoxin

• Bacteria that can affect the liver directly:o Staphylococcus aureus – in toxic shock syndromeo Salmonella typhi – typhoid fever o 20 or 3 0 syphilis

• Bacteria may also proliferate in the biliary treecompromised by partial or complete obstruction

• Bacterial composition reflects the gut flora, and thesevere acute inflammatory response within theintrahepatic biliary tree is called ascending cholangitis

• Major causes of morbidity worldwide wherein the liver isfrequently involved are parasitic and helminthicinfections

• Diseases include malaria, schistosomiasis,strongyloidiasis, cryptosporidiosis, leishmaniasis, andinfections by liver flukes Fasciola hepatica, Clonorchissinensis and Opisthorchis viverrini

• Liver abscesses are common in developing countriesand mostly represent parasitic infections (e.g. amebic,



echinococcal and (less commonly) other protozoal andhelminthic organisms

• Most abscesses are pyogenic, representing acomplication of a bacterial infection elsewhere

• Organisms reach the liver by:1) the portal vein2) arterial supply3) ascending infection in the biliary tract (ascending

cholangitis)4) direct invasion of the liver from a nearby source

5) a penetrating injury• Majority of hepatic abscesses used to result from portal

spread of intra-abdominal infections (e.g., appendicitis,diverticulitis, colitis)

• Morphologyo Pyogenic hepatic abscesses may occur as solitary

or multiple lesions, ranging in sizeo Bacterimic spread thru the arterial or portal system

tends to produce multiple small abscesses,whereas direct extension and trauma usually causesolitary large abscesses

o Biliary abscesses, usually multiple, may containpurulent material from adjacent bile ducts

o Gross and microscopic features are those to beseen in any abscess

o Causative organism occasionally can be identifiedin fungal or parasitic abscesses

o Rarely, abscesses located in the subdiaphragmaticregion, particulary amebic, may burrow into thethoracic cavity producing empyema or a lungabscess

o Rupture of subcapsular liver abscess can lead toperitonitis or localized peritoneal abscesses

• Liver abscesses are associated with fever and in mostinstances, right upper quadrant pain and tender hepatomegaly

• Jaundice may result from extrahepatic biliary obstruction• Surgical drainage is often necessary for larger lesions

while antibiotic therapy may control smaller lesions• Pts may survive with early recognition and Mx

AUTOIMMUNE HEPATITIS

• A syndrome of chronic hepatitis in pts with aheterogenous set of immunologic abnormalities

• Histo features are indistinguishable from chronic viralhepatitis

• Dse may run an indolent or severe course and typicallyresponds dramatically to immunosuppressive therapy

• Salient features include:o Female predominance (70%), particularly young to

perimenopausal womeno Absence of viral serologic markerso Elevated serum IgG levels (>2.5 gm/dl)o High serum titers of autoantibodies in 80% of cases,

incldg antinuclear, anti-smooth muscle, andantimitochondrial antibodies

o An increased frequency of HLA-B8 or HLA-DRw3• Other forms of autoimmune dses present in pts are

Rheumatoid arthritis, thyroiditis, Sjogren syndrome, &ulcerative colitis

• A subgroup of pts exhibits antibodies either toliver/kidney microsomes or “soluble liver antigen”(cytokeratins 8 and 18), suggesting 3 types of autoimmune hepatitis exist

• Clinical presentation is similar to other forms of chronichepatitis

• Autoimmune hepatitis may present in an atypical fashionwith associated dse involving other organ systems,hampering diagnostic efforts

• Clinical autoimmune hepatitis exhibiting destruction of bile ducts (“autoimmune cholangitis”) may makedistinction from primary biliary cirrhosis or primarysclerosing cholangitis

DRUG- AND TOXIN-INDUCED LIVER DISEASE

• The liver is subject to potential damage from an array of pharmaceutical and environmental chemicals because itis the major drug metabolizing and detoxifying organ inthe body

• Injury may result:1) from direct toxicity2) by hepatic conversion of a xenobiotic to an active

toxin3) through immune mechanisms (usually by a drug or

metabolite acting as hapten to convert a cellular protein to an immunogen)

• Drug reactions may be classified as:o predictable (intrinsic) reactions

may occur in anyone who accumulates asufficient dose

o unpredictable (idiosyncratic) reactionsdepend on idiosyncrasies of the host,particularly the host’s propensity to mount animmune response to antigenic stimulus and therate of which the host metabolizes the agentmajor examples:1. chlorpromazine

- agent that causes cholestasis in those ptswho are slow to metabolize it to aninnoculous by product

2. halothane- can cause a fatal immune-mediated

hepatitis in some pts exposed to thisanesthetic on multiple occasions

• It should be noted that:o Injury may be immediate or take weeks to mos. to

develop which may present only after severe liver damage has developed

o Injury may take the form of hepatocytes necrosis,cholestasis, or insidious onset of liver dysfunction

o Drug-induced chronic hepatitis is clinically andhistologically indistinguishable from chronic viralhepatitis

o Histologic markers of viral infection are critical for making the distinction

• Predictable rxns are ascribed to:o Acetaminopheno Tetracyclineo Antineoplastic agentso Amanita phalloides toxino Carbon tetrachlorideo Alcohol (certain extent)

• Idiosyncratic reactions are caused by:o Sulfonamideso Methyldopao Allopurinol

• Reye syndromeo a potentially fatal syndrome of mitochondrial dysfxn

in liver, brain and elsewhere, occurs predominantlyin children given acetylsalicylic acid (aspirin) for therelief of virus-induced fever

o features extensive accumulation of fat dropletswithin hepatocytes (microvesicular steatosis), is

rare• Drug-induced liver dse is followed usually by recovery

on removal of drug• Exposureto a toxin or therapeutic agent should always

be included in the diff. Dx of liver dse



Alcoholic Liver Disease

• The leading cause of liver dse in most western countriesis excessive alcohol consumption

• Adverse effects of chronic alcohol consumption lead todevelopment of overlapping forms of liver dse:

1) Hepatic steatosis2) Alcoholic hepatitis3) Cirrhosis (collectively referred to as alcoholic liver

dse)• Morphology

o Hepatic Steatosis (Fatty liver)Small (microvesicular) lipid dropletsaccumulate in hepatocytes after even moderateintake of alcoholWith chronic intake of alcohol, lipidaccumulates to the point of creating large clear macrovesicular globules, compressing anddisplacing the nucleus to the periphery of thehepatocytesTransformation is initially centrilobular, but mayinvolve the entire lobule in severe casesMacroscopic appearance of fatty liver of chronic alcoholism:- large (up to 4-6 kg)- soft organ that is yellow- greasy- readily fractured- though there is little or no fibrosis at the

outset, fibrous tissue develops around thecentral veins & extends into the adjacentsinusoids with continued alcohol intake

Up to the time that fibrosis appears, fattychange is completely reversible if there isabstention from further intake of alcohol

o Alcoholic HepatitisCharacterized by:1. Hepatocyte swelling and necrosis

- single or scattered foci of cells undergoswelling (ballooning) and necrosis

- swelling results from accumulation of fatand water and proteins that normally areexported

2. Mallory bodies- scattered hepatocytes accumulate tangledskeins of cytokeratin intermediatefilaments and other proteins, visible aseosinophilic cytomplasmic inclusions indegenerating hepatocytes- inclusions are characteristic of but not

specific feature because they are also

seen in primary biliary cirrhosis, Wilsondse, chronic cholestatic syndromes,hepatocellular tumors

3. Neutrophilic reaction- neutrophils permeate the lobule and

accumulate around degeneratinghepatocytes, part. those having Mallorybodies- lymphocytes & macrophages also enter portal tracts and spill into the parenchyma

4. Fibrosis- almost always accompanied by a brisk

sinusoidal and periventricular fibrosis- periportal fibrosis may occasionally

predominate, particulary with repeatedbouts of heavy alcohol intake

- cholestasis and mild deposition of hemosiderin (iron) in hepatocytes andKupffer cells may develop in some cases

Macroscopic appearance:

- liver is mottled red with bile-stainedareas

- liver may be of normal or increased size- often contains visible nodules and

fibrosis indicative of evolution tocirrhosis

o Alcoholic CirrhosisFinal and irreversible form of alcoholic liver dseusually evolves slowly and insidiously

At first, the cirrhotic liver is yellow-tan, fatty, andenlarged, usually weighing more than 2 kgDuring the span of years, it is transformed intoa brown, shrunken, less than 1 kg in weightArguably, cirrhosis may develop more rapidly inthe setting of alcoholic hepatitis within 1-2yearsInitially, developing fibrous septa are delicateand extend through sinusoids from central veinto portal regions as well as from portal tract toportal tractRegenerative activity of entrappedparenchymal hepatocytes regenerates fairlyuniformly sized “micronodules”

The nodularity becomes more prominentScattered larger nodules create a “hobnail”appearance on liver surfaceAs fibrous septa dissect and surround nodules,liver becomes more fibrotic loses fat, andshrinks progressively in sizeParenchymal islands are engulfed by ever wider bands of fibrous tissue and liver isconverted to a mixed micronodular andmacronodular patternIschemic necrosis and fibrous obliteration of nodules eventually create broad expanses of tough, pale scar tissue (Laennec cirrhosis)Bile statis often develops

Mallory bodies are rarely evident at this stageThus, end-stage alcoholic cirrhosis comes toresemble, both micro and macroscopically, thecirrhosis developing from viral hepatitis andother causes

• Pathogenesiso Short-term ingestion of up to 80 gm of ethanol (8

beers or 7 oz of 80-proof liquor) generally producesmild, reversible hepatic changes, such as fatty liver

o Daily intake of 80 gm or more of ethanol generatessignificant risk of severe hepatic injury

o Daily ingestion of 160 gm or more for 10-20 years isassociated more consistently with severe injury

o Only 10-15% if alcoholics, however, developcirrhosis

o Reasons are:Decreased gastric metabolism of ethanolDifferences in body compositionWomen are more susceptible to hepatic injurythan are menGenetic susceptibility may exist but no reliablegenetic markers of susceptibility have beenidentified

o Relationship between hepatic steatosis andalcoholic hepatitis as precursors to cirrhosis bothcausally and temporally is not yet clear

o Cirrhosis may develop without antecedent evidenceof steatosis or alcoholic hepatitis

o In the absence of a clear understanding of thepathogenic factors influencing liver damage, no“safe” upper limit for alcohol consumption can beproposed (despite the current popularity of redwines for amelioration of CVD)



o Detrimental effects of alcohol and its byproducts onhepatocellular function:

Hepatocellular steatosis results from1) shunting of normal substrates away from

catabolism and toward lipid biosynthesisowing to generation of excess NADH by 2major enzymes of alcohol metabolism,alcohol dehydrogenase

2) impaired assembly and secretion of lipoproteins

3) increases peripheral catabolism of fatinduction of CP450 leads to augmentedtransformation of other drugs to toxicmetabolitesfree radicals, generated during microsomalethanol-oxidizing system oxidation of alcohol,react with cellular membranes and proteinsalcohol directly affects microtubular &mitochondrial function and membrane fluidityacetaldehyde (major intermediate metabolite of alcohol en route to acetate prod’n) induces lipidperoxidation and acetaldehyde-protein adductformation, further disrupting cytoskeletal andmembrane fxn

alcohol induces immunologic attack on hepaticneoantigens, possibly the result of alcohol-induced or acetaldehyde-induced alteration inhepatic proteins

o alcohol is food and can become a major caloriesource in the diet of an alcoholic, displacing other nutrients and leading to malnutrition and vitamindeficiency (Vit.B 12)

o compounded by impaired digestive fxn related tochronic gastric and intestinal mucosal damage andpancreatitis

o collagen deposition by perisinusoidal hepaticstellate cells is a response to many convergingevents

Kupffer cell activation, with release of proinflammatory cytokines (TNF-α, IL-1 and 6,TGF-β)

Amplication of cytokine stimuli by PAF, alecithin-related lipid released by endothelialcells and kupffer cellsInflux of neutrophils into parenchyma inresponse to proinflammatory cytokines, withrelease of their noxious substances

o These events are exerted by local toxic effects of alcohol and by alcohol-induced release of bacterialendotoxin into portal circulation form acompromised gut

o Alcohol also induces a vasoconstricting endothelinsfrom sinusoidal endothelial cells

o Endothelins induce the myofibrolast-like hepaticstellate cells to contract, decreasing sinusoidalperfusion and causing regional hypoxia

o Net effect: chronic d/o featuring:SteatosisHepatitisProgressive fibrosisMarked derangement of vascular perfusion

o In essence, alcoholic liver dse can be regarded as amaladaptive state in w/c cells in liver respond inincreasingly pathologic manner to a stimulus(alcohol) that originally was marginally harmful

•

Clinical courseo Hepatic steatosis

may become evident as hepatomegaly withmild elevation of serum bilirubin and alkalinephosphatase levels

There may be no clinical or biochemicalevidence of liver dse alternativelyAlcohol withdrawal and provision of anadequate diet are sufficient Tx

o Alcoholic hepatitisTends to appear relatively acutely, usually after a bout of heavy drinkingSymptoms & lab manifestations may beminimal or those of fulminant hepatic failureBetween these 2 extremes are nonspecificsymptoms of malaise, anorexia, weight loss,upper abdominal discomfort, tender hepatomegalyLab findings- hyperbilirubinemia- elevated alkaline phosphatase levels- neutrophilic leukocytosisacute cholestatic syndrome may appear,resembling large bile duct obstxnmay be superimposed on established cirrhosiswith proper nutrition and total cessation of alcohol consumption, it may clear slowlyin some pts, hepatitis persists despiteabstinence and progresses to cirrhosis

o Alcohol cirrhosisManifestations are similar to other forms of cirrhosisInclude those of portal Htn (with life-threateningvariceal hemorrhage), jaundice, ascites, other stigmata (e.g., grossly distended abdomen,wasted extremities, caput medusae)Lab findings reflect developing hepaticcompromise:- Elevated serum transaminase levels- Hyperbilirubinemia- Variable elevation of serum alkaline

phosphatase- Hypoproteinemia (globulins, albumin, and

clotting factors)- anemiain some instances, liver biopsy may beindicatedcirrhosis may be clinically silent discoveredonly at autopsy or when stress such asinfection or trauma tips the balance towardhepatic insufficiency

o Long-term outlook for alcoholics with liver dse isvariable

o 5-year survival approaches to 90% in abstainers

free of jaundice, ascites, or hematemesis; drops to50% - 60% to those who continue to imbibe

o Causes of death in end-stage alcoholic:1) hepatic coma2) massive GI hemorrhage3) intercurrent infection4) hepatorenal syndrome after a bout of

alcoholic hepatitis5) hepatocellular carcinoma

o Nonalcoholic steatohepatitisAn uncommon condition resembling alcoholichepatitis occurring in pts who do not drinkalcoholFeatures liver biopsy findings of steatosis,mixed inflammatory infiltrate of parenchyma,Mallory hyaline, sinusoidal fibrosisPts are largely asymptomatic withabnormalities in biochemical lab test resultsNonspecific constitutional symptoms may bepresent



Obesity is the most important risk factor Type II DM and hypertriglyceridemia are lesscommon antecedent conditionsChief risk is the dev’t of cirrhosis occurring in aminority of pts

METABOLIC LIVER DISEASE

Nonalcoholic Fatty Liver Disease and Steatohepatitis

• Nonalcoholic fatty liver disease (NAFL) – resemblesalcohol-induced liver disease; occurs in patients who arenot heavy drinkers

• Men and women equally affected• Strong associations with obesity, dyslipidemia,

hyperinsulinemia and insulin resistane, and overt type 2diabetes

• Elevated serum aminotransferases and/or gammaglutamyl transpeptidase values

• Patients are largely asymptomatic; abnormalities only inbiochemical lab tests

• Most common cause of “cryptogenic” cirrhosis

Morphology• Liver biopsy findings: steatosis, multifocal parenchymalinflammation, Mallory hyaline, hepatocyte death,sinusoidal fibrosis

• Large and small vesicles of fat (triglycerides)accumulation within hepatocytes

• Clinically benign end: no appreciable hepaticinflammation, hepatocyte death, or scarring

• STEATOHEPATITIS (aka non-alcoholic steatohepatitis) – intermediate form of liver damage

• CIRRHOSIS – result of years of subclinical progressionof the inflammatory and fibrotic processes.

Hemachromatosis

• Excessive accumulation of body iron – most aredeposited in parenchymal organs such as liver andpancreas

• Results from a genetic defect causing excessive ironabsorption or as a consequence of parenteraladministration of iron

• Hereditary hemochromatosis – homozygous-recessiveinherited disorder

• Secondary hemachromatosis – acquired forms of hemochromatosis with known sources of excess iron

• Total body iron pool: 2-6gm in normal adultso 0.5 gram stored in Liver

98% in hepatocytes• In HH: total iron accumulation may exceed 50 gm, over 1/3 accumulates in liver

• Ff features characterize this disease:o Fully developed cases exhibit: (1)micronodular

cirrhosis in all patients; (2) diabetes mellitus in75% to 80% of patients; and (3) skin pigmentationin 75 to 80% of patients

o Iron accumulation is lifelong

Symptoms first appear in 5 th to 6 th decadesof life

o Hemochromatosis gene located on the short armof chromosome 6 at 6p21.3 close to the HLAgene locus

HFE gene – encodes an HLA class I-likemolecule that regulates intestinalabsorption of dietary iron.Most common HFE mutation: cysteine-to-tyrosine substitution at amino acid 282

(called C282Y), which inactivates this 343-amino-acid-protein.

o Males predominate with slightly earlier clinicalpresentation

Because physiologic iron loss delays ironaccumulation in women

Pathogenesis• In HH, regulation of intestinal absorption of dietary iron

is lost, leading to net iron accumulation of 0.5 to 1.0gm/year.

• Disease manifests after 20 gm of storage iron haveaccumulated

• Critical site for HFE expression is on the basolateralsurface of the small intestinal crypt epithelial cell

• (see Figure 18-27 pg 909 sa Robbins 7 th edition paramas maintindihan, although ako di ko pa dinnaintindihan haha)

o HFE complexes with the transferring receptor,TfR, enabling the binding of plasma transferringand its bound iron

o The TfR-Tf-iron complex is endocytosed into thecrypt enterocyte

o Acidification of the endosome releases iron intothe regulatory iron pool of the crypt cell

This is a sensing mechanism for thesystemic iron balance

o Crypt cells with mutant HFE lack the facilitatingeffect on TfR-dependent iron uptake, thusdecreasing the regulatory iron pool in the cryptcell.

Small intestinal crypt cells arepreprogrammed to absorb dietary ironregardless of the systemic iron overload

o Excessive iron appears to be directly toxic to hosttissues by the ff mechanisms:

Lipid peroxidation via iron-catalyzed freeradical reactions

Stimulation of collagen formationInteractions of reactive oxygen speciesand of iron itself, leading to lethal injury or predisposition to hepatocellular carcinoma

o Most common cause of secondaryhemochromatosis: haemolytic anemiasassociated with ineffective erythropoeisis

Excess iron may result not only fromtransfusions, but also from increasedabsorptionTransfusions alone (aplastic anemias) leadto systemic hemosiderosis -> parenchymalorgan injury tends to occur in extremecases

o

Alcoholic cirrhosis – often associated with amodest increase in stainable iron within liver cells

Morphology• Characterized principally by:

o Deposition of hemosiderin in the following organs(in decreasing order of severity): liver, pancreas,myocardium, pituitary gland, adrenal gland,thyroid and parathyroid glands, joints, and skin

o Cirrhosiso Pancreatic fibrosis

• In the liver, iron becomes evident first as golden-yellowhemosiderin granules in the cytoplasm of periportalhepatocytes

o Stains blue with the Prussian blue stain• With increasing iron load, there is progressive

involvement of the rest of the lobule, along with bile ductepithelium and Kupffer cell pigmentation

• Iron is a direct hepatotoxin• Inflammation is absent



• At this stage, liver is slightly larger than normal, dense,and chocolate brown

• Fibrous septa develop slowly leading to micronodular pattern of cirrhosis in an intensely pigmented liver

• Biochemical determination of hepatic iron concentrationin unfixed tissue – standard for quantitating hepatic ironcontent

o In normal individuals: iron content of unfixed liver is less than 1000 ug per gram dry weight of liver

o Adults with HH: over 10,000 ug iron per gram dryweightr

o Hepatic iron concentrations in excess of 22,000ug per gram – associated with fibrosis andcirrhosis

• Pancreaso Intensely pigmentedo Diffuse interstitial fibrosiso May exhibit some parenchymal atrophyo Hemosiderin is found in both acinar and the islet

cells and sometimes in the interstitial fibrousstroma

• Hearto Often enlargedo Has hemosiderin granules within the myocardial

fibers producing a striking brown coloration tothe myocardium

o Delicate interstitial fibrosis may appear • Skin pigmentation

o Attributable to hemosiderin deposition in dermalmacrophages and fibroblasts

o Most results from increased epidermal melaninproduction

o Combination of these pigments imparts acharacteristic slate-gray color to the skin

• Joint synovial liningso Acute synovitis may develop due to hemosiderin

deposition• Excessive deposition of calcium pyrophosphate

damages the articular cartilage produces disablingpolyarthritis referred to as PSEUDO-GOUT

• Testeso Small and atrophic

Atrophy secondary to a derangement inthe hypothalamic-pituitary axis

o Not usually significantly pigmented

Clinical Features• More often a disease of males• Rarely becomes evident before age 40• Principal manifestations

o Hepatomegalyo Abdominal paino Skin pigmentation (particularly in exposed areas)o Deranged glucose homeostasis or frank diabetes

mellitus due to destruction of pancreatic isletso Cardiac dysfunction (arrhythmias,

cardiomyopathy)o Atypical arthritis

• Some patients, the presenting complaint ishypogonadism

• Classic triad: pigment cirrhosis with hepatomegaly, skinpigmentation, and diabetes mellitus

o May not develop until late in the course of the

disease• Death: may result from cirrhosis or cardiac disease

o A significant cause of death is hepatocellular carcinoma

o Treatment for iron overload does not remove therisk for this aggressive neoplasm

• HH can be diagnosed long before irreversible tissuedamage has occurred

• Screening:o Demonstration of very high levels of serum iron

and ferritino Exclusion of secondary causes of iron overloado Liver biopsy, if indicated

• Screening of family members of probands is importanto Heterozygotes for HH also accumulate excessive

iron, but not to the degree required to causesignificant tissue damage

o Homozygotes may be identified before onset of clinical disease

• Identification of HFE gene opens the way for geneticscreening, limited by the heterogeneity of mutations inthis disease

• Patients with HH diagnosed in the subclinical,precirrhotic stage and treated by regular phlebotomyhave a normal life expectancy

Wilson Disease

• Autosomal-recessive• Marked by the accumulation of toxic levels of copper in

many tissues and organs, principally in the liver, brain,and eye

• Normal: 40% to 60% of daily ingested copper (2 to 5mg) is absorbed in the stomach and duodenum andtransported to the liver loosely complexed with albumin

o Free copper dissociates and is taken up intohepatocytes, where it is incorporated into an a2-globulin synthesized in the endoplasmic reticulumto form ceruloplasmin and resecreted into plasma

• Ceruloplasmin accounts for 90% to 95% of plasmacopper

• Circulating ceruloplasmin is desialylted as part of normalplasma protein aging

o Desialylated ceruloplasmin is endocytosed by theliver, degraded within lysosomes, and its copper is excreted into bile

This is the primary route for copper elimation

o Estimated total body copper: 50 to 150 mg• Gene: ATP7B, on chromosome 13, encodes a 7.5 kB

transcript for a transmembrane copper-transportingATPase, located on the hepatocyte canalicular membrane

• Majority of patients are compound heterozygotescontaining different mutations of the Wilson diseasegene on each allele.

• Defective biliary excretion leads to copper accumulationin the liver in excess of the metallothionein-bindingcapacity, causing toxic liver injury through copper-catalyzed formation of reactive oxygen species.

• Once hepatic capacity for incorporationg copper intoceruloplasmin is exceeded sudden onset of criticalillness.

Morphology• Fatty change: mild to moderate, with vacuolated nuclei

and occasionally, focal hepatocyte necrosis• Acute hepatitis can exhibit features mimicking acute viral

hepatitis, except for the fatty change• Chronic hepatitis exhibits moderate to severe

inflammation and hepatocyte necrosis, withmacrovesicular steatosis, vacuolated hepatocellular nuclei,

o With progression, cirrhosis will develop• Massive liver necrosis

o Rare manifestation



o Indistinguishable from that caused by viruses or drugs

• Excess copper deposition – can be demonstrated byspecial stains (rhodanine for copper, orcein stain for copper-associated protein)

• Demonstration of hepatic copper content in excess of 250 ug per gram dry weight is most helpful for making adiagnosis

• Braino Toxic injury primarily affects the basal ganglia (the

putamen) atrophy and cavitationo Develop eye lesions called Kayser-Fleishcer rings

green to brown deposits of copper inDescemet’s membrane in the limbus of thecornea

Clinical Features• Rarely manifests before 6 years of age• Most common presentation: acute or chronic liver

disease• Neuropsychiatric manifestations, such as mild

behavioural changes, frank psychosis, or Parkinsondisease-like syndrome, are the initial features in most of

the remaining cases.• Biochemical diagnosis: based on a decrease in serum

ceruloplasmin, an increase in hepatic copper content,and increased urinary excretion of copper

• Early recognition and long-term copper chelationtherapy (as with D-penicillamine) can dramatically alter the usual progressive downhill course

• Fulminant hepatitis or unmanageable cirrhosis – liver transplant

a 1-Antitrypsin Deficiency

• Autosomal recessive disorder • Abnormally low serum levels of a1-antitrypsin

o Major function of this protein: inhibition of proteases, particularly elastase, cathepsin G, andproteinase 3

• Leads to the development of pulmonary emphysemalack of this protein permits tissue-destructive enzymes torun amok

• Can also cause liver disease, mainly in neonates andyoung adults

• Most commonly diagnosed genetic liver disease ininfants and children

a 1-Antitrypsin• Small, 394-amino acid plasma glycoprotein synthesized

predominantly by hepatocytes• Gene is located on human chromosome 14; very

polymorphic• General notation: Pi for protease inhibitor and an

alphabetic letter for the position on the gel; two lettersdenote the genotype of the two alleles.

o Most common genotype: PiMM (occurs in 90% of individuals)

o Most common clinically significant mutation: PiZindividuals have high risk for developing

clinical disease

Pathogenesis (di ko nagets wahahaha!)• Normal: The mRNA is translated and the protein is

synthesized and secreted• Deficiency variants: selective defect in migration of this

secretory protein from the ER to Golgi apparatuso Most marked for the PiZ polypeptideo Mutant polypeptide is abnormally folded, and

polymerizes, causing its retention in the ER

• All individuals with the PiZZ genotype accumulatea1,AT-Z in the ER of hepatocytes

• Only 10% of PiZZ individuals develop clinical liver disease

o They exhibit lags in the ER protein degradationpathway designed to degrade abnormallyfolded or unassembled polypeptidees

• The intense autophagocytic response stimulated withinhepatocytes: chief cause of liver injury, possibly byautophagocytosis of mitochondria.

Morphology• Characterized by the presence of round-to-oval

cytoplasmic globular inclusions in hepatocyteso In routine H and E stains – acidophilic and

indistinctly demarcated from the surroundingcytoplasm

• Globules are also present in diminished size andnumber in intermediate deficiency states

• Distinctive feature: the PAS-positive globules• Infrequently, fatty change and Mallory bodies are

present• Diagnostic a1-antitrypsin globules may be absent in

young infant

Clinical Features• Neonatal hepatitis with cholestatic jaundice appears in

10-20% of newborns with the deficiency• Adolescence: presenting symptoms may be related to

hepatitis or cirrhosis• The disease may remain silent until cirrhosis appears in

middle to later life• Hepatocellular CA may develop in 2-3% of PiZZ adults• Treatment and cure for severe hepatic disease:

orthotopic liver transplantation• In patients with pulmonary disease: avoid cigarette

smoking can accelerate the destructive lung diseaseassociated with a1-antitrypsin deficiency.

Neonatal Cholestasis

• Prolonged conjugated hyperbilirubinemia in neonate• Affects approx 1 in 2500 live births• Major conditions causing it:

o Cholangiopathies, primarily biliary atresiao A variety of disorders causing conjugated

hyperbilirubinemia in the neonate (collectivelycalled neonatal hepatitis)

o Table 18-10 pg 912• Affected infants: jaundice, dark urine, light of acholic

stools, and hepatomegaly• Idiopathic neonatal hepatitis represents up to 50% of

cases, biliary atresia another 20%, and a1-antitrypsindeficiency represents 15%

Morphology• Morphologic features of neonatal hepatitis:

o Lobular disarray with focal liver cell necrosiso Panlobular giant cell transformation of

hepatocytes and formation of hepatocyte“rosettes”: radially arrayed hepatocytes

o Prominent hepatocellular and canalicular cholestasis

o Mild mononuclear infiltration of the portal areaso Reactive changes in the Kupffer cellso Extramedullary hematopoiesis

INTRAHEPATIC BILIARY TRACT DISEASE

Secondary Biliary Cirrhosis



• Prolonged obstruction of the extrahepatic biliary tree• Most common cause of obstruction in adults:

extrahepatic cholelithiasis, followed by malignancies of the biliary tree or head of the pancreas and stricturesresulting from previous surgeries

• Obstructive conditions in children:o Biliary atresiao Cystic fibrosiso Choledochal cystso Syndromes in which there are insufficient

intrahepatic blie ducts• Secondary inflammation initiates periportal fibrosis,

which eventually leads to hepatic scarring and noduleformation, generating secondary biliary cirrhosis

• Subtotal obstruction may promote secondary bacterialinfection of the biliary tree aggravates theinflammatory injury

• Enteric organisms (colifroms and enterococci) –common culprits

Morphology• End-stage obstructed liver: extraordinary yellow-green

pigmentation and is accompanied by marked ictericdiscoloration of body tissues and fluids

• On cut surface: liver is hard, with finely granular appearance

• Histology:o Coarse fibrous septae that subdivide the liver in a

jigsaw-like patterno Embedded in the septa are distended small and

large bile ducts, contain inspissated pigmentedmaterial

• Cholestatic feature in the parenchyma may be severe,with extensive feathery degeneration and formation of bile lakes

• Once regenerative nodules have formed, bile stasis maybecome less conspicuous.

• Ascending bacterial infection incites a robustneutrophilic infiltration of bile ducts

• Severe pylephlebitis and cholangitic abscesses maydevelop

Primary Biliary Cirrhosis

• Chronic, progressive, often fatal cholestatic liver disease, characterized by the destruction of intrahepaticbile ducts, portal inflammation and scarring, and theeventual development of cirrhosis and liver failure

• Primary feature: nonsuppurative, inflammatorydestruction of medium-sized intrahepatic bile ducts

• Primarily, a disease of middle-aged women• Female:male predominance in excess of 6:1• Age of onset: 20-80 years; peak incidence: 40-50 years• Onset is insidious; presents with pruritus; jaundice

develops later • Hepatomegaly is typical• Xanthomas and xanthelasmas arise owing to cholesterol

retention• Late features: stigmata of chronic liver disease• Over a period of two or more decades: develop hepatic

decompensation, including portal hypertension withvariceal bleeding and hepatic encephalopathy

• Serum alkaline phosphatase and cholesterol: elevated• Hyperbilirubinemia: late development; signifies incipient

hepatic decompensation• 90% of patients: presence of circulating

“antimitochondiral antibodies”

o These antibodies are against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2),dihydrolipoamide acetyltransferase

o Enzyme complex is located on the inner face of the inner mitochondrial membrane well-shileded from circulating antibodies inundamaged hepatocytes

Pathogenesis• Auto-immune etiology

o Includes aberrant expression of MHC class IImolecules on bile duct epithelial cells andaccumulation of autoreactive T cells around bileducts

• Antibodies against other cellular components (nuclear pore proteins, centomeric proteins, etc) are alsoproduced

• Has extrahepatic manifestations of autoimmunityo Sicca complex of dry eyes and mouth (Sjogren

syndrome; Latin sicca meaning dryness)o Sclerodermao Thyroiditiso Rheumatoid arthritiso

Raynaud phenomenono Membranous glomerulonephritiso Celiac disease

• Etiology and inciting triggers of primary biliary cirrhosisare not clear

Morphology• Prototype of conditions leading to small-duct biliary

fibrosis and cirrhosis• Focal and variable disease

o Different degrees of severity in different portionsof the liver

• Precirrhotic Stageo Portal tracts are infiltrated by a dense

accumulation of lymphocytes, macrophages,plasma cells, and occasional eosinophils

o Terminal and conducting bile ducts are infiltratedby lymphocytes; may exhibit noncaseatinggranulomatous inflammation and undergoprogressive destruction

• The obstruction to intrahepatic bile flow leads toprogressive secondary hepatic damage

o Portal tracts upstream from damaged bile ductsexhibit bile ductular proliferation, inflammation,and necrosis of the adjacent periportal hepaticparenchyma

o Parenchyma develops generalized cholestasis• Relentless portal tract scarring and bridging fibrosis lead

to cirrhosis• Macroscopically:

o As disease progresses, bile stasis stains the liver green

o Capsule remains smooth and glistening until afine granularity appears culminates in a well-developed, uniform micronodularity

o Liver weight: first, normal to increased (due toinflammation); ultimately, liver weight is slightlydecreased

• Most cases, end-stage picture is indistinguishable fromsecondary biliary cirrhosis or the cirrhosis that followschronic hepatitis from other causes

Clinical Features• Onset is extremely insidious, may be symptom free for

many years• Pruritis, fatigue, and abdominal discomfort develop,

followed by secondary features: xanthomas and



xanthelasmas, steatorrhea, and malabsorption-relatedosteomalacia and/or osteoporosis

• Entry into end-stage of disease: general features of jaundice and hepatic decompensation, including portalhypertension and variceal bleeding

• Major cause of death: liver failureo Followed by massive variceal hemorrhage and

intercurrent infection

Primary Sclerosing Cholangitis

• Characterized by inflammation and obliterative fibrosisof intrahepatic and extrahepatic bile ducts, with dilationof preserved segments

• There is “beading” of a barium column in radiographs of the intrahepatic and extrahepatic biliary tree

o Due to irregular strictures and dilations of affectedbile ducts

• Commonly seen in association with inflammatory boweldisease, particularly chronic ulcerative colitis

• Prevalence of primary sclerosing cholangitis inulcerative colitis patients: 4%

• Tends to occur in third through fifth decades of life•

Males predominate, 2:1Pathogenesis• Cause is unknown• Key events:

o Secretion of proinflammatory cytokines byactivated hepatic macrophages

o Followed by infiltration of T cells into the stromaimmediately around bile ducts

Morphology• Fibrosing cholangitis of bile ducts, with a lymphocytic

infiltrate, progressive atrophy of the bile duct epithelium,and obliteration of the lumen

• Onion-skin fibrosis – concentric periductal fibrosis

around affected ductso Followed by solid, cordlike fibrous scar

• In between areas of progressive stricture, bile ductsbecome ecstatic and inflamed

o Result of downstream obstruction• As disease progresses, liver becomes markedly

cholestatic culminates in biliary cirrhosis

Clinical Features• There is persistent elevation of serum alkaline

phosphatase• Progressive fatigue, pruritus, and jaundice may develop• Autoantibodies are present in less than 10% of patients•

Severely afflicted patients: symptoms associated withchronic liver disease such as weight loss, ascites,variceal bleeding, and encephalopathy

• Has increased risk for cholangiocarcinoma• Definitive treatment: liver transplantation

Anomalies Of The Biliary Tree (Including Liver Cysts)

• Lesions may be found during radiographic studies or atautopsy or may become manifest ashepatosplenomegaly and portal hypertension in theabsence of hepatic dysfunction

• Four distinct lesions have been described

MorphologyVon Meyenburg Complexes• Close to or within portal tracts: small clusters of

modestly dilated bile ducts embedded in a fibrous,sometimes hyalinized stroma

• Free of pigmented material

• Arise from residual embryonic bile duct remnants• Occasionally, triangular bile duct hamartoma may lie

under Glisson’s capsulePolycystic Liver Disease• Liver contains multiple diffuse cystic lesions• Cysts are lined by cuboidal or flattened biliary epithelium

and contain straw-colored fluid• Do not contain pigmented material• Detached from the biliary tree•

Occasionally, liver cysts of biliary origin are identified,more commonly in womenCongenital Hepatic Fibrosis• Portal tracts are enlarged by irregular and broad bands

of collagenous tissue, forming septa and dividing theliver into irregular islands

• Variable numbers of abnormally shaped bile ducts areembedded in the fibrous tissue

• Bile duct remnants are distributed along the septalmargin

o Sometimes, curved bile duct profiles are arrangedin a concentric circle around portal tracts

• The increased number of bile ducts profiles are incontinuity with the biliary tree

• Anomaly arises because of persistence of a malformedembryonic form of the biliary tree

Caroli Disease• Larger ducts of the intrahepatic biliary tree are

segmentally dilated and may contain insipissated bile• Pure forms are rare• Usually associated with portal tract fibrosis of the

congenital hepatic fibrosis type

Clinical Features• Von Meyenburg Complexes are common and usually

without clinical significance• Polycystic liver disease may develop abdominal

tenderness or pain in stoopingo Occasionally, requires surgical interventiono Slight female predilectiono Presentation common during pregnancy

• Patients with congenital hepatic fibrosis rarely developcirrhosis

o May still face complications of portalhypertension, particularly bleeding varices

• Caroli disease is frequently complicated by intrahepaticcholelithiasis, cholangitis, and hepatic abscesses, alsoportal hypertension

o Has an increased risk of cholangiocarcinoma• Each of these 4 conditions appears to arise from

intrinsic anomalies in the development of the smaller to

larger portions of the intrahepatic biliary tree• (fig 18-33 pg 916) Well-documented association of

autosomal-dominant polycystic kidney disease withpolycystic liver disease

o Liver cyst in isolation or in abundance representthe most frequent extra-renal manifestation of autosomal-dominant polycystic kidney diseaseand occur in most patients

• Congenital hepatic fibrosis is strongly associated withthe autosomal-recessive form of polycystic kidneydisease

• Alagille syndrome – syndromatic paucity of bile ductso Uncommon autosomal-dominant conditiono Liver is almost normal, but portal tract bile ducts

are completely absento Cause by mutations in the gene Jagged1 on

chromosome 20p, a cell-surface protein thatfunctions as a ligand for the Notchtransmembrane receptors





• Hepatic vein thrombosis is associated with primarymyeloproliferative disorders, inherited disorders of coagulation, antiphospholipid syndrome, paroxysmalnocturnal hemoglobinuria, and intra-abdominal cancers

• Occurance in pregnant women or those taking OCPs isusually through interaction with an underlyingthrombogenic disorder

• 10% of cases: idiopathic in origin• Separate distinction is made for inferior vena cave

thrombosis at its hepatic portion (obliterativeheptocavopathy)

o Frequently idiopathico Nepal: endemic

• Mortality if untreated: high• Prompt surgical creation of a portosystemic venous

shunt: revese flow through the portal vein, improvesprognosis

• In the case of vena caval thrombosis, direct dilation of caval obstruction may be possible during angiography

• Chronic forms are far less lethal, over 2/3 of patients arealive after 5 years

Morphology•

Liver is swollen and red-purple and has a tense capsule• Microscopically:o The affected hepatic parenchyma reveals severe

centrilobular congestion and necrosis• Centrilobular fibrosis: develops when thrombosis is

slowly developing• Major veins may contain totally occlusive fresh thrombi,

subtotal occlusion, or in chronic cases, organizedadherent thrombi

• Thrombosis of obliterative hepatocavopathy may heal toleave only an incomplete membranous web protrudinginto the lumen of the inferior vena cava

Veno-Occlusive Disease (Sinusoidal Obstruction

Syndrome)

• Occurs primarily in the immediate weeks following bonemarrow transplantation

• Incidence: 25% in recipients of allogeneic marrowtransplants; mortality: over 30%

• Diagnosis: made on clinical grounds only (tender hepatomegaly, ascites, weight gain, and jaundice)

o High risk of liver biopsy in these patients• Arises from toxic injury to the sinusoidal epithelium

o Cells round up and slough off the sinusoidal wall,embolizing downstream and obstructingsinusoidal blood flow

o Accompanied by passage of erythrocytes into thespace of Disse and downstream accumulation of cellular debris in the terminal hepatic vein

o It is followed by proliferatin of perisinusoidalstellate cells and subendothelial fibroblasts in theterminal hepatic vein, with deposition of extracellular matrix

• Obliterative changes in the terminal hepatic vein aresecondary to sinusoidal damage alternative name:sinusoidal obstructive syndrome

• 70-85% of patients recover spontaneously• Treatment: largely supportive

Morphology• Characterized by obliteration of hepatic vein radicles by

varying amouns of subendothelial swelling and finereticulated collagen

• Acute disease, there is striking centrolobular congestionwith hepatocellular necrosis and accumulation ohemosiderin-laden macrophages

• As the disease progresses, obliteration of the lumen of the venule is easily identified by using special stains for connective tissue

• Chronic or healed veno-occlusive disease:o Dense perivenular fibrosis radiating out into the

parenchyma, frequently with total obliteration of the venule

o Hemosiderin deposition is evident in the scar tissue

o Congestion is minimal

HEPATIC DISEASE ASSOCIATED WITH PREGNANCY• Most common cause of jaundice in pregnancy: viral

hepatitis (HAV, HBV, HCV, and HBV+HDV)o Pregnancy does not specifically alter the course

of the liver disease, except hepatitis E viralinfection runs a more severe course inpregnant patients, fatality rates of 10-20%

• Unique and very small subgroup develop hepaticcomplications directly attributable to pregnancy:preeclampsia, acute fatty liver of pregnancy, andintrahepatic cholestasis of pregnancy

o Extreme cases of the first 2 conditions is fatal

Preeclampsia and Eclampsia• Preeclampsia

o Affects 7-10% of pregnancieso Characterized by maternal hypertension,

proteinuria, peripheral edema, coagulationabnormalities, and varying degrees of DIC

• Eclampsiao When hyperreflexia and convulsions occur o May be life threatening

• Subclinical hepatic disease may be the primarymanifestation of preeclampsia, as part of a syndrome of hemolysis, elevated liver enzymes, and low plateletsHELLP syndrome

• Patients with hepatic involvement in preeclampsia mayexhibit modest to severe elevation of serumaminotrasnferases and mild elevation of serum bilirubin

• Definitive treatment in severe cases: termination of pregnancy

o Mild cases: managed conservatively• Those who survived severe preeclampsia recover

without sequelae

Morphology• Affected liver in preeclampsia is normal in size, firm, and

pale, with small red patches due to hemorrhage• Occasionally, yellow or white patches of ischemic

infarction can be seen• Microscopically:

o Periportal sinusoids contain fibrin deposits withhemorrhage into the space of Disse leads toperiportal hepatocellular coagulative nerosis

• Blood under pressure may coalesce and expand to forma hepatic hematoma

o Dissection of blood under Glisson’s capsule: maylead to hepatic rupture

Acute Fatty Liver of Pregnancy

• Present in later half of pregnancy, usually in the 3 rd

trimester • Symptoms are directly attributable to incipient hepatic

failure, including bleeding, nausea and vomiting, jaundice, and coma

• Can progress within days to hepatic failure and death• Primary treatment: termination of pregnancy



Morphology• Diagnosis rests on biopsy identification of the

characteristic microvesicular fatty transformation of hepatocytes

• In severe cases: lobular disarray with hepatocytedropout, reticulin collapse, and portal tract inflammation

• Diagnosis depends on:o High index of suspiciono Confirmation of microvesicular steatosis using

special stains for fat (oil-red-O or Sudan black) onfrozen tissue sections

Electron microscopy can ale be used for steatosis

Intrahepatic Cholestasis of Pregnancy

• Onset of pruritus in the 3 rd trimester, followed bydarkening of urine and occasionally light stools and

jaundice heralds the development of this syndrome• Serum bilirubin (conjugated mostly) rarely exceeds

5mg/dl• Alkaline phosphatase may be slightly elevated•

Liver biopsy: mild cholestasis without necrosiso Altered hormonal state of pregnancy appears to

combine with biliary secretion defects toengender cholestasis

• Generally a benign conditiono But mother is at risk for gallstones and

malabsorptiono Incidence of fetal distress, stillbirth, and

prematurity is modestly increased

HEPATIC COMPLICATIONS OF ORGAN OR BONEMARROW TRANSPLANTATION

Drug Toxicity After Bone Marrow Transplantation

• Describes a syndrome of hepatic dysfunction followingthe cytotoxic therapy administered to patients just prior to bone marrow transplantation

• Affects up to one half of patients• Characterized by weight gain, tender hepatomegaly,

edema, ascites, hyperbilirubinemia, and a fall in urinarysodium excretion

• Onset: days immediately following the transplantation• A spectrum of centrolobular necrosis and inflammatory

changes is encountered culminates in veno-occlusivedisease

• Clinical outcome is directly related to the severity of liver

toxicity• Persistent severe liver dysfunction: fatal outcome,succumbs to septicemia, pneumonia, bleeding, and/or multiorgan failure

Graft-Versus-Host Disease and Liver Rejection

• Liver transplants are reasonable tolerated by recipientso This is because the transplanted liver carries

many donor lymphocytes, establishing a state of chimerism in the recipient

Prevents the recipient’s immune systemfrom reacting against donor alloantigens

Morphology• Acute graft-versus-host disease (10-50 days after

transplant)o Liver damage is dominated by direct attack of

donor lymphocytes on epithelial cells andinflammation of the parenchyma and portal tracts

• Chronic graft-versus-host disease (more than 100 daysafter)

o Portal tract inflammationo Selective bile duct destructiono Eventual fibrosis

• Portal vein and hepatic vein radicles may exhibitendothelitis subendothelial lympocytic infiltrate liftsthe endothelium from its basement membrane

• Cholestasis seen in both acute and chronic•

Acute cellular rejectiono Characterized by infiltration of a mixed population

of inflammatory cells into portal tracts, bile ductand hepatocyte injury, and endothelitis

• Chronic rejectiono Severe obliterative arteritis of small and large

arterial vessels results in ischemic changes in theliver parenchyma

o Bile ducts are progressively occluded due todirect attack or obliteration of their arterial supply

• Both may lead to loss of the graft

Nonimmunologic Damage to Liver Allografts

• Revascularization and prefusion of the donor liver mayresult in preservation injury

o Attributable to generation of oxygen radicals in ahypoxic organ with insufficient reserves of oxygenscavengers to prevent damage

o Leads to sinusoidal endothelial injury and Kuppfer cell activation, neutrophil adhesion, plateletaggregation, and local cytokine release

• Hepatocyte ballooning and cholestasis follow, withvariable degrees of centrilobular necrosis

• Severe injury: portal tracts are damaged causeinflammation, bile duct proliferation, and fibrosis

• Hepatic artery thrombosis – sufficiently severe vascular

insult to cause severe compromise in the transplantedliver • Portal vein thrombosis may be insidious and present

only as variceal hemorrhage weeks to months later • Bile duct obstruction – from stricture at the anastomosis

with the native common bile duct

TUMORS AND TUMOR-LIKE CONDITIONS

• The most common hepatic neoplasms are metastaticcarcinomas

• Important in the differential diagnosis of hepatic massesare1. whether there is underlying liver disease, especially

cirrhosis, in which there is a greater risk for primaryhepatocellular carcinoma

2. whether the mass is solitary or multiple

Benign Tumors

• The most common benign lesions are cavernoushemangiomas- These well-circumscribed lesions consist of

endothelial cell-lined vascular channels andintervening stroma

- They appear as discrete red-blue, soft nodules,usually less than 2 cm in diameter, often, directlybeneath the capsule

• Focal nodular hyperplasia – a well-demarcated butpoorly encapsulated nodule with a central fibrous scar ranging up to many cm. in diameter



- Believed to represent nodular regeneration inresponse to local vascular injury and is not aneoplasm per se

• Liver cell adenoma – occur in women of childbearingage who have used OCPs- These tumors may be pale, yellow-tan or bile-

stained, well-demarcated nodules found anywherein the hepatic substance but often beneath thecapsule

- Composed of sheets and cords of cells that mayresemble normal hepatocytes or have somevariation in cell and nuclear size

- Portal tract are absent, instead, prominent arterialvessels and draining veins are distributed throughthe substance of the tumor

- Significant for 2 reasons:1. when they present as an intrahepatic mass2. subcapsular adenomas are at risk for rupture,

particularly during pregnancy (under estrogenicstimulation), causing life-threateningintraabdominal hemorrhage

Primary Carcinoma of the Liver

• Most arise from hepatocytes and are termedhepatocellular carcinoma (HCC)

• Much less common are carcinomas of bile duct origin(cholangiocarcinomas) or tumors that are a mixture of the 2 cell types

• Two rare forms are:1. Hepatoblastoma - an aggressive hepatocellular

tumor of childhood2. Liver angiosarcoma – associated with exposure to

vinyl chloride, arsenic, or Thorotrast

Pathogenesis• Three major etiologic associations have been

established:1. infection with HBV2. chronic liver disease (including HCV and alcohol)3. hepatocarcinogens in food (aflatoxin)

• Many factors including age, sex, chemicals, viruses,hormones, alcohol, and nutrition, interact in thedevelopment of HCC.

• Rare hereditary tyrosinemia most likely give rise to HCC• Cirrhosis appears to be an important but not requisite

contributor to HCC• Extensive epidemiologic evidence links chronic HBV

infection with liver cancer, and there is a strong evidenceimplicating HCV infection- Repeated cycles of cell death and regeneration, as

occurs in chronic hepatitis from any cause, areimportant in the pathogenesis of liver cancers

- The accumulation of mutations during continuouscycles of cell division may eventually transformsome hepatocytes. Genomic instability is morelikely in the presence of integrated HBV DNA,giving rise to chromosomal aberrations such asdeletions, translocations, and duplications

- Molecular analysis of tumor cells in HBV-infectedindividuals reveals that each case is clonal withrespect to HBV DNA integration pattern suggestingthat viral integration precedes or accompanies atransforming event

- The HBV genome encodes a regulatory element,

the HBV X-protein that is a transactingtranscriptional activator of many genes and ispresent in most tumors with integrated HBV DNA. Itappears that in liver cells infected with HBV, the

disruption of cell cycle control. It also exerts antiapoptotic effects.

- As with human papillomaviruses, some studiessuggest that certain HBV proteins bind to andinactivate the tumor suppressor gene TP53

• Aflatoxins – derived from the fungus Aspergillus flavusfound in “moldy” grains and peanuts- Bind covalently with cellular DNA and cause

mutations in protooncogenes or tumor suppressor genes, particularly TP53

• Cholangiocarcinoma – only recognizes causalinfluences are primary sclerosing cholangitis, chronicinfection of the biliary tract by the liver fluke Opisthorchissinensis and previous exposure to Thorotrast

Morphology• Primary liver carcinomas appear grossly as:

1. unifocal – massive tumor 2. multifocal – widely distributed nodules of variable

size3. diffusely infiltrative – permeating widely and

sometimes involving the entire liver • Discrete tumor masses are usually yellow-white,

punctuated sometimes by bile staining and areas of hemorrhage or necrosis• All patterns of HCC have a strong propensity for

invasion of vascular channels• Snakelike masses of tumor invade the portal vein (with

occlusion of the portal circulation) or inferior vena cavaextending to the right side of the heart

• Histologically, HCCs range from well-differentiatedlesions with hepatocytes arranged in cords or smallnests to poorly differentiated lesions made up of largemultinucleated anaplastic tumor giant cells

• Globules of bile may be found within the cytoplasm of cells and pseudocanaliculi between cells

• Acidophilic hyaline inclusions may be present

resembling Mallory bodies• Fibrolamellar carcinoma – single, large, hard “scirrhous”

tumor with fibrous bands coursing through it- Well-differentiated polygonal cells in nests or cords

separated by parallel lamellae of dense collagenbundles

• Cholangiocarcinomas – well-differentiatedadenocarcinomas with abundant fibrous stroma(desmoplasia) explaining their firm, gritty consistency- Clearly defined glandular and tubular structures

lined by somewhat anaplastic cuboidal-to-lowcolumnar epithelial cells

- Bile pigment and hyaline inclusions not found withinthe cells

Clinical Features• Rapid increase in liver size• Sudden worsening of ascites or appearance of bloody

ascites• Fever • Pain• Elevated serum levels of a-fetoprotein = lacks specificity• Complications:

o Profound cachexiao GI or esophageal variceal bleedingo Liver failure with hepatic comao Rupture of the tumor with fatal hemorrhage

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9189574 Liver Robbins