Pathology of the Liver & Biliary Tract I, II, III, and IV

Transcription

1 Grace Guzman, M.D. UIC College of Medicine Assistant Professor of Pathology, UIC M2 Pathology Course Phone: Lectures #59, 60, 63, 64 Tuesday, February 3, :30-11:20, 11:30-12:20 Monday, February 9, :30-11:20, 11:30-12:20 Reading Assignment: My Lecture notes; Robbins Pathologic Basis of Disease (Cotran, Kumar, Robbins), 6th Ed pp EDUCATIONAL GOALS & OBJECTIVES: 1. Define the following terms: a.. Cirrhosis b. Hepatic failure c. Chronic viral hepatitis 2. Know the most common etiology, modes of transmission, pathology and clinical manifestations of chronic viral hepatitis (particularly Hepatitis C) 3. Differentiate PBC from PSC 4. Identify the pathomorphologic features of alcoholic liver disease 5. Differentiate acute allograft rejection from chronic allograft rejection First Hour 1. The students will learn the histologic and functional unit of the liver as well as its function. 2. The students will become familiar with the metabolism of bilirubin from its origin to its excretion in the bile. 3. The students will learn the causes of abnormal bilirubin levels leading to clinical jaundice. 4. The students will learn the pathologic manifestations of extrahepatic biliary obstruction. 5. The students will become acquainted with the chemical manifestations of liver failure. 6. The students will become familiar with all the viral agents that may infect the liver. Second Hour 1. The students will learn the biological and clinical aspects of infectious hepatitis, caused by hepatitis A virus. Page 1 of 27

2 2. The students will learn the components of hepatitis B virus and its mode of transmission. 3. The students will become familiar with the clinical and pathologic aspects of hepatitis B virus. 4. The students will learn the role of hepatitis C virus as an agent of chronic liver disease. 5. The students will learn basic concepts of hepatitis D and G viruses. 6. The pathology of viral hepatitis will be the subject of discussion, both acute and chronic. Third Hour 1. The students will learn all aspects of alcoholic liver disease. 2. The students will learn the similarities and differences of ASH (Alcoholic steatohepatitis) versus NASH (Non-alcoholic steatohepatitis) 3. The students will become familiar with two autoimmune chronic liver diseases that lead to cirrhosis, currently treated by liver transplantation: primary biliary cirrhosis and primary sclerosing cholangitis. 4. The students will become familiar with hereditary liver diseases: Hemochromatosis, Wilson's disease and alpha 1 antitrypsin deficiency. Fourth Hour 1. The students will learn the pathology of hepatic tumors, both benign and malignant. 2. The students will learn the pathology of gallbladder inflammation, cholelithiasis and neoplasms of the extrahepatic biliary tree. 3. The student will become familiar with biliary atresia. Page 2 of 27

3 I. GENERAL MORPHOLOGIC & FUNCTIONAL PATTERNS OF HEPATIC INJURY A. ANATOMY 1. Gross Pathology The liver is the largest viscus of the body, usually contributing 1/50 of the entire body weight ( g) in adults and a much larger proportion (about 1/20), in the newborn child. It does not fall into the pelvis because of its firm attachment to the diaphragm by the coronary ligament, left & right triangular ligaments, and attachment to anterior body wall by the falciform ligament. Two thirds of the blood supply to the liver comes from the portal vein, the other third comes from the hepatic artery. Blood drains into the hepatic veins and enters the inferior vena cava. 2. Microscopic Architecture a. Lobule: Classic hexagonal structure with portal tracts at the periphery and central vein (=terminal hepatic venule) at the center. b. Acinus: (Newer concept based on the hepatic microcirculation). The acini are roughly triangular with the bases being the terminal branches of the portal vein and hepatic artery and apices are the central vein (terminal hepatic venule). The acinus is divided into zones: i. Zone 1: Adjacent to portal venous system, richest in oxygen and nutrient supply. ii. Zone 2: Intermediate between 1 & 3 iii. Zone 3: At the apex, adjacent to the terminal hepatic venules; and affected most by anoxia and most toxins. B. FUNCTION The hepatocyte is unrivaled by any other parenchymal cell type in functional diversity and complexity. 1. Metabolic glucose homeostatis, lipid metabolism 2. Synthetic.albumin, coagulation proteins I, II, V, VII-XIII, specific binding proteins 3. Storage...glycogen, triglycerides, iron, copper, lipid and soluble vitamins 4. Catabolic...ammonia->urea, contain hormones + proteins, detoxification of many foreign compounds, drugs and chemicals 5. Excretory bile excretion 6. Survival..agenesis of the liver is incompatible with life Page 3 of 27

4 C. LABORATORY ASSESSMENT OF LIVER FUNCTION 1. Serum Transaminases: Damaged cells leak contents into the circulation AST = Aspartate aminotransferase (SGOT) ALT = Alanine aminotransferase (SGPT) 2. Alkaline Phosphatase: Enzyme that exists as different isoenzymes in the liver, bone and intestine. In cholestatic disorders there is de novo synthesis which leaks into the circulation by undefined mechanisms. 3. Gamma Glutamyl Transpeptidase (GGT): Elevations in levels of this enzyme differentiate whether or not an elevated alkaline phosphatase is of liver or non-liver origin. GGT levels may be elevated in conditions other than liver disease such as in response to some chemicals and drugs, but when both GGT and alkaline phosphatase are elevated, the liver/biliary tree is the likely source of both of these elevated enzymes. 4. Bilirubin: Bilirubin is primarily a product of RBC destruction. Unconjugated bilirubin is roughly equal to "indirect bilirubin" as measured in the laboratory. It is toxic and may cross the blood brain barrier and in newborns result in kernicterus. Conjugated bilirubin is roughly equivalent to "direct bilirubin" as measured in the laboratory. It is non-toxic and can be excreted in the urine. D. BILIRUBIN METABOLISM Steps in Bilirubin Metabolism Etiology/Pathogenesis 1. Bilirubin production 1. Unconjugated hyperbilirubinemia Breakdown of senescent -Increased destruction of rbcs RBC's - 70% -hemolytic anemia Hemoproteins - 30% -reabsorption of large hematoma -ineffective erythropoesis 2. Uptake/binding 2.Unconjugated hyperbilirubinemia Bilirubin is transported Impaired uptake/binding across the hepatocyte membrane -hepatocellular injury and is taken up by a protein carrier -drugs -newborns -Gilbert s 3. Conjugation 3. Unconjugated hyperbilirubenemia Bilirubin is released from Impaired Conjugation the ligand and -newborns Page 4 of 27

5 conjugated with 2 molecules of glucoronic acid, catalyzed by UDP glucoronosyl transferase -Crigler-Najjar syndrome -Gilbert s 4 Excretion 4. Predominantly conjugated Conjugated bilirubin diffuses hyperbilirirubinemia through the cytosol to the -Dubin Johnson syndrome bile canaliculus where -Rotor s syndrome it is excreted into the bile -hepatocellular injury -toxins -intrahepatic bile duct disease -extrahepatic biliary disease 5. Eventually bile is excreted into the small bowel. Bacterial flora in the GI tract hydrolyses it to free bilirubin that is now unconjugated and reduced to a mixture of pyroles called urobilinogen. Most of the urobilinogen is excreted into feces, however, some return via the enterohepatic circulation and is reexcreted in bile or in the urine. 6. Pathology: The pathologic features seen in the liver depend on the etiology of the hyperbilirubinemia of the hereditary hyperbilirubinemias, the most characteristic pathologic features are seen in Dubin Johnson syndrome which shows abundant pigmented granules within the hepatocyte cytoplasm and gives the liver a jet black color. 7. Clinical Pathologic Correlation: The clinical features depend on the etiology of the hyperbilirubinemia, however most can lead to clinical jaundice. a. Jaundice or icterus describes the yellow-green discoloration of the skin, sclera, and other tissues and is clinically manifested when circulating bilirubin concentration reach levels greater than 2.0 to 2.5 mg/dl. b. Uncongugated hyperbilirubinemia can cross the blood brain barrier in the infant resulting in kernicterus. E. CHOLESTASIS Definition: Cholestasis refers to decreased bile flow which is accompanied by the accumulation in the blood of substances normally excreted in bile (bilirubin, bile salts and cholesterol). 1. Pathology: Cholestatic liver changes a. Canalicular bile plugs b. Intracellular bile in hepatocytes c. "Feathery degeneration" d. Bile ductule proliferation e. Bile lakes and bile infarcts Page 5 of 27

6 2. Clinical Pathologic Correlation: a. Jaundice due to increased bilirubin b. Pruritus due to increased bile acids in serum c. Steatorrhea (abundant white fatty stools) due to malabsorption of fats d. Hemorrhagic disorders due to decreased absorption of vit A, D,and K e. Xanthomas due to increased serum cholesterol 3. Etiology/Pathogenesis: Intrahepatic cholestasis Extrahepatic obstruction - Drug - Gallstones - Cholestasis of pregnancy - Neoplasms - Benign recurrent cholestasis - Strictures - Hepatocellular injury (hepatitis) - Sclerosing cholangitis - Sepsis - Biliary atresia - PSC, PBC - Bile duct anomalies -Congenital - Metabolic disorders F. CIRRHOSIS Definition: A diffuse process characterized by fibrosis and a conversion of normal architecture into structurally abnormal nodules. 1. Pathology: a. Fibrosis; delicate diffuse bands of collagen tissue bridging portal-portal, portal-central or central-central areas to form large diffuse broad scars surrounding nodules of hepatic parenchyma. b. The normal architecture is replaced by interconnecting fibrous scar. c. Regenerative nodules ranging from micronodules (less than 3 mm) to macronodules (greater than 3mm), are created by the regeneration of hepatocytes. 2. Clinical Pathologic Correlation: a. Silent b. Nonspecific symptoms, anorexia, weight loss, weakness 3. Symptoms associate with more advanced liver disease a. progressive liver failure b. complications of portal hypertension i. ascites ii. porto systemic venous shunts Page 6 of 27

7 iii. congestive splenomegaly c. hepatic encephalopathy 3. Etiology/Pathogenesis: a. Collagen deposition in all portions of the hepatic lobule. b. Major source of excess collagen in cirrhosis is believed to be the hepatic stellate cell (Ito cell) c. Exact stimulus for the fibrosis is uncertain, but etiologies include: Alcoholic liver disease a1 -AT deficiency Viral hepatitis Cryptogenic (see Non-alcoholic steatohepatitis) Biliary diseases Metabolic disorders Drug reaction Primary hemochromatosis Infection Wilson's disease G. HEPATIC FAILURE Definition: A clinical syndrome with appreciable morbidity and mortality (70-95% overall mortality) that results from inadequate liver function when either hepatocytes are sufficiently diminished in number or their function is greatly impaired. 1. Pathology: a. Massive hepatic necrosis b. Non-necrotic liver failure (ultrastructural damage without cell necrosis) c. Chronic liver disease 2. Clinical Pathologic Correlation: a. Jaundice b. Hepatic encephalopathy i. C.C.C.C. (confusion, unconsiousness, conculsions, coma ii. Asterixis c. Coagulopathy i. bleeding due to impaired synthesis of coagulation factors (II, VII, IX, X) ii. Increased PT time due to increased factor VII iii. Thrombocytopenia due to hypersplenism, Bone marrow suppression iv. DIC due to necrosis of hepatocytes Activation of Factor XII d. Repatorenal syndrome i. Renal failure in favored theory is decreased Absence of any renal blood flow and shunting of Anatomic changes blood from cortex to medulla Resulting in decreased GFR e. Hypoalbuminemia Page 7 of 27

8 i. edema due to impaired synthesis of albumin f. Pulmonary complications i. decreased arterial several proposed mechanisms O2 saturation g. Endocrine-related problems i. Gynecomastia feminization due to reduced catabolism ii female body habitus of estrogen and weak androgens h. Fetor hepaticus musty or sweet sour body odor due to the formation of mercaptans and portosystemic shunt H. FULMINANT HEPATITIS 1. Hepatic insufficiency progressing from onset to death (or liver transplantation) within 2 to 3 weeks 2. sub fulminant hepatic failure denotes a course of up to 3 months to 65% of cases are viral hepatitis to 30% are from drug or chemical toxicity 5. may present with jaundice, encephalopathy, fetor hepaticus, coagulopathy and bleeding, cardiovascular instability, renal failure, ARDS, electrolyte and acid disturbances, and sepsis 6. mortality is 25 to 90% without transplantation 7. the entire liver or just portions may be involved 8. affected areas are soft, muddy-red or bile stained 9. liver is shrunken 10. entire lobules destroyed, collapsed reticulin network, inflammation minimal 11. regeneration is disorderly, scar may form, coarsely lobulated pattern of necrosis Page 8 of 27

9 II. INFECTIOUS DISORDERS Systemic viral infections that can involve the liver include: a. EBV b. Adenoviruses c. CMV d. Enterovirus e. HSV f. Rubella g. Yellow fever h. Lassa fever i. Marburg + Ebola virus A. ACUTE HEPATITIS 1. Definition a. Pathologist : Inflammation of the liver b. Clinician: Syndrome by which the patient demonstrates laboratory evidence of liver cell necrosis (elevated ALT &AST) often preceded or accompanied by malaise, fever and jaundice 2 Pathology a. Liver cell injury and necrosis i. single cell necrosis (councilman body); dead hepatocyte ii. ballooning degeneration; swollen dying hepatocyte iii. spotty necrosis; localized collection of inflammatory cells and Kupffer cells where a hepatocyte should be iv. piecemeal necrosis; inflammatory cells spilling out beyond the limiting plate and associated with hepatocellular necrosis v. bridging necrosis; necrotic hepatocytes and inflammation extending from portal to portal, portal to central or central to central areas. b. Confluent hepatic necrosis: bridging necrosis to necrosis of all hepatic parenchyma c. Portal and lobular inflammation d. Cholestasis Page 9 of 27

10 4. Hepatitis B serology a. Positive: HBsAg, IgM anti HBc = acute infection b. Positive: IgM anti HBc = acute infection c. Positive: HBsAg only = early acute or chronic inflammation d. Positive: HBsAg, HBeAg, HBV DNA by molecular studies = chronic with continuing infection, high infectivity or early acute infection e. Note: Beware HBe is a marker for active viral replication with shedding of complete virions into blood stream & thus high infectivity 5. Hepatitis F -A double stranded DNA virus, presumably the enteric agent responsible for sporadic non-a, non-b hepatitis in humans, was successfully transmitted to rhesus monkeys by means of a stool extract from a patient -these findings have yet to be confirmed by others before it's existence can be accepted 6. Hepatitis G -In January 1996, a new: blood borne.rna hepatitis virus was identified and designated as Hepatitis G virus Page 10 of 27

11 -similar to Flaviviridae family (HCV) -related to HCV but does not seem to cause liver disease -has a worldwide distribution -parenteral route of exposure -can be transmitted simultaneously with HCV (co-infection) -progression of HIV (human immunodiffenciency virus) is delayed in persons who are co-infected with GB virus-c (GBV-C) -common in patients with HIV infection (Sept 2001 NEJM) B. CHRONIC HEPATITIS 1. Definition: Symptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for more than 6 months. 2. Pathology: Chronic hepatitis with assessment of inflammatory activity [=Grade] (mild to severe) and evaluation of degree of fibrosis and/or cirrhosis [=Stage] 3. Clinical Pathologic Correlation: a. Asymptomatic b. Fatigue, malaise, jaundice, anorexia, fever, nausea c. Extrahepatic manifestations (cryoglobulinemia, glomerulonephritis) d. Chronic liver failure N.B. clinical findings are not specific and correlate poorly with severity of disease 4. Etiology/Pathogenesis: a. Hepatitis B, C, D 5. Other non-infectious cause of chronic hepatitis include the following: a. Autoimmune hepatitis b. Drugs c.. Wilson's Disease Page 11 of 27

12 d. Alpha -1-anti-trypsin deficiency III. DRUG- & TOXIN-INDUCED LIVER DISEASE A. Definition: Xenobiologies (therapeutic agents or environmental toxins) can produce a broad spectrum of liver disease from clinically trivial transient cholestasis to fatal fulminant hepatitis. Hepatic injury secondary to drugs accounts for approximately 5% of all causes of jaundice and up to 25% of cases of fulminant hepatic necrosis. B. Pathology: Basically a drug or toxin can produce any form of liver pathology from hepatocellular injury (acetaminophen-hepatic necrosis) to vascular abnormalities and even neoplasms (anabolic steroids -liver cell adenoma) C. Clinical Pathologic Correlation: In a patient with liver chemistry abnormalities or asymptomatic liver dysfunction - ALWAYS THINK OF POSSIBLE DRUG/TOXIN HEPATOCYTE DAMAGE D. Etiology /Pathogenesis: (see Table 19-4 page 869 in Robbins for list of drugs and toxins) IV. ALCOHOLIC LIVER DISEASE 1. Definition: Long term excessive alcohol consumption resulting in a spectrum of liver pathology. Alcohol and its metabolites are direct hepatotoxic agents. 2. Pathology: a. Hepatic steatosis; grossly, the liver may be enlarged and on cut section is soft and greasy. Microscopically there is first microvesicular steatosis then macrovesicular steatosis. i. Microvesicular steatosis small lipid droplets in cytoplasm ii. Macrovesicular steatosis cytoplasm is replaced by a large lipid vacuole that displaces the nucleus to the side b. Alcoholic Hepatitis i. liver cell necrosis ii. Mallory Bodies - Worm-like perinuclear eosinophilic inclusions composed of cytokeratin intermediate filaments and other proteins. iii. Neutrophilic reaction iv. Fibrosis c. Alcoholic cirrhosis i. Grossly the liver is transformed into a shrunken firm diffusely nodular organ. Page 12 of 27

13 ii. Histologically, there are parenchymal nodules of varying size surrounded by dense fibrous tissue. 3. Clinical Pathologic Correlation: a. Steatosis i. asymptomatic ii. mild increase of bilirubin and alkaline phosphatase b. Alcoholic hepatitis i. asymptomatic ii. Malaise, anorexia, weight loss, abdominal pain, increase bilirubin and increase alkaline phosphatase iii. fulminant hepatic failure iv % risk of death/episode v. 1/3 will develop cirrhosis with repeated episodes c. Alcoholic cirrhosis i. 10% diagnosed at autopsy ii. may present with complications of portal hypertension iii. malaise, weakness, weight loss, anorexia - jaundice, ascites and peripheral edema iv. increase transaminases, increase bilirubin, decrease protein & anemia v. hepatic failure 4. Etiology/Pathogenesis: a. Steatosis i. increase lipid biosynthesis ii. lipoprotein abnormalities iii. increase peripheral catabolism of fat b. Hepatocyte injury i. induction of cytochrome P450 ii. generation of free radicals iii. direct effects of ETOH & acetaldehyde iv. immune reactions c. Fibrogenesis i. multifactorial Page 13 of 27

14 V. NON-ALCOHOLIC STEATOHEPATITIS The term Non-alcoholic steatohepatitis (NASH) was first used in 1980 by Ludwig-in 20 non-etch patients -a part of the spectrum of Non-alcoholic fatty liver disease -Now better known as Non-alcoholic fatty liver disease (NAFLD) -histopathology ranges from simple fatty liver, fatty change with lobular inflammation, hepatocellular injury, Mallory hyalin, may occur with or without fibrosis, to cirrhosis -NASH is a liver disease that - NASH can also occur in lean, until recently has been an otherwise healthy individuals. unrecognized as a common -even in children cause of elevated liver -generally benign enzymes -may be progressive -liver biopsy findings similar to alcoholic (ETOH) hepatitis - may lead to cirrhosis -no history of significant ETOH consumption -often middle aged and obese -has been shown to.be a -cause of cryptogenic cirrhosis -liver biopsy: the gold standard -may coexist with DM or hyperlipidemia -therapy - poorly defined : -weight loss and ursodeoxycholic acid (UDCA) has beneficial effect VI. INBORN ERRORS OF METABOLISM A. HEMOCHROMATOSIS 1. Definition: Although Robbins still refers to the progressive pathologic accumulation of iron in tissues with the potential for cellular damage and functional derangement as "Hemochromatosis," the newer terminology for these groups of diseases is best referred to as Iron Overload Disorders or Iron Storage Diseases. Page 14 of 27

15 2. Pathology: Accumulation of iron in parenchymal tissues a. Liver: Iron accumulates in periportal hepatocytes and may progress to accumulate in Kupffer cells and biliary epithelium. In some iron overload conditions such as parenteral iron overload, Kupffer cells may be the first to accumulate the iron. Fibrosis develops leading to cirrhosis. i. Prussian-blue stain: (also referred to as "the iron stain") stains hemosiderin granules blue-black and is used to grade the amount of iron visually seen on a liver biopsy. ii. Quantitative biochemical hepatic iron concentration: The amount of hepatic iron is measured on a fresh biopsy tissue by biochemical methods. b. Pancreas: Iron accumulates in both the acinar and islet cells. c. Heart: Iron accumulation in myocytes d. Skin: increased melanin in basal melanocytes and iron accumulation in dermal macrophages and fibroblasts resulting in a bronze or slate grey appearance of skin. e. Other tissues: joint and testis will accumulate iron 3. Clinical Pathologic Correlation: a. Hepatomegaly, abdominal pain b. Skin pigmentation c. Abnormal glucose metabolism - diabetes d. Cardiac dysfunction e. cirrhosis and complications f. Hepatocellular carcinoma N.B. all related to increased iron deposition 4. Etiology/Pathogenesis: a. Direct iron toxicity i. lipid peroxidation ii. iron stimulation of collagen formation iii. Iron-DNA interactions b. Primary/Hereditary iron overload: Autosomal recessive disorder, limited to the short arm of chromosome 6 and characterized by continued absorption of excessive iron. c. Secondary iron overload: iron accumulation in the liver and other tissues due to a variety of disease process. Page 15 of 27

16 5. Additional/lmportant Information: Primary iron overload is a treatable disease with a potentially normal life expectancy if diagnosed before irreversible tissue damage has occurred. It is therefore important to identify other family members that may be at risk. Elevated serum iron, total iron binding capacity and ferritin levels are suggestive of iron overload and should be followed by a liver biopsy with quantitative hepatic iron concentration studies. Treatment involves phlebotomy and the use of iron chelating agents. B. WILSON'S DISEASE 1. Definition: An autosomal recessive disorder of copper metabolism associated with chromosome 13, resulting in deposition of copper in many organs; particularly the liver, eye and brain. 2. Pathology: a. Liver: The pathology varies from steatosis (fatty change) to acute hepatitis, chronic hepatitis, cirrhosis and rarely fulminant hepatic necrosis. Although not specific, numerous glycogenated nuclei ("nuclear cleaning") are present in the hepatocytes and increased copper stores can be identified with special stains. Rhodamine or rubeanic acid stain ("the copper stain") stains copper as red granules in hepatocyte cytoplasm. i. quantitative hepatic copper concentration: Because the Rhodamine and rubeanic stains are a bit capricious, the most helpful way to determine t copper is by a biochemical determination of fresh tissue. b. Brain: copper deposits in areas of the brain with toxic injury to the neurons c. Eye: Kayser-Fleischer rings are copper deposits in Descemet membrane appearing as a brown discoloration of the peripheral ring of the cornea. 3. Clinical Pathologic Correlation a. Hepatic symptoms ranging from jaundice to hepatitis and cirrhosis b. Neurologic symptoms include; tremors, spasticity, behavioral abnormalities and dementia c. Ophthalmic: Kayser-Fleischer rings (copper deposits in Descemet membrane in the limbus of the cornea) 4. Etiology/Pathogenesis: Page 16 of 27

17 The exact pathogenesis remains obscure, but involves the liver inability to export copper effectively. 5. Additional Important Information: A potentially treatable disorder with early recognition and long term use of copper chelating agents (penicillamine) to prevent accumulation of copper and progression of disease. MUST CONSIDER THIS DIAGNOSIS IN ANY YOUNG PERSON WITH HEPATIC DISEASE! Important to screen family members. Laboratory screening studies suspicious of Wilson's disease are a low serum ceruloplasmin and increased urinary excretion of copper. C. ALPHA-1-ANTI-TRYPSIN DEFICIENCY 1. Definition: Autosomal recessive disorder marked by abnormally low levels of alpha-l antitrypsin. Alpha 1 AT's major function is the inhibition of proteases, particularly the potent elastase found in neutrophils which are released at sites of cell injury and inflammation. A deficiency of alpha-l antitrypsin may lead to pulmonary emphysema and hepatic damage. 2. Pathology: a. Hepatic pathology varies from neonatal hepatitis with or without cholestasis in the newborn to features of chronic active hepatitis and cirrhosis. b. Hallmark feature is the presence of alpha 1 AT cytoplasmic globules in hepatocytes. The diagnostic globules are not consistently present until about 3 months of age. PAS with diastase stain: alpha1-at globules stain pink with the PAS stain and remain pink even after treatment with the enzyme diastase. If on liver biopsy these globules are identified, they are confirmed as alpha 1-AT globules with an immunohistochemical stain specific for alpha 1-AT. 3. Clinical Pathologic Correlation a. Neonatal hepatitis with cholestatic jaundice in newborn. b. Hepatitis c. Cirrhosis 4. Etiology/Pathogenesis Page 17 of 27

18 The predominant site of a 1-AT synthesis is the hepatocyte, under the codominant alleles at a locus on the long arm of chromosome 14. The a 1- AT gene locus is termed Pi and over 75 variants have been identified. The most common variant associated with disease is the PiZZ homozygote which have a 1-AT levels that are only 10% of the normal level. The exact mechanisms for the development of liver disease are not entirely clear. VII. INTRAHEPATIC BILIARY TRACT DISEASE A. PRIMARY BILIARY CIRRHOSIS (PBC) 1. Definition: Non-suppurative granulomatous destruction of medium size intrahepatic bile ducts resulting in a chronic progressive and often fatal cholestatic liver disease. 2. Pathology: Traditionally conceptualized as 4 stages with the understanding that PBC is focal, variable and may exhibit different degrees of severity in different portions of the liver. (In other words, not an easy diagnosis to make for a pathologist on a liver biopsy) a. Stage 1. Florid duct lesion (granulomatous inflammation) b. Stage 2. Decreased bile ducts with ductular proliferation and portal inflammation c. Stage 3. Fibrosis d. Stage 4. Cirrhosis 4. Clinical Pathologic Correlation a. asymptomatic b. cholestatic symptoms; pruritus, xanthomas, steatorrhea - related to increase serum bile salts, cholesterol and decrease bile in GI tract c. jaundice and hepatic decompensation - late manifestation 5. Etiology/Pathogenesis a. primarily a disease of middle-aged woman b. 90% have antimitochondrial antibodies (+AMA) c. Autoimmune etiology is thought to be the most likely pathogenesis Page 18 of 27

19 B. SECONDARY BILIARY CIRRHOSIS 1. Definition: Prolonged obstruction to the extrahepatic biliary tree resulting in fibrosis leading to cirrhosis 2. Pathology a. cholestasis - initial injury, described earlier b. periportal fibrosis c. cirrhosis, usually with yellow-green hepatic discoloration grossly 3. Clinical Pathologic Correlation a. cholestatic symptoms of pruritus, jaundice, malaise, dark urine, light stools 4. Etiology/Pathogenesis a. Gall stones b. Neoplasms (carcinoma of the head of the pancreas) c. Strictures d. PSC e. Biliary atresia f. bile duct anomalies g. Flukes C. PRIMARY SCLEROSING CHOLANGITIS (PSC) 1. Definition: A fibro inflammatory process that narrows and eventually obstructs bile ducts. This process can occur anywhere from the ampulla of Vater to the intrahepatic intralobular bile ducts 2. Pathology: a. concentric peri ductal fibrosis followed by fibrous obliteration and disappearance of bile duct b. other ducts may be dilated presumably due to fibrous obstruction of downstream bile ducts 3. Clinical Pathologic Correlation a. asymptomatic with elevated alk phosphatase b. cholestatic symptoms c. chronic liver disease d. increased risk of cholangiocarcinoma 4. Etiology/Pathogenesis Page 19 of 27

20 a. commonly associated with inflammatory bowel disease (70% of pts with PSC have co-existing IBD) b. PSC-like illness is seen in AIDS patients with cryptosporidial and CMV biliary disease c. ERCP (Cholangiogram) shows characteristic "beading" or pruning of intrahepatic and/or extrahepatic biliary tree on imaging studies d. Exact etiology is uncertain VIII. CIRCULATORY DISORDERS A. IMPAIRED BLOOD FLOW INTO THE LIVER 1. Hepatic Artery Compromise 2. Portal Vein Obstruction & Thrombosis B. IMPAIRED BLOOD FLOW THROUGH THE liver 1. PASSIVE CONGESTION/CENTRILOBULAR NECROSIS a. Definition: hepatic injury pattern resulting from systemic circulatory compromise. b. Pathology: 1. Passive congestion i. enlarged liver with nutmeg appearance on cut section ii. congestion of centrilobular sinusoids iii. atrophy of centrilobular hepatocytes 2. Centrilobular necrosis i. coagulative necrosis of centrilobular hepatocytes ii. no inflammation iii. influx of blood 2. PELIOSIS HEPATIS 1. Definition: A rare condition characterized by the presence of cystic blood-filled spaces in the liver. 2. Pathology: Macro- or microscopic randomly distributed cystically dilated spaces filled with blood. Page 20 of 27

21 3. Clinical Pathologic Correlation Generally asymptomatic, rarely may result in intraabdominal hemorrhage or hepatic failure 4. Etiology/Pathogenesis a. Associated with drugs; anabolic steroid, rarely oral contraceptives and Danazol. b.aids; usually caused by the organism Bartonella henselae c. Reported with a variety of other chronic diseases C. HEPATIC VEIN OUTFLOW OBSTRUCTION 1. BUDD-CHIARI SYNDROME (HEPATIC VEIN THROMBOSIS) Definition: The term Budd-Chiari syndrome is usually applied to the clinical manifestations of hepatic venous outflow obstruction secondary to hepatic vein thrombosis. The term has also been applied to symptoms related to suprahepatic obstruction of the IVC and diseases affecting small hepatic vein branches. a. Pathology: i. Acute: liver is swollen, with centrilobular congestion and necrosis ii. Slow chronic thrombosis: centrilobular fibrosis/sclerosis, +/- webs b. Clinical Pathologic Correlation: hepatomegaly, ascites, abdominal pain, varying degrees of hepatic dysfunction c. Etiology/Pathogenesis: i. polycythemia vera ii. Pregnancy iii. paroxysmal nocturnal hemoglobinopathy iv. intraabdominal malignancies 2. VENO-OCCLUSIVE DISEASE (VOD) Definition: fibrotic occlusion of small hepatic veins with secondary hepatic congestion. Page 21 of 27

22 a. Pathology: i.. Subintimal edema and hemorrhage involving small hepatic veins ii Centrilobular congestion and hepatocellular necrosis iii Dense perivenular fibrosis, and fibrous obliteration b. Clinical Pathologic Correlation: acute tender hepatomegaly, ascites, weight gain and jaundice c. Etiology/Pathogenesis: i. ingestion of pyrrolizidine alkaloids (herbal teas and contaminated grains) ii. bone marrow transplants (BMT) - 5 % incidence in autologous BMT -25 % incidence in allogenic BMT -drugs, oral contraceptives d. Pathogenesis - sinusoidal endothelial injury IX. TRANSPLANTATION PATHOLOGY A. Drug toxicity: hepatic damage due to drugs given during BMT. Two specific forms of drug injury include VOD and nodular regenerative hyperplasia. B. Graft versus Host Disease (GVHD): Hepatic injury due to attack by immunologically competent transplanted cells with the main targets typically being the GI tract, skin and liver. This usually results after a BMT and the main histologic features of hepatic GVHD are portal inflammation, bile duct damage, cholestasis and endothelialitis. C. Hepatic allograft rejection: Hepatic injury as a result of the recipient's immune system attacking the transplanted donor liver. It may be hyperacute (rare), acute cellular (early in the post-transplant period), or chronic ductopenic (late in the post-transplant period) rejection which result from alloantigens-specific cellular or humoral immune mechanisms. Acute cellular rejection is characterized by portal inflammation, bile duct and endothelialitis. Features of chronic rejection finding include bile duct loss (=ductopenia) and transplant vasculopathy. D. Infections: Due to the immunosuppression, a variety of bacterial, viral, protozoan and fungal infections are common. Page 22 of 27

23 E. Recurrence of primary disease: i.e., recurrence of hepatitis B, hepatitis C or malignant hepatic tumors. X. TUMORS & TUMOROUS CONDITIONS A. TUMOROUS CONDITIONS: 1.Cysts a. multiple intrahepatic cysts 2. Parasitic cysts i. Polycystic disease ii. Congenital hepatic fibrosis iii. Caroli s disease B. FOCAL NODULAR HYPERPLASIA 1. usually solitary, well circumscribed mass 2. usually less than 5 cm. 3. central stellate scar, containing blood vessels, lymphocytes and proliferative bile ducts 4. most commonly seen in year old women 5. association with oral contraceptive use has been a long and hotly debated topic 6. no malignant potential 7. current belief is that it is essentially a vascular malformation with A-V anastomoses and localized overgrowth of all liver constituents C. NODULAR REGENERATIVE HYPERPLASIA Page 23 of 27

24 1. partial or diffuse, nonfibrosing transformation of hepatic parenchyma into hyperplastic nodules 2. associated with a bewildering number and variety of diseases 3. may be a cause of "non-cirrhotic portal hypertension" 4. ifficult diagnosis to make on biopsy, requiring a reticulin stain to appreciate the "nodularity" of the parenchyma D. BENIGN TUMORS: 1. EPITHELIAL TUMOR a. Liver cell adenoma i.. predominately in women of child bearing age ii.. established association with oral contraceptives iii.. may be seen in men on androgen therapy iv.. risk of hemoperitoneum (rupture) v. usually solitary, but may be multiple vi. pale, yellow-tan grossly vii histologically; sheets and cords of normal Hepatocytes viii rarely associated with hepatocellular carcinoma. b. Bile duct adenoma i. may represent aggregates of reactive bile ducts ii. usually subcapsular, small iii. composed of uniform benign epithelial-lined ducts iv. surgeons often biopsy at the time of laparotomy to rule out metastatic disease E. BENIGN NON-EPITHELIAL TUMORS 1. Hemangioma a. most common benign tumor b. complications: bleeding, sequestration of platelets c. dilated vascular spaces with connective tissue support Page 24 of 27

25 2. Hemangioendothelioma a. seen in children b. may be associated with hepatic failure and congestion c.. vessels lined by plump endothelial cells with a supporting fibromyoid stroma F. MALIGNANT PRIMARY HEPATIC TUMORS: 1. HEPATOCELLULAR CARCINOMA (HCC) a. Definition: Primary carcinoma of the liver composed of malignant hepatocytes b. Pathology: i. single, multifocal or diffuse infiltrative, usually bile stained c. Microscopically: i. trabecular, acinar, pseudoglandular patterns ii. bile present iii clear cell and undifferentiated variants d. Clinical Pathologic Correlation: i. vague symptoms of upper abdominal pain, malaise, weight loss ii. serum alpha-fetoprotein (60-70% patients) iii. metastatic disease to lungs, lymph nodes and bones iii. prognosis is poor, but dependent on stage of tumor and clinical status of patient e. Etiology/Pathogenesis i. Hepatitis B/C - World wide incidence of HCC correlates to HBV and HCV infection - HCC most common malignancy in Taiwan and parts of Africa - 200x increased risk in HCC in patients acquiring HBV infection by vertical transmission from mother ii. Aflatoxins - toxic product of Aspergillus flavus and contaminant of food stuff iii. Cirrhosis - important, but not mandatory - associated with Hepatitis B & C, alcohol, iron overload disorders iv. Hereditary Tyrosinemia - Most likely disease to lead to HCC Page 25 of 27

26 - 40% of patients develop tumor despite adequate control 2. FIBROLAMELLAR VARIANT OF HCC a. Definition: A variant of HCC, usually occurring in younger patients b. Pathology: usually single firm mass; malignant welldifferentiated polygonal cells separated by dense collagen bundles c. Clinical Pathologic Correlation: i. age 5-35 years ii 90 % arise in noncirrhotic livers iii non-specific symptoms d. Etiology/Pathogenesis: no clear association with HBV infection 3. INTRAHEPATIC CHOLANGIOCARCINOMA a. Definition: Primary carcinoma of the liver composed of malignant bile duct epithelium which may arise from the large intrahepatic bile ducts at the porta hepatitis to the smallest bile ductules of the periphery of the lobule. b. Pathology: i. single, multiple of diffusely infiltrative c. Microscopically: malignant glandular or tubular structures associated with a dense collagenous stroma, no bile production d. Clinical Pathologic Correlation: i. world wide, cholangiocarcinomas are less common ii. peripheral tumors - usually clinically silent iii. hilar tumors - symptoms of biliary obstruction predominate iv. Klatskin Tumor: Eponym for a cholangiocarcinoma arising at the hepatic hilum, shares many clinicopathologic features with extrahepatic bile duct carcinoma e. Etiology/Pathogenesis i. Thorotrast: radio-opaque agent used years ago to study the liver ii. Parasitic infections: Opisthorchis and Clonorchis iii Fibropolycystic liver diseases: i.e., congenital hepatic fibrosis, Caroli's disease, choledochal cysts 4. HEPATOBLASTOMA a. Definition: The most common primary malignant hepatocellular neoplasms of childhood. b. Pathology: - Solitary masses (5-25 cm) Page 26 of 27

27 - Histologically: immature epithelial cells resembling fetal or embryonic hepatocytes, sometimes with an admixed mesenchymal component c. Clinical-Pathologic Correlation: - usually present within first 3 years of life - hepatomegaly, growing mass - failure to thrive d. Etiology/Pathogenesis: associated with numerous disorders, but no clear etiology 5. ANGIOSARCOMA a. Definition: The most common primary sarcoma of the liver b. Pathology: i. multiple gray hemorrhagic masses (0.1-5 cm) may be a single large mass nonneoplastic liver is usually normal Histologically: proliferation of malignant endothelial cells c. Clinical Pathologic Correlation i. usually occurs in men - 70 years of age ii. nonspecific symptoms; abdominal pain, weight loss iii. may manifest as an acute abdomen due to rupture of the tumor d. Etiology/Pathogenesis: associated with exposure to thorotrast, vinyl chloride and arsenic G. METASTATIC MALIGNANT TUMORS a. Pathology: i. Single or multiple lesions ii.histologically: varies and depends on primary malignancy b. Clinical Pathologic Correlation: Asymptomatic (small lesions) or jaundice and hepatic failure with massive involvement c. Etiology/Pathogenesis: i. Breast, lung and colon for adults: most common ii. Neuroblastoma, Wilms tumor and rhabdomyosarcoma for children Page 27 of 27