• 2010‐P8 Systemic Pathology The Liver and the Biliary Tract • Kenichi Ishibashi, M.D. 11/2, 2010 Kenichi Ishibashi, M.D. 11/2, 2010 • • • Inflammation = hepatitis – Portal tracts, lobules Degeneration – Damage from toxic or immunologic insult – Accumulation of substances, e.g., steatosis Cell death: Centrilobular submassive massive necrosis Cell death: Centrilobular, submassive, massive necrosis Fibrosis: Usually irreversible Cirrhosis Hepatic Injury 1 • • • • 2 Cirrhosis Portal Hypertension Bridging fibrous septa ridging fibrous septa Parenchymal nodules Disruption of the architecture of the entire liver Eti l i Etiologies – – – – – – • Prehepatic P h ti – Occlusive thrombosis, narrowing of the portal vein • Intrahepatic – Cirrhosis – Schistosomiasis, massive fatty change, diffuse granulomatous diseases (sarcoidosis miliary TB) (sarcoidosis, miliary Alcoholic liver disease 60% to 70% Viral hepatitis 10% Biliary diseases 5% to 10% Hereditary hemochromatosis 5% Wilson disease rare Cryptogenic cirrhosis 10% to 15% • Posthepatic – Right‐sided heart failure, constrictive pericarditis, hepatic vein outflow g , p , p obstruction Clinical Sequelae • Ascites A it • Portosystemic venous shunts – Esophageal varices Esophageal varices 65% of cases 65% of cases – Hemorrhoids – Caput medusae 3 • Two major functions • Splenomegaly l l • Hepatic encephalopathy 4 Jaundice Bile • Excessive production of bilirubin Excessive production of bilirubin – Elimination of bilirubin, excess cholesterol, and xenobiotics that are insufficiently water soluble to be excreted in urine soluble to be excreted in urine – Emulsification of dietary fat in the gut by bile acids (cholic acid, chenodeoxycholic acid) – Hemolytic anemias, – ineffective erythropoiesis • Reduced hepatic uptake • Impaired conjugation – – – – • Unconjugated → Conjugated • Reabsorbed in terminal ileum (enterohepatic circulation) Dubin-Johnson Syndrome Physiologic jaundice of the newborn Ph i l i j di f h b Crigler‐Najjar syndromes types I and II Gilbert syndrome y Viral or drug‐induced hepatitis, cirrhosis Bile plug • Decreased hepatocellular Decreased hepatocellular excretion – Dubin‐Johnson syndrome, – Rotor syndrome • Impaired bile flow 5 6 7 Viral hepatitis: HAV 8 HBV infection 9 10 HBV serologic markers 11 12 HCV 13 14 15 16 Immunological pathway in viral hepatitis HCV HBV Acute and chronic hepatitis HBsAg Chronic HBV Acute HBV 17 piecemeal necrosis 18 Hepatic Failure Clinical Features Clinical Features • 80% to 90% of hepatic functional capacity must to destroyed must to destroyed • Massive hepatic necrosis – Fulminant viral hepatitis – Drugs and chemicals, e.g., acetaminophen, carbon Drugs and chemicals, e.g., acetaminophen, carbon tetrachloride, mushroom poisoning • Chronic liver disease Chronic liver disease • Hepatic dysfunction without overt necrosis – Acute fatty liver of pregnancy – Tetracycline toxicity Tetracycline toxicity – Reye syndrome • • • • • • • • Jaundice Hypoalbuminemia Hyperammonemia Fetor hepaticus Palmar erythema Palmar erythema Spider angiomas Hypogonadism Gynecomastia 19 20 21 22 Complications p • Multiple organ failure p g • Coagulopathy • Hepatic encephalopathy H i h l h – Metabolic disorder of the CNS – Elevated blood ammonia level and deranged neurotransmission and deranged neurotransmission – Rigidity, hyperreflexia, seizures – Asterixis • Hepatorenal syndrome p y – Idiopathic renal failure Drug Induced Liver Disease g • Liver is the major drug metabolizing and detoxifying organ in the body • Direct toxicity • Hepatic conversion of a xenobiotic (生体異物) to an active toxin • Immune mechanisms 23 24 Alcoholic Liver Disease • Hepatic steatosis – Micro Micro and and macrovesicular – Initially centrilobular • Alcoholic hepatitis – Hepatocyte swelling and necrosis – Mallory bodies y – Neutrophilic reaction – Fibrosis • Alcoholic cirrhosis – Micronodular – Irreversible 25 Nonalcoholic Fatty Liver Pathogenesis • Shunting Shunting of normal substrates away from catabolism toward lipid of normal substrates away from catabolism toward lipid biosynthesis • Induction of cytochrome P‐450 • Free radicals generated by microsomal ethanol oxidizing system • Alcohol directly affects microtubular and mitochondrial function • Acetaldehyde induces lipid peroxidation • Neutrophil infiltration • Immunologic attack of hepatocytes Immunologic attack of hepatocytes 26 • • • • Elevated serum aminotransferase l d f l l levels Low risk for development of hepatic fibrosis or cirrhosis Associated with obesity, type 2 DM, hyperlipidemia Need to exclude other causes 27 28 Hemochromatosis • Primary or hereditary Primary or hereditary – HLA‐linked autosomal recessive disease recessive disease • Secondary – Transfusion dependent – Chronic liver disease Pathogenesis • Total body iron pool 2 to 6 gm T t lb d i l 2t 6 • Primary defect in regulation of intestinal absorption of dietary , g g/y iron, leading to a net iron accumulation of 0.5 to 1.0 g/yr • HFE gene on 6p – Interacts with transferrin receptor of intestinal enterocyte and modulates interaction with transferrin‐iron complexes modulates interaction with transferrin‐iron complexes • C282Y – disulfide bridge disrupted • H63D • Lipid peroxidation, collagen formation, DNA interactions 29 30 Morphology • Deposition of hemosiderin in the liver, pancreas, myocardium, pituitary, adrenal, thyroid and parathyroid glands, joints, and skin • Cirrhosis, micronodular Ci h i i d l • Pancreatic interstitial fibrosis and parenchymal atrophy → DM Cli i l F Clinical Features • M:F = 5‐7:1 • Symptoms usually appear in the fifth to sixth decades of life. ll h ff h hd d flf • Classic triad: cirrhosis with hepatomegaly, skin pigmentation, DM (late in course) DM (late in course) • Cardiac dysfunction, e.g., arrhythmias, cardiomyopathy • Atypical arthritis At i l th iti • Hypogonadism • Tx: phlebotomy, iron chelators T hl b t i h l t Wilson Disease • Autosomal recessive disorder of copper metabolism • ATP7B on chr 13 ATP ATP7B on chr 13 ATP‐dependent dependent metal ion metal ion transporter on the Golgi of hepatocytes • Failure to excrete copper into bile l bl • Copper causes progressive liver injury Copper causes progressive liver injury • Affects brain, cornea, kidneys, bones, joints, and parathyroid glands th id l d • Dx: ↓ serum ceruloplasmin, ↑ hepatic copper p , p pp content, ↑ urinary copper 31 α1‐Antitrypsin Deficiency Morphology y g p p • Liver – fatty change, acute hepatitis, chronic hepatitis, cirrhosis • A Autosomal recessive disorder l i di d p ,p y p • AAT is a protease inhibitor, particularly neutrophil elastase released at sites of inflammation • AAT gene on chr 14 AAT h 14 – Rhodanine stain for copper – Orcein stain for copper‐associated protein • Brain – Basal ganglia (putamen) shows atrophy and cavitation • Eye – Kayser‐Fleischer rings • Aka hepatolenticular degeneration Clinical Features • Manifestations rare before 6 yo Acute or chronic liver disease – most common most common • Acute or chronic liver disease • Neuropsychiatric manifestations • Copper chelation Copper chelation therapy with D‐penicillamine therapy with D penicillamine • Liver transplantation 32 – M allele normal, Z allele abnormal → misfolding of the nascent polypeptide in the hepatocyte ER, accumulation, degradation • Marked cholestasis with hepatocyte necrosis in newborns Childhood cirrhosis • Childhood cirrhosis • Leads to pulmonary emphysema due to tissue destructive enzymes 33 Reye Syndrome • Rare disease characterized by fatty change in the liver and y y g encephalopathy • Children < 4 yo • 3 to 5 days after a viral illness – Associated with salicylate (aspirin) use • P Present with vomiting, irritability or lethargy, hepatomegaly t ith iti i it bilit l th h t l • 25% progress to coma • Death due to progressive neurologic deterioration or liver Death due to progressive neurologic deterioration or liver failure Tx: symptomatic, supportive • Tx: symptomatic, supportive • Liver – microvesicular steatosis – EM – mitochondrial enlargement with disruption of cristae g p • Brain – cerebral edema – Astrocytes swollen, mitochondrial changes • Skeletal muscles, kidneys, and heart may have microvesicular 35 steatosis. 34 Cholestasis • Systemic retention of not y but also only bilirubin other solutes eliminated in bile, particularly bile salts and cholesterol and cholesterol • Due to hepatocellular dysfunction or biliary y y obstruction • Accumulation of bile pigment within the i t ithi th hepatic parenchyma – Kupffer cells • Bile ductular proliferation • Bile lakes • Portal tract fibrosis 36 Primary Biliary Cirrhosis • Middle‐aged women Middle aged women • M:F = 1:10 • Possibly autoimmune – Autoantibodies to mitochondrial pyruvate Autoantibodies to mitochondrial pyruvate dehydrogenase 90% • Insidious onset, usually presenting with pruritus • Hyperbilirubinemia, jaundice, cirrhosis late • ↑ alkaline phosphatase, cholesterol ↑ lk li h h t h l t l 37 Hepatic Artery Inflow Primary Sclerosing Cholangitis • Liver has dual blood supply. • Thrombosis of hepatic artery in transplanted liver → loss of organ • Inflammation, obliterative onion‐skin fibrosis and segmental dilatation of the fibrosis, and segmental dilatation of the obstructed intrahepatic and extrahepatic bile ducts bile ducts • String of beads on ERCP • 70% associated with inflammatory bowel 70% associated with inflammatory bowel disease, particularly ulcerative colitis • M:F = 2:1, third through fifth decades M F 2 1 thi d th h fifth d d • Progressive fatigue, pruritus, jaundice • Chronic course Increased risk for cholangiocarcinoma • Increased risk for cholangiocarcinoma 39 Portal Vein Obstruction 40 I Impaired Blood Flow Through the Liver i d Bl d Fl Th h th Li • Extrahepatic • Cirrhosis • Sickle cell disease • DIC – potentially fatal subcapsular hematoma in pts with eclampsia • Right‐sided heart failure → congestion of centrilobular sinusoids • Left‐sided heart failure → hypoperfusion and hypoxia → centrilobular necrosis • Peliosis hepatis – primary sinusoidal dilation associated with anabolic steroids, danazol, and oral contraceptives – Peritoneal sepsis leads to phlebitis – Lymphatic metastases to hilar lymph nodes y p y p – Pancreatitis leads to splenic vein thrombosis – Postsurgical thromboses Postsurgical thromboses – Banti syndrome umbilical vein catheterization • Intrahepatic thrombus does not cause an ischemic infarction but results in an area of red‐blue discoloration (infarct of Zahn). – Invasive carcinoma Invasive carcinoma – Hepatoportal sclerosis 38 41 42 Hepatic Vein Thrombosis • Aka Aka Budd‐Chiari Budd Chiari syndrome • Hepatomegaly, weight gain, ascites, abdominal pain • Polycythemia P l th i vera or other myeloprolifera‐tive th l lif ti disorders, pregnancy, the postpartum state, oral contraceptive use PNH intra‐abdominal contraceptive use, PNH, intra abdominal cancers, esp. cancers esp HCC • Massive intrahepatic Massive intrahepatic abscess or parasitic cyst abscess or parasitic cyst • Centrilobular congestion and necrosis Shortly after bone marrow transplantation 25% incidence d Subendothelial swelling and reticulated collagen Due to toxic endothelial injury secondary to chemotherapy and radiation therapy • Metastatic carcinomas – most common – Colon – Lung – Breast B • Benign tumors • Primary liver carcinoma – Hepatocellular carcinoma Hepatocellular carcinoma – Cholangiocarcinomas – Hepatoblastoma – Hepatoblastoma children – Angiosarcoma – associated with vinyl chloride, arsenic, or Thorotrast exposure or Thorotrast exposure Veno Occlusive Disease Veno‐Occlusive Disease • • • • Hepatic Neoplasms p p 43 Benign Tumors 44 Liver Cell Adenoma • Cavernous hemangioma – most common – Well Well‐circumscribed circumscribed, subcapsular, < 2 cm subcapsular < 2 cm • Focal nodular hyperplasia – Young to middle aged adults – Poorly encapsulated y p – Central fibrous scar – Response to local vascular injury Response to local vascular injury 45 • Women of childbearing g age who have used oral contraceptives p • Often subcapsular • Sheets and cords of Sheets and cords of hepatocytes • Portal tracts are absent P t lt t b t • Prominent vessels throughout p p • Risk for rupture, esp during pregnancy 46 Pathogenesis g Hepatocellular Carcinoma Hepatocellular Carcinoma • Infection with HBV • Annual incidence Annual incidence – Genomic instability with integrated HBV DNA – Integration pattern is clonal – HBV X‐protein disrupts cell cycle control – Certain HBV proteins inactivate p53 – Americas, Northern Europe, Australia 3‐7 cases/100,000 /100 000 – Southern Europe 20 cases/100,000 – Southeast China, Taiwan 150 cases/100,000 • Chronic liver disease, esp HCV and Etoh – Cirrhosis plays an important role. • HBV carrier since infancy = 200 fold risk • Hepatocarcinogens in food (aflatoxins from the fungus Aspergillus flavus) • Repeated cycles of cell death and regeneration, i.e., chronic hepatitis, with g p possible mutations • Cirrhosis in 85% to 90% vs 50% • M:F = 3:1 vs 8:1 MF 31 81 • Sixth to seventh decades vs third to fifth 47 48 HCC Morphology p gy • Unifocal, multifocal, or infiltrative • Strong propensity for vascular invasion – Portal vein or IVC involvement • • • • Well‐differentiated – intracellular bile Scant stroma → soft Scant stroma → soft Metastasizes to LN, lung, bone, adrenal Fibrolamellar carcinoma – 20 20‐40 40 yo, M yo, M=FF – No assoc. with cirrhosis or other risk factors – Tumor cells separated by dense collagen Tumor cells separated by dense collagen – Better prognosis 49 50 51 52 Clinical Features Rapid increase in liver size Sudden worsening of ascites Appearance of bloody ascites, fever, pain Appearance of bloody ascites, fever, pain ↑ serum AFP, esp if > 1000 ng/ml Median survival 7 months Death due to GI or esophageal variceal Death due to GI or esophageal variceal bleeding or liver failure with hepatic coma • Surgical resection for smaller tumors l f ll • • • • • • – Recurrence rate 60% at 5 yrs y • Liver transplantation Cholelithiasis Clinical Features • Very common V • Cholesterol stones • • • • – Bile is supersaturated with cholesterol – Gallbladder stasis Gallbladder stasis – F>M – Obesity – Advancing age Asymptomatic Biliar colic Biliary colic Cholecystitis Gallstone ileus • Pigment Pigment stones stones – calcium bilirubinate salts – Asian more than Western – Chronic hemolytic Chronic hemolytic syndromes 53 54 • Acute calculous Acute calculous – – – – Choledocholithiasis • Stones within the biliary tree Cholecystitis • • Obstruction of GB neck or cystic duct RUQ pain radiating to right shoulder F Fever, nausea, leukocytosis l k t i Potential surgical emergency • W t from gallbladder West – f llbl dd Asia – primary ductal and intrahepatic stone formation S Symptoms due to: t d t – – – – • Acute acalculous – seriously ill pts y p • Chronic Biliary obstruction Pancreatitis Cholangitis Hepatic abscess – Recurrent attacks of pain – Nausea and vomiting N d iti – Associated with fatty meals 55 56 Biliary Atresia y Cholangitis g • 1/3 of cases of neonatal cholestasis • 1 in 10,000 live births • Complete obstruction of bile flow caused by Complete obstruction of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts extrahepatic bile ducts • Acquired inflammatory disorder • Normal stools to acholic stools • Bile ductular proliferation on liver bx Bile ductular proliferation on liver bx • Cirrhosis by 3 to 6 months of age. • Require liver transplantation • Acute inflammation of bile ducts • Due to biliary obstruction, usually choledocholithiasis • Bacterial infection from gut, i.e., gram negative aerobes negative aerobes – Fever, chills, abdominal pain, jaundice • Latin America and Near East: Fasciola hepatica, d l h schistosomiasis • Far East: Clonorchis sinensis, Opisthorchis viverrini • AIDS: cryptosporidiosis 57 Gallbladder Carcinoma 58 Cholangiocarcinoma g SSeventh decade hd d F>M Discovered at late stage, usually incidental Exophytic and infiltrating types Adenocarcinoma Local extension into liver, cystic duct, portahepatic LNs h i LN • Mean 5 yr survival 1% y • • • • • • • • • • • • • • 59 Older pts M>F Painless jaundice N/V weight loss Painless jaundice, N/V, weight loss Opisthorchis sinensis (liver fluke), PSC, inflammatory bowel disease Tumors usually small at dx yet not resectable Tumors usually small at dx yet not resectable Klatskin tumor – arises at bifurcation Adenocarcinoma Mean survival 6 to 18 months Mean survival 6 to 18 months 60