Pathology of liver biliary tract and pancreas Assoc

Pathology of liver, biliary tract and pancreas Assoc. Prof. Jan Laco, MD, Ph. D

Hepatology for praxis l 1. Clinicians – complete relevant history of patient – laboratory findings – ultrasonography, … l 2. Pathologist – microscopy findings l 3. Final correct diagnosis

Dystrophic changes 1. Ballooning degeneration l – intracellular edema 2. Cytoskeleton degeneration l – Mallory bodies (CKs) – alcoholic liver disease, NASH, PBC, . 3. Substances accumulation l – glycogen, iron, copper

Dystrophic changes 4. Steatosis – fatty change (TAGs) - hypoxia + toxic injury (alcohol, drugs, poisons) - hepatomegaly, soft, yellow, greasy - macrovesicular (alcohol, DM) - microvesicular (serious) Reye syndrome – children, salicylates, abnormal mitochondria ? - + encephalopathy, mortality 40% acute fatty liver of pregnancy - 3 rd trimestr, jaundice, event. lethal - termination of pregnancy

Hepatic injury 1. monocelullar necrosis - coagulative necrosis – ischemic - apoptosis – toxic, immune-mediated, Councilman bodies 2. focal necrosis – groups of hepatocytes 3. confluent necrosis 3. zonal necrosis - centrilobular (congestion, ALD) x periportal (toxic, eclampsia) 4. bridging necrosis - portal-to-portal, portal-to-central, central-to-central, cirhosis 5. interface hepatitis (piecemeal necrosis) - portal-to-central, immune-mediated 6. submassive necrosis – entire lobulus 7. massive necrosis – almost entire liver - toxic, fulminant hepatitis - acute – subacute – chronic “hepatodystrophy“: yellow-red-grey

Jaundice = yellow discoloration of skin, mucosa, sclera l „icterus“ l bilirubin serum level (> 2. 0 mg/d. L) l unconjugated x conjugated bilirubin l cholestasis – retention of in bile eliminated solutes (bilirubin, bile salts, cholesterol, …)

Jaundice l 1. Unconjugated hyperbilirubinemia (hemolytic, prehepatal icterus) – excessive bilirubin production l hemolytic anemias l ineffective erythropoiesis (pernicious anemia, thalassemia) – reduced hepatic bilirubin uptake l drugs l Gilbert syndrome (some variants) – impaired bilirubin conjugation l physiologic jaundice of the newborn x toxic (Rh) – kern-icterus l Gilbert syndrome ( expression of UGTl. Al) – prev. 7%, AR l Crigler-Najjar syndrome (I and II) – AR – NO / activity of UGTl. Al l diffuse hepatocellular disease (hepatitis, cirrhosis)

Jaundice l 2. conjugated hyperbilirubinemia (obstructive, posthepatal icterus) - decreased hepatic excretion of bilirubin glucuronids - Dubin–Johnson syndrome – AR, pigmented liver (lipofuscin? ) - defect of canalicular transporters - Rotor syndrome – NO liver pigmentation - drugs (OCT) - hepatocellular damage (hepatitis, drugs – anabolics, OCT) - impaired bile flow (obstruction) - intrahepatic (PBC, PSC, Gv. HD) - extrahepatic - gallstones, carcinomas, biliary atresia l 3. mixed hyperbilirubinemia (hepatocellular, hepatal icterus)

Jaundice – laboratory findings l Unconjugated hyperbilirubinemia – unconjugated bilirubin in blood x NO in urine – conjugated bilirubin in bile - dark – urobilinogen in urine l Conjugated hyperbilirubinemia – conjugated bilirubin in blood + in urine - dark – NO conjugated bilirubin in bile - pale – NO urobilinogen in urine l Cholestasis – bile acids, cholesterol – alkalic phosphatase, γ-glutamyltransferase

Hepatic failure Causes: 1. Massive liver necrosis (hepatitis, drugs, poisoning) 2. Chronic liver disease (cirrhosis) 3. Hepatic dysfunction withou overt necrosis - acute fatty liver of pregnancy, Reye syndrome Features: - jaundice hypoalbuminemia – edema (ascites) hyperammonemia foetor hepaticus – sweet-sour hyperestrogenemia – palmar erythema, spider angiomas, gynecomastia coagulopathy (II, VII, IX, X) hepatic encephalopathy – asterixis hepatorenal syndrome – renal failure in hepatic failure, high mortality

Liver disorders in childhood 1. Icterus neonatorum simplex - physiologic jaundice of newborn 2. Icterus neonatorum gravis - Rh incompatibility (hydrops fetalis) 3. Neonatal hepatitis - NOT specific entity - idiopathic, EHBA - AAT, infection (CMV, bacteria, syphilis), drugs, metabolic diseases - conjugated hyperbilirubinemia 4. Congenital cystic malformations of IH bile ducts = Caroli disease /+ congenital liver fibrosis = C. sy

Liver disorders in childhood 5. α 1 - antitrypsin deficiency - AR, low serum level of AAT - cirrhosis + pulmonary emphysema - PAS+ material in hepatocytes 6. Extrahepatic biliary atresia - 1 in 10, 000 - ? acquired inflammatory disorder cirrhosis 7. Reye syndrome - fatty change (liver) + encephalopathy - mitochondrial dysfunction (virus, salicylates) ?

Circulatory disorders 1. impaired hepatic artery inflow - AS, thrombembolism, polyarteritis nodosa - sudden death / intrahepatic branch infarcts 2. portal vein obstruction (pylethrombosis) - pylephlebitis (peritoneal sepsis), hypercoagulation - enlargement of hilar LN, cirrhosis, HCC, … - Banti syndrome – neonatal omphalitis / umbilical vein catheterization splenomegaly - intrahepatic branch – „infarct“ of Zahn (congestion, atrophy)

Circulatory disorders 3. Impaired blood flow through liver - passive congestion / centrilobular necrosis - right-sided c. failure – sinusoids congestion - left-sided c. failure – centrilobular necroses - „nutmeg“ liver - cardiac fibrosis - peliosis hepatis - primary dilation of sinusoids - drugs - complication - hemorrhage

Circulatory disorders 4. Hepatic vein outflow obstruction - hepatic vein thrombosis (Budd-Chiari syndrome) - polycythemia vera, pregnancy, drugs, hepatocellular carcinoma, idiopathic - high mortality - veno-occlusive disease - toxic endothelial injury - fibrotic occlusion of hepatic venules < 1 mm - after BM transplantation, alcaloids, drugs, … - mortality rate … 30%

Hepatitides = diffuse interstitial non-purulent inflammation of liver + injury of hepatocytes l aminotransferases (ALT, AST) l Grossly – non-characteristic, slightly enlarged – yellowish x greenish – hepatodystrophy x fibrosis x cirrhosis

Acute hepatitides l< 6 months l HAV l HBV l HDV l HEV l autoimmune hepatitis l drug injury

Chronic hepatitides > 6 months 1. HBV, event. HBV+HBD 2. HCV 3. drugs 4. autoimmunne hepatitis 5. other viral hepatitides

Viral hepatitides Hepatitis Virus Transmission Chronicity Carriage Fulminant A RNA fecal-oral NO NO 0. 4% B DNA parenteral 5 -10% 1% 1% C RNA parenteral 80% 1% rare D RNA parenteral 5% co 80% super 10% 4% co-i. E RNA fecal-oral NO NO 20% pregnant

Viral hepatitides Hepatitis A virus – i. p. 14 - 45 days, NO HCCa Hepatitis B virus (Dane particle) – HBs. Ag, HBe. Ag, HBc. Ag, DNA polymerase - i. p. 4 - 26 weeks, YES HCCa Hepatitis C virus - i. p. 8 - 12 weeks, YES HCCa Hepatitis D virus - defective virus, i. p. 4 – 7 weeks Hepatitis E virus – endemic in India, Africa, i. p. 1 – 2 months Hepatitis G virus - RNA virus ~ HCV Other viral hepatitides - EBV, CMV, HSV

Hepatocyte injury pathogenesis 1. direct cytopathic effect - hepatitides C and D 2. immune-mediated injury hepatitis B virus presence in cell CD 8 T-lymphocytes cell death - severe course virus elimination - mild (subclinical) course chronic hepatitis carriage

Clinical course 1. carrier state without apparent disease 2. asymptomatic infection - only laboratory signs 3. acute hepatitis - incubation period - preicteric phase – malaise, nausea, headache - icteric phase – jaundice x anicteric course – HBV (50%), HCV - convalescence 4. chronic hepatitis 5. fulminant hepatitis - submassive / massive necrosis

Morphological features 1. acute hepatitis – panlobular location - ballooning, pyknosis of hepatocytes +/- cholestasis, steatosis (HCV) - „ground glass“ hepatocytes (HBV) - necrosis: cytolysis x apoptosis - bridging necrosis - portal inflammation 2. chronic hepatitis – portal location periportal inflammation – lymphocytes, plasma cells - interface hepatitis, bridging necroses - perisinusoidal / periportal fibrosis macronodular cirrhosis -

Autoimmunne hepatitis = chronic hepatitis + immunologic abnormalities - type 1 (85%): anti-nuclear Ab / anti-smooth muscle Ab - type 2 (5%): liver/kidney microsomal type 1 Ab - type 3 (10%): soluble liver/pancreas antigen Ab - female predominance (70%) - NO laboratory signs of viral hepatitis - serum Ig. G level - titers antibodies + other autoimune disease (RA, HT, SS, UC) - corticosteroids - complication – cirrhosis (5% pts. )

Drug- and toxin-induced liver disease Hepatotoxic damage - chloride hydrocarbons, phalloidin, yellow phosphorus, aphlatoxin Idiosyncratic damage – drug (metabolite) hypersensitivity - halothane, chlorpromazine, cytostatics, paracetamol Histological changes - acute and chronic hepatitis – methyl-dopa - zonal necroses / massive necroses - halothane - cholestasis - chlorpromazine - steatosis / steatohepatitis - TTC - fibrosis / cirrhosis – ethanol, methotrexate - granuloma formation - sulfonamides - vascular disorders – veno-occlusive d. , veins thrombosis, peliosis hepatis - tumors – HCA, HCC, cholangiocarcinoma, angiosarcoma

Cirrhosis = irreversible nodular rearrangement of entire liver - hepatocellular death + parenchymal nodules (regeneration) + bridging fibrous septa size: micronodular (< 3 mm) x macronodular (> 3 mm) etiology: 1. alcoholic liver disease (60 -70%) 2. viral hepatitis (10%) – HBV, HCV, HDV 3. biliary diseases (5 -10%) 4. hereditary hemochromatosis (5%) 5. Wilson disease, alpha 1 -antitrypsin deficiency 6. drugs, infancy – galactosemia, tyrosinemia 7. cryptogenic cirrhosis (10 -15%)

Alcoholic liver disease I. alcoholic steatosis (80%) - hepatomegaly (soft, yellow, greasy) - centrilobular macrovesicular steatosis - completely reversible in 2 -4 weeks II. alcoholic steatohepatitis (10 -35%) - hepatocyte swelling / necrosis + Mallory bodies + neutrophils + sinusoidal / perivenular fibrosis III. alcoholic cirrhosis (10%) - brown shrunken organ - micronodular cirrhosis

Non-alcoholic steatohepatitis l NASH l obesity, diabetes mellitus, drugs l increasing incidence l rarely into cirrhosis l most cases of cryptogenic cirrhosis ? ? ?

Biliary cirrhosis I. primary biliary cirrhosis - destruction of IH bile ducts + portal inflammation/scarring cirrhosis - lymphocytic/granulomatous inflammation of IH bile ducts, ductopenia - middle-aged women - anti-mitochondrial Ab (90% pts. ) – pyruvate dehydrogenase (M 2) + SS, sclerodermia, RA, glomerulonephritis, celiac disease II. secondary biliary cirrhosis - prolonged obstruction of EH biliary tree - Mi: ductular proliferation + pigmented material - ascending cholangitis - abscesses

Biliary cirrhosis III. primary sclerosing cholangitis - inflammation + obliterative fibrosis of IH + EH bile ducts + ulcerative colitis (70% pts. ) - middle age -M: F… 2: 1 - p. ANCA (80% pts. ) - Mi: fibrosing cholangitis – fibrous scar clinically: cholestasis (pruritus), jaundice, cholangiography grossly: yellow-green cirrhosis

Hemochromatosis = increased uptake of iron in intestine depositions of hemosiderin liver + pancreas + skin + heart gene HFE, relationship to receptor for tranferin chocolate brown cirrhosis pancreas fibrosis bronze diabetes mellitus skin pigmentations (bronze) cardiomyopathy

Wilson disease = hepatolenticular degeneration disorder of copper metabolism defect at level of ceruloplasmin accumulation: liver + brain + eye cirrhosis basal ganglia (neurologic symptoms) Kayser-Fleischer green brown ring

Liver cirrhosis - complications 1. Portal hypertension (> 10 mm. Hg) - portosystemic shunts - rectum – hemorrhoids - cardioesophageal junction – e. varices - abdominal wall – caput medusae - ascites - splenomegaly - GIT congestion 2. Hemorrhagic diathesis 3. Progressive liver failure 4. Hepatocellular carcinoma

Portal hypertension 1. prehepatic - portal vein thrombosis / stenosis 2. intrahepatic - cirrhosis - massive steatosis - nodular hyperplasia - granulomatous diseases (TBC, sarcoidosis) 3. posthepatic - severe right-sided cardiac failure - constrictive pericarditis - Budd-Chiari syndrome

Neoplasms I. Primary benign tumors 1. cavernous hemangioma - mesenchymal, most common - red-blue soft nodule, subcapsular location !!! percutaneous needle biopsy – bleeding !!!

Neoplasms 2. hepatocellular adenoma - women - oral contraceptives - men - anabolics - well circumscribed pale nodule, several cm - Mi: cords of hepatocyte-like cells, NO portal tracts - rupture (pregnancy – estrogens) - bleeding 3. cholangioadenoma, cholangiohamartoma (von Meyenburg complex) - small multiple subcapsular nodules - Mi: tubular structures (fibrous stroma)

Neoplasms II. primary malignant tumors: 1. hepatocellular carcinoma - Africa, Asia (China), Japan - M : F … 3 -8 : 1, 60 -70 years - chronic hepatitis (HBV, HCV) + cirrhosis + dietary factors - clinically: alpha-fetoprotein - unifocal x multifocal x diffusely infiltrative, yellow-white - invasion of vascular channels ( portal / hepatic veins) - Mi: well / poorly differentiated - fibrolamellar carcinoma – youngs, ~ FNH, prognosis - late metastases – LN, lungs, bones, … - poor prognosis (7 months) cachexia, GIT bleeding, liver failure

Neoplasms 2. cholangiocarcinoma - from epithelium of IH bile ducts - PSC, Thorotrast, Opisthorchis sinensis - Mi: adenocarcinoma + desmoplasia 3. hepatoblastoma - infancy - epithelial +/- mesenchymal component 4. angiosarcoma – mesenchymal, highly malignant - vinyl chloride, Thorotrast 5. metastases - carcinomas of GIT, breast, kidney, malignant melanoma, leukemias, lymphomas

Tumor-like conditions 1. Cysts - in developmental disorders 2. Focal nodular hyperplasia - well circumscribed solitary nodule (2 cm) with central fibrous scar - young adults 3. Nodular regenerative hyperplasia - entire liver, resembling cirrhosis (x fibrous septa) - ? impaired circulation, in various disorders - portal hypertension

Gallbladder I. cholelithiasis (gallstones) - prevalence … 10% - gallstones: cholesterol x pigment x mixed - 1. cholesterol stones (crystalline cholesterol monohydrate): - supersaturated bile with chol. + nucleation (mikroprecipitates of Ca salts) + stasis - age, women, pregnancy, obesity, hyperlipidemia - pale yellow, large, solitary x multiple (faseted surface) - 2. pigment stones (bilirubin Ca salts): - chronic hemolytic syndromes + biliary infection - black, small, multiple - asymptomatic (70 -80% pts. ) x severe „colicky“ pain complications: - cholecystitis - hydrops - biliary enteric fistula (duodenum) – gallstone ileus x perforation – diffuse peritonitis - jaundice (biliary tree obstruction) - acute pancreatitis

Cholecystitis pain, fever, nausea 1. acute calculous cholecystitis (stones present) - enlarged GB, fibrin on serosa, stone in neck - pus in lumen (empyema of GB), gangrenous cholecystitis - Mi: inflammation in the wall 2. acute acalculous cholecystitis (stones absent) - postoperative state, trauma, burns, sepsis 3. chronic cholecystitis (stones present) - from acute cholecystitis x de novo - recurrent attacks - mucosal ulcerations + wall fibrosis / inflammation

Extrahepatic bile ducts I. biliary atresia (see above) II. choledocholithiasis (stones in biliary tree) - from GB x primary III. cholangitis - complication of choledocholithiasis, ascending (Gram- rods) - suppurative - liver abscesses Liver abscess bacteria, fungi, parasites (Echinococcus) source: portal vein x hepatic artery x biliary tree complication: perforation – diffuse peritonitis

Cholesterolosis l common l “strawberry gallbladder“

Neoplasms I. carcinoma of GB - women, 7 th decade, cholelithiasis (+ chronic cholecystitis) - clinically silent – advanced stage - G: exophytic x infiltrating, neck of GB - Mi: adenocarcinoma / squamous differentiation - liver / bile duct invasion + LN + peritoneum, GIT, lung - 5 -year survival: 1% II. carcinoma of EH bile ducts (less common) - older men, PSC - jaundice - G: firm gray nodule in wall x infiltrative - Mi: adenocarcinoma - Klatskin tumor – right and left hepatic duct bifurcation - ampulla of Vater – „ampulloma“

Pancreas I. cysts / cystosis II. cystic fibrosis III. regressive changes (atrophy) IV. pancreatitis V. neoplasms

Cystic fibrosis l most common AR disorder in whites l carrier frequency 1 in 30 l prevalence 1 in 2, 000 l defect glands of secretory process of all exocrine

Cystic fibrosis CFTRs defect of chloride ions transport across epithelium impermeable to chloride ions dehydrated viscid mucus with increased content of Na. Cl l defective l CFTR gene (7 q 31 -32), 300 mutations l 70% patients: δF 508

Cystic fibrosis l GIT - pancreas (80% patients) – viscid mucus in dilated ducts – atrophy (Langerhans islets spared) – fibrocystic disease – malabsorption of fat + vitamins A, D, E, K

Cystic fibrosis l GIT - small GIT glands – newborn: viscid mekonium obstruction of small bowel rupture peritonitis l GIT - bile ducts – secondary biliary cirrhosis l male reproductive tract – infertility (95% males) – vas deferens

Pancreatitis 1. acute interstitial non-purulent pancreatitis - viral inflammation - mumps 2. acute interstitial purulent pancreatitis - rare - ascending x hematogenous 3. acute hemorrhagic pancreatitis / necrosis

Acute hemorrhagic pancreatitis = autodigestion of pancreas (activated pancreatic enzymes) + cellular injury etiology - pancreatic duct obstruction + alcoholism - hyperlipoproteinemia, hypercalcemia, drugs, trauma, shock, viruses - hereditary pancreatitis – AD, predispositiom for carcinoma - proteolysis (trypsin) + fat necrosis (lipases) + hemorrhage (elastases) G: hemorrhage + gray-white necroses fat necrosis (Balser) – chalky, fatty acids + Ca Mi: shadowy outlines complications: - pseudocysts (enlargement), scarring

Chronic pancreatitis = loss of acinar parenchyma + fibrosis ? relationship to acute pancreatitis ? - middle-aged men - alcohol - focal (~ tumor) x diffuse G: firm tissue, duct dilation + secret, calcifications, pseudocysts Mi: acinar atrophy + fibrosis + islets spared complication: - bile duct obstruction – jaundice - exocrine deficiency – malabsorption - DM

Neoplasms of pancreas l 1. Cystadenomas – females – serous x mucinous (benign x borderline x malignant l 2. Intraductal papillary mucinous tumor – males, main ducts – benign x borderline x malignant l 3. Solid-pseudopapillary tumor – young females – locally aggressive, low-grade malignancy l 4. Pancreatoblastoma – malignant tumor in childhood

Carcinoma of pancreas - common - risk factors - smoking - hereditary pancreatitis (40 -fold) - old persons, men, 60 -80 years - asymptomatic x pain, jaundice, migratory thrombophlebitis - head (60 -70%) x body (5 -10%) x tail (20%) x diffuse (20%) G: firm irregular grey-white mass Mi: ductal adenocarcinoma + desmoplasia, +/- mucin local spread (duodenum, retroperitoneum), nerves + regional LN liver, lungs, bones 5 -year survival: < 5%

Endocrine pancreas I. diabetes mellitus - islets atrophy, insulitis, fibrosis, amyloid II. islet cell tumors – rare, neuroendocrine origin - neuroendocrine tumors - pancreas x peripancreatic tissue, small, multiple 1. insulinoma - insulin – hypoglycemia - usually benign 2. gastrinoma - gastrin – severe peptic ulcers – Zollinger-Ellison syndrome - malignant