Pathology of the Liver and Biliary Tract V. Žampachová I. PAÚ Hepatopathy nprediagnostic stage, some suspicious signs present ndetailed diagnosis necessary, varied examination possibilities nclinical findings nlaboratory findings nimaging procedures nmorphological findings Diagnostic steps nprimary x secondary liver disease ndiffuse x focal liver disease nif icterus present → pre-, intra-, posthepatic ntype of pathologic change: hepatitis, fibrosis, advanced - cirrhosis, cholestasis, focal lesion, tumor, … Diagnostic steps netiology: genetic, metabolic, toxic, immunologic, vascular, infection, … nstage: prodromal, acute, chronic (> 6 months), cured nactivity of the process, course (regressive, stationary, progressive), prognosis n n n Remarks on pathophysiology ndifferent forms of blood flow nportal arteries, portal veins nsinusoids lined by fenestrated endothelial cells + limited amount of extracellular matrix, incomplete BM: slow, low-pressure mixed blood flow → enough time for adequate contact of plasma substances with hepatocytes → physiological solute exchange with resorption, excretion ncentral veins: low-pressure venous blood Remarks on pathophysiology nPathological conditions with blood flow/resistance alteration → hepatocyte dysfunction: n↑ blood pressure in central veins (thrombosis, heart failure, etc.) → ↑ BP in sinusoids → transformation of lining cells, loss of fenestration → ↓ solute exchange → hepatocyte dysfunction ninflammation → activation of ECM producing cells → deposition of collagen between endothelial cells and hepatocytes → ↓ solute exchange → hepatocyte dysfunction nshunts between arteries and veins → bypass of lobules n n Patterns of hepatic injury nhepatocyte degeneration and/or pathologic intracellular accumulation (i. e. fatty liver, pigment, …) nhepatocyte necrosis, apoptosis nvascular remodeling ninflammation nregeneration nfibrosis nneoplasia Histopathology nHistological evidence of: nliver cell degeneration or death ninflammatory reaction nregenerative changes nothers n nDiagnostic changes to some extent specific to the causative agent. n nPattern and type of liver cell damage important n Patterns of liver cell death F73341-016-f004 copy Necrosis distribution nInterface hepatitis (piecemeal necrosis) - periportal hepatocytes, mostly in chronic hepatitis, ↑ risk of cirrhosis nCentrilobular → necrosis around central vein (ischaemia; toxins; drugs) nBridging - severe inflammation or toxins nPortal-to-portal nPortal-to-central nCentral-to-central nPanacinar necrosis nentire acinus ndiffuse → liver failure, risk of immediate death. n n Liver necrosis (acetaminophen) Liver necrosis (acetaminophen) Hepatocyte necrosis 11mr Necrosis - repair nNecrosis n nCoagulative → eosinophilic hepatocytes without nuclei (ischaemia) nApoptosis → death of individual liver cells, pyknosis nmost frequent pattern in viral hepatitis nusually possible recovery ntoxic; immunologic nLytic necrosis → hepatocytes swell and rupture n n Fibrosis n n nResponse to inflammation nMostly irreversible (under favorable conditions reversible to some extent) nIntrasinusoidal deposition of collagen → effects on hepatic metabolism and blood flow nIn/around portal tracts or central veins → spreads → links other regions (bridging fibrosis) nBasic lobular architecture partially preserved n n Advanced stage of chronic liver disease („cirrhosis“) n n nComplete loss of original architecture nRegenerating groups of hepatocytes surrounded by fibrotic scar tissue nDue to continued parenchymal injury and fibrosis nCommonly end form of severe liver disease nA process, possible reparative/regeneratory changes and/or worsening of the lesion n nMost severe clinical consequence of liver disease n nResult of: nSudden and massive hepatic destruction nEnd-point of progressive liver damage (insidious or repeated) n nResults in: nInadequate synthesis of albumin, clotting factors, etc nFailure to eliminate endogenous products (e.g. ammonia, bilirubin; hormones) n nOften triggered by intercurrent disease: nSystemic infections nElectrolyte disturbances nStress (e.g. surgery) nGIT bleeding n n Liver failure Liver failure nAcute liver failure: acute illness → encephalopathy + coagulopathy ≤ 6 months (fulminant ≤ 2 weeks). Massive hepatic necrosis and/or massive steatosis. nFulminant hepatitis (viral, autoimmune) nDrugs and chemicals, e.g., acetaminophen, carbon tetrachloride, mushroom poisoning. Alcohol. nBiliary obstruction, commonly due to gallstones. nDirect physical injury to the liver (e.g. laceration in a road traffic accident) nVascular lesion n Hepatic dysfunction without overt necrosis nAcute fatty liver of pregnancy nTetracycline toxicity nReye syndrome n Acute liver failure nPossible recovery from acute liver injury (focal or diffuse) due to the capacity of the organ for cellular regeneration. nLoss of a part of the liver – regrowth, regeneration nLoss of the basic structure - repair n nThe same agent may produce either an acute or a chronic illness, commonly without any preceding clinically evident acute phase. n Chronic liver failure nChronic liver disease → advanced stage of chronic hepatitis, biliary diseases, … nMassive neoplastic infiltration. nFunctional stage important nwell compensated npartially decompansated ndecompansated n n Hepatic signs nHepatomegaly – hepatitis, intracellular accumulation, focal lesion nJaundice – hyperbilirubinemia un-conjugated, + event. dark urine, acholic pale faeces, pruritus nOedema - ↓ protein synthesis, hypoalbuminemia nAscites – portal hypertension + hypoalbuminemia nSplenomegaly - portal hypertension + immune reactions, possible → anemia, thrombocytopenia n Hepatic signs nBleeding - ↓ clotting factors + fibrinolysis inhibitors synthesis nVarices (oesophagus, cardia, caput Medusae) - portal hypertension nSpider naevi, gynecomastia, impotence, palmar erythema – hyperoestrogenism nHepatorenal syndrome - idiopathic renal failure (cortical vasoconstriction, acute tubular necrosis) nEncephalopathy - ↓ detoxification, complex metabolic disorder of the CNS, neuromuscular synapses nElevated blood ammonia level and deranged neurotransmission nRigidity, hyperreflexia, seizures n n n Portal hypertension nPrehepatic nOcclusive thrombosis (tumor, drugs), narrowing of the portal vein (inborn, acquired external pressure…) nIntrahepatic nAdvanced stage of liver disease (cirrhosis) nSchistosomiasis, massive fatty change, diffuse granulomatous diseases (sarcoidosis, miliary TB), massive neoplastic infiltration nPosthepatic nRight-sided heart failure, constrictive pericarditis, hepatic vein outflow obstruction F73341-016-f016 copy Portal hypertension complications nVarices (+ rupture, shunting of toxic products into systemic circulation – ammonia, bacterial by-products – hepatic foetor) nGIT venous congestion → gastric, intestinal phlegmona nAscites commonly + infection - peritonitis nHepatopulmonary sy – dyspnoea, respiratory insufficiency n Cholestasis nResults from: n nHepatocellular dysfunction nBiliary obstruction n nSigns: n nPruritus (↑ serum bile acids) nHyperlipidaemia → skin xanthomas (focal cholesterol accumulation) nMalabsorption → ↓ fat soluble vitamins (A; D; K) n↑ serum alkaline phosphatase n n n n n Cholestasis nMorphology: nAccumulation of bile pigment in hepatic parenchyma nElongated green plugs of bile visible in dilated canaliculi → rupture → extravasion of bile into sinusoids → phagocytosed by Kupffer cells nOedema, periductal neutrophilic infiltrates in portal tract nProlonged obstruction → portal tract fibrosis → biliary cirrhosis n Cholestasis Developmental abnormalities - structural nLess common nAnatomical anomalies nlobar agenesis, anomaly of position, ectopic liver tissue (diff. dg. x tumor) nVascular anomalies naccessory artery, congenital shunts, obstruction; hereditary haemorrhagic teleangiectasia (aneurysms, meshwork of dilated small vessels in various organs) Developmental abnormalities nBile-duct anomalies nbiliary atresia – mostly extrahepatic, possible fetal viral infection, treatment by anastomosis or transplantation n ncongenital dilatation of the bile duct – cysts, autosomal polycystic disease (recessive x dominant) n nbiliary hamartoma – small lesion, slow growth/dilatation, commonly superficial - pseudotumor Polycystic disease n Metabolic disorders nCommonly genetic enzymatic defects (Wilson disease, hemochromatosis, porphyria, etc.). nPrimary hepatic manifestation (accumulation of a metabolite due to an enzymatic defect – i.e. sphingomyelin). nSecondary hepatic manifestation (liver changes resulting from extrahepatic pathology). n nPossible acquired accumulation of various substances (i.e. secondary hemosiderosis, amyloidosis). n n Metabolic liver diseases nHemochromatosis – iron overload nWilson disease – copper overload nBilirubin metabolism defects na1-antitrypsin deficiency nStorage disorders (glycogenoses, mucopolysaccharidoses, lipidoses,…) Hemochromatosis nPrimary or hereditary hemochromatosis nHLA-linked autosomal recessive disease n Primary defect in regulation of intestinal absorption of dietary iron, iron accumulation of 0.5 to 1.0 g/yr (total body iron ~ 2-6g), heterozygous → increased Fe absorption, homozygous → dangerous levels nHeterozygous: 8-10% of West-, North-, Middle Europe nHomozygous: incidence approx. 1 : 300-400 nPossible accelerated progression of other chronic liver diseases (alcohol liver disease, etc.) nTherapy: venesection Hemochromatosis nDeposition of hemosiderin in the liver, pancreas, myocardium (congestive heart failure), pituitary, adrenal, thyroid and parathyroid glands, testes, joints (arthritis), and skin („bronze diabetes“) nChronic hepatitis → micronodular cirrhosis nSignificant risk for HCC (hepatocellular carcinoma) nPancreatic interstitial fibrosis and parenchymal atrophy → DM n n n Secondary hemosiderosis nTransfusion dependent nIneffective erythropoiesis with increased erythroid activity nExcessive oral Fe intake (supplements) nChronic liver disease (alcohol hepatitis - ↑ Fe absorption, chronic hepatitis C) n The dark brown color of the liver, the pancreas, lymph nodes due to extensive iron deposition in hereditary hemochromatosis copy Hemochromatosis nDiff. dg. of brown pigment within the liver nFe (hemochromatosis) nCu (Wilson’s disease) nlipopigment (brown atrophy of liver, lipopigment dystrophy) nbile (cholestasis) Wilson disease nHepatolenticular degeneration nAutosomal recessive disorder of copper metabolism nFailure to excrete copper into bile nCopper → progressive liver injury nAffects brain, cornea, kidneys, bones, joints, and parathyroid glands nDg: ↓ serum ceruloplasmin, ↑ hepatic copper content, ↑ urinary copper Wilson disease - morphology nLiver – fatty change, acute hepatitis, chronic hepatitis, cirrhosis nRhodanine stain for copper nOrcein stain for copper-associated protein nBrain – Basal ganglia (putamen) atrophy and cavitation nEye – Kayser-Fleischer rings, green-brown deposition of Cu in cornea Wilson disease - clinical nManifestations rare before 6 yrs nAcute or chronic liver disease – most common nNeuropsychiatric manifestations nPossible haemolytic attack nCopper chelation therapy with D-penicillamine nLiver transplantation Wilson’s disease : Cu pigment 7mr α1-antitrypsin deficiency nAutosomal recessive disorder nAAT - a protease inhibitor, particularly neutrophil elastase released at sites of inflammation nLiver changes (cholestasis + necrosis even in newborns, children or adults – chronic hepatitis → cirrhosis, ↑ risk of hepatocellular carcinoma) n n nPulmonary emphysema due to tissue destructive enzymes (!combination of factors in smokers) α1-antitrypsin deficiency + HCC Liver AL amyloidosis Liver AL amyloidosis Kappa light chain IHC Hepatitis: etiology nInfectious (acute, chronic) nviruses (most common, hepatotropic - hepatitis viruses; systemic – EBV, CMV, HSV, yellow fever – similar to „viral hepatitis“, rubella, enteroviruses, …) nbacteria (pyogenic bacteria, TBC, malaria, salmonelosis, leptospirosis,…) nparazites (ecchinococcus, schistosoma, …) nprotozoal (amebiasis) n nNon-infectious (acute, chronic) nautoimmune nmetabolic ndrug induced ncryptogenic n n ü ü Viral hepatitis n nhepatitis viruses immunologically distinct → infection usually confers life-long immunity to the specific type/subtype of the infecting virus but not to the others nexceptions - HCV n n nAb detection: IgM → acute disease; n IgG → memory cells n Clinical types nCarrier (?) state – low level asymptomatic infection nHarbours virus (can transmit) nNo apparent disease; sub-clinical symptoms (mostly non-progressive, variable histology) nNormal serum transaminase n nAsymptomatic infection nIncidental identification, acute or chronic, variable histology nfluctuating or ↑serum transaminase, + antiviral antibodies n nAcute viral hepatitis nIncubation → non-specific preicteric phase → (specific icteric phase) → convalescence or chronicity n nChronic viral hepatitis nAsymptomatic, biochemical or serological evidence of continuing or relapsing hepatic disease (> 6 months) nViruses - major cause, may be combination with other factors (alcohol) nVariable clinical features with mostly increased aminotranferase Viral hepatitis: course §Acute (HAV, HBV, HCV, HDV, HEV) §Fulminant (HAV, HBV, HEV) §Chronic (HBV, HBV + HDV, HCV; rare HEV, exceptional HAV) •risk of advanced stage disease/cirrhosis development •risk of hepatocellular carcinoma development Hepatitis A virus nSmall, non-enveloped, single stranded RNA piconovirus nBenign self-limiting disease (usually) nMostly epidemic → poor hygiene and sanitation nFaecal-oral transmission ncontaminated food or drink nVirus shed in stool 2-3 weeks before + 1 week after onset of jaundice nRelatively short incubation period (2-6 weeks) nMild or asymptomatic → benign, self-limiting; rare fulminant nVirus not directly cytophatic to hepatocytes nCD8+, NK immunologically mediated damage of infected cells nMostly no chronic hepatitis or carrier state, AIH trigger? nDiagnosis nIgM-anti-HAV-Ab → acute illness; viral shedding nIgG-anti-HAV-Ab → life-time immunity; previous exposure n Hepatitis B virus nTransmission nblood, body secretions contact (sexual, exceptionally saliva; tears, ) nvertical transmission n n nRelatively long incubation period: 4-26 weeks n nRemains in blood during active episodes of acute or chronic hepatitis, present in all physiological or pathological body fluids (except stool) n n2 phases of HBV infection – proliferative, integrative n n HBV pathology nInfection - HBsAg on the cell surface nRecognition by the immune system - infected cells destroyed nImpaired immunity or tolerance to the antigen – no apparent damage - asymptomatic carriers – transmission possible nhepatocytes with ground-glass cytoplasm - HBsAg nHBeAg, nuclear HBcAg – active replication Hepatitis B virus n nPossible natural courses: n nAcute hepatitis with recovery + virus clearence (~ 90%) nFulminant hepatitis with massive necrosis (0,5%) nChronic hepatitis (~5%) → recovery - rare nProgressive chronic disease → cirrhosis (≤ 20%), HCC nAsymptomatic carrier state → with or without progressive sub-clinical disease n Hepatitis C virus nSingle stranded RNA virus → Flaviviridae nMultiple types, subtypes; defective replication → quasispecies, no vaccination yet n nTransmission: nintravenous drug abuse, blood contamination (close contact), blood products, sexual (rare), vertical n nIncubation period → 2-26 weeks n nAcute mostly asymptomatic, > 80% into chronicity, ~ 20-30% → cirrhosis nHCV RNA detectable in blood in 1-3 weeks ntypical fluctuating aminotransferase levels, even in asymptomatic n n Hepatitis D Virus nDouble strated coat nHBs-Ag → coat → co-infection nHDV-Ag → RNA nTransmission → parental nIncubation → 4 – 7 weeks nRarely cause fulminant or chronic hepatitis n n2 settings nAcute co-infection → HBV & HDV in serum nSupra-infection in chronic HBV carier state n Hepatitis E Virus nNon-enveloped, single stranded RNA virus nWater-borne agent → enterically transmitted → virion in stool nMost common in tropic regions (India, Egypt); association with pigs; rising incidence in Europe nIncubation period → 2 – 8 weeks nUsually self-limiting → full recovery is usual nUsually not associated with chronic liver disease or persistent viraemia nHigh mortality rate amongst pregnant woman n Acute hepatitis: HBV 22mr Edema, hyperemia. Necrosis and lobular collapse - areas of hemorrhage and irregularities on the cut surface of the liver. Morphology - gross Morphology nHepatocyte degenetrative changes – ballooning nHepatocyte apoptosis (eosinophilic bodies) nPortal inflammatory infiltrate + edema nInterface hepatitis – infiltrate + death of periportal hepatocytes nPossible confluent/bridging necrosis nPossible cholestasis in hepatocytes and/or bile canaliculi nKupffer cell reaction + hyperplasia nRegenerative changes Morphology nHAV – numerous plasmocytes nHBV – ground-glass hepatocytes nHCV – hepatocyte fatty change, ductal damage Viral hepatitis: HBsAg, ground glass 9mr Viral hepatitis: HBsAg, Orcein staining 10mr Viral hepatitis: HBcAg, immunohistochemistry HBcAg Acute hepatitis 24mr Acute hepatitis: regeneration 26mr Fulminant hepatitis nGrossly: soft consistency nMicroscopic: complete necrosis of parenchyma nCourse: nliver failure - coma - death n transplantation nregeneration – postnecrotic cirrhosis n n n Fulminant hepatitis: HBV 76mr Other infections nViruses – EBV, CMV (in immunosuppressed) nMalaria nSchistosomiasis nLeishmania Liver abscess nLow-income countries nParasitic liver abscesses more common nE.g. amoeba; helmithic n nHigh-income countries nBacterial or fungal origin more common nComplication of infections elsewhere or systemic n nOrganisms reach liver via nAscending infection in biliary tract (ascending cholangitis) nVascular seeding à portal or arterial nDirect liver invasion from nearby source nPenetrating injury n Liver abscess nRisk factors: debilitating disease with immunodeficiency: nImmunocompromised nChemotherapy nOld age nBone marrow failure n nPyogenic bacteria hepatic abscesses nSolitary or multiple lesions nSmall to masssive in size n n Liver abscess nClinical features nFever nTender hepatomegaly nJaundice (biliary obstruction) n nAntibiotic, antimycotic, antiparasitic nSurgical (drainage, resection) often necessary n nDiagnosis difficult, often delayed → 30 – 90% mortality rate Granulomatous inflammation nInfections – tbc, typhoid, 3rd stage of syphilis, fungal, parasitic nSarcoidosis nGranulomas as part of other diseases (primary biliary cholangitis, drug reaction,…) Sarcoidosis n Reye syndrome nRare disease characterized by fatty change in the liver and encephalopathy nChildren < 4 yo n3 to 5 days after a viral illness nAssociated with salicylate (aspirin) use nPresent with vomiting, irritability or lethargy, hepatomegaly n25% progress to coma nDeath due to progressive neurologic deterioration or liver failure nTh: symptomatic, supportive Chronic hepatitis: etiology nHepatotropic viruses nSteatohepatitis – alcoholic, non-alcoholic NASH nAutoimmune nDrug induced nMetabolic (Wilson disease, hemochromatosis, a1- antitrypsin deficiency) nCryptogenic n n Chronic hepatitis: clinical definition nClinical symptoms of hepatitis more than: n6 months n12 months in HCV Chronic hepatitis - histopathology nDisease activity: grade of necroinflammatory changes in portal spaces and lobules (interface activity; type, grade and localisation of necrosis; grade of inflammatory infiltrate) n nDisease stage: stage of fibrosis and architectural changes (portal fibrotic expansion, bridging fibrosis, nodularity → advanced stage/cirrhosis) Chronic hepatitis - histopathology nOther changes, sometimes significant for specific etiology (portal lymphocytic aggregates in HCV, central perivenular and pericellular fibrosis in alcoholic hepatitis, typical inclusions, etc.) Chronic hepatitis: high grade 29mr Toxic and drug induced liver damage: effect nMost substances completely or partially metabolized in liver → wide area for possible pathologic reactions and changes nInjury due to nDirect toxicity nConversion of drug/non-endogenous substance to active toxin nImmune mechanisms → drug/toxin acting as a hapten nAcute or chronic. § §Expectable (intrinsic): typical reaction, known for drug/dose/patient (i.e. acetaminophen) §Non-expectable (idiosyncratic): atypical immunologic reaction, non-preventable, often combination of multiple factors Toxic and drug induced liver damage §Anorganic substances §Organic substances §Industrial substances §Poisons/venoms §Drugs §Alcohol ü Liver necrosis - paracetamol Toxic and drug induced liver damage : forms nGenerally any form of damage possible (diff. dg.!) §Necrosis (acetaminophen/paracetamol) §Steatosis n macrovesicular (alcohol, corticoids) n microvesicular (tetracyklin, aspirin) §Cholestasis (steroids-anabolic, contraceptives) §Hepatitis mild (aspirin, synthetic penicilines) §Hepatitis serious (halotan) §Chronic periportal hepatitis (sulphonamides) Toxic and drug induced liver damage : forms § §Granulomatous hepatitis (phenylbutazone) §Vascular lesions (contraceptives, cytostatics) §Hyperplasia, neoplasia (contraceptives) § Alcoholic liver disease (ALD) nSteatosis (90%) nAcoholic steatohepatitis nAlcoholic cirrhosis nHepatocellular carcinoma n nDiff. dg: NAFLD/NASH (non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis) Alcoholic liver disease nAlcohol abuse: common cause of serious liver disease in Western societies nAsymptomatic people who drank moderate-to-heavy amounts of alcohol: prevalence of alcoholic hepatitis - 25-30%. nthe 1-year mortality rate after hospitalization for acute alcoholic hepatitis is approximately 40%. Alcoholic liver disease nEstimated minimum daily ethanol intake required for the development of cirrhosis: n40 g for adult males n20 g for adult females ndifferent individual susceptibility (genetic, environmental) nPatients who continue to drink after a diagnosis of alcoholic liver disease: n5-year survival rate ~ 30% for females n70% for males Alcoholic liver disease (ALD) : steatosis 5mr Steatohepatitis Alcoholic hepatitis nsyndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol nsubacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (eg. jaundice, coagulopathy), and manifestations of portal hypertension (eg, ascites, hepatic encephalopathy, variceal hemorrhage). Alcoholic hepatitis nCentrilobular ballooning necrosis of hepatocytes, neutrophilic infiltration, Mallory hyaline inclusions. Steatosis and cirrhosis frequent. nUsually persists and progresses to advanced stage/cirrhosis if heavy alcohol use continues nAlcohol consumption may exacerbate injury caused by other pathogenic factors, incl. hepatitis viruses. Alcoholic hepatitis Mallory-Denk bodies: globular red hyaline material within hepatocytes, not entirely specific for alcoholic etiology. Alcoholic hepatitis : steatohepatitis, cholestasis, Mallory-Denk bodies 39mr NAFLD/NASH: non-alcoholic fatty liver disease/steatohepatitis nSpreading silent epidemics nIn many countries the most common chronic liver disease nPatients with metabolic/insulin resistance syndrome: n„male-type“ obesity (intraabdominal fat accumulation – waist size) nhyperlipidemia nDM of II type, hyperglycaemia n n NASH: non-alcoholic steatohepatitis nOther diseases related to NASH nAcquired metabolic diseases (parenteral nutrition) nInherited metabolic diseases (abetalipoproteinaemia, tyrosinaemia) nSurgery (jejunoileal bypass, extensive resections of small intestine...) nDrugs, toxins (amiodarone, glucocorticoids, tamoxifen, synthetic estrogens…) NASH: non-alcoholic steatohepatitis nHepatomegaly nIncrease of aminotransferases (ALT>AST) nHistology – similar to alcoholic hepatitis without alcohol consumption, glycogenated „clear“ nuclei of hepatocytes, … nNatural history – may lead to advanced stage/cirrhosis, etc. Autoimmune hepatitis - AIH nChronic disease of unknown cause, continuing hepatocellular inflammation and necrosis → advanced stage/cirrhosis nImmune serum markers frequently present, common association with other autoimmune diseases. AIH n70-80% of patients are women nacute hepatitis, chronic hepatitis, or well-established advanced stage/cirrhosis. nsymptoms of acute hepatitis marked by fever, hepatic tenderness, and jaundice. nnon-specific signs: pruritus, skin rash, myalgia, diarrhea, etc. AIH nHepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells nCirculating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver antigen, hepatic lectin) nAssociation with hypergammaglobulinemia and the presence of a rheumatoid factor nResponse to steroid and/or immunosuppressive therapy nBy progressive + relapsing disease - transplantation Advanced stage liver disease/Cirrhosis nAlcoholic liver disease (60%, rising tendency) n nViral hepatitis → HBV, HCV (10%, HBV↓, HCV expected ↓ - antivirotics) n nHereditary haemochromatosis n nAutoimmune liver disease nAutoimmune hepatitis nPrimary biliary cholangitis (PBC) n nRecurrent biliary obstruction (5-10%) n nWilson disease; AAT deficiency (rare) n nCryptogenic (hidden) cirrhosis, usually former NASH (10-15%, ↑) n n Pathogenesis nHepatocellular death → regeneration → recurrent death → nodularity lacking zonal structure n nProgressive stimulus for synthesis + deposition of collagen (chronic inflammatory cytokine production, direct stimulation of stellate cells) → fibrosis n nShunts develop → sinusoids become high pressure, fast flowing vascular channels → no solute exchange n n Morphology nMicronodular cirrhosis nNodules <3mm diameter, common in alcoholic hepatitis; late stage of cirrhosis with low activity n nMacronodular cirrhosis nNodules >3mm diameter, uneven changes, early stage of active cirrhosis n nMixed cirrhosis nIntermediate between the above categories, in progression n nPattern not stable, possibility of progression and/or regression n Advanced stage / Cirrhosis 57mr Advanced stage / Cirrhosis 43mr Advanced stage / Cirrhosis n Advanced stage / Cirrhosis n Advanced stage / Cirrhosis: Masson staining 44mr Advanced stage / Cirrhosis: biliary 48mr CT scan with contrast of the abdomen in transverse view demonstrates a small liver with cirrhosis. The spleen is enlarged from portal hypertension. copy Pathology of intrahepatic bile ducts nInborn defects nCholelithiasis nInflammation – infection – cholangitis, usually ascending. n Secondary biliary cirrhosis n nImmunologically mediated inflammatory disorders nPrimary biliary cholangitis (PBC) nPrimary sclerosing cholangitis (PSC) n nPreneoplastic lesions + tumors n n Cholangitis ninfection of the biliary tract ncholedocholithiasis → biliary tract obstruction → cholangitis. nbiliary tract interventions and stents - common causes of cholangitis. nhepatobiliary malignancies Cholangitis nTriad of fever, jaundice, and right upper quadrant pain. nMultiple organisms in 60% of patients. Aerobic Escherichia coli, Klebsiella, Enterococcus; anaerobic Bacteroides fragilis. Primary sclerosing cholangitis - PSC nprogressive chronic liver disease - cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts → cirrhosis nunknown etiology nautoimmune mechanism nsome cases part of IgG4-associated systemic sclerosing disease n75-90% of patients with PSC have inflammatory bowel disease (IBD). nexposure of genetically predisposed individuals to an environmental antigen that subsequently elicits an aberrant immune response Primary sclerosing cholangitis - PSC nThe median length of survival from diagnosis to death ~ 12 years. n70% of patients with PSC males, nMean age of diagnosis around 40 years nHistology: inflammation and obliterative fibrosis of large intrahepatic/extrahepatic bile ducts. Concentric periductal fibrosis. nRisk of cholangiocellular carcinoma (diff. dg.!) PSC – duct destruction PSC – peribiliary fibrosis Primary biliary cholangitis PBC nMiddle-aged women nM:F = 1:10 nAutoimmune (AMA), + other AI -Sjögren sy., arthritis, thyreoiditis, vasculitis nInsidious onset, usually pruritus, hepatomegaly nHyperbilirubinemia, jaundice, cirrhosis late n↑ alkaline phosphatase, cholesterol nNonsuppurative, granulomatous destruction of medium-sized intrahepatic bile ducts = florid duct lesion n PBC: duct lesion 32mr Secondary biliary cirrhosis nObstruction of extrahepatal bile ducts: atresia, lithiasis, tumor, iatrogenic nMost common cause is extrahepatic cholelithiasis nBiliary atresia, malignancies of the biliary tree and head of the pancreas, and strictures nCholestasis nBile duct proliferation with surrounding neutrophils nPeriportal fibrosis Circulatory disorders of the liver nDisorders of arterial system (liver infarct, ...) nDisorders of portal system (portal vein occlusion) nDisorders of venous system (hepatic vein thrombosis, ...) nDisorders of sinusoids Liver infarct 14 copy Disorders of portal system nThrombosis and occlusion of v. portae nExtrahepatal (phlebitis, pancreatitis, surgery, trauma) nIntrahepatal (invasion of tumor). No ischemic infarction, area of red-blue discoloration (infarct of Zahn). n n Thrombosis of v.portae 15mr copy Hepatic vein thrombosis nBudd-Chiari syndrome nHepatomegaly, weight gain, ascites, abdominal pain nPolycythemia vera, pregnancy, the postpartum state, oral contraceptive use, intra-abdominal cancers (HCC!) nCentrilobular congestion and necrosis → fibrosis Venoocclusive disease nComplication after bone marrow transplantation (→ 25%), nToxic endothelial injury secondary to chemotherapy and radiation nPlant toxins (Bush-tea - pyrrolizidine alcaloids) nObliteration of hepatic veins - subendothelial swelling, collagen and reticulin accumulation, perivenular fibrosis Disorders of sinusoids nOcclusion of sinuses: cirrhosis, eclampsy (DIC), sickle cell anaemia n nSystemic circulation: right-sided heart failure → congestion of centrilobular sinusoids, nutmeg liver (venostasis/steatosis) n Left-sided heart failure → hypoperfusion and hypoxia → centrilobular necrosis n Congestion 13mr copy Focal lesions and tumors nTumor-like lesions nBenign tumors nMalignant tumors: primary, secondary Tumor-like lesions nFocal nodular hyperplasia nNodular regeneratory hyperplasia (lack of fibrosis) nCysts nBiliary hamartoma (von Meyenburg complex) Focal nodular hyperplasia nLocalized benign hepatocellular nodules with central stellate fibrous scar nSingle or multiple nDue to focal increased blood flow - hypertrophy of well-vascularized lobules nMore common in females, oral contraceptives – estrogenes nDiff. dg. x tumors n n Focal nodular hyperplasia D:\Rosai\images\13FF51.jpg D:\Rosai\images\13FF52.jpg FNH n FNH - IHC Hydatid cyst – alveolar echinococcus Hydatid cyst – alveolar echinococcus Biliary hamartoma nFoci of dilatated biliary ducts – cysts nSubcapsular, commonly multiple nBenign condition, abortive polycystic disease nDiff. dg. x metastatic spread Biliary hamartoma n Benign tumors nAdenoma nhepatocellular (lack of portal tracts, risk of bleeding/necrosis, different subtypes, some with ↑ risk of carcinoma) ncholangiocellular - biliary ( accumulation of regular ducts, lack of bile production, <1cm, subcapsular) ncystadenoma (mucinous, rare) n nHaemangioma ncavernous (subcapsular, bleeding risk during punction!) n n n Biliary adenoma n Cavernous haemangioma 52mr Malignant tumors nPrimary nHepatocellular carcinoma (90%) nCholangiocarcinoma (↑ incidence) nMixed hepato-cholangiocellular ca nHepatoblastoma – children nAngiosarcoma – rare n Malignant tumors nSecondary nMetastatic carcinomas – most common (GIT, lung, breast, kidney,…), other metastatic tumors (melanoma,…) nHemopoetic neoplasms – leukemia infiltrates, lymphomas n Hepatocellular carcinoma nDifferent incidence due to the cause nLower in Europe, America, associated with cirrhosis, commonly alcoholic, HCV, NASH nHigh in eastern Asia, HBV carrier since infancy = 200x risk, inactivation of p53; nHigh in Africa – aflatoxin nMost of future HCC could be prevented nHBV vaccination nHCV treatment nLife style (alcohol, NASH) nNon-contaminated food Preneoplastic changes nLiver cell dysplasia – low grade, high grade n usually in cirrhosis, small foci or nodules, microcellular – smaller cells with less cytoplasm + bigger nuclei n Diff. dg. x well diff. HCC n Microcellular change/dysplasia Morphology of HCC nClinical hepatomegaly, right upper quadrant pain, weight loss nUnifocal, multifocal, or infiltrative growth nStrong propensity for vascular invasion nWell-differentiated – intracellular bile nTrabecular, acinar, pseudoglandular, solid nUsually scant stroma → soft nMetastasizes to LN, lung, bone, adrenals, … nCommonly serologic increase of AFP HCC 60mr HCC – bile production by tumor cells 53mr HCC – variable morphology One patient, the same tumor HCC – variable morphology n HCC – variable morphology n HCC – CD34+ capillaries n Fibrolamellar carcinoma n20-40 yrs, M=F nNo assoc. with cirrhosis or other risk factors nSingle, resectable, 5 year survival = 60%, nPAS + inclusions (hyaline globules) nTumor cells separated by dense parallel collagen strands nBetter prognosis n Fibrolamellar carcinoma n Cholangiocarcinoma nFrom intrahepatic biliary ducts n↑ risk in PSC, HCV cirrhosis, some parasitic infections (Clonorchis), polycystic disease nmucin secterion, no bilirubin pigment nirregular ducts, strands of cells ncommonly dense or myxoid stroma ndiff. dg. x metastatic or direct spread – gallbladder, pancreas, colorectal ca nmostly bad prognosis n Cholangiocellular carcinoma 56mr Cholangiocellular carcinoma IHC CK7 n Hepatoblastoma 53tum hepatoblembry n from primitive – stem cells n resembles embryonal/fetal liver n heterogenous elements (cartillage, bone, muscle, …) n infants, children copy Malignant vascular tumors nAngiosarcoma – highly malignant, most common liver sarcoma, associated with professional risk (vinylchloride in plastic industry), thorotrast exposure n nEpithelioid hemangioendothelioma – less malignant, transplantation event. possible Secondary tumors nmore common than primary nusually multiple ntreatment by surgical excision, thermal ablation, alcohol injection; chemotherapy in lymphomas/leukemias Colorectal ca metastasis n Colorectal ca metastasis IHC CK20+ tumor in a CK20 neg. biliary duct HG malignant lymphoma in liver Two secondary liver neoplasias n CLL infiltrate Small cell carcinoma metastasis Liver involvment in systemic disease nLiver affected by diseases of single organs in the vicinity npancreas, bile ducts – obstruction nheart - congestion, nlungs - hypoxemia, nkidney; nsystemic metabolic diseases (DM, amyloidosis) nsystemic infections incl. sepsis nextramedullary hematopoesis nacute fatty liver of pregnancy Central necrosis in heart failure Liver and transplantation nIndication for transplantation ninborn defects (biliary atresia) nirreversible stages of chronic liver disases - hepatitis, PBC, PSC nacute liver failure (toxic, vascular, trauma) nsome tumors (small/solitary HCC; EHE, large complicated hemangiomas); some focal lesions – FNH, parasitic cysts, … n Diseases of the gallbladder n Cholelithiasis nVery common nCholesterol stones nBile is supersaturated with cholesterol nGallbladder stasis nF>M nObesity nAdvancing age nPigment stones – calcium bilirubinate salts nAsian more than Western nChronic hemolytic syndromes Clinical features nAsymptomatic nBiliary colic nCholecystitis nPerforation, fistula nGallstone ileus Cholecystolithiasis 64mr Cholecystitis nAcute calculous nObstruction of GB neck or cystic duct nLocal pain radiating to right shoulder nFever, nausea, leukocytosis nPotential surgical emergency nEmpyema of the gallbladder nGangrenous cholecystitis Cholecystitis nAcute acalculous – seriously ill patients (postoperative, trauma, burns, sepsis,…) nChronic nRecurrent attacks of pain nNausea and vomiting nAssociated with fatty meals nFibroproduction (thickening of the wall, adhesions) nChronic inflammmation (risk of carcinoma development) nDystrophic calcification nHydrops n n Active chronic cholecystitis 63mr Choledocholithiasis nStones within the biliary tree nWest – from gallbladder nAsia – primary ductal and intrahepatic stone formation nSymptoms due to: nBiliary obstruction nPancreatitis nCholangitis nHepatic abscess Gallbladder carcinoma nSeventh decade nF>M nDiscovered at late stage, usually incidental nExophytic and infiltrating types nAdenocarcinoma nLocal extension into liver, cystic duct, portal LN nMean 5 yrs survival 1% Biliary intraepithelial neoplasia nPrecursor lesions nVariable grade of cellular and architectural atypia nBilIN 1 low grade, BilIN 2 intermediate grade nBilIN 3 high grade, commonly already associated with invasive carcinoma nNot visible by imaging methods nIncidental finding in biopsy/cholecystectomy BilIN 3 + invasive carcinoma Peri- and intraneural invasion Liver invasion Other disorders of extrahepatic biliary system nAtresia of bile ducts (unclear etiopathogenesis, inborn disorder, rapid progression, cirrhosis) nPrimary sclerosing cholangitis - PSC nCholesterolosis (strawberry gallbladder) nTumors of papilla Vateri (ampuloma, periampular carcinoma – difficult diagnosis) n