normal structure of liver

Normal structure of liver

Normal function of liver

Metabolic (glucose homeostasis…) Synthetic (albumin, coagulation factors) Storage (glycogen, triglycerides, Fe, Cu, vitamins

soluble in fat) Catabolic (endogenous substances – hormones…,

exogenous substances – drugs, alcohol…) Excretoric (bile)

Histologic examination Necropsy Excision during laparotomy Fine needle punction Percutaneous punction biopsy • unguided• laparoscopic• guided (Sono, CT)• transjugular

Liver biopsy

Representativeness

Quality

Clinical data Diagnosis

Reproducibility

Representativeness

Biopsy represents approx. 1/500 000 of organ Ideal biopsy (Scheuer, MacSween) • 2 cm length• more than 4 (8) portal tracts Borderline representativeness• contact CLINICIAN!! Non-representative

QualityClinical data

Clear and sufficient • clinical outcome, history • etiology • biochemical findings, other markers (oncomarkers,

markers of autoimmunity…)• treatment• previous histology• preliminary diagnosis! Unclear • contact CLINICIAN!! Insufficient and confusing

Quality Diagnosis

Diagnosis• recent diagnostic praxis (grading and staging of chronic

hepatitis…)• recent diagnostic textbooks - contact CLINICIAN!! Methods• biopsy - contact CLINICIAN!! • immunohistochemistry, ELMI - contact CLINICIAN!! • experimental

Recently used diagnostic textbooks

Histologic examination – special stains and methods

Haematoxylin/eosin Fouchet – bile (green), collagen (red) Fe, Cu – Fe pigment, Cu pigment Gömori – reticulin mesh Orcein – HBsAg PAS, Müller – mucopolysaccharides Immunohistochemistry (HBsAg, HBcAg, a1

fetoprotein, CEA, hepatocytes – OCH1E5) ELMI (metabolic diseases) PCR (HBV DNA, HCV RNA,…)

Damage of hepatocytes

Type (ischemic-coagulation necrosis, piecemal necrosis, apoptosis)

Extent (monocellular, focal, submassive, massive, bridging: C-C; C-P)

Localization (centrolobular, periportal, midzonal) Course • regeneration, healing ad integrum• regeneration + fibrosis: cirrhosis• acute liver failure: coma and death

Liver failure

Jaundice Hypoalbuminemia Coagulopathy Hyperamonemia Increase of levels of cytosolic enzymes Endocrine complications Hepatoencephalopathy Hepatorenal syndrome Coma

Necrosis of liver: damage of hepatocytes

Cirrhosis

Nodular rearrangement Morphology • micronodular• macronodular

Cirrhosis: etiology

Alcohol (60-70%) Chronic hepatitis (10%) Cryptogenic (10-15%) Biliary (primary, secondary) Haemochromatosis (primary, secondary) Metabolic diseases (tyrosinemia, galactosemia) -very

rare

Cirrhosis: complications

Portal hypertension Liver failure Hepatocellular carcinoma

Portal hypertension

Prehepatic (tumor, infection, pancreatitis, pregnancy, peroral contraceptives)

Intrahepatic – most frequent (cirrhosis, fibrosis) Posthepatic (congestive cardiac failure, Budd-Chiari

syndrome, venoocclusive disease) Signs: • portosystemic shunts• splenomegaly• ascites

Cirrhosis

Cirrhosis + hepatocellular carcinoma

Cirrhosis: Masson staining

Cirrhosis: Fouchet staining

Cirrhosis

Cirrhosis: active

Cirrhosis: biliary

Dysplasia

Hepatitis: etiology

Infectious (acute, chronic)• viruses (most often)• bacteria (TBC, malaria, salmonelosis, leptospirosis,…)• parazites (ecchinococcus)• protozoal (amebiasis) Non-infectious (acute, chronic)• autoimmune• metabolic• drug induced• cryptogenic

Viral hepatitis

HAV RNA Pikornavirus

HBV DNA Hepadnavirus

HDV RNA Defektní virus

Non A Non B

HCV RNA Flavivirus

HEV RNA Kalicivirus

HFV RNA Togavirus

HGV RNA Flavivirus

Viral hepatitis: HBV+HDV

Viral hepatitis: HBsAg, ground glass

Viral hepatitis: HBsAg, Orcein staining

Viral hepatitis: HBcAg, immunohistochemistry

Viral hepatitis: HBcAg, electron microscopy

Viral hepatitis: course

Acute (HAV, HBV, HCV, HDV, HEV) Chronic (HBV, HBV + HDV, HCV) • risk of cirrhosis development • risk of hepatocellular carcinoma development Fulminant (HBV, HCV)

Acute hepatitis

Gross finding – oedematous, red liver Microscopic finding • focal necrosis• bridging necrosis• panacinar/multiacinar necrosis• periportal necrosis Hepatocytes• polymorphism• balooning degeneration

Acute hepatitis

Inflammation• polynuclear/mononuclear infiltration • activation of Kupfer’s cells Other changes • cholestasis• damage of bile ducts Regeneration

Fulminant hepatitis

Gross finding - soft consistency Microscopic finding – complete necrosis of parenchyma Course • liver failure - coma - death • regeneration – postnecrotic cirrhosis

Acute hepatitis: HBV

Acute hepatitis

Acute hepatitis: regeneration

Fulminant hepatitis: HBV

Fulminant hepatitis: HBsAg, Orcein staining

Chronic hepatitis: etiology

HBV, HBV+HDV, HCV Autoimmune Drug induced Wilson’s disease a1 anti-trypsin deficiency Cryptogenic

Chronic hepatitis: clinical definition

Clinical symptoms of hepatitis more than: 6 months 12 months in HCV

Chronic hepatitis: morphology

Inflammation portal• periportal• lobular Necrosis/apoptosis• piecemal• bridging • focal Fibrosis Deposits (Cu, PAS globules,…)

Chronic hepatitis - portal + steatosis, HCV

Chronic hepatitis: portal

Chronic hepatitis: periportal

Chronic hepatitis: HCV, transition into the cirrhosis

Autoimmune chronic hepatitis

Females, young/middle age Autoantibodies – ANA, AMA Autoimmune „overlap“ syndromes• lupus erythematodes• arthritis

Autoimmune chronic hepatitis - ANA

Autoimmune chronic hepatitis - AMA

NASH: non-alcoholic steatohepatitis

Hepatomegaly Increase of aminotransferases Histological picture – similar to alcoholic hepatitis

without alcohol consumption • macrovesicular steatosis• lobular hepatitis and necrosis• balooning of hepatocytes• fibrosis


Epidemiologic signs of NASH Females Obesity DM of II type, hyperglycaemia


Diseases related to NASH Acquired metabolic diseases (obesity, DM,

hyperlipidemia, parenteral nutrition) Inherited metabolic diseases (Wilson’s disease,

abetalipoproteinaemia, tyrosinaemia) Surgery (jejunoileal bypass, extensive resections of

small intestine...) Drugs, toxins (amiodarone, glucocorticoids, tamoxifen,

synthetic estrogens…)

Toxic and drug induced liver damage

Anorganic substances Organic substances Industrial and plant substances Poisons/venoms Drugs Alcohol

Toxic and drug induced liver damage: effect

Expectable Non-expectable (idiosyncratic)

Toxic and drug induced liver damage : forms

Necrosis Steatosis• macrovesicular (alcohol, corticoids)• microvesicular (tetracyklin, aspirine) 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)

Steatosis (90%) Fibrosis (perivenular, pericellular) Steatofibrosis Alcoholic hepatitis Alcoholic cirrhosis Mallory hyaline Cholestasis Siderosis Hepatocellular carcinoma Dif.dg: NASH

Alcoholic Liver Disease (ALD) : steatosis

Alcoholic Liver Disease (ALD) : steatofibrosis

Alcoholic Liver Disease (ALD) : cholestasis

Alcoholic Liver Disease (ALD) : Mallory hyaline

Alcoholic Liver Disease (ALD) : steatohepatitis

Alcoholic Liver Disease (ALD) : steatohepatitis, cholestasis, Mallory hyaline

Metabolic liver disease

Haemochromatosis Wilson’s disease a1 anti-trypsin deficiency Glycogenoses

Haemochromatosis

Excessive accumulation of iron in parenchymatous organs

Primary (idiopatic), secondary Cirrhosis, diabetes mellitus, pigmentation of skin Dif.dg. of brown pigment within the liver• Fe (haemochromatosis)• Cu (Wilson’s disease)• lipopigment (brown atrophy of liver, lipopigment

dystrophy)

Haemochromatosis

Brown atrophy of liver: dif.dg.

Wilson’s disease

Hepatolenticular degeneration Low levels of ceruloplasmin Increase of Cu in liver and urine Morphology• steatosis• acute hepatitis• chronic hepatitis• glycogen nucleus (also typical in DM)• increased amount of Cu pigment

Wilson’s disease : Cu pigment

Wilson’s disease/DM: glycogen nucleus

a1 anti-trypsin deficiency

Low levels of a1AT (inhibitor of proteases) Emphysema of lungs Liver changes (cholestasis, cirrhosis)• PAS positive acidophilic globular inclusions in the

cytoplasm • ELMI – complementary diagnosis

Circulatory disorders of the liver

Disorders of arterial system Disorders of portal system Disorders of venous system Disorders of lobular system

Disorders of arterial system

Infarct of the liver Rare Thrombosis, compression, obliteration of a. hepatis

branch (polyarteritis nodosa,…) Pale Dif.dg.: • Zahn infarct (occlusion of intrahepatic branch of v.

portae): no necrosis, local congestion of sinusoids and secondary atrophy

Liver infarct

Disorders of portal system

Thrombosis and occlusion of v.portae Extrahepatal (phlebitis, pancreatitis, surgery, trauma) Intrahepatal (invasion of tumor)

Thrombosis of v.portae

Disorders of venous system

Thrombosis of hepatic veins (Budd-Chiari syndrome)• causes: polycytemia vera, pregnancy, contraceptives,

intraabdominal malignant tumors, hepatocellular carcinoma

• centrilobular necrosis and congestion, fibrosis Venoocclusive disorder• complication of bone marrow transplantation (5-25%) –

chemotherapy, radiotherapy• Bush-tea (pyrrolizidine alcaloids)• obliteration of hepatic veins – subendothelial

accumulation of colagen and reticulin, perivenular fibrosis, perivenular hemosiderin

Budd-Chiari

Disorders of lobular system

Occlusion of sinuses• eclampsy• Sickle cell anaemia Systemic circulation• passive congestion• centrilobular necrosis• nutmeg liver (venostasis/steatosis)

Congestion

Pathology of intrahepatal bile ducts

Secondary biliary cirrhosis (SBC) Primary biliary cirrhosis (PBC) Primary sclerosing cholangitis (PSC)

SBC

Obstruction of extrahepatal bile ducts: atresia, lithiasis, tumor, iatrogenic

Striking cholestasis

PBC

Autoimmune (AMA), Majority of females Coincidency: Sjögren sy., arthritis, thyreoiditis,

vasculitis,.. Hepatomegaly, 4 stages • I - granulomatous destruction of ducts• II - ductular proliferation and periportal hepatitis• III - scarring, necrosis, septal fibrosis• IV - cirrhosis

PSC

Autoimmune (ANA) Inflammation and obliterative fibrosis of bile ducts Coincidency: IBD (Inflammatory Bowel Disease –

ulcerative colitis, m.Crohn)

PBC: I.stage

PBC: II.stage

PBC: III.stage

Patology of liver during pregnancy

Preeclampsy/eclampsy• HELLP syndrome: Hemolysis, Elevated Liver enzymes,

Low Platelets• fibrin within the sinusoids• hematomas (fatal rupture of liver) Acute microvesicular steatosis during pregnacy (third

trimester) Cholestasis during pregnancy (third trimester)

Transplantation

Liver disorders related to bone marrow transplantation Liver disorders related to liver transplantation

Liver disorders related to bone marrow transplantation

Time Cause

Before transplantation

Viral hepatitisTumor infiltration

Day 0-25 Drug related damageVenoocclusive disease

Day 25-100 Acute GVHD (destruction of bile ducts, endothelitis, necrosis of hepatocytes)Opportune infections

Day 100- Chronic GVHD (involvement of portal tracts, destruction of bile ducts, endothelitis)Viral hepatitisFulminant hepatitis („rebound“ phenomenona)

Liver disorders related to liver transplantation

Time Cause

1. week Acute rejection (necrosis, inflammation)Technical complication (vascular anastomoses…)Non-functionality (primary)

2. week-2. month Opportune infectionsAcute rejectionDrug related damage

2. month - Chronic vascular rejection (vasculitis)Vanishing bile ducts syndrome Viral hepatitis

Tumors of liver

Tumor-like lesion Benign tumors Malignant tumor

Tumor-like lesions Focal nodular hyperplasia Nodular regeneratory hyperplasia (lack of fibrosis) Cysts Hamartoma (von Meyenburg complex) Inflammatory pseudotumor

Nodular regeneratory hyperplasia

Benign tumors

Adenoma• hepatocellular (lack of portal tracts!)• cholangiogenic (lack of bile production, less than 1cm,

subcapsular) Haemangioma• subcapsular • cavernous• bleeding risk during punction!

Cavernous haemangioma

Malignant tumors

Hepatocellular carcinoma (HCC)• subvariant – fibrolamelar carcinoma Cholangiogenic carcinoma (lack of bile production)• peripherial• extrahepatal -Klatskin tumor Hepatoblastoma (embryonal, teratoid,…) Angiosarcoma, malignant haemangioendothelioma Metastases (most often) • GIT, lung, kidney

Cholangiogenic carcinoma

Biliary system: cholelithiasis

10-20% of population Cholesterol concrements (females, obesity, steroids,

hyperlipidemia) Pigmented/bilirubine concrements (biliary infection,

haemolysis) Blockage of bile ducts (acute cholangoitis, sepsis,

biliary cirrhosis, pancreatitis) Irritation of gallbladder (cholecystitis, carcinoma) Valve-like blockage (hydrops) Perforation, fistula

Cholecystolithiasis

Cholecystitis Acute• empyema of gallbladder• gangrenous cholecystitis• acalculous cholecystitis (postoperative, trauma, burns,

sepsis,…) Chronic• fibroproduction (thickening of the wall, adhesion)• chronic inflammmation• dystrophic calcification (risk of carcinoma development)• hydrops

Chronic cholecystitis

Carcinoma of gallbladder

Adenocarcinoma Infiltrating Exophytic Early invasion into the liver – poor prognosis!

Carcinoma of gallbladder

Other disorders of biliary system

Atresia of bile ducts (rapid progression, uncelar etiopathogenesis, cirrhosis)

Cholesterolosis (strawberry gallbladder) Choledocholithiasis (risk of ascendent cholangoitis,

intrahepatic abscess and sepsis, risk of biliary cirrhosis)

Tumors of papilla Vateri (ampuloma, periampular carcinoma – difficult diagnosis)

Exocrine pancreas: acute pancreatitis

Causes• cholelithiasis, alcohol, surgery, trauma, • idiopathic Most serious form• acute haemorrhagic necrotizing pancreatitis Morphology• nekrosis of pancreas• nekrosis of fat tissue (steatocytonecrosis, Balzer’s necrosis)• haemorrhagy Complication, healing• abscesses• pseudocysts• duodenal obstruction• multiorgan failure

Pancreatonecrosis

Steatocytonecrosis: omentum

Exocrine pancreas: chronic pancreatitis

Causes• alcohol, hyperlipidemia, hypercalcemia, hereditary Morphology• fibrosis• reduction of acines• obstruction of ducts• chronic inflammatory infiltration (lymphocytes, plasmocytes) Complications• calcifications, pseudocysts, thrombosis v . lienalis• diabetes• steatorrhea• jaundice

Chronic pancreatitis

Exocrine pancreas: tumors

Cystic tumors (5%)• mucinous cystadenoma• mucinous cystadenocarcinoma Carcinoma of pancreas• Adenocarcinoma, various degree of differentiation • Head (early diagnosis - jaundice), body, tail (difficult

diagnosis, late detection) • Often - fibroproduction (dif.dg. chron.pancreatitis)• Trosseau syndrome – migratory thrombophlebitis in 10%

Carcinoma of pancreas

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normal structure of liver

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active cirrhosis

frequent cirrhosis

masson staining cirrhosis

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cirrhosisacute liver

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