ustavpatologie.upol.cz
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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
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Necropsy
Excision during laparotomy
Fine needle punction
Percutaneous punction biopsy
unguided
laparoscopic
guided (Sono, CT)
• transjugular
Liver biopsy
Representativeness
Quality
Clinical data
Reproducibility
Diagnosis
Representativeness
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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
Quality
Clinical data
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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
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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
Cirrhosis
Cirrhosis + hepatocellular carcinoma
Cirrhosis: Masson staining
Cirrhosis: Fouchet staining
Cirrhosis
Cirrhosis: active
Cirrhosis: biliary
Dysplasia
Dysplasia
Hepatitis: etiology
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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
HBV
HDV
Non A Non B
HCV
HEV
HFV
HGV
RNA
DNA
RNA
Pikornavirus
Hepadnavirus
Defektní virus
RNA
RNA
RNA
RNA
Flavivirus
Kalicivirus
Togavirus
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
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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
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Gross finding – oedematous, red liver
Microscopic finding
focal necrosis
bridging necrosis
panacinar/multiacinar necrosis
periportal necrosis
Hepatocytes
polymorphism
balooning degeneration
Acute hepatitis
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Inflammation
polynuclear/mononuclear infiltration
activation of Kupfer’s cells
Other changes
cholestasis
damage of bile ducts
Regeneration
Fulminant hepatitis
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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
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
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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: periportal
Chronic hepatitis: HCV, transition into the
cirrhosis
Autoimmune chronic hepatitis
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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
NASH: non-alcoholic steatohepatitis
Epidemiologic signs of NASH
Females
Obesity
DM of II type, hyperglycaemia
NASH: non-alcoholic steatohepatitis
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
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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) : steatosis
Alcoholic Liver Disease (ALD) :
steatofibrosis
Alcoholic Liver Disease (ALD) : cholestasis
Alcoholic Liver Disease (ALD) : Mallory
hyaline
Alcoholic Liver Disease (ALD) : Mallory
hyaline
Alcoholic Liver Disease (ALD) :
steatohepatitis
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
Haemochromatosis
Haemochromatosis
Brown atrophy of liver: dif.dg.
Wilson’s disease
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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
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
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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
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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: 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 hepatitis
Tumor infiltration
Day 0-25
Drug related damage
Venoocclusive 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 hepatitis
Fulminant 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 infections
Acute rejection
Drug 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
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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
HCC
HCC
HCC
HCC
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
Cholecystolithiasis
Cholecystitis
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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
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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
Pancreatonecrosis
Steatocytonecrosis: omentum
Steatocytonecrosis: omentum
Exocrine pancreas: chronic pancreatitis
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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
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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
Carcinoma of pancreas
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