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Hepatitis, Gall Bladder & Biliary Tract Diseases Gall Bladder and Biliary Tract Diseases Objectives ► Causes,clinical features, effects and complications of acute and chronic cholecystitis ► Causes,clinical features, effects and complications of cholangitis ► Types of gallstones factors, pathogenesis, effects ► Predisposing and complication of gall stones Introduction Biliary system -intrahepatic and extrahepatic bile ducts -gallbladder mucus- ► -lined by glandular mucus-secreting epithelial cell layer liver- ► Bile secreted by liver->right and left hepatic ducts- duct- duct- ducts-> common bile duct-> cystic duct-> gall bladder Introduction( cont’d) Bile ► Consists of micelles of cholesterol phospholipid bile salts bilirubin ► Stored and concentrated in the gallbladder ► In response to high fat food content; the gallbladder contracts by stimulation of cholecystokinin and expelled bile into the second part of duodenum through the ampulla of Vater as the sphincter of Oddi relaxes Cholelithiasis ( gallstones) ► Common condition in which gallstones form within the biliary system ► Types of gallstones 1. cholesterol stones* 2. pigment stones* +/- 3. Mixed cholesterol + pigment ( +/- calcium carbonate) * Different risk factors, different pathogenesis Gallstones Gallstones Predisposing factors for cholesterol stones ► Demography- Demography- Northern Europe , North and South America, native Americans; Mexican Americans ► Advancing age ► Female sex hormones-Female gender -Oral contraceptives -Pregnancy ► Obesity ► Rapid weight reduction ► Gallbladder stasis ► Inborn disorder of bile acid metabolism ► Hyperlipidaemic syndromes Pathogenesis of cholesterol stones ► Cholesterol stones can be pure (100%) or mixed with calcium carbonate, phosphates and bilirubin ► Imbalance between the ratio of cholesterol and bile salts - excess of cholesterol -a deficit of bile salts ► When cholesterol concentration exceeds the solubilising capacity of bile ( supersaturation) cholesterol nucleates into solid cholesterol monohydrate crystals Cholesterol stones formation involves 4 simultaneous defects: 1. Bile supersaturation with cholesterol 2. Gallbladder hypomotility promoting nucleation 3. Cholesterol nucleation in bile is accelerated 4. Mucous hypersecretion in gallbladder traps the crystals permitting their aggregation into stones Cholesterol stones Cholesterol stones Inflammed mucosa Thickened gall bladder wall ► Gallstones ► Cholesterolstones ► Inflammed mucosa ► Thickened wall Predisposing factors for pigment stones ► Demography: Asian>Western; rural>urban ► Chronic hemolytic syndromes ► Biliary infection ► Gastrointestinal disorders: ileal disease (eg Crohn’s disease), ileal resection or bypass cystic fibrosis with pancreatic insufficiency Pathogenesis of pigment stones ► Complex mixtures of abnormal insoluble calcium salts of unconjugated bilirubin with inorganic calcium salts ► Biliary tract infection( E. coli, Ascaris lumbricoides, Opisthorchis Sinensis ) causes increase of unconjugated bilirubin in bile ► Intravascular hemolysis causes increased hepatic bilirubin- secretion of conjugated bilirubin- deconjugated in tree- biliary tree-> exceeds the aqueous solubility of free bilirubin Pigment stones - Pigment stones - Inflammed mucosa - Thickened wall Pigment stones Effects and complications of gallstones ► May be asymptomatic for years before develop symptoms ► Inflammation of gallbladder (cholecystitis) ► Mucocoele* ► Predisposition to carcinoma of gallbladder ► system- Obstruction of biliary system- biliary colic and jaundice ► Infection- Infection- cholangitis and liver abscess; gallbladder- empyema of gallbladder->perforation and fistula ► Gallstone ileus ► Pancreatitis Pathological effects of gallstones Gallstone ileus Mucocoele ► Sterileobstruction of the neck of gallbladder by a gallstone ► Lack inflammation- of inflammation-> gallbladder distend with mucous without rupturing ► Careful handling during surgery to avoid spillage of mucous into peritoneal cavity thus risk of pseudomyxoma peritonei# # Peritoneum becomes seeded with mucous –producing epithelial cells and the cavity filled with mucous ► Mucocoele Cholecystitis ► Inflammation of the gallbladder ► May be acute chronic or acute superimposed on chronic ► Almost always occur in association with gallstones ► One of the most common indication of abdominal surgery in U.S cholecystitis- Acute cholecystitis-Cause Acute calculous cholecystitis ► Acute inflammation of the gallbladder due to obstruction of the gallbladder outflow by a gallstone cholecystitis- Acute cholecystitis-Cause Acute acalculous cholecystitis ► Occur in the absence of gallstones eg: non- 1.postoperative state after major non-biliary surgery 2.severe trauma 3.severe burns 4.multiorgan system failure 5.sepsis 6.prolonged intravenous hyperalimentation 7.postpartum state Pathogenesis ( acute calculous cholecystitis) ► Gallbladder outflow obstruction ► Inflammatory reaction ( irritant effects of bile) ► Disruption of protective mucosal layer ► Gallbladder stasis- stasis-> distension compromised blood flow to mucosa ► Later, maybe bacterial contamination Pathogenesis( acute acalculous cholecystitis) ► Thought to result from ischaemia transfusion- ► Dehydration and multiple blood transfusion- > pigment load ► Gallbladder stasis ► Accumulation of microcrystals of cholesterol, viscous bile and mucous=>cystic duct obstruction ► Inflammation and oedema of the wall ► Bacterial contamination and generation of lysolechitins Clinical features ► Right upper quadrant or epigastric pain ► Mild fever, anorexia, tachycardia, sweating, nausea and vomitting ► Tender upper abdomen ► Hyperbilirubinaemia ► Mild- Mild-moderate leucocytosis ► Mild increased of serum alkaline phosphatase Acute cholecystitis Inflammed mucosa Chronic cholecystitis ► May develop insidiously or after repeated episodes of acute cholecystitis ► Is associated with cholelithiasis in 90% of cases ► Evolution is obscure ► ? Gallstones direct role ► Chronic acalculous cholecystitis exhibits symptoms and histology similar to chronic calculous cholecystitis ► Bile supersaturation predisposes to chronic inflammation and stone formation ► Obstruction of gallbladder outflow is NOT a prerequisite ► Most gall bladders removed at elective surgery for gallstones exhibit features of chronic cholecystitis suggesting long term coexistence of gallstones low- and low-grade inflammation cholecystitis- Chronic cholecystitis-Clinical features ► Recurrent attacks of steady or colicky epigastric or right upper quadrant pain ► Nausea, vomitting, fatty food intolerance Morphology ► Thickened gallbladder wall ► Rokitansky- Rokitansky-Aschoff sinuses, mucosal herniations(diverticula) ► Variable degrees of chronic inflammatory cell infiltrate ► Stone may be found in Hartmann’s pouch (pathological dilatation of the gallbladder neck due to increased intraluminal pressure or stone impaction) ► Xanthogranulomatous cholecystitis# ► Hydrops of gallbladder* Chronic cholecystitis with cholelithiasis Cholesterol stones Thickened gall bladder wall Inflamed mucosa Chronic cholecystitis Thickened gall bladder Inflammed mucosa Chronic cholecystitis -histology Rokitansky- -Rokitansky-Aschoff sinuses (arrow) - chronic inflammatory cell infiltration in the lamina propria #- rare; lipid- abundant lipid-laden macrophages and giant cells accumulate within the fibrotic wall * atrophic, chronically obstructed gallbladder , containing only clear secretions cholecystitis- Chronic cholecystitis-Effects and complications ► superinfection- Bacterial superinfection- cholangitis or sepsis ► Gallbladder perforation and local abscess formation ► Gallbladder rupture with diffuse peritonitis ► fistula- Biliary enteric fistula-drainage of bile into adjacent organ, entry of bacteria and air into biliary tree, gallstone ileus ► gallbladder- Porcelain gallbladder-extensive dystrophic gallbldder- calcification of gallbldder-increased risk of carcinoma ► pre- Aggravation of pre-existing medical illness with cardiac, pulmonary, renal or liver decompensation Cholangitis ► Inflammation of the bile ducts usually due to bacterial infection ► Usually precipitated by biliary obstruction most commonly choledocholithiasis# with secondary bacterial infection ► Other causes ( uncommon) Indwelling stents/catheters Tumours Acute pancreatitis Benign strictures # presence of stones within the bile ducts of the biliary tree Cholangitis- Cholangitis- Effects and complication ► Fever ► Chills ► Abdominal pain ► Jaundice ► Inflammed bile ducts ► Neutrophils infiltration ► Suppurative cholangitis ► Liver abscess ► Cholesterosis @ strawberry gallbladder Yellow- ► Yellow-pecked appearance of the gallbladder mucosa due to the presence of cholesterol- cholesterol-laden macrophages ► Clinically unimportant! Disorders of the extrahepatic bile ducts ► Choledocholithiasis ► Ascending cholangitis ► Biliary atresia ► Choledochal cyst Choledocholithiasis ► Presence of stones within the bile ducts of the biliary tree ► Asymptomatic or cause symptoms due to ► Obstruction Secondary biliary cirrhosis ► Pancreatitis Cholangitis ► Hepatic abscess ► Acute calculous cholecystitis Ascending cholangitis ► Bacterial infection of bile ducts = cholangitis ► Result from any obstruction to bile flow ► Ascending cholangitis=infection of the intrahepatic radicals due to bacteria entering the biliary tracts through the sphincter of Oddi Biliary atresia Complete obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life 2 forms (20%)- 1.fetal (20%)- associated with other anomalies 2.perinatal- 2.perinatal- presumed normal at birth but destroyed following birth Choledochal cyst ► Congenital dilatation of the bile ducts ► Children before the age of 10 ► Predispose to stone formation,stenosis and stricture, pancreatitis ► May occur in association with cystic dilatation of the biliary tree ( Caroli disease) ►* Caroli disease ► The larger ducts of the intrahepatic biliary tree are segmentally dilated and may contain inspissated bile ► Pure form is rare ► Usually associated with portal tract fibrosis of the congenital hepatic fibrosisi type HEPATITIS OBJECTIVES Drugs, toxins and viruses which Drugs, ► 1. commonly leads to hepatitis ► 2.Pathogenesis and morphology of the liver caused by alcoholism Clinicopathological features of viral ► 3. hepatitis Microanatomy Acinar concept Lobular concept Microanatomy Acinar concept Hepatitis Definition ► Injury to the liver associated with an influx of acute or chronic inflammatory cells Causes Infection-Viral, ► Infection-Viral, bacterial, parasitic, helminthic ► Drug and toxin induced ► Alcoholic liver disease ► Metabolic ► Autoimmune Viral- ► Viral-foremost in hepatic infection Others- ► Others- miliary tuberculosis - malaria - staphylococcal bacteraemia - salmonellosis - candidiasis - amebiasis Viral hepatitis Infection of the liver caused by a group of viruses having a particular affinity for the liver 1. Hepatitis A virus 4. Hepatitis D virus 2. Hepatitis B virus 5.Hepatitis E virus 3. Hepatitis C virus 6. Hepatitis G virus Systemic viral infection that can involve the liver include 1. Infectious mononucleosis (EBV) Others- 4. Others-rubella, adenovirus 2.Cytomegalovirus herpesvirus, enteroviruses 3.Yellow fever virus Hepatitis A ► May occur sporadic or epidemic ► Does not cause chronic hepatitis or a carrier state Transmission-Faecal- ► Transmission-Faecal-oral spread -nurseries/institution, water contaminated sewage, ingestion of sewage contaminated shellfish ► Direct cytopathic effect on the liver ► Diagnosis: Serology IgM antibody ( recent infection) IgG antibody (protective immunity against reinfection by all strains of HAV) Hepatitis B ► Spread by blood, blood contaminated instruments, blood products and venereally transmission- child- ► Vertical transmission- mother to child- in utero; during delivery or intimate post natal contact ( responsible for most cases of carrier state in underdeveloped countries ► Liver damage by antiviral immune reaction ► Carrier state exists B- Hepatitis B-Serologic Diagnosis 1.HBsAg- 1.HBsAg- appears before onset of symptoms - during overt disease 3- - declines to undetectable levels in 3-6 months HBV- 2.HBeAg, HBV-DNA and DNA polymerase -appear in serum soon after HBsAg -all signify active viral replication anti-HBc- 3.IgM anti-HBc- detectable in serum shortly before onset of symptoms; replaced by IgG anti HBc over months Anti-Hbe- 4. Anti-Hbe- detectable shortly after the disappearance of HBeAg anti-HBs- 5.IgG anti-HBs- does not rise until the acute disease is over -is usually not detectable for a few weeks to several months after the disappearance of HBsAg protection; - may persist for life ; confer protection; is the non- basis for vaccination strategies using non- infectious HBsAg ► HBV cells, is not directly toxic to liver cells, instead it is the immune response to viral antigen expressed on the infected hepatocytes that cause liver cell injury Five clinical patterns of HBV infection ► Asymptomatic infection –may progress to chronic hepatitis or carrier self- ► Acute self-limiting hepatitis but majority recover and have lifelong immunity hepatitis- ► Fulminant acute hepatitis->massive liver necrosis hepatitis- ► Chronic hepatitis-may progress to cirrhosis or aymptomatic carrier state- ► Asymptomatic carrier state-may develop chronic hepatitis Potential outcome of hepatitis B infection in adults Hepatitis C Main characteristics ► Spread by blood, blood contaminated instruments, blood products and possibly venereally ► transmission- Major route of transmission- innoculations and blood transfusions ► Relatively short incubation period (2 –26 weeks) ► Often asymptomatic ► Fluctuating liver biochemistry ► Tendency to chronicity Potential outcome of hepatitis C infection in adults Hepatitis D virus ► Causinginfection only when it is encapsulated by HBsAg ► Dependent on HBV genetic information for multiplication ► Cause hepatitis only in the presence of HBV Hepatitis D virus Delta hepatitis arises in two setting 1. coinfection- Acute coinfection- exposure to both HBV and HDV 2. Superinfection of a chronic carrier of HBV with inoculum of HDV Three possible outcomes 1. Acute, severe hepatitis in a previously healthy HBV carrier 2. Mild HBV hepatitis may be converted to fulminant disease 3. Chronic, progressive disease=> cirrhosis Hepatitis E virus ► Enterically water- transmitted, water-borne infection ► High mortality rate among pregnant women Self- ► Self-limiting disease ► Not associated with chronic liver disease or persistent viraemia Other Hepatitis Viruses Hepatitis G virus (HGV) ► Flavivirus ► Blood, blood products; possibly sexual contact infection- ► 75% of infection-clear ; the remainder= chronic ► Site of replication is most likely mononuclear cells ► Not hepatotropic; does not cause elevation of serum aminotransferases co- ► Commonly co-infects HIV pts; this dual infection is somewhat protective against HIV disease Morphology of acute and chronic hepatitis Morphology of acute and chronic hepatitis are shared among hepatotropic viruses ; can be mimicked by drug reactions A few histologic features may be indicative of particular viruses eg ► cytoplasm- ground glass cytoplasm- hepatitis B ► steatosis- Lymphoid aggregate and steatosis- Hepatitis C Histological features of acute viral hepatitis ► Ballooning degeneration ► Cholestasis ► Macrophage aggregate ► Apoptotic liver cell death ( Councilman bodies) ► Bridging necrosis( in severe acute hepatitis) ► Kupffer cell hyperplasia and hypertrophy ► Portal tract infiltration by mixed inflammatory cells ► hepatitis- Interface hepatitis-necrosis of periportal hepatocytes ► Ductular reaction (esp in Hepatitis C) Ground- Ground-glass hepatocytes Acute viral hepatitis Diagrammatic representation Of morphologic features of acute hepatitis Hepatitis- Hepatitis-Clinicopathologic syndromes ► Acute asymptomatic infection with recovery- recovery- serologic evidence only -HAV and HBV infection ► Acute symptomatic hepatitis with recovery; anicteric or icteric* ► Chronic hepatitis without or with progression to cirrhosis ► Fulminant hepatitis Acute symptomatic infection with recovery 4 phases 1. Incubation period pre- phase- 2. Symptomatic pre-icteric phase-fatigue, nausea, LOA, LOW, low grade fever, headache, arthralgia, rash phase- 3. Symptomatic icteric phase-jaundice; dark urine ( conjugated hyperbilirubinaemia) 4. Convalescence Chronic hepatitis Definition: Symptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for more than 6 months with histologically documented inflammation and necrosis Clinical features of chronic hepatitis ► Variable and are not predictive of outcome ► Fatigue, malaise, loss of appetite, occasional bouts mild jaundice ► Spider angiomas, palmar erythema, mild hepatomegaly, hepatic tenderness, mild splenomegaly Occasionally- ► Occasionally- immune complex disease ie vasculitis; glomerulonephritis ( in HBV and HCV) Histological features of chronic hepatitis ► Lymphoid aggregates ► Bile duct damage ► Steatosis ► Interface hepatitis ► Bridging necrosis Fibrosis- ► Fibrosis-portal tracts, periportal ;bridging fibrosis (linking of fibrous septae between lobules) Chronic hepatitis Diagrammatic representation of morphologic features of chronic hepatitis Fulminant hepatitis ► Occurs when hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2-3 weeks ► Less rapid course ( up to 3 months) is called subfulminant hepatic failure ► * fulminant hepatic failure may be caused by other than viral hepatitis ie drug ( acetaminophen overdose, antidepressant- isoniazid, antidepressant- MOI, halothane and methyldopa), mycotoxin-Amanita phalloides mycotoxin- ► When it is due to viral hepatitis; usually it is due to hepatitis A or Hepatitis B virus . hepatitis- Fulminant hepatitis- morphology Microscopically- ► Microscopically- complete destruction of hepatocytes in contigous lobules ► Collapsed of reticulin network and preserved portal tracts ► With patient survival => time to regenerate surviving hepatocytes and bile ducts ► May recover completely ► However, fibrous scarring may occur in submassive or patchy necrosis resulting in post- post-necrotic cirrhosis hepatitis- Fulminant hepatitis-clinical features ► Jaundice, encephalopathy, fetor hepaticus ► Absence of stigmata of chronic liver disease ie gynaecomastia , spider angiomas Life- ► Life- threatening extrahepatic complications include- include-coagulopathy and bleeding, cardiovascular instability, renal failure, ARDS, acid- electrolyte and acid-base imbalances, sepsis Autoimmune hepatitis ► Chronic form of hepatitis ► 20-40year- Female; 20-40year-olds ► Absence of viral serologic markers ► Elevated serum IgG and γ globulin levels ► cases- High serum autoantibodies in 80% of cases- antinuclear (ANA), antismooth muscle (SMA) antiliver/kidney (antiLKM1) antibodies ► Negative antimitochondrial antibody (AMA) Autoimmune hepatitis ► Prominent lymphocytes and plasma cell infiltrates in the liver ► Relapsing and remitting course ► Treatment: steroids Non- ► Non-responder to treatment: Progress to cirrhosis transplant- ► Liver transplant-excellent prospect in severe case Alcoholic liver disease ► Chronic disorder featuring steatosis, hepatitis, progressive fibrosis, cirrhosis and marked derangement of vascular perfusion due to chronic excessive alcohol consumption. Alcoholic liver disease ► Hepatic steatosis* ► Alcoholic hepatitis* ► Cirrhosis *May develop independently Not necessarily represent a continuum of changes disease- Alcoholic liver disease-morphology ► Hepatic steatosis- fatty change -perivenular fibrosis ► Alcoholic hepatitis- hepatocyte swelling and necrosis - Mallory bodies - neutrophilic reaction fibrosis- - fibrosis- sinusoidal and perivenular ► Alcoholic cirrhosis -fibrosis -hyperplastic nodules Fatty liver Fatty change Alcoholic hepatitis Mallory bodies Mallory bodies Pathogenesis ► Only 10-15% of alcoholics develop cirrhosis 10- ► Women more susceptible to hepatic injury ► No clear understanding of the pathogenetic factors influencing liver damage (? Genetic factors) ► Steatosis results from 1. Shunting of normal substrate away from catabolism and toward lipid biosynthesis 2. Impaired assembly and secretion of lipoprotein 3. Increased peripheral catabolism of fat ► Impaired methionine- hepatic metabolism of methionine-> levels- decreased intrahepatic glutathione levels-> susceptible to oxidative injury induction- ► Cytochrome p450 induction-increased conversion of drugs to toxic metabolites; produces reactive o2 species ► Affects microtubular and mitochondrial function and membrane fluidity epitopes- ► Hepatocellular proteins create new epitopes-> reacts- immune system reacts->inflammation and immune- immune-mediated hepatocellular injury Other effects of alcohol ► Malnutrition, vitamins deficiencies ► Impaired digestive function ► Chronic gastric and intestinal mucosal damage ► Pancreatitis ► Induces release of bacterial endotoxin into portal circulation from the gut=>inflammation in the liver Clinical features ► steatosis- Hepatic steatosis-mild hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase ► hepatitis- Alcoholic hepatitis-usually acute; after bouts of heavy drinking ► Malaise, anorexia, wt loss, upper abdominal discomfort, tender hepatomegaly ► Cirrhosis- Cirrhosis- symptoms related to portal hypertension and chronic liver disease Pathogenesis of alcoholic liver disease Interrelationships among hepatic steatosis, hepatitis and cirrhosis toxin- Drug and toxin-induced Liver disease Mechanisms of injury 1. Direct toxicity 2. Hepatic conversion of a xenobiotic to an active toxin mechanism- 3. Immune mechanism- drug as hapten ( predictable) or idiosyncratic ► Intrinsic (unpredictable) ► Injury may take weeks to months to develop ► Hepatocyte necrosis, cholestasis or insidious onset of liver dysfunction Drug- ► Drug-induced chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis reaction- Intrinsic reaction-examples of drug and toxin ► Acetaminophen (Paracetamol) ► Amanita phalloides toxin ► Carbon tetrachloride ► Alcohol Idiosyncratic reaction ► Sulphonamide ► A-methyldopa ► Allopurinol ► Acetylsalicylic acid (aspirin) Drug and toxin-induced liver injury Metabolic Liver Disease ► Nonalcoholic fatty liver disease ► Wilson disease ► Haemochromatosis anti- ► α-1-anti-trypsin deficiency Nonalcoholic fatty liver disease and steatohepatitis ► alcoholic- Resemble alcoholic-induced liver disease but patients are not heavy drinkers ► Strong association between obesity, dyslipidaemia, hyperinsulinaemia and insulin resistance and overt type 2 diabetes ► Diagnosis of exclusion ► Steatosis, parenchymal inflammation,Mallory bodies, hepatocyte death ► May progress to cirrhosis Wilson disease ► Autosomal recessive ► Accumulation of toxic level of copper in brain, liver, eye ► Decreased serum caeruloplasmin ► Liver: fatty change, acute and chronic hepatitis, cirrhosis ► Brain: atrophy and cavitation of basal ganglia (putamen) ► Eye: ggreen-brown copper deposits in Descemet’s membrane in the limbus of cornea Kayser- Kayser-Fleischer Ring Green-brown copper deposits in Descemet’s membrane in the limbus of cornea Haemochromatosis ► Excessive accumulation of body iron; deposited in parenchymal organs eg liver and pancreas ► Hereditary (primary) haemochromatosis ► Homozygous recessive ► Loss of intestinal regulation of dietary iron absorption ► Fully developed case:micronodular cirrhosis, diabetes mellitus, skin pigmentation Haemochromatosis Secondary haemochromatosis ► Parenteral iron overload ► Ineffective erythropoiesis ► Increased oral iron intake α1-antitrypsin deficiency ► Autosomal recessive ► Low serum levels of α1- antitrypsin (protease inhibitor) Abnormally- ► Abnormally-folded polypeptideretained in ER- autophagocytosis- ER-> autophagocytosis-> liver injury ► Presents with neonatal hepatitis with cholestatic jaundice Adolescence- ► Adolescence-hepatitis/cirrhosis 2- ► HCC develop in 2-3% of PiZZ individual
"Hepatitis_ Gall Bladder and Biliary Tract Diseases"