Pathology

• Infectious disorders of liver

  • Most hepatic infections are viral in origin
  • Others include: miliary T.B, malaria, staph., salmonella, candida, and amebiasis
• Viral hepatitis caused by

  • Infectious mononucleosis (Epstein-Barr virus)
  • Cytomegalovirus: in newborn or immunosuppression
  • Yellow fever: in tropical countries
  • Rubella, adenovirus, herpesvirus, or enterovirus: in children and immunosuppression
  • Hepatotropic viruses (most important)
• Hepatotropic viruses


  • Hepatitis A (HAV)
  • Hepatitis B (HBV)
  • Hepatitis C (HCV)
  • Hepatitis D (HDV)
  • Hepatitis E (HEV)
• Hepatitis A (HAV)


  RNA virus, Fecal–oral infection route, Acute disease
• Hepatitis B (HBV)


  DNA virus, Parenteral infection route, Acute and chronic disease
• Hepatitis C (HCV)


  RNA virus, Parenteral infection route, Acute and chronic disease
• Hepatitis D (HDV)


  RNA virus, Pathogenic when combined with HBV, Acute and chronic disease
• Hepatitis E (HEV)


  RNA virus, Fecal–oral infection route, Acute disease
• Acute viral Hepatitis parenchymal changes

  • Hepatocyte swelling (ballooning degeneration)
  • Cholestasis (canalicular bile plugs)
  • Cytolysis (rupture), or apoptosis (shrinkage) with acidophil bodies (Councilman bodies) formation
  • Hepatocyte necrosis: isolated cells or cell clusters
  • If severe: bridging necrosis (portal-portal, central-central, or portal-central)
• Acute viral Hepatitis regenerative changes

  • Hepatocyte proliferation
  • Sinusoidal reactive changes: Phagocytosed debris in Kupffer cells, Mononuclear inflammatory cells in sinusoids
  • Portal tracts: Inflammation (mononuclear) which may spillover into adjacent parenchyma (but more in chronic)
• Chronic Hepatitis


  Symptomatic, biochemical, or serologic evidence of continuing or relapsing hepatic disease for more than 6 months, with histologically documented inflammation and necrosis
• Causes of Chronic Hepatitis

  • Hepatitis viruses (HBV, HCV, and HBV+HDV)
  • Chronic alcoholism
  • Wilson disease
  • α1-antitrypsin deficiency
  • Drugs (isoniazid, α-methyldopa, methotrexate)
  • Autoimmunity
• Changes in Chronic viral Hepatitis

  • Hepatocyte swelling, necrosis, and regeneration
  • Sinusoidal reactive changes
  • Portal tracts: Inflammation in portal tracts, or Spill over into adjacent parenchyma with cell necrosis (interface hepatitis or piecemeal necrosis)
  • Bridging inflammation and necrosis
  • Fibrosis: Portal or periportal deposition, or formation of bridging fibrous septa
  • Cirrhosis: The end-stage outcome
• Viral specific changes in Chronic Hepatitis

  • HBV: Ground-glass hepatocytes (accumulations of viral antigen in endoplasmic reticulum), and Sanded nuclei (nuclear viral inclusions)
  • HCV: Bile duct epithelial cell proliferation, and Lymphoid aggregate formation
• Serologic Diagnosis in viral hepatitis

  • HAV: Incubation period (2–6 wks), IgM appears in blood at onset of symptoms, Fecal shedding of virus ends as IgM titer rises, IgM begins to decline in few months and is followed by appearance of IgG which persists for years, perhaps for life, providing Protective immunity against Reinfection by all strains of HAV, Hence HAV vaccine is effective
  • HBV: (incubation period 6 to 8 wks), HBsAg appears before onset of symptoms, peaks during overt disease, declines in 3 to 6 months, HBeAg appear soon after HBsAg, and signify active viral replication, IgM anti-HBc shortly before onset of symptoms, concurrent with onset of elevation of serum aminotransferases, Over months, IgM antibody is replaced by IgG anti-HBc, Anti-HBe shortly after disappearance of HBeAg, IgG anti-HBs after disappearance of HBsAg, and may persist for life, conferring protection, The carrier state is defined by presence of HBsAg in serum for 6 months or longer after initial detection, The persistence of circulating HBsAg, HBeAg, usually with anti-HBc and occasionally anti-HBs indicate progressive liver damage
  • HCV: (incubation period 6 and 12 wks), HCV is detectable in blood for 1 to 3 weeks, coincident with elevations in Serum transaminases (ALT), anti-HCV antibodies emerge after 3 to 6 weeks, In chronic HCV infection, circulating HCV persists in many patients despite presence of neutralizing antibodies, Hence, in patients with symptoms of chronic hepatitis, HCV testing must be performed to confirm diagnosis of HCV infection, A clinical feature that is quite characteristic of chronic HCV infection is episodic elevations in serum aminotransferases, with intervening normal or near-normal periods
• Fulminant hepatitis and hepatic failure

  Hepatic insufficiency which progresses from onset of symptoms to hepatic encephalopathy within 2 to 3 weeks
• Causes of Fulminant hepatitis and hepatic failure

  • HAV or HBV
  • Drug and chemical toxicity: acetaminophen
  • Miscellaneous: mycotoxins of mushroom
  • Unknown: 18% of cases
• Clinical features of Fulminant hepatitis and hepatic failure

  • Jaundice, encephalopathy, and fetor hepaticus
• Mortality rate ranges from 25% to 90% in absence of liver transplantation
• Morphology of Fulminant hepatitis and hepatic failure

  • Grossly: necrotic areas have a muddy red appearance
  • Microscopically: complete destruction of hepatocytes in contiguous lobules with massive parenchymal necrosis, leaves only a collapsed reticulin framework and preserved portal tracts
• Alcoholic liver diseases: Hepatic Steatosis (Fatty Liver)


  Small microvesicular lipid droplets in hepatocytes, With chronic intake of alcohol: large macrovesicular, Initially is centrilobular, in severe cases involve entire lobule, Completely reversible if there is abstention from alcohol intake
• Alcoholic Steato Hepatitis (ASH)


  Hepatocyte swelling and necrosis, Mallory bodies: damaged cytokeratin intermediate filaments visible as eosinophilic cytoplasmic inclusions, are characteristic but not specific, Neutrophil infiltration: around degenerating hepatocytes particularly those with Mallory bodies, Fibrosis
• Alcoholic liver cirrhosis


  Irreversible, usually evolves slowly, Cirrhotic liver is brown, shrunken, Uniformly sized micronodules, but with time scattered macronodules create a "hobnail" appearance, Mallory bodies rarely evident, thus it resembles cirrhosis developing from other causes
• Nonalcoholic fatty liver (NAFL)


  Patients are not heavy alcohol drinkers, Strong association with obesity, dyslipidemia, and insulin resistance (type 2) diabetes, Patients are largely asymptomatic, with abnormalities only in lab. tests (elevated serum aminotransferases and/or γ-glutamyl transpeptidase), Liver biopsy shows: Steatosis (Large and small vesicles of fat), No hepatic inflammation, No hepatocyte necrosis, No fibrosis
• Nonalcoholic steatohepatitis (NASH)


  Liver biopsy shows: Steatosis, Multifocal parenchymal inflammation, Cirrhosis may occur
• Types of Hemochromatosis

  • Hereditary (primary) hemochromatosis
  • Acquired (secondary) hemochromatosis
• Hereditary (primary) hemochromatosis


  Autosomal-recessive inherited disorder, Gene located on chromosome 6 called HFE gene, Symptoms first appear in fifth to sixth decades of life, Males predominate (5-7: 1)
• Causes of Acquired (secondary) hemochromatosis

  • Parenteral iron overload: Transfusions, Iron-dextran injections
  • Ineffective erythropoiesis: β-Thalassemia, Sideroblastic anemia
  • Increased oral intake of iron
  • Congenital atransferrinemia
  • Chronic liver disease: Chronic alcoholic liver disease, Porphyria cutanea tarda
• Fully developed cases of Hemochromatosis exhibit

  • Micronodular cirrhosis in all patients
  • Diabetes mellitus in 75% to 80% of patients
  • Skin pigmentation in 75% to 80% of patients
• Death from cirrhosis or cardiac disease, Risk for hepatocellular carcinoma is 200-fold increased
• Screening tests for Hemochromatosis

  • Serum iron and serum ferritin: very high
  • Liver biopsy
  • Genetic screening for HFE gene
• Morphology of Hemochromatosis


  • Gross: Liver is slightly larger than normal, dense, chocolate brown
  • Microscope: Iron is evident as golden-yellow hemosiderin granules (H&E stain) which stain blue with Prussian blue stain, inflammation is absent, and fibrous septa develop slowly leading finally to cirrhosis
• Wilson Disease


  Autosomal-recessive disorder marked by accumulation of toxic levels of copper in many tissues and organs, The gene is ATP7B, located on chromosome 13
• Morphology of Wilson Disease

  • Fatty change, acute and chronic hepatitis, later on cirrhosis, Special stain: rhodanine stain for copper
• Clinical Features of Wilson Disease

  • Rarely manifests before 6 years of age
  • Acute or chronic liver disease
  • Neuropsychiatric manifestations (mild behavioral changes, frank psychosis, or Parkinson disease-like syndrome)
  • Eye lesions called Kayser-Fleischer rings: green to brown deposits of copper in cornea
• Diagnosis of Wilson Disease


  • Decrease in serum ceruloplasmin
  • Increase in hepatic copper content
  • Increased urinary excretion of copper
  • Serum copper level is of no diagnostic value, since may be low, normal, or elevated, depending on stage of evolution of disease
• Treatment: copper chelation therapy (D-penicillamine)
• α1-Antitrypsin Deficiency


  Autosomal-recessive disorder, Low serum levels of protease inhibitor (α1-antitrypsin), Leads to pulmonary emphysema and liver diseases (hepatitis, cirrhosis), Gene which located on chromosome 14 is very polymorphic (75 forms identified), Most common genotype is PiMM (90% of individuals), Most common mutation (homozygotes PiZZ) with circulating α1-antitrypsin level only 10% of normal, Hepatocellular carcinoma in 2% to 3% of PiZZ adults
• Morphology of α1-Antitrypsin Deficiency

  • Round-to-oval cytoplasmic inclusions in hepatocytes which are acidophilic in H &E stains, and strongly PAS-positive