Skip to content

Cirrhosis and Liver Diseases Revision Notes

Nonalcoholic Fatty Liver Disease (NAFLD)

Definition

  • NAFLD encompasses a range of liver conditions:
    • Steatosis (NAFL): Fat accumulation without inflammation.
    • Steatohepatitis (NASH): Fat accumulation with inflammation and hepatocyte injury.
    • Cirrhosis: Advanced scarring of the liver.

Epidemiology

  • Most common cause of liver test elevation globally.
  • Affects ~30% of the US population; 15%-20% risk progression to cirrhosis.
  • Projected 100 million US citizens affected by 2030.
  • Associated with obesity, type 2 diabetes, and cardiovascular diseases.

Histopathology

  • Similar to Alcoholic Liver Disease (ALD) but with distinctions.
  • Features:
    • Steatosis: Mainly macrovesicular.
    • Hepatocyte ballooning.
    • Lobular inflammation: Mild, may include neutrophils.
    • Perisinusoidal fibrosis.
    • Small lipogranulomas.
  • Mallory-Denk bodies:
    • May be absent or poorly formed.
    • Restricted to ballooned hepatocytes in NASH.
  • Fibrosis progression:
    • Begins in pericentral perisinusoidal spaces.
    • Extends to portal and periportal fibrosis.
    • May lead to bridging fibrosis and cirrhosis.
  • Grading and Staging:
    • Based on steatosis, ballooning, inflammation, and fibrosis.
    • NASH Clinical Research Network system widely used.

Differential Diagnosis

  • Marked portal inflammation with lymphoid aggregates or plasma cells suggests:
    • Chronic viral hepatitis.
    • Autoimmune hepatitis (AIH).
  • Cholestasis and broad septa are rare in NASH but common in ALD.

Cirrhosis in NASH

  • Histologic features may disappear as fibrosis progresses.
  • Cryptogenic cirrhosis requires prior biopsy evidence of NASH for diagnosis.

Chronic Hepatitis C

Epidemiology

  • High cirrhosis rate before interferon-sparing therapies.
  • Risk factors for progression:
    • Long infection duration.
    • Alcohol consumption.
    • Coinfection with HBV or HIV.
    • Nonresponse to antiviral therapy.
    • Male gender.
  • Post-cure fibrosis progression occurs in some patients.

Histopathology

  • Cirrhosis patterns:
    • Macronodular or mixed nodularity.
  • Fibrovascular septa vary in width.
  • Portal inflammation:
    • Mononuclear cells: Lymphocytes, plasma cells, eosinophils.
    • Lymphoid aggregates with germinal centers (characteristic).
  • Bile duct damage (Poulsen lesion) may be mild.
  • Interface hepatitis may be present.
  • Lobular inflammation:
    • Spotty and mild.
    • May include acidophilic bodies.
  • Subendothelial inflammation in portal veins (endotheliitis).

Chronic Hepatitis B

Epidemiology

  • Common cause of cirrhosis.

Histopathology

  • Severe necroinflammation, especially during exacerbations.
  • Bridging necrosis with lobular collapse.
  • Ground-glass inclusions:
    • Pale or eosinophilic hepatocyte cytoplasm.
    • Due to hepatitis B surface antigen accumulation.
    • Confirmed with orcein or Victoria blue stains or immunohistochemistry.
  • Coinfection with HDV:
    • More severe damage.
    • Accelerated cirrhosis.
    • Diagnosed via immunohistochemical detection of HDV antigen.

Autoimmune Hepatitis (AIH)

Diagnosis

  • Based on clinical, laboratory, and histopathologic findings.
  • Liver biopsy confirms and excludes other causes.

Histopathology

  • Dense mononuclear infiltrate: Portal, septal, lobular areas.
  • Marked interface hepatitis.
  • Plasma cells are prominent.
  • Hepatic rosettes: Pseudoacinar formations.
  • Severe cases: Confluent or bridging necrosis.
  • Centilobular necrosis with mild portal inflammation can occur.
  • Rapid fibrosis progression if untreated.
  • In cirrhosis, plasma cells and rosettes may diminish.

Burned-out AIH

  • May cause cryptogenic cirrhosis.
  • Features may be absent in advanced stages.

Primary Biliary Cholangitis (PBC)

Definition

  • Autoimmune destruction of intrahepatic bile ducts.
  • Predominantly affects women during or after childbearing years.

Pathogenesis

  • Multifactorial and poorly understood.

Histopathology

  • Florid duct lesion (pathognomonic):
    • Lymphocytic or granulomatous bile duct infiltration.
  • Portal inflammation: Mixed infiltrate with lymphocytes, plasma cells, eosinophils.
  • Ductular reaction, interface hepatitis, and periportal changes.
  • Cholate stasis: Foamy hepatocyte changes due to bile salts.
  • Copper deposition in hepatocytes.
  • Ductopenia in advanced stages.
  • Canalicular cholestasis with bile plugs in late stages.

Diagnosis

  • Positive anti-mitochondrial antibody (AMA).
  • Presence of florid duct lesion is diagnostic.

Overlap Syndrome

  • Features of AIH may occur with or precede PBC.
  • Treatment guided by dominant histopathologic process.

Complications

  • Hepatocellular carcinoma (HCC) risk similar to cirrhotic HCV.
  • Non-response to ursodeoxycholic acid (URSO) increases risk.

Primary Sclerosing Cholangitis (PSC)

Definition

  • Idiopathic inflammation and fibrosis of bile ducts.
  • Affects both extrahepatic and intrahepatic ducts.

Epidemiology

  • Associated with inflammatory bowel disease (especially ulcerative colitis).
  • More common in young men.

Histopathology

  • Onion-skin periductal fibrosis:
    • Concentric fibrosis around bile ducts.
    • Indicates chronic biliary obstruction.
  • Duct atrophy and degeneration.
  • Fibro-obliterative scars replacing ducts.
  • Ductopenia and chronic cholestasis features.

Diagnosis

  • Based on characteristic imaging findings.
  • Liver biopsy less useful due to disease inhomogeneity.

Complications

  • Cholangiocarcinoma (CCA):
    • 400- to 1500-fold increased risk.
    • Often occurs within first year of PSC diagnosis.
  • Increased risk of colorectal carcinoma, gallbladder carcinoma, and HCC.

Hereditary Hemochromatosis (HH)

Definition

  • Autosomal recessive disorder causing iron overload.

Genetics

  • Commonly due to homozygous C282Y mutation in the HFE gene.
  • Results in abnormal expression of hepcidin.

Histopathology

  • Iron deposition:
    • Begins in zone 1 (periportal) hepatocytes.
    • Decreases toward centrilobular areas.
    • Prussian blue stain shows iron granules.
  • Progression:
    • Iron throughout lobule in hepatocytes, Kupffer cells, bile duct cells, portal macrophages.
    • Siderotic nodules (Kupffer cell clusters).
    • Minimal portal/lobular inflammation.
  • Fibrosis:
    • Portal-based.
    • Cirrhosis is typically micronodular.
    • Iron-loaded hepatocytes in cirrhotic nodules.

Diagnosis

  • Confirmed by genetic testing.
  • Hepatic iron index via chemical quantitation.

Differential Diagnosis

  • Secondary iron overload in chronic HCV, HBV, ALD, NASH.
  • Mild iron deposition; higher scores may indicate HH.

Complications

  • Increased risk of HCC in C282Y homozygous patients.

Wilson Disease

Definition

  • Autosomal recessive disorder of copper metabolism.
  • Mutation in ATP7B gene.

Clinical Presentation

  • Young to middle-aged patients with unexplained liver disease.
  • Neuropsychiatric symptoms common.
  • Hemolytic anemia may occur.

Histopathology

  • Variable features:
    • Portal lymphocytic infiltration with interface hepatitis.
    • Steatosis, necrosis, anisocytosis, anisonucleosis.
    • Lipofuscin accumulation.
    • Canalicular cholestasis.
    • Iron accumulation.
  • Cirrhosis is usually micronodular.

Diagnosis

  • Copper stains (rhodanine, rubeanic acid, orcein, Victoria blue):
    • May be negative in early stages.
    • Detect copper in advanced stages.
  • Hepatic copper concentration assay:
    • 250 μg/g dry weight is diagnostic.
  • Genetic testing is complex due to multiple mutations.

Differential Diagnosis

  • Chronic hepatitis, steatohepatitis, PBC, PSC, iron overload, non-Wilson copper toxicosis.

α1-Antitrypsin Deficiency

Definition

  • Genetic disorder due to retention of mutant α1-antitrypsin protein.
  • Leads to hepatocyte injury and death.

Genetics

  • Caused by mutations in the SERPINA1 gene.
  • PiZZ genotype (homozygous) commonly associated with liver disease.
  • PiMZ genotype (heterozygous) may predispose to other liver injuries.

Histopathology

  • Eosinophilic globules in zone 1 hepatocytes:
    • Contain misfolded α1-antitrypsin.
    • Best seen with PAS-diastase (PAS-d) stain.
    • Confirmed by immunohistochemistry.

Clinical Implications

  • Cirrhosis patterns vary: micronodular, macronodular, biliary, or mixed.
  • HCC may develop in cirrhotic livers.
  • Exclude other causes like HCV or alcohol.

Cryptogenic Cirrhosis

Definition

  • Cirrhosis with no identifiable cause.
  • Accounts for 10%-15% of cases.

Possible Etiologies

  • Burned-out NASH:
    • Advanced fibrosis may lack NASH features.
    • Associated with type 2 diabetes and obesity.
    • Common post-transplant recurrence.
  • Autoimmune Hepatitis (AIH):
    • May be seronegative in advanced stages.
  • Primary Sclerosing Cholangitis (PSC).
  • Alcoholic Cirrhosis.
  • Budd-Chiari Syndrome.
  • Genetic mutations in keratins or transporter proteins.

Diagnosis

  • Requires careful review of prior liver biopsies.
  • Exclude other possible causes.