Genetic Liver Diseases Quiz

Internal Medicine: 45-Year-Old Male with Abnormal Liver Chemistries

• Learning Objectives: Understand the pathophysiology of hyperbilirubinemia types, common liver diseases (inherited and acquired), viral hepatitis risk factors, AUDIT-C for alcohol use, laboratory testing for liver disease, liver biopsy indications, and diagnostic error reduction tools.

Historical Features for Elevated Liver Enzymes

• Initial Evaluation: Comprehensive history and physical examination to identify signs/symptoms of liver disease followed by further liver function tests.
• Important History Elements:
  • Jaundice and pruritus (cholestasis)
  • Weight loss and fever (significant liver disease)
  • Rectal bleeding (portal hypertension)
  • Dark urine (bilirubin excretion)
  • Light-colored stools (biliary obstruction)
  • Abdominal pain, diarrhea, increased abdominal girth, edema, nausea, vomiting (with or without hematemesis), altered mental status.

Risk Factors for Liver Disease

• Alcohol Use Disorder: Greater than or equal to 3 drinks per day (men) or greater than or equal to 2 drinks per day (women) is considered harmful drinking.
• Family History: Significant familial history of Wilson's disease, hemochromatosis, alpha-1-antitrypsin deficiency, or Gilbert syndrome.
• Blood Transfusions/Solid Organ Transplants (pre-1992): Potential hepatitis C risk
• Clotting Factor Transfusions (pre-1987): Potential hepatitis C risk
• Occupational Exposure: Exposure to HCV-positive blood (needle sticks).
• Food Consumption: Eating uncooked HAV-contaminated food or water (risk for hepatitis A)

Other Relevant Information

• Diabetes Mellitus: Increases risk of metabolic dysfunction-associated steatohepatitis (MASH)
• HIV: Increased risk of hepatitis C co-infection, particularly in men who have sex with men (MSM).
• Injection Drug Use: High risk factor for hepatitis C transmission
• Vaccination History: Important, especially hepatitis A and B

Bilirubin Production and Metabolism

• Bilirubin production: Approximately 4 mg/kg per day from senescent red blood cells
• Normal process: Conjugation to facilitate bile excretion.
• Measurement: Divide into direct (conjugated) and indirect (unconjugated) fractions to assess mechanisms of elevated bilirubin.

Hyperbilirubinemia Mechanisms

• Increased Production: Hemolysis increases unconjugated bilirubin (e.g., hemolytic anemias, spherocytosis, sickle cell disease, G6PD deficiency)
• Intrahepatic Causes (unconjugated): Gilbert syndrome (hereditary decrease in glucuronosyltransferase) - transient elevations with stress, illness, etc..
• Intrahepatic Causes (conjugated): Inflammation disrupting bilirubin transport, or hepatocyte dysfunction (acute - toxin/ischemia/drugs/viral; chronic - viral, alcohol, Wilson's, hemochromatosis, MASH, alpha-1-antitrypsin deficiency, autoimmune). Rare hereditary conditions like Dubin-Johnson, and Rotor syndromes cause reduced excretion.
• Posthepatic Causes: Extrahepatic cholestasis due to obstruction (gallstones, tumors, primary sclerosing cholangitis).

Additional Liver Conditions

• Autoimmune Hepatitis: More common in women, occurs with other autoimmune diseases.
• Alcohol-Associated Liver Disease: Spectrum from fatty liver to hepatitis to cirrhosis; increased risk with 6-8 drinks/day-risk increases with chronic use.
• Metabolic Dysfunction-Associated Steatohepatitis (MASH): Similar to alcoholic liver damage but without alcohol use - high risk factors: obesity, male sex, diabetes mellitus, and hyperlipidemia.
• Genetic Liver Diseases: Alpha-1 antitrypsin deficiency and hemochromatosis (genetic, elevated aminotransferases; hemochromatosis - iron overload, symptoms, diagnosis by genetic testing and iron studies).
• Wilson's Disease: Genetic disease, impaired copper metabolism, symptoms in young adults.

Diagnostic Considerations

• Pretest probability: crucial element in guiding the diagnostic process (patient demographics, lifestyle, and prior diagnoses)
• Clinical prediction rules: (e.g., Ottawa Ankle Rule, Wells Criteria)
• Multiple potential causes: Evaluate likelihood of each potential diagnosis when multiple causes are possible.
• Hepatitis Serologies: Presence of antibodies confirms past exposure to the virus, but additional testing (RNA) is needed to confirm chronic active infection; testing depends on reasons for suspicion.
• Diagnostic tests: Laboratory values including the role of liver enzymes and specific liver chemistries are useful and crucial to assess the health of the liver.

Management Considerations

• Hepatitis C Treatment: Newer direct-acting antiviral (DAA) medications are effective. Genotype-specific treatments are available.
• Secondary Prevention: Advise on abstaining from alcohol and illicit drugs, managing medications (acetaminophen) and vaccinations (hepatitis A and B).
• Liver Chemistries: Include bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl-transferase (GGT) and alkaline phosphatase to assess liver disease.

Other Important Clinical Considerations

• Alcohol Use Disorders Identification Test (AUDIT-C): screening for alcohol consumption.
• Specific patient questions regarding alcohol use and harmful drinking need specific and appropriate medical attention based on the factors.
• Need for thorough patient history and examination (lifestyle, prescriptions/over-the-counter medications)