3.6 Viral Hepatitis, Steatotic & Alcohol-Associated Liver Disease

Hepatology represents one of the highest-yield domains on the ABIM examination. Board candidates must be proficient in viral hepatitis serology, non-invasive fibrosis scoring for steatohepatitis, alcoholic hepatitis prognostic models, and the comprehensive algorithmic management of decompensated cirrhosis.

1. Viral Hepatitis

Hepatitis B Virus (HBV) Serologic Profiling

HBsAg (+) ➔ Active Infection (Acute or Chronic)
Anti-HBs (+) ➔ Immunity (Vaccination or Resolved Natural Infection)
Anti-HBc IgM (+) ➔ Acute Infection (Sole marker positive during 'Window Period')
Anti-HBc IgG / Total (+) ➔ Prior Natural Infection (Never positive after vaccination alone)
HBeAg (+) / High HBV DNA ➔ Active Viral Replication & High Infectivity

Indications for HBV Antiviral Therapy (AASLD Guidelines)

1. Immune-Active Chronic HBV: Elevated ALT ($>2\times\text{ ULN}$) AND elevated viral load ($\text{HBV DNA} > 20,000\text{ IU/mL}$ if HBeAg positive; $\text{HBV DNA} > 2,000\text{ IU/mL}$ if HBeAg negative).
2. Cirrhosis (Compensated or Decompensated): Any patient with cirrhosis and detectable HBV DNA, regardless of ALT level.
3. Immunosuppression Prophylaxis: Any patient who is HBsAg positive OR Anti-HBc positive undergoing B-cell depleting chemotherapy (e.g., Rituximab), anti-TNF therapy, or high-dose corticosteroids must receive prophylactic oral antiviral therapy to prevent fatal HBV reactivation.

First-Line Antiviral Regimens (High Barrier to Resistance)

• Entecavir (ETV): 0.5 mg PO daily (1.0 mg PO daily in decompensated cirrhosis or lamivudine resistance).
• Tenofovir Disoproxil Fumarate (TDF): 300 mg PO daily (monitor for renal tubular dysfunction and bone mineral density loss).
• Tenofovir Alafenamide (TAF): 25 mg PO daily (preferred in patients with renal insufficiency [$\text{eGFR} \ge 15\text{ mL/min}$], osteoporosis, or age $>60$).

Hepatitis C Virus (HCV)

• Universal Screening: Universal one-time screening for all adults aged $\ge 18$ years (and with every pregnancy) using Anti-HCV Antibody with reflex to quantitative HCV RNA PCR.
• Diagnostic Rule: Anti-HCV Ab (+) followed by HCV RNA (+) indicates active chronic viremia. If Anti-HCV Ab (+) but HCV RNA (-), this represents spontaneously resolved past infection (~20–25% of acute cases) or successfully treated infection.
• Direct-Acting Antivirals (DAAs): Oral, interferon-free regimens administered for 8 to 12 weeks achieve $>95-98%$ Sustained Virologic Response (SVR12), defined as undetectable HCV RNA 12 weeks after treatment completion (equating to virologic cure).
  • Glecaprevir / Pibrentasvir (Mavyret): 3 tablets once daily with food for 8 weeks in treatment-naive non-cirrhotic or compensated cirrhotic patients.
  • Sofosbuvir / Velpatasvir (Epclusa): 1 tablet once daily for 12 weeks.
• Critical Black Box Pre-Treatment Check: Must screen for Hepatitis B (HBsAg, Anti-HBc) prior to initiating DAAs because rapid HCV eradication can trigger fulminant, fatal HBV reactivation.

2. Steatotic & Alcohol-Associated Liver Diseases

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD / MASH)

• Terminology: MASLD (formerly NAFLD) requires hepatic steatosis on imaging/biopsy plus at least 1 cardiometabolic criterion (BMI $\ge 25$, Type 2 DM, HTN, hypertriglyceridemia, or low HDL). MASH (formerly NASH) denotes steatohepatitis with hepatocyte ballooning, lobular inflammation, and progressive fibrosis.
• Non-Invasive Fibrosis Risk Stratification (FIB-4 Index): $\text{FIB-4} = \frac{\text{Age } (\text{years}) \times \text{AST } (\text{U/L})}{\text{Platelet Count } (10^9/\text{L}) \times \sqrt{\text{ALT } (\text{U/L})}}$
  • FIB-4 $< 1.3$ ($<2.0$ if age $>65$): Low risk for advanced fibrosis. Manage in primary care; repeat every 2–3 years.
  • FIB-4 $1.3 - 2.67$: Indeterminate risk. Reflex to Transient Elastography (FibroScan): Liver Stiffness Measurement (LSM) $<8\text{ kPa}$ (low risk), $8-12\text{ kPa}$ (intermediate), $>12\text{ kPa}$ (advanced fibrosis/cirrhosis).
  • FIB-4 $> 2.67$: High risk for advanced fibrosis (F3–F4). Prompt hepatology referral.
• Management: Weight loss of $7-10%$ total body weight (reverses steatohepatitis and fibrosis); GLP-1 receptor agonists (Semaglutide, Tirzepatide); Pioglitazone; and Resmetirom (thyroid hormone receptor-beta agonist approved for non-cirrhotic MASH with moderate-to-advanced fibrosis F2–F3).

Alcohol-Associated Liver Disease & Alcoholic Hepatitis

• Hallmark Laboratory Pattern: AST elevated higher than ALT with an $\text{AST}:\text{ALT Ratio} > 2:1$ (reflecting hepatic pyridoxal 5'-phosphate [vitamin B6] deficiency). AST and ALT levels rarely exceed $300-400\text{ U/L}$. (Transaminases $>500-1,000\text{ U/L}$ suggest ischemic hepatitis, toxic/acetaminophen injury, or acute viral hepatitis).
• Severe Alcoholic Hepatitis: Characterized by acute jaundice, fever, tender hepatomegaly, and coagulopathy in a patient with heavy chronic alcohol intake.
• Prognostic Stratification:
  • Maddrey Discriminant Function (DF): $\text{DF} = 4.6 \times [\text{PT}_{\text{patient}} - \text{PT}_{\text{control}}] + \text{Total Bilirubin (mg/dL)}$
  • Severe disease is defined as Maddrey $\text{DF} \ge 32$ OR MELD Score $> 20$ (predicts 30-day mortality of 30–50%).
• Targeted Pharmacotherapy:
  • Prednisolone 40 mg PO daily for 28 days (prednisolone is preferred over prednisone because it does not require hepatic conversion).
  • Lille Score Assessment at Day 7: Calculate Lille score on day 7 of steroid therapy:
    • Lille Score $< 0.45$ (Responder): Continue Prednisolone to complete the 28-day course, followed by a 2–4 week taper.
    • Lille Score $\ge 0.45$ (Non-Responder): STOP Prednisolone immediately (steroids provide no survival benefit in non-responders and dramatically increase fatal fungal and bacterial infections).
  • Contraindications to Steroids: Active uncontrolled infection/sepsis, active GI hemorrhage, or acute kidney injury.