Liver Disease: Differential Diagnosis & Treatment

I. ACUTE LIVER DISEASE (Elevated Aminotransferases / Jaundice)

Differential Diagnosis at a Glance

Clinical tip: Drug-induced liver disease is underestimated in clinical practice — obtain a full drug history (including OTC and herbal supplements) in every acute hepatitis case. Autoimmune hepatitis presents acutely in up to 30% of cases. — Yamada's Textbook of Gastroenterology, p. 1900

II. CHRONIC LIVER DISEASE

A. Chronic Viral Hepatitis

Chronic Hepatitis B

• Diagnosis: HBsAg >6 months; HBV DNA level; HBeAg/anti-HBe; liver fibrosis staging (transient elastography, FIB-4, APRI)
• Treatment threshold: HBV DNA >2000 IU/mL + elevated ALT or significant fibrosis
• First-line agents (preferred): Entecavir, Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide (TAF) — lowest resistance profiles
• Alternative: Pegylated interferon-α (injectable; not for cirrhotics)
• Avoid: Lamivudine, adefovir, telbivudine (high resistance rates)
• ALT thresholds: ULN 35 U/L (males), 25 U/L (females) per AASLD 2018 guidance

— Sleisenger & Fordtran's, p. 1481–1483

Chronic Hepatitis C

• Treatment: Direct-acting antivirals (DAAs) achieve >95% cure (sustained virologic response), well tolerated, typically 8–12 weeks duration
• Even decompensated cirrhosis due to HCV benefits significantly

— Harrison's, p. 2754

Chronic Hepatitis D

• Only affects HBV-infected patients (coinfection or superinfection)
• Treatment: Pegylated interferon-α (only approved therapy); bulevirtide (entry inhibitor) approved in some regions

B. Alcohol-Associated Liver Disease (ALD)

• Spectrum: Steatosis → Alcoholic hepatitis → Cirrhosis
• Key labs: AST:ALT ratio >2:1; GGT elevated
• Treatment:
  • Abstinence — cornerstone of all stages
  • Severe alcoholic hepatitis (Maddrey's DF ≥32): Prednisolone 40 mg/day × 28 days
  • Pentoxifylline no longer recommended (STOPAH trial)
  • Nutritional support (thiamine, folate)
  • Liver transplantation for end-stage disease

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

• Previously NAFLD/NASH
• Spectrum: Steatosis → MASH (steatohepatitis) → Fibrosis → Cirrhosis
• Many patients with "cryptogenic cirrhosis" have underlying MASH
• Diagnosis: Ultrasound, FibroScan, liver biopsy; exclude other causes
• Treatment:
  • Weight loss (≥7–10% body weight) — first-line
  • Control metabolic risk factors (T2DM, hypertension, dyslipidemia)
  • Resmetirom (THRβ agonist) — FDA approved 2024 for MASH with fibrosis
  • GLP-1 agonists (semaglutide) — emerging evidence
  • Vitamin E (for non-diabetic adults with biopsy-proven MASH)

— Harrison's, p. 2754

D. Autoimmune Hepatitis (AIH)

• Predominantly women; elevated IgG; ANA/ASMA positive (Type 1) or anti-LKM1 (Type 2)
• Liver biopsy: interface hepatitis (piecemeal necrosis), plasma cell infiltrate
• Treatment:
  • Prednisone 40–60 mg/day (induction) → taper
  • Azathioprine 50–150 mg/day (steroid-sparing maintenance)
  • Mycophenolate mofetil — for azathioprine-intolerant patients
  • Burned-out AIH with cirrhosis: immunosuppression often not beneficial; manage complications

E. Cholestatic Liver Diseases

Primary Biliary Cholangitis (PBC)

• Female predominance; elevated ALP/GGT; AMA (antimitochondrial antibody) positive in ~95%
• Symptoms: Fatigue, pruritus; xanthomata, hyperpigmentation
• 4 histologic stages; may overlap with AIH
• Treatment:
  • Ursodeoxycholic acid (UDCA) 13–15 mg/kg/day — first-line (slows progression)
  • Obeticholic acid — second-line for UDCA non-responders
  • Bezafibrate/Fenofibrate — adjunctive
  • Pruritus: cholestyramine, rifampicin, naltrexone
  • Decompensated cirrhosis: Liver transplantation

— Harrison's, p. 2754

Primary Sclerosing Cholangitis (PSC)

• Male predominance; associated with IBD (especially UC) in ~70%
• Multifocal biliary strictures on MRCP/ERCP (beaded appearance)
• No proven medical therapy that alters progression
• Management: ERCP for dominant strictures; antibiotics for cholangitis
• High risk of cholangiocarcinoma (annual surveillance)
• Liver transplantation — definitive treatment

Autoimmune Cholangitis (AIC)

• AMA-negative PBC variant; positive ANA/ASMA
• Treat as PBC (UDCA)

F. Hereditary/Metabolic Liver Diseases

G. Vascular Liver Diseases

III. CIRRHOSIS — Managing Complications

— Harrison's, p. 2754; Sleisenger & Fordtran's

IV. ACUTE LIVER FAILURE (ALF)

• Causes: Acetaminophen (most common in the West), viral hepatitis (HEV in developing countries), AIH, Wilson disease, Budd-Chiari, DILI
• Management:
  • N-acetylcysteine (NAC) — for acetaminophen; also beneficial in non-acetaminophen ALF
  • Treat precipitant (e.g., antivirals for HBV)
  • Manage complications: encephalopathy (lactulose, elevated head of bed), coagulopathy, hypoglycemia, renal failure, cerebral edema (mannitol)
  • Early referral to transplant center — if INR rising, encephalopathy developing
  • King's College Criteria guide transplant listing

Key Diagnostic Tests Summary