What are the steps to diagnose hepatitis?

Diagnosis of Hepatitis

Diagnose hepatitis through serological testing for viral markers (HBsAg, anti-HCV antibodies) combined with HBV/HCV RNA detection by sensitive molecular methods, alongside liver function tests and assessment of disease severity. 1, 2

Initial Clinical Assessment

History and Physical Examination

• Obtain detailed risk factor assessment including sexual history, injection drug use, blood transfusion history, travel to endemic areas, family history of HBV infection and liver cancer, and occupational exposures 1, 3
• Assess alcohol consumption as this significantly impacts disease progression 1
• Query symptoms including duration and severity of jaundice, fatigue, abdominal pain, nausea/vomiting, fever, dark urine, and clay-colored stools 3
• Physical examination should focus on signs of chronic liver disease (which should be absent in acute hepatitis), jaundice, hepatomegaly, splenomegaly, and stigmata of cirrhosis 1, 3

Serological Testing for Hepatitis B

Primary Diagnostic Markers

• HBsAg is the hallmark marker for active HBV infection; positivity for >6 months defines chronic infection 1, 2, 4
• Anti-HBc total indicates current or previous HBV infection 2
• Anti-HBc IgM is positive in acute infection and helps differentiate acute from chronic hepatitis B 1, 2, 5
• Anti-HBs indicates recovery from infection or successful vaccination 2

Replication Status Markers

• HBeAg positivity indicates high viral replication and increased transmission risk 1, 2, 4
• Anti-HBe positivity generally indicates lower viral replication 1, 2

Common Serological Patterns

• Acute HBV infection: HBsAg positive, IgM anti-HBc positive 2, 5
• Chronic HBV infection: HBsAg positive for >6 months, total anti-HBc positive, IgM anti-HBc negative 1, 2
• Past infection with immunity: HBsAg negative, anti-HBs positive, total anti-HBc positive 2
• Vaccine-induced immunity: HBsAg negative, anti-HBs positive, total anti-HBc negative 2

Critical pitfall: During the "window period" of acute infection, both HBsAg and anti-HBs may be negative; only IgM anti-HBc will be positive 2

Serological Testing for Hepatitis C

• Anti-HCV antibodies by enzyme immunoassay (EIA) is the initial screening test 1, 6
• Third-generation anti-HCV tests (EIA-3) contain antigens from HCV core, NS3, NS4, and NS5 genes and offer improved sensitivity 6
• Recombinant immunoblot assay (RIBA) serves as a supplemental test to resolve false-positive EIA results in low-prevalence settings 6

Molecular/Virological Testing

HBV DNA Quantification

• HBV DNA measurement by sensitive molecular methods (lower limit of detection <50 IU/mL, ideally real-time PCR) is essential for diagnosis, assessing viral replication, and treatment decisions 1, 2
• HBeAg-positive chronic hepatitis B: serum HBV DNA ≥20,000 IU/mL (≥10^5 copies/mL) 1, 2
• HBeAg-negative chronic hepatitis B: serum HBV DNA ≥2,000 IU/mL (≥10^4 copies/mL) 1, 2
• Inactive carrier state: HBV DNA <2,000 IU/mL (<10^4 copies/mL) 1, 2

Important caveat: HBeAg-negative chronic hepatitis B can have lower HBV DNA levels but still cause progressive liver disease 2

HCV RNA Detection

• HCV RNA detection by sensitive molecular method (lower limit <50 IU/mL) provides evidence of active infection and is required for acute hepatitis C diagnosis since HCV RNA appears before anti-HCV antibodies 1
• Quantitative PCR is the most sensitive test for HCV viral load, while branched-chain DNA offers better precision 6

Special Situations

• Immunosuppressed patients may be anti-HCV or anti-HBc negative despite active infection; test for HCV RNA or HBV DNA if hepatitis is present 1, 2
• Occult HBV infection is defined as absence of HBsAg with detectable HBV DNA in serum or tissue 4
• Isolated anti-HBc positivity requires follow-up testing and HBV DNA measurement to distinguish window phase, past infection with undetectable anti-HBs, or occult hepatitis B 1, 2

Biochemical Assessment

Liver Function Tests

• ALT/AST to assess liver inflammation and necroinflammatory activity 1, 2
• Alkaline phosphatase and GGT as additional markers of liver injury 1, 2
• Bilirubin to evaluate liver function 2
• Albumin to assess synthetic liver function 2
• Prothrombin time/INR to evaluate coagulation and liver synthetic function 2
• Complete blood count with platelets to assess for cytopenias suggesting advanced disease 1, 3

Diagnostic Criteria for Chronic Hepatitis B

1. HBsAg positive >6 months 1
2. Elevated HBV DNA (≥20,000 IU/mL for HBeAg-positive; ≥2,000 IU/mL for HBeAg-negative) 1
3. Persistent or intermittent elevation in ALT/AST 1
4. Liver biopsy showing chronic hepatitis with moderate-to-severe necroinflammation (optional) 1

Diagnostic Criteria for Inactive HBsAg Carrier State

1. HBsAg positive >6 months 1
2. HBeAg negative, anti-HBe positive 1
3. Serum HBV DNA <2,000 IU/mL 1
4. Persistently normal ALT/AST levels 1
5. Liver biopsy confirms absence of significant necroinflammation (optional) 1

Assessment of Disease Severity

• Abdominal ultrasound is recommended in all patients 1
• Liver biopsy or non-invasive fibrosis assessment (such as transient elastography) should be performed to determine disease activity when biochemical and HBV markers are inconclusive 1, 2
• Transient elastography offers higher diagnostic accuracy for detecting cirrhosis but results may be confounded by severe inflammation with high ALT levels 1
• Non-invasive methods are better at excluding than confirming advanced fibrosis or cirrhosis 1

Testing for Coinfections

• Anti-HCV testing to rule out hepatitis C coinfection 1, 2
• Anti-HDV testing in patients with history of injection drug use or from endemic areas 1, 2
• Anti-HIV testing in high-risk groups 1, 2
• Anti-HAV IgG testing to determine immunity status; vaccinate if negative in patients <50 years with chronic liver disease 1, 2

Additional Screening

• Alpha-fetoprotein for baseline HCC screening 1, 3, 2
• Hepatic ultrasound for baseline evaluation and HCC surveillance in high-risk patients 1, 3

Monitoring Recommendations

For Untreated Chronic HBV Patients

• ALT every 3-6 months 1, 3, 2
• HBV DNA every 6-12 months 2
• HBeAg/anti-HBe status annually 2

For HBeAg-Positive Patients with Normal ALT

• Monitor at 3-6 month intervals 1
• More frequent monitoring when ALT becomes elevated 1
• Consider liver biopsy and treatment if HBV DNA >10^5 copies/mL persists after 3-6 months of elevated ALT 1

For Cirrhotic Patients

• More frequent monitoring with ultrasound every 6 months for HCC surveillance 2

Family and Contact Screening

• All first-degree relatives and sexual partners should be tested for HBV serological markers (HBsAg, anti-HBs, anti-HBc) and vaccinated if negative 1