What is the next step in management for a patient who is negative for hepatitis A and hepatitis D, and has no evidence of hepatitis B, but is presenting with symptoms suggestive of hepatitis?

Evaluation of Hepatitis with Negative HAV, HDV, and HBV Screening

The next step is to test for hepatitis C virus (HCV) with anti-HCV antibody testing, followed by HCV RNA confirmation if positive, as HCV is a leading cause of viral hepatitis when hepatitis A, B, and D are excluded. 1, 2

Immediate Diagnostic Workup

Test for Hepatitis C

• Order anti-HCV antibody testing immediately as HCV is one of the most common causes of viral hepatitis and chronic liver disease when other viral causes are excluded 1, 2
• If anti-HCV is positive, confirm current infection with qualitative HCV RNA testing 1, 2
• If HCV RNA is positive, proceed with quantitative HCV RNA and genotype testing 1, 2

Assess Liver Function and Inflammation

• Measure ALT, AST, alkaline phosphatase, bilirubin, albumin, and prothrombin time to assess severity of liver injury 1
• Complete blood count with platelets to evaluate for cytopenias suggesting advanced disease 1
• These tests help determine urgency of further evaluation and treatment 1, 2

Rule Out Non-Viral Causes

Since viral hepatitis A, B, and D are excluded, consider:

• Alcohol use history - fatty liver and alcohol-related damage are among the most common causes of abnormal liver tests 3
• Medication and drug toxicity - review all medications, supplements, and herbal products 1, 3
• Autoimmune hepatitis - check antinuclear antibodies (ANA), anti-smooth muscle antibodies, and immunoglobulin levels 3
• Metabolic causes - assess for hemochromatosis (ferritin, transferrin saturation), Wilson's disease (ceruloplasmin in patients <40 years), and alpha-1 antitrypsin deficiency 3
• Non-alcoholic fatty liver disease - evaluate metabolic syndrome components 3

Assess Disease Severity

Determine Degree of Fibrosis

• Use transient elastography (FibroScan) or other non-invasive fibrosis markers to assess for cirrhosis, as this determines urgency of treatment and need for surveillance 1
• Liver biopsy is rarely required but may be considered if multiple etiologies are suspected or non-invasive tests are inconclusive 1

Screen for Complications if Advanced Disease Present

• Abdominal ultrasound to evaluate liver architecture and screen for hepatocellular carcinoma 1
• Alpha-fetoprotein for HCC screening if cirrhosis is present 1

Additional Screening Considerations

Test for HIV Coinfection

• HIV testing with FDA-approved antigen/antibody test is recommended as HIV coinfection worsens HCV prognosis and requires modified management 1

Verify Hepatitis B Status More Thoroughly

Even with "negative" hepatitis B screening, ensure complete serologic evaluation was performed:

• HBsAg, anti-HBc (total), and anti-HBs should all be checked 1, 4
• Isolated anti-HBc positivity (HBsAg negative, anti-HBs negative) may indicate occult HBV infection and requires HBV DNA testing 1, 4
• This pattern can occur when anti-HBs has waned or during the "window period" of acute infection 1, 4

Vaccination Status

• Check anti-HAV IgG to determine if hepatitis A vaccination is needed, as acute HAV superinfection causes severe disease and higher mortality in patients with chronic liver disease 1, 5, 6
• Vaccinate against HAV if seronegative, especially if chronic liver disease is confirmed 1, 5, 6

Common Pitfalls to Avoid

• Do not assume "negative hepatitis B" is complete - verify that HBsAg, anti-HBc, and anti-HBs were all tested, as isolated anti-HBc positivity requires further evaluation 1, 4
• Do not delay HCV testing - it is the most likely viral cause when HAV, HBV, and HDV are excluded 1, 2
• Do not overlook non-viral causes - alcohol, medications, and metabolic diseases are common causes of hepatitis 3
• Do not forget to assess fibrosis stage - this determines treatment urgency and surveillance needs 1, 2

If HCV is Confirmed

• Antiviral treatment is recommended for all adults with chronic HCV infection to reduce mortality, cirrhosis, hepatic decompensation, and HCC 1
• Treatment should be initiated based on genotype, extent of fibrosis, and comorbidities 1, 2
• Direct-acting antivirals achieve >95% cure rates 1
• Monitor for HBV reactivation if any serologic evidence of past HBV infection exists (anti-HBc positive), as HCV treatment can trigger HBV reactivation 7