What is the recommended workup and treatment for a patient presenting with suspected viral hepatitis?

Workup for Viral Hepatitis

Initial Serologic Testing

All patients with suspected viral hepatitis should undergo comprehensive serologic testing including HCV antibody with reflex HCV RNA PCR, HBsAg, anti-HBs, anti-HBc total, and anti-HDV testing in HBsAg-positive patients. 1, 2

Hepatitis B Testing Panel

• HBsAg (Hepatitis B surface antigen) identifies current HBV infection, whether acute or chronic 3, 2
• Anti-HBs (Hepatitis B surface antibody) indicates immunity from vaccination or recovery from past infection 2
• Anti-HBc total (Hepatitis B core total antibodies) indicates previous or ongoing HBV infection 3, 2
• HBeAg (Hepatitis B e antigen) serves as a marker of high viral replication 2
• Anti-HBe (Hepatitis B e antibody) usually indicates lower viral replication 2
• HBV DNA quantitative (viral load) assesses level of viral replication and is essential for treatment decisions 1, 2

Hepatitis C Testing Panel

• Anti-HCV antibody is the initial screening test, with reflex to HCV RNA PCR testing 1, 2
• HCV RNA quantitative (viral load) confirms active infection if antibody is positive and is required prior to initiating antiviral therapy 3, 1, 2
• HCV genotype determination is recommended to determine duration of treatment 3

Hepatitis D Testing (in HBsAg-positive patients)

• Anti-HDV total antibodies screens for HDV coinfection or superinfection 3, 1, 2
• Anti-HDV IgM indicates acute HDV infection 2
• HDV RNA confirms active HDV replication 3, 2

Hepatitis A and E Testing

• Hepatitis A antibody testing (IgM and total) should be included to assess for acute infection or immunity 1
• Hepatitis E testing should be considered in patients with recent travel to endemic areas (Russia, Pakistan, Mexico, India) 3

Additional Laboratory Workup

Liver Function and Disease Severity Assessment

• Hepatic function panel including ALT, AST, alkaline phosphatase, GGT, bilirubin, albumin, and prothrombin time/INR 3, 2
• Complete blood count to assess for thrombocytopenia as a marker of portal hypertension 2
• Calculate FIB-4 score for noninvasive assessment of fibrosis 3
• Transient elastography (FibroScan) provides point-of-care information regarding liver stiffness; stiffness >12.5 kPa indicates cirrhosis 3

Coinfection Screening

• HIV testing with FDA-approved HIV-antigen/antibody test is mandatory due to shared risk factors and impact on management 3, 1, 2
• Renal function tests (BUN and creatinine) are recommended 2

Hepatocellular Carcinoma Screening

• Alpha-fetoprotein (AFP) for screening for hepatocellular carcinoma in chronic hepatitis patients 2
• Abdominal ultrasound every 6 months for patients with cirrhosis or advanced fibrosis (FIB-4 >3.25) 3

Cirrhosis Assessment

Liver biopsy is not required for the purpose of initial assessment. 3 A patient is presumed to have cirrhosis if they have:

• FIB-4 score >3.25 3
• Transient elastography indicating cirrhosis (e.g., FibroScan stiffness >12.5 kPa) 3
• Noninvasive serologic tests above proprietary cutoffs indicating cirrhosis (e.g., FibroSure, Enhanced Liver Fibrosis Test) 3
• Clinical evidence of cirrhosis (e.g., liver nodularity and/or splenomegaly on imaging, platelet count <150,000/mm³) 3

Interpretation of Hepatitis B Serologic Patterns

• Acute HBV infection: Positive HBsAg and IgM anti-HBc, negative anti-HBs 2
• Chronic HBV infection: Positive HBsAg for >6 months, total anti-HBc, variable HBeAg, anti-HBe, and HBV DNA levels 2
• Past HBV infection (resolved): Positive anti-HBs and total anti-HBc, negative HBsAg 2, 4
• Vaccine-induced immunity: Positive anti-HBs only, negative HBsAg and anti-HBc 2

Treatment Approach by Etiology

Hepatitis C Management

All patients with chronic HCV infection should receive direct-acting antivirals (DAAs). 3, 1

• Recommended first-line regimens include glecaprevir/pibrentasvir (300 mg/120 mg) taken with food or sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks 3
• Treatment duration is typically 8-12 weeks based on genotype, prior treatment, and cirrhosis status 2
• Assessment of cure (SVR) requires quantitative HCV RNA and hepatic function panel 12 weeks or later following completion of therapy to confirm HCV RNA is undetectable 3

Hepatitis B Management

Treatment decisions are based on HBV DNA levels, ALT levels, and liver disease severity. 1, 2

• First-line agents are nucleos(t)ide analogues with high barrier to resistance (entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide) 1, 2
• Treatment goals include HBV DNA suppression, ALT normalization, HBeAg seroconversion, and ideally HBsAg loss 2
• Patients with resolved HBV infection (HBsAg negative, anti-HBc positive, anti-HBs positive) do not require antiviral therapy unless receiving immunosuppressive therapy 4

Hepatitis D Management

HDV remains the most challenging type of chronic viral hepatitis with less favorable response rates. 5

• HCC surveillance should be performed by ultrasound every 6 months in patients with CHD and advanced fibrosis or cirrhosis 3
• Patients with CHD should receive regular work-up for liver disease at least every 6-12 months 3

Special Considerations and Critical Pitfalls

HBV Reactivation Risk

Screening for HBV before immunosuppressive therapy is mandatory; antiviral prophylaxis is required for high-risk patients. 3, 4

• Highest risk regimens include anti-CD20 antibodies (rituximab), anti-CD52 antibodies, high-dose corticosteroids, and stem cell transplantation 4
• For anti-CD20 therapy or stem cell transplantation, prophylactic entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide should be started and continued for at least 12 months after last dose 4
• Nucleoside analogs should be given prior to and continued for 6 months after completion of chemotherapy in patients with HBsAg positivity to prevent reactivation/acute flare of disease 3

Critical Pitfalls to Avoid

• Do not miss testing for HDV in HBsAg-positive patients, as it significantly worsens prognosis 1
• Do not assume a negative HCV antibody test excludes infection in immunocompromised patients or those with recent exposure; consider HCV RNA testing 1
• Do not overlook the possibility of coexisting autoimmune hepatitis and viral hepatitis, especially in high-prevalence regions 1
• Persons who test positive for HBsAg require additional monitoring during HCV treatment due to HBV reactivation risk 3

Vaccination and Prevention

• Vaccination against hepatitis A and hepatitis B is recommended for all susceptible persons with HCV infection 3
• Vaccination against pneumococcal infection is recommended for all persons with cirrhosis 3
• All patients with chronic hepatitis C should be advised to abstain from alcohol use, as there is no known safe level of alcohol use 3

Monitoring for Cirrhosis Complications

Patients with known or suspected cirrhosis require frequent follow-up and ongoing imaging surveillance. 3

• Avoid hepatotoxic drugs such as excessive acetaminophen (>2 g/d) and certain herbal supplements 3
• Avoid nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) 3
• Ongoing imaging surveillance for HCC and gastroesophageal varices is recommended for patients with cirrhosis 3