Important points in the clinical history of patients with suspected viral hepatitis

• Contacts with jaundiced patients
• IV drug use
• History of blood transfusion
• Surgery or hospitalizations
• Family history of chronic liver disease
• Occupation
• Food and water sources

Serological Tests for Viral Hepatitis

Hepatitis A

• Anti-hepatitis A virus IgM has high sensitivity and specificity and is a marker of acute infection
  
  • This test remains positive for ≥6 months

• Anti-hepatitis A virus should be tested in patients <50 years

Hepatitis B

• Usually characterized by the presence of hepatitis B surface antigen (HBsAg) which suggests infectivity
  
  • Anti-HBs is produced following a resolved infection and is the only hepatitis B virus (HBV) antibody marker present after immunization
  • Persistence of HBsAg for at least 6 months indicate chronic infection

• Anti-HBc (anti-core antibody) is the 1st antibody to appear in the serum and is a marker of natural immunity
  
  • Its presence indicates an immune response against HBV within liver cells and is a specific marker of acute hepatitis B infection 
  • Presence of anti-HBc IgM is diagnostic for acute HBV infection but may occur during a flare of chronic hepatitis B

• Hepatitis B e antigen (HBeAg) is a marker of active viral replication
  
  • This may be negative at the time that the patient is evaluated for acute hepatitis B since viral replication may have already ceased

• HBV DNA tests for HBV replication and aids in the evaluation of treatment efficacy with antiviral agents
• New biomarkers of HBV infection are:
  • Viral covalently closed circular DNA (cccDNA) is a key genomic form that causes persistence of infection and was shown to persist in the liver of infected patients even after long-term nucleos(t)ide analogue therapy and even after HBsAg loss and seroconversion. It is used in clinical trials evaluating treatment concepts to cure HBV infection
  • Hepatitis B core-related antigen (HBcrAG) is composed of several antigens that were expressed from pre-core/core gene and quantification may give additional information regarding the translational activity of the HBV infection beyond HBsAg quantification. It might also be helpful in defining the phase of chronic HBV infection especially in the HBe-negative patients as well as predicting the long-term HCC risk
  • Circulating HBV RNA 
• There are 10 HBV genotypes (A-J) that play a role in the development of liver disease and response to treatment with Interferon 
  • Not recommended for routine testing nor follow-up of chronic hepatitis B patients
• Depending on local health services, the following groups should be tested for chronic HBV infection:
  
  • Persons born in hyperendemic areas, men who have sex with men (MSM), IV drug users, dialysis patients, HIV-positive individuals, pregnant women and family members, household members and sexual contacts of HBV-infected persons, blood or organ donors, healthcare workers, patients needing chemotherapy
    • Individuals who are seronegative should be vaccinated against HBV
    • If Anti-HBc positive only, patient may have had a past resolved HBV infection or a false-positive test and that vaccination may be given if patient is from an endemic area
    • HBsAg-positive patients should be evaluated to assess progression of liver disease and need for antiviral therapy
    • Anti-HBs-positive patients have developed natural immunity and do not need to be vaccinated
• Patients with chronic hepatitis B should also be tested for co-infection with hepatitis C virus (HCV), hepatitis D virus (HDV) and human immunodeficiency virus (HIV), if they are at risk for these infections

Hepatitis C

• Anti-HCV antibodies are the first-line diagnostic test
• Acute hepatitis C can be reliably diagnosed if recent seroconversion to anti-HCV antibodies can be documented; however, antibody tests often do not become positive until 3 months after infection
  
  • If the clinical suspicion is high, the patient should be tested for HCV RNA to establish the diagnosis
  • HCV RNA (or HCV core antigen) can be used to determine acute or chronic infection

• Chronic hepatitis C is continued HCV infection of ≥6 months after acquiring the disease and is diagnosed based on the presence of both anti-HCV antibodies and HCV RNA (or HCV core antigen)
• Recombinant immunoblot assay (RIBA) may be used to establish the cause of a positive anti-HCV test in a person with undetectable HCV RNA
  
  • A negative RIBA indicates that a positive anti-HCV immunoassay result showed a false-positive result and no further testing is necessary
  • A positive RIBA and ≥2 subsequent tests in which HCV RNA cannot be detected suggest that HCV infection has resolved and no further testing is indicated
  • A positive anti-HCV and negative HCV RNA indicate no active HCV infection but should have HCV RNA retesting after 3 months to document recovery

• HCV RNA quantitative testing to determine baseline viral load is recommended before starting antiviral therapy
  
  • End of therapy is indicated by undetectable HCV RNA in a sensitive assay (<15 IU/mL) 12 and 24 weeks after therapy

• HCV genotype, including subtyping of genotype 1a/1b, should be determined, if possible, in all HCV-infected persons prior to treatment to determine type and duration of therapy and chances of response; predominant genotypes in Asia are:
  
  • Genotypes 1b and 2: East Asia (China, Taiwan, South Korea, Japan)
  • Genotype 3: South Asia (India and Pakistan)
    
    • Genotype 3 is considered difficult to treat and is associated with a poor prognosis
  • Genotypes 1 and 6: Southeast Asia (Vietnam, Cambodia, Laos, Indonesia, Myanmar, Malaysia, Philippines, Thailand)

• Liver biopsy may be done if it is thought that the results will influence clinical decision, but biopsy is not mandatory to start therapy in patients with genotypes 2 and 3
  
  • Liver biopsy may be obtained to provide prognostic information

• Depending on local health services, the following groups should be tested for chronic HCV infection:
  
  • Persons who have in the recent or remote past used illicit IV drugs
  • Persons with conditions associated with high prevalence of HCV infection
    
    • Positive HIV, hemophiliacs who received clotting factor prior to 1987, history of hemodialysis, persons who received blood/blood products or organ transplants prior to 1995, children born to HCV-infected mothers, healthcare workers after needle stick injury or mucosal exposure to HCV-positive blood, current sexual partners of HCV-infected persons

Hepatitis D

• Confirmed by positive anti-HDV antibody followed by HDV RNA test
• Hepatitis D occurs as a co-infection with Hepatitis B

Hepatitis E

• IgM anti-HEV, IgG anti-HEV and hepatitis E virus (HEV) RNA indicate acute hepatitis E infection
  
  • HEV RNA is detected from serum and stool of infected patients by PCR

Other lab tests that are recommended in patients suspected to have viral hepatitis:

• Liver function tests (LFTs)
  
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
  • Serum bilirubin, alkaline phosphatase (ALP)

• Prothrombin time, international normalized ratio (INR), renal function tests  
• Noninvasive tests such as the aminotransferase/platelet ratio index (APRI) or fibrosis-4 (FIB-4) may be used to assess the degree of hepatic fibrosis when resources are limited prior to initiating HCV therapy
  
  • Transient elastography may be an option for patients with contraindications to liver biopsy

Consequences of HCV Infection

• 55-85% of patients who acquire acute hepatitis C will remain HCV infected
  
  • 5-20% of these patients may develop cirrhosis over the next 20-25 years
  • HCV-related cirrhosis is associated with risk of developing end-stage liver disease (30% risk over 10 years) as well as hepatocellular carcinoma (HCC)

• In patients with persistent infection, the evolution to cirrhosis is the primary concern
  
  • Usually occurs ≥20 years after initial infection and occurs more often in patients at older ages (especially men), those who drink >50 g of alcohol/day, those who are obese or have substantial hepatic steatosis and in those with HIV infection

Antiviral therapy is currently widely accepted for the following Hepatitis C patient groups:

• ≥18 years of age
• Normal and abnormal ALT levels
• Liver biopsy showing chronic hepatitis with significant fibrosis or cirrhosis (stage F1 or above)
• HCV genotype 2 or 3 regardless of stage
• Compensated liver disease
• Acceptable hematological and biochemical indices
• If there is a history of depression, the condition is well controlled
• Willing to be treated and conform to patient requirements
• Treated previously for HCV infection

Therapy should be individualized in patients with any of the following:

• Failed prior treatment of either Interferon given alone or in combination with Ribavirin or Peginterferon given alone
• Current illicit drug user or alcoholic but willing to participate in substance abuse program or alcohol support program
• No or mild fibrosis on liver biopsy
• Acute hepatitis C
• Coinfected with HIV
• <18 years of age
• Chronic renal disease
• Decompensated cirrhosis
• Liver transplant recipient

Therapy is contraindicated in patients with any of the following¹:

• Major, uncontrolled depressive illness
• Renal, heart or lung transplant recipient
• Autoimmune hepatitis or other condition known to be exacerbated by Interferon and Ribavirin
• Untreated hyperthyroidism
• <3 years of age
• Pregnant or unwilling/unable to comply with adequate contraception
• Severe concurrent disease (eg hypertension, HF, uncontrolled DM, etc)
• Known hypersensitivity to drugs used to treat hepatitis C virus
• Hepatic decompensation

¹Patients have detectable HCV RNA