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HEPATITIS - VIRAL
The majority of acute viral hepatitis infections are asymptomatic or they can cause an anicteric illness that may not be diagnosed as hepatitis.
Hepatitis A generally causes minor illness in childhood with >80% of infections being asymptomatic but more likely to produce clinical symptoms in adults. 
Hepatitis B, C, and D may also be asymptomatic.
Hepatitis A is predominantly transmitted through oral-fecal route.
Hepatitis B is transmitted through perinatal, percutaneous, or sexual routes or close person-to-person contact via open cuts and sores.
Hepatitis C infections are transmitted through perinatal, percutaneous, or sexual routes, blood transfusions, or organ transplants.
Hepatitis D's route of transmission is sexual or percutaneous, especially IV drug use.
Hepatitis E is transmitted primarily through contaminated drinking water and oral-fecal transmission.

History

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

Laboratory Tests

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 HBV antibody marker present after immunization
  • Anti-HBc (anti-core antibody) is the 1st antibody to appear in the serum and is a marker of natural immunity
    • Presence of anti-HBc IgM is diagnostic for acute hepatitis B virus (HBV) infection but may occur during a flare of chronic hepatitis B
    • Its presence indicates an immune response against HBV within liver cells and is a specific marker of acute hepatitis B infection
  • 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
  • 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
  • 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
      • 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 cannot be reliably diagnosed by antibody tests since these 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 is used to determine acute or chronic infection
  • Chronic hepatitis C should be confirmed with anti-HCV antibodies and HCV RNA
  • 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 or 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)
  • PT, international normalized ratio (INR)
  • Noninvasive tests such as the aminotransferase/platelet ratio index (APRI) or FIB4 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

Evaluation

Hepatitis A and E

Features of Hepatic Decompensation
  • Mental dullness, hepatic encephalopathy, bilateral asterixis, ascites, clinical deterioration
  • Serum bilirubin >2.5x upper limit of normal, PT is 3 sec longer than control or INR >1.5

Hepatitis B

  • History and physical exam
  • Measure HBeAg, anti-HBe, HBV DNA and ALT and perform liver ultrasound
    • HBeAg and anti-HBe are important in determining the phase of chronic HBV infection  
    • HBV DNA serum level is used in making diagnosis, establishing the phase of the infection, deciding to treat and monitoring of treatment
  • Complete blood count (CBC), PT, serum albumin to determine severity
  • Screen for hepatocellular carcinoma (HCC) in high-risk patients every 6-12 months using ultrasound and
    alpha-fetoprotein
If patient meets criteria for chronic hepatitis B:
  • Liver biopsy to grade stage of liver disease as chronic hepatitis B may evolve to cirrhosis and hepatocellular cancer
  • Liver biopsy is essential in determining disease activity in cases of inconclusive biochemical and HBV markers

Phases of Chronic Hepatitis B:

HBeAg-positive Chronic HBV Infection (Immune-tolerant) 

  • Presence of serum HBeAg
  • Very high levels of HBV DNA
  • ALT persistently within the normal range (<19 U/L for females and <30 U/L in males)
  • Minimal or no liver necroinflammation or fibrosis
  • Frequently occurred and prolonged in patients infected perinatally and is associated with preserved HBV specific T cell function at least until young adulthood
  • Patients at this stage are highly contagious because of the high levels of HBV DNA

HBeAg-positive Chronic Hepatitis B (Immune-reactive HBeAg-positive) 

  • Presence of serum HBeAg
  • High levels of HBV DNA
  • Elevated ALT
  • Moderate to severe liver necroinflammation and accelerated progression of fibrosis
  • Usually occurs in patients infected during adulthood
  • Patients may have HBeAg seroconversion and HBV DNA suppression that progress to HBeAg-negative infection phase while others may fail to control HBV and progress to the HBeAg-negative chronic hepatitis B phase for many years

HBeAg-negative Chronic HBV Infection (Inactive Carrier) 

  • Absence of serum HBeAg  
  • Undetectable or low (<2,000 IU/mL) HBV DNA levels
  • Normal ALT
  • Minimal liver necroinflammation and variable fibrosis as a result of previous hepatic injury during the HBeAg-positive immune-active phase
  • Low risk of progressing to cirrhosis or HCC but progression to chronic hepatitis B may occur

HBeAg-negative Chronic Hepatitis B (HBeAg-negative Immune Reactivation) 

  • Absence of serum HBeAg usually with detectable anti-HBe
  • Persistent or fluctuating moderate to high levels of serum HBV DNA
  • Fluctuating or persistently elevated ALT
  • There is liver necroinflammation and fibrosis
  • Associated with low rates of spontaneous disease remission

HBsAg-negative (Occult HBV Infection) 

  • Serum negative HBsAg and positive antibodies to HBcAg with or without detectable antibodies to HBsAg
  • Normal ALT
  • Usually, but not always, undetectable serum HBV DNA
  • Liver has frequently detectable HBV DNA (cccDNA) 
  • Several studies have shown that almost all patients with occult HBV infection have normal liver biochemistry and minimal or no liver necroinflammation and fibrosis
  • However, it may still be associated with the development of liver cirrhosis and HCC
Hepatitis C

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 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
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