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Subject 101: Fundamentals and diagnostic challenges of viral hepatitis

Fundamentals and diagnostic challenges of viral hepatitis

Viral hepatitis is one of the leading causes of liver cirrhosis and hepatocellular carcinoma worldwide.1 Although the incidence rates in the Netherlands for viral hepatitis are low, the inhabitancy of populations from high-risk areas (sub-Saharan Africa, Asia) and the intensified travel habits of the Dutch population towards such places warrants adequate knowledge of this topic.2,3

In addition, screening for an acute hepatitis B infection or a lingering chronic infection is advisable in immune-deficient patients, who are for example receiving chemotherapy, biologicals, or high-dose corticosteroids and are therefore at risk of developing a severe hepatitis or significant interference with therapeutic schemes.4 Correct interpretation of serological markers of hepatitis B may however be quite a challenge.

For these two reasons, this article will provide an insight in the most important characteristics of hepatitis A, B, C, D, and E, and will focus specifically on the diagnostic challenges of hepatitis B.

Characteristics of viral hepatitis

While it is tempting to discuss the multiple forms of viral hepatitis alphabetically, remembering each pathogens’ characteristics is easier if two groups are distinguished: the faeco-oral (A and E), and blood-transmitted viral hepatitis (B, C, and D).

In both hepatitis A and E, the virus is transmitted via contaminated food, water, and saliva5,6. Infection is associated with poor sanitation facilities and overcrowding. The clinical course of hepatitis A is similar to hepatitis E, although hepatitis E often has a longer incubation time (3-8 weeks compared to 2-4 weeks in hepatitis A), and symptoms may persist longer. Patients will feel unwell, and may suffer from nausea and anorexia. Virus particles may then already be detectable in serum and faeces. Four weeks after infection, some patients develop jaundice, at which point IgM HAV and IgM HEV (for patients with hepatitis A and E respectively) can be found in serum. Most patients will recover 6 weeks after infection and will not develop any long-term complications. However, hepatitis E does have a 10-20% mortality rate in pregnant women, and patients with pre-existing liver disease or HIV.

The common denominator of hepatitis B, C, and D is transmission via blood. In hepatitis B, infection may also occur via saliva, during labour, in utero, and sexual intercourse (especially in men who have sex with other men), while this is rarely seen in hepatitis C. The clinical picture of acute hepatitis B features anorexia, nausea, and jaundice after an incubation period of 1 to 5 months. The majority of patients will clear the virus. Some may develop hepatic failure in severe hepatitis, while 1-10% may develop a chronic infection. Hepatitis D is an incomplete RNA virus that needs the shell of hepatitis B particles. Therefore, infection with hepatitis D will only occur as a co-infection of hepatitis B, or as a superinfection of chronic hepatitis B.

Acute hepatitis C is often asymptomatic, and most patients with hepatitis C will present years after infection with signs of a chronic infection, as up to 90% of infected patients develop chronic hepatitis C. This may eventually lead to cirrhosis, which can cause liver cancer or decompensated cirrhosis. Serological abnormalities found in a chronic hepatitis C infection are often an elevated ALT and anti-HCV antibodies.

Diagnosing hepatitis B

In order to interpret serological markers in hepatitis B, it is vital to know when different markers are excreted (see table 1): in acute infection, HBV DNA particles will be detectable from 1 month after infection up to 4 months. In the same window, proteins at the surface (HBsAg) and the core (HBcAg) of the virus are present, as well as (IgM) anti-HBc antibodies. If the host is able to clear the virus, HBsAg and HBcAg proteins will disappear, and (IgG) anti-HBc and anti-HBs antibodies produced by the immune system can be found. Presence of anti-HBc and anti-HBs antibodies indicates (recent) exposure to the hepatitis B virus, regardless of clearance or persistence of the virus. In contrast, detection of HBsAg after 6 months of infection may indicate chronic infection. Finally, positive anti-HBsAg titres and absence of other abnormalities indicates that this person has been vaccinated against hepatitis B.


HBsAg HBV-DNA Anti-HBs Anti-HBc
Hepatitis B vaccinated, immune +
Hepatitis B exposed, immune + IgG +
Acute hepatitis B infection + + IgM +
Chronic hepatitis B infection + +/-* IgG +

Table 1 Serological markers of hepatitis B
*depending on viral replication activity


Viral hepatitis can be divided in types that are transmitted faecal-orally (A and E), and types that are commonly transmitted via blood (B, C and D). Since relapse of chronic hepatitis B is a dangerous complication in immune-deficient patient, it is recommended to screen specific serological markers before starting certain therapies. Diagnostic markers can distinguish between the different phases of (previous) infection or vaccination.

T. Kortlever & K. de Wit


  1. Bouvard V, Baan R, Straif K, et al. A review of human carcinogens—Part B: biological agents. Lancet Oncol. 2009;10(4):321–2. 2.
  2. RIVM. Atlas infectieziekten [Internet]. 2018 [cited 2018 Jan 12]. Available from:
  3. Marschall T, Kretzschmar M, Mangen M-JJ, et al. Impact of migration on the prevalence of chronic hepatitis B in the Netherlands. Eur J Gastroenterol Hepatol. 2008;20(12):1214–25.
  4. Takkenberg RB, Zaaijer HL, Ten Cate DF, et al. Reactivatie van het hepatitis B-virus bij patiënten met een hematologische maligniteit. Ned Tijdschr Geneeskd. 2009;(153):B88.
  5. Mohsen W, Levy MT. Hepatitis A to E: what’s new? Intern Med J. 2017;47(4):380–9.
  6. Kumar P, Clark ML. Kumar and Clark’s Clinical Medicine. Elsevier; 2017.

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