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Editors

MaijaLappalainen
MarttiFärkkilä
HennaRautiainen

Viral Hepatitis

Essentials

  • Hepatitis A and E can be best prevented by adequate food and drinking water hygiene, particularly in high-risk countries.
  • Hepatitis B and C can be prevented by exercising due care in high risk occupations and in sexual behaviour. The single most important risk factor for hepatitis C is IV drug abuse.
  • Prophylaxis against hepatitis A by vaccination is indicated before travelling to high-risk countries.
  • Hepatitis B vaccination is indicated in high-risk occupations Vaccines for Preventing Hepatitis B in Health-Care Workers and for risk groups
  • (N.B.: Vaccination recommendations in this article are based on Finnish guidelines.)

Basic principles of diagnosis

  • Recent hepatitis A, B or E infection is demonstrated by the following tests: total anti-HAV antibodies (if positive, anti-HAV IgM), hepatitis B surface antigen (HBsAg), IgM antibodies to hepatitis B core antigen (anti-HBc IgM) and IgM antibodies to hepatitis E virus (anti-HEV IgM).
  • Distinguishing a fresh hepatitis C infection from an old one cannot be done by serology. Active hepatitis C can be detected by testing for HCV nucleic acid (qualitative method) in addition to anti-hepatitis C virus antibodies.
  • If clinically mild hepatitis is associated with symptoms suggestive of mononucleosis (fever, lymphadenopathy, splenomegaly, upper respiratory tract symptoms) or evident cholestasis (increased plasma ALP and bilirubin concentrations), possible mononucleosis can in the early stage be detected by a rapid test, and if needed, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) antibodies can be determined.

Hepatitis A

Incubation period

  • 15-50 days

Route of infection

  • Usually faecal-oral route, but epidemics have also occurred among users of illicit intravenous drugs.

Clinical picture

  • Acute onset
  • Loss of appetite and nausea are the initial symptoms.
  • Fever
  • Jaundice

Laboratory tests

  • Plasma ALT and AST are increased.
  • A specific diagnosis can be made by determining serum anti-HAV IgM.
  • Total antibodies can be determined to assess the need for prophylaxis. A positive test result for total antibodies (and a negative result for IgM antibodies) is indicative of an earlier infection or a successful HAV vaccination that protects against the disease.
  • See picture 1.

Prophylaxis Immunoglobulins for the Prevention of Hepatitis A

  • Avoidance of susceptible foods (especially mussels and other sea food) when travelling in high-risk countries
  • Hepatitis A vaccinationHepatitis A Immunisation in Persons Not Previously Exposed to Hepatitis A is particularly indicated for those who stay a long time in, or travel frequently to, high-risk countries should be vaccinated. A booster vaccination 6-12 months after the first dose is recommended. Current knowledge does not support giving further boosters to immunocompetent persons after the 2-dose program. Travellers should be vaccinated at least 2 weeks before the travel.
    • For children aged 16 or over and for adults, two doses (Havrix® 1440 ELISA-U/ml, 1 ml or Avaxim® 0.5 ml) of vaccine are given at months 0 and 6-12.
    • In children aged 1-15 years, Havrix® at half the adult dose (0.5 ml) is used.
  • Hepatitis A+B combination vaccine Twinrix®
    • Given in three doses at months 0, 1 and 6.
    • A separate vaccine is available for children below 16 years of age.
  • Hepatitis A vaccination is always recommended for tourists travelling to the tropics and to the African and Middle Eastern coasts of the Mediterranean. For the Baltic countries, Russia and Eastern European countries vaccination is recommended if the intended stay is of a long duration or repeated visits are anticipated.
  • If an exposure to hepatitis A virus occurs, the exposed persons are protected primarily by vaccinating. The vaccine should be given no later than 2 weeks after the exposure.

Contagiousness

  • One week after the onset of jaundice the virus is no longer excreted in the faeces.
  • No permanent carrier status has been identified.

Course of the disease and follow-up

  • The disease is self-limiting, and no specific treatment is available.
  • Fulminant hepatitis is a rare complication of the infection and develops in about 0.3% of those infected.
  • Prolonged icterus (cholestatic hepatitis A) may complicate the disease in adults.
  • Extrahepatic symptoms include arthritis, vasculitis and cryoglobulinaemia.
  • The severity of liver damage is estimated by the determination of plasma albumin concentration and prothrombin time. The disease is mild if prothrombin time does not fall below 0.40 and plasma albumin concentration does not fall below 30 g/l.
  • Plasma ALT concentrations should be monitored weekly until they start to decline.

Hepatitis B

Incubation period

  • 1-6 months

Route of infection

  • Parenteral (syringes used in IV drug abuse, blood products)
  • Sexual contact
  • Perinatal transmission

Clinical picture

  • Similar to that in hepatitis A, but the onset is often slower.
  • About 1% of those infected will develop acute fulminant hepatitis, associated with 80% mortality rate without liver transplantation.
  • Joint symptoms in 10-20% of patients
  • Skin symptoms
  • Liver aminotransferase concentrations rise more slowly than in hepatitis A.

Laboratory diagnosis

  • Increased plasma AST and ALT
  • A specific diagnosis is made by determining serum HBsAg and anti-HBc IgM.
  • For the assessment of infectivity, the primary investigation is the determination of hepatitis B e-antigen (HBeAg). If the result is positive, the patient is likely to have active hepatitis and the disease is much more infectious as the virus is actively replicating. The most exact estimation of viraemia is achieved by quantitative determination of HBV-DNA. This should be used particularly if the HbeAg-negative form of chronic HBV infection is suspected.
  • See table T1 and picture 2.

Interpretation of hepatitis B serology

HBsAgHBsAbHBcAbHBcAbMHBeAgHBeAb
  1. Negative in about 10-15% of persons with a past history of an infection. In such cases, anti-HBc is the only marker of infection.
  2. The first test to become positive in acute infection (even before clinical symptoms)
  3. In the exacerbation of a chronic infection, anti-HBc-IgM may turn positive.
  4. Active hepatitis is likely and the disease is easily transmitted as the virus is actively replicating. The most exact estimation of viraemia is quantitative determination of HBV-DNA.
Non-infected---
Vaccinated-+-
Natural immunity-+1) +
Acute infection
  • early
+2) ---+/-
  • late
+-+++++
Carrier
  • infective
++++/-3) +4) -
  • less infective
+-+--+

Prophylaxis

  • Avoidance of high-risk behaviour (unprotected sex with potential virus carriers, use of unclean injection needles).
  • Avoidance of blood contact in occupations that involve contact with human blood.

Vaccination of risk groups

  • In Finland, vaccination against hepatitis B belongs to the general immunization programme and is free of charge for recommended target groups, which include:
    • individuals with regular treatment for a bleeding disorder
    • IV drug abusers
    • significant others of IV drug abusers, such as family members, live-in partners and sexual partners
    • men who have sex with men
  • Due to the increased risk of transmission of the infection, hepatitis B vaccination is free of charge also to:
    • newborn children and sexual partners of patients with a hepatitis B infection and of asymptomatic HBsAg-positive individuals
    • sex workers
    • students who are exposed to the risk of infection within their practical training (e.g. in health care, instrument care, as well as in training prison wardens or policemen)
    • persons who are, due to a needle stick injury or other blood exposure, at risk of contracting hepatitis B infection and the exposure has taken place outside of work setting
    • children below 5 years of age in daycare when there is a HBsAg-positive child in the group
    • newborn children, when at least one of the parents comes from a country where hepatitis B is common
      • If the mother is a HBV carrier, the child should be given, before the first vaccination, also one dose of anti-hepatitis B immunoglobulin (125 IU). A series of 4 vaccinations is given.
    • newborn children of mothers infected with hepatitis C virus.
  • In addition to the target groups, the vaccine can be recommended to all individuals with risk behaviour, such as persons with frequent sexual relationships and also to other close contacts of hepatitis B carriers than those mentioned in the recommendation.
  • Implementation
    • Hepatitis B vaccine 1.0 ml as an intramuscular injection at months 0, 1 and 6.
    • In children below 16 years of age, 0.5 ml as an intramuscular injection at months 0, 1 and 6, in newborns at months 0, 1, 2 and 12.
    • No booster injections are usually necessary after a successful vaccination series.
    • About 10% of those vaccinated do not obtain sufficient immunity. If the risk of being exposed to contracting the virus is high and long-lasting, the presence of immunity should be confirmed serologically about 2 months after the third injection Vaccines for Preventing Hepatitis B in Health-Care Workers. If antibodies have not been formed, further 3 doses are given at 2-month intervals and the generation of immunity is confirmed serologically about 2 months after the third dose. If antibodies have still not formed, the exposure risk must be reduced through e.g. work arrangements.
    • When vaccinating high-risk groups, a vaccination coverage as high as possible should be aimed at; vaccination should be started even in cases when one is not sure that the full series can be carried out.
    • An interrupted vaccination series can be continued from where it was left, even if the time between doses would exceed the recommended time.

Immune prophylaxis after exposure to the virus

Action after exposure to infectious blood

Contagiousness

  • Most patients with hepatitis B infection recover; however, a small proportion (< 5%) of adult patients remain carriers of the virus (in the Nordic countries).
  • The determination of HBeAg and HBV DNA is helpful in the assessment of infectivity in HBsAg positive patients.

Course of the acute disease and follow-up

  • Over 95-99% of adult patients with acute hepatitis B recover spontaneously and become HBsAb-positive. Monitoring in a hospital is required for symptomatic, icteric patients, or if an impairment of liver function is detected.
  • In the active stage of the disease plasma ALT , prothrombin time and, if necessary, prealbumin and bilirubin concentrations are monitored, depending on the severity of the case, daily or weekly until they start to return to normal.
  • HBsAg should determined 3 months after disease onset.

Chronic stage of the disease

  • If the HBsAg test remains positive 6 months after the disease onset, the patient is likely to have become a hepatitis B carrier. The carrier status is confirmed by a positive HBsAg test at 12 months.
  • The risk of hepatocellular carcinoma is increased in chronic hepatitis B. The risk is in correlation with the HBV-DNA level and the development of cirrhosis.

Hepatitis C

Incubation period

  • 20-120 days

Route of infection

  • Parenteral as in hepatitis B but the infectivity is much lower. Sources of exposure include IV drug abuse, tattooing, blood transfusion and unprotected sex with a hepatitis C positive partner. However, the chance of contracting the virus through unprotected sex is fairly low, and safe sex is not considered absolutely necessary in long-term relationships.
  • There are patients who contract hepatitis C without having ever received blood transfusions or belonging to any of the risk groups.

Clinical picture

  • The clinical presentation is usually mild. Only about 10-15% of infected individuals are symptomatic; compared with 50% of those infected with hepatitis B.
  • Extrahepatic manifestations such as cryoglobulinaemia, glomerulonephritis, autoimmune thyroiditis, Sjögren's syndrome, and porphyria cutanea tarda have been reported in patients with chronic hepatitis C. Furthermore, hepatitis C infection increases the risk of developing diabetes and coronary artery disease.

Laboratory diagnosis

  • Fluctuating hepatic transaminase (ALT) concentrations are often the only manifestation of hepatitis C. The concentrations may periodically return to normal.
  • Plasma ALT and AST concentrations rarely exceed 800 U/l.
  • Screening of the infection is based on determining antibodies against hepatitis C, and an active infection is confirmed by a nucleic acid test (HCV RNA).
    • Antibodies can be detected 10 weeks after exposure.
    • HCV nucleic acid test is usually positive at symptom onset.

Contagiousness

  • The majority (70%) of patients with antibodies are also carriers of the virus and may spread the infection.

Course of the disease and follow-up Interferon and Prevention of Hepatocellular Carcinoma in Viral Cirrhosis, Interferon for Hepatitis C Related Cirrhosis

  • Alcohol, smoking, male sex, getting ill at the age of over 40, and HCV genotype 3-a increase the risk of developing liver cirrhosis.
  • The acute phase is often milder than in hepatitis B but the disease becomes chronic in asymptomatic patients more often (in 85-90% of patients).
  • Transaminase assays are not helpful in the acute phase because they tend to fluctuate.
  • Majority of carriers develop chronic hepatitis and about 10% develop cirrhosis within 20 years. Annually about 1% of patients with cirrhosis develop hepatoma, on the average 28 years after contracting the disease.

Delta agent (hepatitis D)

  • Occurs as a superinfection or a co-infection in association with hepatitis B
  • Caused by a satellite virus that can only infect a HBsAg positive person (both viruses can be acquired at the same time, as a co-infection, in which case the hepatitis rarely becomes chronic).
  • Usually IV drug abusers and in hepatitis B carriers.
  • The course of the disease can be fulminant.
  • A specific diagnosis can be made by determining serum antibodies against HDV and, if needed, by demonstration of HDV-RNA.
  • Treatment with interferon alpha has been tried Interferon-Alpha for Hepatitis D (Hdv) Virus Infection.

Hepatitis E

  • Four genotypes of hepatitis E virus are known. The host of genotypes 1 and 2 is human. Genotypes 3 and 4 are zoonoses and their host is swine.
  • So-called epidemic form (genotypes 1 and 2) is a hepatitis-A-like disease that occurs primarily in South and Central Asia, China and Sub-Saharan Africa. Infection is most often transmitted through contaminated drinking water.
  • Genotype 3 exists all over the world, including the industrialized countries. Genotypes 3 and 4 may cause chronic infections to immunosuppressed patients. The infection is usually acquired through contaminated food products, but also infection through blood products is possible.
  • A specific diagnosis can be made by determining serum IgG and IgM antibodies to hepatitis E virus (anti-HEV IgG and anti-HEV IgM). If needed, also HEV RNA can be determined.
  • Hepatitis E should be suspected in patients who have recently returned from the Far East and have an unclear hepatitis, as well as in immunosuppressed patients with unexplained increase in liver enzyme concentrations, but no antibodies against HAV can be detected.
  • During pregnancy hepatitis E may be particularly fulminant with resultant maternal mortality up to 20%.
  • There is no specific treatment for acute hepatitis E (genotypes 1 and 2). Ribavirin has been used to treat chronic infection by genotypes 3 and 4. Symptomatic treatment and follow-up are carried out as in hepatitis A.

Other forms of viral hepatitis

  • Some cases of hepatitis remain without an aetiological diagnosis. It is therefore possible that hepatitis viruses other than those described above do exist.
  • Up to 90% of patients with mononucleosis induced by Epstein-Barr or cytomegalovirus develop hepatitis. The disease is usually mild, and only about 5% of the patients develop jaundice.

Treatment of hepatitis

Acute hepatitis Interferon as Treatment for Acute Hepatitis C

  • The severity is assessed by determining plasma albumin and prothrombin time. The disease is mild if prothrombin time is over 40% and serum albumin above 30 g/l.
  • Pruritus can be treated by antihistamines or cholestyramine (4 g/day).
  • All drugs that are metabolized in the liver should be avoided.
  • The diet should contain plenty of calories and carbohydrates.

Acute fulminant hepatitis (A, B or E)

  • Symptoms and signs
    • Encephalopathy
    • Prothrombin time < 30%, INR > 2.0
    • Bilirubin > 300 µmol/l
    • Hepatorenal syndrome
    • Hypoglycaemia
  • Liver transplantation may be life-saving.
  • Antiviral medication is not helpful in the acute phase.

Chronic hepatitis B Hepatitis B Immunisation in Persons Not Previously Exposed to Hepatitis B or with Unknown Exposure Status, Bile Acids for Viral Hepatitis, Interferon for Chronic Hepatitis B in Adults

  • In HbeAg positive immunoactive patients (ALT concentration increased, HBV-DNA > 2 000 IU/ml), pegylated interferon alpha for 48 months can be used. The treatment provides HbeAg seroconversion in about one third of the patients.
  • Oral tenofovir or entecavir can be used in patients with no response to interferon treatment or as primary medication. The treatment may even last for years while HBV-DNA level is monitored.
  • See table T2

Treatment indications in hepatitis with positive and negative HBeAg

ALT
(N = normal)		HBV-DNA (IU/ml)Liver biopsyTreatment recommendationTreatment goal
>2 × N2 000-20 000Not necessaryFollow-up at 1-3-month intervals considering possible seroconversion: ALT, HBV-DNA
Treatment indicated if HBeAg + > 6 months		HBsAg andHBeAg seroconversion, normalHBV-DNA level
>2 × NHASH(0x2fcfe80) 20 000Not necessaryPEG-IFNα-2a for 48 weeks
1‒2 × NHASH(0x2fcfe80) 20 000Necessary in patients over 30-40 years of ageTreatment only if inflammation (G1‒2) or fibrosis (F HASH(0x2fcfe80) 2).
PEG-IFNα-2a for 48 weeks or tenofovir or entecavir
NormalHASH(0x2fcfe80) 20 000Not necessaryFollow-up: ALT and HBV-DNA at 3-6-month intervals, HBeAg annually
Pharmacotherapy not necessary		‒
Normal< 2 000Not necessaryFollow-up: ALT and HBV-DNA at 3-6-month intervals for a period of 12 months, thereafter every 6 months‒
NormalHASH(0x2fcfe80) 2 000Necessary in patients over 30-40 years of ageTreatment only if inflammation (G1‒2) or fibrosis (F HASH(0x2fcfe80) 2).
Treatment: tenofovir or entecavir		HBsAg seroconversion,normal HBV-DNA level
1‒2 × N2 000‒20 000NecessaryTreatment only if inflammation (G1‒2) or fibrosis (F HASH(0x2fcfe80) 2).
Treatment: tenofovir or entecavir
HASH(0x2fcfe80) 2 × NHASH(0x2fcfe80) 20 000Not necessaryTenofovir or entecavir
HASH(0x2fcfe80) 2 × N< 2 000ConsiderExclude other causes of elevated liver enzymes and determine the level of hepatic fibrosis with noninvasive tests or liver biopsy.-

Chronic hepatitis C Ribavirin Monotherapy for Chronic Hepatitis C, Antiviral Therapy for Recurrent Liver Graft Infection with Hepatitis C Virus, Bile Acids for Viral Hepatitis, Interferon for Chronic Hepatitis C, Correlation of Serum Alt Concentration and Histological Improvement in Patients with Hepatitis C after Treatment with Interferon Alfa, Ribavirin Plus Interferon Versus Interferon for Chronic Hepatitis C, Interferon and Ribavirin Vs. Interferon Alone in the Re-Treatment of Chronic Hepatitis C, Antiviral Treatment for Chronic Hepatitis C in Patients with Human Immunodeficiency Virus

  • Treatment is indicated for all patients with positive HCV nucleic acid test, whose compliance and commitment to the therapy are estimated to be sufficient for following through a 8-12 weeks' regular oral pharmacotherapy and who do not have other factors that significantly affect the prognosis, such as a severe systemic disease.
  • Determining the level of liver damage is indicated in order to evaluate the urgency of treatment and to clarify the need for follow-up after the treatment.
  • The amount of hepatic connective tissue may be assessed by indirect non-invasive methods, e.g. the APRI (AST to Platelet Ratio Index): APRI = (plasma AST/AST upper limit of normal) multiplied by 100 and divided by blood platelet count; see http://www.hepatitisc.uw.edu/page/clinical-calculators/apri.
  • In Finland, three new pangenotypic combinations are available for use in primary care as of 2020. These drugs were subject to a nation-wide tender process which lowered the price significantly, allowing therapy for all infected patients irrespective of the level of liver damage. It is possible to treat the majority of patients with hepatitis C infection in Finland within primary care. Consult local guidance on appropriate treatment location and protocols.
  • The new virus-specific drugs are very well tolerated and adverse effects are few.
  • Drug interactions exist with cytochrome P450 (CYP)/P-glycoprotein (P-gp) inducers, such as carbamazepine and phenytoin. See a pharmaceutical database for further information.

Ability to work

  • In the acute phase sickness leave is allocated according to the normal principles, i.e. the patient may return to work as soon as his/her general condition allows.
  • Chronic carrier state should not prevent the person from working.

    References

    • European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018. [PubMed]
    • Terrault NA, Lok AS, McMahon BJ, ym. Terrault NA, Lok ASF, McMahon BJ ym. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67(4):1560-1599. [PubMed]