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Editors

MaijaLappalainen
MarttiFärkkilä
HennaRautiainen

Viral Hepatitis

Essentials

Basic principles of diagnosis

  • Recent viral hepatitis A, B and E is detected by the determination of IgM antibodies that recognize the virus/viral antigen in question.
  • 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 diagnosis

  • Plasma ALT and AST are increased.
  • A specific diagnosis can be made by determining serum anti-HAV IgM.
  • Total antibodies or anti-HAV IgG 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 protect against the disease.
  • See picture .

Prophylaxis

  • Avoidance of susceptible foods (especially mussels and other sea food) when travelling in high-risk countries
  • Vaccination: see Vaccinations.

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 40% and plasma albumin concentration does not fall below 30 g/l.
  • Plasma ALT concentrations should be monitored weekly until a clear decline is seen and the patient's condition begins to improve.

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: polyarteritis nodosa and papular acrodermatitis
  • 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. Quantitative HBV DNA testing is also available, mainly for the needs of specialized care.
  • See table T1 and picture .

Interpretation of hepatitis B serology

HBsAgHBsAbHBcAbHBcAbMHBeAgHBeAb
Non-infected---
Vaccinated-+-
Natural immunity-+1) +
Acute infection
  • early
+2) ---+/-
  • late
+-+++++
Carrier
  • infective
++++/-3) +4) -
  • less infective
+-+--+
  1. Negative in about 10-15% of persons with a past history of an infection. In such cases, anti-HBc total antibodies are 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.
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

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. No increased risk of contracting HCV through sexual contact with a stable partner has been found when one of the partners is positive, and protection is not considered necessary. The risk of infection is increased in HIV-positive people and in sex between men, especially if there is a risk of mucosal damage. 4
  • In some hepatitis C patients, the mechanism of infection remains unclear.

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 findings

  • 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 untreated patients with HCV antibodies are also carriers of the virus. The assessment of carrier state and contagiousness is based on HCV nucleic acid detection in a blood sample.

Course of the disease and follow-up

  • 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 vary.
  • Majority of carriers develop chronic hepatitis and about 10% develop cirrhosis within 20 years. Annually about 1% of patients with cirrhosis develop hepatocellular carcinoma, 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.
  • The risk of developing cirrhosis is increased by HDV genotype 1, persistent HDV viremia or high concentrations of the virus, elevated HBV DNA level, co-infection (HIV/HCV), advanced age, male sex, alcohol consumption, overweight and diabetes.
  • A specific diagnosis can be made by determining serum antibodies against HDV and, if needed, by demonstration of HDV-RNA.
  • All HDV-RNA-positive patients with chronic hepatitis should be started on PEG-IFNα-2a therapy. The duration of treatment is 48 weeks.
  • A new first-line treatment option, bulevirtide, either as monotherapy or in combination with PEG-IFNα-2a, is becoming available.

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). HEV RNA determination is mainly used in the diagnosis of immunodeficient patients and in epidemic investigations.
  • 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%.

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

  • 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 pharmacotherapy is recommended for acute severe hepatitis B in the early phase of the disease. At a later phase, if liver damage is already advanced and the patient has severe encephalopathy, antiviral medication has not been shown to be of benefit.3

Chronic hepatitis B

  • In HbeAg positive immunoactive patients (ALT concentration increased, HBV-DNA > 2 000 IU/ml), pegylated interferon alpha for 48 weeks 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

TypeALT
(N = normal)		HBV-DNA (IU/ml)Liver biopsyTreatment recommendationTreatment goal
HBeAg+>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(0x2f625d8) 20 000Not necessaryPEG-IFNα-2a for 48 weeks
1‒2 × NHASH(0x2f625d8) 20 000Necessary in patients over 30-40 years of ageTreatment only if inflammation (G1‒2) or fibrosis (F HASH(0x2f625d8) 2).
PEG-IFNα-2a for 48 weeks or tenofovir or entecavir
NormalHASH(0x2f625d8) 20 000Not necessaryFollow-up: ALT and HBV-DNA at 3-6-month intervals, HBeAg annually
Pharmacotherapy not necessary		‒
HBeAg−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(0x2f625d8) 2 000Necessary in patients over 30-40 years of ageTreatment only if inflammation (G1‒2) or fibrosis (F HASH(0x2f625d8) 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(0x2f625d8) 2).
Treatment: tenofovir or entecavir
HASH(0x2f625d8) 2 × NHASH(0x2f625d8) 20 000Not necessaryTenofovir or entecavir
HASH(0x2f625d8) 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

  • Treatment is indicated for all patients with positive HCV nucleic acid detection 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) or by determining the elasticity of the liver using an ultrasound-based method.
  • There are several pangenotypic combination products available for the treatment of hepatitis C.This enables the provision of treatment for all infected patients irrespective of the level of liver damage. It is possible to treat the majority of patients with hepatitis C infection 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.

Chronic hepatitis E

  • Ribavirin and sofosbuvir have been used to treat chronic infection caused by genotypes 3 and 4.

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

    • Färkkilä M. [Viral hepatitis]. In: Färkkilä M, Heikkinen M, Isoniemi H, Puolakkainen P. (eds.). [Gastroenterology and hepatology]. Duodecim Publishing Company Ltd 2018, pp. 806-29. Available in Finnish.
    • European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018. [PubMed]
    • Terrault NA, Lok ASF, McMahon BJ et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67(4):1560-1599. [PubMed]
    • European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67(2):370-398 [PubMed]
    • Tohme RA, Holmberg SD. Is sexual contact a major mode of hepatitis C virus transmission? Hepatology 2010;52(4):1497-505 [PubMed]