Hepatitis b B16.9

Acute or chronic hepatitis caused by the hepatitis B virus, a virus belonging to the group of hepatitis DNA (Hepadnaviridae) viruses The virus is often transmitted parenterally, in industrialised countries now mostly sexually (65% of new infections in Germany). Acute hepatitis B infection causes the typical symptoms of acute viral hepatitis, including anorexia, malaise and jaundice. Fulminant hepatitis and death can occur.

Chronic hepatitis B infection (in 5-10% of cases) is often accompanied by freedom from symptoms in the early stages of low inflammatory activity. It can lead to liver cirrhosis and/or hepatocellular carcinoma.

The hepatitis B virus (HBV), a DNA virus consisting of a core and a surface. The core contains a circular double-stranded DNA and a DNA polymerase (Note: HAV is the only DNA virus from the group of hepatitis pathogens, all other pathogens are RNA viruses!) The virus enters the hepatocytes via a bile acid co-transporter (HBV receptor) and replicates in the nuclei of infected cells. A surface protein is released into the cytoplasm and, for reasons yet unknown, is produced in excess. There are numerous genotypes (A-H). Genotypes A and B respond better to interferon-alpha than genotypes C and D.

Infection pathways of the pathogens:

HBV used to be transmitted primarily parenterally, typically through contaminated blood or blood products. Routine screening of blood donors for hepatitis B surface antigen (HBsAg) has almost eliminated the previously frequent posttransfusion transmission; transmission through contaminated needles is still common in drug addicts. The risk of HBV infection is generally higher in dialysis patients and oncological patients, as well as among staff in medical facilities.

Furthermore, the virus can spread through contact with mucous membranes or other body fluids (e.g. between intimate partners, both heterosexual and homosexual, and in closed psychiatric or prison settings). However, infectivity is lower than that of the hepatitis A virus, and transmission routes often remain unexplained. Sexual transmission has dominated for years in industrialised countries and is estimated to account for 65% of new infections.

Children of an infected mother have a 70 - 90% risk of acquiring hepatitis B during birth (neonatal hepatitis B virus infection). Earlier diaplacental transmission is also possible, but rather rare.

To what extent insect bites play a role in transmission is not clear. Many cases of acute hepatitis B occur sporadically and without a known source of infection.

Hepatitis B infection can cause a wide range of liver diseases, from subclinical carrier stage to severe hepatitis or acute liver failure (fulminant hepatitis,) especially in the elderly, where mortality can be 10-15%.

Incubation period: The virus multiplies and spreads without causing clinical symptoms. (Incubation periods: HBV: 1-6 months). Early highly replicative phase. HB-Virus is completely produced.

Stage of hepatic organ manifestation: Prodromal or preicteric phase: Occurrence of non-specific symptoms such as subfebrile temperatures, loss of appetite, feeling sick, nausea and vomiting, a newly developed aversion to cigarettes and fats (fat intolerance), often pain in the right upper abdomen. Urticaria and arthralgia are common, especially in HBV infection (frequent misdiagnosis: flu-like infection). Possible arthralgias and volatile exanthema, immune complex formation of HBsAG and anti-HBs in HBV. Remark: Frequently (60-70%) asymptomatic course.

Icteric phase (anicteric courses are frequent) 2-4 weeks: After 3-10 days darkening of the urine, followed by icterus. Although icterus increasingly (climax of icterus after 7-14 days) significant improvement of general condition. Hepatomegaly, liver pressure pain, liver edges remain soft and smooth. Low splenomegaly in 15-20% of patients. Itching due to cholestasis.

Healing after 6-8 weeks. Note: Hepatitis is then called chronic if it is not healed after 6 months!

Anikterische Hepatitis possible. Typically manifests itself as a flu-like disease and is usually misunderstood as such.

Note: HBV infection is associated with several extrahepatic manifestations. The pathogenetic role of HBV in these diseases is unclear; autoimmune mechanisms are suspected:

• polyarteritis nodosa and other connective tissue diseases
• Urticaria vasculitis
• Vasculitides
• Membranoproliferative glomerulonephritis
• Essential mixed cryoglobulinemia
• Gianotti-Crosti Syndrome
• Arthritides

Chronic Hepatitis: 5-10% of patients with HBV develop chronic hepatitis or become inactive carriers The younger the age at infection, the higher the risk of developing chronic infection. The risk is:

• For infants: 90%.
• For children aged 1 to 5 years: 25 to 50%.
• Adults: about 5%.

Cirrhosis of the liver can develop. A hepatocellular carcinoma can develop from chronic HBV infection, even without prior cirrhosis.

BSG↑; CRP↑; Liver function tests: Bilirubin mostly elevated: 2-3mg/dl; increase in transaminases (500-3,000U/l); GPT>GOT (GOT/GPT = so-called de Ritis Quotient <1); cholestasis parameters ↑. Possibly only a slight increase of the gamma-GT. Furthermore: determination of prothrombin time or INR; increase of serum iron, possibly increase of gamma globulin fraction in electrophoresis. Blood count: possibly lymphocytosis. Virus serology to determine virus type and antigen/antibody status. This includes HBsAg (in 90% of cases of hepatitis B, always positive in hepatitis D)

Liver values increase early during the prodromal phase, reach their peak before the icterus is at its maximum and then slowly decrease during the convalescence phase. Bilirubin excretion in urine usually precedes the icterus. Hyperbilirubinemia is differently pronounced in acute viral hepatitis. However, their differentiation has no clinical benefit. Alkaline phosphatase is usually only moderately elevated, strong elevations suggest the suspicion of extrahepatic cholestasis and trigger imaging procedures (e.g. sonography).

Hepatitis-B is diagnosed clinically and serologically.

Therefore, in the initial diagnosis of acute hepatitis, viral hepatitis should be differentially diagnosed from other diseases that cause icterus (see below viral hepatitis) (simplified diagnostic approach for potential acute viral hepatitis.) If acute viral hepatitis is suspected, the following tests are performed to screen for hepatitis viruses A, B and C:

• IgM antibodies against HAV (IgM Anti-HAV)
• Hepatitis B surface antigen (HBsAg; in the early phase positive in 90% of cases)
• IgM antibodies against hepatitis B core (anti-HBc IgM; classic parameter of acute infection)
• Antibodies against hepatitis C virus (anti-HCV)

If hepatitis B test results are positive, further serological tests are indicated to differentiate an acute infection from an expired or chronic infection. For hepatitis B, the envelope antigen (HBeAg) and the corresponding antibody anti-HBe are tested to determine the prognosis of the disease and to determine antiviral treatment. If the serologically diagnosed HBV infection is severe, the antibodies of the hepatitis D virus (Anti-HDV: HD superinfection or HD simultaneous infection) should also be determined.

• HBsAg, the surface antigen, occurs characteristically during the incubation phase, usually 1-6 weeks before the clinical symptoms develop and indicates infectivity of the blood. In addition to HBV-DNA, it contains HBV-specific DNA-polyermase and a host-encoded protein kinase. The HBsAg disappears during the convalescence phase! The corresponding (protective) antibody (anti-HBs) appears weeks or months later after clinical convalescence and usually persists for life. Its detection is an indication of an expired HBV infection (anti-ABs positive, anti-HBc-IgG positive) and the existence of relative immunity (e.g. after vaccination, anti-HBs positive, anti-HBc-IgG negative).
• Special feature: In 5-10% of patients HBsAg persists, but the corresponding antibodies do not develop! These patients become asymptomatic carriers of the virus or develop chronic hepatitis.
• Antibodies against HBcAg (IgG and IgM-AK isotypes), the so-called core antigen of the virus (HBc-Ag) are detectable 3-5 weeks after the appearance of HBs-Ag, even before the clinical manifestation of the infection. The anti-HBc IgM persists for 12 months. It is a sensitive marker for the diagnosis of acute hepatitis B infection. The titer of anti-IgG persists for life (titer gradually decreases during life). During acute infection, the anti-HBc antibody consists almost exclusively of the IgM isotype; during chronic infection, it consists mainly of the IgG isotype.
• The HBeAg is a protein, the so-called envelope antigen, which is derived from the core protein. It corresponds to the secretory form of the HBs antigen. HBeAg only occurs in HBsAg-positive serum and is a parameter for the extent of viremia in chronic HBsAg carriers. In contrast, the corresponding antibody (Anti-HBe-AK) indicates lower infectivity. The envelope antigen markers are therefore more helpful in determining the prognosis than in making a diagnosis. Remark: rather uncertain parameter: the better alternative is the direct HBV-DNA detection (hybridization, PCR).

Acute hepatitis is merely treated symptomatically. No specific treatment alleviates the course of acute hepatitis B. Alcohol should be avoided because it increases the liver damage. Restrictions in diet or physical activity including often prescribed bed rest have no scientific basis.

Antiviral therapy only in cases of limited liver function (nucleoside or nucleotide analogues; no interferon). Every 3 months laboratory control (HBs-Ag negative, anti-HBs >10IU/l).

In cholestatic hepatitis, the administration of colestyramine 8 g p.o. once or twice daily can reduce itching.

The vaccination is protective; the use of hepatitis B immunoglobulin and normal immunoglobulin (e.g. Beriglobin®) after exposure may prevent or attenuate clinical disease.

Asymptomatic infection (adults 65%) and cure with virus elimination

Acute hepatitis with cure and virus elimination (adults 30%)

Chronic hepatitis B (depending on age) in about 10% of cases.

Chronically active hepatitis B (chronic aggressive hepatitis)

Chronic persistent hepatitis B. Virus persistence (HbsAg carriers): 5% of immunocompetent adults, 20% of drug addicts, 30% of dialysis patients, 50% of immunosuppressed kidney transplant patients, 90% of newborns in HBV-infected mothers, 35% of infants.

The chronically persistent form can change into an active form, especially under immunosuppressive conditions. Transition may be associated with symptoms of acute hepatitis. Even hepatitis B that is thought to have been through can reactivate. genome probably remains in the hepatocytes in most cases and is immunologically controlled

Fulminant hepatitis in up to 1% of hospitalized patients. When fulminant hepatitis occurs, treatment with oral nucleoside or nucleotide analogues improves the probability of survival. Liver transplantation is the most promising treatment option. Adults rarely survive such a course without transplantation, children tend to have a more favourable outcome.

Patients should be advised to avoid behaviour with a high risk of infection (e.g. exchanging needles to inject drugs; frequently changing sexual partners). Blood and other body fluids (e.g. saliva, semen) are considered infectious. Leaks should be cleaned with virucidal agents. Protective measures are recommended, but isolation of the patient is not of value.

The risk of post-transfusion hepatitis is minimized by avoiding unnecessary transfusions and by testing all blood donors for HBsAg and anti-HCV. This screening has reduced the incidence of posttransfusion hepatitis to approximately 1:100,000 units of transfused blood components.

Vaccinations

Hepatitis B vaccination in endemic areas has significantly reduced local prevalence. Pre-exposure immunoprophylaxis has long been recommended for high-risk individuals. In the USA, vaccination is recommended for all US citizens from birth or in <18 years of age. A universal worldwide vaccination would be desirable but not possible for cost reasons.

• Adults at high risk of HBV infection should be screened and vaccinated if they are not already immune or infected. These high-risk groups include:
• men who have sex with men
• People with sexually transmitted disease.
• Patients who had > 1 sexual partner within the last 6 months
• Healthcare and public safety workers who may be exposed to blood or other infectious body fluids
• People who have diabetes and are <60 years of age (or ≥ 60 years if their risk of acquiring HBV is considered increased)
• People in the final stages of kidney disease, HIV or chronic liver disease
• household contacts and sex partners of people who are HBsAg positive
• people who provide drug abuse treatment and prevention in prisons or institutions
• International travelers in regions with high or moderate HBV endemicity

Two recombinant vaccines are available. Both are safe, even in pregnancy. 3 injections into the deltoid muscle are given as basic immunization at time 0, after 1 month and after 6 months. Children receive lower doses of the vaccine, immunocompromised patients and patients on dialysis receive higher doses.

After vaccination, the anti-HBs levels formed provide protection for 5 years in 80-90% of cases and for 10 years in 60-80% of cases in immunocompetent patients. Booster vaccine doses are recommended for dialysis patients and immunocompromised patients whose anti-HBs titre is low at < 10O IU/l.

Vaccinated individuals who have been exposed to percutaneous HBsAg-positive exposure are tested for anti-HBs; if antibody titres are < 10O IU/l, booster vaccination is necessary.

Post-exposure prophylaxis

In hepatitis B post-exposure immunoprophylaxis, active vaccination is given together with hepatitis B immunoglobulin (HBIG), a high-titer anti-HBs product.

Newborns of HBsAg-positive mothers are given an initial dose of the vaccine combined with 0.5 ml HBIG i.m. in the thigh immediately after birth.

All persons who have had sexual contact with HBsAg-positive individuals or percutaneous or mucous membrane exposure to HBsAg-positive blood are given 0.06 ml/kg HBIG i.m. within days together with the vaccines.

Alternatively, post-exposure prophylaxis with a normal immunoglobulin (e.g. Beriglobin® a pure gamma globulin: 0.02 ml/kg bw)) + simultaneously with active immunization is recommended for patients at risk of acute exposure. Application within 10 days after close contact with HA patients prevents infection in 80% of cases.