Causes, symptoms, diagnosis and treatment of hepatitis B at a glance

Hepatitis B is an acute liver inflammation caused by the hepatitis B virus (HBV), which can lead to chronic liver inflammation compared to hepatitis A.

Definition:

Hepatitis B is a viral hepatitis caused by infections with hepatitis B viruses. These viruses belong to the Hepadnaviridae family and consist of different parts, including a nucleoside of hepatitis B core antigen (HbcAg), a lipid-containing envelope with the surface antigen (HbsAg) and the envelope antigen (HbeAg).

Epidemiology

Hepatitis B is one of the most common infectious diseases worldwide. According to the World Health Organization (WHO), around two billion people worldwide have been infected with HBV. Around 3% of the world's population, approximately 240 million people, are affected by chronic HBV infection. Regions such as Sub-Saharan Africa and East Asia have a particularly high rate of chronically infected people (5-10%), followed by the Middle East and the Indian subcontinent (2-5%). In Western Europe and North America, the rate is less than 1%. In Europe, the number of people chronically infected with HBV is estimated to be around 13.3 million, which corresponds to around 1.8% of the population of Northern Europe. Every year, around 600-900,000 people worldwide die as a result of acute or chronic hepatitis B.

Causes

Hepatitis B is caused by the hepatitis B virus, a small enveloped hepadna virus (Hepadnaviridae family). It consists of several parts: a nucleoside of hepatitis B core antigen (HbcAg) with the DNA, a lipid-containing envelope with the surface antigen (HbsAg) and the envelope antigen (HbeAg). There are nine different genotypes, A-I, several subgenotypes and eight HbsAg subtypes. In Europe, the genotypes A2 and D are mainly found.

Pathogenesis

HBV is transmitted through contaminated blood, blood products, sexually or perinatally. It is found in almost all body fluids. At around 65%, the majority of new hepatitis B infections in Germany are transmitted sexually, followed by 20% through blood, blood products or contaminated instruments such as shared needles in drug users. Perinatal transmission is rare in Germany, as all pregnant women are tested for HbsAg after the 32nd week of pregnancy, thus reducing transmission during birth.

A hepatitis B infection progresses in several phases. The first phase is the highly replicative phase: after a person has become infected, the virus binds to a receptor on the body's own liver cells. It is taken up into the cell by endocytosis, transported into the cell nucleus and uncoated there. The incomplete DNA strand of the virus is completed by the virus polymerase. Many precursor stages of the virus, so-called pregenomes, are formed and released into the cytoplasm. There their RNA is converted into DNA, an envelope is made around the virus DNA and the finished viruses are released again by exocytosis. Together with the viruses, HBeAg is released, a soluble protein that serves as a marker for a hepatitis B infection. If HBeAg is elevated, the virus is multiplying and viremia is high. At this point, the patient is highly infectious. The blood count at this time shows elevated transaminases, HBsAg, HBeAg and HBV DNA.

In the second phase, the late low replicative phase, only HBsAg is produced. Seroconversion occurs: antibodies are produced against HBeAg, the HBeAg titer falls and the anti-HBe titer rises. The transaminases in the blood often fall back to a normal level. HBsAg and anti-HBe remain elevated. Whether HBV DNA is still detectable varies.

The third phase, the healing phase, is characterized by the fact that HBsAg and HBV DNA can no longer be detected in the blood.

In most cases, the body manages to get the HBV infection under control immunologically at an early stage. IFN-γ and TNF-α reduce the HBV DNA load in the blood before the disease can break out. As a result, many infections are asymptomatic and go unnoticed by those affected. If an outbreak of the disease nevertheless occurs, polyclonal and multispecifically activated CD8+ cells attack infected liver cells and destroy them. On the one hand, this starts the healing process. On the other hand, however, cell death occurs in the liver and symptoms of acute hepatitis develop. If a sufficient number of cytotoxic T lymphocytes and TH1 helper cells cannot be formed and recruited, the HBV infection can become chronic. Chronic hepatitis is the result.

The virus can be detected in the blood for the first time around six weeks after infection. However, the incubation period is between 45 and 180 days, on average around 60 to 120 days.

Symptoms

The hepatitis B virus has a long incubation period. After infection, it takes between two and six months for the first symptoms to appear. Around 65% of adult cases are completely asymptomatic. Approximately one third of those infected develop acute hepatitis, which heals. As with all viral hepatitis, the symptoms are non-specific: flu-like symptoms such as fever, fatigue and tiredness, but also upper abdominal pain, a feeling of pressure under the right costal arch, loss of appetite and even aversion to food, dizziness and vomiting. In 10-20% of patients, exanthema, rheumatoid joint complaints, pancytopenia, myalgia, Guillain-Barré syndrome, arthralgia, panarteritis nodosa, sicca syndrome, membranous glomerulonephritis, neuritis, peripheral polyneuropathies or neurological, cardiac or hematological symptoms also occur. After two to fourteen days, the classic jaundice, icterus, occurs. The liver is enlarged and coarse. The vast majority of infections heal completely. Around 1% of patients develop fulminant hepatitis with acute liver failure. These patients have a high risk of dying from hepatitis B.

Chronic hepatitis B:

If the HBsAg titer in the serum remains detectable for longer than six months, this is referred to as a chronic infection. This increases the risk of liver cirrhosis and hepatocellular carcinoma. The disease is asymptomatic for a long time and only becomes clearly symptomatic in the final stage.

Diagnostics

Due to the long incubation phase, the medical history for suspected hepatitis covers at least the past six months. Laboratory diagnostics are then carried out. Clinically, hepatitis B does not differ from other viral hepatitis.

HBsAg, anti-HBs, anti-HBc-IgM, anti-HBc-IgG, HBeAg, anti-Hbe, HBV-DNA and transaminases can be determined in the laboratory. In an acute hepatitis B infection, HBsAg, anti-Hbc-IgM, HbeAg, the transaminases and possibly also HBV DNA are elevated. This makes it easy to distinguish it from cured hepatitis B, as only anti-Hbs, anti-Hbc-IgG and anti-Hbe are elevated. Anti-Hbs can only be detected when HBsAg has been eliminated from the blood and healing has already begun. HBV DNA can be detected as the earliest marker. It is already detectable two to four weeks before HBsAg. HbeAg and anti-Hbe in particular have prognostic relevance. If they are elevated, the virus multiplies strongly. The patient is highly infectious.

If hepatitis B is suspected, HBsAg and total anti-HBc (IgM and IgG) are screened first. If the HBsAg value is positive, the other markers are determined. If anti-HBc-IgM is elevated, acute viral hepatitis is present. Anti-HBs indicates an infection that has healed or is in the process of healing. HBeAg serves as a prognostic marker and as a surrogate parameter for the current phase of the infection - high replicative or late low replicative.

If hepatitis B has already become chronic, HBsAg, anti-Hbc-IgG, HbeAg, HBV-DNA and transaminases are elevated. However, if the infection has already passed, only the anti-Hbc-IgG is elevated.

Therapy

Acute hepatitis B infection usually heals spontaneously. It is therefore treated symptomatically. In the acute phase, bed rest and a high-carbohydrate, low-fat diet can be helpful. Antiviral therapy is only used in cases of impaired liver function or fulminant progression. Indicators may be a drop in the Quick value below 50% or impaired liver synthesis. In the case of fulminant progression, patients should be connected to a transplant center at an early stage in order to provide them with the best possible care.

In order to detect chronicity at an early stage, laboratory tests should be carried out every three months until the HBsAg titer is negative and anti-HBs falls below 10 IU/l.

The situation is different with chronic hepatitis B infection. As it increases the risk of hepatocellular carcinoma (HCC) and liver cirrhosis, all patients with chronic HBV infection should be treated. Chronic HBV infection is only present if the HBsAg titer has been positive for more than six months.

Treatment is carried out with antiviral therapy according to the guidelines, either with PEG interferon α or with antiviral substances. The aim of the therapy is partial or complete seroconversion or at least one HBV DNA below the detection limit:

Interferon-alpha therapy lasts 24 to 48 weeks. Patients are injected with peginterferon once a week. In around 40% of patients, this therapy can stop the virus replication completely. The transaminases return to normal. If therapy in patients with HBeAg does not show at least partial success within twelve weeks (HBsAg > 20,000 IU/ml or a general drop in the HBsAg titer), therapy should be discontinued. Interferon α therapy is associated with considerable side effects. It should therefore not be used in advanced or decompensated liver cirrhosis according to Child B/C or during pregnancy. Alternatively, antiviral therapy with nucleoside and nucleotide analogs (antivirals) can be carried out.

Antiviral therapy reduces the viral load. It is used if interferon α therapy cannot be used due to side effects, contraindications or lack of effect. Patients with low inflammatory activity are also treated antivirally. Entecavir, tenofovir, telbivudine or lamivudine are used. Tenofovir is the antiviral used in pregnant women where treatment cannot be postponed until the birth of the child. In HIV-positive patients without HIV therapy, however, one of the other four antivirals should be chosen, as otherwise HIV resistance may develop. Lamivudine and telbivudine are also rarely used, as they are known to promote resistance.

The therapy lasts at least twelve months until at least a partial seroconversion from HBeAg to anti-HBe occurs. In around 50% of cases, a relapse occurs within twelve months and the viruses multiply again. The therapy is only considered to be finished when complete seroconversion has occurred. This means that HBsAg is negative and anti-HBs positive. As this can often not be achieved, chronic HBV infection usually leads to long-term antiviral therapy.

Prognosis

More than 90% of HBV infections in otherwise healthy adult patients heal completely. 65% of infections are asymptomatic, without those affected noticing anything about the infection. However, in order to detect chronicity at an early stage, all patients with HBV infection should be checked to see whether there is an indication for treatment.

Around 5% of adult, otherwise healthy patients become HBsAg carriers. This means that they are still infected and either develop chronic hepatitis or are asymptomatic carriers. In hemodialysis patients, the proportion is up to 30%, in immunosuppressed kidney transplant patients up to 50%, in newborns of HBV-infected mothers more than 90%, in drug users up to 20%, in infants around 70% and in young children around 35%.

Chronic hepatitis: Of patients with chronic-replicative HBV infection with hepatitis, 20% develop liver cirrhosis within ten years and 3% develop HCC. The higher the viral load, the higher the risk of developing HCC. Therefore, these patients should be screened every six months by ultrasound and AFP determination. 40% of patients treated with peginterferon achieve partial seroconversion at the end of therapy, which means that the viruses no longer replicate. Under antiviral therapy with antivirals, HBV DNA can be reduced below the detection limit in most cases. However, this often requires long-term treatment with antivirals. Partial seroconversion is only achieved in approx. 20% of patients with antiviral therapy and complete seroconversion in only 8%.

Prophylaxis

Vaccination: Similar to hepatitis A, hepatitis B can be vaccinated against. The vaccine can be given monovalently, i.e. alone, in combination as a six-dose vaccine with tetanus, diphtheria, poliomyelitis, pertussis and Hib or in combination with hepatitis A. Today, children are immunized according to the STIKO schedule within the first year of life. This requires four doses of vaccine at the ages of two, three, four and eleven to fourteen months. Adolescents who have not yet been vaccinated can be vaccinated up to the age of 18. This requires three doses of vaccine. The vaccination schedule depends on the manufacturer. People over the age of 18 are only vaccinated if there is a health or occupational risk. This includes immunosuppressed people or people with an underlying disease that could presumably promote a severe course of HBV, police officers, healthcare staff and people working in facilities with a high risk of exposure, as well as certain types of travel. No booster is currently recommended by the STIKO after the basic immunization or the indication vaccination.

People at risk should have their anti-Hbs titre checked every ten years and be revaccinated if the value falls below 100 IU/L. The same applies to people who were first vaccinated as adolescents or adults, as the rate of low responders and non-responders is higher here. If the target value of at least 100 IU/L anti-Hbs titre cannot be achieved, a booster vaccination is given until a sufficient titre is measured.

Post-exposureprophylaxis: Post-exposure prophylaxis (PEP) may be necessary after needlestick injuries, contact with mucous membranes or damaged skin and HBsAg-positive blood. Newborns whose mothers are HBsAg-positive or have an unknown HBsAg status also require PEP with HB vaccine and HB immunoglobulin within twelve hours of birth. Fully vaccinated people whose titer has been at least 100 IU/L within the last ten years are exempt from PEP.

Hygiene measures: To prevent the uncontrolled spread of HBV, there are hygiene protocols for handling potentially infectious material such as blood or semen. Protective gloves must be worn for all contact. If contaminated droplets can occur, a protective gown or apron, mouth and nose protection and protective goggles or a face shield should also be worn. Patients with an active HBV infection should take care not to share nail scissors, toothbrushes, razors and similar items in the home. Condoms should be used consistently during sexual intercourse to protect sexual partners. Dentists and other medical staff providing treatment should also be informed about HBV infection.