Hepatitis B is caused by a DNA virus that belongs to the Hepadnavirus family. HBV infection can develop in an acute or chronic form. HBV represents a global public health problem. It is estimated that there are 248 million HBV carriers worldwide, of which approximately 600,000 die each year from HBV-related liver disease. The implementation of effective vaccination programs in many countries has resulted in a significant reduction in the incidence of new hepatitis B infections. However, HBV infection remains a significant cause of morbidity and mortality.

HBV can be transmitted sexually, parenterally, or perinatally.

The complete viral particle (virion) consists of:

 • An outer envelope formed of the hepatitis B surface anti gen (HBsAg) and components of host-derived lipids

 • A core formed of the core hepatitis B antigen (HBcAg), the viral genome, and the polymerase

HBV also produces subviral particles in the form of filaments and spheres composed only of envelope proteins. These subviral particles do not contain the HBV genome and, therefore, are not infectious.

The HBV genome is a circular, partially double stranded DNA molecule, with a longer L (−) chain consisting of 3200 nucleotides and a shorter S (+) chain varying in length from 1700 to 2800 nucleotides. Although its size is small, the genome can encode many different proteins (genetic economy), such as the S protein expressed on the surface, the functional protein DNA polymerase, which is a target of antiviral therapy, the core antigen, and the E antigen. The core antigen represents the structural protein of the capsid. The E antigen (HBeAg) is generated by a proteolytic cut of C protein. This protein, unlike the core protein, is soluble and, therefore, released in the serum.

HBV is generally not a cytopathic virus. The pathogenesis of HBV-related liver disease is mainly due to immune- mediated mechanisms.

Patients who progress to chronic HBV infection have an altered immune response.

The incubation period of HBV varies from 2 to 6 months.

The spectrum of clinical manifestations of HBV infection varies in both acute and chronic forms. During the acute phase, manifestations range from subclinical hepatitis (70% of cases) to jaundiced hepatitis and, in some cases, fulminant hepatitis (30% of cases). During the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The dis ease may be more severe in patients co-infected with other hepatitis viruses or underlying liver disease. Fulminant liver failure is rare (0.1–0.5% of patients) and is thought to be due to massive immune-mediated lysis of infected hepatocytes.

Complete eradication of HBV rarely occurs after recovery from acute infection, and T cells can control latent infection for decades after clinical recovery.

The natural course of chronic HBV infection is determined by the interaction between viral replication and the host immune response. Other factors that may play a role in the progression of HBV-related liver disease include sex, alcohol consumption, and concomitant infection with other hepatitis viruses. It is important to note that not all patients with chronic HBV infection develop chronic hepatitis. In 20% of cases, chronic hepatitis can progress to cirrhosis within approximately 5 years. Patients with cirrhosis have a high risk of developing hepatocarcinoma.

The evaluation of the different available markers, serological or genetics, depends on the clinical presenting characteristics of the patient, or if screening is to be performed in an asymptomatic person.

Regarding serological markers, HBV infection is characterized by particular changes in serum levels of HBV anti gens and anti-HBV antibodies. Therefore, these markers are used to define different clinical states (Table 1).

Table1. Serological diagnosis of HBV infection

HBsAg and Anti-HBs

HBsAg surface antigen is the serological sign of HBV infection and the first marker to appear. Serum HBsAg can be detected 1–10 weeks after acute HBV exposure, before the onset of clinical symptoms or ALT increase. In most cases, HBsAg is no longer detectable after 2–4 months. The persistence of HBsAg for more than 6 months indicates chronic infection. The disappearance of HBsAg is followed by the appearance of serum antibodies against the surface antigen (anti-HBs). In most patients, anti-HBs persist for life, thus conferring long-term immunity. In some patients, however, anti-HBs may not be detectable until several weeks or months, during which neither HBsAg nor anti-HBs can be detected. In this case, serological diagnosis can be performed by detecting IgM antibodies against the core antigen (IgM anti-HBc), which appear as early as 1–2 weeks after the appearance of HBsAg.

HBcAg and Anti-HBc

The core antigen, HBcAg, is expressed intracellularly in infected hepatocytes; it is not detectable in serum. Antibodies against the core antigen (anti-HBc) can be detected during HBV infection. Specifically, anti-HBc is predominantly of the IgM class in acute infection. Anti-HBc IgM is the only detectable marker of HBV infection during the window period between the disappearance of HBsAg and the appearance of anti-HBs. The presence of anti-HBc IgM is usually considered indicative of acute HBV infection. However, anti-HBc IgM may remain detectable up to 2 years after acute infection. In addition, anti-HBc IgM titer may increase to detectable levels during exacerbations of chronic hepatitis B. Common causes of acute exacerbation of chronic hepatitis B are superinfection with hepatitis D virus or hepatitis C virus. Anti-HBc IgG persists along with anti-HBs in patients recovering from acute hepatitis B and along with HBsAg in patients progressing to chronic HBV infection.

HBeAg and Anti-HBe

HBeAg is a secretory protein generally considered a marker of HBV replication and infectivity. HBeAg is usually associated with elevated serum HBV-DNA levels and higher trans mission rate of HBV infection. HBeAg to anti-HBe seroconversion occurs early in patients with acute infection, before HBsAg to anti-HBsAg seroconversion. However, HBeAg seroconversion may be delayed for years or decades in patients with chronic HBV infection. In such patients, the presence of HBeAg is usually associated with high serum HBV-DNA levels and active liver disease.

Seroconversion from HBeAg to anti-HBe is only associated with a reduction in serum HBV-DNA and remission of liver disease.

HBV-DNA

Qualitative and quantitative assays have been developed to measure serum HBV-DNA to assess HBV replication. The sensitivity limit of these assays depends on the techniques used. Currently, most assays for the assessment of HBV- DNA are based on real-time polymerase chain reaction (PCR).

Recovery from acute hepatitis B is usually accompanied by the disappearance of serum HBV-DNA, as determined by hybridization analysis. However, HBV-DNA may remain detectable in serum for many years when tested by PCR. This observation suggests that the virus persists after “recovery” but is controlled by the immune system. HBV-DNA levels are also detectable in patients with HBeAg-negative chronic hepatitis, although the levels are generally lower than in patients with HBeAg-positive chronic hepatitis.

The main clinical utility of HBV DNA testing in patients with chronic HBV infection is the assessment of HBV replication and eligibility for antiviral therapy. Indeed, the indications for HBV treatment are based on active liver disease and high HBV-DNA levels. HBV-DNA suppression is also used to assess response to antiviral treatment.

Table 2 shows the characteristics of HBV serological markers.

Table 2. Main characteristics of serological markers of HBV

The diagnosis of acute hepatitis B is based on identifying HBsAg and anti-HBc IgM. During the early phase of infection, HBV replication markers, such as HBeAg and HBV-DNA, are also detectable. Recovery is accompanied by the disappearance of HBV -DNA, seroconversion from HBeAg to anti-HBe, and then seroconversion from HBsAg to anti-HBs. Rarely do patients present during the window period when HBsAg has become negative, but anti-HBs are not yet positive. This condition is more common in patients with fulminant hepatitis B because virus clearance tends to be more rapid and anti-HBc IgM is the only marker of acute HBV infection.

Prior HBV infection is characterized by anti-HBs and anti-HBc IgG. Immunity to HBV infection after vaccination is indicated only by the presence of anti-HBs.

The diagnosis of chronic HBV infection is based on the persistence of HBsAg for more than 6 months. Additional tests to assess HBV replication, such as HBeAg and serum HBV-DNA, should be performed to determine if the patient is eligible for antiviral therapy. All patients with chronic HBV infection should be monitored regularly because HBV- DNA and ALT levels vary throughout the infection.

HBeAg-negative patients who have normal or low ALT levels or undetectable HBV-DNA are in an inactive carrier status. These patients generally have a good prognosis, and antiviral treatment is not indicated. However, they should undergo evaluation of ALT and HBV-DNA levels at 3-month intervals during the first year.

مواضيع ذات صلة

Fibrosis

Nonalcoholic Hepatic Steatosis

Fungal testing (Antifungal antibodies; Beta-D-glucan,(1,3)- β-D-glucan, Fungitell, Fungal culture, Fungal antigen assay, Fungal PCR testing)

Folic acid (Folate)

Fibrinogen (Factor I, Quantitative fibrinogen)

Hepatitis A

Fetal hemoglobin (Kleihauer–Betke)

Fetal fibronectin (fFN, Fibronectin)

Ferritin

Fecal calprotectin

Estrogen fractions (Estriol excretion, Estradiol, Estrone)

Erythropoietin (EPO)