Hepatitis B

[aljody]

Signs and symptoms

Acute infection with hepatitis B virus is associated with acute viral hepatitis – an illness that begins with general ill-health, loss of appetite, nausea, vomiting, body aches, mild fever, and dark urine, and then progresses to development of jaundice. It has been noted that itchy skin has been an indication as a possible symptom of all hepatitis virus types. The illness lasts for a few weeks and then gradually improves in most affected people. A few people may have more severe liver disease (fulminant hepatic failure), and may die as a result. The infection may be entirely asymptomatic and may go unrecognized.[16]

Chronic infection with hepatitis B virus either may be asymptomatic or may be associated with a chronic inflammation of the liver (chronic hepatitis), leading to cirrhosis over a period of several years. This type of infection dramatically increases the incidence of hepatocellular carcinoma (liver cancer). Across Europe Hepatitis B and C cause approximately 50% hepatocellular carcinomas.[17][18] Chronic carriers are encouraged to avoid consuming alcohol as it increases their risk for cirrhosis and liver cancer. Hepatitis B virus has been linked to the development of Membranous glomerulonephritis (MGN).[19]

Symptoms outside of the liver are present in 1–10% of HBV-infected people and include serum-sickness–like syndrome, acute necrotizing vasculitis (polyarteritis nodosa), membranous glomerulonephritis, and papular acrodermatitis of childhood (Gianotti-Crosti syndrome).[20][21] The serum-sickness–like syndrome occurs in the setting of acute hepatitis B, often preceding the onset of jaundice.[22] The clinical features are fever, skin rash, and polyarteritis. The symptoms often subside shortly after the onset of jaundice, but can persist throughout the duration of acute hepatitis B.[23] About 30–50% of people with acute necrotizing vasculitis (polyarteritis nodosa) are HBV carriers.[24] HBV-associated nephropathy has been described in adults but is more common in children.[25][26] Membranous glomerulonephritis is the most common form.[23] Other immune-mediated hematological disorders, such as essential mixed cryoglobulinemia and aplastic anemia.[23]
Virology
Main article: Hepatitis B virus
Structure
The structure of hepatitis B virus

Hepatitis B virus (HBV) is a member of the Hepadnavirus family.[12] The virus particle (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. These virions are 42 nM in diameter. The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity.[13] The outer envelope contains embedded proteins that are involved in viral binding of, and entry into, susceptible cells. The virus is one of the smallest enveloped animal viruses, and the 42 nM virions, which are capable of infecting hepatocytes, are referred to as "Dane particles".[27] In addition to the Dane particles, filamentous and spherical bodies lacking a core can be found in the serum of infected individuals. These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the surface antigen (HBsAg), and is produced in excess during the life cycle of the virus.[28]
Genome
The genome organisation of HBV. The genes overlap.

The genome of HBV is made of circular DNA, but it is unusual because the DNA is not fully double-stranded. One end of the full length strand is linked to the viral DNA polymerase. The genome is 3020–3320 nucleotides long (for the full-length strand) and 1700–2800 nucleotides long (for the short length-strand).[29] The negative-sense (non-coding) is complementary to the viral mRNA. The viral DNA is found in the nucleus soon after infection of the cell. The partially double-stranded DNA is rendered fully double-stranded by completion of the (+) sense strand and removal of a protein molecule from the (-) sense strand and a short sequence of RNA from the (+) sense strand. Non-coding bases are removed from the ends of the (-) sense strand and the ends are rejoined. There are four known genes encoded by the genome, called C, X, P, and S. The core protein is coded for by gene C (HBcAg), and its start codon is preceded by an upstream in-frame AUG start codon from which the pre-core protein is produced. HBeAg is produced by proteolytic processing of the pre-core protein. The DNA polymerase is encoded by gene P. Gene S is the gene that codes for the surface antigen (HBsAg). The HBsAg gene is one long open reading frame but contains three in frame "start" (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons, polypeptides of three different sizes called large, middle, and small (pre-S1 + pre-S2 + S, pre-S2 + S, or S) are produced.[30] The function of the protein coded for by gene X is not fully understood but it is associated with the development of liver cancer. It stimulates genes that promote cell growth and inactivates growth regulating molecules.[31]
Replication
Hepatitis B virus replication

The life cycle of hepatitis B virus is complex. Hepatitis B is one of a few known pararetroviruses: non-retroviruses that still use reverse transcription in their replication process. The virus gains entry into the cell by binding to NTCP [32] on the surface and being endocytosed. Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host proteins called chaperones. The partially double stranded viral DNA is then made fully double stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of four viral mRNAs. The largest mRNA, (which is longer than the viral genome), is used to make the new copies of the genome and to make the capsid core protein and the viral DNA polymerase. These four viral transcripts undergo additional processing and go on to form progeny virions that are released from the cell or returned to the nucleus and re-cycled to produce even more copies.[30][33] The long mRNA is then transported back to the cytoplasm where the virion P protein (the DNA polymerase) synthesizes DNA via its reverse transcriptase activity.
Serotypes and genotypes

The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome. The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus. Differences between genotypes affect the disease severity, course and likelihood of complications, and response to treatment and possibly vaccination.[34][35]

Genotypes differ by at least 8% of their sequence and were first reported in 1988 when six were initially described (A-F).[36] Two further types have since been described (G and H).[37] Most genotypes are now divided into subgenotypes with distinct properties.[38]

Distribution of genotypes

Genotype A is most commonly found in the Americas, Africa, India and Western Europe. It is divided into subgenotypes. Of these subgenotype A1 is further subdivided into an Asian and an African clade.

Genotype B is most commonly found in Asia and the United States. Genotype B1 dominates in Japan, B2 in China and Vietnam while B3 confined to Indonesia. B4 is confined to Vietnam. All these strains specify the serotype ayw1. B5 is most common in the Philippines.

Genotype C is most common in Asia and the United States. Subgenotype C1 is common in Japan, Korea and China. C2 is common in China, South-East Asia and Bangladesh and C3 in Oceania. All these strains specify the serotype adr. C4 specifying ayw3 is found in Aborigines from Australia.[39]

Genotype D is most commonly found in Southern Europe, India and the United States and has been divided into 8 subtypes (D1–D8). In Turkey genotype D is also the most common type. A pattern of defined geographical distribution is less evident with D1–D4 where these subgenotypes are widely spread within Europe, Africa and Asia. This may be due to their divergence having occurred before that of genotypes B and C. D4 appears to be the oldest split and is still the dominating subgenotype of D in Oceania.

Type E is most commonly found in West and Southern Africa.

Type F is most commonly found in Central and South America and has been divided into two subgroups (F1 and F2).

Genotype G has an insertion of 36 nucleotides in the core gene and is found in France and the United States.[40]

Type H is most commonly found in Central and South America and California in United States.

Africa has five genotypes (A-E). Of these the predominant genotypes are A in Kenya, B and D in Egypt, D in Tunisia, A-D in South Africa and E in Nigeria.[39] Genotype H is probably split off from genotype F within the New World.[41]

Evolution

A Bayesian analysis of the genotypes suggests that the rate of evolution of the core protein gene is 1.127 (95% credible interval 0.925-1.329) substitutions per site per year.[42]

The most recent common ancestor of genotypes A, B, D evolved in 1895 (95% confidence interval 1819-1959), 1829 (95% confidence interval 1690-1935) and 1880 (95% confidence interval 1783-1948) respectively.[42]
Mechanisms
Pathogenesis

Hepatitis B virus primarily interferes with the functions of the liver by replicating in liver cells, known as hepatocytes. A functional receptor is NTCP.[32] There is evidence that the receptor in the closely related duck hepatitis B virus is carboxypeptidase D.[43][44] The virions bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis. HBV-preS-specific receptors are expressed primarily on hepatocytes; however, viral DNA and proteins have also been detected in extrahepatic sites, suggesting that cellular receptors for HBV may also exist on extrahepatic cells.[45]

During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. Although the innate immune response does not play a significant role in these processes, the adaptive immune response, in particular virus-specific cytotoxic T lymphocytes(CTLs), contributes to most of the liver injury associated with HBV infection. CTLs eliminate HBV infection by killing infected cells and producing antiviral cytokines, which are then used to purge HBV from viable hepatocytes.[46] Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs in the liver.[47]
Transmission

Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood. Possible forms of transmission include sexual contact,[48] blood transfusions and transfusion with other human blood products,[49] re-use of contaminated needles and syringes,[50] and vertical transmission from mother to child (MTCT) during childbirth. Without intervention, a mother who is positive for HBsAg confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for HBeAg. HBV can be transmitted between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV.[51] However, at least 30% of reported hepatitis B among adults cannot be associated with an identifiable risk factor.[52] And Shi et al. showed that breastfeeding after proper immunoprophylaxis did not contribute to MTCT of HBV.[53]
Diagnosis
Hepatitis B viral antigens and antibodies detectable in the blood following acute infection.
Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person.

The tests, called assays, for detection of hepatitis B virus infection involve serum or blood tests that detect either viral antigens (proteins produced by the virus) or antibodies produced by the host. Interpretation of these assays is complex.[54]

The hepatitis B surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. The infectious virion contains an inner "core particle" enclosing viral genome. The icosahedral core particle is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen, or HBcAg. During this 'window' in which the host remains infected but is successfully clearing the virus, IgM antibodies to the hepatitis B core antigen (anti-HBc IgM) may be the only serological evidence of disease. Therefore most hepatitis B diagnostic panels contain HBsAg and total anti-HBc (both IgM and IgG).[55]

Shortly after the appearance of the HBsAg, another antigen called hepatitis B e antigen (HBeAg) will appear. Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the hepatitis B virus do not produce the 'e' antigen, so this rule does not always hold true.[56] During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen (anti-HBe) will arise immediately afterwards. This conversion is usually associated with a dramatic decline in viral replication.
Ground glass hepatocytes as seen in a chronic hepatitis B liver biopsy. H&E stain.

If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by IgG antibodies to the hepatitis B surface antigen and core antigen (anti-HBs and anti HBc IgG).[12] The time between the removal of the HBsAg and the appearance of anti-HBs is called the window period. A person negative for HBsAg but positive for anti-HBs either has cleared an infection or has been vaccinated previously.

Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers.[57] Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum alanine aminotransferase (ALT) levels and inflammation of the liver, as revealed by biopsy. Carriers who have seroconverted to HBeAg negative status, in particular those who acquired the infection as adults, have very little viral multiplication and hence may be at little risk of long-term complications or of transmitting infection to others.[58]

PCR tests have been developed to detect and measure the amount of HBV DNA, called the viral load, in clinical specimens. These tests are used to assess a person's infection status and to monitor treatment.[59] Individuals with high viral loads, characteristically have ground glass hepatocytes on biopsy.
Prevention
Main article: Hepatitis B vaccine

Vaccines for the prevention of hepatitis B have been routinely used since the early 1980s. The first vaccines contained inactivated HBsAg that was derived from human plasma of hepatitis B virus carriers. Modern vaccines contain HBsAg from yeast or mammalian cell cultures using recombinant DNA technology and have no risk of transmitting hepatitis B virus. Most vaccines are given in three doses over a course of months. A protective response to the vaccine is defined as an anti-HBs antibody concentration of at least10 mIU/ml in the recipient's serum. The vaccine is more effective in children and 95 per cent of those vaccinated have protective levels of antibody. This drops to around 90% at forty years of age and to around 75 percent in those over sixty. The protection afforded by vaccination is long lasting even after antibody levels fall below 10 mIU/ml. Vaccination at birth is recommended for all infants of HBV infected mothers. A combination of hepatitis B immunoglobulin and an accelerated course of HBV vaccine prevents perinatal HBV transmission in around 90% of cases.[60]

In assisted reproductive technology, The Practice Committee of the American Society for Reproductive Medicine advises that sperm washing is not necessary for males with hepatitis B to prevent transmission, unless the female partner has not been effectively vaccinated.[61] In females with hepatitis B, the risk of vertical transmission during IVF is no different from the risk in spontaneous conception.[61]
Treatment

The hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously.[62] Early antiviral treatment may be required in fewer than 1% of people, whose infection takes a very aggressive course (fulminant hepatitis) or who are immunocompromised. On the other hand, treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Chronically infected individuals with persistently elevated serum alanine aminotransferase, a marker of liver damage, and HBV DNA levels are candidates for therapy.[63] Treatment lasts from six months to a year, depending on medication and genotype.[64]

Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. As of 2008, there are seven medications licensed for treatment of hepatitis B infection in the United States. These include antiviral drugs lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude), and the two immune system modulators interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys). The use of interferon, which requires injections daily or thrice weekly, has been supplanted by long-acting PEGylated interferon, which is injected only once weekly.[65] However, some individuals are much more likely to respond than others, and this might be because of the genotype of the infecting virus or the person's heredity. The treatment reduces viral replication in the liver, thereby reducing the viral load (the amount of virus particles as measured in the blood).[66] Response to treatment differs between the genotypes. Interferon treatment may produce an e antigen seroconversion rate of 37% in genotype A but only a 6% seroconversion in type D. Genotype B has similar seroconversion rates to type A while type C seroconverts only in 15% of cases. Sustained e antigen loss after treatment is ~45% in types A and B but only 25–30% in types C and D.[67]
Prognosis

Hepatitis B virus infection may be either acute (self-limiting) or chronic (long-standing). Persons with self-limiting infection clear the infection spontaneously within weeks to months.

Children are less likely than adults to clear the infection. More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus. However, this drops to 30% for younger children, and only 5% of newborns that acquire the infection from their mother at birth will clear the infection.[68] This population has a 40% lifetime risk of death from cirrhosis or hepatocellular carcinoma.[65] Of those infected between the age of one to six, 70% will clear the infection.[69]

Hepatitis D (HDV) can occur only with a concomitant hepatitis B infection, because HDV uses the HBV surface antigen to form a capsid.[70] Co-infection with hepatitis D increases the risk of liver cirrhosis and liver cancer.[71] Polyarteritis nodosa is more common in people with hepatitis B infection.