The family Hepadnaviridae (hepatotropic DNA viruses) consists of hepatitis-causing viruses with DNA genomes. Each hepadnavirus has a narrow host range in which it produces both acute and chronic, persistent infections, but HBV is the only member of this family that infects humans. Because highly infectious virus is present in the blood of both symptomatic and asymptomatic patients, chronically infected individuals pose a serious threat to all healthcare workers, immunization of whom is generally required. A highly effective vaccine produced in genetically engineered yeast cells is available and included among routine child hood immunizations. Biologically, HBV is unique among human disease agents in that replication of the DNA genome proceeds via an RNA intermediate, which, in turn, is “reverse transcribed” by a viral enzyme homologous to the retrovirus reverse transcriptase. However, although retroviruses package an RNA genome, Hepadnaviridae package a DNA genome.

A. Structure and replication of hepatitis B virus

 The HBV virion, historically referred to as the “Dane particle,” con sists of an icosahedral nucleocapsid enclosed in an envelope (Figure 1).

Fig1. Electron micrograph of a fraction of serum from a patient with severe hepatitis.

 1. Organization of the hepatitis B virus genome: The short HBV DNA genome is unusual in that it is a partly single-stranded, partly double-stranded, noncovalently closed, circular DNA molecule (that is, one strand is longer than the other) as shown in Figure 2. The short “plus” strand, which can vary in length, is only 50 to 80 percent as long as its complementary strand, the “minus” strand. The circular structure of the genome is maintained by base-pairing the strands at one end. A summary of HBV replication is shown in Figure 2.

Fig2. Replication of hepatitis B virus (HBV).

 2. Viral proteins: The four proteins encoded by viral DNA are: 1) the core protein [hepatitis B nucleocapsid core antigen (HBcAg)]; 2) envelope protein [a glycoprotein referred to as hepatitis B surface antigen (HBsAg)]; 3) multifunctional reverse transcriptase/DNA polymerase, which is complexed with the DNA genome within the capsid; and 4) a nonstructural regulatory protein designated the “X protein.” [Note: HBeAg is produced from an alternate start site upstream of the start for HBcAg, followed by proteolytic processing of the pre-core protein.]

B. Transmission

 Infectious HBV is present in all body fluids of an infected individual. Therefore, blood, semen, saliva, and breastmilk, for example, serve as sources of infection. The titer of infectious virus in the blood of an acutely infected patient can be as high as 108 virus particles per ml but generally is lower in other body fluids. In areas of high endemicity (for example, Southeast Asia, Africa, and the Middle East), the majority of the population becomes infected at or shortly after birth from a chronically infected mother or from infected siblings. Individuals infected at this young age have a significant chance of becoming chronic carriers, maintaining the high prevalence of virus in the population. Individuals infected at an early age also have an increased risk of developing hepatocellular carcinoma later in life. In the United States and other Western countries, the carrier rate is much lower, and primary infection rarely occurs in newborns. Hepatitis B is primarily a disease of infants in developing nations, and, in Western countries, it is mostly confined to adults who usually contract HBV infection through sexual intercourse or blood exposure from shared needles during injecting drug use.

C. Pathogenesis

Fully differentiated hepatocytes are the primary cell type infected by HBV. The primary cause of hepatic cell destruction appears to be the cell-mediated immune response, which results in inflammation and necrosis. The cells involved are cytotoxic T cells, which react specifically with the fragments of nucleocapsid proteins (HBcAg and HBeAg), expressed on the surface of infected hepatocytes. This response also contributes to control of the infection by eliminating virus-producing cells. Enhanced natural killer cell activity, as well as production of interferon-γ also contributes to limiting the extent of infection. Anti-HBsAg antibody, which is the neutralizing antibody, does not appear until well into the convalescence period, when it may aid in clearing any remaining circulating free virus. More importantly, this antibody provides protection against reinfection. However, it is this same humoral antibody that is considered the source of extrahepatic damage seen in 10 to 20 percent of patients, through the formation and deposition of HBsAg/anti-HBsAg antibody immune complexes and the consequent activation of complement.

D. Clinical significance: acute disease

HBV is important medically and in public health, not only as the cause of acute liver disease but also as the cause of chronic, persistent infections that can result in the eventual death of infected individuals from cirrhosis and liver cancer. Chronically infected people serve as the reservoir of transmissible virus in the population. In most individuals, the primary infection is asymptomatic and resolves as a result of an effective cell-mediated immune response (Figure 3).

Fig3. Clinical outcomes of acute hepatitis B virus (HBV) infection.

1. Phases in acute hepatitis B virus infections: Following infection, HBV has a long but variable incubation period of between 45 and 120 days. Following this period, a pre-icteric (prejaundice) phase occurs, lasting several days to a week. This is characterized by mild fever, malaise, anorexia, myalgia, and nausea. The acute, icteric phase then follows and lasts for 1 to 2 months. During this phase, dark urine, due to bilirubinuria, and jaundice (a yellowish coloration of mucous membranes, conjunctivae, and skin) are evident. There usually is an enlarged and tender liver as well. In 80 to 90 percent of adults, a convalescent period of several more months is followed by complete recovery (Figure 4).

Fig4. Symptoms of acute hepatitis B infection. RUQ = right upper quadrant.

2. Monitoring the course of acute hepatitis B virus infection: Whereas liver-specific enzymes are important clinical determinants of all of the viral hepatitides, HBV infection is unusual in that the quantities of virions and virion components in the blood are so great that the time course of their appearance and clearance, along with that of the antibodies directed against them, serve as convenient markers of the stage of the disease and the likely future course.

a. Appearance of viral antigens: During the incubation period, HBsAg and hepatitis B e antigen (HBeAg) are the first indica tors of HBV infection to appear in the blood (Figure 5). Their presence indicates an active infection but does not distinguish between acute and chronic infections. Next, viral DNA, viral DNA polymerase, and complete virions become detectable. These continue to increase during the acute disease phase, when a patient’s blood has the highest titer of infectious virus.

Fig5. Typical course of hepatitis B virus infection. A. Acute infection. B. Chronic infection. HBsAg = hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBcAg = hepatitis B nucleocapsid core antigen; anti-HBsAg, anti-HBeAg, and anti-HBcAg each refer to antibodies to the corresponding antigen.

b. Appearance of antiviral antibodies: Antibodies to HBcAg rise concurrently with liver enzymes in the serum, whereas anti HBeAg antibodies and, still later, anti-HBsAg antibodies do not appear until the beginning of convalescence (generally after the respective antigens have disappeared from the blood, see Figure 5). In those patients in whom the infection resolves completely, anti-HBcAg and anti-HBsAg antibodies remain pre sent for life, providing immunity to reinfection. Continued presence of HBsAg beyond 6 months and absence of anti-HBsAg indicates that the infection has become chronic (Figure 6). A patient suffering chronic HBV infection is capable of eliciting an immune response against HBsAg but the anti-HBs antibody levels are too low to be detectable. All of the antibody that develops is complexed with circulating HBsAg.

Fig6. Interpretation of serologic markers of hepatitis B infection. HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; anti HBcAg, and anti-HBsAg each refer to antibodies to the corresponding antigen.

3. Fulminant hepatitis: In 1 to 2 percent of acute symptomatic cases, much more extensive necrosis of the liver occurs during the first 8 weeks of the acute illness. This is accompanied by high fever; abdominal pain; and eventual renal dysfunction, coma, and seizures. Termed fulminant hepatitis, this condition is fatal in roughly 8 percent of cases. Although it is not clear why the acute disease takes this course, a more highly virulent strain of HBV, coinfection with HDV or another hepatitis virus (for example, HCV), and/or perhaps an uncontrolled immune response by the patient, are thought to play a role.

E. Clinical significance: chronic disease

 In about two thirds of individuals, the primary infection is asymptomatic, even though such patients may later develop symptomatic chronic liver disease, indicating persistence of the virus. Following resolution of the acute disease (or asymptomatic infection), about 2 to 10 percent of adults and over 25 percent of young children remain chronically infected (Figure 7). The high rate of progression to chronic liver disease seen in infants born to HBV-infected mothers is thought to relate to the less competent immune status of newborns. Adults with immune deficiencies also have a considerably higher probability of developing chronic infection than do individuals with normal immune systems.

Fig7. Effect of patient’s age on the tendency of acute hepatitis B virus (HBV) infection to progress to chronic disease.

1. Types of chronic carriers: The asymptomatic carriers of HBsAg are the most common type of persistently infected individuals. They usually have anti-HBeAg antibodies and little or no infectious virus in their blood (see Figures 5B and 6). Later progression of liver damage or recurrence of acute episodes of hepatitis is rare in such patients. Those carriers with minimal chronic hepatitis (formerly, “chronic persistent hepatitis”) are asymptomatic most of the time but have a higher risk of reactivation of disease, and a small fraction does progress to cirrhosis. Severe chronic hepatitis (formerly, “chronic active hepatitis”) results in more frequent exacerbations of acute symptoms, including progressive liver damage, potentially leading to cirrhosis and/or hepatocellular carcinoma (see below), chronic fatigue, anorexia, malaise, and anxiety. These symptoms are accompanied by active virus replication and the corresponding presence of HBeAg in the blood. Serum levels of liver enzymes and bilirubin are increased to varying degrees, reflecting the extent of necrosis. The risk of developing cirrhosis is highest in those carriers with more frequent recurrences of acute disease and those in whom HBeAg is not cleared from the blood, indicating continuing virus replication. Overall life expectancy is significantly shorter in those individuals with cirrhosis.

2. Development of hepatocellular carcinoma (hepatoma): Hepatocellular carcinoma (HCC) is fairly uncommon in the United States, whereas it is 10 to100 times more frequent in areas of high HBV endemicity. In all populations, males experience a higher rate of chronic HBV infections; a higher rate of progression to cirrhosis; and, ultimately, a higher rate of HCC, for which the male-to-female ratio is 6:1. HCC typically appears many years after the primary HBV infection, and the tumor itself is rather slow growing and only occasionally metastasizes. Clinically, a patient with HCC exhibits weight loss, right-upper-quadrant pain, fever, and intestinal bleeding. Although there is no doubt that chronic HBV infection greatly increases the risk of HCC, the mechanisms relating HBV and HCC are not completely understood. By causing continuing liver necrosis, followed by regeneration of the dam aged tissue, chronic HBV infection provides the opportunity for chromosomal rearrangements and mutations. Because HBV is a DNA virus, integration of the viral genome into the host's chromo some can also result in mutation and insertion, with concomitant changes in cell growth control. In fact, recent evidence suggests that the HBV gene product X is actively involved in tumor formation, following integration of the gene into the host's chromosome. HCC is a major cause of death due to malignancy worldwide, and its distribution parallels HBV incidence (approximately 80 percent of primary HCCs occur in HBV-infected individuals).

F. Laboratory identification

 The purpose of diagnostic laboratory studies of patients with clinical hepatitis is to, first, determine which hepatitis virus is the cause of the illness and, second (for HBV), to distinguish acute from chronic infections. The diagnosis of hepatitis is made on clinical grounds, coupled with biochemical tests that evaluate liver damage. Elevations of aminotransferases, bilirubin, and prothrombin time all contribute to the initial evaluation of hepatitis. Commonly known as ELISA, enzyme-linked immunosorbent assay, and other immunologic techniques for detection of viral antigens and antibodies are the primary means to distinguish among HAV, HBV, HCV, and HDV. In addition, identification of the presence or absence of specific antiviral antibodies and viral antigens permits differentiating between acute and chronic HBV infections (see Figure 5).

G. Treatment

1. Acute hepatitis: Specific treatment for acute hepatitis B is usually not needed, because, in about 95 percent of adults, the immune system controls the infection and eliminates the virus within about 6 months. Although drug therapy is usually only required in chronic hepatitis, it may also be required with the acute severe liver impairment that accompanies fulminant hepatitis.

2. Chronic hepatitis: The goal for treatment in patients with chronic hepatitis is to reduce the risk of progressive chronic liver disease and other long-term complications from chronic HBV, such as cirrhosis and hepatocellular carcinoma. The most commonly used drugs include interferon-α or one of a large number of nucleoside/nucleotide antiviral agents (Figure 8). The drug of choice depends on multiple factors, including the antibody and antigen status of the patient. Pegylated interferon-α (if the patient does not have cirrhosis), entecavir, or tenofovir are often preferred for initial treatment. The two most commonly used markers to monitor the efficacy of therapy are seroconversion to anti-HBeAg and sustained suppression of HBV DNA.

Fig8. Drugs used in the treatment of hepatitis B. HBV = hepatitis B virus.

H. Prevention

The purpose of controlling the spread of HBV infection is to prevent cases of acute hepatitis. An additional goal is to decrease the pool of chronically infected individuals who serve as reservoirs for infectious virus in the population and who are at greatly increased risk for developing cirrhosis and liver cancer. The availability of a highly effective vaccine has led to a several-pronged approach: 1) protection of those adults who are at risk because of lifestyle or occupation, 2) protection of newborns from infection by transmission from HBV positive mothers (important because of the high rate of resulting chronic infections), and 3) protection of siblings and other children from infection by chronically infected family members.

1. Active immunization: HBsAg is used to prepare vaccines confer ring protection because antibody to the virion component neutralizes infectivity. HBV vaccination is now recommended as a routine infant immunization, as is the immunization of adolescents who were not given the vaccine as infants. An unusual feature of the recommended vaccination schedule is to initiate an HBV vaccine series at birth. This is possible because infants have adequate antibody response to neonatal vaccination with the HBV vaccine. Other individuals who are candidates for HBV vaccine are shown in Figure 9.

Fig9. Candidates for hepatitis B virus immunization. HBsAg = hepatitis B surface antigen.

2. Passive immunization: Hepatitis B immunoglobulin (HBIG) is pre pared from the blood of donors having a high titer of anti-HBsAg antibody. Immediate administration of HBIG is recommended as the initial step in preventing infection of individuals accidentally exposed to HBV-contaminated blood by needlestick or other means and of those exposed to infection by sexual contact with an HBV-positive partner. In such cases, this should be accompanied by a course of active immunization with the hepatitis B vac cine. It is also strongly recommended that pregnant women should be screened for HBsAg. Infants born to mothers who are HBV positive are given HBIG plus hepatitis B vaccine at birth, followed by additional doses of vaccine at 1 and 6 months.

اخر الاخبار

اخبار العتبة العباسية المقدسة

تزامنًا مع حلول شهر ربيع الأول.. العتبة العباسية المقدسة ترفع مظاهر الحزن والسواد في المرقد الطاهر

بعد انتهاء شهري المحرم وصفر.. قسم الصيانة يباشر إدامة الثريات واستبدال مصابيح المرقد الطاهر

قسم الشؤون الخدمية يشرع بإدامة آليّات النظافة عقب انتهاء زيارة الأربعين

موكب عزاء الشعراء والرواديد ينظم مسيرة عزائية في ختام شهري الأحزان المحرم الحرام وصفر

المزيد

الآخبار الصحية

العنب.. فاكهة صغيرة بمفعول "خارق" للقلب والدماغ

دراسة تحدد "الحلقة المفقودة".. تسبب ارتفاع ضغط الدم

هذه الأطعمة تحمي دماغك من الشيخوخة وتزيد حدة الذكاء

خبراء يحذرون من مخاطر "الدهون المخفية" على القلب

المزيد

الآخبار التكنلوجية

الأرصاد الجوية تلجأ إلى الذكاء الاصطناعي.. لأي غرض؟

في منزلك.. "تعديل بسيط" يخفض ضغط الدم بشكل طبيعي

"ميزة جديدة" من إنستغرام تنافس تيك توك.. طال انتظارها

غوغل في مأزق.. بيانات 2.5 مليار مستخدم بقبضة القراصنة

المزيد

مواضيع ذات صلة

Hepatitis D Virus (Delta Agent)

Poxviridae

West Nile Virus

Epstein-Barr Virus

Herpes simplex virus, types 1 and 2

Herpesviridae: Structure and Replication

Adenoviridae

Human Cowpox

Human Monkeypox

Smallpox virus

Papovaviridae: Subfamily Polyomavirinae

Effects of viral infection on the host cell