Hepatitis B Virus Infection

Infection with HBV (hepatitis B), formerly known as serum hepatitis, is the most prevalent type of acute hepatitis worldwide. Persistent infection with the virus is common, and in highly endemic areas approximately 10% of the population are chronic carriers of HBV; in many individuals infection persists for life. The total number of chronic carriers worldwide exceeds 230 million. Formerly a major cause of transfusion-associated hepatitis, HBV infection is now most frequently spread by sexual contact, intravenous drug abuse and transmission from mothers to their newborn infants.

Three types of viral particles are found in the blood of infected individuals . The complete virion (Dane particle) is 42 nm in diameter. The hepatitis B surface antigen particle (HBsAg), which may be spherical, filamentous or rod-shaped, is 22 nm in diameter. The virion core, also 22 nm in diameter, contains the core antigen (HBcAg), the viral DNA, DNA polymerase, protein kinase activity and the `e' antigen (HBeAg), which is closely associated with infectivity. The genome of HBV is complex and unique; its replication involves the activity of reverse transcriptase which is unique among human DNA viruses. This replication mechanism, and the nucleotide sequence homology between HBV and retroviruses, suggests a possible phylogenetic relationship between these two families of viruses.

Man is the only important reservoir of HBV. Blood and blood products are the best documented sources of the virus, but it is also found in faeces, urine, bile, semen, saliva and other body fluids. The most important vehicles for infection are probably blood, semen and saliva. Transmission commonly occurs via percutaneous inoculation of virus during administration of contaminated blood or blood products, haemodialysis, tattooing, ear piercing, acupuncture, sharing of needles by intravenous drug abusers, or accidental needle stick injuries by hospital personnel, and also during heterosexual and homosexual contact. In areas of the world where the prevalence of chronic HBV infection is very high, transmission from infected mothers to infants occurs frequently during late pregnancy, parturition or during the first two months' postpartum.

The incubation period of acute hepatitis B is usually between two and six months. In patients who develop jaundice, 10-20% have a prodromal serum sickness-like illness with fever, maculopapular erythematous rash, arthralgias and urticaria for several days to several weeks before the appearance of signs of liver disease.

The severity of acute hepatitis B varies widely, and many cases are clinically inapparent. In these subclinical cases and in anicteric cases, serum transaminases are usually elevated. In icteric cases, malaise, fever, headache, anorexia and nausea, sometimes with vomiting, appear 2-7 days before the appearance of jaundice. Anorexia is often pronounced and accompanied by aversion for tobacco; the smell of food or tobacco may induce nausea. Pain and tenderness in the right upper quadrant are common. The liver is often enlarged, palpable and tender. Icterus of the sclerae and other mucous membranes and skin are usually noted when the concentration of serum bilirubin is ³ 3 mg/100 ml.

Laboratory abnormalities include a striking increase in serum transaminases (SGPT > SGOT), with a peak of 1,000 U/ml or greater reached within the first week of illness. Serum bilirubin rises during the first 10-14 days and then declines over the next 2-4 weeks in most cases.

Although most cases of hepatitis B have a relatively mild and self-limited course, fulminant hepatitis with hepatic failure and encephalopathy may occur. The case fatality rate is very high, with death usually occurring within three weeks of onset. Concomitant infection with hepatitis delta virus (HDV) (see below) is associated with an increased risk of fulminant hepatitis.

During the active stage of self-limited hepatitis, both HBsAg and HBeAg can be detected in the blood. These antigens disappear after weeks or months, and antibodies against surface antigen (anti-HBs), core antigen (anti-HBc) and `e' antigen (anti-HBe) appear and persist, at gradually declining titres, for years . In persistent infection HBsAg, with or without

In 5-10% of adults, and virtually 100% of newborns, persistent infection occurs. This may be associated with a histologically normal liver and normal liver function, but it often results in lesions designated `chronic persistent' hepatitis, in which the basic hepatic architecture is preserved , or `chronic active' hepatitis in which there is disruption of lobular architecture and degeneration and regeneration of hepatocytes . The presence of HBeAg in persistent infection is usually associated with chronic hepatitis. Chronic active hepatitis may eventually result in postnecrotic cirrhosis, with extensive fibrosis and distortion of the lobular architecture of the liver.

Hepatitis B infection is also closely associated with development of hepatocellular carcinoma which, after skin cancer, is the most common malignant tumour worldwide. Hepatitis B viral DNA, often integrated into the genome of liver cells, can be demonstrated in approximately 75% of hepatocellular carcinoma cases; exactly how the virus is involved in carcinogenesis is not known. Extrahepatic manifestations of persistent HBV infection, possibly related to circulating immune complexes, include a serum sickness-like syndrome, polyarteritis nodosa and membranous glomerulonephritis.

Vaccines prepared from heat-inactivated serum containing HBsAg, or by recombinant DNA techniques, provide effective protection against HBV infection. Immunization is of no value in individuals with pre-existing antibody to HBsAg or in chronic HBsAg carriers. Administration of hepatitis B vaccine is recommended particularly for individuals with a high risk of infection, such as male homosexuals, intravenous drug abusers, household and sexual contacts of hepatitis B carriers, dialysis patients, recipients of clotting factors VIII or IX, medical and laboratory workers with frequent exposure to blood or blood products, mortuary workers, and residents and staff members of institutions for the mentally retarded. Adults should receive 1 ml vaccine intramuscularly at 0, 1 and 6 months; children under 10 years should receive 0.5 ml on the same schedule. If exposure to HBV occurs via needle stick injury or other means, such as sexual intercourse, oral exchange of saliva by kissing or sharing a toothbrush of an unimmunized individual, prompt administration of serum immunoglobulin with high titres of anti-HBs antibody (HBIG) can provide partial protection. As soon as possible after exposure, 0.06 ml/kg HBIG should be given intramuscularly, followed either by immediate institution of active immunization with hepatitis B vaccine, or by a second dose of HBIG after one month.

No therapeutic measure has been shown to be beneficial in the treatment of acute viral hepatitis. Progression of chronic active hepatitis has been favourably affected by administration of corticosteroids or azathioprine. In some patients, liver function returns towards normal and cirrhosis appears to be prevented. The best results have been observed in HBsAg-negative patients, and in women treated at an early stage of disease. Unfortunately, corticosteroid therapy enhances replication of HBV, and may be associated with the appearance or rise in titre of HBsAg, HBeAg and Dane particles. Corticosteroid therapy is therefore recommended only for patients who are symptomatic, HBsAg negative and have severe histological lesions in liver biopsies.

Two antiviral agents, human leucocyte alpha interferon and adenine arabinoside, have also produced beneficial results in limited trials. Further studies are required to determine their place, if any, in the treatment of chronic hepatitis B infection. Serial determination of alpha-fetoprotein levels and ultrasound examination of the liver in HBsAg carriers with cirrhosis may allow detection of hepatocellular carcinoma at a stage when the tumour can be cured by surgical resection.