Hepatitis D (the delta agent).
The hepatitis D virus was discovered in Italy by Mario Rizzetto in 1977 during an investigation of the distribution of the Hepatitis B virus antigens in liver biopsy specimens of patients chronically infected with Hepatitis B virus. He described a new antigen in the nuclei of infected hepatocytes that was obligatorily associated with hepatitis B surface antigen. This new antigen was named delta. Subsequently, large amounts of this antigen were extracted from the liver of a patient with chronic Hepatitis B virus infection and the delta agent. Using this antigen, a specific and sensitive radioimmunoassay was developed for the detection of both the delta antigen in liver biopsy specimens and the antibody directed at the delta antigen in the serum of infected individuals.
Epidemiology
Hepatitis delta virus has a global distribution. It has been found to be endemic in the Mediterranean basin, the Middle East, Asia, western Africa, Australia, New Zealand, islands in the South Pacific, and the Amazon basin. Epidemics of Hepatitis delta virus have been reported in North and South America, Colombia, and Venezuela. In endemic regions, transmission occurs from close person-to-person contact with transmucosal exchange of body fluids. Perinatal transmission is rare. In nonendemic areas such as northern Europe and North America, transmission is by direct inoculation from infected blood products. Any population that has a high frequency of Hepatitis B virus infection is vulnerable to Hepatitis delta virus infection, especially intravenous drug abusers, hemophiliacs, hemodialysis patients, homosexual men, and prisoners.
Pathogenesis
Hepatitis delta virus is a defective hepatotropic RNA virus that requires the presence of Hepatitis B virus as a «helper virus» for its pathogenicity. It replicates only in hosts who have a concomitant Hepatitis B virus infection. Hepatitis delta virus is a 36-nm spherical particle containing the D antigen and a single-stranded RNA molecule in the interior, which is coated by hepatitis B surface antigen on the exterior. Hepatitis delta virus seems to have a direct cytopathic effect on hepatocytes rather than causing immune-mediated hepatocyte damage, as results from Hepatitis B virus infection.
Individuals who are immune to Hepatitis B virus are protected from Hepatitis delta virus infection. However, persons who are susceptible to both Hepatitis B virus and Hepatitis delta virus infection (negative for all markers of Hepatitis B virus and Hepatitis delta virus) and who are carriers of hepatitis B surface antigen may get hepatitis D.
Acute coinfection
In patients simultaneously exposed to Hepatitis B virus and Hepatitis delta virus, coinfection occurs. The disease is usually self-limited, and the clinical course resembles that of classic acute hepatitis from Hepatitis B virus. Occasionally, coinfection results in extensive liver damage and fulminant hepatic failure. This occurs more commonly in intravenous drug abusers. The diagnosis of coinfection with Hepatitis B virus and Hepatitis delta virus is best made by the detection of positive titers for IgM Hepatitis delta virus antibody, hepatitis B surface antigen, and IgM HBcAb in the patient’s serum.
The coinfection may manifest itself as a single bout of elevated transaminases or more frequently as a biphasic illness with two separate transaminase peaks separated by weeks or even months. Expression of the disease due to Hepatitis delta virus must wait for hepatocytes to be infected first by Hepatitis B virus. If the inoculations with the two viruses are close in time, Hepatitis delta virus overwhelms the synthesis of Hepatitis B virus gene products in the Hepatitis B virus- and Hepatitis delta virus-infected cells and causes the first bout of hepatitis. The second bout of hepatitis is caused by Hepatitis B virus expression. If the two peaks are very close in time, massive hepatic necrosis may occur and may be fatal to the patient. If the two bouts are separated by months, the first bout is usually from Hepatitis B virus. In either event, both viruses usually are cleared, and the patient completely recovers and develops both an HDVAb and HBsAb.
Superinfection
In chronic carriers of hepatitis B surface antigen, Hepatitis delta virus superinfection usually causes severe liver disease, even fulminant hepatic failure. In fact, 60% of fulminant hepatic failure cases thought to be from Hepatitis B virus are actually due to Hepatitis delta virus superinfection. Because most of the hepatocytes are already infected by Hepatitis B virus and contain hepatitis B surface antigen, Hepatitis delta virus disseminates extensively and causes massive hepatic necrosis. Clinically, the disease may resemble fulminant type B hepatitis but can be recognized to be D hepatitis superinfection with the serologic presence of a strong IgM and IgG HDAb response and negative IgM HBcAb.
Anti-Hepatitis delta virus arises late during acute Hepatitis delta virus and is usually not detectable in serum at the onset of symptoms. In some cases of self-limited hepatitis D, anti-Hepatitis delta virus is not detectable. For these reasons the serologic diagnosis of acute hepatitis D is often unsatisfactory and requires testing of both acute- and convalescent-phase serum samples. Hepatitis delta virus antigen is present in both the serum and the liver of infected patients. Immune blotting for serum Hepatitis delta virus antigen is available only in the research setting. However, the Hepatitis delta virus antigen is detectable in the nuclei of hepatocytes and weakly in the cytoplasm in almost all patients with chronic hepatitis D. It has been detected in many pathology laboratories by a variety of immunostaining techniques, which can be applied to formalin-fixed, paraffin-embedded sections.
The hepatitis in these individuals tends to become chronic in almost all cases. In fact, very few patients clear both Hepatitis B virus and Hepatitis delta virus after the superinfection. In Hepatitis delta virus superinfection of hepatitis B surface antigen carriers, patients with negative hepatitis B core antigen serology are probably the only ones in whom chronic Hepatitis delta virus infection develops.
Chronic hepatitis D is characterized by a history of acute hepatitis. If the patient was a «silent carrier» of hepatitis B surface antigen, this acute illness may be the first episode of hepatitis for the patient. If the patient had chronic hepatitis from Hepatitis B virus, the disease may be thought of as an exacerbation or a superimposed hepatitis.
| TABLE. DIFFERENTIAL DIAGNOSIS OF ELEVATED LIVER TESTS SUGGESTING NON-A, NON-B HEPATITIS | ||||||||||||||||||||||||
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Unfortunately, chronic Hepatitis delta virus infection accelerates the progression of liver disease both in patients with ongoing chronic liver disease from Hepatitis B virus and in silent carriers of hepatitis B surface antigen. Most patients develop chronic active hepatitis, which often progresses to cirrhosis over a short span of time. The detection of high titers of anti-Hepatitis delta virus is strongly suggestive of chronic Hepatitis delta virus.
Treatment
Currently there is no specific therapy for delta hepatitis, and the treatment for all forms of the disease is supportive. Steroids and other immunosuppressive drugs have not been effective. There are ongoing studies that suggest that interferon-О± may slow down viral replication. Monitoringof interferon-О± therapy in chronic Hepatitis delta virus is best accomplished by sequential testing for Hepatitis delta virus RNA in serum or in the liver with in situ hybridization.
Currently, the control of delta infection depends on its prevention. Because Hepatitis delta virus infection requires the helper function of Hepatitis B virus, prevention of Hepatitis B virus infection and the hepatitis B surface antigen carrier state will also prevent Hepatitis delta virus infection. Thus, the hepatitis B vaccine helps prevent new Hepatitis B virus and Hepatitis delta virus infections. However, the large number of people carrying the hepatitis B surface antigen remains at risk for development of delta hepatitis. A vaccine against Hepatitis delta virus is not yet available.
Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.