Hepatitis D

Hepatitis D (or delta, the Greek letter "D"), is a form of liver inflammation that occurs only in patients who also are infected by the hepatitis B virus. Infection by the hepatitis delta virus (HDV) either occurs at the same time as hepatitis B develops, or develops later when infection by hepatitis B virus (HBV) has entered the chronic (long lasting) stage.

Delta hepatitis can be quite severe, but it is seen only in patients already infected by HBV. In the late 1970s, Italian physicians discovered that some patients with hepatitis B had another type of infectious agent in their liver cells. Later the new virus HDV was confirmed by experimentally infecting chimpanzees. When both viruses are present, acute infection tends to be more severe. Furthermore, patients with both infections are likelier than those with HBV alone to develop chronic liver disease, and, when it occurs, it is more severe.

About 300 million persons worldwide carry HBV. Of them, at least 5% probably also have delta hepatitis. In North America HDV infection appears to be less frequent: 4% of all patients with acute hepatitis B have HDV infection. The delta virus causes an estimated 2% of all cases of acute viral hepatitis in the United States. The rate of HDV infection varies widely in different parts of the world; it is a very serious infection in some countries and quite mild in others. Chronic delta hepatitis is a more serious disease than either chronic hepatitis B alone or hepatitis C.

Certain individuals-the same ones who are at increased risk of developing hepatitis B are the prime candidates to be infected by HDV.

Not infrequently, HDV infection occurs in patients with chronic HBV infection who also have hemophilia, a bleeding disease. These patients are at risk because they require large amounts of transfused blood and blood products that may contain HDV.

In some areas, one-fourth to one-half of patients with chronic HBV infection who inject themselves with illicit drugs become infected by HDV as well. Drug abusers who share contaminated needles are likely to infect one another.

Patients who get HBV infection by sexual contact may also be infected by HDV, although the delta virus is less often spread in this way than is HBV itself. Between 10 & 25% of homosexual men with chronic HBV infection harbor the delta virus.

Like hepatitis B, HDV infection may develop in healthcare workers who are victims of a needle stick, and it also can be spread within households when personal items such as a razor or toothbrush are shared.

Causes and Symptoms

The delta virus is a small and incomplete viral particle. Perhaps this is why it cannot cause infection on its own. Its companion virus, HBV, actually forms a covering over the HDV particle. In chronically ill patients (those whose virus persists longer than six months), the combined viruses cause inflammation throughout the liver and eventually destroy the liver cells, which are then replaced by scar tissue. This scarring is called cirrhosis.

When HBV and HDV infections develop at the same time, a condition called coinfection, recovery is the rule. Only 2-5% of patients become chronic carriers (have the virus remain in their blood more than six months after infection). It may be that HDV actually keeps HBV from reproducing as rapidly as it would if it were alone, so chronic infection is less likely.

When HBV infection occurs first and is followed by HDV infection, the condition is called superinfection. This is a more serious situation. Between half and two-thirds of patients with superinfection develop severe acute hepatitis. Once the liver cells contain large numbers of HBV viruses, HDV tends to reproduce more actively. Massive infection and liver failure are more common in superinfection. The risk of liver cancer, however, is no greater than from hepatitis B alone.

As with other forms of hepatitis, the earliest symptoms are nausea, loss of appetite, joint pains, and tiredness. There may be fever (not marked) and an enlarged liver may cause discomfort or actual pain in the right upper part of the abdomen. Later, jaundice (a yellowing of the skin and whites of the eyes that occurs when the liver is no longer able to eliminate certain pigmented substances) may develop.

Who is at risk of hepatitis D?

Chronic HBV carriers are at risk for infection with HDV. Individuals who are not infected with HBV, and have not been immunized against HBV, are at risk of infection with HBV with simultaneous or subsequent infection with HDV. Since HDV absolutely requires the support of a hepadnavirus for its own replication, inoculation with HDV in the absence of HBV will not cause hepatitis D. Alone, the viral genome indeed replicates in a helper independent manner, but virus particles are not released.

Diagnosis

HDV infection may be diagnosed by detecting the antibody against the virus. Unfortunately this test cannot detect acute coinfection or superinfection as early as when symptoms first develop. Antibody against HDV usually is found no sooner than 30 days after symptoms appear. Until recently, the virus itself could only be identified by testing a small sample of liver tissue. Scientists now are developing a blood test for HDV that should make diagnosis faster and easier. When HDV is present, liver enzymes (proteins made by the liver) are present in abnormally high amounts. In some patients with coinfection, the enzyme levels peak twice, once when HBV infection starts and again at the time of HDV infection.

How to prevent hepatitis D?

Since HDV is dependent on HBV for replication, control of HDV infection is achieved by targeting HBV infections. All measures aimed at preventing the transmission of HBV will prevent the transmission of hepatitis D. HBV vaccination is therefore recommended to avoid HBV-HDV coinfection.

The vaccine against hepatitis B also prevents delta hepatitis, since it cannot occur unless HBV infection is present. Hopefully, a vaccine can be developed that will keep delta infection from developing in chronic HBV carriers. However, if a person already has HBV infection, any exposure to blood should be strictly avoided. A high level of sexual activity with multiple partners is also a risk factor for delta hepatitis.

However, there is no effective measure to prevent HDV infection of chronic HBV carriers, and prevention of HBV-HDV superinfection can only be achieved through education to reduce risk behaviors. Promising research results indicate that in some woodchucks immunized with recombinant purified HDAg-S complete protection is possible. Hepatitis B Ig and HB vaccine do not protect HBV carriers from infection by HDV.

Epidemiology

The virus exists throughout the world and infection is always associated with serum that is positive for HBsAg. The presence of anti-Delta antibody in a subject who is negative for HBsAg but positive for anti-HBs indicates a previous infection. The infection is endemic in Southern Europe, Africa, the Middle East and, probably, Latin America. Delta is present in most of the countries of the world where it has been looked for, the one possible exception being China and Japan. Most of the countries of the Far East at the moment appears to have quite a low incidence of Delta with the exception of Taiwan. In Taiwan, it was reported that 26% of all acute hepatitis cases have Delta antigen in the serum. Similarly in India where 14% of all acute cases are reported positive for Delta antigen.

The transmission of the Delta agent mirrors that of HBV, being primarily parenterally transmitted. Sexual transmission appears to be less efficient mode of transmission as there is a lower incidence of Delta infection in homosexuals compared to IV drug abusers. "Clustering" occurs within families, the spread within families appear to be horizontal rather than vertical. Although vertical transmission can occur, it does not appear to be an important means of transmission.

The infection is observed particularly frequently among drug addicts, who are repeatably exposed to inoculation with HBV infected blood. This epidemiological category is currently responsible for the spread of virus into Northern Europe and the USA eg. In Sweden, there was no trace of Delta infection before 1973 but since then, the annual incidence amongst HBsAg positive drug addicts have progressively increased, reaching a rate of 72% in 1981. There is also a significant risk of infection in haemophiliacs who receive commercial factor VIII concentrates. Approximately 50% of these patients appear to contract the infection and develops liver disease. In the US, Delta infection was found in 20 - 53% of IV drug abusers, 40 - 80% of haemophiliacs, and 8 - 20% of homosexuals and dialysis patients who are known HBsAg carriers.

Immunological Aspects of Delta Infection

Against the background of an HBV infection, the initial stage of Delta infection is marked by the appearance of the Delta antigen in the liver, this is quickly followed by a phase where the Delta antigen is present in the blood, usually for a brief period and at pre-clinical levels. Consequently, in most cases, Delta antigen is not detected in the blood. The extent of the antibody response against the Delta agent depends on the extent and duration of the presence of Delta anigen in the blood. therefore, in a normally short acute coinfection, the response is usually limited to a brief appearance of anti-Delta IgM and a low, sometimes undetectable titre of IgG. If the infection is sustained, as in most cases of superinfection, the appearance of Delta IgM is followed by high titres of Delta IgG.

If the infection is resolved, then the Delta antigen in the liver as well as the serum is eliminated. Delta-IgG, when it is present, is the only sign of former infection. If the infection becomes chronic, as is very likely in the case of superinfection, the Delta antigen will persists in the liver whilst it will be rapidly eliminated from the serum. Delta IgG should persists at high levels, Delta IgM will also persists for a longer period of time than acute infection. In practice, the Delta antigen/antiboby system behaves in a similar way to the core antigen/antibody system of Hepatitis B.

Clinical Aspects

Coinfection with HBV is necessary for the Delta agent. Those who are immune to hepatitis through vaccination or natural infection will also be immune to HDV. Infection may occur in 2 ways :-

  1. Co-infection with HBV of a patient not previously exposed to HBV.

  2. Super-infection of a HBV carrier.

1. Co-infection

In the case of coinfection, the synthesis of the defective virus must necessarily follow the appearance in the circulation of the HBsAg induced by the coinfecting HBV. Hence one may see more than one rise in liver transaminase and there may be 2 peaks of ALT, although not always. The synthesis of the Delta agent cannot continue after the elimination of HBsAg. The clinical appearance is that of normal hepatitis B. Delta antigen is rarely detected in the serum, though anti-Delta IgM is found in the serum and lasts 2 - 6 weeks. Anti-Delta IgG may be present in a low level or perhaps not detectable at all. In general, the clinical course of acute hepatitis B is more severe in the presence of Delta coinfection. There is a much increased likelihood of developing fulminant hepatitis.

2. Super-infection

The most common form of Delta infection is superinfection of a known HBsAg carrier and it is where Delta infection produces its most deleterious effects. Preexisting HBsAg in the circulation captures the Delta virus, even if it is in small amounts and intensifies its synthesis immediately. Delta infection of a previously healthy carrier may induce an acute hepatitic picture. Infection in a carrier with preexisting hepatitis will aggravate the clinical picture.

Primary Delta infection in a HBsAg carrier is often severe, with a significantly higher number of fulminant hepatitis cases. The most serious aspect of superinfection by Delta is its tendency to become chronic and for the acute hepatitis to progress into chronic hepatitis (chronic active or persistent hepatitis and cirrhosis). At least 70 -90% of superinfected carriers develop chronic infection. (70% of such patients develop chronic active hepatitis, 20% cirrhosis and a minority chronic persistent hepatitis). In an outbreak in Venezuela, there was a 23% mortality rate and 80% of survivors went on rapidly to develop chronic active hepatitis and to cirrhosis. In an Italian study, where the progression rate of acute HBV to chronic active hepatitis without Delta is 1 - 2%, it was 2.4% in coinfections and 91% in superinfections. The rapid evolution of chronic hepatitis Delta may explain the rare occurrence of Delta markers in patients of hepatocellular carcinoma.

Delta superinfection in a HBsAg carrier should induce a quick rise in liver enzymes. Delta antigen appears in the serum followed by Delta IgM and Delta IgG. In contrast to acute coinfection, Delta IgG can reach very high levels. Acute Delta superinfection is accompanied by a drop in HBsAg in the HBV carrier, sometimes to undetectable levels so that true diagnosis could be masked. The serum picture remains the same whether the infection becomes chronic or not. However, in the case of the infection becoming chronic, Delta antigen persists in the liver and can be detected by immmunoperoxidase or immunofluorescence staining techniques.

Diagnosis

HDV infection may be diagnosed by detecting the antibody against the virus. Unfortunately this test cannot detect acute coinfection or superinfection as early as when symptoms first develop. Antibody against HDV usually is found no sooner than 30 days after symptoms appear. Until recently, the virus itself could only be identified by testing a small sample of liver tissue. Scientists now are developing a blood test for HDV that should make diagnosis faster and easier. When HDV is present, liver enzymes (proteins made by the liver) are present in abnormally high amounts. In some patients with coinfection, the enzyme levels peak twice, once when HBV infection starts and again at the time of HDV infection.

  1. Detection of Delta Ag in the liver - Liver biopsy specimens may be stained for Delta Ag by immunofluorescence or immunoperoxidase techniques. This method is particularly useful in the diagnosis of chronic Delta infection.

  2. Serology - Serum Delta Ag, anti-Delta IgM, anti-Delta IgG or Total anti-Delta may be determined by competitive or antibody capture radioimmunoassays. The results must be interpreted in context with the HBV serology results:

                    Anti-HBc                          Anti-Delta

       HBsAg  Total  IgM    HBeAg     Anti-HBe  Total  IgM   Anti-HBs

1.        +        +      +       +             -           +      +         -

2.        +        +      -       +or-        +or-         +     +         -

3.        +        +      -       +or-        +or-         +     -         -

4.        -         +      -       -             +           +      -         -

5.        -         +     -        -            +or-         +     -         +

  1. Acute coinfection with HBV and Delta. (Probably cure).

  2. Acute Delta superinfection (anti-Delta low), or chronic Delta superinfection (anti-Delta low).

  3. Recovery from acute Delta superinfection (anti-Delta low), or, rarely, chronic Delta superinfection (anti-Delta level high), usually without symptoms.

  4. Previous HBV and Delta infection with probable recovery.

  5. Recovery from HBV and Delta infection.

The Delta antigen appears in the serum before or early in the course of clinical illness (a few days to a month or so), and thus it is often missed. However, if it is detected, it would indicate an acute attack. (One case has been reported where there is persistent Delta Ag in the serum. The patient concerned is a IV drug abuser who is also HIV positive.) It is recommended that the following should be tested for Delta infection :-

  1. All drug abusers with jaundice, whether or not HBsAg positive, because of possibility of suppression of surface antigen.

  2. All HBsAg positives (perhaps this is the easiest thing to do from an administrative standpoint).

  3. HBsAg carriers with chronic liver disease.

  4. All fulminant hepatitis even if HBsAg negative.

Is there a vaccination for HDV?

Infection with HDV can be prevented by vaccinating those at risk with the hepatitis B vaccine. However, those who already have hepatitis B cannot prevent infection with HDV because there is no HDV vaccine.

Treatment

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