Hepatitis D is also called “delta hepatitis.” It is a partially defective virus that must enter the hepatitis B virus in order to penetrate and infect liver cells. Therefore, a person must have HBV present, either as a carrier or in clinical infection, in order to acquire HDV infection. When HBV infection is over, HDV infection will also disappear. HDV infection is acquired by the same routes as HBV infection (predominately parenteral, less commonly transmucosal or sexual). In the United States, infection is predominately, but not entirely, spread through blood or blood products. The highest incidence is in intravenous-use drug addicts, followed by transfusion recipients of blood or blood products. HDV infection is relatively uncommon in male homosexuals (0.2% in one study) and in the Orient, in contrast to the high incidence of HBV infection in these two populations. HDV is endemic in southern Europe, the Middle East, South America, the South Pacific, and parts of Africa, as well as in major U.S. cities.

There are three types of clinical infection. In the first type, HBV and HDV infection are transmitted at the same time (simultaneous acute infection or “coinfection”). Clinically, this resembles an HBV infection that is more severe than usual or has a second transaminase peak or clinical episode (“biphasic” transaminase pattern). The mortality rate of acute HDV infection due to fulminating hepatitis is about 5% (range, 2%-20%); this contrasts to a HBV mortality rate of about 1%. On the other hand, less than 5% of HDV acute coinfection patients develop chronic HDV infection compared to 5%-15% incidence of chronic HBV after acute HBV.

In the second type of relationship between clinical HDV and HBV infection, acute HDV infection is superimposed on preexisting chronic HBV disease (HDV “superinfection”). Clinically, this resembles either an acute exacerbation of the preexisting HBV disease (if the HBV infection had previously been symptomatic), or it may appear to be onset of hepatitis without previous infection (if the initial HBV infection has been subclinical). As noted previously, there is considerably increased incidence of fulminating hepatitis. About 80% (range, 75%-91%) of patients with acute HDV superimposed on chronic HBV develop chronic HDV.

HDV antigen and antibodies

Fig. 17-8 HDV antigen and antibodies.

In the third type of HDV-HBV relationship, there is chronic HDV infection in addition to chronic HBV infection. Seventy percent to 80% of patients with chronic HDV hepatitis develop cirrhosis. This contrasts to chronic HBV infection where 15%-30% develop cirrhosis. Cirrhosis is rapidly progressive (developing is less than 2 years) in 15%-20% of chronic HDV infection.

Hepatitis D virus antigen and antibodies

Commercially available immunoassays are available for HDV-IgM and HDV-Total antibodies. In addition, HDV antigen can be detected by immunoassay or by nucleic acid probe, available at some reference laboratories and university centers. HDV antigen is present in serum for only a few days, and most often is not detectable by the time the patient is seen by a physician. Antigen detection is more likely using nucleic acid probe since the probe technique is more sensitive than immunoassay.

There is a very short time span for HDV antigen detection by immunoassay or by DNA probe in acute HDV infection (12.5% of cases positive on admission in one study). Sensitivity of different immunoassay systems for HDV can vary considerably (24%-100% on the same specimen in one study). Duration of elevation for both HDV-Ab (IgM) and HDV-Ab (Total) is also relatively short. Failure of HDV-Ab (Total) to persist for several years resembles IgM antibody more than IgG. HDV-Ab (Total) typically does remain elevated (usually in high titer) if acute HDV progresses to chronic HDV. HDV-Ab (IgM) may also be detectable in chronic HDV (usually in low titer), depending on sensitivity of the test system and degree of virus activity. HDV-Ab (IgM) level of elevation depends on active HDV replication and on degree of liver cell injury. It rises during active viral replication and decreases when replication ceases. HDV-Ab (Total) also tends to behave like IgM antibody but takes longer to rise and to decrease. In acute HDV infection that resolves, HDV-Ab (Total) usually decreases to a low titer and sometimes can become nondetectable. In chronic infection, due to continual presence of the virus, HDV-Ab (Total) is usually present in high titer.

In HDV superinfection (on chronic HBV) HBsAg may temporarily decrease in titer or even transiently disappear.

Delta Hepatitis Coinfection (Acute HDV + Acute HBV) or Superinfection (Acute HDV + Chronic HBV)

HDV-AG

Detected by DNA probe, less often by immunoassay
Appearance: Prodromal stage (before symptoms); just at or after initial rise in ALT (about a week after appearance of HBs Ag and about the time HBc Ab-IgM level begins to rise)
Peak: 2-3 days after onset
Becomes nondetectable: 1-4 days (may persist until shortly after symptoms appear)

HDV-AB (IGM)

Appearance: About 10 days after symptoms begin (range, 1-28 days)
Peak: About 2 weeks after first detection
Becomes nondetectable: about 35 days (range, 10-80 days) after first detection (most other IgM antibodies take 3-6 months to become nondetectable)

HDV-AB (TOTAL)

Appearance: About 50 days after symptoms begin (range, 14-80 days); about 5 weeks after HDV-Ag (range, 3-11 weeks)
Peak: About 2 weeks after first detection
Becomes nondetectable: About 7 months after first detection (range, 4-14 months)

Delta Hepatitis Chronic Infection (Chronic HDV + Chronic HBV)

HDV-Ag

Detectable in serum by nucleic acid probe

HDV-Ab (IgM)

Detectable (may need sensitive method; titer depends on degree of virus activity)

HDV-Ab (total)

Detectable, usually in high titer

In chronic HDV infection, HDV-Ab (Total) is usually present in high titer. HDV-Ab (IgM) is present in low titer (detectability depends on sensitivity of the assay). HDV-Ag is usually not detectable by immunoassay in serum but is often demonstrable by immunohistologic stains in liver biopsy specimens. In these patients, HDV-Ag can often be detected in serum (and most often in liver biopsy specimens) by DNA probe.

Although many use “viral hepatitis” as a synonym for infection by hepatitis viruses A, B, C, D, and E, a wide range of viruses may infect hepatic cells with varying frequency and severity. The most common (but not the only) examples are infectious mononucleosis (E-B virus), and the cytomegalic inclusion virus. Nonviral conditions can also affect the liver (please refer to the box on this page).

Summary: Diagnosis of HDV Infection

Best current all-purpose screening test = ADV-Ab (Total)
Best test to differentiate acute from chronic infection = HDV-Ab (IgM)

Some Causes for Liver Function Test Abnormalities that Simulate Hepatitis Virus Hepatitis

Epstein-Barr virus (Infectious Mononucleosis)
Cytomegalovirus
Other viruses (herpes simplex, yellow fever, varicella, rubella, mumps)
Toxoplasmosis
Drug-induced (e.g., acetaminophen)
Severe liver hypoxia or passive congestion (some patients)
HELLP syndrome associated with preeclampsia
Alcohol-associated acute liver disease (some patients)
Reye’s syndrome

Summary of Hepatitis Test Applications

HBs
-AG
HBs Ag: Shows current active HBV infection
Persistance over 6 months indicates carrier/chronic HBV infection
HBV nucleic acid probe: Present before and longer than HBsAg
More reliable marker for increased infectivity than HBsAg and/or HBeAg
-Ab
HBs Ab-Total: Shows previous healed HBV infection and evidence of immunity
HBc
-Ab
HBc Ab-IgM: Shows either acute or very recent infection by HBV
In convalescent phase of acute HBV, may be elevated when HBs Ag has disappeared (core window)
Negative HBc Ab-IgM with positive HBsAg suggests either very early acute HBV or carrier/chronic HBV
HBc Ab-Total: Only useful to show past HBV infection if HBs Ag and HBc Ab-IgM are both negative
HBe
-Ag
HBe-AbAg: When present, especially without HBe Ab, suggests increased patient infectivity
HBe Ab-Total: When present, suggests less patient infectivity
HDV
-Ag
HDV-Ag: Shows current infection (acute or chronic) by HDV
HDV nucleic acid probe: Detects antigen before and longer than HDV-Ag by EIA
-Ab
HDV-Ab (IgM): High elevation in acute HDV; does not persist
Low or moderate elevation in convalescent HDV; does not persist
Low to high persistent elevation in chronic HDV (depends on degree of cell injury and sensitivity of the assay)
HDV-Ab (Total): High elevation in acute HDV; does not persist
High persistent elevation in chronic HDV
HCV
-Ag
HCV nucleic acid probe: Shows current infection by HCV (especially using PCR amplification)
-Ab
HCV-Ab (IgG): Current, convalescent, or old HCV infection
HAV
-Ag
HAV-Ag by EM: Shows presence of virus in stool early in infection
-Ab
HAV-Ab (IgM): Current or recent HAV infection
HAV-Ab (Total): Convalescent or old HAV infection