Hepatitis Delta Increases the Risk of Liver Cirrhosis and Hepatocellular Carcinoma in People with Hepatitis B

By Liz Highleyman

Hepatitis delta virus (HDV) is a defective RNA virus that cannot replicate on its own, but requires the presence of hepatitis B virus (HBV). A blood-borne virus, HDV may either be transmitted along with HBV or acquired through a subsequent exposure. Chronic HDV infection tends to produce more aggressive liver disease than HBV alone, but its natural history is not fully understood.

Schematic representation of a particle of Hepatitis delta virus (HDV).

As described in the January 28, 2009 advance online edition of Gastroenterology, R. Rome from the University of Milan in Italy and colleagues tracked the course of HDV infection in 299 patients over a mean period of 233 months (more than 19 years).

The investigators analyzed data from patients admitted to Maggiore Hospital in Milan from 1978 through 2006 who had been HDV positive for at least 6 months. HDV infection was defined by the presence of HDV antigen in liver tissue or detectable serum HDV RNA in HDV antibody positive, hepatitis B surface antigen (HBsAg) positive individuals. Most (77%) were men and the average age was 30 years.

At enrollment, 7 patients had acute hepatitis, 101 had mild-to-moderate chronic liver disease, 76 had severe chronic liver disease, and 104 had histological or clinical evidence of liver cirrhosis. 90 patients were treated with interferon alfa, 62 with corticosteroids, and 12 with nucleoside/nucleotide analogs; 135 received no therapy.

Results

Over the mean 19-year follow-up period, 82 patients (27%) developed cirrhosis.

Among the 186 patients with pre-existing or new-onset cirrhosis, 46 (25%) developed hepatocellular carcinoma (HCC).

A similar number experienced liver decompensation: 43 developed ascites (abdominal fluid accumulation), 44 developed jaundice, and 1 developed encephalopathy.

Female sex, heavy alcohol consumption, and ongoing HDV replication were predictive of liver decompensation.

Ongoing HBV replication and interferon therapy were predictors of HCC.

By the end of the study period, 186 patients (62%) were still alive, 63 (21%) had died, and 29 (10%) had received a liver transplant.

The predominant cause of death was liver failure, in 37 patients (59%).

Ongoing HDV replication was the only independent predictor of mortality.

Based on these findings, the study authors concluded, "Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality."

These rates are somewhat higher than those observed among people with HBV alone in most studies, but not dramatically so. A recent Korean study, for example, found an annual cirrhosis incidence of 3% over a mean 10 years of follow-up.*

In a related laboratory study reported in the February 2009 issue of Hepatology, P. Pugnale from University Hospital in Geneva Switzerland and colleagues found that HDV in human hepatoma cells interfered with the JAK-STAT signaling pathway, which enables interferon to induce antiviral immune activity. They suggested that this might help explain why HDV-infected individuals are more likely to be non-responsive to interferon therapy.

"Interference of HDV with interferon-alpha signaling could represent an important mechanism of viral persistence and treatment resistance," they concluded.

2/24/09

References

R Rome, E Del Ninno, M Rumi, and others. A 28-year Study of the Course of Hepatitis Delta Infection, a Risk Factor for Cirrhosis and Hepatocellular Carcinoma. Gastroenterology. January 30, 2009 [Epub ahead of print]. (Abstract)

P Pugnale, V Pazienza, K Guilloux, and others. Hepatitis delta virus inhibits alpha interferon signaling. Hepatology 49(2): 398-406. February 2009. (Abstract)

Other citation
*BK Park, YN Park, SH Ahn, and others. Long-term Outcome of Chronic Hepatitis B Based on Histological Grade and Stage. Journal of Gastroenterology and Hepatology 22(3): 383-388. March 2007.