Serum caspase activity and liver fibrosis in patients with hepatitis C

Caspase levels are associated with liver injury

Caspase activity in the sera of patients with chronic hepatitis C infection (HCV) may be a more sensitive measure of liver injury than conventional surrogate markers like aminotransferases, according to a new study published in the November 2004 issue of Hepatology. Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD), published by John Wiley & Sons, Inc., is available online via Wiley InterScience.

Liver biopsy is currently the optimal way to determine the actual progression of liver disease, however, it is an invasive procedure with a risk of complications. The current non-invasive method of assessing liver damage involves measuring serum aminotransferase levels. Unfortunately, many patients with HCV infection who have chronic liver damage exhibit persistently normal aminotransferase levels.

In search of a more accurate non-invasive way to assess early liver damage, researchers led by Klaus Schulze-Osthoff and Heike Bantel of the University of Dusseldorf and Hannover Medical School investigated caspase activity levels in the sera of HCV patients, since recent studies have suggested that caspase activation is involved in very early liver damage. Caspases are believed to mediate the key changes surrounding the death of liver cells.

To explore the relationship between sera caspase levels, sera aminotransferase levels, and actual liver damage, the researchers obtained sera from 59 randomly selected patients with chronic HCV infection. They measured aminotransferase levels and found that twenty-seven percent of the patients were in the normal range. The researchers then examined the sera of the 59 patients, as well as that of seven healthy controls, to detect levels of a caspase-generated neopeptide of CK-18.

In the sera of the healthy controls, only low levels of the neopeptide were detectable. “In striking contrast,” the authors report, “HCV patients with different grades of disease activity revealed considerably elevated levels of the caspase-generated cleavage fragment.” Additionally, more than half of the HCV patients with aminotransferase levels in the normal range had elevated caspase levels.

The researchers then performed liver biopsies on the 16 study participants who had normal aminotransferase levels. They recruited an additional 9 HCV patients with normal aminotransferase levels for statistical accuracy. Comparing the biopsy findings with sera data, they found that elevated caspase levels were significantly associated with higher stages of fibrosis. “Our data imply that compared to detection of aminotransferases, measurement of caspase-mediated CK-18 cleavage in serum might be the more sensitive method to detect higher stages of liver fibrosis in chronic HCV infection,” the researchers report.

While longitudinal studies with larger patients cohorts are necessary, say the authors, one might conclude from this study that patients with normal aminotransferase levels but elevated caspase activation more likely have progressive fibrosis and therefore should be monitored carefully.