Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein.

AIMS: To determine the effect of diltiazem on intestinal CYP3A activity and protein and mRNA expression in vivo in healthy subjects. METHODS: Intestinal biopsies were obtained from ten healthy controls and from ten healthy subjects after receiving diltiazem 120 mg bid for 7 days. Intestinal CYP3A activity, CYP3A4 protein and mRNA concentrations were quantified in both groups. Intestinal CYP3A activity was determined by incubation of small bowel homogenate with midazolam (25 microM) and NADPH for 5 min and the rate of formation of 1'-hydroxymidazolam was quantified. RESULTS: All subjects in the treatment group had detectable diltiazem concentration in the serum. While there was no significant difference in CYP3A4 protein and mRNA expression between the control and treatment groups, the formation of 1'-hydroxymidazolam (446 pmol min(-1) mg(-1) 6 (control) vs. 170 (CI 112, 228) pmol min(-1) mg(-1) 95% confidence interval (CI 269, 623) (diltiazem group)) was significantly reduced (P < 0.05). CONCLUSION: Diltiazem decreased small bowel CYP3A activity by 62% as a result of irreversible inhibition with no corresponding change in intestinal CYP3A4 mRNA or protein concentrations.

Positron emission tomography for detecting occult hepatocellular carcinoma in hepatitis C cirrhotics awaiting for liver transplantation.

Patients with hepatitis C cirrhosis may sometimes have persistently elevated alpha feto protein (AFP) despite a lack of evidence for disease by ultrasound or computed tomography (CT). While this pattern may represent a benign manifestation of hepatitis C cirrhosis (HCC), it raises concern for the possibility of an occult hepatocellular carcinoma. It has previously been shown that positron emission tomography (PET scan) may detect occult cholangiocarcinoma in high-risk patients with primary sclerosing cholangitis. We hypothesized that PET scanning might similarly serve for occult HCC in hepatitis C cirrhotics. PET scanning was performed on eight hepatitis C cirrhotics who were on the liver transplantation list and displayed persistently elevated AFP (>100 ng/mL) but no detectable lesions on abdominal CT scan. The results of PET detection of occult HCC were compared to those obtained with lipiodol-enhanced CT scanning and with histologic examination of the live explant. Explant histology or prolonged clinical follow-up showed two subjects to have conclusive evidence of HCC; the remainder, no evidence of malignancy. Although PET imaging did not reveal abnormal lesions in any subject; lipiodol-enhanced CT scans revealed abnormal lipiodol retention in both subjects with HCC. These preliminary findings suggest that PET has no role in detecting occult HCC in high-risk patients. Additionally, these data suggest that some hepatitis C cirrhotics with persistently elevated AFP but no detectable lesions by conventional CT scan may show occult HCC using lipiodol-enhanced CT scans.

Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation.

BACKGROUND: Most transplant centers in the United States immunize patients awaiting liver transplantation against hepatitis B to prevent acquisition of hepatitis B through transplantation (de novo hepatitis B). A recent study showed that only 16% of patients with cirrhosis awaiting liver transplantation responded to single-dose recombinant vaccine. METHODS: We studied the immunogenicity of double-dose recombinant vaccine in patients with cirrhosis awaiting liver transplantation. RESULTS: Over a 4-year period (January 1994 to December 1997), 140 patients with cirrhosis without past or current hepatitis B infection were given double-dose recombinant vaccine (40 microg of Engerix B; SmithKline Beecham, Philadelphia, PA) at 0, 1 to 2, and 2 to 4 months. Hepatitis B surface antibody (HBsAb) was measured 1 to 3 months after completing vaccination. The response rate was 37%. However, HBsAb titers became undetectable in 35% of the responders during the post-transplant follow-up period. One hundred and thirty-seven patients underwent 144 liver transplantation procedures during the study period, and 3 patients developed de novo hepatitis B (2.2%). Livers transplanted from hepatitis B core antibody (HBcAb)-positive donors was the source of de novo hepatitis B in all cases. Two of the 3 patients who developed de novo hepatitis B were immunized before transplantation and one of them was a responder. CONCLUSION: Although the response rate to double-dose recombinant vaccines is higher than the previously reported response to single-dose vaccine, it still is less than optimal.

Screening for hepatocellular carcinoma in patients with advanced cirrhosis.

OBJECTIVE: Most available data on screening for hepatocellular carcinoma (HCC) in patients with cirrhosis originate from Asia and Europe. These data may not be applicable to patients from the United States because of geographic variation in the underlying etiology and other factors. Our aim was to assess the risk of HCC in U.S. patients with cirrhosis undergoing standardized screening. METHODS: All cirrhotic patients evaluated for liver transplantation at our institution from January 1, 1994-December 31, 1997 were included in this study. The screening strategy included initial screening, which was offered to all patients and consisted of alpha-fetoprotein (AFP), abdominal ultrasound, and computed tomography (CT) scan, and extended screening, which was performed only on transplant-eligible patients and consisted of semiannual AFP and ultrasound. RESULTS: During the study period, 285 patients with cirrhosis were evaluated for transplantation and underwent initial screening. Of these, 166 were eligible for transplantation and underwent extended screening during a median follow-up of 15 months (range 6-42 months). Twenty-seven HCC were found, 22 during initial screening and five during extended screening. The cancer-free proportions of the cohort who underwent extended screening at 1, 2, and 3.5 yr were 98.6% +/- 1.4%, 96.4 +/- 1.8%, and 77.1% +/- 1.7%, respectively (mean +/- SE). Hepatitis C, either alone or in part, was the etiology in 63% of patients with HCC. The sensitivity of CT scan (88%) was significantly higher than AFP >20 ng/ml (62%) and ultrasound (59%) for detecting HCC (p < 0.001). CONCLUSIONS: In patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening (7%). Hepatitis C was the most common etiology for cirrhosis in study. In U.S. patients with established cirrhosis, CT scan exhibited higher sensitivity for detecting HCC than ultrasound or AFP.