Search

Increased prevalence of hepatitis C virus (HCV) infection has been found in patients with hepatocellular carcinoma (HCC). The expression of insulinlike growth factor II (IGF-II) has been linked to hepatocarcinogenesis in the experimental animal and in humans. Since reactivation of fetal IGF-II transcripts has been observed in human HCC, we have analyzed the levels of adult P1 and fetal P3 and P4 IGF-II promoter-derived transcripts in the liver of patients with HCV-related chronic active hepatitis (CAH), cirrhosis, and HCC by means of a semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) assay. Transcripts derived from adult P1 promoter were increasingly expressed from normals to patients with CAH and cirrhosis, but were undetectable in the tumorous area of 5 of 7 HCC patients and present at low levels in the nontumorous area of all HCC patients. Transcripts derived from fetal P3 promoter were not detectable in normal subjects, while they were expressed abundantly in most CAH and all cirrhotic patients. Transcripts from fetal P4 promoter were detected at high levels in 3 of 9 CAH patients and in the majority of cirrhotic patients. Increased expression of fetal promoter-derived transcripts was also found in the liver of HCC patients, although levels were lower than in cirrhosis. Also, the activity of fetal P3 and P4 promoters was higher in the nontumorous than in the tumorous area of the liver of HCC patients. The expression of IGF-II transcripts was correlated with the rate of cell mitotic activity by measuring the expression of the proliferating cell nuclear antigen (PCNA) gene. PCNA messenger RNA (mRNA) levels progressively increased from normals to CAH and to cirrhotic patients, and persisted at a high level in the tumorous and in the nontumorous area of HCC subjects, thus showing that the increase of IGF-II transcripts in CAH and cirrhosis is accompanied by an activation of cell mitosis in these samples. These data suggest that the activation of IGF-II gene expression from adult and fetal promoters may play a role in premalignant proliferation observed in HCV-related chronic liver disease.

A total of 1,053 cirrhotic patients were included in a prospective study to determine whether malnutrition is a risk factor for mortality in cirrhotic patients. Child-Pugh classification as well as clinical and biochemical variables were used to assess the severity of cirrhosis. Nutritional status was evaluated both by anthropometric and clinical measurements. Patients were defined as malnourished when midarm muscle area (MAMA) and/or midarm fat area (MAFA) were below the 5th percentile of an age- and sex-matched population. During follow-up, 419 patients died. The estimated survival rate was 82.7% at 1 year, 65.1% at 3 years, and 50.7% at 5 years. The presence of muscle depletion and/or of a steep reduction in fat deposits was associated with a higher risk of mortality (midarm muscle area, < 5th percentile, relative risk = 1.79; midarm fat area, < 5th percentile, relative risk = 1.35). When patients were stratified according to the Child-Pugh classification, cumulative survival was lower in patients with a reduction in muscle mass in Child-Pugh classes A and B (log rank: P = .027; P = .022, respectively) but not in class C. Conversely, a significant reduction in adipose tissue deposits appeared to have no independent impact on survival in any Child-Pugh class. When examined using a multivariate Cox proportional hazard analysis, age, sex, bilirubin, cholinesterase, ascites, and esophageal varices were selected, whereas the parameters of nutritional status were not. This suggests that malnutrition, while strongly associated with the deterioration of liver function, cannot be considered an independent risk factor for mortality in a general population of cirrhotic patients.

Cholesterol gallstone disease and obesity are common and often associated disorders that could be affected by dysfunction of the receptor for cholecystokinin (CCK). Extending earlier studies that identified a defect at the level of receptor-G protein coupling in cholesterol gallstone disease, we characterized the primary structure of the gallbladder CCK receptor in patients undergoing a cholecystectomy. Represented were patients with cholesterol gallstones, as well as controls with pigment gallstones or without gallbladder disease. Both groups were composed of the range of body habitus from lean to morbidly obese. No evidence of any sequence mutation or polymorphism in the CCK receptor gene was found in any patient. This should lead future investigations of the pathogenesis of these problems toward the possible contribution of the plasmalemmal environment in affecting the association between normal receptors and G proteins.

Cholesterol gallstone disease and obesity are common and often associated disorders that could be affected by dysfunction of the receptor for cholecystokinin (CCK). Extending earlier studies that identified a defect at the level of receptor-G protein coupling in cholesterol gallstone disease, we characterized the primary structure of the gallbladder CCK receptor in patients undergoing a cholecystectomy. Represented were patients with cholesterol gallstones, as well as controls with pigment gallstones or without gallbladder disease. Both groups were composed of the range of body habitus from lean to morbidly obese. No evidence of any sequence mutation or polymorphism in the CCK receptor gene was found in any patient. This should lead future investigations of the pathogenesis of these problems toward the possible contribution of the plasmalemmal environment in affecting the association between normal receptors and G proteins.