Cyclosporine inhibits profibrotic effects of interleukin-4 and transforming growth factor ß on human intrahepatic fibroblasts cultured in vitro.

BACKGROUND: Hepatic fibrosis, an outcome of chronic liver diseases, is characterized by an accumulation of collagen, which is produced by activated human intrahepatic fibroblasts (HIF). Transforming growth factor (TGF) ß is an important inducer of fibrogenesis, in collaboration with other cytokines, such as interleukin (IL) 4. IL-4 is overexpressed in severe recurrent hepatitis C after liver transplantation, exerting profibrotic effects. In contrast, cyclosporine (CsA) had been shown to decrease fibroblast activation and collagen production. We therefore investigated the effects of CsA on TGF-ß and IL-4 profibrotic activities on HIF in vitro. METHODS: Isolated HIF were cultured without or with human TGF-ß, human IL-4, CsA, or combined TGF- ß+CsA or IL-4+CsA. We performed real-time polymerase chain reaction for collagen types I, III, and IV and alpha-SMA, a marker of fibroblast activation we also measured total collagen in supernates. TGF-ß and IL-4 increased the expressions of alpha smooth muscle action (SMA) collagen I, III, and IV mRNAs (P < .05 vs untreated cells) as well as the overall collagen level in the supernates (P < .01). CsA decreased the expression of mRNAs encoding alpha-SMA and collagens (P < .01). Expressions of alpha-SMA and collagens I, III, and IV mRNAs were significantly lower under combined treatments (TGF-ß vs TGF-ß+CsA [P < .01] and IL-4 vs IL-4+CsA [P < .01]). Collagen level was decreased by combined treatments (TGF-ß vs TGF-ß+CsA [P < .05] and IL-4 vs IL-4+CsA [P = .05]). CONCLUSION: CsA inhibited the profibrotic effects of TGF-ß and IL-4 by decreasing the activation and production of collagen by HIF. CsA may decrease fibroblast activation and collagen accumulation, exerting beneficial effects on fibrosis progression, particularly among patients with recurrent hepatitis C.

APRI and FIB-4 Scores Are Useful After Liver Transplantation Independently of Etiology.

Noninvasive liver fibrosis scores are evaluated in hepatitis C virus-infected patients but are less known in liver transplant recipients. Fibrosis is a frequent, multifactorial event in these patients. This preliminary retrospective study reviewed the diagnostic performance of 3 simple scores for liver fibrosis in transplant patients: namely, APRI (aspartate aminotransferase to platelet ratio index), FORNS (platelets, gamma-glutamyltransferase, patient age, and cholesterol), and FIB-4 (patient age, aspartate aminotransferase, alanine aminotransferase, and platelets). Ninety-four biopsies were collected from 50 liver transplant recipients at a mean period after orthotopic liver transplantation (OLT) of 30.7 months (range, 12-108 months). The indications for OLT were hepatitis C in 23% of cases, hepatitis B in 14%, alcoholic disease in 33%, cholestatic disease in 19%, and others in 11%. According to the Metavir classification, 72% of biopsies revealed no significant histological fibrosis (F0-1 = group 1) and 28% showed significant fibrosis (F2-4 = group 2). A correlation was observed between the histological stage of fibrosis and albumin, gamma-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and hyaluronic acid levels. APRI and FIB-4 correlated significantly with the histological stage of fibrosis both globally and in the subgroup of nonhepatitis C liver recipients. When APRI and FIB-4 tests were applied to predict fibrosis (area under the receiver operating characteristic curve), the results were 0.87 and 0.78, respectively. Values were not significant with the FORNS test. In conclusion, APRI and FIB-4 enabled accurate prediction of significant fibrosis after OLT. In the nonhepatitis C subgroup, we found similar predictive performances. These simple scores may be applied in clinical practice in the context of follow-up after OLT independent of hepatitis C status.

Significance of serum tumor markers carcinoembryonic antigen, CA 19-9, CA 125, and CA 15-3 in pre-orthotopic liver transplantation evaluation.

Tumor markers are elevated in a variety of nonneoplastic clinical situations, including liver diseases. Their sensitivity and specificity are lower for tumor screening in these cases. In this study, we investigated the frequency and significance of elevated tumor markers in the pre-orthotopic liver transplantation (OLT) evaluation among patients with end-stage liver disease who did not develop tumors after a long follow-up post-OLT. We performed a retrospective analysis of clinical and biological parameters of 100 OLT candidates comparing data for CA 125, CA 19-9, CA 15-3, and carcinoembryonic antigen (CEA) levels. CA 125, CA 19-9, CA 15-3, and CEA levels were elevated in 59%, 53%, 29%, and 28% of cases, respectively. CA 125, CA 15-3, and CEA were associated with disease severity (Child-Pugh classification). CA 125 was also elevated among patients with ascites, esophageal varices, or alcohol-related cirrhosis. Elevated CA 19-9 levels were associated with increased CA 15-3 and CEA levels. CA 15-3 levels were also increased among patients with elevated alkaline phosphatase, while elevated CEA was related to ascites, bilirubin, and prothrombin time (PT) levels, as well as alcohol-related cirrhosis. There was no association between hepatocellular carcinoma and tumor markers. In conclusion, CA 125, CA 19-9, CA 15-3, and CEA were frequently elevated among end-stage liver disease patients. These elevations were not associated with tumor diseases in this population.