Platelet-derived growth factor has been shown to play an important role in the repair process after acute tissue injury and in the pathogenesis of several fibrogenic disorders. The aim of this study was to evaluate whether increased expression of platelet-derived growth factor and its beta-receptor subunit occurs in a model of acute liver injury. Male Sprague-Dawley rats were given a single intragastric dose of carbon tetrachloride and killed at intervals of 24, 48 and 72 hr and 1 wk. Control animals were included in each group. Platelet-derived growth factor-B chain mRNA expression, analyzed by RNase protection assay, was not detectable in control samples or in samples obtained 24 hr or 1 wk after carbon tetrachloride. However, the presence of protected fragments of 130 kb was clearly detected after 48 hr and was still present, although less abundant, after 72 hr. The distribution of platelet-derived growth factor protein in liver tissue sections, evaluated by immunohistochemistry, was restricted to centrilobular veins and portal tracts in normal liver. In carbon tetrachloride-treated rats, prominent staining was observed in areas corresponding to hepatocellular necrosis and inflammatory infiltration. This feature, already present at 24 hr after carbon tetrachloride, became more marked at 48 hr with a gradual resolution after 72 hr. The expression of platelet-derived growth factor-receptor beta-subunit mRNA, evaluated by in situ hybridization, was markedly increased after carbon tetrachloride with a peak at 24 hr and was mainly localized over mesenchymal cells in the hepatic sinusoids.(ABSTRACT TRUNCATED AT 250 WORDS)
Hepatic artery thrombosis (HAT) after liver transplantation is a potentially life-threatening complication that occurs in 2-25% of patients, depending on several risk factors and the patient population studied. Arterial thrombosis occurring early after liver transplantation is associated with acute fulminant hepatic failure, biliary tract necrosis and leaks, or relapsing bacteremia and is associated with a high rate of graft loss and patient mortality. The onset of late posttransplant HAT (after 6 months) has been thought to have a more benign and often asymptomatic course. The reasons for the differences between the manifestations of early and late HAT are not well understood. We reviewed the adult liver transplant experience at the University of Cincinnati and found four patients with late HAT, three of whom developed severe intrahepatic biliary necrosis. Two patients were successfully retransplanted and 1 patient who refused retransplantation died. One patient had mild, transient graft damage due to gradual arterial stenosis and the development of arterial collaterals prior to thrombosis. Late HAT has a significant potential for irreversible graft damage requiring retransplantation. Screening for the development of hepatic artery stenosis prior to late thrombosis may be worthwhile.
Cirrhotic patients with hereditary hemochromatosis (HHC) have an increased risk of primary liver cancer (PLC). The purpose of this study was to determine the prevalence of primary liver cancer in patients with HHC undergoing orthotopic liver transplantation (OLT). Five liver transplant centers were surveyed; clinical and pathological data on 37 patients with HHC undergoing OLT were retrospectively collected and analyzed. The diagnosis of HHC was established by a combination of serum transferrin-iron saturation, hepatic iron index (HII), and/or pattern of liver iron staining. The diagnosis of HHC had been unsuspected before OLT in 13 of 37 (35%). Primary liver cancer was found in the explants of 10 of 37 patients (27%) and was unsuspected in 7 of 10 (70%); 8 were hepatocellular carcinoma, and 2 were cholangiocarcinoma; foci of hepatocyte dysplasia were ereditary hemochromatosis (HHC) is the most H common genetic disease in Caucasians, with a prevalence of 3 to 5 per 1,000.' The complications of HHC result from the deposition of iron in multiple organs, leading to cirrhosis, cardiomyopathy, arthropathy, hypogonadism, and diabetes mellitus. There is a strong association between HHC and primary liver cancer (PLC), particularly in HHC patients with fibrosis or c i r r h o~i s .~,~ The reported prevalence of PLC in HHC ranges from 7.5% to 36%,4,5 and PLC is reported to be the cause of death in up to 45% of HHC patient^.^ However, there are no data on the prevalence of PLC among HHC patients undergoing orthotopic liver transplantation (OLT) or the frequency with which a definite diagnosis of HHC is established before OLT. Therefore, the primary purpose of this study was to examine the prevalence of known and incidental PLC in HHC patients undergoing OLT. Secondary goals were to examine 1-year survival rate following OLT in HHC patients, and to determine how often the diagnosis of HHC was established before OLT.found in 6 additional patients. Mean (GEM) hepatic iron content and HI1 in 20 patients without prior phlebotomy or bleeding were 17.2 mg/g dry weight (k2.9) and 5.5 (+0.8), respectively. The overall 1-year survival rate after OLT in the 37 HHC patients was 58% (v 55% for HHC patients with PLC). We draw the following conclusions: (1) the diagnosis of HHC is often unsuspected before OLT, and HHC should be evaluated pretransplantation by direct and indirect markers; (2) HHC patients undergoing OLT have a high prevalence of primary liver cancer, the majority being unsuspected; and (3) HHC patients have poorer than average survival after OLT, which cannot be explained solely by the presence of concomitant PLC.
Hepatitis C is a major cause of liver disease leading to cirrhosis. Although interferon (IFN) is the only approved therapy, treatment is characterized by low response rates and dose-limiting side effects. We evaluated the addition of thymosin ␣1 (TA1), an immunomodulatory peptide, to the standard treatment regimen for hepatitis C to determine if combination therapy shows biological activity using outcome measures including normalization of alanine aminotransferase levels, histological activity, and viral load during treatment. We performed a randomized, double-blind, placebo-controlled trial to compare the biological activity of a combination TA1 and IFN with that seen for IFN alone in patients with chronic hepatitis C infection. One hundred nine patients were randomized for intention to treat and received 1.6 mg of TA1 subcutaneously twice weekly and 3 MU of IFN three times weekly; 3 MU of IFN three times weekly and placebo TA1; or placebo for both agents. All patients had chronic HCV infection with confirmation of chronic hepatitis on liver biopsy. Biochemical responders were followed up until alanine aminotransferase (ALT) levels became abnormal or for 26 weeks, and relapsers were retreated for 26 weeks in the same treatment arm. One hundred three patients completed treatment for 26 weeks, and six patients dropped out. The groups were similar with regard to sex, gender distribution, baseline histological activity index (HAI) score, risk factors, and viral titers. End-of-
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