Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

T he role of the liver in the pathogenesis of type 2 diabetes is attracting increasing interest. In a recent study (1), directly determined liver fat content was shown to correlate with several features of insulin resistance in normal weight and moderately overweight subjects independent of BMI and intraabdominal or overall obesity. However, direct measurements of liver fat require ultrasound, computed tomography scan, or proton spectroscopy, and such techniques are unlikely to be recommended for this purpose in routine clinical practice. Fortunately, circulating concentrations of a number of variables appear to give insight into the extent of liver fat accumulation. Among these are ␥-glutamyltransferase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Of these three, ALT is the most specific marker of liver pathology and appears to be the best marker for liver fat accumulation (2). In addition, circulating concentrations of plasminogen activator inhibitor-1 may give insight into the extent of liver fat content (3) but, unlike ALT, its measurement is perhaps not as simple, standardized, or routinely available in laboratories.In light of the above observations, it is of interest that ALT has been shown to predict incident type 2 diabetes in two prospective studies (4,5). Ohlson et al. (4) determined risk factors for diabetes in 766 men, 47 of whom developed diabetes over 13.5 years of follow-up. They reported that elevated ALT predicted diabetes independently of classical predictors inclusive of BMI, blood pressure, triglycerides, and family history. However, diabetes ascertainment was not uniform in their study, and the potential utility of ALT to predict diabetes was not examined in any detail. Vozarovoa et al. (5) examined the ALT levels in a cohort of 370 Pima Indians with normal glucose tolerance, 63 of whom developed diabetes over an average follow-up of 6.9 years. In their analyses, individuals in the top decile for ALT (Ն70 units/l) had a relative risk of 2.5 (95% CI 1.7-3.7) for diabetes compared with those in the bottom decile (ALT Յ12 units/l), with adjustment for age, sex, percentage body fat, clamp-derived insulin resistance, and acute insulin response. The only minor weaknesses in that study were the absence of data on alcohol consumption and routine clinical measures known to predict diabetes, namely fasting lipids and blood pressure. Moreover, they

Introduction: Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in our population. Methods: We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6-9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients. Results: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p,0.001), blood urea (p = 0.019) and, from day 6-9 results, serum bilirubin (p,0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6-9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment. Conclusions: Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity

No abstract

Current therapy for preventing the first variceal bleed includes beta-blocker and variceal band ligation (VBL). VBL has lower bleeding rates, with no differences in survival, whereas betablocker therapy can be limited by side effects. Carvedilol, a non-cardioselective vasodilating beta-blocker, is more effective in reducing portal pressure than propranolol; however, there have been no clinical studies assessing the efficacy of carvedilol in primary prophylaxis. The goal of this study was to compare carvedilol and VBL for the prevention of the first variceal bleed in a randomized controlled multicenter trial. One hundred fifty-two cirrhotic patients from five different centers with grade II or larger esophageal varices were randomized to either carvedilol 12.5 mg once daily or VBL performed every 2 weeks until eradication using a multibander device. T he most serious complication of portal hypertension is variceal hemorrhage. The annual incidence of esophageal varices in patients with cirrhosis is approximately 5%, 1 and a third of these will bleed. 2,3 Current therapy with propranolol results in a reduction in the first variceal bleed and mortality compared with placebo. 4,5 There have been two recent metaanalyses with 16 trials studied in total. 6,7 The one showed variceal band ligation (VBL) to be more effective than beta-blockers in primary prevention of variceal hemorrhage, although there was no difference in survival. 7 The other showed similar overall results, although when trials with unclear bias control and follow-up less than 20 months were excluded, the difference in bleeding was not present. 6 Carvedilol is a potent non-cardioselective betablocker, with weak vasodilating properties due to alpha-1 blockade. 8 A fall in both intrahepatic and portocollateral resistance contributes to the enhanced effects on portal pressure reduction through blockade of alpha-1 receptors as has been shown with prazosin. 9-11 A reduction in the hepatic venous pressure gradient (HVPG) of 8%-43% was observed with carvedilol in nine published hemodynamic studies involving 158 patients. [12][13][14][15][16][17][18][19][20] Carvedilol was also found to have a greater portal hypotensive effect than propranolol in randomized controlled hemodynamic studies. 15,17

BACKGROUNDInfection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown. METHODSWe conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment. RESULTSA total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group. CONCLUSIONSIn patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom.

Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125.