Ewan H. Forrest

Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score

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.

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

BACKGROUND Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS 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 ).

Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed

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 beta‐blocker 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. Seventy‐seven patients were randomized to carvedilol and 75 to VBL. Baseline characteristics did not differ between the groups (alcoholic liver disease, 73%; median Child‐Pugh score, 8; median age, 54 years; median follow‐up, 20 months). On intention‐to‐treat analysis, carvedilol had lower rates of the first variceal bleed (10% versus 23%; relative hazard 0.41; 95% confidence interval 0.19‐0.96 [P = 0.04]), with no significant differences in overall mortality (35% versus 37%, P = 0.71), and bleeding‐related mortality (3% versus 1%, P = 0.26). Six patients in the VBL group bled as a result of banding ulcers. Per‐protocol analysis revealed no significant differences in the outcomes. Conclusion: Carvedilol is effective in preventing the first variceal bleed. Carvedilol is an option for primary prophylaxis in patients with high‐risk esophageal varices. (HEPATOLOGY 2009.)

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

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.

Reduction in renal blood flow following acute increase in the portal pressure: evidence for the existence of a hepatorenal reflex in man?

BACKGROUND: To investigate the relation between changes in portal haemodynamics and renal blood flow (RBF) in patients with cirrhosis. PATIENTS/METHODS: Twenty patients with cirrhosis and transjugular intrahepatic portosystemic stent-shunts were divided into two groups which were well matched. At routine portography, either changes in unilateral RBF (group I) or changes in cardiac output (group II) before and after shunt occlusion were studied. Blood was obtained from the renal and systemic circulations for the measurement of neurohumoral factors before and after shunt occlusion in group I patients. RESULTS: After shunt occlusion, there was a progressive reduction in unilateral RBF from a mean (SD) of 289 (32) to 155 (25) (-43.5%) (p < 0.001). These changes correlated significantly with the changes in the portal atrial gradient (p < 0.001). There was no significant change in heart rate, mean arterial pressure and right atrial pressure. No significant changes were found in the concentrations of the various neurohumoral factors measured. There was a less notable but significant reduction in the cardiac output (-10.9%) (p = 0.02) unaccompanied by significant reduction in the pulmonary capillary wedge pressure or mean arterial pressure. CONCLUSIONS: These results suggest the existence of hepatorenal reflex in man which is important in the regulation of RBF, although other mechanisms may also be contributory.

Non-alcoholic fatty liver disease

#### Summary points Non-alcoholic fatty liver disease (NAFLD) is now more common than alcoholic liver disease owing to the rapid rise in the prevalence of obesity,1 and NAFLD is the most common cause of abnormal liver function tests.2 Its prevalence worldwide is thought to be approximately 20% in the general population and up to 70% in patients with type 2 diabetes mellitus.3 The first recognisable stage of NAFLD is hepatic steatosis, when fat content exceeds 5% of liver volume. Simple steatosis is usually benign in terms of risk of progression to …

The Glasgow Alcoholic Hepatitis Score Identifies Patients Who May Benefit From Corticosteroids.

Introduction: There is no consensus on the pharmacological treatment of alcoholic hepatitis. The Glasgow alcoholic hepatitis score (GAHS) has been shown to be more accurate than the modified Maddrey’s discriminant function (mDF) in the prediction of outcome from alcoholic hepatitis. This study aimed to determine whether the GAHS was able to identify those patients who would benefit from corticosteroids. Methods: 225 patients with an mDF greater than or equal to 32 from five hospital centres in the United Kingdom were reviewed. Patient survival relative to the GAHS and the use of corticosteroids was recorded. Results: 144 patients with an mDF greater than or equal to 32 (64%) also had a GAHS greater than or equal to 9. There was no difference in survival between untreated or corticosteroid-treated patients for those with a GAHS less than 9. For patients with a GAHS greater than or equal to 9 the 28-day survival for untreated and corticosteroid-treated patients was 52% and 78% (p = 0.002), and 84-day survival was 38% and 59% (p = 0.02), respectively. Conclusions: Among patients with an mDF greater than or equal to 32, there was no appreciable benefit from treatment with corticosteroids in patients with a GAHS less than 9. Patients with a GAHS greater than or equal to 9 have an extremely poor prognosis if they are not treated with corticosteroids, or if such treatment is contraindicated.

Longterm follow up of transjugular intrahepatic portosystemic stent shunt (TIPSS) for the treatment of portal hypertension: results in 130 patients.

BACKGROUND: Transjugular intrahepatic portosystemic stent shunts (TIPSS) are increasingly being used to manage the complications of portal hypertension. This study reports on the follow up on 130 patients who have undergone TIPSS. PATIENTS AND METHODS: One hundred and thirty patients (81 male), mean (SD) age 54.7 (12.5) years underwent TIPSS. The majority (64.6%) had alcoholic cirrhosis and 53.2% had Childs C disease. Indications were: variceal haemorrhage (76.2%), refractory ascites (13.1%), portal hypertensive gastropathy (4.6%), others (6.1%). Shunt function was assessed by Doppler ultrasonography and two then six monthly portography and mean follow up for survivors was 18.0 months (range 2-43.5). RESULTS: The procedure was successful in 119 (91.5%). Sixty three episodes of shunt dysfunction were observed in 45 (37.8%) patients. Variceal rebleeding occurred in 16 (13.4%) patients and was always associated with shunt dysfunction. Twenty (16.8%) patients had new or worse spontaneous encephalopathy after TIPSS and 11 (64.7%) patients had an improvement in resistant ascites. Thirty day mortality was 21.8% and one year survival 62.5%. CONCLUSION: TIPSS is an effective treatment for variceal bleeding, resistant ascites, and portal hypertensive gastropathy. Rebleeding is invariably associated with shunt dysfunction, the frequency of which increases with time, therefore regular and longterm shunt surveillance is required.

The effect of nitric oxide synthase inhibition on portal pressure and azygos blood flow in patients with cirrhosis

It has been proposed that the hyperdynamic circulation found in cirrhosis is mediated by nitric oxide released through the induction of nitric oxide synthase. To investigate this the effect of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), was studied upon the portal circulation. After a 30-min infusion of 3 mg/kg of L-NMMA there was a significant fall in heart rate from 83.2 +/- 4.4 to 74.2 +/- 3.9 bpm (p = 0.005), and a significant rise in mean arterial pressure from 91.6 +/- 2.2 to 103.7 +/- 3.2 mmHg, p = 0.004). There was, however, no change in hepatic venous pressure gradient (16.7 +/- 1.5 to 16.1 +/- 1.7 mmHg, p = 0.477) nor in azygos venous blood flow (366 +/- 126 to 368 +/- 145 ml/min, p = 0.683). On subgroups analysis by Child-Pugh grade, significant changes occurred in heart rate and mean arterial pressure only in grade A and B patients (p = 0.0061 and p = 0.0068, respectively). Regional peripheral blood flow was studied using hand thermography. All patients who had an isothermic hands (relatively cold fingers compared to palmar temperature) at the start of the study developed an isothermic pattern after the L-NMMA infusion. This study demonstrates a significant systemic effect of nitric oxide synthase inhibition in patients with cirrhosis but no effect upon the portal or portosystemic collateral circulations at this dose.

Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care†

Our objective was to address two shortfalls in the hepatitis C virus (HCV) literature: (1) Few data exist comparing post‐treatment liver‐related mortality/morbidity in HCV‐sustained virologic response (SVR) patients to non‐SVR patients and (2) no data exist examining liver‐related morbidity among treatment response subgroups, particularly among noncirrhotic SVR patients, a group who in the main are discharged from care without further follow‐up. A retrospective cohort of 1,215 previously naïve HCV interferon patients (treated 1996‐2007) was derived using HCV clinical databases from nine Scottish clinics. Patients were followed up post‐treatment for a mean of 5.3 years. (1) By Cox‐regression, liver‐related hospital episodes (adjusted hazard ratio [AHR]: 0.22; 95% confidence interval [CI]: 0.15‐0.34) and liver‐related mortality (AHR: 0.22; 95% CI: 0.09‐0.58) were significantly lower in SVR patients, compared to non‐SVR patients. (2) Rates of liver‐related hospitalization were elevated among all treatment subgroups, compared to the general population: Among noncirrhotic SVR patients, adjusted standardized morbidity ratio (SMBR) up to 5.9 (95% CI: 4.5‐8.0); among all SVR patients, SMBR up to 10.5 (95% CI 8.7‐12.9); and among non‐SVR patients, SMBR up to 53.2 (95% CI: 49.4‐57.2). Considerable elevation was also noted among patients who have spontaneously resolved their HCV infection (a control group used to gauge the extent to which lifestyle factors, and not chronic HCV, can contribute to liver‐related morbidity), with SMBR up to 26.8 (95% CI: 25.3‐28.3). Conclusions: (1) Patients achieving an SVR were more than four times less likely to be hospitalized, or die for a liver‐related reason, than non‐SVR patients and (2) although discharged, noncirrhotic SVR patients harbor a disproportionate burden of liver‐related morbidity (i.e., up to six times that of the general population). Furthermore, alarming levels of liver‐related morbidity in spontaneous resolvers is an important finding warranting further study. (HEPATOLOGY 2011;)