Dermot Gleeson

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 ).

Prospective validation of the Rockall risk scoring system for upper GI hemorrhage in subgroups of patients with varices and peptic ulcers

OBJECTIVES:The Rockall risk assessment score was devised to allow prediction of the risk of rebleeding and death in patients with upper GI hemorrhage. The score was derived by multivariate analysis in a cohort of patients with upper GI hemorrhage and subsequently validated in a second cohort. Only 4.4% of patients included in the initial study had esophageal varices, and analysis was not performed according to the etiology of the bleeding. Our aim was to assess the validity of the Rockall risk scoring system in predicting rebleeding and mortality in patients with esophageal varices or peptic ulcers.METHODS:Admissions (n = 358) over 32 months to a single specialist GI bleeding unit were scored prospectively. The distribution of episodes of rebleeding and mortality by Rockall score were statistically analyzed using Fishers exact test with 99% CIs calculated using a Monte Carlo method. The Child-Pugh score was determined in patients with esophageal varices.RESULTS:The Rockall score was predictive of both rebleeding and mortality in patients with variceal hemorrhage (both ps < 0.0005), as was the Child-Pugh score (p = 0.001 and p < 0.0005, respectively). The initial Rockall score was predictive of mortality in patients with peptic ulcers (p = 0.01), although the complete score was not (p > 0.05). The complete score did, however, predict rebleeding in these patients (p = 0.001).CONCLUSION:This is the first study to validate the Rockall score in specific subgroups of patients with esophageal varices or peptic ulcers and suggests that it is particularly applicable to variceal hemorrhage.

Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region

BACKGROUND/AIMS Primary biliary cirrhosis is an autoimmune disease in which increased prevalence in first-degree relatives and an association with HLA DR8 suggest a genetic background. TNFalpha is a mediator of inflammation and immunity, and is implicated in the pathogenesis of primary biliary cirrhosis, ex vivo studies having shown reduced production of TNFalpha by lymphocytes from patients. Our group has previously described a biallelic promoter-region polymorphism of the TNFA gene at position -308, and demonstrated that the rare allele, TNF*2, has increased promoter function compared with the common allele, TNF*1. A further biallelic base change has been described in the TNFA gene at -238. We conducted a case-control study to assess association of these gene polymorphisms with primary biliary cirrhosis. METHODS Ninety-one patients and 213 controls were genotyped for both TNFA loci using restriction fragment length polymorphism analysis of PCR products. RESULTS The high production TNFA-308*2 allele was significantly under-represented among subjects with primary biliary cirrhosis (27.5% PBC, 41.6% controls, p=0.02, pc=0.04, OR for carriage of TNF*1/*1 genotype=1.89, CI=1.10-3.32). No association was shown with the TNFA -238 polymorphism. CONCLUSION Primary biliary cirrhosis is associated with reduced carriage of TNF*2. This is in keeping with a protective role of TNFalpha against the disease.

Socioeconomic deprivation, urban-rural location and alcohol-related mortality in England and Wales

BackgroundMany causes of death are directly attributable to the toxic effects of alcohol and deaths from these causes are increasing in the United Kingdom. The aim of this study was to investigate variation in alcohol-related mortality in relation to socioeconomic deprivation, urban-rural location and age within a national context.MethodsAn ecological study design was used with data from 8797 standard table wards in England and Wales. The methodology included using the Carstairs Index as a measure of socioeconomic deprivation at the small-area level and the national harmonised classification system for urban and rural areas in England and Wales. Alcohol-related mortality was defined using the National Statistics definition, devised for tracking national trends in alcohol-related deaths. Deaths from liver cirrhosis accounted for 85% of all deaths included in this definition. Deaths from 1999-2003 were examined and 2001 census ward population estimates were used as the denominators.ResultsThe analysis was based on 28,839 deaths. Alcohol-related mortality rates were higher in men and increased with increasing age, generally reaching peak levels in middle-aged adults. The 45-64 year age group contained a quarter of the total population but accounted for half of all alcohol-related deaths. There was a clear association between alcohol-related mortality and socioeconomic deprivation, with progressively higher rates in more deprived areas. The strength of the association varied with age. Greatest relative inequalities were seen amongst people aged 25-44 years, with relative risks of 4.73 (95% CI 4.00 to 5.59) and 4.24 (95% CI 3.50 to 5.13) for men and women respectively in the most relative to the least deprived quintiles. People living in urban areas experienced higher alcohol-related mortality relative to those living in rural areas, with differences remaining after adjustment for socioeconomic deprivation. Adjusted relative risks for urban relative to rural areas were 1.35 (95% CI 1.20 to 1.52) and 1.13 (95% CI 1.01 to 1.25) for men and women respectively.ConclusionsLarge inequalities in alcohol-related mortality exist between sub-groups of the population in England and Wales. These should be considered when designing public health policies to reduce alcohol-related harm.

Spectrum of liver histology in presumed decompensated alcoholic liver disease.

BACKGROUND:In presumed decompensated alcoholic liver disease (ALD; liver decompensation, heavy alcohol intake, and negative results of noninvasive screening for other causes), liver biopsy is often performed to assess severity of liver injury and to rule out other liver diseases.AIM:The aim of the study is to describe the spectrum of liver histology in such patients.METHODS:We reviewed all patients with presumed decompensated ALD seen between 1998 and 2004, in whom liver tissue was available for histology (N = 110).RESULTS:A total of 104 of the 110 patients had at least one of the histological features suggestive of ALD: fat, Mallorys hyalin, neutrophilic infiltrate, and hepatocyte ballooning. These features were more prevalent in tissue obtained within a month after presentation with decompensation than in that obtained before decompensation or more than 1 month after. These features were also associated with more severe liver dysfunction. Histology revealed a major additional diagnosis (Budd-Chiari syndrome) in only one case. In 41 patients biopsied within a month of first presentation with decompensation, Child score and Maddrey discriminant function (DF), but none of the histological features, were predictive of survival by Cox multivariate analysis. Of the 26 of these 41 patients with a Maddrey DF >32, 22 (85%) had alcoholic hepatitis.CONCLUSIONS:In patients with presumed decompensated ALD, other liver diseases are uncommon. Routine liver biopsy is of limited added value but biopsy should be considered in those in whom the noninvasive workup, or failure to recover despite abstinence, raises the possibility of other liver diseases.

Effectiveness of an upper-gastrointestinal haemorrhage unit: a prospective analysis of 900 consecutive cases using the Rockall score as a method of risk standardisation

Objectives To assess the effectiveness of a centralised upper-gastrointestinal haemorrhage (UGIH) unit. Methods The UK Audit of acute UGIH resulted in the formulation of a simple numerical scoring system. The Rockall score categorises patients by risk factors for death and allows case-mix comparisons. A total of 900 consecutive patients admitted to a UGIH unit between October 1995 and July 1998 were analysed prospectively. Patients were given an initial Rockall score and, if endoscopy was performed, a complete score. This method of risk stratification allowed the proportion of deaths (in our study) to be compared with the National Audit using risk standardised mortality ratios. Results The distribution of both initial and final Rockall scores was significantly higher in our study than in the National Audit. A total of 73 (8.1%) patients died, compared with the National Audit mortality of 14%. Risk-standardised mortality ratios using both initial and complete Rockall scores were significantly lower in our study when compared with those in the National Audit. Conclusion A specialised UGIH unit is associated with a lower proportion of deaths from UGIH, despite comprising a greater number of high-risk patients than the National Audit. This lower mortality therefore cannot be attributed to a more favourable case mix and demonstrates that further improvements in mortality for UGIH can be made.

Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial

AbstractBackgroundAlcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey’s discriminant function (DF) ≥32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published.Methods/designSTOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups: 1.Group A: placebo / placebo2.Group B: placebo / prednisolone3.Group C: pentoxifylline / placebo4.Group D: pentoxifylline / prednisolone The trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year.DiscussionSTOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power.Trial registrationEudraCT reference number: 2009-013897-42ISRCTN reference number: ISRCTN88782125

Calcium and carbonate ion concentrations in gallbladder and hepatic bile

Calcium carbonate is a major component of gallstones, but there are few data on calcium and carbonate (CO3(2-)) concentrations in human bile. Therefore, in patients undergoing cholecystectomy for gallstones, total [CaTOT] and free ionized [Ca2+] calcium concentrations, pH, PCO2, and total [CO2] were measured and [CO3(2-)] was derived in gallbladder and hepatic bile (aspirated anaerobically at surgery or from T tubes). Gallbladder bile had lower pH (6.96 vs. 7.30) and total [CO2] (14.1 vs. 21.6 mmol/L), higher PCO2 (53.8 vs. 40.2 mm Hg), lower [CO3(2-)] (2.52 vs. 6.11 x 10(5) mol/L) and lower [Ca2+] x [CO3(2-)] ion product (1.88 vs. 4.74 x 10(-8) mol/L) than did hepatic bile. Gallbladder bile pH correlated positively with total [CO2], [CO3(2-)], and [Ca2+] x [CO3(2-)] but negatively with PCO2. Patients with surface gallstone calcification had similar gallbladder bile [CaTOT] and [Ca2+] but higher gallbladder bile pH (7.30 vs. 6.90), lower PCO2 (42.9 vs. 57.2 mm Hg), higher [CO3(2-)] (7.29 vs. 1.84 x 10(-5) mol/L), and higher [Ca2+] x [CO3(2-)] ion product [4.73 vs. 1.45 x 10(-8) (mol/L)2] than those with radiolucent gallstones. There were no differences in these parameters between patients with cholesterol stones and those with pigment stones. These data suggest that the human gallbladder acidifies bile by secreting hydrogen ion and that impairment of this secretion is one cause of calcified gallstone formation in humans.

Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis

Azathioprine (AZA) is used to maintain remission in autoimmune hepatitis (AIH), but up to 18% of patients are unresponsive. AZA is a prodrug, and the formation of active thioguanine nucleotide (TGN) metabolites varies widely. We aimed to assess the relationship between AZA metabolite concentrations (i.e., TGNs and methylmercaptopurine nucleotides [MeMPNs]), thiopurine methyltransferase (TPMT) activity, therapeutic response, and toxicity in adult patients with AIH prescribed a stable dose of AZA for the maintenance of remission. Red blood cell (RBC) TGNs and MeMPNs were measured in serial blood samples over a 2‐year period. The average TGNs (avTGNs) and MeMPNs (avMeMPNs) concentrations for each patient were used for analysis. Therapeutic response was defined as the ability to maintain remission, defined as a normal serum alanine aminotransferase (ALT) level (ALT <33 IU/mL). Patients who maintained remission (n = 53), compared to those who did not (n = 17), tended to be on lower doses of AZA (1.7 versus 2.0 mg/kg/day; P = 0.08), but had significantly higher concentrations of avTGN (237 versus 177 pmol/8 × 108 RBCs; P = 0.025). There was no difference in MeMPN concentrations or TPMT activities between the two groups. There was a negative correlation between ALT and avTGN (rs = −0.32; P = 0.007). An avTGN concentration of >220 pmol/8 × 108 RBCs best predicted remission, with an odds ratio of 7.7 (P = 0.003). There was no association between TGN, MeMPN, or TPMT activity and the development of leucopenia. Two patients developed AZA‐induced cholestasis and the avMeMPN concentration was higher in those patients, compared to those who did not (14,277 versus 1,416 pmol/8 × 108 RBCs). Conclusion: TGN concentrations of >220 pmol/8 × 108 RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA‐induced cholestasis was associated with increased MeMPN concentrations. (HEPATOLOGY 2012)

Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis.

Objectives:Biochemical remission is widely considered a satisfactory treatment end point in autoimmune hepatitis (AIH). The significance of persisting histological activity despite biochemical remission is unknown. We aimed to assess the frequency and prognostic significance of persisting histological inflammation in patients with AIH who had achieved biochemical remission with treatment.Methods:We studied 120 patients (median age at diagnosis 57 years; 81% female) with AIH by International Criteria (59% definite), who received immunosuppressive treatment and underwent a follow-up liver biopsy after at least 6 months of sustained biochemical remission (defined as normal serum ALT and globulin).Results:Fifty-five patients (46%) had persisting histological activity (Ishak histological activity index (HAI) ≥4). These patients had higher serum ALT (24 vs. 18 IU/l, P=0.003) and AST (27 vs. 23 IU/l, P=0.03) at the time of follow-up biopsy, compared with patients who achieved histological remission (HAI ≤3). They had less frequent regression of fibrosis on follow-up biopsy compared with those achieving histological remission (32 vs. 60%, P=0.004) and had excess mortality (standardized mortality ratio 1.4 vs. 0.7, P<0.05). The excess mortality was due to liver disease. On multivariate analysis, persisting histological activity was independently associated with all-cause death/transplantation (HR 3.1 (95% CI 1.2–8.1); P=0.02); an association with liver-related death/transplantation fell short of significance (HR 9.7 (95% CI 0.84–111.6; P=0.07).CONCLUSIONS:Persisting histological activity, despite biochemical remission, is frequent in patients with treated AIH and is associated with lower rates of fibrosis regression and reduced long-term survival.