Albert Parés

Simplified criteria for the diagnosis of autoimmune hepatitis

Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life‐saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff ≥6) and 81% sensitivity and 99% specificity (cutoff ≥7) in the validation set. Conclusion: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher. (HEPATOLOGY 2008.)

S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.

BACKGROUND/AIM The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. METHODS A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. RESULTS At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). CONCLUSIONS The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.

Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage.

The factors influencing the histological evolution of alcoholic hepatitis without cirrhosis have been evaluated in 26 patients (14 males and 12 females) submitted to repeated liver biopsies over a mean period of 1.7 years (1-3). Drinking habits during follow-up were checked by inquiries to patients and relatives and by serial determination of ethanol in urine. At the end of the follow-up, 9 patients (34.6%) had progressed to cirrhosis, 5 (19.2%) still had alcoholic hepatitis and 12 (46.1%) had normal liver or only minimal changes. Nine patients continued drinking heavily, 4 reduced their daily intake markedly and 13 stopped drinking. Improvement of liver lesions was observed in 9 of the abstainers and in 3 non-abstainers that had markedly reduced their alcohol consumption. Among the 9 patients with persistent heavy alcohol consumption, 5 developed cirrhosis and 4 still showed alcoholic hepatitis in their last biopsy. Cirrhosis also developed over 1-2 years in 4 females who had stopped drinking, indicating a marked influence of sex on the course of alcoholic hepatitis. Progression of the disease to cirrhosis despite abstinence occurred in a high proportion of women (4/7) but not in men (0/6). These observations indicate that discontinuation of heavy alcohol consumption often results in improvement of liver lesion in patients with alcoholic hepatitis. However, the risk of progression to cirrhosis remains elevated in women.

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute‐on‐chronic liver failure: The RELIEF trial

Acute‐on‐chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n = 95) or to standard therapy (SMT) (n = 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per‐protocol (PP) analysis (PP population n = 156). Up to 10 6‐8‐hour MARS sessions were scheduled. The main endpoint was 28‐day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28‐day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44‐1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P = 0.02) and bilirubin (P = 0.001) and a more frequent improvement in HE (from grade II‐IV to grade 0‐I; 62.5% versus 38.2%; P = 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE. (HEPATOLOGY 2013)

Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid

BACKGROUND & AIMS We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. METHODS We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. RESULTS OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. CONCLUSIONS Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.

Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial

Abstract Background/Aim: The aim of this study was to assess the efficacy of ursodeoxycholic acid (UDCA) for primary biliary cirrhosis in a randomized, double-blind placebo-controlled trial. Methods: Consecutive patients ( n =192) were randomized to receive 14–16 mg UDCA/kg/day or placebo. Patients underwent a complete history, physical examination, liver chemistries, immunological determinations and liver biopsy at entry and at the end of the trial, which lasted for at least 2 years. Patients were seen every 3 months and the median follow-up was 3.4 years (range 0.3 to 6.1 years). Results: Patients receiving UDCA (99) or placebo (93) were comparable with regard to age, sex, biochemical parameters and liver histology. UDCA treatment was associated with decreases in alkaline phosphatase, gammaglutamyl transferase, alanine aminotransferase, and cholesterol levels, effects which were conspicuous after 3 months of treatment and remained similar during the follow-up. During the study 31 patients (10 receiving UDCA and 21 placebo) discontinued the trial because of noncompliance ( n =11), voluntary withdrawal ( n =19) or adverse effects ( n =1). Treatment failure (death or liver transplantation) was observed in 17 patients receiving UDCA and in 11 patients receiving placebo. Times to death or liver transplantation and to clinical complications were not significantly different in patients receiving UDCA or placebo. Histological analysis indicates that UDCA improved portal inflammation and prevented histological stage progression. By contrast, histological stage as well as ductular proliferation and ductopenia progressed in patients receiving placebo. Conclusions: Although UDCA treatment did not significantly affect time to death or liver transplantation and to clinical complications, the effects on both cholestasis and liver histology suggest that UDCA is safe and may be useful for preventing the progression of primary biliary cirrhosis.

Cholangiocarcinoma in Primary Sclerosing Cholangitis: Risk Factors and Clinical Presentation

Background: Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC. Methods: Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC. Results: CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively; P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively; P = 0.009 in multivariate analysis). Conclusions: A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.

COMPARISON OF RIFAMPICIN WITH PHENOBARBITONE FOR TREATMENT OF PRURITUS IN BILIARY CIRRHOSIS

The anti-pruritic effects of rifampicin (10 mg/kg) and phenobarbitone (3 mg/kg) were assessed in 22 patients with primary biliary cirrhosis in a crossover randomised clinical trial. Each agent was given for 14 days, with a 30-day washout period between treatments. 21 patients completed the course of rifampicin and 18 that of phenobarbitone; rifampicin was withdrawn from 1 patient when anaemia and renal failure developed, whereas 3 patients stopped taking phenobarbitone because of a rash and the 4th merely refused the drug. Rifampicin had a greater anti-pruritic effect than phenobarbitone. The symptom improved in 19 patients taking rifampicin and in 8 taking phenobarbitone, the degree of improvement being greater with rifampicin than with phenobarbitone. Pruritus disappeared in 9 patients receiving rifampicin, and three of them were free of itch when switching over to phenobarbitone. Both drugs were equally effective in inducing hepatic microsomal function but rifampicin has the additional effect of reducing cholestasis. Its anti-pruritic effect should be tested in long-term clinical trials.

Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis

BACKGROUND/AIMS This study aimed at evaluating the effect of ursodeoxycholic acid (UDCA) treatment on histologic progression in primary biliary cirrhosis (PBC). METHODS Using combined individual histologic findings from four clinical trials, we selected the patients in whom paired liver-biopsy specimens were available with a time interval of about 36 months between biopsies. A total of 367 patients were selected (UDCA: 200 vs. placebo: 167). RESULTS Overall, there was no significant difference in the progression of the histologic stage between the two groups. By contrast, in the subgroup of patients with initial stages I-II (n=177) there was a significant decrease in the histologic stage progression in the UDCA group relative to the placebo group (P<0.03). Overall, there was a significant delay in the progression of periportal necroinflammatory lesions (P=0.03), and an improvement in the degree of ductular proliferation (P=0.02) in the UDCA group compared with the placebo group. There was no significant difference in the progression of other specific lesions. CONCLUSIONS A 2-year UDCA treatment reduces periportal necroinflammation and improves ductular proliferation, and when initiated at the earlier stages I-II of the disease also delays the progression of histologic stage. These data support the early initiation of the drug to prevent these histologic features of PBC.

Epidemiology of primary sclerosing cholangitis in Spain

The incidence of primary sclerosing cholangitis has been estimated on the basis of its frequent association with ulcerative colitis, but direct epidemiologic studies have not yet been carried out. In the current study we report a survey of clinical and epidemiological aspects of primary sclerosing cholangitis in Spain. A questionnaire was circulated to physicians in 33 hospitals throughout Spain to ascertain the number and the clinical, biochemical and immunologic characteristics of patients with primary sclerosing cholangitis from January 1, 1984 to December 31, 1988. Twenty-three centers, from 12 Spanish regions, covering a population of 19.23 million answered the questionnaire. Forty-three patients (60.5% males) with a mean age of 42.3 years (range 12 to 75 years) were seen during the 5-year period. At presentation, 16% of the cases were asymptomatic. Ulcerative colitis was present in 44.2% of cases, and one patient had Crohns disease. The overall annual incidence ranged from 0.16 to 0.68 cases/million from 1985 to 1988, and the annual prevalence increased from 0.78 cases/million in 1984 to 2.24 cases/million in 1988. No geographical differences were found, but there was a trend to detect more cases in industrialized regions. In conclusion, there was a continuing rise in the annual incidence and prevalence of primary sclerosing cholangitis in Spain over a 5-year period.