K.J. van Erpecum

A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis

BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).

Highly symptomatic adult polycystic disease of the liver. A report of fifteen cases.

Fifteen patients were evaluated because of highly symptomatic adult polycystic liver disease. All of them had abdominal pain, two patients had obstructive jaundice, one had ascites and a large right-sided pleural effusion, and one had oesophageal varices. In 4 patients percutaneous aspiration of the largest cysts was performed, but this form of treatment only provided temporary relief. In 9 patients a fenestration operation was carried out. One of these patients died per-operatively due to irreversible shock. The abdominal complaints disappeared post-operatively in 7 of the other 8 patients, although a decrease of the liver span was uncommon. In the two patients with obstructive jaundice the serum bilirubin level normalized after the operation, and in the patient with oesophageal varices this abnormality disappeared post-operatively. Biochemical analysis of cyst fluid was performed in 7 of the cases. The mean ratios of the levels of most of the non-protein-bound inorganic ions and other small molecules in cyst fluid and serum were about 1, whereas those of all proteins and protein-bound constituents were generally far below 1.

Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.

Acromegalic patients treated three times daily with subcutaneous injections of the somatostatin analogue octreotide frequently develop gallstones, due to suppressed cholecystokinin release and impaired gall‐bladder emptying.

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes

Aliment Pharmacol Ther 2011; 34: 335–343

Cholesterol and pigment gallstone disease: comparison of the reliability of three bile tests for differentiation between the two stone types

Gallbladder biles and stones were obtained at 116 cholecystectomies for symptomatic gallstone disease. All 33 patients younger than 50 years had cholesterol stones, whereas 40% of the older patients had pigment stones. We compared the reliability of three different bile tests for the differentiation between cholesterol and pigment stone patients. Whereas both the presence of cholesterol monohydrate crystals in fresh gallbladder bile and a nucleation time less than or equal to 20 days in ultrafiltered gallbladder bile had a specificity of 100% for cholesterol gallstone disease, biliary supersaturation with cholesterol (cholesterol saturation index greater than 1.0) had a low specificity. The sensitivity of nucleation time less than or equal to 20 days for cholesterol gallstone disease was 78% in concentrated gallbladder biles (biliary total lipid concentration greater than or equal to 5 g/dl) but only 21% in dilute biles (biliary total lipid concentration less than 5 g/dl). In contrast, examination for the presence of cholesterol crystals in fresh bile was reasonably sensitive both in concentrated and dilute gallbladder biles (sensitivity, 84% and 72%, respectively). In addition, duodenal bile obtained from 16 patients (10 cholesterol, 6 pigment) before cholecystectomy showed cholesterol crystals in 7 of the cholesterol but in none of the pigment stone patients. We conclude that examination of fresh bile for cholesterol crystals is a specific and reasonably sensitive test for cholesterol gallstone disease.

Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands

Abstract Background and aims. Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). Methods. Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. Results. The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3–19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5–2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1–44 years). Familial occurrence was reported in three cases. Conclusion. This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.

EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones

Gallstones or cholelithiasis are a major public health problem in Europe and other developed countries and affect up to 20% of the population. Gallstone disease is the most common gastrointestinal disorder for which patients are admitted to hospitals in European countries [1]. The interdisciplinary care for patients with gallstone disease has advanced considerably during recent decades thanks to a growing insight into the pathophysiological mechanisms and remarkable technical developments in endoscopic and surgical procedures. In contrast, primary prevention for this common disease is still in its infancy. The EASL Clinical Practice Guidelines (CPG) on the prevention, diagnosis and therapy of gallstones aim to provide current recommendations on the following issues:

Gallstones: an intestinal disease?

Current evidence suggests that impaired intestinal motility may facilitate gallstone formation by influencing biliary deoxycholate levels or by modulating interdigestive gall bladder motility (fig 2), although a primary intestinal defect in gallstone pathogenesis has not yet been demonstrated. In the cold war period, most interesting events, from a political point of view, occurred at the border between capitalist and communist systems, near the iron curtain. Similarly, the gall bladder and biliary tract can be viewed as the border between liver and intestinal tract, where many interesting things occur with profound impact on both systems. Combined efforts by researchers in the field of hepatology and gastrointestinal motility should brake down the Berlin wall of ignorance of one of the most common diseases in the Western world.

Interdigestive gallbladder emptying, antroduodenal motility, and motilin release patterns are altered in cholesterol gallstone patients

The role of interdigestive gallbladder emptying in gallstone formation is unknown. In fasting healthy subjects, gallbladder emptying is associated with antral phase III of the migrating motor complex (MMC) and high plasma motilin. Therefore, gallbladder volumes and motilin levels were measured during 13 MMC cycles in 10 cholesterol gallstone patients and compared with 20 MMC cycles in 10 healthy subjects. MMC cycle length was longer in gallstone patients than in healthy subjects (158.2 ± 17.0 vs 105.5 ± 10.4 min, respectively; P < 0.05), due to longer phase I (39.8 ± 5.7 vs 17.2 ± 3.7 min, respectively; P < 0.05). In contrast to healthy subjects, gallstone patients had no significant fluctuations of gallbladder volume during the MMC cycle, and motilin concentrations were not different in MMC cycles with phase III originating in antrum or duodenum. During MMC cycles with phase III originating in the duodenum, motilin levels were twice as high in gallstone patients as in healthy subjects (P < 0.002). In conclusion, cholesterol gallstone patients have an abnormal MMC and motilin release pattern. Their interdigestive gallbladder emptying is reduced and dissociated from the MMC. These disturbances may contribute to gallstone formation.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.