BACKGROUND AND AIMS: Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigatorinitiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC. METHODS: Patients with moderate to severe pruritus (!5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebocontrolled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was !50% reduction of pruritus (VAS; intention-to-treat). RESULTS: Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to !50% reduction of severe or moderate pruritus (P ¼ .003). For secondary end points, bezafibrate reduced morning (P ¼ .01 vs placebo) and evening (P ¼ .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P ¼ .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (À35%, P ¼ .03 vs placebo) correlating with improved pruritus (VAS, P ¼ .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P ¼ .14). CONCLUSIONS: Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC.

A daily dose of 25 microg of vitamin K fails to prevent bleedings in apparently healthy infants with unrecognized cholestasis because of biliary atresia. One milligram of weekly oral prophylaxis offers significantly higher protection to these infants and is of similar efficacy as 2 mg of intramuscular prophylaxis at birth. Our data underline the fact that event analysis in specific populations at risk can help to evaluate and improve nationwide prophylactic regimens.

Primarybiliarycholangitis (

Background & Aims: IgG4-related disease (IgG4-RD) of the biliary tract and pancreas is often difficult to distinguish from pancreatobiliary cancer. The blood IgG4/IgG RNA ratio has been reported to discriminate IgG4-RD from primary sclerosing cholangitis/pancreatobiliary cancer with high accuracy. This study aimed to prospectively assess the diagnostic accuracy of the blood IgG4/IgG RNA ratio for distinguishing IgG4-RD from cancer in patients with a suspected pancreatobiliary malignancy. Methods: In this prospective, single center, observational study, patients presenting at a specialized multidisciplinary, hepato-pancreato-biliary clinic with suspicion of pancreatobiliary malignancy were included. The IgG4/IgG RNA ratio (threshold 5.0%) was determined by quantitative PCR in addition to standard diagnostic procedures. Clinical, biochemical, radiological, and histo-/cytopathological findings were analyzed. For the diagnosis of IgG4-RD, the HISORt criteria were used as a reference standard. Malignancy was defined by the presence of neoplastic tissue at histo-/cytopathological examination. Results: Overall, 213 consecutive patients (mean age 68 years) with a suspected pancreatobiliary malignancy were analyzed, of whom 3 patients were diagnosed with IgG4-RD and 178 patients were diagnosed with malignancy (165 patients with primary pancreatobiliary malignancy). The IgG4/IgG RNA ratio was true positive in 3 patients and false positive in 87 (40.8%) patients. In 123 (57.7%) patients the test was true negative. The sensitivity of blood IgG4/IgG RNA ratio was 100%, the specificity 58.6%, the positive predictive value 3.3%. Conclusion:In the setting of a high a priori risk of malignancy, an elevated IgG4/IgG RNA ratio did not accurately discriminate pancreatobiliary cancer from IgG4-RD as illustrated by low specificity and concordant low positive predictive value. We advise against the use of this test to discriminate IgG4-RD from pancreatobiliary malignancies.

Background and Aims Adenosine triphosphate‐binding cassette subfamily B member 4 (ABCB4) deficiency may lead to progressive familial intrahepatic cholestasis type 3 (PFIC3), biliary cirrhosis, low phospholipid‐associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptive‐induced cholestasis (CIC) or may remain asymptomatic. The long‐term course, quality of life and histology were investigated in ABCB4 deficiency. Methods Adult carriers of ABCB4 gene variants from two regional academic centres were analysed by history taking, electronic patient files, physical examination, blood analysis, abdominal ultrasound (US) and liver elastography. Patients completed a 36‐Item Short Form Health Survey (SF‐36) for quality of life and a Visual Analogue Scale (VAS) for pruritus. Available liver specimens were re‐classified according to the Nakanuma scoring system, so far validated for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) only. Quality of life data were compared to published data of patients with PBC, PSC and the general population. Results Sixty‐seven patients were identified, 64 (96%) were alive at the time of analysis and 62 (93%) were (at some time) treated with ursodeoxycholic acid (UDCA). Two patients died of cholangiocarcinoma (CCA), and one of decompensated biliary cirrhosis. Three additional deaths of CCA were reported in first‐degree relatives. Transplant‐free survival was 91% (median follow‐up 14 years). Liver stiffness was normal (<6.3 kPa) in 75%, intrahepatic stones were detected at ultrasound (US) in 33% and microcalcifications in 22% of cases. Quality of life (n = 48) was lower than in the general population particularly in energy/fatigue and general health domains and comparable to that in PSC. Staging according to Nakanuma in 15 specimens reflected the clinical course. Conclusions ABCB4 deficiency has a mild clinical course, but impaired quality of life and limited risk of CCA. The Nakanuma scoring system appears feasible for histological evaluation in ABCB4 deficiency.