Marlyn J. Mayo

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.

Sertraline as a first-line treatment for cholestatic pruritus†

Pruritus is frequently the most debilitating symptom of cholestatic liver diseases. Moreover, existing therapies are often ineffective. Recent small, retrospective case series reports suggest that serotonin reuptake inhibitors can improve pruritus. This study was undertaken to establish the dose of sertraline and to evaluate its efficacy for cholestatic pruritus. Twenty one subjects with chronic pruritus due to liver disease (including primary biliary cirrhosis, primary sclerosing cholangitis, chronic hepatitis C, and postnecrotic cirrhosis) initially underwent an open‐label, dose escalation to determine the dose with optimal efficacy and tolerability. After a washout period, 12 of the subjects entered a randomized, double‐blind, placebo‐controlled trial. Participants quantified their pruritus using a 0‐10 visual analog scale, and pruritus was assessed for distribution, timing, degree of disability, and physical evidence of scratching. The optimum sertraline dose (75‐100 mg/day) was well tolerated. In the controlled portion of the study, itch scores improved in patients taking sertraline, but worsened in patients taking placebo (P = 0.009). Changes in itch distribution, duration, direction, and physical evidence of scratching paralleled changes in the visual analog pruritus score. Conclusion: Sertraline seems to be an effective, well‐tolerated treatment for pruritus due to chronic liver disease. These results suggest that serotonergic pathways are important in the perception of itch. (HEPATOLOGY 2007;45:666–674.)

The 5-D itch scale: a new measure of pruritus

Background  Itching is a subjective and multidimensional experience which is difficult to quantify. Most methodologies to assess itching suffer from being unidimensional, for example only measuring intensity without impact on quality of life, or only measuring scratching activity. None has actually been demonstrated to be able to detect change over time, which is essential to using them as an outcome measure of response to an intervention. The 5‐D itch scale was developed as a brief but multidimensional questionnaire designed to be useful as an outcome measure in clinical trials. The five dimensions are degree, duration, direction, disability and distribution.

Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay

Primary biliary cirrhosis (PBC) is sometimes diagnosed based on a positive antimitochondrial antibody in the appropriate clinical setting without a liver biopsy. Although a liver biopsy can assess the extent of liver fibrosis and provide prognostic information, serum fibrosis markers avoid biopsy complications and sampling error and provide results as a continuous variable, which may be more precise than categorical histological stages. The current study was undertaken to evaluate serum fibrosis markers as predictors of clinical progression in a large cohort of PBC patients. Serial liver biopsy specimens and serum samples were collected every 2 years in 161 PBC subjects for a median of 7.3 years. Clinical progression was defined as development of one or more of the following events: varices, variceal bleed, ascites, encephalopathy, liver transplantation, or liver‐related death. Serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and procollagen III aminopeptide were measured and entered into the previously validated enhanced liver fibrosis (ELF) algorithm. The ability of ELF, histological fibrosis, bilirubin, Model for End‐Stage Liver Disease (MELD), and Mayo Risk Score to differentiate between individuals who would experience a clinical event from those who would not was evaluated at different time points. Event‐free survival was significantly lower in those with high baseline ELF. Each 1‐point increase in ELF was associated with a threefold increase in future complications. The prognostic performance of all tests was similar when performed close to the time of the first event. However, at earlier times in the disease process (4 and 6 years before the first event), the prognostic performance of ELF was significantly better than MELD or Mayo R score. Conclusion: The ELF algorithm is a highly accurate noninvasive measure of PBC disease severity that provides useful long‐term prognostic information. (HEPATOLOGY 2008.)

Extrahepatic Manifestations of Hepatitis C Infection

Hepatitis C virus (HCV) affects 1.8% of the American population, and approximately 38% of patients with HCV will manifest symptoms of at least 1 extrahepatic manifestation during the illness. Renal disease, neuropathy, lymphoma, and Sjögren syndrome with or without mixed cryoglobulinemia are all strongly associated with HCV infection. Porphyria cutanea tarda and diabetes have also been linked to HCV. Most extrahepatic manifestations of chronic HCV infection are immunological, and the chronic infection seems to be necessary for their development. The molecular study of the unique way in which the HCV virus interacts with the human immune system is beginning to provide plausible explanations of the pathogenic role of HCV in some of these syndromes, but many pathogenetic links remain completely obscure.

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo‐controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwigs histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6‐8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;42:1184–1193.)

Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis

OBJECTIVES:Generalized pruritus is a common complication of cholestatic liver diseases, although its pathogenesis remains elusive. Current treatments are often inadequate and may be poorly tolerated, so the clinician is sometimes faced with a patient in misery and no good therapeutic options. Because, in our experience, several patients with primary biliary cirrhosis (PBC) claimed that sertraline had improved their pruritus, we sought to determine whether sertraline use was associated with changes in pruritus medications or self-reported severity of pruritus in a large cohort of patients with PBC.METHODS:The self-reported severity of pruritus was followed prospectively in 40 patients with PBC for a mean of 7.5 ± 1.3 yr. These data were then retrospectively examined to determine the effect of sertraline on pruritus in all subjects who had received sertraline at some time during the study.RESULTS:For 28 of 32 patients with pruritus, itching was stable or fluctuated slightly over the follow-up period. No patient experienced rapid progression of pruritus, and four patients experienced a sustained resolution of their pruritus. Ten subjects started sertraline and continued it long enough (>6 months) to determine its lasting effect on pruritus. Three of these individuals did not have significant pruritus before or after sertraline. Of the seven patients with pruritus, six (86%) recorded a significant reduction or resolution of pruritus in their weekly diaries and also decreased or completely stopped other medications for pruritus.CONCLUSIONS:Sertraline use is associated with an improvement in cholestatic pruritus. This novel observation implies that serotonergic fibers are important in regulating the perception of itch.

Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production.

The mechanisms mediating hepatic accumulation of inflammatory cells in cholestatic liver disease remain enigmatic. Our thesis is that Hedgehog (Hh) pathway activation promotes hepatic accumulation of immune cells that interact with cholangiocytes. We believe that myofibroblastic hepatic stellate cells (MF‐HSCs) release soluble Hh ligands that stimulate cholangiocytes to express chemokines that recruit mononuclear cell types with cognate receptors for these chemokines, thereby orchestrating a repair‐related mechanism for liver inflammation. To address this thesis, we used three experimental systems that allow the definition of Hh‐dependent mechanisms that induce phenotypic changes in cholangiocytes. First, cholangiocytes were cultured alone or in the presence of Hh‐producing MF‐HSCs in a transwell coculture system and/or treated with MF‐HSC–conditioned medium with or without Hh‐neutralizing antibodies. Changes in the cholangiocyte phenotype were then evaluated by microarray analysis, quantitative reverse‐transcriptase polymerase chain reaction (QRT‐PCR), and/or enzyme‐linked immunosorbent assay for chemokine (C‐X‐C) motif ligand 16 (Cxcl16). Bile duct ligation was chosen to model biliary fibrosis in mice with an overly active Hh pathway, control littermates, and healthy rats, and the gene profile was evaluated by QRT‐PCR in whole liver tissue. Second, a transwell chemotaxis assay was used to examine natural killer T (NKT) cell migration in response to cholangiocytes and particularly cholangiocyte‐derived Cxcl16. Finally, we studied liver samples from primary biliary cirrhosis patients and controls by QRT‐PCR to compare differences in the Hh pathway and Cxcl16. Co‐immunostaining of cytokeratin‐7 and Cxcl16 was then performed to localize the phenotypic source of Cxcl16. We found that MF‐HSCs release soluble Hh ligands that stimulate cholangiocytes to produce Cxcl16 and recruit NKT cells. Hh pathway activation during cholestatic liver injury also induces cholangiocyte expression of Cxcl16. Conclusion: During biliary injury, Hh pathway activation induces cholangiocyte production of chemokines that recruit NKT cells to portal tracts. (HEPATOLOGY 2009.)

Safety and utility of ERCP during pregnancy

BACKGROUND ERCP is an important diagnostic and therapeutic tool in patients with biliary and pancreatic disease. Its utility and safety during pregnancy is largely unknown because it is not often required and because its use has been only infrequently reported in the published literature. OBJECTIVE Our purpose was to report the clinical experience with ERCP during pregnancy. DESIGN Retrospective review, single academic center. PATIENTS All (consecutive) pregnant women who underwent ERCP at Parkland Memorial Hospital from 2000 to 2006. MAIN OUTCOME MEASUREMENTS History, clinical data, hospital course, procedure-related complication rates and outcomes, and delivery and fetal outcomes were abstracted from medical records. RESULTS During the study period, 68 ERCPs were performed on 65 pregnant women. The calculated ERCP rate was 1 per 1415 births. The common indications for ERCP in pregnancy were recurrent biliary colic, abnormal liver function tests, and dilated bile duct on US. ERCP was technically successful in all patients. The median fluoroscopy time was 1.45 minutes (range 0-7.2 minutes). There was no perforation, sedation-related adverse event, postsphincterotomy bleeding, cholangitis, or procedure-related maternal or fetal deaths. Post-ERCP pancreatitis was diagnosed in 11 patients (16%). None of these 11 patients had local or systemic complications. Fifty-nine patients had complete follow-up. Endoscopic therapy at the time of ERCP was undertaken in all patients. Furthermore, 9 patients (32.1%) underwent cholecystectomy in the first and second trimesters for either acute cholecystitis (6) or symptomatic gallstones (3). Term pregnancy was achieved in 53 patients (89.8%). Patients having ERCP in the first trimester had the lowest percentage of term pregnancy (73.3%) and the highest risk of preterm delivery (20.0%) and low-birth-weight newborns (21.4%). None of the 59 patients with long-term follow-up had spontaneous fetal loss, perinatal death, stillbirth, or fetal malformation. LIMITATION Retrospective review. CONCLUSIONS ERCP can be performed safely during pregnancy. Further, ERCP performed in pregnancy leads to specific therapy in essentially all patients. However, ERCP may be associated with a higher rate of post-ERCP pancreatitis than in the general population.

Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes was determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably 3 inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.