Muhammad F. Dawwas

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10−8) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid

UNLABELLED BACKGROUND, & AIMS: Studies of primary biliary cirrhosis (PBC) phenotypes largely have been performed using small and selected populations. Study size has precluded investigation of important disease subgroups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes. METHODS We performed a cross-sectional study using the United Kingdom-PBC, patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures). RESULTS Seventy-nine percent of the patients reported current UDCA, therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response rate; P < .05); male sex was an independent predictor of nonresponse on multivariate analysis. Age at diagnosis was associated strongly and independently with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than age 70, to less than 50% for those younger than age 30 (P < .0001). Patients who presented at younger ages also were significantly more likely not to respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than mens (P < .0001). The increase in fatigue severity in women was related strongly (r = 0.58; P < .0001) to higher levels of autonomic symptoms (P < .0001). CONCLUSIONS Among patients with PBC, response to UDCA, treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at younger than age 50. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.

The impact of serum sodium concentration on mortality after liver transplantation: A cohort multicenter study

Modification of the current allocation system for donor livers in the United States to incorporate recipient serum sodium concentration ([Na]) has recently been proposed. However, the impact of this parameter on posttransplantation mortality has not been previously examined in a large risk‐adjusted analysis. We assessed the effect of recipient [Na] on the survival of all adults with chronic liver disease who received a first single organ liver transplant in the UK and Ireland during the period March 1, 1994 to March 31, 2005 (n = 5,152) at 3 years, during the first 90 days, and beyond the first 90 days, adjusting for a wide range of recipient, donor, and graft characteristics. Compared to those with normal [Na] (135–145 meq/L; n = 3,066), severely hyponatremic recipients ([Na] <130 meq/L, n = 541), had a higher risk‐adjusted mortality at 3 years (hazard ratio [HR] 1.28; 95% confidence interval [CI], 1.04–1.59; P < 0.02). The excess mortality was, however, confined to the first 90 days (HR 1.55; 95% CI, 1.18–2.04; P < 0.002) with no significant difference thereafter. This was also true for hypernatremic recipients ([Na] >145 meq/L, n = 81), who had an even greater risk‐adjusted mortality compared to normonatremic recipients (overall: HR 1.85; 95% CI, 1.25–2.73; P < 0.002; ≤90 days: HR 2.29; 95% CI, 1.42–3.70; P < 0.001; >90 days: HR 1.12; 95% CI, 0.55–2.29; P = 0.8), whereas mildly hyponatremic recipients ([Na] 130–134 meq/L, n = 1,127) had similar risk‐adjusted mortality to those with normal [Na] at the same time points. In conclusion, recipient [Na] is an independent predictor of death following liver transplantation. Attempts to correct the [Na] toward the normal reference range are an important aspect of pretransplantation management. Liver Transpl 13:1115–1124, 2007.

The pattern of late mortality in liver transplant recipients in the United Kingdom.

Background. Late survival is not improving after liver transplantation. In this study, possible reasons for this were investigated. Methods. Mortality rates and causes of death were ascertained in 4483 adult primary liver allograft recipients surviving 1 year or more from engraftment, identified through the UK Transplant Database and transplanted between 1994 and 2007. Associations with death, cause of death, and retransplantation were assessed. Results. Mortality in those surviving beyond 1 year in UK liver transplant recipients was more than twice that expected in the general population and had not improved during the study period, independent of cause of liver disease, recipient age, recipient gender, and donor age. The major causes of death were malignancy (30.6%), multisystem failure (10.0%), infection (9.8%), cardiac disease (8.7%), and graft failure (9.8%). Associations with death after 1 year were pretransplant etiologies alcohol-related liver disease (hazard ratio [HR]=2.10), autoimmune hepatitis or cryptogenic (HR=1.68), hepatitis C virus (HR=2.51), and hepatocellular carcinoma (HR=4.19). Associations with retransplantation were recipient age (HR=0.95 per year), donor age (HR=1.02 per year), and hepatitis C virus (HR=2.04). Hepatocellular carcinoma and recipient age were associated with cancer-related death (odds ratio=1.87 and 1.02 per year). Recipient age was associated with cardiac death (odds ratio=1.06 per year). Conclusions. Strategies to reduce late mortality after liver transplantation are required. These may include prevention of disease recurrence, improved recipient selection, and addressing risk factors for death in late survivors of liver transplantation.

Survival after liver transplantation in the United Kingdom and Ireland compared with the United States

Background and objective: Surgical mortality in the US is widely perceived to be superior to that in the UK. However, previous comparisons of surgical outcome in the two countries have often failed to take sufficient account of case-mix or examine long-term outcome. The standardised nature of liver transplantation practice makes it uniquely placed for undertaking reliable international comparisons of surgical outcome. The objective of this study is to undertake a risk-adjusted disease-specific comparison of both short- and long-term survival of liver transplant recipients in the UK and Ireland with that in the US. Methods: A multicentre cohort study using two high quality national databases including all adults who underwent a first single organ liver transplant in the UK and Ireland (n = 5925) and the US (n = 41 866) between March 1994 and March 2005. The main outcome measures were post-transplant mortality during the first 90 days, 90 days to 1 year and beyond the first year, adjusted for recipient and donor characteristics. Results: Risk-adjusted mortality in the UK and Ireland was generally higher than in the US during the first 90 days (HR 1.17; 95% CI 1.07 to 1.29), both for patients transplanted for acute liver failure (HR 1.27; 95% CI 1.01 to 1.60) and those transplanted for chronic liver disease (HR 1.18; 95% CI 1.07 to 1.31). Between 90 days and 1 year post-transplantation, no statistically significant differences in overall risk-adjusted mortality were noted between the two cohorts. Survivors of the first post-transplant year in the UK and Ireland had lower overall risk-adjusted mortality than those transplanted in the US (HR 0.88; 95% CI 0.81 to 0.96). This difference was observed among patients transplanted for chronic liver disease (HR 0.88; 95% CI 0.81 to 0.96), but not those transplanted for acute liver failure (HR 1.02; 95% CI 0.70 to 1.50). Conclusions: Whilst risk-adjusted mortality is higher in the UK and Ireland during the first 90 days following liver transplantation, it is higher in the US among those liver transplant recipients who survived the first post-transplant year. Our results are consistent with the notion that the US has superior acute perioperative care whereas the UK appears to provide better quality chronic care following liver transplantation surgery.

Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease.

RATIONALE α1-Antitrypsin deficiency is one of the most common heritable human diseases, predisposing to liver and lung injury. Significant heterogeneity in phenotypic expression is well documented, but less is known of the prevalence, severity, and correlates of chronic liver disease among individuals presenting with lung disease. OBJECTIVES To determine the frequency of and risk factors for severe liver fibrosis and cirrhosis among individuals with PiZZ-related lung disease. METHODS A well-characterized cohort of 57 PiZZ adults attending a tertiary referral respiratory clinic was screened prospectively for clinical, laboratory, radiologic, and (when appropriate) histologic evidence of chronic liver disease. MEASUREMENTS AND MAIN RESULTS Thirty-six (63.2%) of 57 had a history or clinical findings suggestive of liver disease; or had one or more abnormalities of liver function, or liver ultrasound, and 24 of these underwent liver biopsy. Ten (17.5%) had evidence of severe fibrosis or cirrhosis and were more likely to have higher body mass index (P = 0.04), alanine transaminase (P = 0.0001), alkaline phosphatase (P = 0.0009), prothrombin time (P = 0.0005), and maximal vital capacity (VCmax) (P = 0.04); lower platelet count (P = 0.007); abnormal liver echogenicity (P < 0.001); and splenomegaly (P = 0.001) at ultrasound. Screening with liver ultrasound provided a sensitivity and negative predictive value for severe fibrosis or cirrhosis of 100%, as were the specificity and positive predictive value for platelet count less than or equal to 174,000 per mm(3) and splenomegaly. Among individuals undergoing liver biopsy, fibrosis stage correlated with increasing VCmax (P = 0.02) and % predicted VCmax (P = 0.05), and decreasing residual volume/total lung capacity (TLC) (P = 0.02) and % predicted residual volume/TLC (P = 0.05). CONCLUSIONS Significant chronic liver disease is common in PiZZ individuals with lung disease and can be screened effectively by a combination of conventional tests of liver function, platelet count, and liver ultrasound.

Adult orthotopic liver transplantation in the United Kingdom and Ireland between 1994 and 2005.

Background. The UK and Ireland Liver Transplant Audit collects information on all liver transplantations that are carried out in both countries. In this paper, we describe these transplantations and their outcomes in adult patients according to primary liver disease diagnosis, type of transplantation and period. Methods. A prospective cohort study of 7906 orthotopic liver transplantations carried out between April 1994 and June 2005 in the United Kingdom and Ireland. Multivariable logistic regression was used to investigate improvements in mortality according to period of transplantation adjusted for recipient and donor characteristics. Results. A total of 6,850 transplantations were done in adults (patients 16 years or older). Of these, 836 (12.2%) were first super-urgent procedures (33.7% men; median age 36 years), and 5,072 (74.0%) first elective procedures (60.0% men; median age 52 years). The percentage of patients who received a donor organ with abnormal appearance gradually increased, especially in patients receiving an elective transplant. Mortality at 90 days after first super-urgent transplant decreased from 29.6% (95% confidence interval: 23.5% to 36.9%) before October 1, 1996 to 16.0% (11.7% to 21.7%) after October 1, 2002. Considering the same time periods, mortality at 90 days after first elective transplant decreased from 10.6% (8.9% to 12.7%) to 7.7% (6.3% to 9.3%). Multivariable analysis demonstrated that these improvements cannot be explained by changes in the risk profile of recipients and donors. Conclusions. Patients undergoing a liver transplantation in the most recent years had a better survival than patients with similar characteristics transplanted 10 years earlier. Posttransplant survival has improved despite a deteriorating quality of donor organs.

The impact of serum potassium concentration on mortality after liver transplantation: a cohort multicenter study.

Background. Potassium plays a key role in human metabolism in both health and disease. The impact of recipient serum potassium concentration [K] on mortality after liver transplantation has not been described previously. Methods. We assessed the effect of recipient [K] on the survival of adult first single-organ liver transplant recipients in the United Kingdom and Ireland between March 1, 1994, and February 28, 2007 (n=5942), adjusting for recipient, donor, and graft characteristics. Results. The overall risk-adjusted mortality significantly varied by [K], being higher among hyperkalemic ([K]>5.0 mmol/L) recipients (n=424, hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.01–1.88) and those with [K] of 4.5–5.0 mmol/L (n=1154, HR 1.47, 95% CI 1.13–1.91), compared with hypokalemic ([K]<3.5 mmol/L) recipients (n=360). However, the excess mortality was confined to the first posttransplant year among hyperkalemic recipients (HR 1.61, 95% CI 1.10–2.35) with no significant difference thereafter (HR 1.03, 95% CI 0.62–1.73). This was also true for recipients with [K] of 4.5 to 5.0 mmol/L (≤1 year: HR 1.70, 95% CI 1.22–2.38; >1 year: HR 1.09, 95% CI 0.71–1.66). In contrast, those with [K] of 3.5 to 3.9 mmol/L (n=1518) and [K] of 4.0–4.4 mmol/L (n=2091) had similar risk-adjusted mortality at the above time points. When [K] was used as a continuous variable in the multivariable analysis, a mmol increase in [K] was associated with an increased adjusted risk of mortality of 27% (95% CI 12%–44%) at 1 year and 19% (95% CI 7%–31%) at 5 years. Conclusion. Recipient [K] is an independent predictor of death after liver transplantation. This finding could be of clinical utility in the management, risk stratification, selection, and prioritization of appropriate candidates for transplantation among patients with end-stage liver disease.

Developing a prognostic model for 90-day mortality after liver transplantation based on pretransplant recipient factors.

Background. Current statistical prognostic models for mortality after liver transplantation do not have good discriminatory ability. Furthermore, the methodology used to develop these models is often flawed. The objective of this paper is to develop a prognostic model for 90-day mortality after liver transplantation based on pretransplant recipient factors, employing a rigorous model development method. Methods. We used data on 4,829 patient that were prospectively collected for the UK & Ireland Liver Transplant Audit. Switching regression was employed to impute missing values combined with a bootstrapping approach for variable selection. Results. In all, 452 patients (9.4%) died within 90 days of their transplantation. The final prognostic model was well calibrated and discriminated moderately well between patients who did and who did not die (c-statistic 0.65, 95% CI [0.63, 0.68]). Although discrimination was not excellent overall, the results showed that those patients with a “low” chance of dying within 90 days of their transplant and those with a “high” chance of dying could be differentiated from patients with a “intermediate” chance. Conclusions. Our model can provide transplant candidates with predictions of their early posttransplantation prospects before any donor information is known, which is essential information for patients with end-stage liver disease for whom liver transplantation is a treatment option.

Endoscopic sphincterotomy for sphincter of oddi dysfunction: inefficacious therapy for a fictitious disease.

STAFF OF CONTRIBUTORS Joseph Anderson, White River Junction, VT Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Massimo Colombo, Milan, Italy Gregory A. Cote, Charleston, SC B. Joseph Elmunzer, Charleston, SC Alex Ford, Leeds, United Kingdom Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, San Francisco, CA Michelle Kang Kim, New York, NY W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Uma Mahadevan, San Francisco, CA Laurent Peyrin-Biroulet, Vandoeuvre-lès-Nancy, France Mark Pimentel, Los Angeles, CA Jesus Rivera-Nieves, San Diego, CA Joel H. Rubenstein, Ann Arbor, MI Sameer Saini, Ann Arbor, MI Ekihiro Seki, La Jolla, CA Shamita B. Shah, Stanford, CA Pratima Sharma, Ann Arbor, MI Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Akbar Waljee, Ann Arbor, MI Alastair J. M. Watson, Norwich, United Kingdom