George F. Mells

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.

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10−8), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2 > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non–human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2 > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

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 UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis

The biochemical response to ursodeoxycholic acid (UDCA)—so‐called “treatment response”—strongly predicts long‐term outcome in primary biliary cholangitis (PBC). Several long‐term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long‐term prognostic models of PBC using data from the UK‐PBC Research Cohort. We performed Coxs proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA‐treated participants. We used nonautomatic backward selection to derive the best‐fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver‐related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA‐treated participants. The best‐fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5‐, 10‐, and 15‐year risk scores were highly accurate (areas under the curve: >0.90). Conclusions: The prognosis of PBC patients can be accurately evaluated using the UK‐PBC risk scores. They may be used to identify high‐risk patients for closer monitoring and second‐line therapies, as well as low‐risk patients who could potentially be followed up in primary care. (Hepatology 2016;63:930–950)

Novel insights into autoimmune liver diseases provided by genome-wide association studies

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify molecular targets for pharmacotherapy. Early genetic studies consisted of HLA association studies and non-HLA candidate gene association studies, designed to identify association with selected HLA or non-HLA loci. HLA association studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak associations detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide association studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clinical conditions. The specific genetic basis of these PBC and PSC associated inflammatory themes as determined by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors.

Reducing the risks of cardiovascular disease in liver allograft recipients.

Liver allograft recipients are at increased risk of death from cerebrovascular and cardiovascular disease. We propose the following strategy of risk-reduction, based on currently available literature. Lifestyle: standard advice should be given (avoidance of smoking, excess alcohol and obesity, adequate exercise, reduction of excess sodium intake). Hypertension: target blood pressure should be 140/90 mmHg or lower, but for those with diabetes or renal disease, 130/80 mmHg or lower. For patients without proteinuria, antihypertensive therapy should be initiated with a calcium channel blocker and for those with proteinuria, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker. If monotherapy fails to achieve adequate response, calcium channel blockers and ACE-inhibitors or angiotensin II receptor blockers should be combined. If hypertension remains uncontrolled, an alpha-blocker may be added. Consideration should be given to changing immunosuppression and avoiding use of calcineurin inhibitors. Diabetes: recipients should be regularly screened for diabetes. For patients with new-onset diabetes after transplant, stepwise therapy should be guided by HbA1c concentrations, as with type II diabetes mellitus. Hyperlipidemia: annual screening of lipid profile should be undertaken, with treatment thresholds and targets based on those advocated for the high risk general population. Dietary intervention is appropriate for all patients. A statin should be considered as the first line treatment to achieve specified targets. In patients receiving a calcineurin inhibitor, Pravastatin should be commenced at a dose of 10 mg/day. In patients receiving other forms of immunosuppression, pravastatin may be commenced at a dose of 20 mg/day. Liver tests should be monitored and patients warned to report myalgia. If monotherapy is inadequate, ezetimibe or a fibrate may be added. Consideration may be given to change in immunosuppression if combination lipid-lowering therapy proves inadequate.

Impact of primary biliary cirrhosis on perceived quality of life: The UK-PBC national study†‡§

Primary biliary cirrhosis (PBC) has a complex clinical phenotype, with debate about the extent and specificity of frequently described systemic symptoms such as fatigue. The aim of this study was to use a national patient cohort of 2,353 patients recruited from all clinical centers in the UK to explore the impact of disease on perceived life quality. Clinical data regarding diagnosis, therapy, and biochemical status were collected and have been reported previously. Detailed symptom phenotyping using recognized and validated symptom assessment tools including the PBC‐40 was also undertaken and is reported here. Perception of poor quality of life and impaired health status was common in PBC patients (35% and 46%, respectively) and more common than in an age‐matched and sex‐matched community control group (6% and 15%, P < 0.0001 for both). Fatigue and symptoms of social dysfunction were associated with impaired perceived quality of life using multivariate analysis. Fatigue was the symptom with the greatest impact. Depression was a significant factor, but appeared to be a manifestation of complex symptom burden rather than a primary event. Fatigue had its greatest impact on perceived quality of life when accompanied by symptoms of social dysfunction, suggesting that maintenance of social networks is critical for minimizing the impact of fatigue. Conclusion: The symptom burden in PBC, which is unrelated to disease severity or ursodeoxycholic acid response, is significant and complex and results in significant quality of life deficit. The complexity of symptom burden, and its lack of relation to disease severity and treatment response, suggest that specific approaches to symptom management are warranted that address both symptom biology and social impact. (Hepatology 2013;58:‐)

Late Protocol Liver Biopsies in the Liver Allograft: A Neglected Investigation?

As outcomes from liver transplantation have improved, attention has focused on long‐term outcomes: patient and graft survival is affected by many factors, including the consequences of both overimmunosuppression (eg, renal failure and cancer) and underimmunosuppression (eg, rejection). The use of protocol (rather than event‐driven) biopsies of the liver allograft, except for those grafted for HCV infection, has been largely abandoned. The aim of this study was to determine if protocol biopsies can improve the management of liver allograft recipients. A retrospective analysis of liver allograft recipients who had undergone protocol liver biopsies between 2000 and 2006 was performed. One hundred seventy‐eight patients with normal liver tests (alcoholic liver disease, 49; autoimmune hepatitis, 20; and primary biliary cirrhosis, 107) who had undergone 235 protocol biopsies were identified. No significant complication from the biopsy was recorded. Liver histology was reported as normal or nearly normal in only 57 (24%). Chronic hepatitis (not obviously related to disease recurrence) was present in 78 (33%). Interpreted in the light of the calculated creatinine clearance, the biopsy findings indicated that overall immunosuppression (IMS) should be maintained or increased with standard calcineurin inhibitor (CNI)–based IMS in 25% of cases, that overall IMS should be reduced in 15% of cases, and that overall IMS should be maintained or increased by the substitution of non‐nephrotoxic agents for CNIs in 9% of cases. The histological findings led to a documented change in IMS in 76 (32%) (increased IMS, 11; decreased IMS, 58; and switch from CNI, 7). In conclusion, protocol liver biopsy provides important histological information about graft function that is not available from standard liver tests and safely allows modification of IMS to ensure that long‐term side effects of drug therapy (eg, renal failure) are minimized while graft function is sustained. Liver Transpl 15:931–938, 2009.

Long-Term Care of the Liver Allograft Recipient

As outcomes after liver transplant surgery continue to improve, management of the long-term consequences of the procedure and the associated immunosuppression become increasingly important. Liver allograft recipients have, compared with age and sex-matched controls, increased risk for cardiovascular and cerebrovascular events and death, for bone disease, and for some cancers. Early recognition and treatment of modifiable risk factors, especially of hypertension (present in up to 77% recipients), diabetes (in up to 22%), obesity (up to 40%), renal impairment (in up to 50%), and hyperlipidemia (in up to 66%) are necessary to maintain prolonged and healthy survival. Early recognition of de novo cancers (which occur in up to 26% recipients) indicates the need for additional monitoring for skin cancer and lymphoproliferative disorders, as well as cancers of the lung, colon, and upper gastrointestinal track. Early recognition of bone disease and appropriate intervention will allow introduction of strategies to reduce bone fracture. In this article, we review the evidence for the extent and treatment of these modifiable conditions in the allograft recipient.

The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort

BACKGROUND & AIMS Liver transplantation improves survival in end-stage primary biliary cirrhosis (PBC), but the benefit for systemic symptoms including fatigue is less clear. The aim of this study was to utilise the comprehensive UK-PBC Research Cohort, including 380 post-transplant patients and 2300 non-transplanted patients, to answer key questions regarding transplantation for PBC. METHODS Cross-sectional study of post-transplant PBC patients and case-matched non-transplanted patients. Detailed clinical information was collected, together with patient systemic symptom impact data using validated assessment tools. RESULTS Over 25% of patients in the transplant cohort were grafted within 2 years of PBC diagnosis suggesting advanced disease at presentation. Transplanted patients were significantly younger at presentation than non-transplanted (mean 7 years) and >35% of all patients in the UK-PBC cohort who presented under 50 years had already undergone liver transplantation at the study censor point (>50% were treatment failures (post-transplant or unresponsive to UDCA)). Systemic symptom severity (fatigue and cognitive symptoms) was identical in female post-transplant patients and matched non-transplanted controls and unrelated to disease recurrence or immunosuppression type. In males, symptoms were worse in transplanted than in non-transplanted patients. CONCLUSIONS Age at presentation is a major risk factor for progression to transplant (as well as UDCA non-response) in PBC. Although both confirmatory longitudinal studies, and studies utilising objective as well as subjective measures of function, are needed if we are to address the question definitively, we found no evidence of improved systemic symptoms after liver transplantation in PBC and patients should be advised accordingly. Consideration needs to be given to enhancing rehabilitation approaches to improve function and life quality after liver transplant for PBC.