Imran Patanwala

The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: Results of a 9 year follow-up

BACKGROUND & AIMS Long-term outcome in primary biliary cirrhosis (PBC) remains unclear. Whilst response to ursodeoxycholic acid (UDCA) is associated with good outcome, this effect is not universal. Early data from our group have suggested that one factor associated with a poorer outcome in PBC is fatigue. The aim of this study was to explore the inter-relationship between UDCA use, response, and fatigue in determining outcome over 9 years in a unique, comprehensive patient cohort. METHODS Longitudinal prospective study of a geographically-defined complete cohort of PBC patients in North-East England and matched community controls. RESULTS Survival to death or transplant was significantly lower in PBC patients than in the case-control population (88/136 (65%) v 114/136 84% (p<0.001 by log-rank test), with better survival in UDCA responders (defined using the Paris criteria) than in patients not treated with UDCA at study outset. Compared to the whole control group survival was reduced in PBC patients fatigued at study outset but not in those without fatigue (p<0.0001); an effect independent of the beneficial effect of UDCA response and of conventional parameters of liver disease severity. UDCA responders without fatigue at the study outset had a 9 year survival which was identical to controls. Patients without fatigue at the study outset who developed fatigue during follow-up had significantly worse survival than patients who remained without fatigue throughout (p<0.05). Fatigued controls had worse survival than non-fatigued controls (p = 0.05). CONCLUSIONS Survival in a comprehensive cohort of PBC patients is substantially reduced compared with case-matched community controls. Development of fatigue and non-treatment with UDCA were specifically (and independently) associated with increased risk of death in PBC.

Folic acid handling by the human gut: implications for food fortification and supplementation

Background: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply. Objective: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa. Design: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope–labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein. Results: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose). Conclusions: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid. This trial was registered at clinicaltrials.gov as NCT02135393.

A validated clinical tool for the prediction of varices in PBC: The Newcastle Varices in PBC Score

BACKGROUND & AIMS Gastro-oesophageal varices (GOV) can occur in early stage primary biliary cirrhosis (PBC), making it difficult to identify the appropriate time to begin screening with oesophageo-gastro-duodenoscopy (OGD). Our aim was to develop and validate a clinical tool to predict the probability of finding GOV in PBC patients. METHODS A cross-sectional retrospective study analysing clinical data of 330 PBC patients who underwent an OGD at the Freeman Hospital, Newcastle was used to create a predictive tool, the Newcastle Varices in PBC (NVP) Score, that was externally validated in PBC patients from Cambridge (UK) and Toronto (Canada). RESULTS 48% of the Newcastle, 31% of the Cambridge, and 22% of the Toronto cohorts of PBC patients had GOV. Twenty-five percent (95% CI 18-32%) of the Newcastle cohort had GOV diagnosed at an index variceal bleed. Of the others, 37% (95% CI 28-46%) bled after a median of 1.5 years (IQR 3.75). Transplant-free survival was significantly better in those without GOV than in those with GOV (p<0.001), but similar in patients with GOV that bled and those that did not (p=0.1). The NVP score (%Probability)=1/[1+exp^-(9.186+0.001*alkaline phosphatase in IU-0.178*albumin in g/L-0.015*platelet × 10(9)) was validated in 2 external cohorts and was highly discriminant (AUROC 0.86). Cost consequences analyses revealed the NVP score to be as accurate as, but more economical than using either OGD directly or other risk scores for screening PBC patients. CONCLUSIONS The NVP score is an inexpensive, non-invasive, externally validated tool that accurately predicts GOV in PBC.

The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Comparison of the PBC-40 and PBC-27 tools for quality of life assessment in english speaking primary biliary cirrhosis patients

Introduction The PBC-40 is a patient-derived, disease-specific, quality of life (QOL) measure for Primary Biliary Cirrhosis (PBC). It is the only QOL measure developed using optimal methods in liver disease, that has proven to be of real value in the study of the pathogenesis of important symptoms in PBC, in increasing our understanding of patient experience and as an outcome measure in clinical trials. Derived in an English speaking population it had not, until a recent validation study in Italian and Japanese language groups, been validated in other languages. This study re-examined domain structure using the original PBC-40 items, and proposed an abbreviated form consisting of 27 of the original 40 items with a modification in the domain structure. Methods To evaluate the English version of the PBC-27 in comparison with the original PBC-40 in a randomly selected group of PBC patients (n=40) and utilising novel versions of both measures developed as experimental tools for use in age and sex matched normal subjects (n=40). Results The experimental normal subject versions of the PBC-40 and PBC-27 both proved psychometrically robust and were acceptable to control subjects. Unsurprisingly both measures were highly discriminatory between PBC patients and controls for all symptom domains, confirming the utility of both measures for the assessment of QOL in PBC patients. When comparing the discriminatory ability of the two measures between the PBC and control populations, the PBC-40 outperformed the PBC 27 with regards to fatigue (auc 0.8 (0.69–0.91), p<0.0001 vs 0.78 (0.66–0.9), p<0.0001) and cognition assessment (0.74 (0.63–0.86), p=0.0001 vs 0.70 (0.57–0.84), p<0.005) as well as other symptoms domain compared with the combined symptoms and dryness domains of the PBC-27. In contrast, both measures performed equally in discriminating between patients and controls with regard to the social and emotional domains (although in the former instance the PBC-27 was unduly reliant on a single item relating to holiday). In this population there was no difference in completion rates and acceptability between the shorter and the longer measures. Conclusion The PBC-27 is valid for use in English-speaking populations and is highly effective at quantifying symptoms in English-speaking PBC patients. Any advantages associated with compliance and usability for a shorter measure are, however, outweighed by lowered sensitivity for cognitive and fatigue symptom severity (the two domains with the greatest impact). When compared to the PBC-40 the optimum measure may be a hybrid containing the fatigue and cognitive domains of the PBC 40 and the shortened social domain of the PBC 27.

Hepatology training in the UK

Objectives To establish the perceived adequacy of the hepatology training component of the unified gastroenterology and hepatology training programme in the UK by assessing the attitudes and experiences of trainees in the programme. Design and intervention Online cross-sectional questionnaire survey linked to the annual British Society of Gastroenterology/Trainee in Gastroenterology survey in 2010. Setting and participants National survey of all specialist gastroenterology trainees in the UK. Results 283/489 (58%) trainees responded, 68% were male. 54% of all trainees wanted to deliver liver services as consultants. 25% of trainees complete training without exposure to a liver unit providing comprehensive specialist hepatology services. Median time spent in such a unit for the others was 8 months (IQR 6). Significantly fewer trainees lacked confidence in managing liver-related conditions if they had spent time training in a specialist liver unit and with increasing years in training. One in three trainees is dissuaded from a career in hepatology. One in five trainees wished to work part time as consultants—an option preferred significantly more by women. Conclusions Hepatology training in the UK is perceived by trainees as being suboptimal. A national strategy aimed at improving and standardising hepatology training and making specialist liver unit experience available for every trainee is required.

P20 Functional capacity is significantly impaired in primary biliary cirrhosis and related to orthostatic symptoms

Introduction Primary biliary cirrhosis (PBC) is associated with a significant and diverse symptom burden independent of conventional markers of disease severity. It is unclear how this symptom load impacts upon function in day to day living and, if functional impairment is present, which symptom(s) are predominantly responsible. Aim We assessed patient-reported functional ability and its inter-relationship with symptoms in PBC. Method 81% (75/93) of the PBC symptom study cohort, originally derived in 2005, consisting of all PBC patients resident within the geographical area defined by zip codes NE1-NE25 (Newcastle-upon-Tyne and surrounding suburbs) completed a further set of postal-return symptom assessment tools in 2009. This included the disease specific symptom assessment tool the PBC-40, a marker of autonomic symptom burden, the Orthostatic Grading Scale (OGS), and the patient reported outcome measure health assessment questionnaires (PROMIS HAQ), that assesses functional ability (which was also completed by a liver disease control group (primary sclerosing cholangitis n=31 (PSC) and matched controls (n=55)). Results Over 4 yrs of follow-up, total symptom burden, assessed using the cumulative PBC-40 domain scores, increased significantly (p=0.03). The predominant factor was a significant rise in Cognitive domain scores indicating worsening cognitive symptoms (p<0.0001). Functional impairment (PROMIS HAQ) was substantial in the PBC patients and exceeded that seen in the PSC controls. When the individual functional domains of the PROMIS HAQ were considered, we found that the PBC group had significant impairment in arising, eating, walking, reach and grip activity but not in dressing or hygiene. Functional impairment correlated positively with greater PBC-40 Fatigue, Cognitive and Social & Emotional domain scores and higher autonomic symptom burden determined by OGS score. Change in the PBC-40 Cognitive and Social & Emotional domain scores between 2005 and 2009 strongly predicted functional ability in 2009 Multivariate analysis confirmed that total PROMIS HAQ scores were predicted independently by PBC-40 Social & Emotional domain scores (p=0.02; β=0.3) and orthostatic symptoms (p=0.04; β=0.3). Conclusion PBC is associated with a substantial impairment of functional capacity to a greater degree than has previously been appreciated. The distribution of symptoms of PBC evolves over time, with cognitive symptoms making an ever-greater contribution to the overall burden. The major determinant responsible for both functional impairment and the specific symptoms contributing to it appears to be autonomic dysfunction which is potentially modifiable by treatment.

Corrigendum to “The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: Results of a 9 year cohort follow-up” J. Hepatol. 2010 Nov; 53(5):911–917

Corrigendum to ‘‘The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: Results of a 9 year cohort follow-up’’ J. Hepatol. 2010 Nov; 53(5):911–917 David E. Jones1,⇑, Ahmad Al-Rifai, James Frith, Imran Patanwala, Julia L. Newton Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK; Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, UK

P36 Morbidity and mortality associated with varices in patients with primary biliary cirrhosis

Introduction Several studies have shown that gastro-oesophageal varices (GOV) are relatively common in patients with PBC, and can occur in pre-cirrhotic and asymptomatic patients as well as in patients with advanced disease. An important practical problem faced by clinicians managing PBC patients with GOV is the approach to their long-term management especially, defining the appropriate timing for referral for liver transplantation. Aim To address the clinical impact of varices on morbidity and mortality in PBC in a large, long-term follow-up cohort of patients. Method A retrospective study was designed to identify all PBC patients had had endoscopy (OGD) at the Freeman Hospital, Newcastle for any clinical indication. PBC patients with and without GOV at OGD were characterised by extensive review of their clinical records. Data obtained included survival and transplantation history. The log rank test was used to compare transplant free survival between groups. Results 330 PBC patients (91.5% female, median age 64 yrs) were identified as ever having had an OGD at the Freeman Hospital. 159 [48% (95% CI 43% to 54%)] were found to have GOV. Subgroups with and without GOV were equivalent in terms of age, sex and time to endoscopy (Abstract P36 table 1). 39 (25%, 95% CI 18% to 32%) patients had GOV diagnosed at OGD performed at the time of their index bleed. In total, 83 (52%, 95% CI 44% to 60%) patients suffered 245 episodes of variceal bleeding during a median follow-up of 11 yrs (IQR 8). Of the 120 that did not present with a bleed 44 (37%, 95% CI 28% to 46%) bled a median of 1.5 yrs (IQR 3.75) after varices had been diagnosed In patients with varices that bled, there was no significant difference in the proportion that were on non-selective β blockers as compared with those that did not receive/tolerate these agents (48% vs 52%, p=0.75 Fishers exact test). Unfortunately, data on the physiological adequacy of β blockade was not available. Importantly, 21 (13%, 95% CI 8% to 19%) PBC patients with varices had early stage (Scheuer Stage I, I-II, II) disease, and of these 3 (14%, 95% CI 3% to 36%) presented with a variceal bleed as the first presentation of their varices and a further 5 (24%, 95% CI 8% to 47%) bled during follow-up. Transplant free survival after diagnosis of PBC was significantly better in those without varices when compared to those with varices (p<0.001). There was no significant difference in survival in patients with varices that bled and those that did not (p=0.1) (Abstract P36 figure 1).Abstract P36 Table 1 Baselines demographics of the PBC patients with and without varices Varices (N=159) No varices (N=171) p Value Median age endoscopy (IQR) 64 yr (13) 64 yr (15) 0.394 Females (%) 90% 93% 0.173 Median time lag of OGD from PBC diagnosis (IQR) 4 yr (5) 5 yr (17) 0.952Abstract P36 Figure 1 Kaplan–Meier curves comparing transplant free survival of PBC patients (A). with and without varices and (B). varices that bled vs varices that did not. Conclusion The development of GOV heralds a poor prognostic outlook for patients with PBC. Bleeding from these GOV does not further worsen survival in these patients and therefore prophylaxis against bleeding may not offer a survival advantage in these patients, who should be considered early for transplantation. The apparent importance of GOV in terms of prognosis, and decision making to optimise outcome means that we should re-look at strategies to screen for GOV in PBC.

P01 UDCA response criteria identify a sub-group of PBC patients with an inherently good prognosis rather than a specific disease response

Introduction Recent follow-up cohort studies have identified biochemical parameters in UDCA-treated patients which identify “responders” with survival identical to normal control populations, in contrast to “non-responders” who have survival indistinguishable from that predicted by the Mayo Risk Score for untreated patients. The most widely accepted criteria for UDCA “response”, proposed by Corpechot, consist of alkaline phosphatase (ALP) <3× uln, alanine transaminase (ALT) <2× uln and bilirubin <1× uln. However, Bilirubin and ALP levels are independent predictors of outcome in PBC irrespective of UDCA treatment. ALT, in addition, is a biomarker for overlap syndrome, a prognostic feature itself. Aim UDCA response criteria identify a group of patients with an inherently low risk rather than UDCA response per se. Method In a comprehensive cohort of patients, geographically defined in 1999 followed up for 10 years, a group of patients (n=94) not treated with UDCA were identified. This cohort, matched prospectively to individual community case controls, represents an opportunity to study the natural history of non-UDCA treated PBC. Results In the whole cohort (including UDCA treated patients), survival was significantly better in the UDCA-responding patients (defined using the Corpechot criteria) than in the non-UDCA-treated patients (p<0.05 log-rank test) although as in other studies survival was not the same as in age and sex match controls (p<0.05). Of the 94 non-UDCA receiving patients, 80 and 14 had, after 1 year of follow-up, biological features which, if they had received UDCA, would have been compatible with UDCA-response and UDCA-non response, respectively. Un-transplanted survival was significantly better in the non-UDCA patients meeting response criteria (58/80 (72%) at 10 years follow-up) than in non-UDCA treated patients meeting non-response criteria (5/14 (36%), p=0.01; χ2 9.4, p<0.01 log-rank test). The magnitude of this effect was similar to that associated with UDCA response in other series. The absence of UDCA treatment precludes, of course, this being a phenomenon of actual UDCA response. Conclusion UDCA response criteria identify a group of patients who, at the time of criterion measurement, have a good prognosis. It does not appear to matter whether attainment of these parameters is a natural feature of untreated disease or a consequence of treatment. These criteria therefore have an important role in identifying high and low risk patients, and a sub-group of PBC patients with poor prognosis for whom additional therapies should be sought. They do not, however, provide specific information about the actions of UDCA.