The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines.
Gut
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.
10.1136/gutjnl-2017-315259
Novel therapeutic targets in primary biliary cirrhosis.
Dyson Jessica K,Hirschfield Gideon M,Adams David H,Beuers Ulrich,Mann Derek A,Lindor Keith D,Jones David E J
Nature reviews. Gastroenterology & hepatology
Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy-ursodeoxycholic acid (UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.
10.1038/nrgastro.2015.12
The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: results of a 9 year follow-up.
Jones David E,Al-Rifai Ahmad,Frith James,Patanwala Imran,Newton Julia L
Journal of hepatology
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.
10.1016/j.jhep.2010.05.026
The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice.
Al-Harthy Nadya,Kumagi Teru,Coltescu Catalina,Hirschfield Gideon M
Hepatology (Baltimore, Md.)
UNLABELLED:Quality of life is an important concern for patients with chronic liver disease. We sought to describe the frequency, severity, and associations of fatigue, in patients with primary biliary cirrhosis (PBC). We performed association testing between PBC-40 multidomain disease-specific quality of life responses and clinical findings. Three hundred twenty-seven patients from a single clinic with PBC (94% female, 92% AMA-positive) were evaluated. The average age was 57 years and average disease duration 7.2 years. Verbally reported fatigue was noted in 48% but present in the overwhelming majority on PBC-40 completion, with 44% having moderate or severe symptoms. Of those not complaining of fatigue clinically, 25% documented moderate or severe fatigue by questionnaire. Age had an inverse relationship with fatigue (P < 0.01), whereas body mass index (BMI) was positively associated (P < 0.01), as was the presence of pruritus (P < 0.001), sicca symptoms (P < 0.001), depression (P < 0.001), fibromyalgia (P < 0.004), and scleroderma (P < 0.05). For those with varices (P < 0.05) or cirrhosis clinically (P < 0.05), higher fatigue scores were noted, although those who initially presented with noncirrhotic disease had higher scores at the time of testing (P < 0.005). Fatigue was associated with greater use of prescription medication (P < 0.01), in particular for antipruritics (cholestyramine: P < 0.001; rifampin: P < 0.001), proton pump inhibitors (P < 0.002), beta-blockers (P < 0.02), and antidepressants (P < 0.001), whereas those taking calcium and vitamin D appeared less fatigued (P < 0.05). In a multivariate model, calcium and vitamin D use, BMI, stage of disease at diagnosis, as well as symptomatic fatigue or pruritus, were significant. Biochemical response to UDCA was not associated with lower fatigue scores. CONCLUSION:Attempts at defining the biological basis of fatigue in patients with PBC, and improving its treatment, must account for its multifactoral causes.
10.1002/hep.23683
The Impact of Autoimmune Hepatitis and Its Treatment on Health Utility.
Wong Lin Lee,Fisher Holly F,Stocken Deborah D,Rice Stephen,Khanna Amardeep,Heneghan Michael A,Oo Ye Htun,Mells George,Kendrick Stuart,Dyson Jessica Katharine,Jones David E J,
Hepatology (Baltimore, Md.)
Patient reporting suggests that the physical and psychological effects of autoimmune hepatitis (AIH) can be substantial. However, health-related quality of life (HRQOL) in patients with AIH remains incompletely characterized, and health utility remains to be explored. Treatment for AIH often includes the use of corticosteroids, which are agents that can be associated with significant adverse effects. Here we explore the impact of AIH and its treatments on patient-reported HRQOL and health utility in a large cohort of prevalent cases from the United Kingdom Autoimmune Hepatitis (UK-AIH) national study. Data were collected from 990 adult participants with a clinical diagnosis of AIH using validated HRQOL tools including the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) and clinical data forms. The EQ-5D-5L dimension scores were compared with UK population norms and with a disease control cohort with primary biliary cholangitis (PBC). Within the AIH cohort, regression analysis was used to explore associations between HRQOL and demographic and clinical variables with a particular focus on the impact of AIH therapies including corticosteroid use. HRQOL, measured by the EQ-5D-5L utility index, is shown to be significantly impaired in our cohort of AIH patients compared with population norms. Within the AIH cohort, corticosteroid use was found to be significantly associated with impaired HRQOL, even when controlling for biochemical disease activity status. CONCLUSION:Our data show evidence of HRQOL impairment in a large cohort of AIH patients compared with the general population. Furthermore, corticosteroid use is strongly associated with decreased HRQOL, independent of remission status. This highlights the need for better corticosteroid-free therapy approaches and it emphasizes the need for future novel therapeutic trials in AIH. (Hepatology 2018; 00:000-000).
10.1002/hep.30031
The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.
Carbone Marco,Bufton Sally,Monaco Andrea,Griffiths Laura,Jones David E,Neuberger James M
Journal of hepatology
BACKGROUND & AIMS:The role of liver transplantation (LT) for the relief of fatigue in patients with primary biliary cirrhosis (PBC) is unclear, and while many centers exclude fatigue as an indication for transplantation, there have been no studies to prospectively evaluate the impact of LT on fatigue. We aimed at assessing the severity of fatigue in LT candidates with PBC and the impact of LT on fatigue. METHODS:In a prospective, longitudinal study, we used the PBC-40 questionnaire in 49 adult patients with PBC at listing and at 6, 12, and 24 months after LT and in two sex- and age-matched cohorts of community controls and non-transplanted PBC patients. Correlation analysis was used to assess the relationship between liver function and fatigue. ANOVA was used to compare the variation of fatigue score before and after LT. RESULTS:There was no correlation between MELD and fatigue before LT (r(2)=0.01). Overall, the fatigue score after LT was substantially lower than before LT, falling from 40.7 ± 11.4 pre-transplant to 27.7 ± 9.5, 28.7 ± 10.1, 26.2 ± 10.1 (p<0.0001) at 6, 12, and 24 months after LT, respectively. The same improvement of fatigue was observed in both low-MELD (<17) and high-MELD (≥ 17) patients. Improvement in fatigue was also evident in the comparison with a "non-transplant PBC" control group (31.1 ± 11.6, p=0.03). However, 44% of the total cohort, and 47% of those with low-MELD, for whom the probability of dying of LT may be higher than that of dying without LT, had moderate to severe fatigue (defined as a fatigue score ≥ 29) at two years after LT. Moreover, fatigue scores at two years were higher in the transplant PBC cohort compared to a cohort of community controls (17.8 ± 5.9, p<0.0001). CONCLUSIONS:Liver transplantation is associated with improvement in fatigue in patients with PBC. However, a substantial proportion of patients continue to suffer from significant fatigue after two years. Whether the improvement is enough to justify organ allocation in patients with fatigue alone, without liver failure, is still an open issue. Certainly, in the era of organ shortage, with many patients dying waiting for a graft, this may not represent the optimal use of donated deceased organs.
10.1016/j.jhep.2013.04.017
Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
Mells George F,Pells Greta,Newton Julia L,Bathgate Andrew J,Burroughs Andrew K,Heneghan Michael A,Neuberger James M,Day Darren B,Ducker Samantha J,Sandford Richard N,Alexander Graeme J,Jones David E J,
Hepatology (Baltimore, Md.)
UNLABELLED: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.
10.1002/hep.26365