Guidelines Development Group (GDG)

The Guidelines Development Group (which met twice in person and regularly by email) had a broad constitution. All members declared their conflicts of interest to the BSG prior to guideline writing. Consensus was reached for therapeutic guidance where perceived conflicts were possible. Feedback was received from the British Liver Trust, LIVErNORTH, Royal College of General Practitioners, Nurse Representation (Sam Ducker) and the British Association for the Study of the Liver, as well as the Liver Section of the BSG. In addition to this, draft guidelines were posted on the UK-PBC website for a time limited period for open comment.

These guidelines have been produced using a systematic review of publications identified using PubMed, Medline and Cochrane database searches in line with the Appraisal of Guidelines Research & Evaluation (AGREE) instrument II (www.agreetrust.org). The primary keywords for baseline searches (completed in June 2017) were ‘primary biliary cirrhosis’, ‘primary biliary cholangitis’ and ’autoimmune overlap syndrome’. Additional keywords were included for specific searches such as ‘therapy’ and ‘ursodeoxycholic acid’.

Evidence levels (as per Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system)

The recommendations are based on the GRADE classification system (Strong/Weak; quality of evidence: High/Moderate/Low/Very low).

GRADE classifies recommendations as strong or weak. Strength of recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, quality of evidence, variability in values and preferences, and resource use. The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a weak recommendation is warranted. The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted. The more values and preferences vary, or the greater the uncertainty in values and preferences, the higher the likelihood that a weak recommendation is warranted. The higher the costs of an intervention—that is, the greater the resources consumed—the lower the likelihood that a strong recommendation is warranted. Strong recommendations mean that most informed patients would choose the recommended management and that clinicians can structure their interactions with patients accordingly. Weak recommendations mean that patients’ choices will vary according to their values and preferences, and clinicians must ensure that patients’ care is in keeping with their values and preferences.

Epidemiology

The epidemiology of PBC has been studied extensively.19 PBC meets the criteria for rare disease status (prevalence <50/100 000) in all populations studied.20 Data from the largest UK study, in the north-east of England, suggest a prevalence of definite or probable disease of 35/100 000, with an annual incidence of 2–3/100 000.21 22 Comparison with other Northern European and North American cohorts suggest these rates are broadly typical.23–30 Reported prevalence appears stable following several years of increase. This may reflect a now fully evolved change in diagnostic activity and practice linked to increased awareness of the disease.

PBC prevalence is asymmetrical within the population with markedly higher rates being seen in women than men (the difference is 10-fold).19 UK data suggest that PBC is diagnosed at a later stage in men, potentially reflecting perception bias among clinicians.12 PBC is also typically a disease of older patients with the median age at diagnosis being 65 years. The dual effects of age and sex mean that PBC can reach a prevalence of as high as 1 in 800 in women over the age of 45 years. PBC is yet to be reliably diagnosed pre-menarche (youngest report is of a girl aged 15 years).31 There are potentially important differences in the clinical expression of PBC between men and women and between older and younger patients, although the basic approach to management is the same in all demographic groups.12 The impact of ethnicity on presentation is not well described, but there are reports internationally of how ethnicity affects the presentation of autoimmune liver disease, and clinicians should be aware that classical descriptions of disease are frequently derived from Caucasian-only populations.32–36

Familial PBC is clearly recognised, with familial rates similar to those seen in other autoimmune conditions. The reported sibling relative risk for PBC is 10.37 The relative risk for familial disease is greatest, at 35, for the daughters of mothers with PBC, reflecting in part the disease demographics. Patients with PBC typically have an increased incidence, in both themselves and their families, of other autoimmune diseases (over half of patients with PBC have another autoimmune condition), reflecting shared genetic predisposition (most notably but not exclusively celiac disease, scleroderma, thyroid disease and Sjögren’s).37–43

Aetiology

PBC is an immune-mediated biliary injury. Evidence supports the interaction of immunogenetic and environmental factors in the aetiology of PBC.3 The presence of genetic susceptibility is supported by the increased concordance rate in monozygotic twins44 and confirmed by the identification of significant numbers of associated genetic loci in Genome Wide Association Studies (GWAS) and other large-scale, high-quality genetic approaches.45–54 Identified genetic associations mirror the pattern and nature seen in autoimmune diseases with the combination of a significant number of genetic associations with low OR for risk, typically in genes regulating the magnitude and nature of the immune response.55 Study of the genetic basis of PBC remains a research tool and has, as yet, had no impact on clinical practice.56 The existence of disease clustering points to environmental triggers, and research has supported both infectious and chemical triggers.22 28 57–61 Case–control study approaches, which explore risk history in patients and matched controls, have confirmed cigarette smoking and recurrent urinary tract infections (UTIs) as being strongly associated with PBC; cholestasis and/or pruritus during prior pregnancy is also associated with future diagnosis of PBC.40 42 43 62 Other identified (but not confirmed) associations include hair dyeing and perming.63 At present there is no consensus as to causality of any environmental association, and the science relating to disease triggering is again a research tool with no immediate clinical relevance in terms of disease prevention in at-risk individuals. It is relevant to document smoking history, recurrent UTIs and pregnancy-related cholestasis; additionally, smoking is associated with more advanced disease at presentation, and guidance regarding cessation is appropriate.

Modes and routes of presentation

Increased awareness of the serological associations of PBC and the widespread use of blood test-based screening in the community has led to an evolution of the mode of presentation of PBC in recent years, away from presentation with clinically overt disease (eg, advanced liver disease)64 towards presentation following identification of liver biochemical abnormality on screening65(figure 1). Increasing awareness of PBC as a cause of chronic fatigue and pruritus may have led to an increase in diagnosis following symptomatic presentation. Given the efficacy of UDCA treatment in slowing disease progression, it makes sense that early diagnosis may facilitate better outcomes. Treatment failure is seen more commonly in those presenting with cirrhosis and in the ductopenic variant of PBC. Despite awareness of PBC and its target demographic, occasional patients still present with very advanced disease at the point of needing liver transplantation.

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Figure 1

The BSG/UK-PBC consensus care pathway for patients with primary biliary cholangitis (PBC). While care needs always to be personalised to the patient, there are consensus pathways that are important for patients with PBC, which encompass the important ‘pillars’ of care that are believed to provide optimal management of disease and its complications.

Blood tests

The diagnostic accuracy of the combination of cholestatic serum liver tests and PBC-specific serological markers (>95% for both sensitivity and specificity) means that blood tests lie at the heart of PBC diagnosis.10

Imaging

The role of imaging in the diagnosis of PBC is largely to exclude alternative diagnoses, particularly biliary and infiltrative disease, such that for the vast majority a screening ultrasound suffices. Particular attention to exclusion of primary sclerosing cholangitis (PSC) and its mimics by magnetic resonance cholangiopancreatography (MRCP) is warranted for seronegative patients. Gallstones are a frequent finding in patients with PBC and are typically clinically silent. The over-interpretation of the presence of gallstones in patients of the typical PBC demographic, with the failure to consider PBC as the underlying diagnosis, is a potential reason for delayed diagnosis of PBC. MRCP is typically normal in patients with PBC. Enlargement of the peri-portal lymph nodes is common in PBC (and liver disease generally) and can cause concern about the possible presence of malignancy. Biopsy of such nodes typically shows the presence of reactive/inflammatory changes and the enlargement is thought to be part of the underlying disease process in PBC. Clinical judgement should be used as to whether the rare concern about the possibility of haematological or other forms of malignant disease is sufficient to warrant biopsy exclusion on a case-by-case basis. In end-stage PBC, imaging to screen for the complications of cirrhosis should be routine as for cirrhosis of other aetiology.

Histological features of PBC

Histopathological evaluation of liver biopsy tissue in PBC can be challenging and interpretation of histological findings needs to be correlated with clinical and immunological features, given the frequent patchy nature of PBC throughout the liver as well as the importance of recognising that, in early stage disease, characteristic features may be absent. As with all liver biopsy interpretation, but notably in the context of biliary disease, adequate biopsy size is essential. The adequacy of any biopsy is of course related to the clinical question, but broadly a liver biopsy should be of large enough size to view a representative amount of parenchyma and number of portal tracts (proposed to be more than 11).92 Hallmarks of PBC include destructive granulomatous lymphocytic cholangitis affecting interlobular and septal bile ducts leading to progressive bile duct loss, chronic cholestasis, fibrosis and cirrhosis. Other features that are seen include lymphocytic interface activity, parenchymal necro-inflammation and nodular regenerative hyperplasia.93 94 The significance of features such as interface hepatitis is best interpreted through joint clinicopathological discussion. While historically staging of liver disease with biopsy was frequently undertaken, increasingly it is recognised that risk stratification is more relevant to clinical practice, and staging of disease (as is required to determine the need for surveillance of cirrhotic complications) can usually be adequately evaluated non-invasively. Nevertheless, in those for whom biopsy is indicated either because of clinical trial entry or because of concern over diagnosis and/or presence of overlap features, histological stage, presence of ductopenia (>50% bile duct loss) and severity of lymphocytic interface activity are significant predictors of fibrosis progression.18 95 96

Role of liver biopsy and other staging investigations

Liver biopsy for the diagnosis of PBC in cases with clear cut autoantibody reactivity and cholestatic liver biochemistry is not recommended as it does not add to the diagnostic accuracy.10 It is also not uncommon to see areas of non-involved liver within even cirrhotic liver which, if sampled at biopsy, can confound diagnosis.97 Moreover, the yield for diagnostic lesions characteristic of PBC falls to less than 50% in early disease (ie, false-negative biopsies are likely in very early stage disease).98 Liver tissue abnormality in PBC can be highly patchy in nature, with reports of all disease stages from 1 to 4 (cirrhosis) being found in the same explanted organ at liver transplantation.99 For these reasons, staging biopsy to determine disease progression and establish or exclude the presence of cirrhosis is also not recommended routinely. The existing concept of AIH overlap disease which potentially may benefit from corticosteroid therapy, and the emerging concept of high-risk disease with a low level of response to UDCA and the concomitant need for second-line therapy, mean that liver biopsy may have a value in disease stratification and selection of appropriate additional or second-line therapy in PBC. The precise value and timing of prognostic liver biopsy in PBC remains to be established, as does the role of specific pathological scoring systems. A brief discussion of histological scoring systems100–104 which have been used in PBC is included in the legend to figure 2.

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Figure 2

The histopathology of PBC classical staging systems for PBC divide the histological injury of PBC into four stages: florid duct lesions and portal inflammation without interface activity (stage 1), interface hepatitis, ductular proliferation and periportal fibrosis (stage 2), bridging necrosis or bridging fibrosis (stage 3), and cirrhosis (stage 4).93 These systems are easy to apply and are quite reproducible. However, their practical utility is limited because of the uneven distribution of diagnostic histological lesions of PBC and different disease stages co-existing at any time.93 Furthermore, they incorporate features such as inflammation, which are more appropriately regarded as a manifestation of disease activity (histological ‘grade’) rather than disease progression (histological ‘stage’). A more recent scoring system described by Nakanuma and colleagues sums up individual scores for fibrosis, bile duct loss and severity of chronic cholestasis based on copper-associated protein deposition to assess disease stage and provides a separate system for grading necroinflammatory activity based on cholangitic and hepatitic features.100 Similar to the classical staging systems, the Nakanuma staging system correlates well with clinical and laboratory features. Subsequent studies have suggested that the Nakanuma system is more useful than previously described staging systems in predicting adverse outcomes in patients with PBC101 102 and may also be helpful in predicting treatment responses.79 Another recently described histological scoring system for PBC based on prognostically significant lesions (ie, fibrosis, bile duct loss and lymphocytic interface hepatitis) showed better interobserver agreement and correlation with biochemical abnormalities than traditional scoring systems, but predictive value for adverse outcomes could not be assessed.103 Problems with sampling variability apply to all of the histological staging systems that have been described for patients with PBC, which limits the utility of liver biopsy to assess disease severity in routine clinical practice, but they may still have a role in the context of clinical trials where liver biopsies have been used for risk stratification and as a surrogate marker of treatment outcomes. (A) Early PBC is characterised mainly by portal lesions and mild necroinflammatory changes in the acini. Portal tracts may show cholangiocentric granulomatous inflammation composed of lymphocytes, occasionally numerous plasmacytes, and polymorphs including eosinophils. Lymphoid follicles with germinal centres may form. The lymphoid inflammatory infiltrate extends to the biliary epithelium (cholangitis) (arrow), disrupting the basement membrane sometimes leading to bile duct destruction (florid duct lesion). Granulomas, ranging from small collections of histiocytes to easily discerned non-caseating epithelioid granulomas, may be present in portal tracts near damaged bile ducts and less often in the acini. In the progressive lesion of PBC, lymphocytic interface hepatitis may predominate blurring the portal tract boundary and extending into the acinus (arrowheads). Ductular proliferation at the portal-parenchymal interface may be prominent with associated stromal oedema and neutrophilic inflammation. Parenchymal necroinflammatory activity and hepatocellular injury are usually mild. Small and large cell change and hepatocellular regeneration may be seen (H&E, x20). (B) Keratin 7 immunostaining highlights loss of bile ducts (arrowhead indicates a keratin 7-positive bile duct epithelial remnant) leading to chronic cholestasis with features of feathery degeneration, Mallory-Denk bodies, copper-associated protein deposition in periportal/periseptal hepatocytes (cholate stasis), cholestatic rosettes and biliary metaplasia of hepatocytes (arrow) (keratin 7 immunostain, DAB chromagen, x10). (C) Loss of canals of Hering in acinar zone 1 (arrowheads) detected by keratin 19 immunostaining has recently been proposed as an early feature of PBC in the absence of the classic destructive biliary lesions.104 Focal intraepithelial inflammation (cholangitis) is noted in the K19-positive interlobular bile duct (arrow) (keratin 19 immunostain, DAB chromagen, x20).

Both enhanced liver fibrosis (ELF)105 and transient elastography (TE)106 107 (eg, FibroScan) have, in cross-sectional studies, shown accuracy in determining disease stage as confirmed by biopsy. There are no data, at the individual patient level, regarding change in these parameters with time and their relationship to change in the disease characteristics. While their use is increasing in clinical practice because of access to ELF testing and/or TE machines, their optimal use is currently a research question and the findings are not, in routine practice, as yet linked into paradigms for location and intensity of patient follow-up. Systematic evaluation of these approaches, together with recently described laboratory parameter-based scoring formulae,108 109 in identifying high- and low-risk patients in whom to target enhanced hospital-based monitoring and return to management in primary care, respectively, is warranted.

Drug therapy to prevent disease progression

Obeticholic acid (OCA)

OCA is a semi-synthetic hydrophobic bile acid analogue that is highly selective for farnesoid X receptor (FXR), having exponential activation potency relative to the endogenous counterpart chenodeoxycholic acid. OCA also induces expression of gut-derived hormones, in particular fibroblast growth factor 19 (FGF-19). The nuclear receptor FXR is a central transcriptional sensor of bile acid metabolic cascades, and FXR is highly expressed in the liver and in enterocytes. The main FXR target gene in the gut is FGF-19, which is an enterokine secreted into the portal blood on bile acid stimulation. FGF-19 reaches the liver where it activates the duo fibroblast growth factor receptor 4 (FGFR4)/beta KLOTHO on the hepatocyte basolateral membrane triggering intracellular pathways that repress cholesterol 7-α-hydroxylase (CYP7A1), which is the rate-limiting enzyme in bile acid synthesis. FXR signalling directly regulates genes involved in bile acid synthesis, secretion, transport, absorption and detoxification; additionally, FXR signalling impacts on inflammation, metabolic regulation and liver fibrosis.157

Relevant trial data reflect studies spanning phase II and III drug development. In a phase II randomised double-blind controlled trial of OCA in PBC, the therapeutic efficacy of three doses (10, 25 and 50 mg/day) as add-on therapy to UDCA in a multicentre study restricted to patients having persistent elevations in serum ALP (>1.5 × ULN) was evaluated.91 The primary endpoint was a significant reduction in serum ALP from baseline, and was met across all three doses of OCA versus placebo. Moreover, 87%, 69% and 7% of all OCA-treated patients completing therapy achieved a decline in serum ALP of at least 10%, 20% or complete normalisation (vs 14%, 8% and 0% with placebo). In a phase III clinical trial (PBC OCA International Study of Efficacy), patients with PBC with high-risk PBC (prior biochemical non-response according to modified Toronto criteria; ALP >1.67 x ULN and/or elevated total bilirubin <2 x ULN) were evaluated in a randomised placebo-controlled manner.158 The primary endpoint during the 12-month double-blind period was attainment of both an ALP value <1.67 × ULN (with a ≥15% reduction from baseline) and a normal serum bilirubin. In an intention-to-treat analysis, biochemical response was met in 10% of the placebo group and in 47% and 46% in the 10 mg and 5–10 mg dose-titrated OCA groups, respectively (P<0.0001 for both). Moreover, the mean decrease in serum ALP from baseline was 39% and 33% in the 10 mg and titrated OCA groups, respectively, versus 5% for patients in the placebo group (P<0.0001 for both). Both OCA groups met predefined secondary endpoints including reduction in serum AST and total serum bilirubin (both OCA groups P<0.001 vs placebo).

Longer-term efficacy of OCA and generalisability to the patient population as a whole needs confirmation in prospective follow-up studies. Survival benefit has yet to be demonstrated and, for that purpose, a long-term randomised trial is currently ongoing. In using OCA, attention is important to assessing the likelihood of benefit, and in those patients with advanced disease dose adjustment is important. More experience is needed in patients with advanced liver disease and, while there were patients with cirrhosis in the pivotal trial of Nevens et al,158 there were no patients with decompensation. As per the drug label, OCA is dose adjusted to 5 mg weekly initially (with a maximum dose of 10 mg twice weekly) in Child Pugh B or C liver disease. It may well also be prudent when initiating therapy in a patient with Child Pugh A liver disease to also dose adjust in the presence of portal hypertension. Cirrhotic patients, particularly once evidence of portal hypertension exists, should have intensified early safety evaluation (e.g. repeat blood tests monthly at outset) and, in the context of development of decompensation or progression of liver disease, OCA dose adjustment or treatment cessation may be indicated.

Treatment with OCA is associated with a dose-dependent exacerbation in pruritus leading to treatment discontinuation in 1–10% of patients. These observations emphasise the importance of dose titration with or without timely provision of therapy (rifampicin may be preferred, given potential interactions with bile acid sequestrants leading to fecal OCA loss) for symptom control. OCA-treated patients may also exhibit (reversible) alterations in serum lipid levels; specifically, most notably a small decrease in HDL. It is not yet known whether these consequences impact the long-term cardiovascular risk.

NICE has appraised OCA (https://www.nice.org.uk/guidance/ta443) and recommended OCA within its marketing authorisation as an option for treating PBC in combination with UDCA for people whose disease has responded inadequately to UDCA or as monotherapy for those who cannot tolerate UDCA. NICE recommended that clinicians assess the response to OCA after 12 months and that treatment should only continue if there is evidence of clinical benefit.

Off-label therapies

Off-label use of drugs such as budesonide and fibrates has not gained much traction in clinical practice in the UK, in contrast to other countries such as France and Japan. Recommendations for unlicensed therapies in the UK are not presently made pending review and publication of phase III trials as below; this is in keeping with recent guidelines from EASL.6

In patients with PBC exhibiting ‘florid’ interface hepatitis on biopsy, there are reports demonstrating the efficacy of budesonide in improving liver histology and biochemistry when used in combination with UDCA. A randomised placebo-controlled trial (n=39) was the first to study budesonide (9 mg/day) as add-on therapy to UDCA in patients with early-stage PBC.159 Over the 2-year study period, patients with combination therapy exhibited a significant reduction in serum ALP as well as improvement in liver histology according to the Ludwig classification system. Moreover, in a subsequent 3-year randomised non-blinded study performed in non-cirrhotic PBC patients (n=77), budesonide 6 mg/day plus UDCA (n=46) was associated with a 25% regression in liver fibrosis.160 However, despite encouraging results, note must be taken of a high rate of fibrosis progression (an increase of 70%) in patients receiving UDCA monotherapy. In a US open label study of 22 biochemical non-responders (ALP persistently >2 x ULN), only a very minimal additional benefit of budesonide to UDCA was reported, with a significant increase in the Mayo PBC score prognostic index and significant deterioration in bone mineral density; true comparison is challenging, however, because this cohort may have had patients at later stages of disease.161 Most notably, a phase III double-blind randomised placebo-controlled trial evaluating UDCA+budesonide vs UDCA +placebo awaits reporting (Eudra CT number 2007-004040-70).

Fibrates exert potent anticholestatic effects through the variable activation of peroxisome proliferator-activated receptors (PPAR), in addition to downregulation of several pathways leading to bile acid synthesis.162 It is important for practising clinicians to take clinical note that, while there is long-standing interest regarding these agents in cholestatic liver disease, in the UK drug labelling has documented contraindication to their use in PBC because of concerns over reported hepatotoxicity. Fibrates at high dose inhibit some CYP enzymes, in particular CYP2C9. At therapeutic doses, fibric acid derivatives increase serum alanine transaminase (ALT) and AST levels which may relate to known transcriptional effects on liver transaminase synthesis. For creatinine elevations it may also be that hyperproduction from muscle occurs, and concern over nephrotoxicity requires ongoing investigation and caution. Other adverse effects are recognised: 5–10% of patients, mostly with bezafibrate, develop musculoskeletal pain.

Studies from the 1990s evaluated the use of bezafibrate (400 mg/day) as an adjunctive therapy to UDCA, in which normalisation of serum ALP was reported in ~45% of UDCA non-responders versus ~18% taking placebo.163 More recently, a non-blinded prospective randomised controlled study (n=27; 100–120 months of treatment) reported that serum ALP levels were significantly lower following combination therapy (UDCA+bezafibrate) and associated with a trend toward improved overall survival (log rank P=0.057).164 Data from an open-label study (n=28) also provide evidence of a significant improvement in itch severity with bezafibrate, wherein all 12 patients who reported itch prior to starting treatment achieved complete or partial symptom resolution.165 Moreover, 20 and 24 UDCA non-responders attained a serum ALP reduction >40% within 6 and 12 months, respectively, with combination bezafibrate therapy.

Improvements in serum ALP is also evident through pilot studies using fenofibrate+UDCA combination therapy, with a pooled complete biochemical response rate evident in 69% of patients according to one systematic review and meta-analysis.166 167 In a retrospective uncontrolled study, improvements in short-term, liver decompensation-free and transplant-free survival using combination UDCA+fenofibrate therapy independently of liver biochemical changes and across a cohort of 120 prior UDCA non-responders (P<0.001) were described.168 However, concern remains about patient ascertainment, and deterioration of some patients with rising bilirubin values.

The biochemical improvements associated with fibric acid derivatives have not been shown to sufficiently alter long-term probability of liver-related death or need for transplantation when stratified according to the UK-PBC risk score,169 and may be counterbalanced by a possible negative impact on renal function.164 As such, meta-analysis of existing bezafibrate randomised clinical trials show no significant improvement in patient survival compared with UDCA monotherapy,170 although liver transplantation and liver-related death were not presented as clinical endpoints. Peer-reviewed results from a phase III clinical trial of bezafibrate in PBC (https://clinicaltrials.gov/ct2/show/NCT01654731) are, however, awaited.

Symptom management

The symptoms associated with PBC are important and have a significant impact on life quality for patients.171 Data from the UK-PBC patient cohort have shown that there is significant variation in management between centres and individual clinicians.12 It is hoped that these guidelines will help standardise the approach to symptom management by clinicians. It is our expert opinion that screening for the presence of symptoms by asking about them specifically, followed by offering formal quantification of their impact in patients reporting their presence, can be helpful in understanding the impact on individual patients (approaches can include Likert or visual analogue scales, which are well established for itch particularly and the use of more complex patient-derived measures such as the multi-domain PBC-40 QoL measure172 173). Therapies for symptoms should be continuously evaluated rather than on an ad hoc basis, and it is important to re-evaluate symptoms and response to therapy. There is also a risk of recurring symptoms on stopping therapy and most patients require treatment long term. The symptoms of PBC typically do not correlate with disease severity and do not improve with UDCA therapy.12

Pruritus

Pruritus is one of the characteristic cholestatic symptoms in PBC and results in impaired health-related quality of life (HRQoL).174 Approximately 80% of patients experience pruritus at some time during the course of their disease.175 It can occur at any stage of the disease process, but it is important to note that itch can improve as liver disease worsens.64 Patients with the ductopenic variant of PBC have particular problems with itch.127 Follow-up of patients and evaluation of change in pruritus and potential side effects is appropriate when changes are made in anti-pruritic therapy.

Bile duct obstruction must be excluded as the cause of pruritus, given the increased risk of gallstone disease in PBC,176 although in practice this distinction is rarely problematic. Bile sequestrants are used as first-line therapy but tolerability is often an issue with side effects including bloating and constipation.177 Cholestyramine is a non-absorbable resin that may help relieve pruritus. It is important to note that bile sequestrants must be given 2–4 hours before or after other medications (in particular UDCA) as they interfere with intestinal absorption.178 Patient education is important here (by clinicians and pharmacists) to avoid drug interactions. There is limited evidence to suggest that UDCA has any effect on pruritus.12 179 Colesevelam is a newer, often better tolerated, bile sequestrant which may have a role in management given the better side effect profile compared with cholestyramine. Despite clinicians describing anecdotal experience of benefit, and significant decreases in serum bile acid levels, a recent placebo-controlled trial failed to demonstrate effectiveness.180

Rifampicin is a useful second-line agent probably acting through its pregnane X receptor (PXR) agonist function.181 Several prospective randomised placebo-controlled trials have shown rifampicin to be effective in the management of cholestatic pruritus.182–185 This effect has been confirmed in meta-analyses.186 187 There are concerns over potential side effects with rifampicin (including hepatotoxicity and haemolysis), so patients commenced on treatment need regular blood tests.188 It is also important to remember that rifampicin affects vitamin K metabolism and can lead to an increase in the international normalised ratio (INR), most notably in icteric patients.189 Additionally, appropriate consideration should be given to balancing benefits against risks of antimicrobial resistance.

Opiate antagonists (oral naltrexone and parenteral naloxone) are increasingly used as third-line therapy as they reduce the sensation of itching and scratching activity.186 190–192 Naltrexone should be started at a low dose to avoid opiate withdrawal-like reactions in the first few days of treatment.193 Long-term tolerability can be an issue, with many patients having ongoing opiate withdrawal-like reactions or reduced threshold to pain.194 195

Other drugs which are used empirically in the management of cholestatic itch, typically in patients with pruritus unresponsive to other agents, are selective serotonin reuptake inhibitors (SSRIs; eg, sertraline) and gabapentin. SSRIs presumably act via altering the concentrations of neurotransmitters within the central nervous system. There are some reports of efficacy in the literature, but only a single small placebo-controlled trial.196 Side effects of SSRIs include dry mouth and patients should be warned about this. Gabapentin has been suggested as a potential treatment due to the theoretical benefit of increasing the threshold to experience nociception. However, a small trial failed to show benefit over placebo.197 Further evaluation of gabapentin may be warranted given the clinical experience. Antihistamines sometimes have a non-specific anti-pruritic effect which may be due to their sedative properties but are not recommended as specific therapy; they are, however, useful adjuncts for some. Table 2 shows an approach to the treatment of cholestatic pruritus.

Cholestatic pruritus is an area of active research with a number of experimental agents and approaches under development and evaluation. Trials of novel agents, including bile acid reuptake inhibitors and drugs targeting the autotaxin/lysophosphatidic acid pathway recently implicated in cholestatic pruritus, are ongoing or in development.181 198 New therapies are likely to emerge in the near future but need evaluation in a clinical setting. Physical approaches, such as nasobiliary drainage,181 199 MARS (molecular absorbance recirculating system) and ultraviolet (UV) light therapy are all experimental with case reports/series showing benefit but no formal trial evaluation.200 201 UV light therapy is relatively easy to access in comparison to the other treatments. Nasobiliary drainage appears to provide transient relief of itching but requires repeated treatments, is technically complicated and is difficult to tolerate; pancreatitis is recognised as a potentially significant complication. These techniques require further investigation. In extreme situations, temporary relief has been obtained with plasmapheresis or albumin exchange.202 203

Liver transplantation for cholestatic pruritus is highly effective in terms of rapid reduction in pruritus severity (frequently within the first 24 hours of transplantation).204 Pruritus that is ‘persistent and intractable’ after therapeutic trials is one of the variant syndromes which are indications for liver transplantation according to current guidelines.

Fatigue

Although fatigue is not specific to PBC, it is frequently reported by patients (over 50%) and when severe, as it is in 20% of patients, is a significant cause of QoL impairment.12 171 205–208 There are peripheral and central components to it, with central fatigue frequently associated with cognitive impairment (poor memory and concentration) which can be mistaken for HE.209 210 Fatigue is, with the exception of very endstage patients where it is the norm,211 not related to severity of liver disease and is not responsive to UDCA therapy.12 The approach to fatigue and its management therefore needs to run, as is the case for pruritus, in parallel with the management of the underlying disease process. Post-transplant patients with PBC typically have ongoing fatigue, and transplant for severe fatigue in the absence of other indications is not appropriate.12 211 High quality clinical trials in this area have been limited to date, and there is no licensed therapy. Fatigue in PBC as in other chronic diseases is inherently complex in nature and a structured approach to it is essential if improvement is to be seen.212 A structured approach to management, quantifying fatigue and its impacts (through the use of tools such as the PBC-40 QoL measure), addressing contributing and exacerbating factors and supporting patients to cope with its impact has been shown to be effective.212 It is important, when addressing fatigue, to identify other disease processes and therapies linked to PBC either directly or indirectly which may be contributing to fatigue. These include other autoimmune conditions such as hypothyroidism or autoimmune anaemias and demography-associated conditions and therapies such as type 2 diabetes and antihypertensive therapy.38 The steps to management of fatigue in PBC, which should be taken sequentially, are outlined in table 3. There is no evidence to suggest that exercise is harmful in PBC fatigue. Indeed, there are pilot data to suggest that structured exercise initiated at levels which can be tolerated by fatigued patients may be beneficial.213

Sicca complex

Sicca complex is common in PBC, with symptoms of dry eyes and/or dry mouth frequently seen in patients.38 214 Most patients have sicca symptoms rather than primary Sjögren’s syndrome. Other symptoms may include dysphagia and vaginal dryness. Clinicians should specifically enquire about these symptoms. Artificial tears and saliva are often helpful. Pilocarpine or cevimeline (muscarinic receptor agonists) can be used if symptoms are refractory.215 216 Patients with severe xerostomia should be given oral hygiene advice to prevent the development of dental caries. Clinicians should also be vigilant of the risk of oral candidiasis in patients with severe xerostomia. Vaginal moisturisers may be helpful but the use of oestrogen creams should be directed in primary care or by a gynaecologist (there are no concerns from a hepatology perspective). Specific guidelines for the management of sicca symptoms and Sjögren’s syndrome should be consulted for further details.217 If serological positivity (anti-Ro/La) or extraglandular features are found, evaluation for multisystem disease associated with Sjögrens disease by an expert clinician may be appropriate. Further patients with refractory symptoms should also be referred for specialist management, as evolving new therapies may be available.

Miscellaneous

Up to one-quarter of patients with PBC have Raynaud’s phenomenon which occurs due to spasmodic arterial contraction in the extremities (usually fingers and toes, but sometimes ears and nose).38 Patients should be asked specifically about the classical symptoms of their extremities turning white, then blue and finally red, often associated with pain/burning/tingling when the blood flow returns. Practical measures, such as wearing gloves, using hand warmers and avoiding cold environments, are often all that are needed for mild symptoms. For more marked symptoms, vasodilators such as calcium channel blockers can be used.218 Specialist rheumatological advice should be sought for severe symptoms and those at risk of digital ulceration. Approximately 8% of patients with PBC have limited scleroderma (CREST syndrome: Calcinosis, Raynaud’s phenomenon, oEsophageal dysmotility, Sclerodactyly, Telangiectasia).38 These symptoms and signs should be sought and, if present, patients should be referred for rheumatology advice. Social isolation, fatigue, anxiety and depression are important predictors of poor perceived QoL in PBC.219 Primary care providers should consider assessing patients for features of depression and, where appropriate, a trial of antidepressants may be helpful.

How to manage the clinical needs of a patient with PBC and advanced liver disease

Patients with decompensated liver disease are easy to recognise, allowing institution of appropriate management. It can be more difficult, however, to identify patients with PBC with well-compensated cirrhosis and even liver biopsy can be falsely reassuring due to the patchy nature of disease severity within the liver. There are no defined cut-offs and it is an assessment of relative risk which allows clinicians to decide when a patient requires screening for the complications of cirrhosis.

A practical approaching to identifying cirrhosis in clinical practice is to consider cirrhosis as defined by either confirmation by liver biopsy or on the basis of radiological findings (nodular liver with enlarged spleen) with either a history of complications of liver disease (ascites, variceal bleeding, encephalopathy, pervious bacterial peritonitis) or supportive laboratory findings (low platelets, low albumin, prolonged prothrombin time or INR). Liver stiffness measurement (LSM), assessed by vibration-controlled transient elastography (VCTE), has been shown as one of the best surrogate markers for the detection of cirrhosis or severe fibrosis (ie, bridging fibrosis) in patients with PBC.107 220 With increasingly greater access to VCTE now occurring across secondary and tertiary care, many clinicians now use VCTE as an adjunctive tool to help establish whether a patient has significant underlying liver fibrosis/cirrhosis; the results must, however, be interpreted in the clinical context of the patient. In one study, diagnostic thresholds of liver stiffness in discriminating fibrosis stages ≥F1, ≥F2 ,≥F3 and=F4 were 7.1, 8.8, 10.7 and 16.9 kPa, respectively.107 One large collaborative study showed LSM and IQR/median as the two independent criteria of VCTE reliability221; EASL-Asociación Latinoamericana para el Estudio del Hígado (ALEH) clinical practice guidelines provide current recommendations on performing VCTE, and clinical interpretation of LSM measurements should account for whether such recommendations are implemented locally—for example, in particular time of VCTE and whether the patient is fasting.222

As a result, a combination of clinical markers are used including:

1. Evidence of portal hypertension: thrombocytopenia, splenomegaly and/or varices

2. Histology: biopsy-proven cirrhosis

3. Predictive formulae: for example, Newcastle Varices Score

4. Imaging: ultrasound, cross-sectional evidence of cirrhotic liver/splenomegaly or TE

5. Serum markers of fibrosis: for example, ELF test

In terms of monitoring patients for the development of advanced disease, those who are non-responders to treatment who did not have advanced disease at presentation should have life-long follow-up and annual monitoring for evidence of progression (eg, ultrasound, TE (evidence not clear but accumulating),106 107 223 routine blood tests).105 Those patients with mild disease and near normal liver biochemistry tests do not require this intensity of follow-up and should have yearly LFTs.

Once a patient with cirrhosis has been identified or the clinical decision has been taken to monitor as if cirrhotic, they should be followed up in accordance with other relevant treatment guidelines for patients with cirrhosis.4 5 224–226 Clinical decompensation is, along with bilirubin >50µmol/L, a predictor of adverse outcome in PBC and such patients should be discussed with a hepatologist experienced in managing advanced disease and who is linked to a transplant programme.

Hepatocellular carcinoma (HCC)

Patients with PBC who have cirrhosis are at increased risk of HCC as in other forms of chronic liver disease.227 228 The majority of HCC in patients with PBC occurs in those with cirrhosis, although there are reports of HCC in patients who are non-cirrhotic.229 There are some important factors which identify patients as being at increased risk (in addition to cirrhosis). Non-responders to treatment are at greater risk and men are more likely to get HCC than women in PBC (of note given that PBC is much less common in men).229 230 Screening should be undertaken in accordance with international guidelines.224–226 There is currently an absence of specific UK guidelines. International guidelines currently advise abdominal ultrasound at 6-monthly intervals. Alpha-fetoprotein (AFP) has recently been removed from some international guidelines but is still widely used in clinical practice alongside abdominal ultrasound. The discussion of the health economics of HCC screening in PBC is outside the remit of these guidelines, but note should be taken of increasing locoregional therapies for HCC applicable to patients of all ages.

Portal hypertension

The incidence of varices in patients with PBC is significant, with approximately one-third of patients with advanced disease developing oesophageal varices over a median of 5.6 years.5 At present, relevant guidelines for endoscopic screening do not risk stratify patients. All patients known to have PBC with cirrhosis require endoscopic screening according to prior guidelines.231–233 The possibility of occult cirrhosis should also be considered in all patients and factored into decisions about the appropriateness of endoscopic screening. Table 4 shows the various tools available to help identify patients at risk of varices and who might benefit from endoscopic screening. The Baveno VI guidelines use the term ‘compensated advanced chronic liver disease (cACLD)’ to reflect the spectrum of disease in asymptomatic patients and encourage the use of TE in clinical practice.231 Patients with a liver stiffness <20 kPa and platelet count >150 000 are at very low risk of having varices that require treatment, although it is acknowledged that patients with PBC were not well represented in the studies to date. Annual assessment using TE and platelet count should be considered. This approach may decrease the number of screening endoscopies required. These tools can be used to help decision making regarding which patients require endoscopic screening, but clinical concern about the presence should always be followed up with endoscopy.

It is important to note that patients with PBC can develop varices even in the absence of established cirrhosis, although in clinical practice pre-sinusoidal varices are relatively unusual.234–236 Non-cirrhotic portal hypertension can occur in PBC and the possibility of its presence should be considered in all PBC patients with a GI bleed.

Transjugular intrahepatic portosystemic shunt (TIPS) should be considered for patients with variceal bleeding that fails to respond to endoscopic or pharmacological therapy.237 238 Patients with portal hypertension may also develop ascites which should be managed according to current guidelines.233 239 240 TIPS has a role in the management of patients with refractory ascites, with a recent randomised controlled trial showing that covered TIPS stents increase the proportion of cirrhotic patients with recurrent ascites surviving transplantation-free for 1 year compared with repeated large volume paracentesis.241 Portal hypertension in PBC often has a slowly progressive course and patients may do well with a TIPS.

Hepatic encephalopathy (HE)

HE can be the cause of significant life quality impairment in patients with advanced disease but is relatively unusual in PBC (and should not be mistaken for the much commoner cognitive impairment associated with fatigue). Where present, HE in PBC characteristically affects older patients. The first-line management is with lactulose (at a dose achieving 2–3 soft stools per day). Some patients may require regular enemas in addition to lactulose. In any patient with HE, it is important to rule out secondary causes such as constipation, dehydration, infection and upper GI bleeding. For patients with refractory encephalopathy, rifaximin is frequently used and is now NICE approved.242 Rifaximin is a non-absorbable antibiotic that improves HE, reduces hospital admission rates due to HE and the incidence of recurrent HE.243–245 It must be remembered that patients with HE cannot drive.

Transplantation

Liver transplantation is an established and successful procedure that prolongs the life of patients with chronic liver disease and, in certain settings, improves their QoL as well. PBC was among the very early indications for liver transplantation and remains a strong disease indication for surgery.246 Liver transplantation, however, remains a challenging procedure and, in most settings, organ availability has a significant impact on determining the precise timing and indications for surgery.

In the UK, patients should have a clear indication for transplantation as well as, usually, a UKELD score of 49 or greater (ie, meet minimal listing criteria based on a biochemical marker of disease severity calculated using the latest bilirubin, INR, creatinine and sodium). Patients with certain variant indications are eligible for listing for transplantation in the absence of an elevated UKELD score, and for patients with PBC this may be relevant (pruritus in particular).247

The UKELD score is effective in risk stratification in the context of transplantation and most UK patients are listed for transplantation based on an elevated UKELD score with accompanying liver failure/end-stage liver disease (jaundice, ascites, encephalopathy, variceal bleeding, sarcopenia, HCC) that is not responsive to medical therapy. Fatigue in isolation is not an indication for transplantation. Intractable pruritus unresponsive to medical therapy is an indication for transplantation with good outcomes in terms of pruritus.

In practice it is optimal to ensure patients who may be potentially eligible for transplantation are referred early and/or discussed with centres linked to transplant programmes because this facilitates ready access to transplant services. In practice, in view of the varied nature and timescale for overt decompensation, clinicians should actively consider whether transplantation is the best treatment in any patient with advanced PBC as evidenced by a UKELD score >49, jaundice, portal hypertension or signs of early decompensation (eg, ascites, encephalopathy, sarcopenia).

Recurrent PBC (rPBC) post liver transplant is well recognised but clinically relevant for only a few.246 248 It can only be confirmed histologically given that many complications post-transplant (biliary, rejection, vascular) present with an elevated ALP, and serologic features of PBC persist post-transplant so are not additive diagnostically. Protocol liver biopsies are no longer commonly performed and there may be minor changes in liver biochemistry that are not histologically evaluated in patients, therefore the rate of rPBC is an estimate in the literature but is at least ~20% by 10 years. Across studies the reported prevalence rate of rPBC, however, ranges from 0% to 35%. The median time to rPBC ranges between 3 and 5.5 years. Graft loss is possible with rPBC but rare (~1%), and recurrent disease can occur in a second graft. Seemingly, the use of tacrolimus is associated with increased risk of PBC recurrence in the allograft, and some have advocated cyclosporine in patients with PBC as a result249; the low clinical relevance of rPBC has, however, meant that practice has not changed. Others have proposed all patients are routinely given UDCA post-transplant, but no consensus exists on this248; however, there are recent data supporting UDCA as preventing recurrence. No overwhelming evidence for particular immunosuppressive strategies exist; in particular, there is no evidence to support long-term prednisolone, although in the early post-transplant period a slightly higher rate of acute rejection can be expected.

Fat-soluble vitamin supplementation

While it is rare for patients to develop overt fat-soluble vitamin (vitamin A, D, E, and K) deficiency, this is well described in those with chronic cholestasis, particularly once individuals become jaundiced.250 251 Routine measurement of vitamin levels is not usually additive or necessary but, in patients with advanced icteric disease, consideration should be given to oral supplementation of vitamins A, D, E and K using standard preparations.

Osteoporosis

Osteoporosis affects 20–44% of patients with PBC with the resultant risk of fragility fractures, while the majority of patients have osteopenia.111 Risk factors for osteopenic bone disease in PBC include female gender, menopausal status, low body mass index (through the effects of disordered bile acid homeostasis and the pancreatic insufficiency seen in some patients with PBC), older age, advanced disease and chronic cholestasis with resultant vitamin D deficiency.112 Patients with PBC also have higher markers of bone resorption (urinary hydroxyproline) and lower markers of bone formation (osteocalcin).112

Patients should be given general lifestyle advice to prevent loss of bone density (weight-bearing exercise, smoking cessation, minimising alcohol intake, etc). Falls are seen with increased frequency in PBC due to associated autonomic dysfunction and add to the increased fracture risk presented by osteoporosis.252 Patients with a clinical history of falls should be referred to a specialist falls clinic for multidisciplinary assessment, including for the presence of autonomic dysfunction.252

All patients with cirrhosis and those with other recognised risk factors (eg, female gender, post-menopausal women, low body mass index, older age) should be assessed for osteoporosis and fracture risk. The FRAX score (the WHO fracture risk assessment tool can be used with or without bone mineral density (BMD) values) or QFracture (BMD values cannot be incorporated into the risk algorithm) should be used to estimate 10-year predicted absolute fracture risk. Following risk assessment with FRAX (without a BMD value) or QFracture, consider measuring BMD with dual-energy X-ray absorptiometry (DXA) in people whose fracture risk is in the region of an intervention threshold and recalculate absolute risk using FRAX with the BMD value.253

National guidelines should be referred to for treatment algorithms.253 Vitamin D deficiency should be corrected and an adequate dietary intake assured. The use of calcium alongside vitamin D supplementation depends on the adequacy of dietary intake. If a bisphosphonate is required, alendronic acid is usually used first line.254–257 Specialist referral should be considered for patients who are unable to tolerate alendronate or risedronate. Treatment options include strontium ranelate, raloxifene, denosumab and teriparatide. There is a widely held view that oral bisphosphonates are unsafe in patients with varices because of the risk of superficial erosion and enhanced bleeding risk. The evidence to support this view is limited. Intravenous bisphosphonates can be used if there is clinical concern. There are limited data regarding the use of hormone replacement therapy and its efficacy in osteoporosis prevention in PBC.258 259

When should patients be considered for clinical trials?

For many years following the original UDCA trials there has been little or no trials activity in PBC. This is now changing with a number of trials targeting areas of perceived unmet clinic need in the condition,260 261 with progress to new licensed second-line therapies such as OCA,158 which has FDA and EMA approval, as well as NICE evaluation in the UK. Currently there are trials in three distinct areas and patients should be offered the opportunity to participate if they fall into targeted groups (see https://clinicaltrials.gov/ct2/results?term=primary+biliary+cirrhosis+OR+primary+biliary+cholangitis&Search=Search).

Management of special populations

Pregnancy and PBC

While most patients are diagnosed at an age when pregnancy is not a relevant consideration, a significant minority of patients with PBC are women of reproductive age. In this younger age range of PBC, pregnancy may either be a reason for diagnosis (failure of resolution of obstetric cholestasis) or may be complicated by worsening pruritus. Significant medical risks are infrequent but can be relevant if patients have cirrhosis and portal hypertension. In this setting, management is no different from any other aetiology of cirrhosis (eg, gastroscopy if concern over portal hypertension; exclusion of splenic artery aneurysm by ultrasound).

PBC specific experience is limited to case series, but expert clinical opinion is that UDCA is safe during conception, pregnancy and post-partum.277 Additionally, cholestyramine and rifampicin (second trimester onwards) are considered safe in pregnancy, although the data are limited.155 278 Rarely, itch during pregnancy becomes unbearable and plasmapheresis may help.279 In those with notable cholestasis, fat-soluble vitamin deficiency should be avoided. Post-partum cholestatic flares have been described and clinical follow-up in the post-partum period is important.

Pre-pregnancy counselling should be pragmatic; recognition that in those with a marked ductopenic variant of PBC, disease progression from intense added cholestasis during pregnancy does need consideration. Similarly, patients with portal hypertension have the greatest risks associated with pregnancy and should be appropriately counselled. Variceal bleeding can occur in patients with cirrhosis of any aetiology as a consequence of pregnancy-related increase in portal pressure. Such patients should be electively endoscoped in the second trimester and managed appropriately. Pregnant patients with PBC should be screened for anti-Ro and anti-La antibodies, as their presence would change obstetric practice regarding fetal screening for bradycardia.

Familial screening

Awareness of the increased risk of PBC seen in the first-degree relatives of patients with PBC and the role played by genetic factors in disease pathogenesis can give rise to anxiety among patients with regard to the risk that their relatives run of developing the condition. There can be particular concern in the daughters of mothers with PBC because of the female predominance of the disease. Screening for any disease must balance any benefit resulting from earlier diagnosis of the condition against the individual and healthcare costs associated with the screening activity. In the case of PBC, the sibling relative risk is 10 (siblings of a patient with PBC have a 10.5-fold higher risk of developing the disease than age- and sex-matched community controls), while the relative risk rises to 35 for the daughters of patients with PBC.37 The prevalence of PBC in the UK population has been estimated as being 350/million (700/million women), giving a prevalence for PBC among the daughters of mothers with the disease of ~2%. Given the low likelihood of screening being positive, the lack of time-dependent therapy where early diagnosis materially alters the nature of therapy, and anecdotal reports of people being screened for PBC subsequently having difficulty getting life and travel insurance, formal screening for PBC in relatives of patients is not recommended. Patient anxiety, however, needs to be taken into account and may be a relevant factor to consider in deciding about ad hoc familial screening.

Patient support and patient education

NICE recommends in the guideline ‘Patient Experience in Adult NHS Services: Improving the Experience of Care for People Using Adult NHS services’ that clear, consistent, evidence-based, tailored information is available to patients throughout all stages of their care.225 In PBC, evidence exists from qualitative research to show that factors such as knowledge, information, consistency, a positive approach, simplification and repetition lead to a positive diagnosis experience.280 Findings were used to develop a patient information DVD with expert clinicians describing PBC and patients talking about their experiences. This DVD allows consistent evidence-based information to be provided to patients. It is available to patients and professionals by contacting the patient charity LIVErNORTH (info@livernorth.org.uk; http://www.livernorth.org.uk/pages/factsheet.htm#DVD). Answers to some frequently encountered concerns over PBC care are shown in box 1 and table 5. NICE (https://www.nice.org.uk) also recommends that patients are given both oral and written information. Leaflets are available from a number of national and local patient support groups and are written by clinicians with patient input (The British Liver Trust, The PBC Foundation and LIVErNorth). Leaflets can be obtained by contacting UK-PBC via the website (http://www.uk-pbc.com/). Leaflets should be made readily available to patients.

The use of international web sites by patients is not recommended as the clinical practice described may differ from that in the UK, causing confusion.

Fatigue has been shown to be the symptom with the biggest impact on patients. Fatigued patients perceive a poor QoL compared with controls and their levels of social engagement are lower.171 219 Very little is written in relation to social isolation and improving support mechanisms in PBC, but there are a number of telephone helplines and patient support groups that offer free qualified peer support to patients. It is recommended (based on expert opinion) that details of helplines can be suggested to patients who may be at risk of social isolation. Information can be found on the following web pages:

• http://www.pbcfoundation.org.uk/Home/CMSPageView/532 (The PBC Foundation)

• http://www.livernorth.org.uk/pages/contact.htm (LIVErNorth)

• http://www.liver4life.org.uk/helpline.html (Liver4Life)

There may be scope for psychological approaches, such as cognitive behavioural therapy, to be used to support patients with PBC. Such approaches have been found to be effective in other chronic conditions for managing distress resulting from debilitating symptoms. Blackburn et al explored the psychological impact of fatigue in PBC using semi-structured interviews and validated assessment tools for psychological symptoms. Patients with PBC who report high levels of fatigue were found to be more vulnerable to emotional distress and are more likely to perceive that their QoL has been negatively affected.281 We therefore advise that a patient with profound psychological distress associated with fatigue should be referred to appropriate psychological services for assessment.