Dr Jez Thompson discusses the European Association for the Study of the Liver guideline on diagnosis and management of patients with this progressive, long-term condition

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Read this article to learn more about:

  • tests that should be performed to confirm the diagnosis of primary biliary cholangitis (PBC)
  • stratification of patients based on their disease stage
  • management of PBC, associated symptoms, and possible complications
  • the importance of setting up appropriate care pathways and providing support to patients.

Key points

Commissioning messages

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The European Association for the Study of the Liver (EASL) recently published EASL clinical practice guidelines: The diagnosis and management of patients with primary biliary cholangitis.1 The guideline provides a useful framework to help GPs recognise the symptoms of primary biliary cholangitis (PBC) and diagnose the condition, and valuable information on its specialist management.

The EASL guideline recommends the development of local care pathways in which the roles of GPs and specialists are defined in the management of patients with this long-term condition, and that reflect the needs of the individual patient.1

Some of the medicines discussed in this article currently (October 2017) do not have UK marketing authorisation for the indications mentioned. The prescriber should follow relevant professional guidance, taking full responsibility for all clinical decisions. Informed consent should be obtained and documented. See the General Medical Council’s guidance on Good practice in prescribing and managing medicines and devices2 for further information.

Primary biliary cholangitis

Primary biliary cholangitis (formerly known as primary biliary cirrhosis) is an uncommon but important chronic and progressive liver condition that results in cholestasis, and may lead to end-stage cirrhosis if left untreated.1

In European populations, the estimated incidence of PBC is 1–2 per 100,000 population per year, with estimates of prevalence varying widely and lying between 1.9 and 40.2 per 100,000 population.1 However, both incidence and prevalence are thought to be increasing.3

The condition overwhelmingly affects women (female to male of ratio 9:1), has a peak incidence in the fifth decade, and does not affect children.1 Overall it is thought that around 1 in 1000 women over 40 years of age have PBC.1,4

Primary biliary cholangitis is an autoimmune disease characterised by serologic reactivity to antimitochondrial antibody (AMA) and PBC-specific antinuclear antibody (ANA), and is associated with Hashimoto’s thyroiditis, Sjögren disease, systemic sclerosis, and coeliac disease.1 Clinically, the condition is characterised by symptoms and signs of cholestasis, and typical histological features of chronic, non-suppurative, granulomatous, lymphocytic small bile duct cholangitis.1

As PBC is a slowly progressing disease that presents later in life, some patients with the condition never develop symptoms and, for those that do, initial symptoms may be non-specific. Common symptoms include tiredness (which can be severe) and pruritus; though the severity of these symptoms does not always reflect the severity of the underlying disease.1 Other symptoms reported by patients with PBC include dry eyes, dry mouth (sicca symptoms), right upper quadrant discomfort, nausea, and anorexia.5 As the condition progresses and bile metabolism and flow become impaired patients may complain of dark urine, pale stools, and jaundice. Late in the disease there may be symptoms and signs of cirrhosis such as oesophageal varices, ascites, and hepatic encephalopathy.5

Diagnosis

The diagnosis of PBC should be considered by GPs in a number of different circumstances: the investigation of generalised symptoms such as unexplained tiredness, nausea, and itch; the investigation of cholestatic-pattern abnormalities in liver function tests; and investigation of unexplained symptoms and signs of cholestasis including jaundice.

The EASL guideline recommends taking a detailed history and examination when assessing patients with potential cholestatic liver disease. History taking should include medical, social, travel, family, and drug histories (including use of herbal remedies, alcohol, smoking, and substance misuse).1

Physical examination should include assessment of liver and spleen enlargement as well as looking for signs of liver disease such as jaundice, xanthelasma, palmar and plantar erythema, nail abnormalities, and evidence of scratching.1

Abdominal ultrasound is the recommended imaging technique for excluding mechanical bile duct obstruction, mass lesions, and gallbladder abnormalities in patients with cholestasis.1 All forms of imaging are unlikely to detect morphological abnormalities when cholestasis has an intrahepatic cause such as early PBC. However, imaging of patients with more advanced PBC may reveal portal hypertension and other features of advanced liver disease.1

Blood tests of patients with PBC typically show raised levels of alkaline phosphatase (ALP) and gamma-glutamyltranspeptidase (GGT).1 Levels of transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) are likely to be raised if there is significant liver inflammation.1 In more advanced disease, particularly with developing cirrhosis, there may be elevated levels of bilirubin, a low platelet count, and reduced levels of albumin.1 The EASL guideline recommends that, when intrahepatic cholestasis is suspected, elevated ALP and the presence of AMA at a titre >1:40 points strongly to a diagnosis of PBC.1 In patients who are AMA-negative but are presenting with cholestasis, the presence of PBC-specific ANA (present in approximately 30% of patients with PBC) may also be used as a positive diagnostic marker.1

When there is ongoing diagnostic uncertainty, magnetic resonance cholangiopancreatography—providing accurate imaging of the biliary tree—may be a useful next-stage investigation.1 If a cause of chronic intrahepatic cholestasis has not been found following blood tests and extended imaging, liver biopsy may demonstrate the characteristic histology of PBC.1

Patient stratification

General practitioners should refer patients with suspected or diagnosed PBC for specialist hepatology assessment according to locally agreed care pathways. Once PBC has been confirmed, patients will be evaluated to assess their stage of disease using non-invasive tests, and this assessment should be repeated at any follow-up appointments.

In general, diagnosis at a younger age (<45 years) and advanced disease at the time of presentation are negative predictive factors for the effectiveness of treatment.1

Serum markers of fibrosis can be used to separate patients with PBC into risk groups, with serum hyaluronic acid being the first marker to show significant association with clinical outcomes.6,7 The enhanced liver fibrosis (ELF) score has also demonstrated predictive capacity; this is a proprietary blood test panel which combines the results of three serum biomarkers that indicate the level of liver fibrosis to create an ‘ELF score’.1 More recently, the aspartate aminotransferase:platelet ratio index (APRI) has been validated as a predictor of clinical outcomes.8

Liver stiffness measurement by vibration-controlled transient elastography is an effective surrogate marker for the detection of cirrhosis or severe fibrosis in patients with PBC, and may have potential for development as an indicator for PBC progression.1

See Figure 1 below for the EASL PBC management flow chart.

Figure 1: EASL clinical practice guideline in PBC consensus management flow chart

Figure 1: EASL clinical practice guideline in PBC consensus management flow chart

Source: Hirschfield G, Beuers U, Corpechot C et al. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67 (1): 145–172. Reproduced with permission.

In patients with PBC, a structured approach to their life-long care is important and recommended. Care should focus around three ‘pillars’ of practice, a) stratification of risk and treatment; b) staging and surveying disease; and c) active patient management. While care always needs to be tailored to the individual patient and the health care environment, these three guiding themes are central to effective patient management.

PBC=primary biliary cholangitis; UDCA=ursodeoxycholic acid; AIH=autoimmune hepatitis; ALP=alkaline phosphatase; AST=aspartase transaminase;HCC=hepatocellular carcinoma

Treatment

The treatment of PBC has three aims:1

  • to prevent the development of end-stage liver disease
  • to manage the symptoms associated with the disease
  • to manage the complications of liver disease.

Liver transplantation may be necessary for some patients; see heading ‘Liver transplantation’ and text below.1 Patients with symptoms resistant to treatment should be referred for specialist assessment.1

Preventing the development of end-stage liver disease

The dominant class of pharmacotherapy used in treating PBC is bile acid-based treatments.1 Oral ursodeoxycholic acid (UDCA) has been widely studied and is recommended by EASL as the first-line bile acid-based treatment,1 and by NICE as part of NICE Technology Appraisal 443 on Obeticholic acid for treating primary biliary cholangitis.9 Ursodeoxycholic acid stimulates the secretion of bile acids, bilirubin, and numerous other cholephils in cholestasis.1 Obeticholic acid (OCA) is a semi-synthetic bile acid analogue that works in a different way to improve biliary function in PBC, and is recommended by EASL and NICE as a second-line treatment, either as monotherapy when UDCA is not tolerated, or in conjunction with UDCA when the clinical response to UDCA is inadequate.1,9

A range of other medications has been trialled for the treatment of PBC. This includes budesonide, a synthetic corticosteroid that results in minimal systemic side-effects compared with other steroids, and fibrates such as bezafibrate. The EASL guideline states that there is currently insufficient evidence to recommend using these medications in the treatment of PBC.1 [NB budesonide and bezafibrate are not licensed for the treatment of PBC.]

Managing the symptoms associated with the disease

The symptoms of PBC can have a major impact on a patient’s quality of life. The EASL guideline advises that patients should be asked routinely about the presence of symptoms, particularly pruritis, sicca syndromes, and fatigue.1 The impact of symptoms can be assessed using tools such as visual analogue scales and quality of life indices, and therapies prescribed for managing symptoms should be continuously evaluated and adjusted.1

Pruritis

Treatment with UDCA does not improve pruritis and OCA may exacerbate it. Bile duct obstruction (for example by gallstones) and other—particularly allergic—causes of itch must be excluded if there is significant pruritis. Treatments available to help pruritis include: emollients and oatmeal extracts to improve dry skin; use of cold water for bathing or showering; and psychological support to reduce scratching. Bile sequestrants such as cholestyramine may be helpful in first-line treatment of pruritis, and rifampicin is a second-line treatment option.1 The oral opioid antagonists naltrexone and nalmefene may be used as third-line agents to relieve itching. Liver transplantation has also been found to effectively and rapidly reduce the severity of pruritis.1

Fatigue

If fatigue is a significant problem, other causes of tiredness should be screened for and treated, including anaemia and hypothyroidism. Psychological approaches to strengthen coping strategies, and to promote activity and social contact, may also be of benefit.1

Sicca symptoms

Sicca symptoms can be addressed with artificial tears and saliva, and good oral hygiene advice can help prevent the development of dental caries. Vaginal moisturisers may help dryness, and oestrogen creams may be prescribed in primary care.1

Managing the complications of liver disease

Treatment of complications associated with PBC may include the management of osteoporosis. Management of osteoporosis may involve providing nutrition advice, encouraging smoking cessation and weight bearing exercise, and the taking of calcium supplements, vitamin D supplements, or bisphosphonates as appropriate to the individual.1

Fat-soluble vitamin deficiency is uncommon in PBC, but measurement of vitamin D and a lower threshold for supplementation should be considered.1 Serum lipids are frequently raised in PBC, though the mechanism of PBC-related hyperlipidaemia is distinct from other conditions, and patients with PBC are not considered at higher cardiovascular risk. Patients are not treated routinely for PBC-associated hyperlipidaemia unless there are other cardiovascular risk factors.1

Other important complications of PBC, as with any form of cirrhosis, include portal hypertension and hepatocellular carcinoma. NICE Guideline 50 on Cirrhosis in over 16s: assessment and management recommends screening for varices by endoscopy whenever cirrhosis is diagnosed, and surveillance for those without varices every 3 years. People with cirrhosis who do not have hepatitis B infection should be screened for hepatocellular carcinoma every 6 months by ultrasound, with or without measurement of serum alpha-fetoprotein.10

Liver transplantation

Although the prevalence of PBC is increasing, liver transplantation for the condition has become less common.11 Indications for liver transplantation include the complications of cirrhosis and severe pruritus that is refractory to medical treatment.1

Overall, the outcome of liver transplantation is good, with 5-year survival rates of 80–85%. Some symptoms, including fatigue, may persist after transplantation.1

Symptomatic PBC has been reported to recur in approximately 20% of patients following transplantation but the rate of histological recurrence is likely to be higher.1

Pregnancy and PBC

Pregnancy in patients with cirrhosis carries an increased risk of maternal and foetal complications. The EASL guideline recommends offering female patients with PBC pre-conception counselling and specialist monitoring during pregnancy.1

Pruritis may worsen in pregnancy and its management may require specialist advice. The guideline notes that rifampicin may be recommended by specialists during the third trimester, and should only be prescribed in secondary care.1 Variceal bleeding may occur in a small number of pregnant women with PBC; the EASL guideline recommends that pregnant women with PBC and cirrhosis should undergo elective endoscopy for the evaluation of varices in the second trimester.

However, pregnancy is typically well tolerated in non-cirrhotic patients with PBC. In these patients, EASL recommends the continued use of UDCA during pregnancy even though the supporting data are limited.1

Care pathways

The EASL guidance identifies the importance of well-defined local pathways in the delivery of clinical care for patients with PBC.1 It suggests the development of models in which the needs of high-risk patients and those with a high symptom burden are met, while avoiding the over-specialised management of low-risk and asymptomatic patients.1

Structured follow up for all patients with PBC must be life-long and include a review of treatment needs and symptom severity at least once a year.1 Achieving this will require development of local pathways and policies that define the roles of GPs, secondary care, tertiary care, and transplant experts in the care of individual patients with PBC. 

Recognising that further work needs to be done in this area, the European Reference Network (ERN) Rare Liver Network will shortly be publishing recommendations for the delivery of improved care pathways to go alongside the EASL PBC guideline.1

Patient support

Qualitative research has shown that factors such as the provision of knowledge and information for patients in an accessible and user-friendly format can lead to a more positive experience for patients with PBC.1

Good quality leaflets and web-based information are available from a number of patient support groups, and are written or reviewed by clinicians with a specialist interest.1 Useful information and resources can be found at www.pbcfoundation.org.uk and www.britishlivertrust.org.uk

Conclusion

Primary biliary cholangitis is an uncommon but important autoimmune condition, predominantly presenting in women between the ages of 40 and 60, which if left untreated may lead to cirrhosis. General practitioners must consider the diagnosis when investigating generalised symptoms such as: unexplained tiredness, nausea, and itch; cholestatic-pattern abnormalities in liver function tests; and unexplained jaundice. Medical treatments are available that reduce the risk of progression to end-stage liver disease, and to treat the symptoms of PBC. Patients with established liver disease should be monitored under specialist care for the development of oesophageal varices and hepatocellular carcinoma.

Key points

  • Take a detailed history and carry out a thorough clinical examination when evaluating patients with features or test results suggesting cholestatic liver disease
  • Ultrasound examination is the first-line non-invasive imaging procedure to differentiate intra- from extrahepatic cholestasis
  • Patients with unexplained cholestasis should be investigated with screening for AMA and PBC-specific ANA
  • Liver biopsy is not recommended for the diagnosis of PBC unless PBC-specific antibodies are absent, other co-existent liver disease is suspected, or other comorbidities are present
  • All patients with PBC need structured life-long follow-up, including annual assessment of treatment needs and symptom status
  • Local pathways should be developed to coordinate the work of GPs, secondary care, and tertiary care specialists in caring for patients with PBC
  • Once diagnosed, all patients with PBC should be stratified based on their stage of disease using a combination of non-invasive tests at baseline and during follow up
  • Oral UDCA is recommended as the first-line pharmacotherapy for all patients with PBC and is usually continued for life:
    • oral OCA—either as monotherapy for those who are intolerant to UDCA, or in combination with UDCA for those with an inadequate response to UDCA—is the recommended second-line treatment
  • EASL recommendations on the management of symptoms include:
    • cholestyramine as the first-line therapy for pruritis, with rifampicin as a second-line option
    • if fatigue is a major factor, secondary causes such as anaemia or hypothyroidism should be identified and treated
    • sicca symptoms can be modified with artificial tears and saliva
    • good oral hygiene advice can prevent the development of caries
    • vaginal moisturisers may help dryness, and oestrogen creams may be used in patients with PBC
    • patients with symptoms resistant to treatment should be referred for specialist assessment
  • Metabolic complications of liver disease should be assessed:
    • osteoporosis should be screened for in all patients with PBC and treated appropriately
    • hyperlipidaemia is a feature of cholestasis, but should not be automatically associated with an increase in cardiovascular risk
    • pharmacological treatment with cholesterol-lowering agents should be considered on a case-by-case basis
  • Patients should be considered for liver transplantation when they present with complications of cirrhosis, have markers of high disease severity, or have severe and treatment-resistant pruritus.
  • Patients with PBC should be informed of the support and educational materials available from patient support groups.
AMA=antimitochondrial antibodies; PBC=primary biliary cholangitis; ANA=antinuclear antibody; UDCA=ursodeoxycholic acid; OCA=obeticholic acid; EASL=European Association for the Study of the Liver. 

Some of the medicines discussed in this article currently (October 2017) do not have UK marketing authorisation for the indications mentioned. The prescriber should follow relevant professional guidance, taking full responsibility for all clinical decisions. Informed consent should be obtained and documented. See the General Medical Council’s guidance on Good practice in prescribing and managing medicines and devices2 for further information.

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GP commissioning messages

written by Dr David Jenner, GP, Cullompton, Devon

  • Primary biliary cholangitis is a rare disease with an incidence of approximately 1–2 per 100,000 population per year
  • GPs need to be aware of the condition and understand the importance of testing AMA and PBC-specific ANA levels
  • Local diagnostic pathways for the management of suspected liver disease can be built into apps or websites by commissioners so that GPs can easily access guidance on which tests to perform and when to refer
  • Specialised nursing services may be able to provide:
    • post-diagnosis support to people with PBC
    • advice to primary care healthcare professionals on the management of people with PBC
  • Clinical algorithms for the investigation of abnormal LFTs should be developed as part of local care pathways
    • these would help GPs manage this common diagnostic quandary and also help accurate diagnosis of other conditions, such as haemochromatosis.

AMA=antimitochondrial antibody, PBC=primary biliary cholangitis; ANA=antinuclear antibody; LFTs=liver function tests.

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References 

  1. Hirschfield G, Beuers U, Corpechot C et al. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67 (1): 145–172.
  2. General Medical Council. Good practice in prescribing and managing medicines and devices. GMC, 2013. Available at: www.gmc-uk.org/Prescribing_guidance.pdf_59055247.pdf
  3. Boonstra K, Kunst A, Stadhouders P et al. Rising incidence and prevalence of primary biliary cirrhosis: a large population-based study. Liver Int 2014; 34 (6): e31–38. 
  4. NHS Choices. Primary biliary cirrhosis (primary biliary cholangitis). www.nhs.uk/conditions/Primary-biliary-cirrhosis/ (accessed 26 September 2017).
  5. British Liver Trust. Primary biliary cholangitis/cirrhosis. www.britishlivertrust.org.uk/liver-information/liver-conditions/primary-biliary-cirrhosis/ (accessed 26 September 2017).
  6. Nyberg A, Engstrom-Laurent A, Loof L. Seruym hyaluronate in primary biliary cirrhosis—a biochemical marker for progressive liver damage. Hepatol 1988; 8: 142–146.
  7. Poupon R, Balkau B, Guechot J, Heintzmann F. Predictive factors in ursodeoxycholic acid-treated patients with primary biliary cirrhosis: role of serum markers of connective tissue. Hepatol 1994; 19: 635–640.
  8. Trivedi P, Bruns T, Cheung A et al. Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response. J Hepatol 2014; 60: 1249–1258.
  9. NICE. Obeticholic acid for treating primary biliary cholangitis. NICE Technology Appraisal 443. NICE, 2017. Available at: www.nice.org.uk/guidance/ta443
  10. NICE. Cirrhosis in over 16s: assessment and management. NICE Guideline 50. NICE, 2016. Available at: nice.org.uk/guidance/ng50
  11. Carbone M, Neuberger J. Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014; 60: 210–223.