Approach
Two goals of treatment of PBC should be considered in all patients.[15]
To slow or stop progression of the disease to prevent the development of cirrhosis and its complications (or managing those complications and the resulting risk to life if cirrhosis is already present).
To manage the symptoms of the disease to improve patient quality of life. To a significant degree the treatments that modify progression of the disease do not modify the symptoms of the disease (and vice versa), and it is therefore important that appropriate symptomatic management be undertaken in addition to disease-modifying treatment.
The diagnosis of PBC can give rise to significant concern in patients because of the negative connotations associated with a diagnosis of liver disease (perception of others that lifestyle-related issues are contributory; something that is not the case in PBC), and concern regarding risk to life and potential need for transplantation.
In the majority of patients the disease is likely to be only slowly progressive. Discussion with patients regarding the need for long-term disease-modifying treatment needs to be counterbalanced by information regarding the relatively slowly progressive nature of the disease. It is not at present possible to identify, at disease outset, the relatively small group of patients who do have a more rapidly progressive disease. Time spent at the point of diagnosis discussing the nature and implications of PBC with patients is well spent.
Modification of disease progression
Ursodeoxycholic acid is the recommended first-line treatment for the modification of disease progression. Second-line options include obeticholic acid, elafibranor, or seladelpar; these may be used in combination with ursodeoxycholic acid for patients with an inadequate response to ursodeoxycholic acid, or as monotherapy in patients who cannot tolerate ursodeoxycholic acid.
Ursodeoxycholic acid
First-line treatment suitable for use in all patients is ursodeoxycholic acid (a bile acid analogue).[14][15] Expert consensus is that ursodeoxycholic acid shows therapeutic benefit and has a very benign safety profile, and the drug is recommended for all patients to modify disease progression. However, up to 40% of patients fail to respond adequately to ursodeoxycholic acid in terms of biochemical improvement and are at significantly increased risk of dying of PBC or needing liver transplantation.[47][48] Non-response is more common in patients presenting below the age of 50 years.[47]
Obeticholic acid
Obeticholic acid is a bile acid analogue that has additional actions over and above those of ursodeoxycholic acid through its farnesoid X receptor (FXR) agonist properties. It is approved by the US Food and Drug Administration (FDA) for the treatment of PBC in combination with ursodeoxycholic acid in adults who have an inadequate response to ursodeoxycholic acid (for at least 1 year), or as monotherapy in adults unable to tolerate ursodeoxycholic acid. It is only approved for the treatment of patients without cirrhosis or patients with compensated cirrhosis and no evidence of portal hypertension.[14][15] The pivotal trial of obeticholic acid used an alkaline phosphatase of >1.67 times the upper limit of normal and/or a bilirubin level at or above the upper limit of normal as entry criteria, and this is, therefore, an appropriate definition of inadequate response to ursodeoxycholic acid for clinical practice.[49] An improvement in disease-related symptoms or survival has not been established in clinical trials as yet.
Obeticholic acid is contraindicated in patients with decompensated cirrhosis (or a prior decompensated event), compensated cirrhosis with evidence of portal hypertension, and complete biliary obstruction.[50] The FDA restricted the use of obeticholic acid in patients with PBC with advanced cirrhosis because it can cause serious liver injury leading to liver decompensation or liver failure in this patient population.[51] However, the FDA has also identified cases of serious liver injury in post-marketing clinical trial data among patients who did not have cirrhosis.[52]
Liver function tests should be performed and frequently monitored in all patients taking obeticholic acid, in order to detect worsening liver function as early as possible. However, it is not clear whether this monitoring is sufficient to address the risk of serious liver injury.[52] Closely monitor patients with compensated cirrhosis, concomitant hepatic disease, and/or severe intercurrent illness for new evidence of portal hypertension or increases in total and direct bilirubin and prothrombin time (above the upper limits of normal). Obeticholic acid should be permanently discontinued in patients with any evidence of liver disease progression, including those who develop clinical or laboratory evidence of hepatic decompensation, those who have compensated cirrhosis and develop portal hypertension, or those who experience clinically significant hepatic adverse effects. Obeticholic acid should also be discontinued in patients with no evidence of efficacy. Patients should be advised about the signs and symptoms of worsening liver injury to contact their healthcare professional immediately if any of these signs or symptoms develop.[52]
Severe pruritus has been reported with obeticholic acid, which may require a dose reduction, temporary interruption of treatment, and/or additional pharmacological treatments (e.g., bile acid resins, antihistamines). Monitor lipids during treatment as dose-dependent reductions in HDL-C have been reported.
In June 2024, the European Medicines Agency (EMA) recommended revoking the conditional marketing authorisation for obeticholic acid as they considered that the benefit-risk balance was no longer favourable based on results from a phase 3 confirmatory study, which did not confirm the clinical benefit of obeticholic acid in patients with PBC.[53] However, the decision to revoke the marketing authorisation was temporarily suspended in September 2024, and the marketing authorisation remains valid for the time being. The FDA’s advisory panel has also voted against full approval of the drug, but it currently remains available under accelerated approval while the advisory panel decision is being reviewed.
Elafibranor
Elafibranor is a peroxisome proliferator-activated receptor (PPAR)-alpha and -delta agonist. Elafibranor is approved by the FDA and EMA for use in combination with ursodeoxycholic acid in patients with an inadequate response to ursodeoxycholic acid, or as monotherapy in patients who cannot tolerate ursodeoxycholic acid. It is also recommended for this indication by the National Institute of Health and Care Excellence in the UK.[54]
In one phase 3 trial, elafibranor significantly improved biochemical response (alkaline phosphatase level <1.67 times the upper limit of normal, with a reduction of ≥15% from baseline, and total bilirubin at or below the upper limit of normal) and reduced serum alkaline phosphatase compared with placebo at 52 weeks.[55] The most common adverse effects associated with elafibranor included abdominal pain, diarrhoea, nausea, and vomiting.[55] Elevated creatine phosphokinase levels and muscle injury were also more common in patients who received elafibranor, including one patient who developed serious rhabdomyolysis.[55] Elafibranor is not recommended for patients who have or develop decompensated cirrhosis.
Seladelpar
Seladelpar is a PPAR-delta agonist. Seladelpar is approved by the FDA and EMA for use in combination with ursodeoxycholic acid in patients with an inadequate response to ursodeoxycholic acid, or as monotherapy in patients who cannot tolerate ursodeoxycholic acid.
In one phase 3 trial, seladelpar significantly improved biochemical response, alkaline phosphatase normalisation, and reduced moderate-to-severe pruritus at 12 months compared with placebo.[56] Adverse effects more common with seladelpar included headache, abdominal pain, nausea, and abdominal distention.[56] Seladelpar is not recommended for patients who have or develop decompensated cirrhosis.
Non-response with features of autoimmune hepatitis
In some cases, non-response reflects the presence of a more inflammatory process with some features typical of autoimmune hepatitis. Treatment for patients with suspected PBC/autoimmune hepatitis overlap is directed at the predominant histological pattern of injury.[15] See Autoimmune hepatitis (Management approach).
Management of end-stage disease
Established end-stage disease is managed symptomatically and prognostically as for any other form of cirrhosis. See Cirrhosis (Management approach).
Liver transplantation is an effective treatment for patients with end-stage disease in whom the risk of the procedure does not outweigh the expected benefit.[15][57] It is now recognised that PBC can recur in the transplanted organ in up to one third of patients.[58] Studies have shown the administration of ursodeoxycholic acid and ciclosporin (a calcineurin inhibitor) may have a role in reducing disease recurrence.[58][59]
Management of symptoms
Symptoms of PBC can significantly affect quality of life independently of the effect of disease on survival. Management of these symptoms is an important treatment goal in its own right. The principal symptoms requiring treatment are pruritus and fatigue.
Pruritus:
Pruritus is a specific feature of some (but not all) patients with PBC. The severity of pruritus in PBC is not related to the severity of the underlying disease and is, accordingly, not well treated by disease-modifying drugs. Itch can be a significant problem causing marked impairment of quality of life. It is, however, usually controllable by medical therapy.[60] Prior to commencing specific treatment for cholestatic itch, it is important to exclude other potential causes for itch. The physician should rule out dermatological and systemic disease (including chronic renal impairment and haematological malignancy) and obstructive lesions within the biliary tree because PBC is associated with an increased risk of gallstones and associated complications. It is key in all patients with presumed cholestatic itch that the extrahepatic bile duct be assessed by ultrasound to exclude an additional obstructive element.
Following exclusion of such an obstructive lesion, the first-line treatment is colestyramine.[14][15][61] This can be difficult for patients because of the flavour, but the addition of fruit juice may help with this. It is important that it be spaced away from ursodeoxycholic acid and all other oral drugs by at least 4 hours because of the potential for colestyramine to bind to ursodeoxycholic acid and to alter absorption of other drugs and fat-soluble vitamins.
Second-line treatment is instituted if patients are either unresponsive to, or intolerant of, colestyramine. Either rifampicin or naltrexone is recommended.[14][15][62][63] Rifampicin can cause hepatocellular dysfunction, and it should be introduced cautiously and with liver serum biochemistry monitoring. Deterioration in liver function and elevation of serum liver enzymes with rifampicin are indications for its discontinuation.[62][63][64] Some patients may experience an opiate withdrawal-like reaction after starting naltrexone. The dose should be increased gradually.[15]
Selective serotonin-reuptake inhibitors (e.g., sertraline) may be used in the management of cholestatic itch, when patients are unresponsive to the above treatments.[15]
Although there is good evidence for efficacy, drugs other than colestyramine remain unlicensed for the treatment of cholestatic itch.
There are limited series data to support physical approaches to pruritus treatment, which include molecular adsorbent recirculating system (MARS), plasmapheresis, or nasobiliary drainage, in patients resistant to medical treatment. MARS is a proprietary system that can be utilised in conjunction with renal replacement systems to provide an additional albumin dialysis element. The theory behind its use in pruritus (it has also been proposed for use in liver failure) is that the presumed pruritogen in the circulation is albumin bound and can only be removed by using MARS to establish an albumin gradient.
Antihistamines (e.g., hydroxyzine, diphenhydramine) 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.[15]
Transplantation is an occasionally indicated treatment for severe and resistant cholestatic itch, if all other treatments have been exhausted.[15][65]
Fatigue:
At present there are no licensed interventions for the management of fatigue in PBC.[14][15][66] There are reports associating fatigue with sleep disturbance and with autonomic dysfunction, suggesting that review and modification of lifestyle issues and drugs that may worsen either sleep abnormality or autonomic dysfunction is appropriate.[41][42] All other treatments for fatigue are experimental. Patients with significant fatigue can become socially isolated causing worsening of their perceived quality of life. Minimising this is an important element of patient coping strategy.
It is important to identify other disease processes and therapies linked to PBC either directly or indirectly, which may be contributing to the fatigue. These include other autoimmune conditions such as hypothyroidism or autoimmune anaemias, and comorbidities such as type 2 diabetes.[15]
Management of associated problems
Osteoporosis, Sjögren's syndrome, and other autoimmune diseases that are associated with PBC are managed as they would be in the absence of PBC. Osteoporosis is a common complication in patients with PBC, although the degree of increased risk is unclear.[14][15] The potential for fat-soluble vitamin malabsorption in cholestasis means that, among other approaches, calcium and vitamin D supplementation should be considered for the prevention of osteoporosis in all patients with PBC, although the evidence basis to support this is limited. See Osteoporosis and Sjögren’s syndrome.
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