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 elafibranor and 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]
Elafibranor
Elafibranor is a peroxisome proliferator-activated receptor (PPAR)-alpha and -delta agonist. Elafibranor is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (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.[49]
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.[50] The most common adverse effects associated with elafibranor included abdominal pain, diarrhoea, nausea, and vomiting.[50] Elevated creatine phosphokinase levels and muscle injury were also more common in patients who received elafibranor, including one patient who developed serious rhabdomyolysis.[50] 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.[51] Adverse effects more common with seladelpar included headache, abdominal pain, nausea, and abdominal distention.[51] Seladelpar is not recommended for patients who have or develop decompensated cirrhosis.
Obeticholic acid
Obeticholic acid, a bile acid analogue with farnesoid X receptor (FXR) agonist properties, was recommended for the treatment of PBC in combination with ursodiol in patients who had an inadequate response to ursodeoxycholic acid, or as monotherapy in patients who were unable to tolerate ursodeoxycholic acid. However, the drug was voluntarily withdrawn from the US market by the manufacturer in September 2025 following a request by the FDA, due to the risk of serious liver injury. Patients are advised to discuss with their healthcare professional about transitioning to another treatment, if appropriate. The FDA has also placed a hold on all clinical trials involving obeticholic acid.[52] In Europe, the marketing authorisation for obeticholic was revoked by the EMA in 2024. However, obeticholic acid may still be available in some countries.
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][53] It is now recognised that PBC can recur in the transplanted organ in up to one third of patients.[54] Studies have shown the administration of ursodeoxycholic acid and ciclosporin (a calcineurin inhibitor) may have a role in reducing disease recurrence.[54][55]
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.[56] 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][57] 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][58][59] 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.[58][59][60] 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][61]
Fatigue:
At present there are no licensed interventions for the management of fatigue in PBC.[14][15][62] 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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