Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

early-stage disease

1st line – ursodeoxycholic acid

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ACUTE
|
early-stage disease
1st line – 

ursodeoxycholic acid

All patients should be treated with pharmacotherapy to modify disease progression. First-line treatment suitable for use in all patients is ursodeoxycholic acid.​[14][15]

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.[47]

Ursodeoxycholic acid can cause nausea or weight gain but has no significant side effects.[67] Changing the pattern of dosing (building up the dose slowly or changing to multiple daytime dose from single night-time dose and vice versa) can improve tolerance. Treatment must be spaced away from colestyramine (by at least 4 hours) to avoid binding and reduction in the efficacy of both drugs.

Primary options

ursodeoxycholic acid: 12-16 mg/kg/day orally given in 3 divided doses

Consider – obeticholic acid or elafibranor or seladelpar

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ACUTE
|
early-stage disease
Consider – 

obeticholic acid or elafibranor or seladelpar

Additional treatment recommended for SOME patients in selected patient group

Obeticholic acid, elafibranor, or seladelpar may be used in combination with ursodeoxycholic acid for patients with an inadequate response to ursodeoxycholic 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.​[14][15]​ 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). It is only approved for the treatment of patients without cirrhosis or patients with compensated cirrhosis and no evidence of portal hypertension. 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] 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.

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 inadequate response to 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 placebo-controlled trial of patients with PBC with an inadequate response to ursodeoxycholic acid, 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]

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. 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 treatment included headache, abdominal pain, nausea, and abdominal distention.[56]

Elafibranor and seladelpar are not recommended for patients who have or develop decompensated cirrhosis.

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.

Primary options

obeticholic acid: 5 mg orally once daily for 3 months, may increase to 10 mg once daily if inadequate response

OR

elafibranor: 80 mg orally once daily

OR

seladelpar: 10 mg orally once daily

2nd line – obeticholic acid or elafibranor or seladelpar

Back
ACUTE
|
early-stage disease
2nd line – 

obeticholic acid or elafibranor or seladelpar

All patients should be treated with pharmacotherapy to modify disease progression. Obeticholic acid, elafibranor, or seladelpar may be used as monotherapy in patients who cannot tolerate ursodeoxycholic acid.

Obeticholic acid is a bile acid analog that has additional actions over and above those of ursodeoxycholic acid through its farnesoid X receptor (FXR) agonist properties.​[14][15]​ It is approved by the US Food and Drug Administration (FDA) for the treatment of PBC as monotherapy in adults unable to tolerate ursodeoxycholic acid. 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] 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.

Elafibranor is a peroxisome proliferator-activated receptor (PPAR)-alpha and -delta agonist. Elafibranor is approved by the FDA and EMA for use 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]

Seladelpar is a PPAR-delta agonist. Seladelpar is approved by the FDA and EMA for use 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]

Elafibranor and seladelpar are not recommended for patients who have or develop decompensated cirrhosis.

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.

Primary options

obeticholic acid: 5 mg orally once daily initially for 3 months, may increase to 10 mg once daily if inadequate response

OR

elafibranor: 80 mg orally once daily

OR

seladelpar: 10 mg orally once daily

Plus – antipruritic treatment

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ACUTE
|
early-stage disease
|
with cholestatic pruritus
Plus – 

antipruritic treatment

Treatment recommended for ALL patients in selected patient group

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.

Ursodeoxycholic acid and obeticholic acid are associated with paradoxical itch in some patients. If itch develops or worsens shortly after commencing these treatments, discontinuation or addition of anti-pruritic therapy should be considered.

First-line treatment is colestyramine.[14][15]​​[61]​​ Colestyramine is safe but can be poorly tolerated because of its bitter taste. Adding fruit juice can be helpful. 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]​ Patients should also be warned about reddish-orange discolouration of tears, sweat, and secretions.

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]

Antihistamines (e.g., hydroxyzine and 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]

There are limited series data to support physical approaches to pruritus treatment (using, for example, 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.

Primary options

colestyramine: 4 g orally once to twice daily

Secondary options

rifampicin: 150 mg orally once daily initially, increase gradually according to response, maximum 600 mg/day given in 4 divided doses

OR

naltrexone: 25-50 mg orally daily

Tertiary options

sertraline: 50-100 mg orally once daily

OR

hydroxyzine: 25 mg orally every 6-8 hours when required

OR

diphenhydramine: 25-50 mg orally every 4-6 hours when required, maximum 300 mg/day

Plus – lifestyle modification

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ACUTE
|
early-stage disease
|
with fatigue
Plus – 

lifestyle modification

Treatment recommended for ALL patients in selected patient group

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 sleep abnormality or autonomic dysfunction is appropriate.[41][42]​ All other treatments for fatigue are experimental.

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]

developing end-stage liver disease or refractory pruritus

1st line – liver transplantation

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ACUTE
|
developing end-stage liver disease or refractory pruritus
1st line – 

liver transplantation

Liver transplantation is an effective treatment for end-stage PBC. Transplantation is an occasionally indicated treatment for severe and resistant cholestatic itch, if all other treatments have been exhausted.[15][65]

Mayo risk score and Model for End-Stage Liver Disease (MELD) are effective at predicting risk of death in advanced liver PBC and can be useful tools in the timing of transplantation.

Donor organ shortages, and the potential for rapid deterioration to occur in patients with advanced disease, mean that the timing of referral to a transplant unit needs to be considered carefully.

Bilirubin concentration is a useful indicator. Patients with concentrations of 51.3 micromol/L (>3 mg/dL) should be considered for referral to a transplant unit, and patients with concentrations of bilirubin 102.6 micromol/L (>6 mg/dL) should be actively considered for transplantation.

It is now recognised that PBC can recur in the transplanted organ in up to one third of patients.[58]

At present there is no consensus regarding approaches to either the prevention or treatment of post-transplant recurrence, although use of ursodeoxycholic acid in both contexts is widespread. Studies have shown the administration of ursodeoxycholic acid and ciclosporin (a calcineurin inhibitor) may have a role in reducing disease recurrence.​[58][59]​ Further studies in this area are needed.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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