Primary biliary cholangitis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

PBC primarily affects small bile ducts through immune-mediated cholangiocyte injury. It is diagnosed most often in middle-aged women but should be considered in any adult with persistent cholestatic liver tests. Associations include autoimmune thyroid disease, sicca symptoms, systemic sclerosis and coeliac disease. Raised IgM, xanthelasma and hepatomegaly can support the picture. The former term 'primary biliary cirrhosis' is obsolete because many people are identified long before cirrhosis develops.

Diagnosis generally rests on cholestatic biochemistry and disease-specific antibodies after ultrasonography excludes mechanical obstruction. Isolated antibody positivity with repeatedly normal liver tests is not the same as established PBC and needs planned review rather than automatic lifelong treatment. Conversely, antibody-negative cholestasis may still be PBC and merits expert assessment, MR imaging when ducts are in question and sometimes biopsy. Marked aminotransferase or IgG elevation raises AIH-PBC overlap, which requires histological and specialist treatment decisions rather than casually combining labels.

UDCA improves transplant-free outcomes when given at an adequate weight-based dose. Residual risk is judged from bilirubin, ALP, albumin, platelets and age using validated scores such as UK-PBC or GLOBE. Modern second-line options are changing quickly: elafibranor has NICE TA1016 and seladelpar has NICE TA1171, with product-specific hepatic, muscle, interaction and commissioning safeguards. These medicines complement risk stratification; they do not replace surveillance for cirrhosis or symptom treatment. Pruritus, fatigue, sicca symptoms and osteoporosis deserve separate attention because biochemical response may not improve each symptom.

Key points

PBC is a chronic autoimmune destruction of small intrahepatic bile ducts that causes cholestasis, progressive fibrosis and eventually portal hypertension in some patients.
A persistent alkaline-phosphatase-predominant pattern plus antimitochondrial antibodies usually establishes the diagnosis after extrahepatic obstruction has been excluded.
PBC-specific antinuclear antibodies, particularly anti-gp210 or anti-sp100 where available, support diagnosis when antimitochondrial antibodies are absent.
Liver biopsy is not routinely required for a typical antibody-positive case but helps with seronegative disease, suspected AIH overlap or another competing injury.
Pruritus and fatigue can be severe despite modest liver-test abnormality, while advanced fibrosis may progress with relatively few symptoms.
Ursodeoxycholic acid at approximately 13 to 15 mg/kg daily is lifelong first-line disease modification and should be started without waiting for symptoms.
Biochemical response is assessed after adequate UDCA exposure, using alkaline phosphatase, bilirubin and a validated PBC risk model rather than symptoms alone.
NICE now recommends both elafibranor and, since June 2026, seladelpar for eligible previously treated adults within their marketing authorisations and commissioning arrangements.
Bile-acid sequestrants can reduce itch but must be separated from UDCA and other medicines because they impair absorption.
Follow-up is lifelong and includes bone health, thyroid disease, lipid interpretation, portal-hypertension care, hepatocellular carcinoma surveillance where indicated and transplant referral for advanced disease.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Autoimmune susceptibility

Loss of tolerance to mitochondrial antigens targets small intrahepatic bile ducts, with strong female predominance and familial clustering.

Genetic and environmental interaction

Multiple immune-regulatory variants interact with incompletely defined environmental triggers; no single exposure explains most individual cases.

Associated autoimmune disease

Autoimmune thyroid, sicca, systemic sclerosis and other immune conditions commonly coexist and may shape symptoms and monitoring needs.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Small-duct immune injury
Autoreactive lymphocytes damage interlobular bile ducts, producing a chronic cholangitic inflammatory response and progressive duct loss.
2
Cholestasis and duct loss
Progressive ductopenia retains bile acids and other constituents, causing alkaline-phosphatase elevation, pruritus and further hepatocyte injury.
3
Fibrosis and portal hypertension
Repeated cholestatic injury activates scar formation, eventually distorting hepatic architecture into cirrhosis and decompensation in some patients.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Asymptomatic cholestasis

Repeated alkaline phosphatase and gamma-glutamyl transferase elevation is found on routine testing, often before bilirubin rises or examination becomes abnormal.

Cholestatic pruritus

Generalised itch, often worse at night and affecting palms or soles, produces excoriations and sleep loss without a primary inflammatory rash.

Autoimmune cluster

Dry eyes or mouth, Raynaud phenomenon, thyroid disease, systemic sclerosis or coeliac disease accompanies otherwise unexplained cholestatic liver tests.

Advanced portal diseaseRed flag

Splenomegaly, falling platelets, varices, ascites, jaundice or muscle loss indicates advanced fibrosis or portal hypertension and changes surveillance and transplant planning.

Possible overlap hepatitis

Disproportionately high ALT, raised IgG or interface hepatitis features suggest additional AIH and require specialist histological assessment before adding immunosuppression.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serial liver biochemical profileFirst step
Why
Confirm persistent cholestasis and establish severity or treatment response.
Interpretation and limitations
ALP and gamma-GT reflect cholestasis; bilirubin, albumin, INR and platelets provide prognostic information. A rapid change should trigger a search for obstruction, infection, drug injury or decompensation.
02
Antimitochondrial antibody testing
Why
Identify the characteristic PBC serological marker.
Interpretation and limitations
A convincing AMA result with persistent cholestatic tests and no obstruction is usually sufficient for diagnosis. Low-level positivity in otherwise normal biochemistry requires context and longitudinal review.
03
PBC-specific antinuclear antibodies and immunoglobulins
Why
Support seronegative PBC and look for an overlap phenotype.
Interpretation and limitations
Anti-gp210 or anti-sp100 supports PBC where available; raised IgM is common. High IgG with marked transaminases directs attention to AIH overlap.
04
Hepatobiliary ultrasonography
Why
Exclude extrahepatic obstruction and assess liver, spleen and portal complications.
Interpretation and limitations
Non-dilated ducts support an intrahepatic cholestasis but do not prove PBC. Stones, duct dilation, a mass, splenomegaly or ascites redirects investigation or stages complications.
05
Transient elastography
Why
Estimate fibrosis and refine prognosis without routine biopsy.
Interpretation and limitations
Interpret liver stiffness with bilirubin, platelets and disease context because inflammation and cholestasis can elevate values; longitudinal direction is more useful than one isolated threshold.
06
Liver biopsy
Why
Resolve antibody-negative disease, overlap hepatitis or a competing diagnosis.
Interpretation and limitations
Florid duct lesions, ductopenia and portal granulomatous inflammation support PBC. Interface activity and plasma cells may change treatment; patchiness means an adequate specimen and expert pathology matter.
07
UK-PBC or GLOBE risk calculation
Why
Quantify residual transplant or mortality risk after treatment.
Interpretation and limitations
Use validated inputs after an adequate UDCA interval and alongside clinical stage. A low score does not dismiss severe itch, while a high score prompts second-line and transplant-level review.
08
Bone density and endocrine assessment
Why
Detect osteoporosis and associated autoimmune disease.
Interpretation and limitations
DEXA frequency follows baseline risk and result. Check thyroid function and vitamin D or coeliac testing according to symptoms and local PBC bundle rather than ordering untargeted panels.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Extrahepatic biliary obstruction

Duct dilatation, stone or pancreaticobiliary mass on imaging indicates mechanical cholestasis that should be excluded before a serological PBC diagnosis.

Primary sclerosing cholangitis

Multifocal intrahepatic or extrahepatic strictures, male predominance and IBD association favour PSC over small-duct autoimmune PBC.

Autoimmune hepatitis or DILI

Marked hepatocellular inflammation, raised IgG, interface hepatitis or a compatible medicine latency suggests AIH, overlap disease or drug injury.

Additional chapter-specific clues

Obstruction or cholangitis mimicRed flag

Pain, fever, rigors, abrupt bilirubin rise or dilated ducts suggests stones, stricture or malignancy rather than uncomplicated small-duct autoimmune disease.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ConfirmationSeparate PBC from obstructive cholestasisFirst stepAlkaline phosphatase remains elevated without an obvious transient explanation.

1Repeat and fractionate the clinical problem through medicine, alcohol, pregnancy and symptom review, and assess bilirubin, albumin, INR and platelets.
2Perform ultrasound to exclude dilated ducts, stones or mass and request AMA with immunoglobulins and PBC-specific ANA when appropriate.
3Diagnose a typical antibody-positive case without routine biopsy, but use MRCP or histology when serology, ducts, transaminases or IgG are discordant.
4Stage fibrosis, screen associated conditions and record baseline symptom burden before commencing lifelong disease modification.

02First-line treatmentOptimise ursodeoxycholic acidFirst linePBC is confirmed or strongly established by a specialist.

1Calculate the daily UDCA dose from current weight, choose a licensed formulation and explain that regular long-term use changes prognosis rather than providing immediate symptom relief.
2Review administration, tolerability and adherence and recalculate after meaningful weight change; separate any bile-acid sequestrant by several hours.
3Reassess ALP, bilirubin and liver synthetic markers during treatment and formally evaluate response after an adequate interval using a validated risk model.
4Continue UDCA in responders while maintaining fibrosis, bone, thyroid, portal and cancer surveillance matched to stage.

03Inadequate responseEscalate through current commissioned optionsEscalationBiochemical risk remains elevated despite an adequate adherent UDCA course or UDCA is not tolerated.

1EscalationConfirm dose, adherence, diagnosis, overlap disease, obstruction and stage, and document the risk score rather than escalating from one fluctuating ALP result.
2Discuss NICE-approved options such as elafibranor or seladelpar in a specialist PBC service, applying current marketing authorisation and local commissioning criteria.
3Check prior decompensation, current Child-Pugh status, muscle or liver risks and interacting medicines before product selection, and continue UDCA when tolerated.
4Monitor product-specific safety and biochemical response and refer for transplant assessment when bilirubin, synthetic function or clinical decompensation indicates advanced disease.

04PruritusTreat itch as a separate clinical targetCholestatic itch disrupts sleep, skin integrity, mood or daily function.

1Exclude biliary obstruction, renal or thyroid disease and a primary dermatological cause, then quantify itch and its impact rather than relying on ALP.
2Offer emollient and cooling measures and start a bile-acid sequestrant through the BNF pathway with careful spacing from all other oral medicines.
3Second lineFor persistent severe symptoms, use specialist second-line antipruritic therapy with interaction, hepatotoxicity, mood and withdrawal safeguards.
4EscalationEscalate intractable itch to a regional liver service because it can justify advanced therapies or transplant assessment even before conventional synthetic failure.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

First-line disease modification that improves biochemical response and transplant-free outcome when taken consistently at an adequate dose.

Ursodeoxycholic acid

Use a licensed PBC formulation at approximately 13–15 mg/kg daily, within the product range of 12–16 mg/kg, divided initially if required and continued indefinitely; recalculate when weight changes.

Exclude complete biliary obstruction and follow the exact product advice in advanced disease. Diarrhoea or initial itch can affect adherence; bile-acid sequestrants reduce absorption and require wide dose separation.

Second-line PBC therapy that improves cholestatic biochemistry and can reduce associated pruritus in eligible adults.

Seladelpar

NICE TA1171 supports use within its marketing authorisation; the current Livdelzi SmPC dose is 10 mg by mouth once daily with or without food, added to UDCA after inadequate response or used alone when UDCA is not tolerated.

Specialist initiation and local commissioning apply. Establish hepatic status first; the SmPC does not recommend use with current or prior decompensated cirrhosis and contraindicates complete biliary obstruction. Monitor worsening ALT, AST, bilirubin or ALP and separate from bile-acid resins by at least four hours.

First pharmacological option for cholestatic itch through binding bile acids in the gut; it does not modify PBC progression.

Bile-acid sequestrant for pruritus

A clinician selects cholestyramine or another locally used resin and the licensed BNF regimen, beginning at a tolerable dose and scheduling it at least four to six hours away from UDCA and other essential oral medicines.

Poor taste, bloating, constipation and medicine malabsorption limit use. Review fat-soluble vitamin and anticoagulant issues with prolonged therapy and never let symptom relief delay obstruction investigation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cirrhosis and decompensation

Progressive fibrosis causes ascites, varices, encephalopathy and transplant need, making biochemical response and fibrosis assessment prognostically important.

Pruritus, malabsorption and bone disease

Chronic cholestasis causes disabling itch and impairs fat-soluble vitamin handling, while low bone density and fracture risk require active monitoring.

Hepatocellular carcinoma

Cancer risk rises once advanced fibrosis or cirrhosis develops, linking disease staging to the appropriate surveillance programme.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track ALP, bilirubin, aminotransferases, albumin, INR and platelets at a frequency matched to stage and any second-line medicine, recording the trend rather than isolated values.
Recalculate UDCA against current body weight and explicitly review adherence, formulation and dose separation at every biochemical non-response review.
Use UK-PBC, GLOBE or the locally adopted validated model after adequate treatment exposure to trigger timely second-line or transplant referral.
Assess itch, sleep, fatigue, sicca symptoms and mental wellbeing directly because laboratory improvement may not reflect symptom burden.
Repeat bone-density and thyroid assessment according to baseline findings, menopause, steroid exposure, fracture risk and the current PBC care bundle.
For advanced fibrosis provide portal-hypertension care and six-monthly HCC surveillance, and treat any first decompensation as a transplant-planning event.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

AMA needs a phenotype

Antimitochondrial antibodies strongly support PBC in persistent cholestasis, but isolated positivity with normal tests deserves surveillance rather than an automatic diagnosis.

Itch ignores stage

Severe pruritus can occur early and bilirubin can remain normal; symptom severity neither proves nor excludes advanced fibrosis.

Dose by today’s weight

A once-correct UDCA prescription becomes inadequate after weight gain, so apparent biochemical failure may be a calculation problem.

Bilirubin carries prognosis

A rising value in PBC has greater prognostic weight than minor aminotransferase fluctuation and should prompt obstruction, progression and transplant review.

Second line is now plural

Elafibranor and seladelpar have NICE recommendations, making hepatic stage, symptom goals, safety and current commissioning central to a shared choice.

11Common pitfallsFrequent interpretation and management errors.

01
Calling every isolated alkaline phosphatase elevation PBC without confirming hepatic origin and excluding biliary obstruction.
02
Withholding UDCA because the patient has no symptoms, even though treatment aims to prevent future progression.
03
Leaving a fixed UDCA dose unchanged after substantial weight change and misclassifying the patient as a non-responder.
04
Using biochemical improvement to dismiss disabling itch or fatigue without direct symptom assessment.
05
Starting a new second-line medicine without determining whether previous or current hepatic decompensation makes it unsafe.
06
Giving cholestyramine beside UDCA, seladelpar or other oral medicines and unintentionally reducing their absorption.