Primary biliary cholangitis

• Primary biliary cholangitis (PBC) is a chronic autoimmune disease in which lymphocytes attack and destroy the small bile ducts inside the liver.
• It was formerly called primary biliary cirrhosis; the name was changed to remove the stigma and inaccuracy of "cirrhosis", because many patients never develop cirrhosis if treated early.
• Most patients are middle-aged women, and blood tests show a raised alkaline phosphatase (ALP); the hallmark antibody is antimitochondrial antibody (AMA), present in about 90 to 95 percent.
• Ursodeoxycholic acid (UDCA) at 13 to 15 mg/kg/day is the first-line drug for life; about one quarter to one third of patients need add-on therapy, and two newer PPAR-based agents (elafibranor and seladelpar) were approved in 2024.
• The disease is slow but serious: untreated it becomes cirrhosis; treated early, survival approaches that of healthy people.

By the end of this page you should be able to:

1. Explain why PBC is a cholestatic, autoimmune small-duct disease and how it differs from primary sclerosing cholangitis (PSC).
2. List the typical presentation and the extrahepatic conditions that cluster with it.
3. Use the diagnostic criteria based on cholestatic biochemistry, AMA (or PBC-specific antinuclear antibodies), and, when needed, biopsy.
4. Stratify risk using ALP, bilirubin, response criteria (Paris II, Toronto, GLOBE) and elastography.
5. Prescribe first-line and second-line therapy, with correct doses, plus symptom, bone and vitamin management.
6. State when to refer or list for liver transplantation and what recurrence means.

The name change matters clinically as well as to patients. "Cirrhosis" was inaccurate for a disease that is often diagnosed at the asymptomatic, pre-cirrhotic stage, and the old name carried stigma. Early recognition and treatment prevent end-stage disease in most patients, so "cirrhosis" no longer describes the majority of people living with the condition^[2].

Pathologically the characteristic lesion is a florid duct lesion: a small interlobular bile duct surrounded by a dense granulomatous infiltrate of lymphocytes, with destruction of the duct epithelium. Granulomas are a classic feature but are not required for the diagnosis. As stages advance, interlobular ducts disappear and fibrosis, then cirrhosis, follows.

PBC is one of the two major autoimmune cholestatic diseases of the liver, the other being primary sclerosing cholangitis. Unlike PSC, PBC is confined to the intrahepatic small ducts and is much more responsive to drug therapy.

PBC affects people of all sexes, races and ethnicities, but the distribution is striking.

• Sex and age. Earlier case-finding studies reported a median female-to-male ratio as high as 10 to 1; contemporary data show a female-to-male ratio closer to 4 to 6 to 1, because the disease is increasingly recognised in men^[1]. Still, most clinicians will describe PBC as a disease of middle-aged women, typically identified between 40 and 60 years of age, and it is exceptionally rare under 25. Modern series have also caught up with the reality that males are diagnosed later, with more advanced disease, a lower biochemical response to UDCA, higher rates of liver-related death or transplantation, and a higher risk of hepatocellular carcinoma.
• Incidence and prevalence. Pooled global incidence and prevalence are estimated at about 1.76 and 14.6 per 100,000 persons per year respectively, with higher rates in North America and Europe than in the Asia-Pacific region, and a steady rise in prevalence in all regions as case finding improves and as UDCA has reduced mortality^[1]. In the United States the prevalence in women rose from 33.5 to 57.8 per 100,000 persons over 12 years. In males it more than doubled, from 7.7 to 15.4 per 100,000.
• Other autoimmune disease. PBC clusters with other organ-specific autoimmune disorders. Sjogren's syndrome, autoimmune thyroid disease, systemic sclerosis (scleroderma) and celiac disease are the classic companions, and autoimmune hepatitis can overlap (see below). Comorbid osteoporosis and sicca symptoms are common. Metabolic dysfunction-associated steatotic liver disease is found in about 30 percent of patients^[2] and is associated with worse treatment outcomes.
• Genetics and environment. Identical twins have a 63 percent concordance, the relative risk in first-degree relatives is about 9 to 10, and there is a strong HLA and non-HLA genetic association. Environmental triggers invoked include smoking, nail polish and hair dye use, and living in industrial or polluted areas; some patients report a foreign-body or infectious trigger, although no single agent is established^[1].

PBC was renamed in recognition of a diverse, often asymptomatic population. Saying "a patient with PBC is a middle-aged woman with pruritus" is now an inadequate picture of the disease.

The cause is an autoimmune bile duct injury in a genetically predisposed person. The lipoic acid-containing enzymes of the inner mitochondrial membrane, in particular the E2 component of the pyruvate dehydrogenase complex, are the antigenic target; molecular mimicry between this self-antigen and xenobiotics or microbial antigens is the leading mechanistic hypothesis. The result is loss of immune tolerance to biliary epithelial cells, a T-cell-driven lymphocytic cholangitis, and a highly characteristic antibody (AMA) long before symptoms develop.

Risk factors can be summarised as follows:

• Female sex, with the ratio discussion above.
• Increasing age, with a peak in the sixth to eighth decades in contemporary cohorts.
• Family history of PBC or of other autoimmune disease.
• Smoking and toxic environmental exposure, which are the best-established modifiable factors.
• Associated autoimmune disease, which functions both as a clue to diagnosis and as part of the risk profile.

There is no established protective factor and no vaccine. Counselling therefore centres on early biochemical detection rather than prevention.

The sequence explains most of what is seen clinically.

1. Small-duct cholangitis. Activated CD4 and CD8 T-cells home to the interlobular bile ducts and destroy the epithelium. The portal infiltrate includes granulomas around ducts - the florid duct lesion. With repeated injury the bile duct epithelium attempts regeneration.
2. Ductopenia. Over years the number of interlobular bile ducts falls. With fewer ducts, bile flow is impaired and bile acids accumulate in the canalicular and peri-ductular spaces.
3. Cholestatic hepatocyte injury. Hydrophobic bile acids are toxic to hepatocytes and to cholangiocytes; mitochondrial injury, apoptosis and senescence of the epithelium follow. Mitochondrial autoantigens released from damaged cells amplify the immune response.
4. Fibrosis. Chronic cholestasis activates hepatic stellate cells; collagen is laid down in expanding portal tracts, producing the typical biliary fibrosis that progresses portal-to-portal.
5. Cirrhosis and portal hypertension. Untreated, PBC progresses at roughly one histological stage every 1.5 to 2 years, with about half of untreated patients developing cirrhosis within 4 years^[1]. Portal hypertension, varices, ascites and hepatic encephalopathy follow as in any cirrhosis, with an additional cholestasis-related burden of pruritus, fat malabsorption, bone disease and liposoluble vitamin deficiency.

The key teaching point is that the liver failure of PBC is downstream of duct destruction, not of hepatocyte necrosis in the first instance. This is why drugs that alter bile acid signalling (UDCA, obeticholic acid, fibrates) are the central therapy, and why antiviral or immunosuppressive strategies have only a place in overlap disease.

Although biopsy is no longer required for most patients, the histology anchors the concept:

• Stage 1 (portal). Portal inflammation, with the florid duct lesion.
• Stage 2 (periportal). Extension of inflammation into the periportal parenchyma and bile ductular proliferation.
• Stage 3 (septal). Bridging fibrosis.
• Stage 4. Cirrhosis.

Older schemes used a 4-stage (Ludwig) system; newer assessments separate chronic cholangitis and hepatitis activity. Ductopenia and increasing interface hepatitis are the histological features that best predict progression. On immunohistochemistry the small bile duct epithelium shows aberrant expression of mitochondrial (PDC-E2) antigen, which helps explain the autoimmune targeting.

Most patients are asymptomatic when diagnosed: the disease is found because of an incidental raised ALP on routine blood tests. Biochemistry precedes symptoms by years, and the absence of symptoms at diagnosis does not by itself imply early stage. Symptoms, once present, do not correlate well with the degree of cholestasis or fibrosis, and nearly everyone would develop them within two decades if left untreated.

• Fatigue. The most common complaint, present in up to 80 percent of patients during the disease course and often rated the most disabling symptom. Its origin is poorly understood and it responds poorly to treatment, so contributing causes (anaemia, hypothyroidism, sleep apnoea, depression, disturbed sleep from pruritus) must be sought actively.
• Pruritus. Present at some point in most patients, classically worse at night and in warm weather, can be severe enough to disturb sleep and quality of life.
• Right upper quadrant discomfort is uncommon and, when present, usually reflects capsular stretch in an enlarged liver.
• Jaundice appears later, as disease advances. Dark urine and pale stools follow when cholestasis is marked.
• Dry eyes and dry mouth (sicca) from associated Sjogren's syndrome, in up to 66 percent of patients depending on how it is sought^[1].
• Weight loss and fevers are not typical but occur with advanced disease, and fever should always raise the question of cholangitis or another process.
• Steatorrhoea and fat-soluble vitamin deficiency (A, D, E, K) in established cholestasis, with their own consequences (night blindness, bleeding tendency, osteomalacia).
• Symptoms of associated autoimmune disease - dry mouth and eyes, hypothyroid symptoms, dysphagia from the sicca or from coexisting autoimmune hepatitis, joint pains from rheumatoid arthritis.

• General: may be entirely normal in early disease.
• Skin: jaundice, xanthelasma (periorbital cholesterol deposits), excoriations from pruritus, hyperpigmentation, spider naevi in cirrhosis.
• Abdomen: hepatomegaly is common; splenomegaly appears with portal hypertension; ascites is a late sign.
• Eyes: no specific sign, but complex (sicca) can be evident.
• Signs of cirrhosis and portal hypertension: caput medusae, gynaecomastia, testicular atrophy, palmar erythema, flapping tremor if encephalopathic - later disease only.

A clinical pearl worth remembering: pruritus can be the presenting symptom years before any biochemical abnormality is noticed, and PBC can be part of the differential of unexplained itch with completely normal liver tests early on.

PBC must be separated from other causes of cholestasis and from other autoimmune liver diseases. The feature that separates each is usually structural, serological or anatomical.

• Serum ALP raised, usually with gamma-glutamyl transferase (GGT) raised in parallel; AST and ALT are often mildly raised but should not dominate.
• Bilirubin is normal early; rising bilirubin signals advanced disease and is the most powerful prognostic marker.
• Immunoglobulin M (IgM) is characteristically raised; raised IgG in addition to IgM or an ALT more than five times the upper limit of normal should raise concern for an overlap with autoimmune hepatitis.
• AMA is positive in 90 to 95 percent of cases, with the M2 (pyruvate dehydrogenase complex E2) pattern; in the right clinical setting (raised ALP, positive AMA at a titre above 1 to 40), this is diagnostic without biopsy^[1][4]. AMA alone, in the absence of cholestasis, does not establish PBC; such individuals are usually followed because only a minority progress to disease^[1].
• PBC-specific antinuclear antibodies - anti-gp210 and anti-sp100 - are found in up to half of AMA-negative patients and are nearly diagnostic when present in a patient with cholestasis. Anti-gp210 in particular is associated with more severe disease and faster progression^[1]. Other PBC-specific antibodies (anti-KLHL12, anti-hexokinase 1) are not yet in routine use.
• AMA-negative PBC is not rare and has a similar natural history to AMA-positive disease once cirrhosis is present. It is diagnosed by cholestatic biochemistry plus PBC-specific autoantibodies, and does not require a biopsy when those criteria are met^[4].

• Abdominal ultrasound is the first-line imaging test in every patient with raised ALP, to exclude extrahepatic biliary obstruction.
• Magnetic resonance cholangiopancreatography (MRCP) is recommended in unexplained cholestasis, to exclude PSC or other duct disease. In PBC the large ducts are normal; duct wall beading suggests PSC instead.
• Transient elastography (VCTE) is now a routine part of the assessment. A liver stiffness measurement under 8 kPa is low risk, 8 to 15 kPa medium risk, and above 15 kPa high risk of liver-related events over ten years. A value at or above 10 kPa indicates severe fibrosis and is a trigger for closer follow-up and, when relevant, second-line therapy^[1][2].

A biopsy is not required to diagnose PBC when two of the following three are present: cholestatic biochemistry (raised ALP), AMA or PBC-specific autoantibodies (sp100 or gp210 if AMA negative), and histological evidence of nonsuppurative destructive cholangitis^[4]. Biopsy is reserved for:

• an unclear diagnosis after serological and imaging work-up, or seronegative disease;
• suspected overlap with autoimmune hepatitis, particularly when the ALT is more than five times the upper limit of normal;
• suspected concomitant fatty liver disease or drug-induced injury;
• staging when this would change management.

If a biopsy is taken, it should include enough portal tracts to be representative and adequate.

The AASLD approach is the simplest to apply in practice: PBC can be diagnosed when two of three criteria are met^[4]:

1. biochemical evidence of cholestasis (raised ALP);
2. presence of AMA, or, if AMA is negative, other PBC-specific autoantibodies such as sp100 or gp210;
3. histological evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts.

The EASL guidance (2017) makes the same practical points: cholestatic biochemistry plus AMA is diagnostic, and neither approach requires biopsy in typical AMA-positive disease^[3].

For staging, clinical stages are usually inferred from biochemistry and elastography rather than repeated biopsy. Advanced fibrosis is commonly taken as LSM at or above 10 kPa on VCTE; values above 15 kPa identify high-risk disease.

Risk stratification is the heart of PBC management, because treatment intensity follows from it. About one quarter to one third of patients, and in some studies up to 40 percent, have an inadequate response to UDCA after one year^[1][2].

• Biochemistry. A raised ALP is log-linearly associated with liver transplantation and death: higher values mean lower transplant-free survival. After one year on treatment, ALP above 2 times the upper limit of normal has the strongest predictive ability, but 1.5, 1.67 and 3.0 times ULN are all informative^[1]. Total bilirubin adds precision, and even values within the normal range above 0.6 times ULN predict worse outcomes. ALP normalisation is emerging as the optimal target, because patients with ALP at or below 1 times ULN have better complication-free survival than those in the 1 to 1.5 times ULN band, especially high-risk or younger patients with significant stiffness^[2].
• Response criteria. Several binary criteria are used to define an inadequate UDCA response, all applied after 12 months unless stated. Paris I requires ALP at least 3 times ULN or AST at least 2 times ULN or bilirubin above 1 mg/dL. Paris II, which is designed for early disease, requires ALP at least 1.5 times ULN or AST at least 1.5 times ULN or bilirubin above 1 mg/dL. The Toronto criterion uses ALP at least 1.67 times ULN, but applied at 24 months. The "Rochester" (Mayo) entry at 6 months uses ALP at least 2 times ULN or a Mayo score at least 4.5. The POISE composite used in trials (ALP under 1.67 times ULN with a fall of at least 15 percent and normal total bilirubin) is a response definition rather than a failure definition^[1]. No single criterion is agreed, which is a genuine source of variation between centres.
• Composite scores. The GLOBE and UK-PBC scores, built from age plus laboratory values (bilirubin, ALP, albumin, platelets), are externally validated and excellent for estimating liver-related death or transplant at 3 to 15 years. They are not, however, a tool for deciding who needs second-line therapy, because no cut-off for escalation has been defined and they are not validated on treatment with new agents.
• Elastography. As above, LSM under 8 kPa is low risk, 8 to 15 kPa medium risk and above 15 kPa high risk, with 10-year event rates of roughly 20 to 50 percent and 50 to 90 percent in the medium- and high-risk bands^[1]. Re-checking stiffness after one year on UDCA refines the estimate.

PBC is usually an outpatient diagnosis. What requires prompt action is recognising decompensated cirrhosis, severe pruritus or obstructive jaundice, and managing them accordingly. Most patients start UDCA and enter a structured follow-up programme at diagnosis.

• Perform abdominal ultrasound at diagnosis to exclude obstruction.
• Measure VCTE where available.
• Screen for varices endoscopically if cirrhosis is present or suspected (AASLD recommends at diagnosis in suspected cirrhosis).
• Screen for hepatocellular carcinoma with cross-sectional imaging every six months in men and in patients with cirrhosis, as in other chronic liver disease.
• Check thyroid function and screen for sicca, bone disease and fat-soluble vitamin deficiency.

• A simple, varied diet is advised; PBC-related hyperlipidaemia usually does not increase cardiovascular risk in the absence of the usual risk factors, so lipid-lowering therapy is reserved for those with metabolic syndrome risk.
• Exercise and weight-bearing activity reduce bone loss and help energy.
• Alcohol is limited as in any chronic liver disease.
• Smoking cessation, because smoking is a risk factor.
• Practical strategies for fatigue: treat contributors, schedule rest, maintain physical activity, and avoid social isolation, which worsens fatigue.

Ursodeoxycholic acid (UDCA) is the first-line therapy for all patients with PBC, regardless of stage or symptoms^[1][4]. It is a hydrophilic bile acid that increases the biliary pool of protective hydrophilic bile acids, promotes bile flow, alkalinises bile via upregulation of AE2, reduces MHC expression and stabilises mitochondrial membranes. The dose is 13 to 15 mg/kg/day, taken as a single daily dose or divided doses with meals; higher doses give no extra benefit and dose escalation is not recommended^[1]. It is taken for life: adherence matters, and intermittent use wastes the effect. Side effects are mild - diarrhoea, flatulence, hair thinning and weight gain - and UDCA is considered safe in pregnancy and breastfeeding^[1].

UDCA should be given at least one hour before or four hours after a bile acid sequestrant such as cholestyramine, because the sequestrant binds it^[4].

Response is assessed after 12 months (AASLD recommends 12 months to decide on second-line therapy^[4]), although some guidelines now advocate evaluating as early as 6 months, using an ALP cut-off around 1.9 times ULN, to identify non-responders sooner^[2]. UDCA has been shown to improve liver chemistries, delay histological progression, delay varices and, in large cohorts, improve 10-year transplant-free survival (about 80 percent versus about 61 percent in untreated patients) and reduce the risk of liver transplant or death at all histological stages^[1]. It does not, however, relieve pruritus or fatigue, which is why symptom-directed therapy runs alongside it.

Second-line therapy is considered for all patients with an insufficient response to UDCA after one year (or after six months if non-response is clear). It is also used as monotherapy in the roughly 5 percent who are intolerant to UDCA.

Obeticholic acid (OCA) is a farnesoid X-receptor (FXR) agonist that reduces bile acid synthesis. It is used as second-line combination therapy (or monotherapy if UDCA-intolerant) and produced a POISE composite biochemical response in about 46 to 47 percent of treated patients versus about 10 percent with placebo at one year^[2]. Dose-dependent pruritus leads to discontinuation in 10 to 25 percent of patients, and FXR activation worsens the lipid profile (lower HDL, higher LDL). Caution is mandatory in cirrhosis. The AASLD 2021 focused update makes OCA contraindicated in advanced cirrhosis, defined as cirrhosis with current or prior evidence of decompensation (encephalopathy, coagulopathy) or portal hypertension (ascites, gastro-oesophageal varices, persistent thrombocytopenia), with careful monitoring recommended in any cirrhotic patient receiving the drug^[5]. In practice OCA is avoided in cirrhosis with Child-Pugh B or C or with any evidence of portal hypertension, and used with caution at a maximum of 5 mg daily in compensated cirrhosis without portal hypertension^[1]. There are also regulatory flux notes worth knowing: OCA was voluntarily withdrawn from the US market in 2025 on FDA request and its EMA authorisation was revoked in 2024, although it remains authorised in the UK^[2]. Because availability varies by country, local formularies should always be checked.

Fibrates are strong PPAR-alpha agonists with additional beta/delta activity (bezafibrate in particular). They are endorsed as off-label second-line agents by AASLD, EASL and APASL for UDCA non-responders. Bezafibrate 400 mg daily added to UDCA normalised all liver chemistries in 31 percent of patients in the BEZURSO trial (none in the placebo arm), with 67 percent achieving ALP normalisation and a 15 percent fall in liver stiffness; a Japanese nationwide study showed lower all-cause and liver-related mortality or transplant with bezafibrate add-on^[1]. Fibrates are discouraged in decompensated liver disease, raise serum creatinine reversibly and can cause myalgias and aminotransferase elevations; liver and renal function must be monitored. Bezafibrate is not commercially available in the United States, where fenofibrate is the off-label option. Where available, bezafibrate 400 mg daily can also serve as a first-line treatment for cholestatic itch^[1].

PPAR agonists approved in 2024. Two newer agents, both approved by the FDA under the accelerated pathway (as well as by the EMA and UK MHRA), have widened the options:

• Seladelpar, a selective PPAR-delta agonist, achieved the POISE composite biochemical response in 62 percent of treated patients versus 20 percent with placebo at 12 months, and also reduced pruritus scores (about 3.2 versus 1.7 points on the pruritus numeric rating scale) and fatigue in patients with severe itch^[2].
• Elafibranor, a dual PPAR-alpha/delta agonist, achieved the composite response in 51 percent versus 4 percent with placebo, and improved fatigue and sleep in open-label follow-up, although it did not significantly improve pruritus in the main trial^[2]. Safety signals include muscle injury and elevated creatine phosphokinase (elafibranor), fractures (both newer agents) and, for elafibranor, fetal harm. Seladelpar should be avoided with complete biliary obstruction or strong CYP2C9 or OAT3 inhibitors; elafibranor has important interactions with rifampicin, statins and hormonal contraceptives^[2].

Up to half of patients who fail UDCA will also fail the first second-line agent. Triple therapy (UDCA plus OCA plus a fibrate) is used in some centres on real-world data but lacks prospective validation.

Pruritus should be treated in a stepwise way alongside disease therapy:

1. General measures: emollients, cool environment, short nails, avoiding heat and tight clothing (low cost, safe, modest efficacy).
2. Cholestyramine (anion-exchange resin), the first-line drug: 4 g once daily, titrated up to 16 g daily in divided doses, taken at least 2 to 4 hours apart from UDCA and other drugs because it binds them. Side effects are bloating and constipation.
3. Fibrates (bezafibrate 400 mg daily where available) if first-line therapy fails or is intolerable.
4. Rifampicin (150 to 300 mg twice daily): a pregnane X receptor agonist that increases bile acid metabolism and decreases pruritogens; monitor liver biochemistry in the first weeks and after dose escalation; warn patients about orange-red discolouration of tears, urine and sweat. (AASLD gives this dose twice daily; some earlier European guidance used 150 to 300 mg once daily. Where guidelines differ, the assessment, schedule and dose should be chosen by the treating team^[4].)
5. Naltrexone (25 to 50 mg daily) and sertraline (75 to 100 mg daily) are later-line options; naltrexone causes opioid-withdrawal-type symptoms in roughly one third of patients and should be started low and titrated.
6. Refractory cases can be considered for plasmapheresis, nasobiliary drainage, phototherapy or molecular adsorbent recirculating system (MARS) in specialist centres.

Fatigue is harder: no drug has proven efficacy, and stimulants such as modafinil are not effective, although modafinil may help daytime sleepiness from another cause. Management is to find and treat contributors (anaemia, hypothyroidism, sleep apnoea, depression, poorly controlled pruritus disturbing sleep), and to use behavioural strategies and activity pacing.

Sicca symptoms are managed with artificial tears, saliva substitutes, pilocarpine or cevimeline for moderate-to-severe mouth dryness, and dental surveillance. Cholestyramine doses and other drug doses above are adult doses; always check a local formulary.

Osteoporosis is common and fractures are its clinical consequence. Every patient should be assessed for bone mineral density with dual-energy X-ray absorptiometry (DEXA) at baseline and on follow-up.

• Calcium 1,000 to 1,500 mg daily and vitamin D 1,000 International Units daily, in diet and supplements as needed^[4].
• If osteoporotic, oral alendronate 70 mg weekly (or another effective bisphosphonate), avoided where there is acid reflux or known varices because of oesophageal injury risk; intravenous zoledronic acid, ibandronate or pamidronate are alternatives in those patients^[4].
• Assess for and correct fat-soluble vitamin deficiency with water-miscible (parenteral where necessary) preparations of vitamins A, D, E and K^[4]; water-miscible forms are recommended in fat malabsorption^[1]. Vitamin A at 10,000 to 25,000 International Units daily (50,000 daily for one month if visual symptoms), vitamin D 50,000 International Units weekly for 8 to 12 weeks, vitamin K 2.5 to 10 mg twice weekly and vitamin E 200 to 2,000 mg daily are illustrative adult repletion schedules from published summaries, but dosing should be guided by measured levels and local guidance^[1].
• Hyperlipidaemia from cholestasis usually does not increase cardiovascular risk in the absence of metabolic syndrome; treat cardiovascular risk as in the general population, and avoid gemfibrozil/fibrate combinations that raise injury risk without hepatobiliary benefit.
• Liposoluble vitamin A, D, E or K deficiencies can also cause night blindness, coagulopathy and osteomalacia; vitamin K is given before invasive procedures in severe cholestasis.

Transplantation is the only curative treatment for end-stage PBC, and outcomes are excellent: 5-year post-transplant mortality of about 8 percent in patients under 40 and 15 percent in older patients, with low re-transplantation rates^[1]. The need for transplant has fallen over years because of early diagnosis and UDCA, but indications remain.

Indications are analogous to those in other chronic liver diseases: end-stage disease with severe symptoms. Concretely, guidelines list end-stage disease with cirrhotic complications; EASL also names bilirubin persistently above 3 mg/dL (about 51 micromol/L), MELD above 15 or intractable pruritus, and AASLD uses a MELD score exceeding 14 as its referral threshold^[1][4]. Be aware that intractable pruritus does not attract MELD exception points because of inadequate evidence of increased pre-transplant mortality.

Recurrence after transplant is common but slow to matter: reported rates range from 9 to 61 percent depending on definition and follow-up, and recurrence can occur decades later. AMA stays positive after transplant and cannot itself diagnose recurrence, which rests on histology. Prophylactic UDCA after transplant is associated in retrospective studies with less recurrence and graft loss, and UDCA is safe post-transplant when recurrence is confirmed^[1][3]. Fatigue often persists post-transplant even without recurrence, so counselling must be honest.

All patients are followed for life, at intervals tailored to stage and response, usually every 3 to 6 months with liver biochemistry, and with elastography repeated to track stiffness. Patients who achieve normal ALP and bilirubin have the best prognosis; non-responders' trajectories determine whether second-line therapy, trial entry or transplant assessment is next.

• Cirrhosis with its usual consequences (portal hypertension, variceal bleeding, ascites, encephalopathy, hepatorenal and hepatopulmonary syndromes).
• Portal hypertension develops in a substantial minority and is managed by standard measures: beta-blockade or endoscopic banding for varices, TIPS where appropriate, screening for oesophageal varices in cirrhosis.
• Hepatocellular carcinoma at an incidence of about 4.17 per 1,000 person-years, highest in men with cirrhosis (about 9.82 per 1,000 person-years). Screening every six months with cross-sectional imaging (and alpha-fetoprotein in many programmes) is advised in men and in all patients with cirrhosis, regardless of treatment status^[1]. Inadequate response to UDCA is itself a predictor of HCC risk.
• Osteoporosis and fractures, from cholestasis, vitamin D deficiency and, sometimes, cholestyramine or bisphosphonate interactions.
• Deficiency of the vitamins that need bile for absorption (A, D, E, K) and the downstream problems (night blindness, coagulopathy, osteomalacia).
• Dyslipidaemia secondary to cholestasis, usually not atherogenic unless metabolic risk factors coexist.
• Xanthelasma and prurigo as cosmetic and symptomatic burdens.

Prognosis has improved over decades because of earlier diagnosis and UDCA. Untreated, 5-, 10- and 15-year transplant-free survival is about 79, 59 and 32 percent; with UDCA it rises to about 90, 78 and 66 percent, and PBC progresses at only one stage every 1.5 to 2 years on therapy^[1]. Early diagnosis, good biochemical response (ALP normalised), younger age, female sex, lower stiffness and white ethnicity are favourable; older age, male sex, Hispanic or Indigenous ethnicity, cirrhosis at diagnosis and non-response are adverse. Untreated, about half of patients are cirrhotic within 4 years.

A useful framing for a patient: PBC is not today what it was 40 years ago; treated early and responding well, life expectancy approaches normal, and liver transplant is a realistic backstop if needed.

A subset of patients have features of both conditions, either concurrently or developing years after the PBC diagnosis. EASL and AASLD agree on the practical approach^[4]:

• Consider the diagnosis in a patient with PBC whose ALT is more than five times the upper limit of normal, or who has IgG elevation with an ANA or smooth-muscle antibody pattern.
• Biopsy to confirm: the Paris original criteria are commonly used to define overlap (two of three PBC features - ALP above 2 times ULN or GGT above 5, AMA above 1 to 40, or a florid duct lesion - together with two of three AIH features - ALT above 5 times ULN, IgG above 2 times ULN or a smooth-muscle antibody, or interface hepatitis).
• Base treatment on the predominant histological pattern: UDCA plus immunosuppression (usually prednisolone, with azathioprine) rather than either alone. Prednisolone and budesonide are considered acceptable in pregnancy if needed, but mycophenolate is not.
• Prognosis is worse than for PBC alone, with faster fibrosis.

A practical point: a rising ALT in a stable PBC patient on UDCA is not automatically "overlap" - check for drug injury, alcohol, fatty liver and viral hepatitis first.

Most pregnancies in women with PBC and non-cirrhotic livers proceed well, with better liver tests during pregnancy but a risk of postpartum flare and worsening pruritus^[4]. UDCA is safe in pregnancy and breastfeeding and is continued. OCA and fibrates are not recommended in pregnancy or lactation because of a lack of safety data. Pruritus is treated stepwise with cholestyramine (4 to 16 g daily in divided doses, taken at least two hours away from other drugs), rifampicin or, where used, S-adenosyl-L-methionine^[4]; antenatal rifampicin dosing should follow the current pregnancy guidance and local formulary. Cirrhotic patients need portal hypertension assessment before conception and high-risk obstetric care.

As above, males present later with more advanced disease and a worse response. Late-onset or de novo disease after 70 is increasingly recognised. Adolescents or children with an autoimmune cholestatic picture almost always have a different disease (autoimmune hepatitis, inherited cholestasis) - true PBC is a disease of adults.

Most new diagnoses are now in the sixth and seventh decades; frailty, bone disease and polypharmacy (especially cholestyramine and UDCA interactions) matter more than in young patients.

PBC is under-diagnosed where laboratory testing is sparse, and untreated disease carries a heavy burden. Practical suggestions:

• Any patient with an unexplained itch and raised ALP on a routine test should be investigated before concluding "liver function is fine". If only one test is available, an ALP with attention to the upper limit is the most informative.
• Ultrasound to exclude obstruction is available in most district hospitals and is the first imaging step; MRCP is a referral-level investigation.
• AMA can be sent to a regional lab; in its absence, anti-gp210 or anti-sp100 immunoassays are useful if available and affordable. Where no antibodies are available at all, biopsy is justified when cholestasis is unexplained.
• UDCA is available and inexpensive in most settings and should be started at diagnosis. Dosing by body weight (13 to 15 mg/kg/day) and a steady supply matter more than formulation.
• Second-line agents are scarce and expensive: bezafibrate is more accessible and affordable than OCA in much of Asia, Africa and Latin America, and can be added when budget and monitoring allow; fibrates are discouraged in decompensated disease.
• Cholestyramine is cheap and effective for itch; cholestyramine shortages should trigger rifampicin (which is inexpensive but hepatotoxicity requires monitoring) rather than nothing.
• Calcium, vitamin D and sun exposure are cheap bone protections. Bisphosphonates require monitoring of renal function.
• VCTE is increasingly available but is not essential: a clinical estimate with platelet count and AST:platelet ratio (APRI) provides some staging, although neither is validated for PBC.
• Refer early to a hepatology centre when cirrhosis, high bilirubin or transplant candidacy appears likely; transport and finance are common barriers, and documentation (records of biochemistry trend) helps receiving centres.
• Palliative symptom control and honest counselling about long-term drug adherence are as important as any test.

A clear mental separation between the two is worth the effort: they share the label "autoimmune cholangitis" but differ in patient, associated disease, imaging, histology and, above all, treatment response.

• PBC is an autoimmune destruction of the small intrahepatic bile ducts, renamed from "primary biliary cirrhosis" because cirrhosis is not inevitable.
• It affects women predominantly, with modern female-to-male ratios of about 4 to 6 to 1 rather than the historical 9 to 10 to 1, and peaks in middle age.
• The classic case is an asymptomatic woman with a raised ALP and a positive AMA (M2); anti-gp210 and anti-sp100 help when AMA is negative.
• UDCA 13 to 15 mg/kg/day, for life, is the first-line drug and improves survival and prevents cirrhosis; assess response at 12 months.
• Second-line options: obeticholic acid (caution, and contraindicated, in cirrhosis), bezafibrate or other fibrates (off-label), and the 2024 PPAR agents seladelpar and elafibranor.
• Pruritus is treated stepwise: cholestyramine, fibrates (where available), rifampicin, then naltrexone/sertraline.
• ALP, bilirubin, Paris II or Toronto criteria, GLOBE score and elastography guide risk.
• Complications: cirrhosis, portal hypertension, hepatocellular carcinoma, osteoporosis, fat-soluble vitamin deficiency; transplant is curative with good outcomes and a significant but slow recurrence rate.
• Overlap with autoimmune hepatitis occurs in a minority of patients and is managed by treating the predominant histological pattern.

Cholestasis and jaundice; Cholelithiasis and biliary colic; Primary sclerosing cholangitis; Autoimmune hepatitis; Cirrhosis; Portal hypertension; Hepatocellular carcinoma; Osteoporosis; Sicca syndrome; Liver transplantation. Plain-text references only; no links are inserted until those topics are verified.