Autoimmune Liver Disease (PBC, PSC & AIH)

Meet the patient

A 52-year-old woman comes to clinic with six months of fatigue she blames on "the change", and pruritus that has her scratching her palms and soles at 3am. Her LFTs show an isolated ALP of 320 with a normal bilirubin and ALT. The registrar writes "fatty liver, recheck in six months".^[1][2]

The two questions that decide her next year are the two that decide every autoimmune liver case: is the ALP or the ALT leading? (cholestatic versus hepatitic) and whose autoimmune signature is this? Hold those two and the three diseases sort themselves out — and the wrong drug never gets reached for.^[1][2]

Three diseases on one grid — the grid that sorts them

Read these three diseases as a grid of target (bile ducts versus hepatocytes) and duct size (small versus large), and you will never confuse them.^[1][6][12]

• PBC is an autoimmune epithelitis of the small intrahepatic ducts that affects predominately females — AMA-positive cholestasis; approximately half of patients are nowadays completely asymptomatic at diagnosis.^[1][2]
• PSC is inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, producing multifocal strictures and eventual biliary cirrhosis, with a markedly increased lifetime risk of cholangiocarcinoma.^[6][17]
• AIH may affect any patient irrespective of age, sex, or ethnicity. The spectrum runs from asymptomatic cases to acute liver failure. Diagnosis is scored from autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis — not from one test.^[10][12]

PSC-AIH overlap is about 5% of PSC. The IgG4-sclerosing cholangitis mimic sits beside PSC on the grid but, unlike PSC, is steroid-responsive.^[6][8]

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The headline numbers every stem turns on:^[2][6][7]

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PBC — the predominantly female patient with AMA and a raised ALP

PBC is an autoimmune epithelitis of small intrahepatic bile ducts that affects predominately females. Untreated, it culminates in end-stage biliary cirrhosis. Diagnosis is usually based on serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Approximately half the patients are nowadays completely asymptomatic at diagnosis — picked up on a routine raised ALP, exactly like the patient at the top of this topic.^[1][2]

Antimitochondrial antibodies are a key diagnostic marker. PBC-specific antinuclear antibodies (anti-gp210 and anti-sp100) bear diagnostic and prognostic significance and are of major diagnostic importance in AMA-negative cases.^[2]

Clinically PBC declares itself with pruritus, fatigue, hyperpigmentation, dry-gland syndrome and xanthelasmas, and concurrent extrahepatic autoimmune diseases are frequent. Risk stratification uses demographic factors, clinical and biochemical findings, liver autoimmune serology and fibrosis stage.^[2]

The classic trap: a woman with fatigue and pruritus is labelled "menopause" or "fatty liver" while her cholestatic ALP sits unexplained. An unexplained cholestatic picture with a positive AMA is PBC — start UDCA, do not "recheck in six months".^[1][2]

PSC — the cholestatic ALP with IBD and a beaded MRCP

PSC is a chronic, progressive cholestatic disease of unknown aetiology with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, leading to multifocal strictures and eventual biliary cirrhosis. Ulcerative colitis occurs in 60% to 80% of PSC cases. In the other direction, a 2026 meta-analysis pooled PSC prevalence in IBD at 15.2 per 1,000 — 20.6 per 1,000 in ulcerative colitis versus 10.2 per 1,000 in Crohn's disease — against 8.06 per 100,000 in the general population. Large-duct (classic) PSC is about 90%, small-duct PSC about 5%, and PSC-AIH overlap about 5%.^[6][7]

MRCP is now the preferred noninvasive imaging modality. ERCP remains central to the diagnosis of cholangiocarcinoma and management of PSC-related complications.^[6][17]

PSC is complicated by recurrent bacterial cholangitis and by cholangiocarcinoma (lifetime incidence 10% to 20%, annual risk 1% to 2%). Concurrent PSC and ulcerative colitis markedly increase colorectal cancer risk, warranting surveillance colonoscopy every 1 to 2 years.^[6][17]

The classic trap: the UC patient with a raised ALP written off as "fatty liver" or "drug effect". A cholestatic ALP in IBD is PSC until MRCP says otherwise.^[6]

AIH — autoantibodies, high IgG and characteristic histology

AIH is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, or ethnicity. At baseline the spectrum varies from asymptomatic cases to acute liver failure with massive hepatocyte necrosis.^[12]

Diagnosis rests on convergence. The simplified criteria (Hennes 2008) retained autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis (sex and age were candidate criteria that fell away). Training used 250 AIH patients and 193 controls; validation used 109 AIH patients and 284 controls. In the validation set the score had 88% sensitivity and 97% specificity (cutoff 6 or more) and 81% sensitivity and 99% specificity (cutoff 7 or more). The authors proposed probable AIH at a cutoff greater than 6 points and definite AIH at 7 points or higher. Early diagnosis matters because immunosuppression is life-saving.^[10]

In childhood AIH, type 1 is SMA and/or ANA; type 2 is anti-LKM1. There is a female predominance in both. Steroids plus azathioprine induce remission in 80% of childhood cases; relapses are common; long-term treatment is usually required, with only some 20% of type 1 patients able to discontinue therapy successfully.^[18]

How the immune attack does its damage — and why all three end in cirrhosis

The antigenic target decides the biochemistry. In PBC the small duct is the target (autoimmune epithelitis); in PSC the duct wall is fibrosed (multifocal strictures on MRCP); in AIH the hepatocyte is attacked (hepatitic pattern). Untreated PBC culminates in end-stage biliary cirrhosis; PSC progresses to biliary cirrhosis plus cancer risk; AIH-associated cirrhosis needs surveillance for portal hypertension and hepatocellular carcinoma, and decompensated AIH cirrhosis is a transplant disease.^[1][2][12]

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The traps — mimics before immunosuppression, IgG4 before you call it PSC

The discriminator is rarely a single test — it is the convergence of serology, immunoglobulins, imaging and histology. Two named traps fail candidates every year.^[1][10]

The classic trap — other hepatitis before steroids. The simplified AIH criteria make exclusion of viral hepatitis a scoring domain because a hepatitic picture with autoantibodies is not automatically AIH.^[10]

Everyone forgets — IgG4-sclerosing cholangitis. This is a steroid-responsive, fibroinflammatory condition more commonly found in older men and strongly associated with autoimmune pancreatitis. It can closely mimic PSC, secondary sclerosing cholangitis and cholangiocarcinoma. First-line therapy is corticosteroids; relapsing or refractory disease needs steroid-sparing immunomodulators or rituximab. Prognosis is excellent when promptly diagnosed and treated with steroids — classic PSC, by contrast, has no medical therapy shown to modify progression.^[6][8][9]

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Investigations — pattern, antibodies, imaging, histology

Work these patients up in a fixed order: pattern first, then the antibody and immunoglobulin panel, then imaging, then histology where the picture is not diagnostic or an overlap is suspected.^[1]

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The autoimmune panel is the centrepiece:^[1][2]

^{[2] [8] [10] [18]}

Imaging. MRCP is now the preferred noninvasive imaging modality for PSC. ERCP remains central to evaluating dominant strictures for cholangiocarcinoma (brush cytology, FISH and biopsies have limited sensitivity) and to treating strictures; balloon dilation is first-line therapy for PSC strictures in the 2026 review.^[6][17]

Surveillance. In PSC with ulcerative colitis, surveillance colonoscopy every 1 to 2 years. In AIH-associated cirrhosis, surveillance for portal hypertension and hepatocellular carcinoma, and liver transplantation in decompensated cirrhosis.^[6][12]

The simplified AIH score — turn the work-up into a number

The simplified diagnostic criteria for AIH (Hennes 2008) turn a messy work-up into a score you can defend in a viva. The final score retained four domains:^[10]

^[10]

In the validation set: cutoff of 6 or more — 88% sensitivity, 97% specificity; cutoff of 7 or more — 81% sensitivity, 99% specificity. The authors proposed probable AIH at greater than 6 points and definite AIH at 7 points or higher.^[10]

Management — the right drug for the right disease

Therapy is disease-specific. High-dose UDCA harmed PSC patients in a randomised trial; immunosuppression is the answer for AIH; UDCA is first-line for PBC. Pick the pattern, then pick the drug.^[1][5][11]

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PBC — UDCA first-line

First-line: ursodeoxycholic acid 13 to 15 mg/kg/day. After 6 to 12 months, perform a new risk-stratification based on biochemical response using GLOBE or UK-PBC. The deep-response target is bilirubin under 0.6 times the upper limit of normal together with normalisation of alkaline phosphatase. Up to one-third of patients show an unsatisfactory response to UDCA.^[2][3]

In non-responders, the Hellenic 2026 consensus recommends add-on PPAR agonists — elafibranor (PPAR-alpha/delta) or seladelpar (PPAR-delta). If those are unavailable, fibrates (bezafibrate preferred, or fenofibrate) are an off-label option. EASL 2017 had listed licensed UDCA and OCA, with fibric acid derivatives and budesonide off-label.^[1][2][3]

OCA — what changed. Cho (2025) still described obeticholic acid as an approved second-line FXR agonist, with pruritus and the potential risk of hepatic decompensation in advanced disease. The Hellenic 2026 consensus states that OCA should no longer be considered a feasible add-on, because the EMA and FDA have revoked access. In a decompensated PBC patient, the move is transplant assessment, not OCA.^[2][3]

COBALT randomised OCA 5 to 10 mg versus placebo: the intent-to-treat primary endpoint was balanced (28.6% versus 28.9%, HR 1.01) after crossover confounding; against a propensity-weighted external control, OCA was associated with 10.1% versus 21.5% events (HR 0.39).^[4]

Symptom control. AASLD and EASL recommend a stepwise approach: cholestyramine first-line, then rifampicin, naltrexone and sertraline. The Hellenic statements put cholestyramine first and rifampicin second. Only LPA and autotaxin appear to consistently correlate with itch intensity. PBC care is meant to be structured, life-long and individualised.^[1][2][14]

PSC — no therapy proven to modify progression

No medical therapy has demonstrated the ability to modify disease progression. UDCA is frequently used empirically and may improve alkaline phosphatase, but long-term benefit is unproven. High-dose UDCA (28 to 30 mg/kg/day versus placebo, Lindor 2009, 150 adults, terminated at 6 years for futility) must be avoided: after adjustment, the risk of a primary endpoint (cirrhosis, varices, cholangiocarcinoma, transplant or death) was 2.3 times greater on UDCA, death, transplantation or minimal listing criteria 2.1 times greater, and serious adverse events 63% versus 37%. Liver tests improved; survival did not.^[5][6]

Dominant strictures are evaluated at ERCP with brush cytology, FISH and biopsies (limited sensitivity for CCA). Balloon dilation is first-line therapy for PSC strictures in the 2026 endoscopic review.^[17]

Liver transplantation provides the only curative treatment for advanced disease, yet PSC recurs in up to one-third of transplant recipients.^[6]

AIH — corticosteroids plus azathioprine

A prospective cohort used prednisolone 0.5 to 1 mg/kg/day alone or with azathioprine 1 to 2 mg/kg/day (or mycophenolate as an alternative first-line). Treatment usually needs to be maintained for life, as relapses are common after azathioprine cessation.^[19]

In non-cirrhotic AIH, Manns 2010 compared budesonide 3 mg three times daily (or twice daily) versus prednisone 40 mg/day tapered to 10 mg/day, both with azathioprine 1 to 2 mg/kg/day. The composite primary end point occurred in 47.0% on budesonide versus 18.4% on prednisone; complete biochemical remission at 6 months was 60% versus 38.8%; 72.0% versus 46.6% avoided steroid-specific side effects. Patients with cirrhosis were excluded — do not extrapolate budesonide to cirrhosis.^[11]

EASL 2025 frames AIH as needing surveillance for portal hypertension and hepatocellular carcinoma once cirrhotic, and liver transplantation for decompensated cirrhosis.^[12]

Overlap: PSC with AIH overlap is about 5% of PSC and combines the imaging of PSC with the serology of AIH.^[6]

Acute emergencies — three time-critical bundles

Acute severe AIH in one 2024 cohort was defined as acute presentation with INR 1.5 or above, without cirrhosis or hepatic encephalopathy. All patients received high-dose corticosteroid therapy. Delayed initiation (after versus before 5 days from presentation) independently predicted non-response and worse transplant-free survival; baseline INR also predicted outcome. Non-responders need liver transplantation.^[13]

Acute bacterial cholangitis follows the Tokyo Guidelines 2018 flowchart: mild disease — antibiotics are usually sufficient and most patients do not require drainage; moderate disease — early endoscopic or percutaneous transhepatic biliary drainage; severe disease — organ support first, then biliary drainage as soon as possible once the patient stabilises.^[15]

Severe intractable pruritus is treated up the stepwise ladder — cholestyramine, then rifampicin, then naltrexone, then sertraline. A variceal bleed in cirrhotic-stage disease: transfuse to haemoglobin around 7 to 8 g/dL, prophylactic antibiotics (norfloxacin or ceftriaxone), a vasoactive drug as soon as bleeding is suspected (terlipressin preferred where available — the only agent with proven survival benefit), and endoscopic therapy within the first 12 hours once stable, with variceal band ligation the recommended endoscopic treatment.^[14][16]

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Complications and the surveillance that catches them

Complications fall into three groups: cirrhotic (shared), disease-specific, and treatment-related. Guidelines mandate surveillance once cirrhosis is established in AIH.^[12]

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The recurring pitfalls are wrong-therapy and missed-mimic errors:^[5]

^{[3] [5] [6] [8] [10] [11] [12] [17]}

Prognosis — who does well, who does not

Treated PBC is built for risk-stratified care: response to UDCA 13 to 15 mg/kg/day assessed at 6 to 12 months with GLOBE or UK-PBC determines who needs second-line add-on — the deep-response target being normalised ALP with bilirubin under 0.6 times the upper limit of normal.^[2]

PSC carries the hardest outlook of the three: no therapy modifies progression, cholangiocarcinoma lifetime incidence 10 to 20%, and although transplant is the only curative treatment, PSC recurs in up to one-third of recipients.^[6][17]

AIH spans the widest range — from asymptomatic to acute liver failure — and in acute severe disease, corticosteroid non-responders follow a transplant pathway; decompensated AIH cirrhosis is likewise a transplant disease.^[12][13]

Special populations

Paediatric autoimmune liver disease is covered by EASL 2025 (adults and children). Childhood series distinguish type 1 (ANA/SMA) from type 2 (anti-LKM1); long-term treatment is usually required.^[12][18]

PSC with IBD is a distinct high-risk population: surveillance colonoscopy every 1 to 2 years.^[6]

Post-liver-transplant patients need surveillance for recurrence — PSC recurs in up to one-third of transplant recipients.^[6]

The trials that set practice

^{[5] [2] [4] [11] [10]}

The mantra, and the FLAIR mnemonic

The mantra — repeat it under the 3am LFT printout: ALP cholestatic, transaminases hepatitic — pick the right disease before you reach for the drug.^[1]

The high-yield one-liners to carry into the exam:^[2]

• PBC = predominantly females, AMA, raised ALP, small-duct disease, UDCA 13 to 15 mg/kg/day; AMA-negative disease is supported by anti-gp210 / anti-sp100.^[2]
• PSC = UC in 60 to 80%, multifocal strictures on MRCP, cholangiocarcinoma lifetime 10 to 20%, NO therapy proven to modify progression; high-dose UDCA is harmful.^[5][6]
• AIH = autoantibodies, IgG, histology and viral exclusion — scored; corticosteroids plus azathioprine (budesonide only if non-cirrhotic in the Manns trial).^[10][11]
• PBC and PSC are cholestatic (ALP); AIH is hepatitic (transaminases). PSC-AIH overlap exists (about 5% of PSC).^[6]
• Pruritus ladder = cholestyramine first, then rifampicin, then naltrexone, then sertraline.^[14]
• IgG4-sclerosing cholangitis is the steroid-responsive mimic of PSC (older men, autoimmune pancreatitis).^[8][9]
• PSC plus UC = surveillance colonoscopy every 1 to 2 years.^[6]
• Hellenic 2026: OCA is no longer a feasible add-on (EMA/FDA revoked access) — PPAR agonists are the recommended second-line; still do not start OCA in advanced disease.^[2][3]
• Score AIH before you treat it — cutoff of 6 or more: 88% sensitivity, 97% specificity (validation).^[10]
• Acute severe AIH (INR 1.5 or above, no cirrhosis, no encephalopathy) — corticosteroids early; non-responders go to transplant assessment.^[13]

Ward-round test — four stems, thirty seconds each

Stem 1 — the 52-year-old woman from the top of the topic (answer)ShowHide

The woman you met in Meet the patient: fatigue, pruritus at 3am, isolated ALP 320, normal bilirubin and ALT. What is the diagnosis, the confirmatory test, and the first drug with its dose? Model: This is primary biliary cholangitis — the demography (predominantly female), the cholestatic isolated ALP, and the pruritus. Confirm with antimitochondrial antibody; if AMA-negative, anti-gp210 and anti-sp100 carry diagnostic (and prognostic) weight. About half of PBC patients today are completely asymptomatic at diagnosis. Start ursodeoxycholic acid 13 to 15 mg/kg/day, and reassess the biochemical response at 6 to 12 months with GLOBE or UK-PBC before considering a PPAR add-on. The "fatty liver, recheck in six months" note was the trap.^[1][2]

Stem 2 — the young UC patient with a raised ALP (answer)ShowHide

A 28-year-old man with ulcerative colitis, well otherwise, has an ALP of 280 picked up on IBD surveillance bloods. Bilirubin and ALT normal. The registrar calls it "fatty liver". What do you do? Model: This is PSC until proven otherwise — a cholestatic ALP in IBD, in a disease where ulcerative colitis accompanies 60 to 80% of PSC. Order MRCP — now the preferred noninvasive imaging modality. Then surveillance colonoscopy every 1 to 2 years, lifelong vigilance for cholangiocarcinoma (lifetime incidence 10 to 20%), and honesty that no medical therapy modifies progression — high-dose UDCA is actively harmful. ERCP is for dominant strictures and cancer evaluation.^[5][6][17]

Stem 3 — the older man with a stricture, a big pancreas and a high IgG4 (answer)ShowHide

A 68-year-old man presents with painless jaundice, weight loss, a long irregular common-bile-duct stricture on MRCP, and a diffusely enlarged pancreas. Serum IgG4 is markedly raised. Is this PSC, and what is the treatment? Model: This is NOT classic PSC — it is IgG4-related sclerosing cholangitis, the steroid-responsive mimic. The clues: an older man, the strong association with autoimmune pancreatitis, a stricture that can mimic PSC, secondary sclerosing cholangitis or cholangiocarcinoma, and the raised serum IgG4. Treat with corticosteroids — first-line therapy; relapsing disease may need immunomodulators or rituximab. Classic PSC does not have a proven disease-modifying drug, which is the distinction before labelling a patient "PSC" and withholding steroids.^[8][9]

Stem 4 — the decompensated cirrhotic offered obeticholic acid (answer)ShowHide

A PBC patient with ascites, jaundice and an INR of 1.8 has an inadequate UDCA response. The registrar adds obeticholic acid 5 mg daily. What is wrong with this plan? Model: Cho (2025) already flagged the potential risk of hepatic decompensation in advanced disease. This patient is already decompensated. The Hellenic 2026 consensus additionally states that EMA and FDA have revoked access to OCA, so it is no longer a feasible add-on. The right move is liver transplant assessment and, for a compensated inadequate responder, a PPAR agonist (elafibranor or seladelpar) rather than OCA.^[2][3]

References19ShowHide

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2. [2]Dalekos GN, Gatselis N, Androutsakos T, et al. Consensus statements of the Hellenic Autoimmune Liver Diseases Study Group on the diagnosis and current management of primary biliary cholangitis Ann Gastroenterol, 2026.PMID 41868880
3. [3]Cho EJ. Emerging Therapeutics for Primary Biliary Cholangitis Korean J Gastroenterol, 2025.PMID 40709422
4. [4]Kowdley KV, Hirschfield GM, Coombs C, et al. COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls Am J Gastroenterol, 2025.PMID 39140490
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14. [14]Trivella J, Levy C. Safety considerations for the management of cholestatic itch Expert Opin Drug Saf, 2021.PMID 33836644
15. [15]Miura F, Okamoto K, Takada T, et al. Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis J Hepatobiliary Pancreat Sci, 2018.PMID 28941329
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18. [18]Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children: what is different from adult AIH? Semin Liver Dis, 2009.PMID 19676002
19. [19]Dalekos GN, Arvaniti P, Gatselis NK, et al. Long-term results of mycophenolate mofetil vs. azathioprine use in individuals with autoimmune hepatitis JHEP Rep, 2022.PMID 36411768