autoimmune and metabolic liver diseases
Contents
Four conditions that every hepatology workup must consider: AIH (hepatocellular, ANA/ASMA/IgG, steroid-responsive), PBC (cholestatic, AMA-positive, ursodiol), PSC (cholestatic, MRCP beading, IBD-associated, no proven medical therapy), and Wilson’s disease (age <40, low ceruloplasmin, Kayser-Fleischer rings). Overlap syndromes exist. Biopsy is often needed to confirm AIH and to diagnose overlap. All four can progress to cirrhosis if untreated.
comparison table
| feature | AIH | PBC | PSC | Wilson’s disease |
|---|---|---|---|---|
| pattern | hepatocellular | cholestatic | cholestatic | hepatocellular (can be fulminant) |
| demographics | F > M, bimodal (teens, 40–60s) | F >> M, age 40–60 | M > F, age 30–40 | age <40 (usually <20) |
| key serology | ANA, ASMA, anti-LKM1, elevated IgG | AMA (95%), elevated IgM | p-ANCA (~60%), no specific antibody | low ceruloplasmin, high 24-h urine copper |
| imaging | normal ducts | normal ducts | MRCP: multifocal strictures + dilatation (“beading”) | may show hepatic steatosis or cirrhosis |
| biopsy | interface hepatitis, plasma cells, rosettes | florid bile duct lesion, granulomatous cholangitis | onion-skin periductal fibrosis (but often not biopsied) | copper staining (rhodanine), variable |
| associations | other autoimmune diseases (thyroid, celiac, T1DM) | Sjögren’s, thyroid disease, celiac | IBD (~70%, usually UC) | neuropsychiatric, Kayser-Fleischer rings, haemolytic anaemia |
| first-line Tx | predniso(lo)ne + azathioprine | ursodiol (UDCA) 13–15 mg/kg/day | no proven medical Tx; manage complications | penicillamine or trientine + zinc |
| cancer risk | HCC if cirrhosis | HCC if cirrhosis | cholangiocarcinoma (lifetime ~10–15%) + HCC + gallbladder cancer | HCC if cirrhosis |
autoimmune hepatitis (AIH)
diagnosis
- Simplified IAIHG criteria: ANA or ASMA ≥1:40, elevated IgG, compatible histology, exclusion of viral hepatitis → score ≥7 = definite AIH
- Biopsy strongly recommended — interface hepatitis with plasma cell infiltration is characteristic; also helps grade severity and exclude overlap
- ANA/ASMA can be negative in ~20% — check anti-LKM1 and anti-SLA (type 2 AIH)
treatment
Induction: predniso(lo)ne 0.5–1 mg/kg/day (typically 40–60 mg) + azathioprine 50 mg/day
Maintenance: taper prednisolone over 6–8 weeks → azathioprine 1–2 mg/kg/day monotherapy once biochemical remission (normal ALT + IgG)
- check TPMT before starting azathioprine — homozygous deficiency → severe myelosuppression
- mycophenolate is second-line if azathioprine-intolerant
- treatment withdrawal is rarely successful — most patients relapse; plan for long-term maintenance
AIH can present as acute severe hepatitis (ALT >1000 U/L) mimicking DILI. If in doubt, biopsy before committing to immunosuppression. Corticosteroid trial without biopsy is reserved for patients too unstable to wait.
acute severe AIH
- prednisolone 1 mg/kg/day; if no improvement in ALT and bilirubin by day 7–14 → discuss early transplant referral
- do not delay treatment waiting for biopsy if clinical picture is clear and patient is deteriorating
primary biliary cholangitis (PBC)
diagnosis
Diagnosis established when ≥2 of 3 present (biopsy not always required):
- cholestatic biochemistry (elevated ALP)
- AMA positive (≥1:40) or AMA-M2 specific
- compatible histology
AMA-negative PBC exists (~5%) — check anti-sp100, anti-gp210.
treatment and response
Ursodiol (UDCA) 13–15 mg/kg/day — start at diagnosis, continue lifelong.
Assess response at 12 months using biochemical criteria:
| criteria | adequate response |
|---|---|
| Paris-II | ALP <1.5× ULN + AST <1.5× ULN + bilirubin normal |
| Toronto | ALP <1.67× ULN |
Inadequate response → add obeticholic acid (second-line; avoid if decompensated cirrhosis — worsens outcomes) or consider bezafibrate (off-label, European data supportive).
- pruritus management: cholestyramine → rifampicin → naltrexone → sertraline → IBAT inhibitors (linerixibat)
- fat-soluble vitamin supplementation (A, D, E, K) if cholestasis is prolonged
- osteoporosis screening — DEXA, calcium, vitamin D
primary sclerosing cholangitis (PSC)
diagnosis
- cholestatic biochemistry + MRCP showing multifocal strictures and dilatation (“beading”) of intrahepatic and/or extrahepatic bile ducts
- biopsy rarely needed (onion-skin fibrosis is classic but patchy and often missed on needle biopsy)
- screen for IBD — colonoscopy with biopsies in all new PSC diagnoses (even without GI symptoms)
management
- no proven disease-modifying therapy — ursodiol is commonly used but has not shown survival benefit in PSC; high-dose UDCA (28–30 mg/kg) is harmful
- ERCP for dominant strictures causing clinical cholangitis or worsening jaundice — brush cytology + FISH to exclude cholangiocarcinoma
- annual colonoscopy with chromoendoscopy if concurrent IBD (elevated colorectal cancer risk)
Lifetime cholangiocarcinoma risk ~10–15%. New or worsening jaundice, weight loss, or rising CA 19-9 in PSC warrants urgent cross-sectional imaging + MRCP + ERCP with brushings. No validated screening protocol exists — maintain high clinical suspicion.
- Gallbladder polyps ≥8 mm → cholecystectomy (high malignancy risk in PSC)
Wilson’s disease
diagnosis
Suspect in any unexplained liver disease age <40, unexplained neuropsychiatric symptoms, or Coombs-negative haemolytic anaemia with liver disease.
| test | finding |
|---|---|
| ceruloplasmin | <0.2 g/L (low) — but normal in ~5% of Wilson’s |
| 24-h urine copper | >0.64 µmol/day (>40 µg/day) |
| slit-lamp exam | Kayser-Fleischer rings (absent in ~50% of hepatic-only presentations) |
| hepatic copper (biopsy) | >4 µmol/g dry weight — gold standard |
| Leipzig score | ≥4 = diagnosis established |
Fulminant Wilson’s presents with Coombs-negative haemolytic anaemia, very high bilirubin, low ALP (ALP:bilirubin ratio <4), low uric acid, and rapidly rising INR. Emergency transplant evaluation — medical chelation alone is insufficient in fulminant disease.
treatment
Initial (de-coppering): penicillamine (250 mg QID, titrate up) or trientine (preferred if neurological disease — penicillamine can paradoxically worsen neuro symptoms)
Maintenance: lower-dose chelator + zinc (inhibits intestinal copper absorption)
- lifelong treatment — non-adherence → fatal decompensation
- monitor 24-h urine copper and free copper to assess response
- first-degree relatives: screen with ceruloplasmin + liver enzymes + slit-lamp ± genetic testing
overlap syndromes
- AIH–PBC overlap (~10% of PBC): features of both interface hepatitis (elevated ALT, IgG) and cholestatic disease (AMA positive). Treat with UDCA + immunosuppression.
- AIH–PSC overlap: cholestatic biochemistry + MRCP changes + interface hepatitis on biopsy. Often seen in younger patients. Add immunosuppression to PSC management.
- Biopsy is typically needed to confirm overlap.
common traps
- Attributing cholestatic enzymes to “fatty liver” — MASLD causes hepatocellular elevation; a cholestatic pattern demands AMA and duct imaging before assuming steatosis.
- Withdrawing AIH treatment after remission — relapse rate >80%. Most patients need lifelong azathioprine.
- Using high-dose UDCA in PSC — doses >20 mg/kg increase adverse events without benefit. Standard UDCA (13–15 mg/kg) is controversial but not harmful.
- Missing Wilson’s in “autoimmune hepatitis” — Wilson’s can have positive ANA and elevated IgG, mimicking AIH. Check ceruloplasmin in any patient <40 with hepatitis.
- Forgetting colonoscopy in PSC — IBD is present in ~70% and may be subclinical. Colorectal cancer risk is elevated regardless of PSC disease activity.
related: approach to elevated liver enzymes · cirrhosis · hereditary hemochromatosis · MASLD · decompensated cirrhosis