Hepatitis - autoimmune
Description
- Chronic interface hepatitis with autoantibodies + hypergammaglobulinaemia, responsive to immunosuppression
- The triad: inc AST/ALT + liver autoantibodies + inc IgG
| Type 1 | Type 2 | |
|---|---|---|
| Antibodies | ANA, ASMA, anti-actin, anti-SLA/LP, +/- ANCA | Anti-LKM-1 (or LKM-3), anti-LC1 |
| Age | Any; bimodal (adolescent + 40-60) | Children/young adults |
| Course | Variable | More severe, more often cirrhotic at diagnosis, relapse on withdrawal |
| IgG | Raised | May be normal; IgA deficiency common |
- Anti-SLA/LP - most specific for AIH; predicts relapse and need for long-term therapy
- AMA suggests overlap with PBC
- Seronegative AIH ~10-20% - absence of antibodies does not exclude it
Overlap syndromes
- AIH-PBC (AMA+, cholestatic LFTs, florid duct lesions)
- AIH-PSC - younger patients, IBD; do MRCP if cholestatic or IBD present
Epidemiology
- Incidence ~1-2/100,000/yr; prevalence ~15-25/100,000
- F:M ~4:1 (type 2 up to 10:1)
- Bimodal: adolescence and peri/postmenopausal
- ~25-40% already have cirrhosis at diagnosis
- Type 2 <10% of cases in adults
Aetiopathogenesis
- Loss of tolerance to hepatocyte antigens in a genetically predisposed host, often after an environmental trigger
- T-cell mediated interface hepatitis with plasma cell infiltrate
- *HLA-DRB103:01 and 04:01 (adults, Northern European) - DRB103 = earlier onset, worse course
- AIRE mutation (APECED/APS-1) -> AIH in ~20%
Triggers
- Viral: HAV, HBV, EBV, measles
- Drugs (drug-induced AIH-like hepatitis) - nitrofurantoin, minocycline, methyldopa, statins, infliximab, immune checkpoint inhibitors
- Distinguish: drug-induced usually remits after withdrawal and does not relapse off steroids
- Herbal/complementary preparations
Diagnosis
Presentation - highly variable
- Asymptomatic inc transaminases found incidentally (~25%)
- Insidious fatigue, arthralgia, amenorrhoea, jaundice
- Acute hepatitis mimicking viral hepatitis - and can be fulminant
- Established cirrhosis or decompensation at first presentation
- There is no typical presentation - consider AIH in any unexplained hepatitis
The three laboratory hallmarks
1. inc AST/ALT (hepatitic pattern; ALP relatively spared)
2. Autoantibodies - ANA, ASMA (type 1); anti-LKM-1, anti-LC1 (type 2); anti-SLA/LP
3. inc IgG / hypergammaglobulinaemia (polyclonal)
Liver biopsy - required
- Interface hepatitis (piecemeal necrosis) with dense lymphoplasmacytic infiltrate
- Emperipolesis and hepatocyte rosettes
- Centrilobular necrosis in acute presentations
- Stage fibrosis
- Biopsy is required for diagnosis and to stage; transjugular route if coagulopathic
Exclude first
- Viral hepatitis (A/B/C/E, EBV, CMV), Wilson disease (young patients - caeruloplasmin), alcohol, MASLD, drug injury, haemochromatosis, alpha-1 antitrypsin
- MRCP if cholestatic or coexisting IBD -> PSC overlap
Scoring
- Simplified IAIHG score - autoantibody titre, IgG, histology, exclusion of viral hepatitis
- >=6 probable, >=7 definite AIH
Management
Verified against EASL Clinical Practice Guidelines on the management of autoimmune hepatitis, 2025 - two substantive changes from earlier practice: mycophenolate is now a first-line alternative to azathioprine, and budesonide is no longer recommended first-line (and is contraindicated in cirrhosis).
Who to treat
| Absolute indication | AST >10x ULN; AST >5x ULN with IgG >2x ULN; bridging or multiacinar necrosis on histology; incapacitating symptoms |
| Relative | Relentless progression; milder biochemical or symptomatic abnormality |
| Not indicated | Minimal/no symptoms with minimal histological change or inactive cirrhosis, and AST <5x ULN |
- Active inflammation on biopsy justifies treatment even with modest transaminases - "inactive cirrhosis" is the exception, not mild disease
Induction
- Prednisolone >=0.5 mg/kg/day PLUS one of:
- Azathioprine (start after 2 weeks, once bilirubin falling; check TPMT/NUDT15), OR
- Mycophenolate mofetil 1.5-2 g/day - comparable or better efficacy, fewer adverse effects
- Teratogenic - contraindicated in pregnancy and in women planning conception; azathioprine is the safe choice there
- Budesonide is NOT first line and is contraindicated in cirrhosis (portosystemic shunting -> loses first-pass advantage, and portal vein thrombosis risk)
- Steroid taper guided by biochemical response, usually over 6-12 months
Target
- Complete biochemical response = normal ALT AND normal IgG, ideally by 6 months
- Normalising ALT alone is not remission - IgG must normalise too
- Failure to achieve it by 6 months -> reassess adherence, diagnosis, then escalate
Maintenance
- Azathioprine or MMF monotherapy, or with prednisolone <=5 mg/day
- Continue at least 3 years and >=24 months of complete biochemical response before considering withdrawal
- Biopsy showing histological remission before withdrawal - biochemical remission alone under-calls residual activity
- Relapse after withdrawal is common (~50-80%), higher in type 2 and anti-SLA/LP positive - many need lifelong therapy
Second line / refractory
- Tacrolimus (trough 6-10 microgram/L) or ciclosporin
- Higher-dose MMF; rituximab, infliximab in specialist centres
- 6-thioguanine or allopurinol-thiopurine combination in shunters
- UDCA may be added for cholestatic/overlap features
Acute severe / fulminant AIH
- High-dose IV corticosteroid, but escalate to transplant assessment early - steroids in established ALF increase sepsis risk without changing outcome
- No improvement within ~7 days -> transplant
Transplantation
- For treatment failure, decompensated cirrhosis, HCC or fulminant presentation
- Recurrent AIH in the graft ~20-30% - maintain immunosuppression, avoid rapid steroid withdrawal
- De novo AIH can occur in grafts transplanted for other indications
Everyone
- Bone protection with prolonged steroids: calcium, vitamin D, DEXA, bisphosphonate
- Vaccinate (HAV, HBV, influenza, pneumococcal, COVID) before immunosuppression
- Screen and monitor for steroid diabetes, hypertension, cataract
- HCC surveillance 6-monthly if cirrhotic
Associations
Common
- Autoimmune thyroid disease (Hashimoto, Graves)
- Synovitis / inflammatory arthropathy
Less common
- Rheumatoid arthritis
- Coeliac disease - test everyone
- Type 1 diabetes
- ITP, autoimmune haemolytic anaemia
- Vitiligo, alopecia, nail dystrophy, lichen planus
- CREST/systemic sclerosis, Sjogren
- Ulcerative colitis (consider PSC overlap)
- Membranous/other glomerulonephritis
Syndromic
- APECED / APS-1 (AIRE defect) - AIH in ~20%
- Chronic mucocutaneous candidiasis + hypoparathyroidism + Addison disease
Natural history & complications
- Untreated severe disease: ~40% mortality at 6 months; ~40% of survivors develop cirrhosis
- Treated: 10-year survival >80-90%, approaching normal life expectancy if complete biochemical response achieved
- Relapse on withdrawal 50-80% - highest in type 2, anti-SLA/LP positive, and where IgG never normalised
- Type 2 runs a more severe course than type 1
Complications
- Cirrhosis and its complications
- HCC ~1-2% per year
- Risk factors: long-standing cirrhosis, portal hypertension, persistent inflammation, immunosuppression >3 years
- Cirrhosis-dependent - surveillance is for cirrhotics
- Treatment toxicity: steroid complications, thiopurine cytopenias/hepatotoxicity/malignancy
- Extrahepatic autoimmune disease accrual
Monitor
- ALT + IgG at 1, 3, 6 months then 3-6 monthly - IgG is the relapse early-warning
- FBE, LFT on thiopurine/MMF
- Fibrosis stage; 6-monthly ultrasound if cirrhotic
- Bone density; contraception counselling on MMF
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