Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic, immune-mediated necroinflammatory liver disease characterised by interface hepatitis, hypergammaglobulinaemia (especially IgG), circulating autoantibodies and an excellent response to immunosuppression. It is a great NEET PG favourite because it neatly ties together antibody patterns, histology buzzwords, a named scoring system, and a clean drug-of-choice answer.

Definition & overview

AIH is a disease of immune tolerance failure in which T-cell-driven injury targets hepatocytes. It is classically progressive and, if untreated, marches towards cirrhosis, portal hypertension and ultimately hepatocellular carcinoma (HCC). It has a striking female preponderance (≈4:1) and a bimodal age distribution — peaking around puberty/adolescence and again in the perimenopausal/older age group (40–60 years).

It is one of the three classic autoimmune liver diseases, the others being primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). AIH is predominantly a hepatocellular (transaminase-dominant) disease, whereas PBC and PSC are cholestatic (ALP-dominant) diseases. Recognising this hepatocellular-vs-cholestatic split is the single most useful framework when you face an autoimmune liver question.

High-yield: AIH = hepatitic picture (ALT/AST ↑↑) + raised IgG + autoantibodies + interface hepatitis on biopsy, responding to steroids. PBC/PSC = cholestatic picture (ALP/GGT ↑↑).

Classification (Type 1 vs Type 2)

AIH is divided by its dominant autoantibody profile. This table is the most frequently examined fact in the topic.

Feature	Type 1 AIH	Type 2 AIH
Autoantibodies	ANA, anti-smooth muscle antibody (ASMA / anti-actin), anti-SLA/LP	Anti-LKM1 (liver-kidney microsomal type 1), anti-LC1 (liver cytosol)
Target antigen	F-actin (ASMA)	Cytochrome CYP2D6
Typical age	Any age; adults and adolescents	Children & young adults
Geography	Worldwide (commonest type, ~80%)	More common in Europe (esp. southern); rarer
Severity / relapse	Variable	Tends to be more aggressive, frequent relapse, more often presents as acute/fulminant
Associated	Anti-SLA/LP marks more severe disease & relapse	May associate with APECED / APS-1 (AIRE mutation)

High-yield: Anti-LKM1 antibody → Type 2 AIH → children. Anti-LKM1 also seen in hepatitis C (cross-reactivity), so always interpret with the clinical context.

High-yield: Anti-SLA/LP (soluble liver antigen/liver-pancreas) is the most specific antibody for AIH and predicts more severe disease and relapse after drug withdrawal.

A useful mnemonic for Type 1: "SAN-1" → Smooth muscle Ab, ANA, Number 1 (commonest). Type 2 = "LKM in Kids."

Etiology & pathophysiology

The exact trigger is unknown, but the model is loss of self-tolerance in a genetically susceptible host, precipitated by an environmental trigger (molecular mimicry).

• Genetic susceptibility: strongest association with HLA-DR3 (DRB1*0301) and HLA-DR4 (DRB1*0401). DR3 → younger patients, more severe, relapse-prone; DR4 → older patients, more extrahepatic autoimmunity, milder.
• Triggers (molecular mimicry): viral infections (hepatitis A, B, C, EBV, measles), and drugs — classically minocycline, nitrofurantoin, methyldopa, hydralazine, statins, anti-TNF agents, and checkpoint inhibitors can induce a drug-induced AIH-like syndrome.
• Effector mechanism: CD4⁺ T-helper cells recognise a hepatocyte autoantigen presented on HLA class II, recruiting CD8⁺ cytotoxic T cells and producing inflammatory cytokines. Impaired regulatory T-cell (Treg) function permits unchecked injury. B cells generate the diagnostic autoantibodies and the hypergammaglobulinaemia.

The injury concentrates at the interface between the portal tract and the hepatic lobule — hence "interface hepatitis."

Clinical features

AIH is a chameleon. Presentations span:

1. Asymptomatic — incidental transaminitis (up to 25–30%).
2. Insidious chronic hepatitis — fatigue, malaise, anorexia, amenorrhoea, arthralgia, right-upper-quadrant discomfort. This is the commonest pattern.
3. Acute hepatitis — jaundice, anorexia; may mimic viral hepatitis. Up to 25% present acutely.
4. Acute liver failure / fulminant hepatitis — more typical of Type 2; encephalopathy and coagulopathy.
5. Established cirrhosis / decompensation — ascites, variceal bleed, encephalopathy at first presentation in ~one-third.

Extrahepatic autoimmune associations (very examinable): autoimmune thyroiditis, type 1 diabetes mellitus, coeliac disease, rheumatoid arthritis, ulcerative colitis, vitiligo, Coombs-positive haemolytic anaemia, Sjögren syndrome. Always screen an AIH patient for coeliac and thyroid disease.

High-yield: A young woman with fatigue, amenorrhoea, raised transaminases, hypergammaglobulinaemia, positive ANA/ASMA, and another autoimmune disease (e.g. thyroiditis) = textbook Type 1 AIH.

Diagnosis & investigations

There is no single confirmatory test — diagnosis is a composite of biochemistry, serology, IgG, histology, and exclusion of other causes (viral hepatitis, drugs, Wilson disease, alpha-1 antitrypsin deficiency, haemochromatosis, NAFLD).

Biochemistry

• AST/ALT markedly raised (transaminase-dominant, often >5–10× ULN; can be >1000 in acute flares).
• ALP only mildly raised (a high ALP suggests cholestatic overlap/PBC).
• Bilirubin raised in active disease.
• Hypoalbuminaemia and prolonged PT/INR indicate synthetic dysfunction/severity.

Immunology

• Hypergammaglobulinaemia — polyclonal rise in IgG (or total globulins ≥1.1× ULN) is a hallmark. Normal IgG makes AIH less likely.
• Autoantibodies as per Type 1/2 above. Add anti-SLA/LP if standard antibodies are negative ("seronegative AIH").

Investigation of choice — Liver biopsy

Liver biopsy is the investigation of choice / confirmatory test. Diagnostic histological features:

• Interface hepatitis (piecemeal necrosis) — the defining lesion; lymphoplasmacytic infiltrate eroding the limiting plate.
• Dense plasma-cell-rich portal infiltrate.
• Hepatocyte rosettes (regenerating hepatocytes encircling a central lumen).
• Emperipolesis (one cell, usually a lymphocyte, lying within the cytoplasm of a hepatocyte).
• Bridging/multiacinar necrosis in severe cases; variable fibrosis/cirrhosis.

High-yield buzzwords: interface hepatitis + plasma cell infiltrate + hepatocyte rosettes + emperipolesis = AIH on histology.

Diagnostic flow

Raised transaminases → exclude viral hepatitis & drugs → check IgG + autoantibody panel (ANA, ASMA, anti-LKM1, anti-SLA/LP) → liver biopsy → apply IAIHG scoring → trial of steroids confirms (response supports diagnosis).

Scoring systems

The International Autoimmune Hepatitis Group (IAIHG) devised both a comprehensive and a simplified score (2008), the latter being far more exam-relevant.

Parameter	Criteria	Points
ANA or ASMA	≥1:40	+1
ANA or ASMA	≥1:80 (or anti-LKM1 ≥1:40, or anti-SLA positive)	+2 (max 2 for all antibodies combined)
IgG	> upper limit normal	+1
IgG	> 1.10× upper limit normal	+2
Liver histology	Compatible with AIH	+1
Liver histology	Typical of AIH	+2
Absence of viral hepatitis	Yes	+2

Interpretation: ≥6 = probable AIH; ≥7 = definite AIH. (Maximum score 8.)

High-yield: Simplified IAIHG score uses just 4 domains — autoantibodies, IgG, histology, and exclusion of viral hepatitis. Score ≥7 = definite AIH, ≥6 = probable AIH.

Management & drug of choice

The goal is to induce and maintain biochemical and histological remission (normal transaminases AND normal IgG). AIH is one of the most steroid-responsive chronic liver diseases — a hallmark feature.

Indications to treat

• AST/ALT ≥10× ULN, or ≥5× ULN with γ-globulin ≥2× ULN.
• Bridging/multiacinar necrosis on biopsy.
• Symptomatic disease. Mild, asymptomatic, minimally active disease may be observed in selected (often elderly) patients, weighing drug toxicity.

First-line / drug of choice

Prednisolone (or prednisone) is the drug of choice for induction, given either alone or, preferably, combined with azathioprine (steroid-sparing maintenance agent).

• Induction: prednisolone (e.g. ~0.5–1 mg/kg/day, often 40–60 mg/day) tapered over weeks as transaminases fall.
• Combination: prednisolone + azathioprine (1–2 mg/kg/day) allows lower steroid dose and fewer steroid side effects. Azathioprine is not used as sole induction agent (slow onset) but is excellent for maintenance.
• Budesonide + azathioprine is an alternative induction regimen for non-cirrhotic patients (high first-pass hepatic metabolism → fewer systemic steroid effects). Avoid budesonide in cirrhosis (portosystemic shunting → systemic steroid exposure and risk).

High-yield: Drug of choice = prednisolone; maintenance/steroid-sparing = azathioprine. Budesonide is for non-cirrhotic patients only.

Before starting azathioprine, check TPMT (thiopurine methyltransferase) activity — low/absent TPMT predicts severe myelosuppression.

Maintenance, monitoring & withdrawal

• Aim for complete biochemical response (normal ALT/AST and normal IgG) — the strongest predictor of histological remission.
• Continue therapy for at least 2–3 years and at least 24 months after complete normalisation; consider biopsy before withdrawal (residual inflammation predicts relapse).
• Relapse is common (50–90%) after withdrawal, especially with anti-SLA/LP positivity, HLA-DR3, or persistent histological activity → many need lifelong therapy.

Second-line / refractory disease

• Mycophenolate mofetil (azathioprine intolerance), tacrolimus/ciclosporin, rarely rituximab or anti-TNF (infliximab) in specialist hands.

Liver transplantation

Indicated for acute liver failure unresponsive to steroids and decompensated cirrhosis. AIH can recur in the graft (~20%) and de novo AIH can arise post-transplant.

Complications

• Cirrhosis — develops in a large proportion if untreated or undertreated.
• Portal hypertension — varices, ascites, hypersplenism.
• Hepatocellular carcinoma (HCC) — risk is concentrated in cirrhotic AIH; surveillance ultrasound ± AFP every 6 months once cirrhosis is present.
• Acute liver failure — particularly Type 2.
• Treatment-related: steroid toxicity (osteoporosis, diabetes, Cushingoid features), azathioprine myelosuppression and pancreatitis.

High-yield: Untreated AIH → cirrhosis → HCC. Once cirrhosis is established, enrol in 6-monthly HCC surveillance.

Key differentials & overlap syndromes

Condition	Pattern	Key antibody / clue	Distinguishing point
AIH	Hepatocellular (ALT↑)	ANA, ASMA, anti-LKM1; ↑IgG	Interface hepatitis, steroid-responsive
PBC	Cholestatic (ALP↑)	Anti-mitochondrial antibody (AMA, M2); ↑IgM	Middle-aged women, pruritus, fatigue; treat with UDCA
PSC	Cholestatic (ALP↑)	p-ANCA; associated with UC	MRCP beading; ↑cholangiocarcinoma risk
Viral hepatitis (B/C)	Hepatocellular	HBsAg / anti-HCV; HCV can give anti-LKM1	Serology positive; treat antivirals not steroids
Wilson disease	Hepatocellular	↓Ceruloplasmin, Kayser-Fleischer rings	Young patient, neuropsychiatric, low ALP
Drug-induced AIH	Hepatocellular	Temporal drug link (minocycline, nitrofurantoin)	Resolves on drug withdrawal

Overlap syndromes

• AIH–PBC overlap: features of both — hepatocellular + cholestatic biochemistry, ANA/ASMA and AMA, interface hepatitis with bile-duct injury. Treat with UDCA + immunosuppression. This is the overlap explicitly mentioned in classic AIH teaching.
• AIH–PSC overlap ("autoimmune sclerosing cholangitis"): more in children/young adults with IBD; abnormal MRCP plus AIH features.

High-yield: AMA → PBC; anti-LKM1/ASMA → AIH; p-ANCA + UC + beaded ducts on MRCP → PSC. Mixing these up is the commonest exam trap.

Recently asked / exam angle

• Antibody → type → drug triads dominate: "Anti-LKM1 positive child with hepatitis" → Type 2 AIH; "ANA + ASMA + ↑IgG in young woman" → Type 1 AIH; drug of choice → prednisolone + azathioprine.
• Histology image / description: interface hepatitis with plasma cells, rosettes and emperipolesis → AIH. Expect a single-best-answer histology stem.
• Most specific antibody: anti-SLA/LP (also marks severe/relapsing disease).
• AMA vs other antibodies: AMA is for PBC, not AIH — a recurring distractor.
• Investigation of choice: liver biopsy. Score for diagnosis: simplified IAIHG (≥7 definite).
• Budesonide caveat: non-cirrhotic only; avoid in cirrhosis.
• HLA association: HLA-DR3 and DR4.
• Drug-induced AIH culprits: minocycline, nitrofurantoin, methyldopa, hydralazine, statins, checkpoint inhibitors.

Rapid revision

1. AIH = chronic immune-mediated hepatocellular liver disease; female 4:1, bimodal age.
2. Type 1 = ANA + ASMA (anti-actin), commonest, any age. Type 2 = anti-LKM1 (CYP2D6), children, more aggressive.
3. Anti-SLA/LP = most specific antibody; predicts severe, relapsing disease.
4. HLA-DR3 (severe, young, relapse) and HLA-DR4 are the susceptibility alleles.
5. Hallmark labs: transaminases ↑↑, polyclonal ↑IgG (hypergammaglobulinaemia), low ALP.
6. Liver biopsy = investigation of choice: interface hepatitis, plasma cells, hepatocyte rosettes, emperipolesis.
7. Diagnosis confirmed by simplified IAIHG score — ≥6 probable, ≥7 definite (4 domains: antibodies, IgG, histology, viral exclusion).
8. Drug of choice = prednisolone; add azathioprine as steroid-sparing maintenance (check TPMT first).
9. Budesonide + azathioprine for non-cirrhotic; avoid budesonide in cirrhosis.
10. Remission = normal transaminases and normal IgG; treat ≥2–3 years; relapse 50–90% on withdrawal.
11. Untreated → cirrhosis → HCC (6-monthly surveillance once cirrhotic); transplant for ALF/decompensation (can recur in graft).
12. AMA → PBC; p-ANCA + UC + MRCP beading → PSC. AIH–PBC overlap treated with UDCA + immunosuppression.