Autoimmune Hepatitis
Chronic liver inflammation from immune-mediated destruction. Predominantly young women. Type 1 (ANA/ASMA+) is most common. AST/ALT can exceed 1000 in acute flares. High relapse rate if treatment stopped. Elevated IgG is the hallmark serologic finding.
🔍 Overview
Overview
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease caused by loss of immune tolerance to hepatocytes. It predominantly affects young women (female:male ratio 4:1) but can occur at any age. Can present as acute hepatitis (AST/ALT often >1000) or chronic liver disease with insidious progression to cirrhosis. Associated with other autoimmune conditions (thyroiditis, UC, RA, celiac).
Types
- Type 1 (80%) -ANA and/or anti-smooth muscle antibody (ASMA) positive. Adults predominantly. Most common worldwide.
- Type 2 -Anti-liver-kidney microsomal antibody (anti-LKM1) positive. More common in children. Tends to be more severe.
🚨 Management
Induction
- Standard induction: Prednisone 40-60 mg daily, tapering over 4-8 weeks to 5-10 mg daily, PLUS Azathioprine (Imuran) 50 mg daily at week 2, uptitrated to 1-2 mg/kg.
- Alternative: Budesonide (Entocort) 9 mg daily -first-pass hepatic metabolism means fewer systemic side effects. BUT: do NOT use in cirrhotic patients (portosystemic shunts bypass first-pass metabolism, negating the benefit). Manns, Gastroenterology 2010
Maintenance
Azathioprine monotherapy (1-2 mg/kg daily) once steroids are tapered. Aim to maintain on the lowest effective azathioprine dose. Relapse rate is 80-90% if treatment is stopped -most patients need lifelong therapy.
TPMT Testing
Check TPMT before starting azathioprine -homozygous TPMT deficiency causes fatal myelosuppression. Heterozygous patients need dose reduction. Also monitor CBC regularly on azathioprine (q2 weeks for first 2 months, then q3 months).
🧪 Workup
Diagnostic Workup
- AST/ALT -often markedly elevated (>1000 in acute flares). Hepatocellular pattern.
- IgG levels -elevated IgG is the hallmark. Polyclonal hypergammaglobulinemia.
- ANA -positive in Type 1 (not specific for AIH)
- ASMA (anti-smooth muscle antibody) -more specific for Type 1 AIH
- Anti-LKM1 -diagnostic of Type 2 AIH
- Liver biopsy -interface hepatitis (lymphoplasmacytic infiltrate at the portal-parenchymal junction) is classic. May show bridging necrosis in severe cases.
- Rule out other causes:
- Viral hepatitis -Hep A IgM, HBsAg, anti-HBc, anti-HCV, Hep E IgM
- Drug-induced liver injury -thorough medication history
- Wilson disease -ceruloplasmin (especially in patients <40)
- Simplified AIH Scoring System -uses ANA/SMA titers, IgG levels, liver histology, and exclusion of viral hepatitis. Score >=7 = definite AIH.
💊 Medications
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Prednisone INDUCTION | 40-60 mg daily, taper to 5-10 mg over 4-8 weeks | PO | Standard induction. Monitor glucose, BP, bone density on prolonged use. |
| Azathioprine (Imuran) MAINTENANCE | 50 mg daily initially, uptitrate to 1-2 mg/kg | PO | Check TPMT BEFORE starting. Fatal myelosuppression if homozygous deficient. Monitor CBC q2 weeks x 2 months, then q3 months. AASLD 2020 |
| Budesonide (Entocort) | 9 mg daily (3 mg TID) | PO | Alternative to prednisone. First-pass metabolism = fewer systemic effects. Do NOT use in cirrhosis. |
| Mycophenolate (CellCept) | 1-2 g daily | PO | Second-line for azathioprine-intolerant patients. Teratogenic -avoid in pregnancy. |
| Tacrolimus (Prograf) | 1-6 mg daily (target trough 3-5 ng/mL) | PO | Salvage therapy for refractory AIH. Monitor trough levels and renal function. |
🏥 Rounds
Pimp Questions
❓ Why can't you use budesonide in cirrhotic patients with AIH?
Budesonide has high first-pass hepatic metabolism -normally 90% is cleared by the liver, so systemic exposure is minimal. In cirrhosis, portosystemic shunts bypass the liver, so budesonide enters systemic circulation at high levels -losing its advantage over prednisone and causing full systemic steroid side effects. Use prednisone instead.
❓ What is the most important lab to distinguish AIH from other causes of hepatitis?
IgG level. Elevated IgG (polyclonal hypergammaglobulinemia) is the hallmark of AIH and is part of the simplified diagnostic criteria. While ANA and ASMA are useful, they are not specific -ANA can be positive in many conditions. IgG elevation combined with autoantibodies and interface hepatitis on biopsy is the diagnostic triad.
❓ Why must you check TPMT before starting azathioprine?
Azathioprine is metabolized by thiopurine methyltransferase (TPMT). Patients with homozygous TPMT deficiency (~0.3% of population) accumulate toxic metabolites causing fatal myelosuppression -severe pancytopenia. Heterozygous patients (~10%) need dose reduction. Testing prevents a completely preventable catastrophic drug reaction.
❓ What happens when you try to stop AIH treatment?
The relapse rate is 80-90% when treatment is withdrawn, even after achieving biochemical remission. Most patients require lifelong immunosuppression with low-dose azathioprine. Consider attempting withdrawal only after: (1) sustained biochemical remission for >2 years, (2) confirmed histologic remission on repeat biopsy, and (3) very close follow-up with labs q2-4 weeks after stopping.
Clinical Examples
📋 Case 1, Classic Type 1 AIH Presentation
Patient: 32F with 3 weeks of fatigue, jaundice, RUQ pain. AST 1180, ALT 1420, T. bili 7.6, INR 1.2. IgG 3400 (markedly elevated). ANA 1:320, ASMA 1:160. Viral hepatitis negative. Biopsy: interface hepatitis with plasma cells.
Key findings: Type 1 AIH (ANA/ASMA positive). Simplified AIH score ≥ 7 = definite. Interface hepatitis with lymphoplasmacytic infiltrate is the hallmark histologic finding.
Management:
- Prednisone 40-60 mg daily (or budesonide 9 mg daily if non-cirrhotic), expect ALT improvement within 2 weeks
- Add azathioprine 50 mg daily after 2 weeks → titrate to 1-2 mg/kg (check TPMT first!)
- Goal: biochemical remission (normal ALT + IgG) within 6-12 months
- Taper prednisone slowly over 3-6 months → maintain on azathioprine monotherapy
- Relapse rate 80-90% if treatment stopped, most patients need lifelong azathioprine
Teaching point: AIH responds dramatically to steroids, if ALT does not improve within 2 weeks, reconsider the diagnosis. The combination of prednisone + azathioprine allows faster steroid taper and fewer steroid side effects.
📋 Case 2, Acute Severe AIH (Fulminant Presentation)
Patient: 24F with 1 week of rapidly worsening jaundice, confusion. AST 2800, ALT 3200, T. bili 18, INR 3.8, albumin 2.4. IgG 4200. ANA 1:640. Developing hepatic encephalopathy grade II.
Key findings: Acute severe AIH with impending liver failure (INR > 1.5 + encephalopathy = acute liver failure criteria). Must decide quickly: steroids or transplant listing.
Management:
- Methylprednisolone 60 mg IV daily, trial of steroids for 7 days maximum
- If improving (bilirubin decreasing, INR improving by day 7): continue steroids, add azathioprine
- If NOT improving or worsening: list for emergent liver transplant (MELD exception)
- LILLE score or similar at day 7 to objectively assess steroid response
- ICU monitoring, lactulose for encephalopathy, FFP only if actively bleeding (don't mask INR trend)
Teaching point: Acute severe AIH gets a 7-day steroid trial, this is both diagnostic and therapeutic. If no response, proceeding with steroids delays transplant listing. The key is having a clear timeline and objective response criteria before starting.
📋 Case 3, AIH Flare on Azathioprine (Non-Compliance)
Patient: 40F with known AIH in remission on azathioprine 150 mg daily. Stopped taking it 3 months ago (felt well). Now AST 680, ALT 820, IgG 2800, bilirubin 4.2. Previously well-controlled.
Key findings: AIH flare from medication non-compliance. This is the most common reason for relapse. Predictable, 80-90% relapse when therapy is withdrawn.
Management:
- Restart prednisone 30-40 mg daily (re-induce remission)
- Restart azathioprine at previous effective dose (150 mg daily)
- Taper prednisone once ALT normalizing → maintain azathioprine indefinitely
- Counsel: AIH requires lifelong therapy in most patients. Stopping medication risks flare → fibrosis progression
- Repeat liver biopsy if concern for interval fibrosis progression from uncontrolled inflammation
Teaching point: Each untreated flare accelerates fibrosis. Patients who relapse after stopping therapy should generally never attempt withdrawal again, the risk-benefit clearly favors lifelong low-dose azathioprine over recurrent flares and progressive liver damage.
Sample Presentation
Ms. Patel is a 28-year-old woman with no significant past medical history presenting with 2 weeks of fatigue, jaundice, and RUQ discomfort. Labs: AST 1,240, ALT 1,580, total bilirubin 8.4, INR 1.3, albumin 3.2. IgG markedly elevated at 3,200 (normal <1600). ANA 1:320, ASMA 1:160. Hepatitis A, B, C, E serologies negative. Ceruloplasmin normal. Liver biopsy: interface hepatitis with lymphoplasmacytic infiltrate. Simplified AIH score: 8 (definite AIH).
Key Points: Classic Type 1 AIH in a young woman -markedly elevated transaminases, elevated IgG, positive ANA/ASMA, interface hepatitis on biopsy. Check TPMT, start prednisone 60 mg daily, add azathioprine 50 mg at week 2. Monitor for steroid side effects. Counsel that lifelong therapy is likely needed (80-90% relapse rate if stopped).
Monitoring
- LFTs (AST/ALT) -q2-4 weeks during induction, then q3 months on maintenance. Goal: normalization of transaminases.
- IgG level -normalize with successful treatment. Useful marker of disease activity.
- CBC -monitor for azathioprine myelosuppression. q2 weeks for first 2 months, then q3 months.
- TPMT result -must have before starting azathioprine.
- Liver biopsy -consider repeat biopsy before treatment withdrawal to confirm histologic remission (biochemical remission does NOT guarantee histologic remission).
- Hepatocellular carcinoma screening -if cirrhosis present, standard HCC screening (ultrasound + AFP q6 months).
- Bone density -DEXA if prolonged steroid use.
📋 Summary
Summary
Suspect It in the Right Patient
Predominantly young women, though it occurs at any age and in men. Presentation ranges from an incidental transaminase rise to acute hepatitis, and AST and ALT can exceed 1,000 in a flare, which puts it on the same differential as viral and drug-induced hepatitis. Roughly a third already have cirrhosis at diagnosis, because the earlier disease was silent.
The Serologic Hallmark Is a Raised IgG
An elevated IgG with autoantibodies is the classic pattern. Type 1: ANA and anti-smooth muscle antibody, the commonest form, all ages. Type 2: anti-LKM-1, mostly children and young adults, and typically more aggressive. Seronegative autoimmune hepatitis exists, so negative antibodies with a compatible picture do not exclude it.
Biopsy Before Committing to Treatment
Interface hepatitis with a plasma cell infiltrate is the characteristic finding, and the biopsy also stages fibrosis, which changes the prognosis and the monitoring. Exclude the mimics first: viral hepatitis, drug-induced liver injury, Wilson disease in anyone under 40, alpha-1 antitrypsin deficiency, and the overlap syndromes with PBC and PSC.
Induce With Steroids
Prednisone 40 to 60 mg daily, or a lower steroid dose combined with azathioprine from the start, which reduces the cumulative steroid exposure. Budesonide is an option in non-cirrhotic disease because of high first-pass metabolism, but not in cirrhosis, where portosystemic shunting removes that advantage and raises systemic exposure and portal vein thrombosis risk.
Check TPMT Before Azathioprine
Homozygous TPMT deficiency causes fatal myelosuppression, and heterozygotes need a dose reduction. Monitor the CBC every 2 weeks for the first 2 months, then every 3 months. This is a single test that prevents a preventable death, and it must be sent before the first dose, not after.
Do Not Stop Treatment Early
The relapse rate is high, and most relapses follow premature withdrawal. Continue maintenance for at least 2 to 3 years, and only consider withdrawal after biochemical remission with a normal IgG plus histologic remission on repeat biopsy. Many patients need lifelong therapy, and repeated relapse-and-retreat cycles cause more cumulative damage than staying on maintenance.
Track Response by ALT and IgG
Biochemical remission is a normal ALT with a normal IgG, and normalizing the transaminase alone is not enough, since ongoing histologic activity persists with a normal ALT. Check labs every 1 to 2 weeks initially, then every 3 to 6 months. Second-line agents for non-responders: mycophenolate, tacrolimus or cyclosporine.
Manage the Long-Term Consequences
Bone protection with calcium, vitamin D and a bone density scan, because these patients are on steroids for years. Screen for hepatocellular carcinoma every 6 months once cirrhotic. Vaccinate against hepatitis A and B before immunosuppression. Acute severe presentation with encephalopathy needs transplant center referral, since steroid failure there is rapid and the window for listing is short.
📄 One Pager
Text version
GI · One Pager
Autoimmune Hepatitis
Elevated IgG plus autoantibodies plus interface hepatitis in a young woman: steroids induce, azathioprine maintains, and stopping therapy relapses 80 to 90% of the time.
Diagnosis
- Elevated IgG is the hallmark (polyclonal hypergammaglobulinemia), and it is what separates AIH from other hepatitides
- AST/ALT hepatocellular pattern, often >1000 in acute flares
- ANA and/or ASMA positive in Type 1 (80%, adults). ANA is not specific for AIH; ASMA is more specific
- Anti-LKM1 is diagnostic of Type 2 (more common in children, tends to be more severe)
- Liver biopsy shows interface hepatitis (lymphoplasmacytic infiltrate at the portal-parenchymal junction), bridging necrosis if severe
- Simplified AIH Score ≥7 = definite AIH, built from ANA/SMA titers, IgG, histology, and exclusion of viral hepatitis
Rule Out Before You Commit
- Viral hepatitis: Hep A IgM, HBsAg, anti-HBc, anti-HCV, Hep E IgM, because immunosuppressing active viral hepatitis is harmful
- Drug-induced liver injury: thorough medication history, DILI can mimic the biochemistry exactly
- Wilson disease: ceruloplasmin, especially in patients <40 where it is most likely to be missed
- Who gets it: predominantly young women (female:male 4:1), any age. Look for associated autoimmunity (thyroiditis, UC, RA, celiac)
Induction to Maintenance, Step by Step
1
Check TPMT first: homozygous deficiency plus azathioprine causes fatal myelosuppression. Heterozygotes need dose reduction. This is a completely preventable catastrophe
2
Induce with prednisone 40 to 60 mg daily: AIH responds dramatically to steroids. If ALT does not improve within 2 weeks, reconsider the diagnosis
3
Add azathioprine 50 mg daily at week 2, uptitrate to 1 to 2 mg/kg. The combination allows a faster steroid taper and fewer steroid side effects
4
Taper prednisone to 5 to 10 mg over 4 to 8 weeks, then off, leaving azathioprine monotherapy at the lowest effective dose
5
Target biochemical remission (normal ALT + normal IgG) within 6 to 12 months, then continue indefinitely: relapse is 80 to 90% if therapy is stopped, so most patients need lifelong treatment
Key Drugs
Prednisone (induction)40 to 60 mg PO daily, taper to 5 to 10 mg over 4 to 8 weeks
Azathioprine (Imuran, maintenance)50 mg PO daily, uptitrate to 1 to 2 mg/kg. TPMT first
Budesonide (Entocort)9 mg PO daily (3 mg TID). Not in cirrhosis
Mycophenolate (CellCept)1 to 2 g PO daily if azathioprine-intolerant. Teratogenic
Tacrolimus (Prograf)1 to 6 mg PO daily, target trough 3 to 5 ng/mL, salvage only
Monitoring
- AST/ALT q2 to 4 weeks during induction, then q3 months on maintenance, because normalization of transaminases is the treatment goal
- IgG level alongside LFTs, it normalizes with successful treatment and is a useful marker of ongoing disease activity
- CBC q2 weeks for the first 2 months, then q3 months, to catch azathioprine myelosuppression before it becomes pancytopenia
- Repeat liver biopsy before any withdrawal attempt, because biochemical remission does NOT guarantee histologic remission
- HCC screening (ultrasound + AFP q6 months) if cirrhotic, standard cirrhosis surveillance applies
- DEXA if steroids are prolonged, to catch steroid bone loss. Also watch glucose and BP on prednisone
Pitfalls
- Starting azathioprine without TPMT. Homozygous deficiency (~0.3%) means toxic metabolite accumulation and fatal pancytopenia
- Budesonide in a cirrhotic. Its whole advantage is ~90% first-pass hepatic clearance; portosystemic shunts bypass the liver, so you get full systemic steroid exposure with no benefit. Use prednisone
- Stopping therapy because the patient feels well. Non-compliance is the most common reason for relapse, and each untreated flare accelerates fibrosis
- Calling it AIH without excluding viral hepatitis, DILI, and Wilson. The autoantibodies are not specific enough to stand alone
- Continuing steroids past day 7 in acute severe AIH that is not responding, which just delays transplant listing
Escalate / Refer When
- INR >1.5 plus encephalopathy = acute liver failure. Methylprednisolone 60 mg IV daily as a 7-day maximum steroid trial, both diagnostic and therapeutic
- No improvement in bilirubin or INR by day 7: list for emergent transplant (MELD exception). Assess objectively (LILLE score or similar) rather than by gestalt
- ALT not improving within 2 weeks of steroids: reconsider the diagnosis, this disease normally responds fast
- Azathioprine intolerance or refractory disease: mycophenolate second-line, tacrolimus as salvage, both hepatology-directed
- Withdrawal attempt only if sustained biochemical remission >2 years, confirmed histologic remission on repeat biopsy, and labs q2 to 4 weeks after stopping
Key Evidence
- Manns, Gastroenterology 2010: budesonide 9 mg daily is a valid prednisone alternative for induction in non-cirrhotic AIH, with fewer systemic steroid effects
- AASLD 2020: underpins the azathioprine maintenance strategy, TPMT testing before starting, and CBC monitoring q2 weeks × 2 months then q3 months
- Diagnostic triad to carry: elevated IgG + autoantibodies (ANA, ASMA, anti-LKM1) + interface hepatitis on biopsy
Related Topics
Acute Alcoholic HepatitisAcute Liver FailureBowel ObstructionCholangitis & CholecystitisCirrhosis & AscitesClostridioides difficile (C. diff)