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What is Autoimmune Hepatitis?

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease where the body’s immune system mistakenly attacks its liver cells. This leads to ongoing liver inflammation, which, if left untreated, can result in cirrhosis, liver failure, or even the need for a liver transplant.

Autoimmune Hepatitis can occur de novo in a transplanted liver.

Symptoms of Autoimmune Hepatitis

Symptoms of autoimmune hepatitis can vary widely. Some individuals may be asymptomatic, with elevated liver enzymes noted only during routine lab tests. Others may experience a range of symptoms, including:

• Fatigue
• Malaise (general feeling of discomfort)
• Jaundice (yellowing of the skin and eyes)
• Abdominal pain or discomfort
• Enlarged liver (hepatomegaly)
• Joint pain (arthralgias)
• Skin rash
• Irregular blood vessels on the skin (spider angiomas)
• Loss of menstrual periods

It can also present as cirrhosis or acute liver failure in some cases.

Risk Factors for Autoimmune Hepatitis

Multifactorial = Genetics+ Immunologic+Environment

This condition can affect both children and adults, and although it’s more common in women, it can occur in any gender or age group.

• Genetic predisposition (family history of autoimmune diseases)
• Viral infections (like hepatitis A, B, or C)
• Environmental triggers (certain medications or toxins)
• Hormonal factors (women are more commonly affected)
• Coexisting autoimmune conditions (thyroid disorders, type 1 diabetes, celiac disease)

Types of Autoimmune Hepatitis

Autoimmune Hepatitis should be considered in all patients.

Most adult females (71-95%) have a bimodal peak in the 2nd and 5th decades of life.

Type 1 Autoimmune Hepatitis

• Most common form
• 4 times more common in females
• Seen in any age
• Associated with antinuclear antibodies (ANA) or anti-smooth muscle antibodies (ASMA)
• Half of the population has other autoimmune diseases like Coeliac disease, Rheumatoid arthritis, and Ulcerative colitis.

Type 2 Autoimmune Hepatitis

• Rare and typically seen in children and teenagers
• Associated with liver kidney microsomal antibody (anti-LKM1) and anti-LC antibodies (liver cytosol )

Type 3 Autoimmune Hepatitis

• Proposed based on the presence of: Anti-SLA/LP (Soluble Liver Antigen / Liver Pancreas Antibody)
  Sometimes overlaps with AIH-1 and may indicate a more severe or atypical form.

⚠️ Note on Type 3 AIH:
The designation of Type 3 AIH has been largely abandoned. This is because anti-SLA/LP antibodies are often found in Type 1 AIH patients as well. Therefore, patients with anti-SLA positivity are now generally classified under Type 1 AIH.

Overlap Syndrome

Features of both autoimmune hepatitis and other liver diseases, like primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC)

🔍 When to Suspect an Overlap Syndrome

• If a patient with AIH has cholestatic liver enzyme elevation (ALP/GGT), think of AIH-PBC or AIH-PSC overlap.
• In children, always consider underlying sclerosing cholangitis (PSC), even if enzymes are not very high.
• In adults, if ALP/GGT are high, PBC-specific autoantibodies (like AMA) should be tested first.

🧪 Must-Do Investigations

1. Magnetic Resonance Cholangiography (MRC):
   • Recommended in all childhood AIH cases at diagnosis, even without elevated cholestatic enzymes.
   • Also advised in young adults with cholestasis, incomplete treatment response, or recurring activity.
   • In adults, MRC should be done if:
     • There’s persistent cholestasis
     • And AMA or other PBC antibodies are negative
2. Autoantibody Testing:
   • Look for AMA (anti-mitochondrial antibody) and other PBC-specific antibodies first in any adult AIH patient showing cholestasis.

🧠 Why This Matters: Overlap syndromes may need different treatment strategies, and delayed diagnosis can lead to rapid progression to cirrhosis or bile duct complications.

Autoimmune Hepatitis in Adults vs Paediatrics

• Adults: Often present with fatigue, joint pain, or incidental abnormal liver tests. Cirrhosis at diagnosis is common.
• Paediatrics: Symptoms may be more acute and progress rapidly.
• Treatment goals are similar, but children may respond differently and require ongoing growth and developmental monitoring.

How Is Autoimmune Hepatitis Diagnosed?

1. Clinical History & Physical Exam
   • Fatigue, jaundice, abdominal discomfort, joint pain
2. Liver Function Tests (LFTs)
   • Elevated ALT, AST, and sometimes bilirubin
3. Autoantibody Tests
   • ANA, ASMA, anti-LKM1, anti-SLA
4. Immunoglobulin G (IgG) Levels
   • Often elevated in AIH
5. Viral Hepatitis Exclusion
   • Rule out hepatitis A, B, C, and other viral causes
6. Liver Biopsy
   • Confirms diagnosis; shows interface hepatitis, plasma cell infiltration
7. Scoring Systems
   • International AIH Group scoring to support diagnosis

⭐ 1. AIH–PBC Overlap Syndrome (Most Defined)

The Paris Criteria are the most widely accepted and validated.

📌 Paris Criteria (AIH–PBC Overlap)

Diagnosis requires ≥2 AIH features AND ≥2 PBC features.

AIH Features

At least 2 of the following 3:

1. ALT ≥5 × ULN
2. IgG ≥2 × ULN OR positive SMA
3. Histology showing moderate/severe interface hepatitis

PBC Features

At least 2 of the following 3:

1. ALP ≥2 × ULN OR GGT ≥5 × ULN
2. Positive AMA (anti-mitochondrial antibody)
3. Histology showing florid bile duct lesions or destructive cholangitis

📍 Paris criteria have ~90–95% sensitivity and specificity.

📍 These criteria are accepted by EASL & AASLD for defining AIH–PBC overlap.

⭐ 2. AIH–PSC Overlap Syndrome

There is no formal fixed diagnostic criterion, but hepatologists use combined evidence:

Diagnosis requires all three domains:

A. AIH Features

• Elevated ALT
• High IgG
• Positive ANA/SMA
• Histology: interface hepatitis ± plasma cells

(IAIHG (International Autoimmune Hepatitis Group) scoring may support the AIH component, but does not confirm overlap.)

B. PSC Features

• MRCP showing:
  • Multifocal strictures
  • Beading
  • Pruning of the bile ducts

OR

• Histology with:
  • Periductal fibrosis (“onion skin”)
  • Ductopenia
  • Bile duct injury

C. Exclusion of secondary causes

• No secondary sclerosing cholangitis
• No dominant obstruction masquerading as PSC

📍 Because PSC lacks clear biomarkers, diagnosis relies on imaging + histology + autoimmune activity.

📍 AIH–PSC overlap is more common in younger patients and may present with fluctuating ALT + cholestasis.

⭐ 3. How Transplant Teams Clinically Recognise Overlap

Even if formal criteria are imperfect, MDTs rely on:

1. Mixed biochemical pattern

High ALT + high ALP/GGT together.

2. Dual pathology on biopsy

Interface hepatitis + bile duct injury.

3. Autoantibodies

ANA/SMA + AMA (for AIH–PBC)
or ANA/SMA with PSC imaging (AIH–PSC).

4. Treatment pattern

Partial response to AIH therapy + persistent cholestasis suggests overlap.

⭐ Summary Table

🔬 Autoantibodies and Significance

• Serum IgG: Elevated levels above the upper limit of normal (ULN) are considered significant.
• ANA (Antinuclear Antibody) and ASMA (Anti-Smooth Muscle Antibody): Titers ≥1:40 are significant.
• LKM (Liver Kidney Microsomal Antibody): A titer ≥1:40 is considered significant.
• SLA (Soluble Liver Antigen): If positive, it strongly supports autoimmune hepatitis, especially in seronegative cases.
• Other Autoimmune Screening:
  • P-ANCA (Perinuclear Anti-Neutrophil Cytoplasmic Antibody)
  • TTG (Tissue Transglutaminase Antibody)
  • AMA (Anti-Mitochondrial Antibody)
  • These are useful in differentiating or detecting overlapping autoimmune disorders such as celiac disease, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), or autoimmune overlap syndromes.

Pre-Treatment Workup Before Starting Autoimmune Hepatitis Therapy

Before starting immunosuppressive therapy, these pre-treatment assessments are recommended:

• Complete blood count (CBC) and differential
• Liver and renal function tests
• Blood glucose and HbA1c
• Viral markers: Hepatitis A, B, C; HIV; CMV; EBV
• Chest X-ray (to rule out latent TB)
• Quantiferon TB Gold or Mantoux test (for latent tuberculosis)
• Immunoglobulin levels (especially IgG)
• Baseline bone mineral density (DEXA scan), especially if steroids are planned
• Abdominal ultrasound or elastography (to assess liver fibrosis)
• Pregnancy test for women of reproductive age

These tests ensure safe initiation of corticosteroids or other immunosuppressive agents and help monitor for potential complications.

Treatment options for PBC, AIH, and AIH–PBC Overlap

• First-line:
  • Corticosteroids (e.g., prednisone or budesonide)
  • Azathioprine (as a steroid-sparing agent)
• Second-line (if poor response):
  • Mycophenolate mofetil, cyclosporine, or tacrolimus
• Lifestyle measures:
  • Avoid alcohol, maintain a healthy weight, and manage comorbidities
• Monitoring:
  • LFTs, IgG levels, and side effects of long-term immunosuppression

Most patients go into remission with medication. With improved or normal AST/ALT and TgG levels.

Some may relapse if drugs are stopped too early.

1. Primary Biliary Cholangitis (PBC)

Clinical Issues

Fatigue and pruritus are common presenting symptoms.

First-Line Therapy

Ursodeoxycholic acid (UDCA)

• Dose: 13–15 mg/kg/day (indefinite therapy)
• Benefits:
  • Improves biochemical markers (ALP, bilirubin)
  • Delays histologic progression
  • Improves transplant-free survival
• Labs typically improve within months.
• UDCA does not reliably improve fatigue or pruritus.

Second-Line Therapy

Obeticholic acid (OCA) — FXR agonist reducing bile acid synthesis

• Indications:
  • Inadequate biochemical response to UDCA after ≥1 year
  • UDCA intolerance (as monotherapy in compensated disease)
• Effects:
  • Reduces ALP
  • Can worsen pruritus in a dose-dependent manner

Treatment Goals

• Normalise ALP and bilirubin
• Normalisation correlates strongly with improved survival and reduced transplant need

Pruritus Management

• First-line: Cholestyramine or colestipol
  • Administer ≥1 hour after other medications
• Second-line: Naltrexone
• Third-line: Rifampicin (use with monitoring)

2. Autoimmune Hepatitis (AIH)

Clinical Issues

Fatigue, malaise, and up to one-third have cirrhosis at diagnosis.

Treatment Goals

• Prevent progression
• Achieve biochemical remission (normalised AST, ALT, IgG)

Induction Therapy

• Prednisone monotherapy, or
• Prednisone + azathioprine (standard)

Before Starting Azathioprine

• Check thiopurine methyltransferase (TPMT) activity
• Monitor CBC for cytopenias
• Avoid in decompensated cirrhosis (cytopenia risk)

Alternative Steroid

Budesonide + azathioprine

• Faster remission
• Fewer steroid adverse effects
• Contraindicated in cirrhosis (shunting decreases effect; thrombotic events reported)
• Contraindicated in acute severe AIH or acute liver failure

Monitoring and Prognosis

• Improvement in transaminases should occur within 2 weeks
• Achieving remission within 6 months is associated with:
  • Lower progression to cirrhosis
  • Lower transplant requirement
• Recent multicenter data confirm that lower on-treatment aminotransferases predict better long-term outcomes.

3. AIH–PBC Overlap Syndrome

General Approach

Combination therapy is standard because patients have both hepatitic and cholestatic pathology.

Recommended Treatment

• UDCA (always)
• PLUS
• Prednisone ± azathioprine

Evidence Summary

• Combination UDCA + immunosuppression:
  • Improves liver enzymes
  • Stabilizes fibrosis
  • Preserves 5-year transplant-free survival
• Superior to:
  • Prednisone alone
  • UDCA alone
• Severe interface hepatitis predicts failure of UDCA monotherapy → supports need for immunosuppression.

Prognostic Note

• Studies show that AIH–PBC overlap patients have:
  • More portal hypertension
  • Higher mortality
  • Higher likelihood of needing liver transplantation
    compared to isolated PBC.

More large-scale studies are still required, but current evidence strongly supports combination therapy.

Role of therapeutic plasma exchange

Plasma exchange is not routine for chronic AIH or overlap syndromes; it is a rescue/bridging therapy supported mainly by evidence from acute liver failure (ALF)/acute-on-chronic liver failure (ACLF) and case series in autoimmune etiologies — consider plasma exchange in acute severe AIH or AIH-related ALF/ACLF to remove pathogenic antibodies/cytokines and buy time for immunosuppression or transplant evaluation.

Role of CRRT in Autoimmune Hepatitis (AIH)

Best for hyperammonemia, renal failure, and metabolic instability in AIH-ALF / AIH-ACLF. CRRT is a supportive, life-saving therapy in AIH only when the disease presents with ALF/ACLF physiology. It reduces ammonia, controls metabolic instability, supports the kidneys, prevents cerebral oedema, and bridges to LT. It does not treat the autoimmune process itself.

🔍 Monitoring for Long-Term Complications in AIH

Once autoimmune hepatitis (AIH) has progressed to cirrhosis, the journey doesn’t stop; it simply shifts focus from treatment to careful monitoring. This helps catch serious complications early and improve long-term outcomes.

🧭 What Should Be Monitored?

1. Portal Hypertension
   A common complication of cirrhosis, where increased pressure in the liver’s blood vessels can lead to:
   • Variceal bleeding (internal bleeding from swollen veins)
   • Fluid accumulation in the abdomen (ascites)
   • Confusion due to toxins in the brain (hepatic encephalopathy)
2. Liver Cancer (Hepatocellular Carcinoma – HCC)
   Even when AIH is under control, cirrhosis increases the risk of liver cancer over time.
   Regular screening helps detect HCC at an early, treatable stage.

📅 Surveillance Guidelines

• Every AIH patient with cirrhosis should undergo:
  • Ultrasound of the liver
  • AFP blood test (tumour marker for HCC)
• If portal hypertension is suspected:
  • Endoscopy may be recommended to look for varices
  • Non-invasive tools like FibroScan or liver stiffness monitoring may guide follow-up

Are There Any Special Criteria to List a Patient With Overlap Syndrome for Liver Transplant?

Short answer: No separate or exclusive “special listing criteria” exist for overlap syndromes (AIH–PBC or AIH–PSC).
However, the threshold for listing may differ because these patients can deteriorate through two parallel mechanisms—autoimmune inflammation and cholestatic destruction—so the timing of listing often occurs earlier than MELD alone predicts.

Below is what transplant teams specifically consider in addition to standard MELD-based listing criteria:

1. Standard Listing Criteria Still Apply

• MELD ≥ 15 or progressive rise
• Any decompensation: ascites, variceal bleed, encephalopathy
• Hepatorenal syndrome
• HCC within accepted criteria

These are identical to other causes of cirrhosis.

2. Additional Indications Unique to Overlap Syndromes

These are not “special rules,” but rather special clinical triggers that justify listing, even with modest MELD scores.

A. Autoimmune Hepatitis Component

Patient should be listed when ANY of the following occur:

• Steroid non-response or steroid intolerance
• Biochemical non-response despite optimal immunosuppression
  • Persistently high ALT/AST, IgG
• Recurrent flares with progressive fibrosis despite compliance
• Acute severe AIH or acute liver failure pattern (INR, bilirubin rise)

This is because AIH can crash suddenly.

B. PBC Component

List when:

• Intractable pruritus not responding to full therapy (UDCA ± OCA)
• Progressive cholestasis: bilirubin > 6–10 mg/dL
• Biochemical non-response to UDCA, especially ALP > 1.67× ULN
• Fatigue or pruritus severely affecting life, even with low MELD

PBC patients often have low MELD scores despite being very sick with cholestasis.

C. PSC Component

List when:

• Recurrent bacterial cholangitis (≥2 episodes/yr)
• Dominant strictures not amenable to dilation
• Progressive jaundice with no reversible obstruction
• High suspicion of cholangiocarcinoma (but separate criteria apply)
• Debilitating pruritus or recurrent sepsis

PSC overlap patients may need listing even with low MELD.

3. Non-MELD Determinants Used in Overlap Syndromes

These often justify listing despite “normalish” MELD:

• Refractory Pruritus

Severe, sleep-disturbing, and quality-of-life–limiting => valid indication.

• Recurrent Cholangitis

Systemic sepsis risk justifies transplant listing.

• Progressive Cholestatic Failure

Even when creatinine is normal (thus MELD underestimates severity).

• Treatment Exhaustion

All medical therapies tried → continued progression → list.

4. When MELD Does NOT Reflect Disease Severity

Overlap syndromes can remain at MELD 12–16 yet have severe cholestasis or frequent cholangitis.
This is where transplant committees accept MELD exception points or evaluate “beyond MELD” factors.

5. Practical Listing Statement

For a patient with overlap syndrome, the transplant listing is appropriate when either:

(1) Standard decompensation criteria are present,

OR

(2) Progressive cholestasis / recurrent cholangitis / AIH non-response is causing ongoing decline, even if MELD is lower.

Liver Transplant Success Rate in Autoimmune Hepatitis

Liver transplant outcomes in autoimmune hepatitis are excellent:

• 1-year survival: Over 90%
• 5-year survival: 80–85%
• 10-year survival: Still above 70% in many centres

75% graft survival at 5 years.

Patients with AIH do as well, provided there is good compliance with medications and follow-up.

Can Autoimmune Hepatitis Recur After Liver Transplant?

Yes, recurrence is possible. Studies suggest:

• Recurrence rate: 36- 68%
• Timing: Often within 2–5 years post-transplant
• Risk factors for recurrence:
  • Younger age at transplant
  • Inadequate immunosuppression
  • High IgG or autoantibodies pre-transplant

Despite recurrence, most patients can be managed successfully with reintroduction or adjustment of immunosuppressive therapy (treat like AIH).

Monitoring Guidelines After Liver Transplant in Autoimmune Hepatitis

Note: for interpretation and to know more about the FIB-4 index, check this link>>https://livertransplanthelp.com/fib-4-index-calculator/

• Routine follow-ups with LFTs and autoantibody levels
• FIB-4 Index score trend, especially useful at the community level or primary health care centres
• Liver biopsy if LFTs are persistently abnormal
• Drug level monitoring (tacrolimus, cyclosporine)
• Bone health surveillance (DEXA every 1–2 years)
• Regular screening for infections and malignancies due to long-term immunosuppression

Latest Advances in Autoimmune Hepatitis and Transplant

• Budesonide is a steroid with fewer systemic side effects
• Biologics like rituximab for refractory cases
• Improved HLA typing to assess transplant rejection risk
• Non-invasive fibrosis monitoring with FibroScan and elastography
• Personalised immunosuppression protocols to reduce side effects and recurrence

Autoimmune Hepatitis and Pregnancy

Preconception and pregnancy counselling are important.

• AIH flare risk, especially postpartum, up to 6 months postpartum.
• Advised remission 1 year before conception.
• Mycophenolate Mofetil is contraindicated during pregnancy

• AIH can be managed during pregnancy with careful monitoring.
• Prednisone is generally safe in pregnancy.
• Close collaboration between a hepatologist, an obstetrician, and a paediatrician is essential.
• Risks include:
  • Preterm birth
  • Flare-ups during pregnancy or postpartum
• Liver transplant recipients can conceive successfully, but timing and medications must be carefully planned.

Download: Key Updates from the 2025 EASL Autoimmune Hepatitis Guidelines

For readers who want a quick, structured overview of the latest recommendations, you can download the consolidated “2025 EASL AIH Key Updates” document below. This summary captures the major changes in diagnostic criteria, autoantibody testing, biopsy interpretation, first-line and second-line therapies, treatment goals, withdrawal strategies, management of overlap syndromes, and updated guidance for special populations, including children, pregnant patients, the elderly, and those with cirrhosis or acute severe presentations. It is designed as a practical reference for clinicians, trainees, and healthcare professionals involved in the care of AIH.

📥 Download Here: 2025 EASL AIH Key Updates (PDF)

Download her full text EASL 2025 guideline 📥

Frequently asked questions

Stay informed, stay strong. Autoimmune hepatitis may sound daunting, but with timely diagnosis and expert care, including liver transplant when needed, you or your loved one can live a full, vibrant life.

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