Autoimmune Hepatitis

Autoimmune Hepatitis (AIH)

Autoimmune hepatitis (AIH) is a chronic, progressive, immune-mediated inflammatory liver disease.It results from loss of tolerance to hepatic autoantigens, leading to T-cell–mediated hepatocyte injury.

Needs Exclusion of other causes of hepatitis (viral, drug-induced, metabolic).

 Pathophysiology

1. Immunogenetic Susceptibility

• HLA associations:
  
  • AIH type 1: HLA-DR3, DR4
  • AIH type 2: HLA-DR7, DQ2
  • AIH type 3: Similar to type 1
• Trigger: Environmental factors (viral infections, drugs like minocycline or nitrofurantoin) in genetically predisposed individuals.

2. Immune Mechanism

• CD4+ T-helper cells activate cytotoxic CD8+ T cells and B cells.
• Autoantibodies form against hepatocellular antigens (e.g., ANA-anti-nuclear antibodies, SMA-anti-smooth muscle antibodies, LKM1-anti-liver/anti-kidney microsome).
• Cytokine-mediated inflammation → interface hepatitis → bridging necrosis → fibrosis → cirrhosis.

 Classification 

Type	Autoantibodies	Typical Age / Sex	Associated Conditions
Type 1	ANA, SMA	Adolescents / Adults (♀)	Thyroiditis, RA, UC, DM1
Type 2	Anti-LKM1, anti-LC1	Children / Young adults	Celiac disease, other AI disorders
Type 3	Anti-SLA/LP	Adults	Often overlaps with Type 1

Clinical Features

1. Presentation

• Variable onset: Acute, chronic, or asymptomatic elevation of liver enzymes.
• Symptoms:
  
  • Fatigue, malaise, anorexia, arthralgia
  • Jaundice(69%), right upper quadrant pain
  • Amenorrhea (women)
• Acute severe hepatitis (may mimic viral hepatitis)
• Chronic liver disease / cirrhosis features in late stages: ascites, spider nevi, splenomegaly, hepatic encephalopathy.

2. Physical Findings

• Hepatomegaly(78%), splenomegaly
• Stigmata of chronic liver disease
• Extrahepatic autoimmune features:
  
  • Arthritis, thyroiditis, vitiligo, hemolytic anemia, glomerulonephritis
  • Autoimmune hepatitis may present concurrently with other autoimmune diseases like Graves disease, rheumatoid arthritis, celiac disease, type I diabetes, ulcerative colitis, hemolytic anemia, and immune thrombocytopenia. Specifically, autoimmune hepatitis is present in approximately 10% of individuals with autoimmune polyendocrine syndrome type 1.

Autoimmune hepatitis should be considered in all individuals with both acute and chronic liver disease.Once suspicion is raised:

Step 1 — Exclude other causes

• Viral hepatitis panel (A, B, C, E)
• Alcohol history, drug history
• Metabolic tests (ceruloplasmin, ferritin, α1-antitrypsin)

Step 2 — Check Autoimmune Markers

• ANA, SMA, anti-LKM1, anti-SLA/LP, pANCA
• Quantitative IgG

Step 3 — Imaging

• Ultrasound or transient elastography to assess fibrosis, exclude obstruction

Step 4 — Confirm with Liver Biopsy

• Interface hepatitis with plasma cells → diagnostic hallmark

Laboratory Findings

Parameter	Typical Findings
Transaminases (AST, ALT)	Markedly elevated (up to >1000 IU/L)
Bilirubin	Elevated in acute phase
Serum IgG	Elevated (>1.1× upper limit of normal)
Autoantibodies	ANA, SMA, anti-LKM1, anti-SLA
Other tests	Negative viral serology (HBsAg, anti-HCV)

 Diagnostic Criteria (Simplified IAIHG Scoring System, 2008)

Parameter	Score
ANA or SMA ≥1:40 or LKM1 ≥1:40	1
ANA or SMA ≥1:80 or LKM1 ≥1:80 or SLA positive	2
IgG > ULN	1
IgG > 1.1 × ULN	2
Liver histology compatible	1
Liver histology typical	2
Absence of viral hepatitis	2

• Probable AIH: ≥6 points
• Definite AIH: ≥7 points

 Histopathology

Liver biopsy is essential for diagnosis and prognosis.

Typical features:

• Interface hepatitis (piecemeal necrosis): Lymphoplasmacytic infiltrate at portal–parenchymal junction,However, it is nondiagnostic as it is present in most cases of viral hepatitis. 
• Plasma cell infiltration
• Rosetting of hepatocytes
• Bridging necrosis (severe disease)
• Fibrosis / cirrhosis (chronic)

 Differential Diagnosis(all has to be excluded to make AIH diagnosis)

Condition	Distinguishing Features
Viral hepatitis	Positive viral serology
Drug-induced hepatitis (DILI)	Temporal drug relation; RUCAM score
Wilson’s disease	↓ Ceruloplasmin, KF rings, high urinary copper
NAFLD/NASH	Metabolic syndrome, obesity
Primary biliary cholangitis (PBC)	AMA positive, cholestatic ALP rise
Primary sclerosing cholangitis (PSC)	MRCP: beading; often overlap with IBD

 Overlap Syndromes

1. AIH–PBC overlap:
   
   • Features of both diseases
   • AMA positive, raised ALP
   • Histology: bile duct injury + interface hepatitis

2. AIH–PSC overlap:

1. • Seen in young males
   • MRCP: beaded ducts + elevated IgG and autoantibodies

 Management (AASLD / EASL Guidelines)

1. Indications for Treatment

Treat all with:

• AST/ALT >10× ULN, or
• AST/ALT >5× ULN + IgG >2× ULN, or
• Bridging necrosis / interface hepatitis on biopsy.

2. First-Line Therapy(combination therapy is preferred over monotherapy)

Drug	Dose	Comments
Prednisone (or prednisolone)	30–60 mg/day	Taper to maintenance (5–10 mg/day)
+ Azathioprine	50 mg/day (1–2 mg/kg/day)	Steroid-sparing, maintenance drug

• Combination preferred (better remission, fewer steroid side effects).. Monotherapy with prednisone is preferred in cases of pregnancy, intolerance to azathioprine, an absence of thiopurine methyltransferase (TPMT) activity, or severe cytopenia. Immunosuppressive therapy should not be started in patients with preexisting comorbid conditions such as vertebral compression, brittle diabetes, uncontrolled hypertension, psychosis.
• For monotherapy, a typical induction dose of prednisone is 60 mg daily for 1 week followed by 40 mg in the second week, and 30 mg daily in the third and fourth week. The maintenance dose of prednisone is 20 mg daily until the endpoint or deep clinical remission. The prednisone should be tapered over time and eventually discontinued. 
• The American Association for the Study of Liver Diseases recommends at least 3 years of treatment. 
• Upon completion of prednisone, patients are classified as in remission, relapsed, or treatment failure based on their histological and laboratory response to steroids, and the presence or absence of clinical symptoms. 
• Remission occurs when the patient becomes asymptomatic with normalization of inflammatory markers, transaminases, gamma globulin, and histological improvement in liver biopsy.
• Relapse can occur after a patient in remission stops therapy. About 50% of patients have disease relapse within 6 months of discontinuing therapy. Relapse is defined by the elevation of AST (three times the upper limit of normal), the reappearance of histological findings after discontinuing therapy.
• Response: Normalization of ALT, IgG, and histology.

3. Second-Line / Refractory

• Mycophenolate mofetil (MMF)
• Cyclosporine / Tacrolimus
• 6-Mercaptopurine
• Budesonide (non-cirrhotic AIH; less systemic effect)

4. Liver Transplantation

• For fulminant hepatic failure, decompensated cirrhosis, or treatment failure.
• Recurrence in graft in 20–30%.

Monitoring and Follow-up

Parameter	Frequency
AST, ALT, IgG	Every 1–3 months during induction
CBC, bilirubin, INR	Regularly during therapy
Azathioprine toxicity	CBC, LFTs, TPMT levels
Biopsy (optional)	To confirm histological remission

 Key Points 

• Female predominance (70–80%)
• Interface hepatitis + plasma cells = hallmark
• Type 1 = ANA/SMA positive; Type 2 = anti-LKM1 positive
• Elevated IgG (not IgM as in PBC)
• Responds dramatically to corticosteroids
• Overlap with PBC and PSC possible
• Azathioprine maintenance prevents relapse
• Transplant indicated for fulminant hepatic failure.
• Once cirrhosis develops, upper endoscopy should be performed for esophageal varices surveillance. Regular screening for hepatocellular carcinoma should be done with biannual liver ultrasound and alpha-fetoprotein. 

 References

1. Harrison’s Principles of Internal Medicine, 21st Edition.
2. AASLD Practice Guidance: Diagnosis and Management of Autoimmune Hepatitis (2020).
3. EASL Clinical Practice Guidelines: Autoimmune Hepatitis (2015).
4. Linzay CD, Sharma B, Pandit S. Autoimmune Hepatitis. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459186/