What is autoimmune hepatitis?

Autoimmune Hepatitis: A Comprehensive Overview

Definition and Core Pathophysiology

Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory liver disease of uncertain cause that, if untreated, often progresses to cirrhosis, liver failure, and death. 1

The disease develops when environmental triggers, genetic predisposition, and failure of immune tolerance mechanisms converge to initiate a T cell-mediated immune attack against liver antigens in susceptible individuals. 2 Specifically:

• Autoreactive CD4 and CD8 T cells break self-tolerance to hepatic autoantigens, creating a self-perpetuating cycle of inflammation with portal lymphocytic/lymphoplasmacytic infiltrates causing progressive hepatic necroinflammation and fibrosis. 2
• Autoreactive B cells produce autoantibodies in the absence of effective B regulatory cell inhibition. 2
• Professional antigen-presenting cells present autoantigenic peptides to T cell receptors, activating naive helper and cytotoxic T cells. 2

Epidemiology and Demographics

AIH affects all ages, both genders, and all ethnicities, though with notable variations: 1

• Female predominance is striking: 71-95% in adults and 60-76% in children. 1
• Clinical manifestations vary significantly by race and ethnicity: 1, 2
  • Alaskan Natives: high frequency of icteric presentation at diagnosis 1
  • Hispanics: more commonly present with established cirrhosis 1
  • African Americans: accelerated disease progression and higher recurrence rates after liver transplantation 1
  • Asian patients: typically late-onset, mild disease 2
  • South American patients: commonly children with severe inflammation 2

Genetic Predisposition

HLA associations are the primary genetic risk factors, particularly HLA-DRB103:01, DRB104:01, and DRB1*13:01 alleles. 2

• These HLA class II alleles determine which autoantigenic peptides can be presented to autoreactive T cells. 2
• Type 1 AIH patients with HLA DR3 (DRB10301) are younger with higher treatment failure rates and relapse frequency, while those with HLA DR4 (DRB10401) are older with better corticosteroid response. 2
• Non-HLA genetic associations include polymorphisms in CTLA-4, TNF-α, Fas, vitamin D receptor, and IL-23 receptor, though with far lower odds ratios than HLA alleles. 1

Environmental Triggers

While the exact triggering event often cannot be identified in individual patients, documented triggers include: 2

• Viral infections: Hepatitis A, hepatitis C, and other viruses through molecular mimicry between viral epitopes and liver autoantigens 2
• Medications: TNF-α antagonists, immune checkpoint inhibitors, minocycline, nitrofurantoin, isoniazid, propylthiouracil, and α-methyldopa 1, 2
• Intestinal dysbiosis: Circulating gut-derived lipopolysaccharides with weakening of the intestinal mucosal barrier 2

Clinical Presentation

The clinical spectrum is remarkably broad, ranging from asymptomatic disease to fulminant hepatic failure. 1, 3

Patients may present with:

• Asymptomatic elevation of liver enzymes discovered incidentally 1
• Chronic indolent disease with fatigue and nonspecific symptoms 4
• Acute hepatitis with jaundice and marked transaminase elevation 1
• Acute liver failure with hepatic encephalopathy and coagulopathy (INR ≥2) 1
• Established cirrhosis with or without decompensation 1

A critical pitfall: AIH can develop after liver transplantation (termed "de novo AIH") and may manifest in the postpartum period due to immune reconstitution. 2

Diagnostic Criteria

Diagnosis requires a constellation of characteristic features and exclusion of other liver diseases—there is no single pathognomonic finding. 1

Essential Diagnostic Components:

1. Biochemical Features 1, 5

• Predominant serum aminotransferase elevation (AST/ALT)
• Alkaline phosphatase to AST (or ALT) ratio typically <1.5 5
• Hypergammaglobulinemia with IgG or γ-globulin ≥1.5 times normal for definite diagnosis 1
• Bilirubin and aminotransferases ranging from just above normal to >50 times normal 5

Important caveat: Some patients may show apparently "normal" IgG levels at diagnosis if their baseline IgG is naturally very low, but these patients typically have IgG in the upper range of normal and show marked fall upon treatment initiation. 1

2. Autoantibodies 1, 5

Indirect immunofluorescence on freshly frozen rodent substrate (kidney, liver, stomach) is the preferred technique for routine testing. 1

• Type 1 AIH (80% of cases): Positive ANA and/or SMA 2, 5

  • Significant titers: ≥1:40 in adults, ≥1:20 in children 1
  • Peak incidence in females aged 16-30 years, though 50% are >30 years and 23% are ≥60 years 2

• Type 2 AIH: Positive anti-LKM1 and/or anti-LC1 2, 5

  • More common in children and in European/South American countries 2
  • Significant titers: ≥1:10 in children 1

• Anti-SLA/LP antibodies: Detected by ELISA or immunoblotting (not by immunofluorescence) 1, 5

  • Highly specific for AIH when present 1

Critical note: The International Autoimmune Hepatitis Group does not endorse classification into types as distinct clinical entities, as both respond similarly to corticosteroids and classification does not alter treatment decisions. 2

3. Histological Features 1, 5

Liver biopsy is essential to establish diagnosis and evaluate disease severity. 1, 5

• Interface hepatitis (disruption of limiting plate with inflammatory extension into acinus) is the histologic hallmark 1
• Portal plasma cell infiltration typifies the disorder but is neither pathognomonic nor required 1
• Compatible features include lymphocytic infiltration, emperipolesis, and hepatic rosette formation 1
• Absence of biliary lesions, granulomas, or prominent changes suggesting alternative diagnoses 1

Serum aminotransferase and γ-globulin levels do not predict histologic pattern or presence of cirrhosis, making biopsy indispensable. 1

4. Exclusion of Other Diseases 1, 5

Must exclude:

• Viral hepatitis: No markers of current hepatitis A, B, or C infection 1
• Genetic liver diseases: Normal α1-antitrypsin phenotype, normal ceruloplasmin, iron, and ferritin 1
• Toxic/drug-induced injury: Daily alcohol <25 g/day for definite diagnosis (<50 g/day for probable), no recent hepatotoxic drug use 1
• Wilson disease, hemochromatosis, nonalcoholic fatty liver disease, primary biliary cholangitis, primary sclerosing cholangitis 1, 5

Diagnostic Scoring Systems

Two validated systems exist: 5

1. International Autoimmune Hepatitis Group (IAIHG) comprehensive scoring system: Includes gender, ALP:AST ratio, globulin/IgG levels, autoantibodies, viral markers, drug history, alcohol intake, histology, and concurrent autoimmune diseases 5

2. Simplified Scoring System (2008): Includes autoantibodies, IgG levels, liver histology, and absence of viral hepatitis 5

Associated Autoimmune Conditions

AIH is associated with a wide variety of other autoimmune diseases, and extended screening is reasonable at diagnosis and during follow-up. 6

Most common associations: 6

• Autoimmune thyroiditis: 10.2-14.1% of AIH patients (most common concurrent disease) 6
• Inflammatory bowel disease: Particularly ulcerative colitis, which carries ~10% risk of developing primary sclerosing cholangitis 6
• Sjögren syndrome: 2.8-7% of patients, causing severe dry eyes and potential liver involvement 6
• Systemic lupus erythematosus: 2.2-3% of patients 6
• Rheumatoid arthritis: 2-4% of patients 6

First-degree relatives of AIH patients have increased occurrence of immune-mediated diseases, necessitating careful family history. 6

Natural History and Prognosis

Untreated moderate to severe AIH progresses to cirrhosis in 82% of patients within 5 years, with 45% mortality. 5

• With treatment, approximately 80% of patients achieve remission 5
• Treatment can reverse liver fibrosis, preventing progression to advanced cirrhosis 7
• Progression to advanced hepatic fibrosis, cirrhosis, death from liver failure, or need for liver transplantation are possible outcomes without treatment 1

Treatment Principles

Treatment with immunosuppressive agents has been life-saving and is indicated for patients with moderate to severe AIH, young patients, symptomatic patients, and patients with cirrhosis. 5

Standard First-Line Therapy 5

• Prednisone and azathioprine combination is the standard induction therapy
• Treatment goals: normalization of transaminases and IgG levels, resolution of symptoms, and histological improvement with reduction of inflammation 5

Treatment Endpoints 1, 5

• Biochemical remission: Normalization of serum AST, ALT, and IgG levels 1
• Histological remission: Absence of inflammation in liver tissue after treatment 1
• Reaching normal immunoglobulin levels correlates well with improvement of inflammatory activity, though mild activity (HAI 5-6) may coexist with normal IgG 1

Second-Line Options 8, 3

• 20-40% of patients require second- or third-line therapies due to intolerance or insufficient response 8
• Mycophenolate mofetil is considered for azathioprine intolerance or poor response 3
• More potent immunosuppressants (cyclosporine, mycophenolate mofetil) for refractory or aggressive disease 9

Long-Term Management 5, 7

• Most patients need lifelong maintenance therapy 7
• Regular monitoring: liver function tests, IgG levels 5
• Hepatocellular carcinoma screening in cirrhotic patients 5
• Esophageal varices surveillance in cirrhotic patients 5
• UV-protective measures and dermatological monitoring for non-melanoma skin cancer in patients on immunosuppressants 5

Repeated follow-up in experienced hands improves quality of care and quality of life. 7

Special Populations

Pregnancy

• AIH may manifest in the postpartum period due to immune reconstitution following delivery 2
• Treatment decisions require careful consideration of maternal and fetal risks 4

Post-Transplant

• Recurrent disease after liver transplantation is usually mild and manageable in adults 1
• In children, recurrence occurs more frequently and may be more difficult to treat 1
• De novo AIH can develop after liver transplantation 2

Viral Hepatitis Co-infection

• In countries with high viral hepatitis prevalence, co-existence of AIH and viral hepatitis may occur 1
• AIH typically has more aggressive course and worse prognosis than viral hepatitis alone 1
• With interferon-free HCV regimens, treating HCV first in milder cases followed by reassessment is now feasible 1

Key Clinical Pitfalls to Avoid

• Do not dismiss "normal" IgG levels if they are in the upper range of normal—observe for marked fall with treatment 1
• Do not overlook AIH in patients with viral hepatitis—co-existence is possible and AIH may remain untreated if viral hepatitis is considered the sole diagnosis 1
• Do not delay liver biopsy—serum markers cannot predict histologic severity or presence of cirrhosis 1
• Do not assume absence of portal plasma cells excludes AIH—this finding is characteristic but not required 1
• Do not wait to identify the specific environmental trigger—what matters clinically is recognizing the syndrome early through its characteristic features 2
• Do not assume Type 1 and Type 2 AIH require different treatment approaches—both respond to corticosteroids and classification does not alter management 2