Autoimmune hepatitis
Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease in which the body's immune system mistakenly attacks healthy liver cells, causing ongoing inflammation that can lead to fibrosis, cirrhosis, and liver failure if untreated.[1] It is characterized by the presence of autoantibodies and elevated liver enzymes, with two main types: Type 1, the most common form affecting adults and children of all ages, and Type 2, which is rarer and typically more severe in young people.[2] AIH occurs worldwide, with prevalence estimates ranging from 4 to 43 cases per 100,000 adults and 2 to 10 per 100,000 children in the United States as of earlier studies, though recent data suggest increasing rates.[1][3] It disproportionately affects females, who comprise 71–95% of adult cases and 60–76% of pediatric cases.[1] The exact cause of AIH remains unknown, but it likely involves a combination of genetic predisposition and environmental triggers, such as viral infections (e.g., hepatitis A, B, or C) or certain medications, that prompt the immune response to target the liver.[2] Common symptoms include fatigue, jaundice, abdominal pain, joint aches, and itchy skin, though early stages may be asymptomatic and diagnosed incidentally through blood tests.[4] Diagnosis typically involves blood tests for autoantibodies and liver function, imaging, and often a liver biopsy to confirm inflammation and rule out other liver diseases.[2] Treatment relies on immunosuppressive medications like corticosteroids (e.g., prednisone) and azathioprine or mycophenolate mofetil to induce remission, per 2025 guidelines; with most patients achieving control of the disease and preventing complications when therapy is started early; however, lifelong monitoring is usually required, and advanced cases may necessitate liver transplantation.[1][5] Without treatment, AIH progresses in about 50% of cases to death within five years, but with appropriate management, over 90% of patients survive at least 10 years.[2]Overview and Classification
Definition and Characteristics
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an immune-mediated attack on hepatocytes, resulting in interface hepatitis, hepatocellular necrosis, and progressive liver damage that can lead to fibrosis, cirrhosis, or liver failure if untreated.[6][7] This condition arises from a failure of immune tolerance, where the body's immune system targets liver cells as if they were foreign invaders, causing ongoing inflammation primarily at the portal-lobular interface.[6] Unlike viral or alcoholic liver diseases, AIH is distinguished by its autoimmune etiology and potential responsiveness to immunosuppression, though it has no definitive cure.[4][6] The disease typically exhibits an insidious onset in the majority of cases, with about 25% of patients remaining asymptomatic at diagnosis, often detected incidentally through elevated liver enzymes.[6] It predominantly affects females, with a female-to-male ratio of approximately 3.6:1, reflecting a strong gender bias possibly linked to hormonal or genetic factors.[6] AIH can occur at any age but shows a bimodal age distribution, with peaks in adolescence and young adulthood (ages 10-20) and in middle age (ages 40-60).[8][9] It is frequently associated with other autoimmune disorders, such as thyroiditis, rheumatoid arthritis, and celiac disease, occurring in about half of patients.[4][6] A key histological characteristic of AIH is the presence of a plasma cell-rich inflammatory infiltrate at the portal-lobular interface, accompanied by piecemeal necrosis and, in advanced stages, bridging fibrosis or cirrhosis.[6][7] The presence of autoantibodies supports the diagnosis and helps characterize the disease; while AIH has traditionally been classified into two main types based on autoantibody profiles, the 2025 European Association for the Study of the Liver (EASL) Clinical Practice Guidelines recommend against routine subclassification, as it does not alter core disease features or management.[4][10] Immunosuppressive therapy, typically involving corticosteroids with or without azathioprine, can induce remission in 60-80% of cases, highlighting the condition's treatability despite its chronic nature.[6][7]Types
Autoimmune hepatitis (AIH) is serologically characterized by specific autoantibodies that aid in diagnosis, with most cases (approximately 80-90%) associated with antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies (SMA). These profiles are seen across all age groups, with a bimodal distribution peaking around puberty and in the fourth to sixth decades of life, and often coexist with extrahepatic autoimmune conditions, such as thyroiditis or rheumatoid arthritis. A minority of cases (10-20%), more commonly in children and young adults under 25 years old, feature anti-liver kidney microsome type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) antibodies, which may present more aggressively. Antibodies against soluble liver antigen (anti-SLA) are now regarded as a marker within the broader AIH spectrum rather than defining a distinct entity.[6][10][11] Overlap syndromes occur when AIH features overlap with those of primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), complicating up to 10% of cases and requiring modified diagnostic scoring systems like the Paris criteria. AIH-PBC overlap is marked by antimitochondrial antibodies (AMA) positivity alongside AIH markers, while AIH-PSC overlap involves perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cholangiographic evidence of bile duct involvement. These variants exhibit mixed hepatitic and cholestatic profiles, often leading to more severe disease progression and tailored management approaches.[10]Clinical Presentation
Signs and Symptoms
Autoimmune hepatitis often presents with a range of symptoms that can be nonspecific and insidious, prompting clinical suspicion through correlation with elevated liver enzymes. The most common symptom is fatigue, which affects a majority of patients and may be profound, impacting daily activities.[6] Other frequent symptoms include jaundice, occurring in approximately 69% of severe cases, pruritus, anorexia, nausea, right upper quadrant abdominal pain, arthralgias, and low-grade fever.[6] These manifestations typically develop gradually but can guide initial evaluation when accompanied by laboratory abnormalities.[12] Physical signs at presentation may include hepatomegaly in about 78% of patients, reflecting liver inflammation, as well as splenomegaly in advanced cases.[6] Cutaneous signs such as spider angiomata and palmar erythema can appear due to hyperestrogenism from impaired liver function, while ascites may be evident if cirrhosis has developed.[4] Up to 25% of cases are asymptomatic at diagnosis, often discovered incidentally through routine screening showing elevated liver enzymes.[6] In such instances, the absence of symptoms underscores the importance of serological testing in at-risk individuals.[13] An acute presentation occurs in roughly 25% of patients and can mimic viral hepatitis, featuring flu-like symptoms such as malaise, rapid-onset jaundice, and dark urine without identifiable viral markers.[13] This form may progress quickly, necessitating prompt differentiation from infectious causes. Extrahepatic manifestations are common, particularly in type 1 autoimmune hepatitis, where up to 50% of patients have concurrent autoimmune conditions like thyroid disease, rheumatoid arthritis, or inflammatory bowel disease.[4] Skin involvement may include rashes such as erythema nodosum, vitiligo, or psoriasis, while sicca syndrome can occur in overlap with primary Sjögren's syndrome.[12] These associated features highlight the systemic nature of the disease and may precede or coincide with hepatic symptoms.[6]Complications
If left untreated, autoimmune hepatitis often progresses to cirrhosis due to ongoing hepatocellular inflammation and fibrosis.[6] Cirrhosis in AIH is characterized by portal hypertension, which can manifest as esophageal varices, ascites, and splenomegaly, increasing the risk of decompensation and the need for liver transplantation.[14] Even with treatment, de novo cirrhosis develops in 6-40% of cases, particularly in those with delayed response or relapses.[14] Liver failure represents a severe complication of AIH, occurring as acute liver failure in approximately 3-6% of newly diagnosed cases, more commonly in type 2 AIH affecting younger patients.[15] Chronic decompensation in advanced cirrhosis may lead to coagulopathy, hepatic encephalopathy, and hepatorenal syndrome, with acute severe AIH carrying a 31-43% risk of death or transplantation despite corticosteroid therapy.[14] Untreated AIH is associated with a 5-year survival rate of only 50% and a 10-year survival of 10%, largely due to progression to end-stage liver disease.[6] Patients with AIH-related cirrhosis face an elevated risk of hepatocellular carcinoma (HCC), with an annual incidence of 1.1-1.9% in cirrhotics, though lower than in other chronic liver diseases (overall 0.3% annually).[14][10] Guidelines recommend biannual ultrasound surveillance with or without alpha-fetoprotein testing in cirrhotic patients to facilitate early detection.[6] The risk is further heightened by factors such as obesity and overlap with primary sclerosing cholangitis.[16] Chronic corticosteroid therapy, a mainstay of AIH treatment, contributes to osteoporosis and increased fracture risk, affecting 5-10% of patients over 2-3 years of use.[14] This bone loss is exacerbated by underlying liver dysfunction and malnutrition, with nearly 20% of AIH patients over age 50 developing osteoporosis; routine assessment using tools like the FRAX score and supplementation with vitamin D and calcium are advised.[17] AIH is frequently associated with other autoimmune conditions, occurring in 24-42% of patients and potentially compounding liver disease burden through shared inflammatory pathways.[14] Common comorbidities include autoimmune thyroiditis (e.g., Graves' disease or Hashimoto's thyroiditis) in up to 10-20% of cases, celiac disease in approximately 6%, and type 1 diabetes mellitus, which may necessitate integrated management to prevent exacerbation of hepatic inflammation.[4][18][19]Etiology and Pathogenesis
Causes and Risk Factors
The exact cause of autoimmune hepatitis (AIH) remains unknown, but it arises from a complex interplay of genetic susceptibility and environmental triggers that disrupt immune tolerance to hepatic antigens, leading to chronic liver inflammation.[4][12] Genetic factors confer significant risk, with the strongest associations involving human leukocyte antigen (HLA) class II alleles, particularly HLA-DR3 (DRB103:01) and HLA-DR4 (DRB104:01), which are linked to type 1 AIH in Caucasian populations and carry odds ratios of 4 to 7 for disease susceptibility.[20] These alleles facilitate antigen presentation that may promote autoreactive T-cell responses in genetically predisposed individuals. Familial clustering occurs in 2-5% of cases, underscoring a heritable component, though the absolute risk to relatives remains low.[14] Environmental triggers are implicated in initiating or exacerbating the autoimmune process, including viral infections such as hepatitis A virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, and hepatitis E virus, which can induce molecular mimicry between viral and liver antigens.[20][21] Certain medications, including nitrofurantoin and minocycline, are well-documented precipitants of drug-induced AIH, comprising approximately 90% of such instances and often resolving upon drug discontinuation.[6] Other contributors include exposure to toxins like carbon tetrachloride, genetic variants associated with alpha-1 antitrypsin deficiency, and gut microbiome dysbiosis, which may alter immune homeostasis.[22][20] Hormonal influences contribute to the marked female predominance in AIH, with a female-to-male ratio of 3:1 to 4:1, potentially mediated by estrogen's immunomodulatory effects that favor Th2 responses and autoimmunity.[20] Disease flares are more common during pregnancy or the postpartum period, attributed to shifts in hormonal levels and temporary immunosuppression followed by rebound activity.[23] Additional risk factors encompass vitamin D deficiency, which affects a high proportion of patients and may impair regulatory T-cell function, as well as coexisting autoimmune disorders such as thyroiditis or rheumatoid arthritis, which elevate overall susceptibility through shared genetic pathways.[24][14] Smoking shows mixed associations, with some studies indicating a protective effect against AIH development, possibly due to anti-inflammatory nicotine effects, though recent evidence suggests it may confer risk in certain contexts.[25]Pathophysiological Mechanisms
Autoimmune hepatitis (AIH) arises from a breakdown in immune self-tolerance, primarily involving a failure of regulatory T cells (Tregs), which normally suppress autoreactive responses. In susceptible individuals, reduced numbers and impaired function of CD4+ Foxp3+ Tregs allow autoreactive CD4+ T cells to escape regulation and target hepatocyte-specific antigens, such as cytochrome P450 enzymes (e.g., CYP2D6) and formiminotransferase cyclodeaminase (FTCD).[26][27] This loss of tolerance is exacerbated by genetic factors, such as HLA class II variants, that enhance antigen presentation to these autoreactive T cells by professional antigen-presenting cells like dendritic cells.[28] The ensuing inflammatory cascade is dominated by Th1 and Th17 CD4+ T cell subsets, which secrete pro-inflammatory cytokines including interferon-gamma (IFN-γ) and interleukin-17 (IL-17). These cytokines promote the recruitment and activation of lymphocytes, macrophages, and plasma cells to the portal tracts and interface zones of the liver, initiating interface hepatitis and piecemeal necrosis of hepatocytes.[29][27] Cytotoxic CD8+ T cells and natural killer cells further contribute to hepatocyte apoptosis through Fas-FasL interactions and perforin-granzyme pathways, perpetuating the necroinflammatory damage.[28] Autoantibodies, such as anti-liver kidney microsomal type 1 (anti-LKM1) antibodies directed against CYP2D6, play a supportive rather than directly pathogenic role in AIH. They may enhance antigen presentation by opsonizing hepatocytes, facilitating uptake by antigen-presenting cells, and can activate complement pathways, leading to hepatocyte lysis and amplification of inflammation.[30][27] However, their presence is more indicative of B-cell involvement in the dysregulated immune response than a primary driver of tissue injury. Chronic inflammation in AIH triggers fibrogenesis through activation of hepatic stellate cells (HSCs), which transdifferentiate into myofibroblasts under the influence of cytokines like transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). Activated HSCs deposit excessive extracellular matrix components, such as collagen types I and III, in the periportal and lobular regions, leading to progressive fibrosis and potential cirrhosis if unchecked.[31][32] Molecular mimicry represents a key initiating mechanism, where environmental triggers like viral infections (e.g., hepatitis A or Epstein-Barr virus) or drugs (e.g., nitrofurantoin) present epitopes structurally similar to liver autoantigens, provoking cross-reactive T- and B-cell responses. This breach in tolerance sustains the autoimmune attack, linking external factors to the core immunological dysfunction in AIH.[33][28]Diagnosis
Laboratory Findings
Laboratory findings in autoimmune hepatitis typically reveal a hepatocellular pattern of liver injury, with markedly elevated serum transaminases. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are increased in nearly all patients, often averaging 200-300 U/L and ranging up to 50 times the upper limit of normal (ULN), reflecting significant hepatocyte damage.[34] In advanced disease with cirrhosis, the AST:ALT ratio may exceed 2:1 due to ongoing fibrosis and mitochondrial injury. Alkaline phosphatase (ALP) is usually only mildly elevated, while gamma-glutamyl transferase (GGT) shows variable increases, helping to distinguish autoimmune hepatitis from cholestatic liver diseases.[6] Hypergammaglobulinemia is a hallmark feature, primarily driven by polyclonal elevation of immunoglobulin G (IgG), which is increased in the majority of untreated cases, often to 3-4 g/dL or higher (up to 5-6 g/dL in severe presentations). This elevation exceeds 1.5 times the ULN in 80-90% of patients and supports the autoimmune etiology.[34][35] Hematological abnormalities may include normocytic anemia, often due to chronic disease or hypersplenism in advanced cases with portal hypertension, and thrombocytopenia, which can arise from splenic sequestration or immune-mediated destruction.[34][36] In jaundiced patients, total bilirubin is frequently elevated, particularly in acute or severe presentations. Synthetic dysfunction in decompensated disease manifests as hypoalbuminemia and prolonged prothrombin time (PT).[34] To exclude infectious mimics, viral serologies for hepatitis A, B, C, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are typically negative. Iron studies, including serum ferritin and transferrin saturation, remain normal, aiding differentiation from hereditary hemochromatosis.[34] These biochemical patterns often prompt further evaluation with autoantibody testing.[37]Autoantibodies
Autoimmune hepatitis (AIH) is characterized by the presence of specific autoantibodies that aid in diagnosis and subtyping, with testing typically performed after initial elevation of liver enzymes. These markers are detected primarily through indirect immunofluorescence (IIF) on rodent liver, kidney, and stomach substrates, followed by confirmatory assays like enzyme-linked immunosorbent assay (ELISA) or immunoblot for specificity.[38][39] Antinuclear antibodies (ANA) are the most common autoantibody in type 1 AIH, present in 70-80% of cases, with titers greater than 1:40 considered significant in adults and greater than 1:20 in children.[39] Common patterns include homogeneous or speckled on HEp-2 cell substrates, targeting nuclear antigens such as DNA or histones, though the exact targets remain unknown in at least 30% of positive cases.[38] ANA positivity supports the diagnosis of type 1 AIH when combined with other features, but low titers may persist even in remission.[39] Anti-smooth muscle antibodies (ASMA), also known as SMA, occur in 60-80% of type 1 AIH patients, targeting filamentous actin (F-actin) or other cytoskeletal proteins like desmin, with titers exceeding 1:40 indicative of disease.[40][38] Detection via IIF shows vascular glomerulus (VG) or vascular glomerulus and tubules (VGT) patterns on rodent kidney sections, and higher titers correlate with disease activity, particularly in pediatric cases.[38] ASMA enhances diagnostic specificity when coexistent with ANA in type 1 AIH.[39] In type 2 AIH, anti-liver kidney microsomal type 1 antibodies (anti-LKM1) serve as a hallmark, detected in approximately 70% of patients with titers greater than 1:40.[39] These antibodies target cytochrome P450 2D6 (CYP2D6), visualized by IIF as bright cytoplasmic staining in hepatocytes and proximal renal tubules, and confirmed by ELISA or immunoblot.[38] Anti-LKM1 titers often correlate with disease severity and must be distinguished from those in hepatitis C to avoid misdiagnosis.[40] Anti-liver cytosol type 1 antibodies (anti-LC1) are found in 20-40% of type 2 AIH cases, particularly useful in ANA-negative patients, targeting formiminotransferase cyclodeaminase with titers exceeding 1:40.[40] IIF reveals diffuse cytoplasmic hepatocyte staining that intensifies toward the center of liver lobules, and solid-phase assays provide confirmation; anti-LC1 may appear as the sole marker in some type 2 cases and correlates with more aggressive disease.[38] Anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP) are detected in 10-30% of AIH patients across types 1 and 2, offering high specificity (up to 95%) and association with severe disease requiring lifelong immunosuppression.[39] These target O-phosphoseryl-tRNA:Sec (selenocysteine) tRNA synthase and are not visible by IIF, necessitating ELISA or immunoblot for detection at any detectable titer.[38] Atypical perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) occur in 20-96% of type 1 AIH, especially in overlap syndromes with primary sclerosing cholangitis, showing perinuclear staining on neutrophils via IIF and targeting antigens like beta-tubulin.[38] They may represent the only serological marker in up to 50% of seronegative AIH cases but require careful interpretation to exclude other vasculitides.[39]Histological Findings
Histological examination of the liver is essential for confirming the diagnosis of autoimmune hepatitis (AIH), revealing characteristic patterns of inflammation and fibrosis that distinguish it from other liver diseases.[41] The biopsy typically shows a mix of portal and lobular inflammation dominated by lymphocytes and plasma cells, with interface hepatitis as the defining feature.[42] These findings help assess disease severity and guide therapeutic decisions, particularly in cases with atypical serological profiles.[41] Interface hepatitis, present in up to 98% of AIH cases, is characterized by a dense lymphoplasmacytic infiltrate at the portal-lobular junction, leading to piecemeal necrosis of the limiting plate and hepatocyte dropout.[41] This periportal inflammation extends into the parenchyma, causing erosion of the hepatocyte plate and contributing to the progressive nature of the disease.[42] In severe cases, the infiltrate may spill over into the lobule, accentuating the interface activity.[42] Lobular activity manifests as spotty necrosis scattered throughout the hepatic lobule, accompanied by apoptotic bodies, ballooning degeneration of hepatocytes, and rosette formation as a regenerative response to injury.[42] These changes indicate ongoing hepatocyte damage and inflammation beyond the portal areas, often correlating with elevated aminotransferase levels.[41] Confluent necrosis may also occur in acute presentations, further highlighting the dynamic inflammatory process.[41] Plasma cells are a prominent and diagnostically significant component, often appearing in clusters of five or more per high-power field within portal tracts and lobules.[42] Their abundance, exceeding one per ten high-power fields in many cases, underscores the chronic inflammatory milieu, with eosinophils occasionally present to suggest an immune-mediated etiology.[41] Immunohistochemical staining for CD38 can confirm plasma cell identity when morphology is ambiguous.[41] Fibrosis begins with portal tract expansion due to inflammatory infiltrates and progresses to bridging fibrosis, connecting portal tracts or extending to central veins in advanced stages.[42] In longstanding or untreated disease, this culminates in cirrhosis with regenerative nodules and distorted architecture.[41] Staging is commonly performed using the Ishak system (0-6, where 0 indicates no fibrosis and 6 denotes cirrhosis) or the METAVIR score to quantify fibrosis extent and predict outcomes.[42] These systems exclude features like steatosis seen in non-alcoholic steatohepatitis or bile duct damage characteristic of primary biliary cholangitis or primary sclerosing cholangitis.[41] Liver biopsy serves as the gold standard for diagnosis, particularly in seronegative AIH or overlap syndromes, where it confirms the inflammatory pattern and rules out alternative etiologies such as viral hepatitis.[42] Histological features contribute key points in diagnostic scoring systems, enhancing specificity when integrated with clinical and laboratory data.[41]Diagnostic Scoring
The diagnosis of autoimmune hepatitis (AIH) relies on standardized scoring systems developed by the International Autoimmune Hepatitis Group (IAIHG) to integrate clinical, serological, biochemical, and histological features into a quantitative assessment. These systems aim to classify cases as probable or definite AIH, facilitating consistent diagnosis across clinical settings. The revised original scoring system, introduced in 1999, evaluates pretreatment parameters including gender (female: +2 points), autoantibody titers (e.g., ANA or SMA ≥1:40: +1 point, ≥1:80: +2 points, ≥1:160: +3 points; LKM1 ≥1:10: +2 points, ≥1:40: +3 points), immunoglobulin G levels ( > upper limit of normal [ULN]: +1 point, >1.5× ULN: +3 points), absence of viral hepatitis markers (-3 to -5 points for positive markers), and histological features such as interface hepatitis (+3 points) or rosette formation (+1 point). Additional points are assigned for factors like concurrent immune disease (+2 points) and subtracted for alcohol consumption >25 g/day (-2 points) or other liver diseases (-4 points). A pretreatment score exceeding 15 indicates probable AIH, while a score greater than 17 denotes definite AIH.| Parameter Category | Specific Features | Points Assigned |
|---|---|---|
| Gender | Female | +2 |
| Autoantibodies | ANA, SMA, or LKM1 titers (various thresholds) | +1 to +3 |
| IgG | >ULN; >1.5× ULN | +1; +3 |
| Histology | Interface hepatitis; plasma cells; rosettes | +1 to +3 |
| Viral Markers | Absence of hepatitis A, B, C | +2 to -5 (negative/positive) |
| Other Exclusions | Alcohol; other liver diseases | -2 to -4 |
| Parameter | Cutoff/Feature | Points |
|---|---|---|
| Autoantibodies (ANA, SMA, LKM1, SLA/LP) | ≥1:40; ≥1:80 | +1; +2 (max 2) |
| IgG | >ULN; >1.1× ULN | +1; +2 |
| Histology | Compatible features; typical AIH | +1; +2 |
| Viral Hepatitis | Absence | +2 |