Autoimmune Hepatitis

Autoimmune Hepatitis Residents Conference 5/31/2005 Michael Le, MD

Overview • Prevalence • Clinical manifestations • Pathogenesis • Subtypes • Diagnosis • Prognostic indices • Treatment

Autoimmune Hepatitis • self-perpetuating hepatocellular inflammation • unknown cause • characterization: • histologic features of interface hepatitis • hypergammaglobulinemia • serum autoantibodies • affects all ages, may be asymptomatic, frequently has an acute onset, and can also present as fulminant hepatitis.

Prevalence • Mean annual incidence among white northern Europeans: 1.9 cases per 100,000 per year • US: 100,000-200,000 people • W>M 3.6:1, unexplained. • all ages, ethnic groups. • Frequency of AIH among pts with chronic liver disease in North America is 11-23% • Accounts for 5.9% in the National Institutes of Health Liver transplantation database. • Prevalence of AIH is greatest among northern European white groups who have a high frequency of HLA-DR3 and HLA-DR4

Clinicalmanifestations

Pathogenesis • Unknown mechanism • Most popular hypotheses: interactive factors: • Triggering agent • A genetic predisposition • various determinants of autoantigen display • immunocyte activation • effector cell expansion.

Pathogenesis • Triggering agents • infectious agents, drugs, toxins. • Multiple agents suggest that triggering epitope is a short amino acid sequence that is common in many antigens. • Possible long lag time b/w exposure to the trigger and onset of the disease • Triggering factor may not be needed for perpetuation of the disorder.

Pathogenesis • Loss of self-tolerance – • molecular mimicry of a foreign antigen • self antigen • Only the cytochrome monooxygenase P-450 IID6 (CYP2D6) has been recognized as an autoantigen. • multiple self-antigens or foreign antigens may satisfy the minimal structural requirements and serve as immunogenic peptides

Pathogenesis • genetic predisposition • Susceptibility HLA allelles encoding MHC class II: • influences the presentation of these autoantigens to CD4+ helper T cell thereby initiating an immune response. • the initiation of the immune response is dependent on the antigen binding groove of the class II MHC molecule. The sequence of amino acids that make up this antigen binding groove is encoded by a person’s HLA alleles. Thus, there are specific alleles that make a person more susceptible to developing AIH by influencing the immune response, and in turn the clinical manifestations and behavior of AIH. • Autoimmune promoters: • polymorphisms for TNF-α gene and cytotoxic T lymphocyte antigen 4 gene have been associated with increased immune reactivity and disease severity of AIH type I • Other: Vitamin D receptor (VDR) gene, point mutation of the tyrosine phosphatase CD45 gene, polymorphisms of the Fas gene, MHC class 1 chain-related A gene.

APC MHC Class II CD4 Peptide Antigen Cytokines TCR CD4 T Cell

DRB1 gene DRB1*0301 DRB1*0401 DRB1*0404 DRB1*0405 L L E Q K R lysine

DRB1 gene DRB1*0301 DRB1*0401 DRB1*0404 DRB1*0405 L L E Q R R arginine

Pathogenesis • Mechanism of Liver cell destruction via cellular and humoral mechanisms • Cell-mediated cytotoxicity • TH1 response (IL-2, IFN-γ, TNF-α)  clonal expansion of cytotoxic T lymphocytes that infiltrate and destroy hepatocytes. • Genetic polymorphism that affects TNF- production may facilitate this pathway. • Antibody-dependent cell-mediated cytotoxicity • TH2 response (IL-4,5,6,8,10,13)  B cell stimulation  Ab production immunocyte complexes on hepatocyte surface  targeted by NKT cells • Anti-inflammatory effects that counters TH1 action • Combination of mechanisms • Predominant mechanism depends on the phenotypic differentiation of CD4+ helper T cell, which in turn reflects the cytokine milieu, which in itself reflects the polymorphisms of the cytokine genes that favor excessive production of some modulators, such as TNF-, or deficient in others.

AIH subtypes • AIH type 1 • AIH type 2 • AIH type 3 • on the basis of immunoserologic markers. • The International Autoimmune Hepatitis Group has not endorsed this subclassification. • Used mainly for descriptive value

AIH type 1 • Most common form worldwide • characterized by the presence or absence of SMA and/or ANA in serum • Surrogate markers: Perinuclear antineutrophil cytoplasmic antibodies which occur in PSC and chronic UC, are found in 90% of patients who have type 1 AIH. • Bimodal age distribution (10-20; 45-70) • Female:male 3.6:1 • Risk factors for type 1 AIH • in whites of northern European descent [HLA-DR3 (DRB1*0301)] and –DR4 (DRB1*0401)]

AIH type 1 • Associated with concurrent extrahepatic diseases • Autoimmune thyroiditis (12%) • Graves disease (6%) • Chronic UC (6%) * (cholangiography to exclude PSC) • <1% RA, pernicious anemia, systemic sclerosis, Coomb’s test-positive HA, ITP, symptomatic cryoglobulinemia, leukocytoclastic vasculitis, nephritis, erythema nodosum, SLE, fibrosing alveolitis. • 40% of AIH type 1 presents with an acute onset of symptoms/signs indistinguishable from that of acute viral or toxic hepatitis and the disease may appear fulminant in fashion. • target autoantigen is unknown, but ASGPR (asialoglycoprotein receptor) found on hepatocyte surface is a candidate • Responds well to glucocorticoids

AIH type 2 • Characterized by presence of anti-LKM1 (liver/kidney microsome type 1) in serum • P-ANCA is not found • Mainly children (2-14 yo) but also seen in adults (in Europe, 20% of pts are adults; in US, 4% of pts are >18 yrs) • Only AIH with an identified target autoantigen: cytochrome monooxygenase P-450 IID6 (CYP2D6) found in the cytosol of hepatocytes. • Recognized homologies b/w epitopes of CYP2D6 and genome of HCV. • <10% of Europeans with chronic Hep C have detectable anti-LKM1 • Suggests molecular mimicry and antibody crossreactivity, multiple exposures to virus mimicking self may be a way to break self-tolerance and induce AIH type 2. • Anti-LKM1 + pts with chronic Hep C in US pts is rare – differences in indigenous virus or host susceptiblity? • Acute or fulminant presentation is possible • Thus essential to screen all pts who have an acute decompensation for type-specific autoantibodies. • Associated with HLQA-B14, -DR3, -C4A-QD • Susceptibility factor in German and Brazilians: DRB1*07 • Like AIH type 1, also responds well to glucocorticoids

AIH type 2 • Distinct form of anti-LKM positive AIH • Occurs in association with autoimmune polyendocrinopathy disorder (APECED) aka Polyglandular autoimmune syndrome type I (APS1) • rare autosomal recessive disorder • Caused by a signal gene mutation of the APS1 gene which encodes a transcription factor, autoimmune regulator (AIRE) which is expressed in epithelial and dendritic cells within the thymus where it regulates clonal deletion of autoreactive T cells, thus can affect self tolerance • Features of this disease are ectodermal dystrophy, mucocutaneous candidiasis, multiple endocrine gland failure (parathyroids, adrenals, ovaries) • Marked by the presence of numerous organ and non-organ specific autoantibodies and multiple concurrent autoimmune diseases. • most common among Finns, Sardinians, and Iranian Jews • Pts with APECED and AIH have an aggressive liver disease that does not respond well to standard immunosuppressive regimens.

AIH type 3 • Least established form of the disease • Designation largely abandoned • Characterized by presence of antibodies to soluble liver antigen and liver/pancreas (anti-SLA, anti- LP) • 30-50 yo • Target autoantigens: thought to be Glutathione S-transferase, but a transfer ribonucleoprotein (tRNP) 50-kd protein was described in 2000 as the more likely target. • Clinical and laboratory features that are indistinguishable from AIH type 1 • Also responds well to glucocorticoids

AIH subtypes

Variant forms

Diagnosis • Determination of serum aminotransferase and –globulin levels • Rule out ddx • Detection of ANA and /or SMA, or in their absence, anti-LKM1 • Liver tissue examination

Diagnosis • Determination of serum aminotransferase and –globulin levels • Predominant serum aminotransferase abnormality • Hypergammaglobulinemia (definite dx: ≥1.5; probable dx: any degree below) • exclusion of other chronic liver diseases that have similar features • hereditary causes: (Wilson disease, alpha1-antitrypsin deficiency, genetic hemochromatosis • Infectious causes: chronic viral hepatitis A, B, C • drug-induced liver disease (ETOH, minocycline, nitrofurantoin, INH, propylthiouracil, methyldopa) • NASH • immune cholangiopathies of PBC, PSC, autoimmune cholangitis

Diagnosis • Detection of ANA and /or SMA, or in their absence, anti-LKM1 • conventional immunoserologic tests for AIH: • antinuclear antibodies (ANA), • present alone (13%), along with SMA (54%) • also be found in PBC, PSC, chronic viral hepatitis, drug-related hepatitis, NASH, alcohol-induced liver disease • smooth muscle antibodies (SMA), • Directed against actin and nonactin components (tubulin, vimentin, desmin, skeletin) • present (87%), sole marker (33%), with ANA (54%) • antibodies to liver/kidney microsome type 1 (anti-LKM1) • Typically occurs in absence of SMA and ANA • rare in the US (4% of adults with AIH in US) • perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs) are common in type 1 AIH, • useful in evaluation patients who lack conventional autoantibodies. • Used to reclassify patients with cryptogenic chronic hepatitis as AIH, but they have not been formally assimilated into the diagnostic algorithm • Do not have diagnostic specificity nor do they have prognostic implications.

Diagnosis • Detection of ANA and /or SMA, or in their absence, anti-LKM1 • NEW antibodies: • investigational in nature, but sufficient promise to support a probable diagnosis, not generally available, assays are not standardized • actin (anti-actin) • has less sensitivity, but greater specificity than SMA for AIH type 1 • asialoglycoprotein receptor (anti-ASGPR) • transmembrane glycoprotein on the hepatocyte surface which can capture, internalize, display potential antigens • Seen in AIH type 1 • soluble liver antigen/liver-pancreas (A), • Seen in AIH type 3 • used to reclassification of patients with cryptogenic chronic hepatitis as AIH • liver cytosol type 1 (anti-LC1). • Have been proposed as an antigenic target. • Seen in AIH type 2 • Prevalence is higher in pts < 20, Rare in pts >40

Diagnosis • Liver tissue examination • Liver bx is essential to establish diagnosis and assess disease severity to determine need for treatment • histologic features of interface hepatitis (hallmark of the syndrome) • portal plasma cell infiltration typifies the disorder • lack of portal plasma cell infiltration does not preclude dx • 1999 update: lobular hepatitis is now part of histologic spectrum • aminotransferase and gamma-globulin levels do not predict histologic pattern of injury or the presence or absence of cirrhosis. • Histologic changes, such as ductopenia or destructive cholangitis, may indicate a variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis. • Findings of steatosis or iron overload may suggest alternative diagnoses: • NASH • Wilson disease • Chronic Hep C • Drug toxicity • genetic hemochromatosis

Interface hepatitis

Plasma cell infiltration

Lobular Hepatitis

PBC

PSC

Diagnostic Criteria

Scoring System

Prognosis

Prognosis • 40% develop with cirrhosis • 54% develop esophageal varices w/in 2 years • 20% die from variceal hemorrhage if they don’t receive any treatment • hepatocellular carcinoma can occur in this pts but risk is small. • Presence of ascites or hepatic encephalopathy identifies pts with a poor prognosis. • 13-20% of patients can have spontaneous resolution regardless of disease activity. • A critical determinant of survival in the untreated patient is early tolerance of the disease. • Of pts who survive the early, most active stage of the disease, inactive cirrhosis develops in 41% of pts. • Untreated patients who have initial severe disease and survive the first 2 years of illness typically survive long term

When to treat

Treatment

Treatment • Prednisone alone is appropriate for • severe cytopenia, • undergoing a short treatment trial (< 6 months), • pregnant or contemplating pregnancy, • active malignancy • thiopurine methyltransferase deficiency. • Combination regimen is appropriate: • for pts who will be treated continuously for at least six months • for pts at increased risk for drug-related complications (postmenopausal women, individuals with emotional instability, osteoporosis, brittle diabetes, labile hypertension • if receiving prednisone, pts should periodically undergo eye exams for cataracts, glaucoma • if receiving azathioprine, pts should be monitored for leucopenia and thrombocytopenia. • Recommend adjunctive therapies when individual risks are perceived: • regular program of exercise, calcium and vitamin D supplementation, hormonal replacement therapy may help preserve bone density. • For pts with osteopenia: consider Bisphosphonates: • alendronate 10 mg/day, • etidronate 400 mg/day for 2 weeks q 3 months

Indication for liver transplantation • Pts’ with ascites and hepatic encephalopathy identifies pt’s with poor prognosis. They can still respond to glucocorticoid therapy and should be treated before a decision regarding liver transplantation is made. • Indicated in decompensated pt with hepatic encephalopathy, ascites, and/or variceal hemorrhage during therapy for treatment failure • When decompensated patient with multilobular necrosis have at least one laboratory parameter that fails to normalize or hyperbilirubinemia that does not improve during a 2 week treatment period, the immediate mortality rate is high and evaluation for liver transplantation is warranted. • Effective in pts who deteriorate during or after corticosteroid tx. • After transplantation, the autoantibodies and hypergammaglobulinemia disappear within 2 years • the 5 year survival rate is 96%. Actuarial 10 year survival 75% • Recurrent disease after transplantation is common but has been described mainly in patients who have inadequate immunosuppression. • RARE cases (3-5%) pts can develop AIH de novo after undergoing transplantation for non-autoimmune liver disease. Immunosuppression with CyA is a common feature. TX with prednisone or azathioprine is effective.

Treatment endpoints

Drug-related side effects • Regardless of regimen, facial rounding, dorsal hump formation, obesity, acne or hirsutism occur in 80% of pts after 2 years. • 18 months on higher dose prednisone (20 mg/day)  osteopenia with vertebral compression, diabetes, cataracts, emotional lability, hypertension • Protracted therapy, especially retreatment after relapse is associated with increase risk of complications. • Azathioprine 50 mg/day: 10% of pts can be complicated by cholestatic hepatotoxicity, veno-occlusive disease, pancreatitis, nausea, emesis, rash, and cytopenia • Avoided in pts contemplating pregnancy, or is pregnant b/c of theoretic risk of teratogenicity. • Side effects will reverse if dose is reduced or termination of therapy • Treatment can usually be continued with single tolerated drug (prednisone or azathioprine) in an adjusted dose.

Relapse • Frequency of relapse: • 50% within 6 months, and most 70-86% experience exacerbation within 3 years. • 20% - improvement to normal tissue after cessation of treatment: • 50% -improvement to portal hepatitis • 100% - Progression to cirrhosis or persistence of interface hepatitis • Pt’s who had 2 relapses require indefinite therapy with either low dose prednisone (10 mg/day or less) or azathioprine (2 mg/kd/day). • Lowest dose prednisone possible (usually 10 mg daily or less) to prevent symptoms and maintain serum aminotransferase below 5-fold normal • Prednisone and azathioprine regimens have not been compared directly and there is no objective basis for preferring one to the other. • In 2000, mycophenolate mofetil was reported pts resistant to or intolerant of azathioprine, but future studies needed.

New Therapies

AIH Summary • self-perpetuating hepatocellular inflammation of unknown cause • Genetic predispostion • Diverse clinical features • 3 subtypes AIH and variants • Dx: • interface hepatitis • hypergammaglobulinemia • serum autoantibodies • Rule out other liver diseases • Consider in all pts with acute & chronic liver diseases and those with allograft dysfunction after transplantation • Prednisone, Azathioprine • Evolving treatment options

Is it over yet?

Autoimmune Hepatitis