autoimmune hepatitis residents conference 5/31/2005 michael le, md

Autoimmune Autoimmune HepatitisHepatitis

Residents ConferenceResidents Conference

5/31/20055/31/2005

Michael Le, MDMichael Le, MD

OverviewOverview

PrevalencePrevalence Clinical manifestationsClinical manifestations PathogenesisPathogenesis SubtypesSubtypes DiagnosisDiagnosis Prognostic indicesPrognostic indices TreatmentTreatment

Autoimmune HepatitisAutoimmune Hepatitis

self-perpetuating hepatocellular self-perpetuating hepatocellular inflammation inflammation

unknown causeunknown cause characterization: characterization:

histologic features of interface hepatitis histologic features of interface hepatitis hypergammaglobulinemiahypergammaglobulinemia serum autoantibodiesserum autoantibodies

affects all ages, may be asymptomatic, affects all ages, may be asymptomatic, frequently has an acute onset, and can frequently has an acute onset, and can also present as fulminant hepatitis.also present as fulminant hepatitis.

PrevalencePrevalence Mean annual incidence among white northern Mean annual incidence among white northern

Europeans: 1.9 cases per 100,000 per yearEuropeans: 1.9 cases per 100,000 per year US: 100,000-200,000 peopleUS: 100,000-200,000 people W>M 3.6:1, unexplained.W>M 3.6:1, unexplained. all ages, ethnic groups.all ages, ethnic groups. Frequency of AIH among pts with chronic Frequency of AIH among pts with chronic

liver disease in North America is 11-23%liver disease in North America is 11-23% Accounts for 5.9% in the National Institutes of Accounts for 5.9% in the National Institutes of

Health Liver transplantation database.Health Liver transplantation database. Prevalence of AIH is greatest among northern Prevalence of AIH is greatest among northern

European white groups who have a high European white groups who have a high frequency of HLA-DR3 and HLA-DR4frequency of HLA-DR3 and HLA-DR4

ClinicalClinical manifestationsmanifestations

PathogenesisPathogenesis

Unknown mechanismUnknown mechanism Most popular hypotheses: Most popular hypotheses:

interactive factors:interactive factors: Triggering agentTriggering agent A genetic predisposition A genetic predisposition various determinants of autoantigen various determinants of autoantigen

displaydisplay immunocyte activationimmunocyte activation effector cell expansion.effector cell expansion.


Triggering agentsTriggering 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.


Loss of self-tolerance –Loss of self-tolerance – molecular mimicry of a foreign antigen molecular mimicry of a foreign antigen self antigenself antigen

Only the Only the cytochrome monooxygenase P-450 cytochrome monooxygenase P-450 IID6 (CYP2D6)IID6 (CYP2D6) has been recognized as an has been recognized as an autoantigen. autoantigen.

multiple self-antigens or foreign multiple self-antigens or foreign antigens may satisfy the minimal antigens may satisfy the minimal structural requirements and serve as structural requirements and serve as immunogenic peptidesimmunogenic peptides

PathogenesisPathogenesis genetic predispositiongenetic predisposition Susceptibility HLA allelles encoding MHC class II:Susceptibility HLA allelles encoding MHC class II:

influences the presentation of these autoantigens to CD4+ influences the presentation of these autoantigens to CD4+ helper T cell thereby initiating an immune response.helper T cell thereby initiating an immune response.

the initiation of the immune response is dependent on the the initiation of the immune response is dependent on the antigen binding groove of the class II MHC molecule. The antigen binding groove of the class II MHC molecule. The sequence of amino acids that make up this antigen binding sequence of amino acids that make up this antigen binding groove is encoded by a person’s HLA alleles. Thus, there are groove is encoded by a person’s HLA alleles. Thus, there are specific alleles that make a person more susceptible to specific alleles that make a person more susceptible to developing AIH by influencing the immune response, and in developing AIH by influencing the immune response, and in turn the clinical manifestations and behavior of AIH. turn the clinical manifestations and behavior of AIH.

Autoimmune promoters: Autoimmune promoters: polymorphisms for TNF-polymorphisms for TNF-αα gene and cytotoxic T lymphocyte gene and cytotoxic T lymphocyte

antigen 4 gene have been associated with increased immune antigen 4 gene have been associated with increased immune reactivity and disease severity of AIH type Ireactivity and disease severity of AIH type I

Other: Vitamin D receptor (VDR) gene, point mutation of the Other: Vitamin D receptor (VDR) gene, point mutation of the tyrosine phosphatase CD45 gene, polymorphisms of the Fas tyrosine phosphatase CD45 gene, polymorphisms of the Fas gene, MHC class 1 chain-related A gene.gene, MHC class 1 chain-related A gene.

APC

TCR

PeptideAntigen

CD4

CD4 T Cell

MHCClass II

Cytokines

DRB1 gene

L L E Q K R

lysine

DRB1 gene

L L E Q R R

arginine

PathogenesisPathogenesis Mechanism of Liver cell Mechanism of Liver cell

destruction via cellular and destruction via cellular and humoral mechanismshumoral mechanisms

Cell-mediated cytotoxicityCell-mediated cytotoxicity TH1 response (IL-2, IFN-TH1 response (IL-2, IFN-γγ, TNF-, TNF-αα) )

clonal expansion of cytotoxic T clonal expansion of cytotoxic T lymphocytes that infiltrate and lymphocytes that infiltrate and destroy hepatocytes.destroy hepatocytes.

Genetic polymorphism that affects Genetic polymorphism that affects TNF-TNF- production may facilitate this production may facilitate this pathway.pathway.

Antibody-dependent cell-mediated Antibody-dependent cell-mediated cytotoxicitycytotoxicity

TH2 response (IL-4,5,6,8,10,13) TH2 response (IL-4,5,6,8,10,13) B B cell stimulation cell stimulation Ab production Ab production immunocyte complexes on immunocyte complexes on hepatocyte surface hepatocyte surface targeted by targeted by NKT cellsNKT cells

Anti-inflammatory effects that Anti-inflammatory effects that counters TH1 actioncounters TH1 action

Combination of mechanismsCombination of mechanisms Predominant mechanism depends Predominant mechanism depends

on the phenotypic differentiation of on the phenotypic differentiation of CD4+ helper T cell, which in turn CD4+ helper T cell, which in turn reflects the cytokine milieu, which reflects the cytokine milieu, which in itself reflects the polymorphisms in itself reflects the polymorphisms of the cytokine genes that favor of the cytokine genes that favor excessive production of some excessive production of some modulators, such as TNF-modulators, such as TNF-, or , or deficient in others.deficient in others.

AIH subtypesAIH subtypes

AIH type 1AIH type 1 AIH type 2AIH type 2 AIH type 3AIH type 3 on the basis of immunoserologic on the basis of immunoserologic

markers.markers. The International Autoimmune The International Autoimmune

Hepatitis Group has not endorsed this Hepatitis Group has not endorsed this subclassification.subclassification.

Used mainly for descriptive valueUsed mainly for descriptive value

AIH type 1AIH type 1 Most common form worldwide Most common form worldwide characterized by the characterized by the presence or absence of presence or absence of

SMA and/or ANA in serum SMA and/or ANA in serum Surrogate markers: Surrogate markers: Perinuclear Perinuclear

antineutrophil cytoplasmicantineutrophil cytoplasmic antibodies which antibodies which occur in PSC and chronic UC, are found in occur in PSC and chronic UC, are found in 90% of patients who have type 1 AIH.90% of patients who have type 1 AIH.

Bimodal age distribution (10-20; 45-70)Bimodal age distribution (10-20; 45-70) Female:male 3.6:1Female:male 3.6:1 Risk factors for type 1 AIHRisk factors for type 1 AIH

in whites of northern European descent [HLA-DR3 in whites of northern European descent [HLA-DR3 (DRB1*0301)] and –DR4 (DRB1*0401)] (DRB1*0301)] and –DR4 (DRB1*0401)]

AIH type 1AIH type 1 Associated with concurrent extrahepatic diseasesAssociated with concurrent extrahepatic diseases

Autoimmune thyroiditis (12%)Autoimmune thyroiditis (12%) Graves disease (6%)Graves disease (6%) Chronic UC (6%) * (cholangiography to exclude PSC)Chronic UC (6%) * (cholangiography to exclude PSC) <1% RA, pernicious anemia, systemic sclerosis, Coomb’s <1% RA, pernicious anemia, systemic sclerosis, Coomb’s

test-positive HA, ITP, symptomatic cryoglobulinemia, test-positive HA, ITP, symptomatic cryoglobulinemia, leukocytoclastic vasculitis, nephritis, erythema leukocytoclastic vasculitis, nephritis, erythema nodosum, SLE, fibrosing alveolitis.nodosum, SLE, fibrosing alveolitis.

40% of AIH type 1 presents with an acute onset of 40% of AIH type 1 presents with an acute onset of symptoms/signs indistinguishable from that of acute symptoms/signs indistinguishable from that of acute viral or toxic hepatitis and the disease may appear viral or toxic hepatitis and the disease may appear fulminant in fashion. fulminant in fashion.

target autoantigen is unknown, but ASGPR target autoantigen is unknown, but ASGPR (asialoglycoprotein receptor) found on hepatocyte (asialoglycoprotein receptor) found on hepatocyte surface is a candidate surface is a candidate

Responds well to glucocorticoidsResponds well to glucocorticoids

AIH type 2AIH type 2 Characterized by presence of Characterized by presence of anti-LKM1anti-LKM1 (liver/kidney microsome (liver/kidney microsome

type 1) in serum type 1) in serum P-ANCA is not foundP-ANCA is not found Mainly Mainly children children (2-14 yo) but also seen in adults (in Europe, 20% (2-14 yo) but also seen in adults (in Europe, 20%

of pts are adults; in US, 4% of pts are >18 yrs)of pts are adults; in US, 4% of pts are >18 yrs) Only AIH with an identified target autoantigen: Only AIH with an identified target autoantigen: cytochrome cytochrome

monooxygenase P-450 IID6 (CYP2D6) monooxygenase P-450 IID6 (CYP2D6) found in the cytosol of found in the cytosol of hepatocytes.hepatocytes.

Recognized Recognized homologieshomologies b/w epitopes of CYP2D6 and genome of b/w epitopes of CYP2D6 and genome of HCVHCV.. <10% of Europeans with chronic Hep C have detectable anti-LKM1<10% of Europeans with chronic Hep C have detectable anti-LKM1 Suggests molecular mimicry and antibody crossreactivity, multiple Suggests molecular mimicry and antibody crossreactivity, multiple

exposures to virus mimicking self may be a way to break self-tolerance exposures to virus mimicking self may be a way to break self-tolerance and induce AIH type 2.and induce AIH type 2.

Anti-LKM1 + pts with chronic Hep C in US pts is rare – differences in Anti-LKM1 + pts with chronic Hep C in US pts is rare – differences in indigenous virus or host susceptiblity?indigenous virus or host susceptiblity?

Acute or fulminant presentation is possibleAcute or fulminant presentation is possible Thus essential to screen all pts who have an acute decompensation for Thus essential to screen all pts who have an acute decompensation for

type-specific autoantibodies.type-specific autoantibodies. Associated with HLQA-B14, -DR3, -C4A-QDAssociated with HLQA-B14, -DR3, -C4A-QD Susceptibility factor in German and Brazilians: DRB1*07 Susceptibility factor in German and Brazilians: DRB1*07 Like AIH type 1, also responds well to glucocorticoidsLike AIH type 1, also responds well to glucocorticoids

AIH type 2AIH type 2 Distinct form of anti-LKM positive AIHDistinct form of anti-LKM positive AIH Occurs in association with Occurs in association with autoimmune polyendocrinopathy autoimmune polyendocrinopathy

disorder (APECED)disorder (APECED) aka aka Polyglandular autoimmune syndrome Polyglandular autoimmune syndrome type I (APS1)type I (APS1)

rare autosomal recessive disorder rare autosomal recessive disorder Caused by a signal gene mutation of the APS1 gene which Caused by a signal gene mutation of the APS1 gene which

encodes a transcription factor, autoimmune regulator (AIRE) encodes a transcription factor, autoimmune regulator (AIRE) which is expressed in epithelial and dendritic cells within the which is expressed in epithelial and dendritic cells within the thymus where it regulates clonal deletion of autoreactive T thymus where it regulates clonal deletion of autoreactive T cells, thus can affect self tolerancecells, thus can affect self tolerance

Features of this disease are Features of this disease are ectodermal dystrophy, ectodermal dystrophy, mucocutaneous candidiasis, multiple endocrine gland failuremucocutaneous candidiasis, multiple endocrine gland failure (parathyroids, adrenals, ovaries)(parathyroids, adrenals, ovaries)

Marked by the presence of numerous organ and non-organ Marked by the presence of numerous organ and non-organ specific autoantibodies and multiple concurrent autoimmune specific autoantibodies and multiple concurrent autoimmune diseases.diseases.

most common among Finns, Sardinians, and Iranian Jewsmost common among Finns, Sardinians, and Iranian Jews Pts with APECED and AIH have an Pts with APECED and AIH have an aggressive liver diseaseaggressive liver disease that that

does not respond well to standard immunosuppressive does not respond well to standard immunosuppressive regimens.regimens.

AIH type 3AIH type 3 Least established form of the disease Least established form of the disease Designation largely abandonedDesignation largely abandoned Characterized by presence of antibodies to Characterized by presence of antibodies to

soluble liver antigen and liver/pancreas (soluble liver antigen and liver/pancreas (anti-anti-SLA, anti- LPSLA, anti- LP))

30-50 yo30-50 yo Target autoantigens: Target autoantigens: thought thought to be to be

Glutathione S-transferase, but a transfer Glutathione S-transferase, but a transfer ribonucleoprotein (tRNP) 50-kd protein was ribonucleoprotein (tRNP) 50-kd protein was described in 2000 as the more likely target.described in 2000 as the more likely target.

Clinical and laboratory features that are Clinical and laboratory features that are indistinguishable from AIH type 1indistinguishable from AIH type 1

Also responds well to glucocorticoidsAlso responds well to glucocorticoids

AIH subtypesAIH subtypes

Variant formsVariant forms

DiagnosisDiagnosis

Determination of serum Determination of serum aminotransferase and –globulin aminotransferase and –globulin levels levels

Rule out ddxRule out ddx Detection of ANA and /or SMA, or in Detection of ANA and /or SMA, or in

their absence, anti-LKM1 their absence, anti-LKM1 Liver tissue examinationLiver tissue examination

DiagnosisDiagnosis Determination of serum aminotransferase Determination of serum aminotransferase

and –globulin levelsand –globulin levels Predominant serum aminotransferase abnormalityPredominant serum aminotransferase abnormality Hypergammaglobulinemia (definite dx: ≥1.5; Hypergammaglobulinemia (definite dx: ≥1.5;

probable dx: any degree below)probable dx: any degree below) exclusion of other chronic liver diseases exclusion of other chronic liver diseases

that have similar features that have similar features hereditary causes: (Wilson disease, alpha1-hereditary causes: (Wilson disease, alpha1-

antitrypsin deficiency, genetic hemochromatosis antitrypsin deficiency, genetic hemochromatosis Infectious causes: chronic viral hepatitis A, B, CInfectious causes: chronic viral hepatitis A, B, C drug-induced liver disease (ETOH, minocycline, drug-induced liver disease (ETOH, minocycline,

nitrofurantoin, INH, propylthiouracil, methyldopa) nitrofurantoin, INH, propylthiouracil, methyldopa) NASH NASH immune cholangiopathies of PBC, PSC, immune cholangiopathies of PBC, PSC,

autoimmune cholangitisautoimmune cholangitis

DiagnosisDiagnosis Detection of ANA and /or SMA, or in their absence, anti-Detection of ANA and /or SMA, or in their absence, anti-

LKM1 LKM1 conventionalconventional immunoserologic tests for AIH: immunoserologic tests for AIH:

antinuclear antibodies (ANA),antinuclear antibodies (ANA), present alone (13%), along with SMA (54%)present alone (13%), along with SMA (54%) also be found in PBC, PSC, chronic viral hepatitis, drug-related also be found in PBC, PSC, chronic viral hepatitis, drug-related

hepatitis, NASH, alcohol-induced liver diseasehepatitis, NASH, alcohol-induced liver disease smooth muscle antibodies (SMA),smooth muscle antibodies (SMA),

Directed against actin and nonactin components (tubulin, Directed against actin and nonactin components (tubulin, vimentin, desmin, skeletin)vimentin, desmin, skeletin)

present (87%), sole marker (33%), with ANA (54%)present (87%), sole marker (33%), with ANA (54%) antibodies to liver/kidney microsome type 1 (anti-LKM1)antibodies to liver/kidney microsome type 1 (anti-LKM1)

Typically occurs in absence of SMA and ANATypically occurs in absence of SMA and ANA rare in the US (4% of adults with AIH in US)rare in the US (4% of adults with AIH in US)

perinuclear anti-neutrophil cytoplasmic antibodiesperinuclear anti-neutrophil cytoplasmic antibodies (pANCAs) (pANCAs) are common in type 1 AIH, are common in type 1 AIH,

useful in evaluation patients who lack conventional autoantibodies.useful in evaluation patients who lack conventional autoantibodies. Used to reclassify patients with cryptogenic chronic hepatitis as Used to reclassify patients with cryptogenic chronic hepatitis as

AIH, but they have not been formally assimilated into the AIH, but they have not been formally assimilated into the diagnostic algorithmdiagnostic algorithm

Do not have diagnostic specificity nor do they have prognostic Do not have diagnostic specificity nor do they have prognostic implications.implications.

DiagnosisDiagnosis Detection of ANA and /or SMA, or in their absence, Detection of ANA and /or SMA, or in their absence,

anti-LKM1 anti-LKM1 NEW NEW antibodies:antibodies:

investigational in nature, but sufficient promise to investigational in nature, but sufficient promise to support a support a probable diagnosisprobable diagnosis, not generally available, assays are not , not generally available, assays are not standardizedstandardized

actin (anti-actin)actin (anti-actin) has less sensitivity, but greater specificity than SMA for AIH type 1has less sensitivity, but greater specificity than SMA for AIH type 1

asialoglycoprotein receptor (anti-ASGPR)asialoglycoprotein receptor (anti-ASGPR) transmembrane glycoprotein on the hepatocyte surface which can transmembrane glycoprotein on the hepatocyte surface which can

capture, internalize, display potential antigenscapture, internalize, display potential antigens Seen in AIH type 1Seen in AIH type 1

soluble liver antigen/liver-pancreas (A),soluble liver antigen/liver-pancreas (A), Seen in AIH type 3Seen in AIH type 3 used to reclassification of patients with cryptogenic chronic hepatitis used to reclassification of patients with cryptogenic chronic hepatitis

as AIHas AIH liver cytosol type 1 (anti-LC1).liver cytosol type 1 (anti-LC1).

Have been proposed as an antigenic target.Have been proposed as an antigenic target. Seen in AIH type 2Seen in AIH type 2 Prevalence is higher in pts < 20, Rare in pts >40Prevalence is higher in pts < 20, Rare in pts >40

DiagnosisDiagnosis Liver tissue examinationLiver tissue examination

Liver bx is essential to establish diagnosis and assess disease Liver bx is essential to establish diagnosis and assess disease severity to determine need for treatmentseverity to determine need for treatment

histologic features of histologic features of interface hepatitisinterface hepatitis (hallmark of the syndrome) (hallmark of the syndrome) portal plasma cell infiltration typifies the disorderportal plasma cell infiltration typifies the disorder

lack of portal plasma cell infiltration does not preclude dxlack of portal plasma cell infiltration does not preclude dx 1999 update: lobular hepatitis is now part of histologic spectrum1999 update: lobular hepatitis is now part of histologic spectrum aminotransferase and gamma-globulin levels do not predict aminotransferase and gamma-globulin levels do not predict

histologic pattern of injury or the presence or absence of cirrhosis.histologic pattern of injury or the presence or absence of cirrhosis. Histologic changes, such as ductopenia or destructive cholangitis, Histologic changes, such as ductopenia or destructive cholangitis,

may indicate a variant syndrome of AIH and PSC, AIH an PBC, or may indicate a variant syndrome of AIH and PSC, AIH an PBC, or autoimmune cholangitis.autoimmune cholangitis.

Findings of steatosis or iron overload may suggest alternative Findings of steatosis or iron overload may suggest alternative diagnoses:diagnoses:

NASHNASH Wilson diseaseWilson disease Chronic Hep CChronic Hep C Drug toxicity Drug toxicity genetic hemochromatosisgenetic hemochromatosis

Interface hepatitisInterface hepatitis

Plasma cell infiltrationPlasma cell infiltration




lack of portal plasma cell infiltration does not preclude dxlack of portal plasma cell infiltration does not preclude dx 1999 update: lobular hepatitis is now part of histologic spectrum 1999 update: lobular hepatitis is now part of histologic spectrum aminotransferase and gamma-globulin levels do not predict aminotransferase and gamma-globulin levels do not predict





Lobular HepatitisLobular Hepatitis

PBCPBC

PSCPSC

Diagnostic CriteriaDiagnostic Criteria

Scoring SystemScoring System

PrognosisPrognosis

PrognosisPrognosis 40% develop with cirrhosis 40% develop with cirrhosis

54% develop esophageal varices w/in 2 years54% develop esophageal varices w/in 2 years 20% die from variceal hemorrhage if they don’t receive 20% die from variceal hemorrhage if they don’t receive

any treatmentany treatment hepatocellular carcinoma can occur in this pts but risk hepatocellular carcinoma can occur in this pts but risk

is small.is small. Presence of Presence of ascites or hepatic encephalopathyascites or hepatic encephalopathy

identifies pts with a identifies pts with a poor prognosis.poor prognosis. 13-20% of patients can have spontaneous resolution 13-20% of patients can have spontaneous resolution

regardless of disease activity.regardless of disease activity. A critical determinant of survival in the untreated A critical determinant of survival in the untreated

patient is early tolerance of the disease.patient is early tolerance of the disease. Of pts who survive the early, most active stage of the Of pts who survive the early, most active stage of the

disease, inactive cirrhosis develops in 41% of pts.disease, inactive cirrhosis develops in 41% of pts. Untreated patients who have initial severe disease and Untreated patients who have initial severe disease and

survive the first 2 years of illness typically survive long survive the first 2 years of illness typically survive long termterm

When to treatWhen to treat

TreatmentTreatment

TreatmentTreatment Prednisone alone is appropriate for Prednisone alone is appropriate for

severe cytopenia,severe cytopenia, undergoing a short treatment trial (< 6 months), undergoing a short treatment trial (< 6 months), pregnant or contemplating pregnancy, pregnant or contemplating pregnancy, active malignancyactive malignancy thiopurine methyltransferase deficiency.thiopurine methyltransferase deficiency.

Combination regimen is appropriate:Combination regimen is appropriate: for pts who will be treated continuously for at least six monthsfor pts who will be treated continuously for at least six months for pts at increased risk for drug-related complications for pts at increased risk for drug-related complications

(postmenopausal women, individuals with emotional instability, (postmenopausal women, individuals with emotional instability, osteoporosis, brittle diabetes, labile hypertensionosteoporosis, brittle diabetes, labile hypertension

if receiving prednisone, pts should periodically undergo eye exams if receiving prednisone, pts should periodically undergo eye exams for cataracts, glaucomafor cataracts, glaucoma

if receiving azathioprine, pts should be monitored for leucopenia if receiving azathioprine, pts should be monitored for leucopenia and thrombocytopenia.and thrombocytopenia.

Recommend adjunctive therapies when individual risks are Recommend adjunctive therapies when individual risks are perceived: perceived:

regular program of exercise, calcium and vitamin D supplementation, regular program of exercise, calcium and vitamin D supplementation, hormonal replacement therapy may help preserve bone density.hormonal replacement therapy may help preserve bone density.

For pts with osteopenia: consider Bisphosphonates: For pts with osteopenia: consider Bisphosphonates: alendronate 10 mg/day, alendronate 10 mg/day, etidronate 400 mg/day for 2 weeks q 3 monthsetidronate 400 mg/day for 2 weeks q 3 months

Indication for liver Indication for liver transplantationtransplantation

Pts’ with Pts’ with ascites and hepatic encephalopathyascites and hepatic encephalopathy identifies pt’s with identifies pt’s with poor poor prognosisprognosis. They can still respond to . They can still respond to glucocorticoid therapy and glucocorticoid therapy and should be treated before a decision regarding liver transplantation is should be treated before a decision regarding liver transplantation is mademade. .

Indicated in Indicated in decompensated ptdecompensated pt with hepatic encephalopathy, ascites, with hepatic encephalopathy, ascites, and/or variceal hemorrhage and/or variceal hemorrhage during therapy for treatment failure during therapy for treatment failure

When When decompensated patientdecompensated patient with multilobular necrosis have at with multilobular necrosis have at least one laboratory parameter that fails to normalize or least one laboratory parameter that fails to normalize or hyperbilirubinemia that does not improve during a 2 week treatment hyperbilirubinemia that does not improve during a 2 week treatment period, the period, the immediate mortality rate is highimmediate mortality rate is high and evaluation for and evaluation for liver liver transplantationtransplantation is warranted. is warranted.

Effective in pts who deteriorate during or after corticosteroid tx.Effective in pts who deteriorate during or after corticosteroid tx. After transplantation, the autoantibodies and After transplantation, the autoantibodies and

hypergammaglobulinemia disappear within 2 years hypergammaglobulinemia disappear within 2 years the 5 year survival rate is 96%. Actuarial 10 year survival 75%the 5 year survival rate is 96%. Actuarial 10 year survival 75% Recurrent disease after transplantation is common but has been Recurrent disease after transplantation is common but has been

described mainly in patients who have inadequate described mainly in patients who have inadequate immunosuppression.immunosuppression.

RARERARE cases (3-5%) pts can develop cases (3-5%) pts can develop AIH de novoAIH de novo after undergoing after undergoing transplantation for non-autoimmune liver disease. transplantation for non-autoimmune liver disease. Immunosuppression with CyA is a common feature. TX with Immunosuppression with CyA is a common feature. TX with prednisone or azathioprine is effective. prednisone or azathioprine is effective.

Treatment endpointsTreatment endpoints

Drug-related side effectsDrug-related side effects Regardless of regimen, facial rounding, dorsal hump Regardless of regimen, facial rounding, dorsal hump

formation, obesity, acne or hirsutism occur in 80% of formation, obesity, acne or hirsutism occur in 80% of pts after 2 years.pts after 2 years.

18 months on higher dose prednisone (20 mg/day) 18 months on higher dose prednisone (20 mg/day) osteopenia with vertebral compression, diabetes, osteopenia with vertebral compression, diabetes, cataracts, emotional lability, hypertensioncataracts, emotional lability, hypertension

Protracted therapy, especially retreatment after relapse Protracted therapy, especially retreatment after relapse is associated with increase risk of complications.is associated with increase risk of complications.

Azathioprine 50 mg/day: 10% of pts can be complicated Azathioprine 50 mg/day: 10% of pts can be complicated by cholestatic hepatotoxicity, veno-occlusive disease, by cholestatic hepatotoxicity, veno-occlusive disease, pancreatitis, nausea, emesis, rash, and cytopeniapancreatitis, nausea, emesis, rash, and cytopenia Avoided in pts contemplating pregnancy, or is pregnant Avoided in pts contemplating pregnancy, or is pregnant

b/c of theoretic risk of teratogenicity.b/c of theoretic risk of teratogenicity. Side effects will reverse if dose is reduced or Side effects will reverse if dose is reduced or

termination of therapytermination of therapy Treatment can usually be continued with single Treatment can usually be continued with single

tolerated drug (prednisone or azathioprine) in an tolerated drug (prednisone or azathioprine) in an adjusted dose.adjusted dose.

RelapseRelapse Frequency of relapse:Frequency of relapse:

50% within 6 months, and most 70-86% experience 50% within 6 months, and most 70-86% experience exacerbation within 3 years.exacerbation within 3 years.

20% - improvement to normal tissue after cessation of 20% - improvement to normal tissue after cessation of treatment: treatment:

50% -improvement to portal hepatitis50% -improvement to portal hepatitis 100% - Progression to cirrhosis or persistence of interface 100% - Progression to cirrhosis or persistence of interface

hepatitishepatitis Pt’s who had Pt’s who had 2 relapses2 relapses require indefinite therapy with require indefinite therapy with

either either low doselow dose prednisone (10 mg/day or less) or prednisone (10 mg/day or less) or azathioprine (2 mg/kd/day).azathioprine (2 mg/kd/day). Lowest dose prednisone possible (usually 10 mg daily or less) Lowest dose prednisone possible (usually 10 mg daily or less)

to prevent symptoms and maintain serum aminotransferase to prevent symptoms and maintain serum aminotransferase below 5-fold normalbelow 5-fold normal

Prednisone and azathioprine regimens have not been Prednisone and azathioprine regimens have not been compared directly and there is no objective basis for compared directly and there is no objective basis for preferring one to the other.preferring one to the other.

In 2000, mycophenolate mofetil was reported pts resistant In 2000, mycophenolate mofetil was reported pts resistant to or intolerant of azathioprine, but future studies needed.to or intolerant of azathioprine, but future studies needed.

New TherapiesNew Therapies

AIH SummaryAIH Summary self-perpetuating hepatocellular inflammation of unknown self-perpetuating hepatocellular inflammation of unknown

causecause Genetic predispostionGenetic predispostion Diverse clinical featuresDiverse clinical features 3 subtypes AIH and variants3 subtypes AIH and variants Dx: Dx:

interface hepatitis interface hepatitis hypergammaglobulinemiahypergammaglobulinemia serum autoantibodiesserum autoantibodies Rule out other liver diseasesRule out other liver diseases

Consider in all pts with acute & chronic liver diseases and those Consider in all pts with acute & chronic liver diseases and those with allograft dysfunction after transplantationwith allograft dysfunction after transplantation

Prednisone, AzathioprinePrednisone, Azathioprine Evolving treatment optionsEvolving treatment options

Is it over yet?

ReferencesReferences Sleisenger & Fordtran’s Gastrointestinal and Sleisenger & Fordtran’s Gastrointestinal and

Liver Disease, Pathophysiology, Diagnosis, Liver Disease, Pathophysiology, Diagnosis, Management. 7Management. 7thth Edition. Feldman, Edition. Feldman, Friedman, Sleisenger. Chapter 75. Friedman, Sleisenger. Chapter 75. Autoimmune Hepatitis.Autoimmune Hepatitis.

www.uptodateonline.com. Keyword: www.uptodateonline.com. Keyword: Autoimmune hepatitis.Autoimmune hepatitis.

““Current Concepts in Autoimmune Current Concepts in Autoimmune Hepatitis”. Czaja, Albert J. Annals of Hepatitis”. Czaja, Albert J. Annals of Hepatology 2005: 4(1): January-March:6-24Hepatology 2005: 4(1): January-March:6-24

““Treatment Challenges and Investigational Treatment Challenges and Investigational Opportunities in Autoimmune Hepatitis”. Opportunities in Autoimmune Hepatitis”. Czaja, Albert J. Hepatology 2005:41:207-215.Czaja, Albert J. Hepatology 2005:41:207-215.

autoimmune hepatitis residents conference 5/31/2005 michael le, md

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