Autoimmune Hepatitis-Better Understanding

Chairperson: Dr Sanjeev Kumar

Speaker : Dr Sushant Wattal

Introduction & Definition Un resolving inflammation of liver of

unknown cause. Environmental triggers, failure of

immune tolerance, genetic predisposition.

T-cell mediated immune attack upon liver antigens.

Progressive necro-inflammatory and fibrotic process leading on to cirrhosis and liver failure.

Epidemiology Women are affected more frequently than

men(3.6:1). All ethnic groups and all age groups

affected. Mean Incidence is 1 to 2 per 100,000

persons per year in Norway, Sweden, North-America.

When untreated 6 month mortality is 40%, while treated cases show a 10 year survival of 80-90 %.

Pathogenesis Exact pathogenesis is unknown. Popular hypothesis- includes triggering agent

(infectious agent, drug, toxin), genetic predisposition(HLA – B1,B8,DR3,DR4).

Loss of immune tolerance and activation of cell mediated immunity against liver antigens.

Humoral immunity plays a role in extra-hepatic manifestations of arthritis, vasculitis and glomerulonephritis by immune complex deposition and complement activation.

Clinical FeaturesSymptomsFatigueJaundiceUpper abdominal discomfortPruritusNone(at presentation)AnorexiaMyalgiasDiarrhoeaCushingoid featuresFever( <=40 deg celsius)

Occurrence (%)8677483625-343030281918

Clinical Features contd.Physical SignsHepatomegalyJaundiceSpider AngiomataConcurrent immune diseaseSplenomegalyNoneAscitesEncephalopathy

Occurrence786958<38>32<252014

Laboratory FeaturesLab Feature

Elevated ASTHypergammaglobulinemiaIncreased immunoglobulin G levelHyperbilirubinemiaALP >2 fold normal

Immunoserologic Markers

SMA,ANA or Anti- LKM1Atypical p-ANCAAnti sialoglycoprotein receptorAnti ActinAnti Liver Cytosol 1Anti Soluble Liver Antigen

Occurrence (%)

10092918333

Occurrence

10092(type 1 AIH only)827432(type 2 AIH only)11-17

Diagnosis AIH is a diagnosis of exclusion. Other causes of chronic hepatitis must

be ruled out. Viral hepatitis, Wilson’s disease, Drug

induced hepatitis, Alcoholic and Non alcoholic Fatty liver disease, Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis.

Simplified scoring system for diagnosis of AIH

Category Variable Score

1) AUTO ANTIBODIES ANA or SMA Anti LKM-1

Anti SLA

1:40 >=1:40 >1:80

Positive

+1+2+2

+2

2) IMMUNOGLOBULIN-G LEVEL

> Upper limit of normal >1.5 times upper limit

+1+2

3) HISTOLOGY Compatible with AIHTypical of AIH

+1+2

4) VIRAL DISEASE No viral markers +2DEFINITE DIAGNOSIS >=7PROBABLE DIAGNOSIS 6

Diagnostic Algorithm for AIH

Elevated serum AST & Gamma Globulin levelsAST:ALP >3

AMA negativeCeruloplasmin normal

Normal Alpha 1 Antitrypsin phenotypeNormal or near normal serum iron

HBsAg, Anti HCV, IgM Anti HAV and Anti HEV negative

LIVER BIOPSYInterface Hepatitis +/- Lobular Hepatitis

Diagnostic Algorithm contd.Auto immune hepatitis

DEFINITEGamma globulin level >=1.5

normalANA, SMA, or ANTI LKM1 >=1:80

No exposure to drugs or blood products

Alcohol intake<25 g/day

PROBABLEGamma globulin level <1.5

normalANA, SMA, or ANTI LKM1<=1:40Previous exposure to drugs or

blood productsAlcohol Use

Other liver related auto antibodies

Classification Two types of AIH (Type 1 and Type 2). Based on serological markers. A proposed third type (type 3) has

been abandoned and considered a more severe form of type 1 AIH.

Anti-SLA is found in both type 1 AIH and in type 2 AIH and indicator of severe disease and poor outcome.

Type 1 Autoimmune Hepatitis

Characterized by the presence of ANA, SMA or both, and constitutes 80% of AIH cases.

70 % of patients are female, with a peak incidence between ages 16 and 30 years.

Associations with other autoimmune diseases are common (15%-34%); these include autoimmune thyroid disease, synovitis, celiac disease and ulcerative colitis.

Type 2 Autoimmune Hepatitis

Characterized by the presence of anti-LKM1 and/or anti-LC1 and/or anti-LKM-3.

Most patients with type 2 AIH are children, and serum immunoglobulin levels are usually elevated except for IgA, which may be reduced.

Auto-Antibodies in AIHAntibody Target Antigen Liver DiseaseANA Chromatin,

ribonucleoproteins, ribonucleoprotein complexes

Type1 AIH,PBC,PSC, Drug-induced, Chronic hepatitis B&C,NAFLD

SMA Microfilaments(filamentous actin) & intermediate filaments (vimentin,desmin)

Type1 AIH,PBC,PSC, Drug-induced,Chronic hepatitis B&C,NAFLD

LKM 1 Cytochrome P450 2D6 (CYP2D6)

Type 2 AIH Chronic hepatitis C

LC 1 Formiminotransferase cyclo deaminase (FTCD)

Type 2 AIH Chronic hepatitis C

pANCA (atypical)

Nuclear lamina proteins Type1 AIH PSC

SLA tRNP(SER)Sec AIH,Chronic hepatitis C

Other Auto Antibodies in AIH

Antibody Target Antigen Liver DiseaseLKM 3 family 1 UDP glucuronosyl

transferases (UGT1A)Type 2 AIH, Chronic hepatitis D

ASGPR Asialoglycoprotein receptor AIH PBC Drug induced hepatitisChronic hepatitis B, C, D

LKM2 Cytochrome P450 2C9 Ticrynafen induced hepatitis

LM Cytochrome P450 1A2 Dihydralazine induced hepatitisAPECED hepatitis

Liver Biopsy Recommended at presentation to establish the

diagnosis and to guide the treatment decision. Interface hepatitis is the histological hallmark

and plasma cell infiltration is typical. Neither histological finding is specific for AIH,

and the absence of plasma cells in the infiltrate does not preclude the diagnosis.

Eosinophils, lobular inflammation, bridging necrosis, and multiacinar necrosis may be present.

Portal lesions generally spare bile ducts.

Interface Hepatitis Hallmark of AIH. The limiting plate of the portal tract is

disrupted by a lympho plasmacytic infiltrate.

Variant Forms of AIHAIH+PBC

AIH+PSC AIH+Cholestatic features

Autoantibody negative AIH

Clinical& Lab Features

Features of AIH, AMA +

AIH Features plus Ulcerative colitis, AMA -,Abnormal cholangiogram

ANA and or SMA+AMA -, No ulcerative colitis, Normal cholangiogram

AIH Features,No Autoantibody,HLA DR3 or DR4 +

Histology

Cholangitis, cholestasis

Cholangitis, cholestasis

Cholangitis, cholestasis

Interface Hepatitis

Auto Antibody Negative AIH 13% of chronic hepatitis of unknown

cause satisfy criteria for AIH but lack the characteristic autoantibodies.

Commonly called CRYPTOGENIC CHRONIC HEPATITIS.

Clinical, biochemical and histological features are characteristic of AIH.

They have the similar HLA types and respond to steroids like AIH.

Concurrent Immune Diseases

Autoimmune thyroiditis, Graves’ disease, synovitis and ulcerative colitis are the most common immune-mediated disorders associated with AIH in North American adults.

Type I diabetes mellitus, vitiligo, and autoimmune thyroiditis are the most common concurrent disorders in European anti-LKM1+ AIH patients.

Concurrent Immune Diseases contd.

In children with AIH, autoimmune sclerosing cholangitis can be present, with or without IBD.

Cholangiographic studies should be considered to exclude PSC in adults if there has been no response to corticosteroid therapy after 3 months.

All children with AIH and all adults with both AIH and IBD should undergo cholangiographic studies to exclude PSC.

Absolute Indications For Treatment of AIH

Incapacitating symptoms and relentless clinical progression.

Serum AST or ALT levels are >=10 fold the upper limit of normal.

If AST or ALT levels are >=5 fold the upper limit of normal with gamma globulin >=2 fold the upper limit of normal.

Bridging or Multi-lobular Necrosis on histology

Relative Indications For Treatment of AIH

Mild or no symptoms. Serum AST is 3-9.9 fold ULN. Serum AST is >=5 fold ULN BUT

gamma globulin is <2 fold ULN. Interface Hepatitis on histology

Treatment NOT INDICATED Asymptomatic with minimal laboratory

changes. Serum AST <3 fold the ULN. Burned out or Inactive Cirrhosis – patients

do not benefit from therapy and have increased drug induced side effects (Hypo-albuminemia, hyper-bilirubinemia and porto-systemic shunting affect protein binding and increase free prednisone)

Treatment NOT INDICATED Portal hepatitis and Decompensated

Cirrhosis with variceal bleeding. Severe pre treatment CYTOPENIA or known

deficiency of thiopurine methyltransferase deficiency.

Brittle diabetes, vertebral compression, psychosis, osteoporosis and uncontrolled hypertension where steroids can be harmful.

Previous intolerances to azathioprine or prednisone.

Treatment Regimens for AIH in Adults

Mainstay of management of AIH is Glucocorticoid therapy.

Although some advocate the use of prednisolone, prednisone is just as effective and favoured by most authorities.

Two treatment regimens are used and are equally effective but it is the combination therapy which is preferred.

Combination Immunosuppressive Therapy

It is usually preferred as over a span of 18 months it reduces the serious life threatening side effects of steroids from 66% down to under 20 %.

Begin with 30 mg/d of prednisone along with 50 mg/d(1-2mg/kg in europe) of azathioprine.

With azathioprine maintained at 50mg/d the prednisone dose is tapered over a month to a maintainance level of 10mg/d.

Steroid Monotherapy Regimen

Preferred in patients in whom azathioprine cant be given.

Severe pre treatment cytopenia, known thiopurine methyl transferase deficiency, pregnancy, active malignancy and if treatment is to be given for a short course <6 months.

Treatment RegimensMonotherapy Combination Therapy

Prednisone only(mg/d)

Prednisone(mg/d)

AzathioprineU.S.A(mg/d)

AzathioprineEU(mg/kg/d)

Week 1 60 30 50 1-2Week 2 40 20 50 1-2Week 3 30 15 50 1-2Week 4 30 15 50 1-2Maintainance until end point

20 10 50 1-2

Corticosteroid Side Effects and Monitoring

Cosmetic changes, including facial rounding, dorsal hump formation.

Striae, weight gain, acne, alopecia and facial hirsuitism, occur in 80% of patients after 2 years of corticosteroid treatment regardless of the regimen.

Severe side effects include osteopenia with vertebral compression, brittle diabetes, psychosis, pancreatitis, opportunistic infection, labile hypertension, and malignancy.

Managing steroid side effects

regular weight baring exercise program, vitamin D and calcium supplementation and administration of bisphosphonates wherever needed.

Patients on long-term corticosteroid treatment should be monitored for bone disease by baseline and annual bone mineral densitometry of the lumbar spine and hip.

Pre treatment vaccination against HAV and HBV should be performed if there has been no previous vaccination .

Azathioprine-Related Side Effects

include nausea, emesis, rash, opportunistic infection, villous atrophy, malabsorption, bone marrow suppression and malignancy.

The principal side effect of azathioprine is cytopenia and the most common cause of cytopenia in these patients is hypersplenism associated with cirrhosis.

Patients undergoing azathioprine therapy should have blood leukocyte and platelet counts assessed at 6-month intervals.

Thiopurine methyl tranferase

Patients with near-zero erythrocyte concentrations of its activity are at risk for myelo-suppression during azathioprine treatment.

The rarity of severe azathioprine-induced myelo-suppression, the low dose of azathioprine used in conventional treatment (50 mg-150 mg daily), and the inability to reliably predict risk by phenotypic and genotypic assessments have not supported routine screening for thiopurine methy-ltransferase activity in AIH.

Pre treatment cytopenia, cytopenia developing during therapy, or the administration of higher than conventional doses of azathioprine (>150 mg daily) justifies determination of enzyme activity.

AIH and Pregnancy Autoimmune hepatitis can improve

during pregnancy and this improvement may allow reductions in immunosuppressive therapy during pregnancy.

Pre-conceptional counselling is advised and termination of immunosuppressive therapy should be attempted where possible.

AIH and Pregnancy Patients must be counselled regarding the uncertain

risk of azathioprine(CAT D) in pregnancy, and azathioprine should be discontinued, if possible, in patients during pregnancy.

Postpartum exacerbation of AIH must be anticipated by resuming standard therapy 2 weeks prior to anticipated delivery and by closely monitoring serum AST or ALT levels at 3-week intervals for at least 3 months after delivery.

Contraception should be advised in women with advanced liver disease and features of portal hypertension because they are at risk for variceal hemorrhage during pregnancy.

TREATMENT ENDPOINTS Remission Treatment failure Incomplete response Relapse Drug toxicity

Remission Disappearance of symptoms, normal serum

aminotransferases, bilirubin and gamma globulin levels, normal hepatic tissue or inactive cirrhosis is the ideal treatment endpoint and the goal of initial therapy.

Liver biopsy assessment prior to termination of treatment is the only method by which to ensure full resolution of the disease and an optimal endpoint of therapy.

Interface hepatitis is found in 55% of patients with normal serum AST and gamma-globulin levels and these individuals typically relapse after cessation of treatment, therefore, a liver biopsy is recommended before termination of therapy.

Remission contd. Termination of therapy should be considered after

at least 2-year treatment, when liver function tests and immunoglobulin levels have been repeatedly normal.

Termination of therapy after induction of remission requires a gradual, well-monitored dose reduction over a 6-week period of close surveillance.

Laboratory tests are performed at 3-week intervals during drug withdrawal and for 3 months after termination of therapy. Thereafter, they are repeated at 3 months and then every 6 months for 1 year and then annually life-long.

Treatment failure Treatment failure connotes clinical, laboratory and

histological worsening despite compliance with conventional treatment schedules or development of jaundice, ascites or hepatic encephalopathy.

This demands institution of high dose therapy with prednisone alone (60 mg daily) or prednisone(30 mg daily) in conjunction with azathioprine(150 mg daily) for at least 1 month.

Thereafter, dose reduction of prednisone is done by 10mg and azathioprine by 50 mg for each month of improvement until standard treatment doses are achieved.

The development of hepatic encephalopathy, ascites, and/or variceal bleed during therapy for treatment failure is an indication for liver transplantation.

Treatment Failure contd. If high dose therapy of steroids and

azathioprine fails to induce remission then alternative drugs are used such as cyclosporine, tacrolimus, or mycophenolate mofetil.

In treatment failure mycophenolate mofetil or cyclosporine have had the most empiric use as alternative medications. Mycophenolate mofetil (2 g daily orally) is the most promising current agent.

Incomplete Response Clinical, laboratory and histological

improvement which is insufficient to satisfy criteria for a treatment endpoint after continuous therapy for at least 36 months.

Reduction in doses of prednisone by 2.5 mg/month until lowest level possible (10 mg daily) to prevent worsening of serum AST or ALT abnormalities.

Indefinite azathioprine therapy (2 mg/kg daily) as an alternative treatment if corticosteroid intolerance.

Relapse after drug withdrawal

Relapse connotes recrudescence of disease activity after induction of remission and termination of therapy.

It is characterized by an increase in the serum AST level to more than three-fold the ULN and/ or increase in the serum gamma globulin level to more than 2g/dL.

The first relapse after drug withdrawal should be retreated with a combination of prednisone plus azathioprine at the same treatment regimen as with the initial course of therapy and then tapered to mono therapy with either azathioprine (2 mg/kg daily) as a long-term maintenance therapy or with indefinite low dose prednisone (10 mg daily) in patients intolerant of azathioprine.

Drug Toxicity Drug toxicity justifies premature

discontinuation or alteration of conventional therapy.

therapy with the tolerated agent (prednisone or azathioprine) can be maintained in adjusted dose to prevent worsening in the clinical and laboratory features.

Hepatocellular Carcinoma occurs in 4% of patients with type 1 AIH, and the

10-year probability of developing this neoplasm is 2.9%.

Risk factors include male sex, portal hypertension manifested by ascites, oesophageal varices, or thrombocytopenia, immunosuppressive treatment for at least 3 years, and cirrhosis of at least 10 years duration.

A focused surveillance strategy based on hepatic ultrasonography at 6-month intervals is recommended for these individuals

Transplantation for AutoimmuneHepatitis-Indications

AIH and acute liver failure Decompensated cirrhosis with a MELD

score >=15 Hepatocellular carcinoma meeting

criteria for transplantation.

Prognosis 40% of all patients develop cirrhosis. 54% develop oesophageal varices in 2 years. Poor prognosis if ascites or hepatic

encephalopathy present. 13-20% can have spontaneous resolution. Of patients who survive the early and active

stage of disease, approximately 41% of them develop inactive cirrhosis.

Of patients who have severe initial disease and survive the first two years, typically survive long term.

Take Home Messages Suspect AIH as a cause of acute or chronic

hepatitis when other causes such as viral, hereditary, metabolic, cholestatic, and drug-induced diseases, have been excluded.

Two types based on the presence of ANA and SMA (type1 AIH) or anti-LKM1 and anti-LC1 (type 2 AIH).

Immunosuppressive treatment should be instituted in patients with serum AST or ALT levels greater than 10-fold ULN, at least five-fold ULN in conjunction with a serum gamma-globulin level at least 2-fold ULN, and/or histological features of bridging necrosis or multi-lobular necrosis.

Take Home Messages contd. Immunosuppressive treatment should not be

instituted in patients with minimal or no disease activity or inactive cirrhosis, but these patients must continue to be followed closely, i.e., 3-6 months.

Apart from alcoholic hepatitis (DF>32), it is the only hepatitis for which STEROIDS should be given.

AIH must always be suspected because early treatment can reduce the mortality and progression to cirrhosis significantly.