AUTOIMMUNE HEPATITIS

• CHAIRPERSON : DR.SANJEEV KUMAR• SPEAKER: DR.RAJESH KUMAR GOYAL

AUTOIMMUNE HEPATITIS

• Chronic hepatitis of unknown etiology• Can progress to cirrhosis• Characteristics include: – presence of autoimmune antibody– evidence of hepatitis (interface being

characteristic)– elevation of serum globulins– Continuing/unresolving hepatocellular

inflammation and necrosis

OTHER NAMES

• Active chronic hepatitis or chronic active hepatitis

• Chronic aggressive hepatitis• Lupoid hepatitis• Plasma cell hepatitis• Autoimmune chronic active hepatitis

• Diagnosis of autoimmune hepatitis requires the exclusion of other chronic liver diseases that have similar features, including wilson disease ,chronic viral hepatitis, drug induced liver disease, non alcoholic fatty liver disease, and the immune cholangiopathies of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)

BACKGROUND

• First described in 1950’s• Accounts for 5.6% of liver transplants in the

US• Affects women more than men (3.6:1)• If untreated approximately 40% die within 6

months• 40% develop cirrhosis

EPIDEMIOLOGY

• Frequency of AIH among patients with chronic liver disease in North America is between 11%- 22%

• Accounts for 5.6% of liver transplants in the US

• Prevalence greatest among northern European white persons

• Japenese have a lower frequency

PATHOGENESIS

EVIDENCE SUPPORTING AUTOIMMUNE PATHOGENESISHistopathological lesions composed of cytotoxic Tcells

and plama cellsCirculating autoantibodiesHyperglobulinemiaOther autoimmune disorders: thyroiditis, RA ,

autoimmune hemolytic anemia, ulcerative colitis, membranoproliferative glomerulonephritis, diabetes mellitus, celiac disease, sjogren’s syndrome

Histocompatibility haplotypes associationsResponse to steroids and immunosuppression.

Pathogenesis

• Exact pathogenesis is unknown • Predisposition to autoimmunity is

inherited ,whereas the liver specificity of this injury is triggered by environmental factors (chemical, drugs like minocycline or viral)

• Genetic predisposition is also present (HLA –B1, B8, DR3,DR4)

• Cell mediated immune attack is directed against the liver cells

• CD4 T lymphocytes are capable of becoming sensitized to hepatocyte membrane protein and of destroying liver cells

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

CLINICAL FEATURES

Symptoms

• Fatigue• Jaundice• Upper abdominal discomfort• Pruritus• None(at presentation)• Anorexia• Myalgias• Diarrhoea• Cushingoid features• Fever( <=40 deg celsius)

Occurrence (%)

• 86• 77• 48• 36• 25-34• 30• 30• 28• 19• 18

CLINICAL FEATURES contd.• Physical Signs

• Hepatomegaly• Jaundice• Spider Angiomata• Concurrent immune disease• Splenomegaly• None• Ascites• Encephalopathy

• Occurrence

• 78• 69• 58• <38

• >32• <25• 20• 14

LABORATORY FEATURES• Lab Feature

• Elevated AST• Hypergammaglobulinemia• Increased immunoglobulin G level• Hyperbilirubinemia• ALP >2 fold normal

• Immunoserologic Markers

• SMA,ANA or Anti- LKM1• Atypical p-ANCA• Anti sialoglycoprotein receptor• Anti Actin• Anti Liver Cytosol 1• Anti Soluble Liver Antigen

• Occurrence (%)

• 100• 92• 91• 83• 33

• Occurrence

• 100• 92(type 1 AIH only)• 82• 74• 32(type 2 AIH only)• 11-17

ASSOCIATED CONDITIONS

• Hashimotos thyroiditis and other thyroid abnormalities like myxoedema and thyrotoxicosis.

• Endocrine changes like cushingoid appearance, acne , hirsutism.

• Pulmonary changes like pleurisy,transitory pulmonary infiltrates and collapse.

• Acute,recurrent and non- deforming polyarthrits of large joints.

• Mild aneamia, leucopenia, thrombocytopenia can occur.

DIAGNOSTIC ALGORITHM FOR AUTOIMMUNE HEPATITIS

Simplified scoring system for diagnosis of AIH

Category Variable Score

1) AUTO ANTIBODIES ANA or SMA

Anti LKM-1

Anti SLA

1:40 >1:80>1:40

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 +2

DEFINITE DIAGNOSIS >=7PROBABLE DIAGNOSIS 6

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• Classically in young females• ANA or Anti-Smooth Muscle antibody positive• Titer usually > 1:100• 10% will have an antibody to Soluble Liver antigens

(SLA)• Other Antibodies: anti-DNA, pANCA, Anti-

mitochondrial, Anti-Actin (AAA), cytoskeletal antibody, nuclear envelope proteins lamin A and C, plasma membrane sulfatides

• Anti-actin antibodies have greater specificity

TYPE 1 AIH Contd.Bimodal Age distribution (ages 10-20 and 45-70)Female:male (3.6:1)HLA DR3 or DR4 assosciationAssociated with extrahepatic manifestations(38%):

Autoimmune thyroiditis(12%), Graves disease(6%), Chronic UC(6%).

Less commonly with RA, pernicious anemia, systemic sclerosis, ITP, SLE,coombs positive hemolytic anemia, leucocytoclastic vasculitis, erythema nodosum

40% present with acute onset of symptoms similar to toxic hepatitis or acute viral hepatitis

TYPE 2 AUTOIMMUNE HEPATITIS• Seen in children (2-14 years).• HLA DRB1 or DQB1 assosciation• Presence of anti-Liver/Kidney Microsome Antibodies

(anti- LKM1 )directed against cytochrome p450 2D6 {same as LKM seen in patients with chronic hepatitis C}

• Anti-Liver Cytosol antibody (ALC-1)• Concurrent autoimmune disease like autoimmune

thyroiditis,vitiligo and type 1 diabetes mellitus can be present.

• Acute or fulminant presentation possible

TYPE 3 AUTOIMMUNE HEPATITIS

It is now considered as a more severe form of type 1 AIH

• Antibodies to soluble liver antigen / liver pancreas antigen

• Lack ANA and anti- LKM 1 antibodies• More in women, part of spectrum of type 1

AIH

AUTOANTIBODIES IN AIH

• ANA : Present mainly in type 1 AIH. It is targeted against chromatin and ribonucleoproteins

• SMA: Present in type 1 AIH. It is targeted against various microfilaments like actin , vimentin, desmin

• LKM 1 : Present in type 2 AIH and chronic hepatitis c. it is directed against cytochrome p450 2D6

• SLA : prsent in type 3 AIH. Directed against t rnp

• LKM 2 : Present in drug induced hepatitis. Directed against cytochrome p450 2c9

• LKM3: present in type 3 AIH and chronic hepatitis D. directed against UDGT1A

VARIANT FORMS OF AIH

• AUTOIMMUNE HEPATITIS + PRIMARY BILIARY CIRRHOSIS (PBC)

• AUTOIMMUNE HEPATITIS + PRIMARY SCLEROSING CHOLANGITIS(PSC)

• AUTOIMMUNE HEPATITIS + CHOLESTATIC FEATURES

• AUTOANTIBODY-NEGATIVE AUTOIMMUNE HEPATITIS

AIH + PRIMARY BILIARY CIRRHOSIS

• Along with features of AIH pt also have Antimitochondrial antibodies

• Histological features of cholangitis and bile duct loss are present

• Treatment with prednisone is done if alkaline phosphatase level is ≤2 × ULN

• Treatment with prednisone and UDCA is done if AP >2 × ULN

AIH + PRIMARY SCLEROSING CHOLANGITIS

• Along with features of AIH pt may have abnormal cholangiographic changes

• Inflamatory bowel disease may be present• Antimitochondrial antibodies are absent• Histological features of cholangitis and

cholestasis may be present• Treatment includes prednisone and UDCA

AIH + CHOLESTATIC FEATURES

• Along with features of AIH pt have antinuclear antibodies or antismooth muscle antibodies

• Histological features of cholangitis and cholestasis are present

• No inflamatory bowel disease is present• Absence of antimitochondrial antibodies and

cholangiographic changes• Treatment with prednisone and UDCA

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.

• Age, female predominance, frequency of immunologic diseases, histologic features and lab findings are similar with classic AIH.

• Associated withHLA-B8, DR-3• Respond to treatment with glucocorticoids.

HISTOLOGY

• Chronic hepatitis with marked piecemeal necrosis and lobular involvement

• Numerous plasma cells• Interface hepatitis: hallmark finding• Necroinflammatory activity• Evidence of hepatocellular regeneration (“rosette

formation” , regenerative “pseudolobules”)• Bile duct injuries and granulomas are uncommon

DIFFERENTIAL DIAGNOSIS

• Primary biliary cirrhosis• Post-necrotic cryptogenic cirrhosis• Primary sclerosing cholangitis• Acute viral hepatitis• Chronic viral hepatitis• Wilsons disease• Alcoholic hepatitis• Non alcoholic fatty liver disease

TREATMENT OF AUTOIMMUNE HEPATITIS

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.

PREDNISONE ONLY• Prednisone 60mg PO daily which is tapered

down to 30mg at the 4th week of treatment and then maintenance of 20mg daily til the endpoint

• Reasons for Prednisone only: Cytopenia TPMT deficiency Malignancy Pregnancy• Therapy response expected in upto 80% of cases

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.

Preferred treatment regimens

Combination therapy Single drug therapy

Prednisone (mg/day) Azathioprine (mg/d) Prednisone (mg/day)

30mg × 1 week 50 mg until the end point

60mg × 1 week

20mg × 1 week 40mg × 1 week

15mg × 2 weeks 30mg × 2 weeks

10mg until the end point

20mg until the end point

CORTICOSTEROID SIDE EFFECTS

• Cosmetic side effects like alopecia, dorsal hump, facial rounding,hirsutism,striae,weight gain can occur in 80% of the pt. after 2 years of treatment

• Severe side effects like cataract, diabetes mellitus, emotional instability, hypertension, osteopenia, vertebral compression can occur

• Rare side effects includes malignancy, opportunistic infections and pancreatitis

Azathioprine-Related Side Effects

• The mc side effects of azathioprine is cytopenia occuring in 46% of the pt. associated with cirrhosis

• Other side effects include arthralgias, fever, nausea, vomiting and rash and bone marrow faliure

• Pt. undergoing azathioprine therapy should have blood leucocyte and platelet counts assessed at 6 months interval

AZATHIOPRINE IN PREGNANCY

• Placenta is only a partial barrier to the metabolites of azathioprine and its use has been associated with congenital malformations in newborn

• Azathioprine is not an essential medication in the treatment of autoimmune hepatitis and can be discontinued during pregnancy.

• Pt with autoimmune hepatitis in pregnancy can be successfully managed by adjustments in the dose of prednisone.

TREATMENT ENDPOINTS

• Remission• Treatment failure• Incomplete response• Relapse• Drug toxicity

Remission

• Remission connotes absence of symptoms, resolution of all lab indices of active inflammation and histologic improvement to normal liver tissue or inactive cirrhosis.

• Evaluation of the liver tissue before drug withdrawl is essential to establish remission because histologic activity may be present in 55% of pt. who satisfy other requirements of remission.

Remisson contd.

• If a remission has ensued, judged clinically, biochemically and by liver biopsy, the drug should be tapered off slowly over about 2 months.

• If relapse occurs indefinite low dose prednisone or indefinite azathioprine (50-100mg) can be given.

Treatment Faliure

• Treatment faliure is characterised by worsening of serum AST or bilirubin levels by at least 67%of the previous values, progressive histologic activity or onset of ascites or encephalopathy.

• High dose therapy with prednisone alone (60 mg daily) or prednisone(30 mg daily) in conjunction with azathioprine(150 mg daily) constitues the standard treatment in this group.

Treatment faliure contd.

• Alternative management regimens include the administration of cyclosporine, mycophenolate mofetil, ursodeoxycholic acid, budesonide, 6-mercaptopurine, methotrexate and cyclophosphamide.

• If liver decompensation occurs despite the high dose therapy liver transplantation should be considered.

Incomplete Response

• Incomplete response connotes clinical improvement that is insufficient to satisfy the remission criteria.

• Faliure to achieve remissoin within three years indicates that the remission is unlikely and warrants discontinuation of conventional treatment.

• The administration of azathioprine(2mg/kg daily) as the sole drug or low dose predisone regimen can be done

Drug toxicity

• Drug toxicity justifies premature withdrawl of medication or a reduction in dose.

• Treatment can usually be continued with the single tolerated drug (prednisone or azathioprine) in an adjusted dose.

• Cyclosporine, 6-mercaptopurine and cyclophosphamide also have been used successfully

TAKE HOME MESSAGE• 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.

• 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.

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

THANK YOU