Autoimmune Hepatitis. Hili N. Morillas, MD November 1, 2004 Morning Report

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1 Autoimmune Hepatitis Hili N. Morillas, MD November 1, 2004 Morning Report

2 Definition! An unresolving inflammation of unknown cause.! Characterized by the presence of interface hepatitis and portal plasma cell infiltration, hypergammaglobulinemia, and autoantibodies.

3 Differential Diagnosis! Wilson s Disease! Chronic viral hepatitis! α 1 -antitrypsin deficiency! Drug induced liver injury! Genetic hemochromatosis

4 Clinical Manifestations! May present at any age and in either sex! Occurs most frequently in women between the ages of or in late middle age! Can mimic acute viral hepatitis! Insidious onset! May not be recognized until liver damage is advanced

5 Clinical Manifestations! Common symptoms at presentation: - Fatigue (85%) - Abdominal pain (10-40%) - Anorexia (20%) - Fever (20%)! Common physical findings: - Hepatomegaly (78%) - Jaundice (69%) - Decompensated cirrhosis (10 to 20%)

6 Extrahepatic Manifestations! Occur frequently! Maculopapular skin rashes (20%) - Allergic capillaritis - Lichen planus - Leg ulcers - Vitiligo! Synovitis (6-36%)

7 Extrahepatic Manifestations! Increased incidence of autoimmune diseases: - Autoimmune thyroiditis - Sjogren s syndrome - Renal tubular acidosis - Glomerulonephritis - Peripheral neuropathy - Fibrosing alveolitis

8 Epidemiology! Annual incidence in Northern Europeans is 1.9/100,000.! Point prevalence is 16.9/100,000.! 5.9% of transplantations in the U.S.! Women are affected more than men, 3.6:1! All ages and ethnic groups are susceptible.

9 Natural History! Acute onset of illness is common (40%).! 40% of patients with severe untreated disease die within 6 months of diagnosis.! Cirrhosis develops in at least 40% of survivors.! Less severe lab and histological findings still develop cirrhosis 49% within 15 years.! Hepatic failure in 10%.

10 Diagnosis! Liver biopsy is essential to establish diagnosis, disease severity, and the need for treatment.! Interface hepatitis is the histologic hallmark with portal plasma cell infiltration.! However, this is not disease specific.

11 Interface Hepatitis Intense lymphoplasmacytic infiltrate expanding portal area and infiltrating across the limiting plate into the adjacent lobule

12 More Histology The portal infiltrate is very plasma cell rich, a pattern commonly seen in autoimmune hepatitis.

13 Diagnosis! Autoantibodies must be present Not pathogenic nor disease specific Expression can vary during disease course Low titers don t exclude disease High titers don t establish the diagnosis Levels do not reflect treatment response! Serologic markers are: ANA, SMA, and anti-lkm1

14 Autoantibodies associated with AIH! ANA is the traditional marker for AIH (67%) Alone 13% SMA 54%! SMA present in 87% of pts with AIH Alone (33%)! Anti-LKM1 Typically occurs in the absence of ANA and SMA

15 Classification of AIH! Type 1 Most common Associated with ANA or SMA All ages affected Associated with panca! Type 2 Characterized by anti-lkm1 More common in Europe and South America Not associated with panca! Type 3 Anti-SLA/LP (soluble liver antigen/liver pancreas) Same clinical features as type 1

16 Diagnostic Criteria for AIH Requisites Genetic Liver Disease Definite Nl α 1 -antitrypsin, ceruloplasmin, iron, ferritin Probable Partial α 1 -antitrypsin deficiency; copper, ceruloplasmin, iron, ferritin level abnormality No active viral infection Hep A, B, C markers negative Hep A, B, C markers negative Toxin and alcohol injury Alcohol < 25g/d No hepatotoxic drug use. Alcohol < 50g/d No hepatotoxic drug use. Lab Features Autoantibodies AST/ALT, IgG > 1.5 times normal ANA, SMA, anti-lkm1 > 1:80 AST/ALT, hypergammaglobulinemia of any level ANA, SMA, anti-lkm1 > 1:40 Histologic Findings Interface hepatitis Interface hepatitis

17 AASLD Recommendations! Dx of AIH requires determination of serum aminotransferase and γ-globulin levels; detection of ANA/SMA or anti-lkm1; liver tissue examination! Diagnostic criteria should be applied to all patients! If diagnosis is not clear, scoring method should be used

18 Treatment Indications! Serum AST > 10-fold upper limit of normal! Serum AST > 5-fold upper limit of normal and γ-globulin level > twice normal! Histologic features of necrosis

19 Treatment Regimens! Prednisone Alone! Low dose prednisone with azathioprine Preferred treatment regimen Lower rate of corticosteroid induced side effects! Continue treatment until remission, treatment failure, incomplete response or drug toxicity

20 Treatment Regimen Treatment Week Week 1 Week 2 Week 3 Week 4 Maintenance Prednisone (mg/d) Combination Prednisone (mg/d) with Azathioprine (50 mg/d)

21 Treatment! Complications of Prednisone! Usually after more than 18 months of chronic use and doses that exceed 10 mg daily Vertebral compression Diabetes Cataracts Hypertension Psychosis Osteoporosis

22 Treatment! Complications of azathioprine! Develop in less than 10% of patients taking 50 mg daily Cholestatic hepatitis Veno-occlusive disease Pancreatitis Nausea and emesis Rash Bone marrow suppression

23 Treatment! Prednisone alone Cytopenias Short treatment course (< 6 months) Pregnancy Active malignancy Thiopurine methyltransferase deficiency! Combination therapy Postmenopausal Osteoporosis Brittle diabetes Obesity Acne Emotional lability Hypertension

24 Treatment Endpoints! No minimum or maximum duration of treatment! Remission connotes disappearance of symptoms, improvement of AST to less than twice the normal level and improvement of liver tissue to normal.! Patients should be given opportunity to enter remission after clinical, laboratory or histologic resolution! Histologic improvement lags behind by 3-6 months

25 References! Czaja and Freese. Diagnosis and Treatment of Autoimmune Hepatitis. Hepatology, Vol. 36, No. 2, 2002.! Up To Date