Autoimmune hepatitis in special patient population

1. Autoimmune hepatitis in special patient population RaikaJamali M.D. Gastroenterologist and hepathologist, Assistant Professor of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

2. Aims of this presentation: • Different clinical phenotypes of AIH are described, • Different presentation of AIH among different ethnic groups are presented, • Management of AIH in the elderly and the pregnant

3. Non-classical phenotypes at presentation • Acute onset, centrilobular (zone 3) necrosis • Asymptomatic state, • Absent autoantibodies, • Cholestatic features

4. Acute onset • AIH can present acutely as: • a previously unrecognized chronic liver disease that has exacerbated spontaneously • or as an inflammatory process that is newly developed • Sequential examinations of liver tissue have disclosed transitions from the pattern of centrilobular inflammation to that of classical interface hepatitis, • Of 72 patients with acute liver failure of indeterminate nature that were included in an Acute Liver Failure Registry, 42 (58%) were considered to have probable AIH. • 28% of patients lacked serological markers.

5. An acute severe (fulminant) presentation is rare, • Acute onset has been variably responsive to corticosteroid therapy depending in part on the timeliness of the diagnosis and treatment. • Clinical and laboratory improvements should be evident within 2 weeks of therapy • patients with acute severe (fulminant) presentations who do not improve during 2 weeks should be considered for liver transplantation • The Model of End Stage Liver Disease (MELD) can be useful in identifying problematic patients early • MELD scores 12 points at presentation identify 97% of patients who fail corticosteroid therapy, die of liver failure, or require liver transplantation

6. Asymptomatic mild disease • AIH is asymptomatic at presentation in 25–34% of patients • Up to 70% of asymptomatic patients become symptomatic • Inflammatory activity can fluctuate spontaneously, • Asymptomatic phase should not be discounted as non-threatening • Cirrhosis, liver failure and hepatocellular carcinoma are possible consequences of asymptomatic mild AIH, • The 10-year survival of untreated patients with mild disease is significantly lower than that of treated patients with severe disease (67% versus 98%). • AIH can resolve spontaneously, but resolution occurs less frequently

7. The uncertainty that mild disease remains mild and the opportunity to quickly suppress inflammatory activity before other consequences favor treatment in all patients • Budesonide with azathioprine had fewer side effects than prednisone and azathioprine treatment,

8. Autoantibody-negativity • Conventional serological markers of AIH: • Antinuclear antibodies (ANA), • Smooth muscle antibodies (SMA), • Antibodies to liver kidney microsome type 1 (anti-LKM1), • Antibodies to soluble liver antigen (anti-SLA) • None is pathogenic, • ANA and SMA also lack disease-specificity. • Misclassification of autoantibody-negative patients may delay the corticosteroid treatment. • The autoantibodiesmay appear and disappear, • The absence of the characteristic autoantibodies at presentation does not preclude their appearance later. • The response to corticosteroid therapy supports the diagnosis

9. It may be a disease whose signature serological marker is undiscovered, or it may be an example of classical disease with fluctuating autoantibody levels. • Nonstandard autoantibodies, including • atypical perinuclear anti-neutrophilic cytoplasmic antibodies (pANCA), • antibodies to liver cytosol type 1 (anti-LC1), • antibodies to uridine diphosphate glucuronosyltransferases (anti-UGT), may identify some patients • The search for an elusive serological marker should not delay institution of corticosteroid treatment in patients with otherwise compatible features • Clinical and laboratory improvement should be evident within two weeks

10. Cholestatic features • Classic AIH is defined by the absence of cholestasis, • Some patients can have concurrent features of primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), or a cholestatic syndrome in the absence of PSC and PBC. • They have been designated as variant or “overlap” syndromes • Patients with: • a more than two-fold elevation of the serum alkaline phosphatase level above the ULN, • “florid duct lesion” on histological examination, • cholangiographic features of PSC can respond poorly to steroid regimens, • They are candidates for treatment with corticosteroids in combination with ursodeoxycholic acid (13–15 mg/kg daily)

11. High doses of ursodeoxycholic acid (28–30 mg/kg daily) long-term have been associated with increased frequencies of death from liver failure, need for liver transplantation, and they should be avoided . • Cholangiography is important in AIH, • Recent studies have suggested that some patients with classical AIH have unsuspected PSC. • ERCP in children with autoimmune hepatitis has disclosed biliary changes in 50%, and MRCP in adults with classical AIH has demonstrated biliary changes in 10%.

12. Ethnic and regional variations in non-white populations • Black North American patients have cirrhosis at presentation more commonly than white North American patients and a poorer prognosis. • Alaskan natives commonly have acute icteric presentations, and they have advanced fibrosis (often without symptoms) • Japanese patients typically have mild, late onset disease that may respond to treatment • South American patients are commonly young children with severe liver inflammation . • Cholestatic clinical features and histological findings of biliary injury are more frequent in African, Asian, Turkish and Arab patients than in white northern European patients, • Rapidly progressive disease is frequent in Somali patients who are almost exclusively male

13. HLA DRB1*03 is associated with early age onset disease and treatment failure. • HLA DRB1*04 is common in women and associated with concurrent immune features and treatment response. • The rarity of HLA DRB1*03 among the Japanese, and the almost exclusive association of Japanese disease with HLA DRB1*04 may explain its late age onset and mild nature.

14. HLA DRB1*13 has been associated with the AIH of South American children, and the DRB1*1301 allele has been associated with protracted HAV infection. • Acute HAV is endemic in South America, and the HAV has been implicated as an etiological trigger for AIH.

15. Different geographical regions may have indigenous infectious or environmental agents that can trigger diverse forms of AIH. • The ethnic variations recognized in the phenotypes of autoimmune hepatitis are powerful motivations for instituting studies that identify and correct these risk factors.

16. Male occurrence • The incidence of AIH in males is 0.2–0.5 cases per 100,000 persons per year • Women outnumber men with AIH by 3.5:1 • This predominance may reflect: • a stronger innate immune reactivity in women than men • to a greater variety of antigenic exposures. • The bases for the female predominance in AIH are uncertain, but hypotheses have implicated • microchimerism, • hormonal factors, • genetic predispositions, • acquired preferential X chromosome inactivation

17. The higher frequency of concurrent immune diseases in women. • Women also have a higher frequency of HLA DRB1*04 than men. • The importance of the genetic over the hormonal basis for the female predilection is underscored by the preservation of female predominance among children and the elderly. • Autoimmune hepatitis must not be overlooked in male patients. • There should be the same expectation of a satisfactory response regardless of gender

18. Elderly patients • 20% of patients develop AIH after the age of 60 years, • Ascites, cirrhosis, or advanced hepatic fibrosis are common manifestations at presentation, • Have few symptoms.

19. Concurrent immune manifestations and co-morbid conditions (osteopenia, hypertension, obesity, diabetes and malignancy) weaken enthusiasm for treatment. • Respond well to low dose corticosteroid • Lower death from liver failure or need for liver transplantation than young adults.

20. The bases for the rapid improvement of the elderly during corticosteroid therapy are unclear, but • They may include age-related weakening in the immune response (“immunosenescence”) • HLA DRB1*04 occurs more frequently in patients aged > 60 years than adult patients aged < 30 years,

21. A rigorous bone maintenance regimen should be instituted, • Regular weight-bearing exercises should be encouraged. • Calcium (1–1.5 g daily) and vitamin D3 (400 IU daily) are appropriate supplementations, • Bisphosphonates should be considered in individuals with osteopenia. • Regular bone density assessments are warranted to ensure the effectiveness of this strategy

22. Pregnant patients • Pregnancy in women with AIH is associated with risks to the mother and the fetus • Disease activity may actually improve during pregnancy and reduction in the dose of the medication may be possible. • Anticipation of a postpartum exacerbation justifies resumption of full dose corticosteroid therapy during the late third trimester. • Azathioprine has been designated as a category D drug in pregnancy

23. Treatment strategy in AIH

25. Further reading: • Czaja AJ. Autoimmune hepatitis in special patient populations. Best Pract Res Clin Gastroenterol. 2011;25(6):689–700 • Mostafa Shafiei and Sayed Moayed Alavian. Autoimmune Hepatitis in Iran: What We Know, What We Don’t Know and Requirements for Better Management. Hepat Mon. 2012 February; 12(2): 73–76.