Autoimmune Hepatitis in Children: What is Different from Adult AIH? Giorgina Mieli-Vergani, M.D., Ph.D.,1 and Diego Vergani, M.D., Ph.D.1

ABSTRACT

Autoimmune hepatitis (AIH) is characterized by inflammatory liver histology, circulating non-organ-specific autoantibodies, and increased levels of immunoglobulin (Ig) G in the absence of a known etiology. Two types of childhood AIH are recognized according to seropositivity: smooth muscle antibody (SMA) and/or antinuclear antibody (ANA), which is AIH type 1; and antibodies to liver-kidney microsome type 1 (antiLKM1), which is AIH type 2. There is a female predominance in both. Autoimmune hepatitis type 2 presents more acutely, at a younger age, and commonly with IgA deficiency; however, duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in the two groups. Immunosuppressive treatment with steroids and azathioprine, which should be instituted promptly to avoid progression to cirrhosis, induces remission in 80% of cases. Relapses are common, often due to nonadherence. Drugs effective in refractory cases include cyclosporine and mycophenolate mofetil. Long-term treatment is usually required, with only some 20% of AIH type 1 patients able to discontinue therapy successfully. In childhood, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease tends to progress. KEYWORDS: Autoimmune hepatitis, sclerosing cholangitis, children

A

utoimmune hepatitis (AIH) is a progressive inflammatory liver disorder mainly affecting females. It is characterized serologically by high levels of transaminases and immunoglobulin (Ig) G, and the presence of autoantibodies; and characterized histologically by interface hepatitis, in the absence of a known etiology.1 Autoimmune hepatitis responds to immunosuppressive treatment, which should be instituted as soon as the diagnosis is made. In pediatrics, as well as in young

adults, AIH often presents acutely and has a more aggressive course than in middle-age and elderly patients. In children, there are two liver disorders in which the liver damage is likely to arise from an autoimmune attack: classical AIH and AIH/sclerosing cholangitis overlap syndrome (autoimmune sclerosing cholangitis [ASC]), the latter being characterized by bile duct damage as well as interface hepatitis. A possible autoimmune pathogenesis has also been postulated for the

1 King’s College London School of Medicine at King’s College Hospital, Institute of Liver Studies, London, United Kingdom. Address for correspondence and reprint requests: Professor Giorgina Mieli-Vergani, M.D., Ph.D., Paediatric Liver Centre, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom (e-mail: [email protected]).

Autoimmune Hepatitis; Guest Editors, Michael P. Manns, M.D., and Diego Vergani, M.D., Ph.D. Semin Liver Dis 2009;29:297–306. Copyright # 2009 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-0029-1233529. ISSN 0272-8087.

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so-called ‘‘post–liver transplant de novo AIH,’’ a condition originally described in children and later confirmed in adults. Data collected at King’s College Hospital tertiary referral center show an increase in the yearly incidence of AIH and ASC in childhood, although referral bias may play a role. In the 1990s, these conditions represented 2.3% of
400 children older than 4 months who were newly referred within 1 year; since 2000, the yearly incidence has increased to 12%.

untreated, it generally progresses rapidly to cirrhosis and liver failure. Most patients are girls (75%). The epidemiology of childhood AIH is unknown, but type 1 AIH accounts for two thirds of the cases and presents often around puberty, whereas type 2 AIH tends to present at a younger age and also during infancy. IgG is usually raised at presentation in both types, although 15% of children with AIH type 1 and 25% of those with AIH type 2 have normal levels.2 IgA deficiency is common in AIH type 22. Severity of disease is similar in the two types, but anti-LKM1-positive patients have higher levels of bilirubin and transaminases at presentation than those who are ANA/SMA-positive and present significantly more frequently with fulminant hepatic failure (Table 1).2 Excluding children with the fulminant presentation, a severely impaired hepatic synthetic function, as assessed by the presence of prolonged prothrombin time and hypoalbuminemia, is more common in ANA/SMApositive than in anti-LKM1-positive patients (Table 2). The severity of interface hepatitis at diagnosis is similar in both types, but cirrhosis on initial biopsy is more frequent in type 1 than in type 2 AIH, suggesting a more

CHILDHOOD AUTOIMMUNE HEPATITIS Clinical Features Two types of AIH are recognized: AIH type 1, which also affects adults, is characterized by the presence of smooth muscle antibody (SMA) and/or antinuclear antibodies (ANAs); AIH type 2, which is mainly a pediatric condition, is positive for antibodies to liver-kidney microsome type 1 (anti-LKM1)2 and/or anti-liver cytosol type 1 (anti-LC1)3. Autoimmune hepatitis responds satisfactorily to immunosuppressive treatment. If left

Table 1 Clinical, Immunological, and Histological Features at Presentation of AIH Type 1, AIH Type 2, and Autoimmune Sclerosing Cholangitis* AIH Type 1

AIH Type 2

ASC

Median age in years

11

7

12

Females (%)

75

75

55

Mode of presentation (%) Acute hepatitis

47

40

37

3

25

0

Insidious onset

38

25

37

Complication of chronic liver disease

12

10

26

22

20

48

20

12

44

43

40

37

0 100

0 25

100 96

0

100

4

45

11

74

Acute liver failure

Associated immune diseases (%) Inflammatory bowel disease (%) Family history of autoimmune disease (%) Abnormal cholangiogram (%) ANA/SMA (%) Anti-LKM1 (%) pANNA (%) Anti-SLA (%)y

58

58

41

Increased IgG level (%)

84

75

89

Partial IgA deficiency (%)

9

45

5

Low C4 level (%)

89

83

70

Increased frequency of HLA DR*0301 Increased frequency of HLA DR*0701

Yes No

Noz Yes

No No Yes

Increased frequency of HLA DR*1301

No

No

Interface hepatitis (%)

66

72

35

Biliary features (%)

28

6

31

Cirrhosis (%)

69

38

15

2,52

*From patients referred to the King’s College Hospital Tertiary Pediatric Liver Centre. y Measured by radioligand assay. z But increased in HLA DR*0701 negative patients. AIH, autoimmune hepatitis; ASC, autoimmune sclerosing cholangitis; ANA, antinuclear antibody; SMA, smooth muscle antibody; anti-LKM1, antibodies to liver-kidney microsome type 1; pANNA, peripheral antinuclear neutrophil antibody; anti-SLA, antibody to soluble liver antigen; IgG, immunoglobulin G; IgA, immunoglobulin A; C4, C4 component of complement; HLA, human leukocyte antigen.

AUTOIMMUNE HEPATITIS IN CHILDREN: WHAT IS DIFFERENT FROM ADULT AIH?/MIELI-VERGANI, VERGANI

Table 2 Biochemical Indices at Presentation in Children with Autoimmune Hepatitis and Autoimmune Sclerosing Cholangitis* AIH Bilirubin (nv < 20 mmol/L)

35 (4–306)

Albumin (nv > 35 g/L)

35 (25–47)

ASC

stigmata (spider nevi, palmar erythema, leukonychia, striae), firm liver, and splenomegaly. At ultrasound, the liver parenchyma of these patients is often nodular and heterogenous.

20 (4–179) 39 (27–54)

AST (nv < 50 IU/L)

333 (24–4830)

102 (18–1215)

INR (