Liver involvement in pediatric celiac disease

Table 1 Studies reporting the prevalence of cryptogenic hypertransaminasemia in children and adolescents with celiac disease

Ref.	Study design	Study population with CD	Diagnosis of CD	Number of patients with elevated transaminases	Effect of GFD	Comment
Bonamico et al[9], 1986	Observational	65 untreated symptomatic children aged 6-mo to 18 yr	Intestinal biopsy	37 (56.9%) had elevated (> 45 U/L) ALT (3.1%) or AST (29.2%) or both (24.6%)	Only 5 cases had a follow-up for 3-4 wk after GFD: normalization of transaminases was achieved in all	Excluded were Hepatitis A and B, but not other causes of liver disease
Farre et al[13], 2002	Prospective	114 untreated symptomatic children aged 9-mo to 17 yr	Serology (EMA IgA or IgG and tTGA IgA) and/or intestinal biopsy	37 (32.0%) had elevated1 ALT-or- AST (14.9%) or both (14.9%)	35 of 37 had a follow-up for 9-18 mo after GFD: normalization of transaminases was achieved in all
Arslan et al[14], 2005	Observational	27 untreated symptomatic children with a mean age of 6 (SD 5) years	Serology (EMA IgA and AGA IgA/IgG) and/or intestinal biopsy	7 (25.9%) had elevated ALT (> 45 U/L)	All patients had normalization of transaminases after 2-11 mo of GFD
Di Biase et al[15], 2010	Prospective	350 untreated children with suspected CD aged 1 to 16 yr	Serology and intestinal biopsy according to the ESPGHAN criteria	140 (40.0%) had elevated AST (≥ 38 U/L) and/or ALT (≥ 41 U/L); four with values > 5 times upper normal levels	Normalization of transaminases after 6 mo of GFD was achieved in 133 (97.8%) of 136 children with transaminase values < 5 times upper normal levels	The four children with transaminase values > 5 times upper normal levels as well as the 3 children with persistent elevated transaminases had further laboratory investigation and were found to be affected by autoimmune hepatitis

¹Normal reference values for AST < 50 U/L from 1 to 6 years, < 38 U/L from 6 to 18 years; for ALT < 31 U/L from 1 to 18 years. CD: Celiac disease; GFD: Gluten-free diet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; IgA: Immunoglobulin A; IgG: Immunoglobulin G; EMA: Anti-endomysial antibodies; tTGA: Anti-tissue transglutaminase antibodies; AGA: Anti-gliadin antibodies; ESPGHAN: European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

Table 2 Studies reporting the prevalence of positive celiac serology or biopsy-proven celiac disease in children and adolescents with autoimmune liver diseases

Ref.	Study design	Study population with AILD	Number of patients with CD	Effect of GFD
Caprai et al[39], 2008	Retrospective	140 patients aged 7-125 mo with AILD	23 (16.4%) (19 with AIH; 2 with AIC; and 2 with overlap syndrome) had CD on the basis of serology (EMA IgA and/or tTGA IgA) Diagnosis of CD preceded the diagnosis of liver disease in 18 of the 23 patients	All patients achieved remission on GFD and immunosuppressive therapy, but 14 relapsed because of discontinuation of therapy or during spontaneous gluten challenge
Diamanti et al[40], 2008	Retrospective	40 patients aged 3-13.2 yr with AIH	5 (12.5%) had CD on the basis of serology and histological findings In four patients CD was diagnosed after AIH onset	On GFD four patients showed a mild decrease in transaminases, but never a complete normalization
Tosun et al[41], 2010	Retrospective	15 patients aged 4-15 yr with AIH	7 (46.0%) had CD on the basis of serology and histological findings CD and AIH were diagnosed concomitantly	Not available
El-Shabrawi et al[42], 2011	Prospective	26 patients aged 3.5-21 yr with AIH	CD serology (tTGA IgA and/or EMA IgA) was positive in 4 (15.4%). Three out of these four AIH (11.5%) showed histological findings of CD	Not available
Nastasio et al[43], 2013	Retrospective and Prospective	79 children and adolescents with AIH	15 (19.0%) had CD on the basis of serology and histological findings Diagnosis of CD preceded the diagnosis of liver disease in 8 of the 15 patients	All 15 patients on GFD achieved sustained remission when treated with immunosuppressive therapy

AILD: Autoimmune liver diseases; CD: Celiac disease; GFD: Gluten-free diet; AIH: Autoimmune hepatitis; EMA: Anti-endomysial antibodies; tTGA: Anti-tissue transglutaminase antibodies.

Table 3 Studies reporting the prevalence of autoimmune hepatitis in children and adolescents with celiac disease

Ref.	Study design	Study population with CD	Diagnosis of CD	Number of patients with AIH	Effect of GFD
Ventura et al[44], 1999	Prospective	909 children and adolescents with CD (group 1, < 2 yr of age; group 2, 2-10 yr; group 3, > 10 yr)	Serology and intestinal biopsy according to the ESPGHAN criteria	10 (1.1%) had AIH, of whom 2.9% in group 2 and 0.8% in group 3	Not available
Di Biase et al[15], 2010	Prospective	350 untreated children with suspected CD aged 1 to 16 yr	Serology and intestinal biopsy according to the ESPGHAN criteria	7 (2.0%) had AIH, of whom 5 type I AIH	During treatment with GFD, steroids and azathioprine for 5 yr, all AIH persistently normalized clinical and biochemical parameters. After withdrawal, 6 patients maintained a sustained remission (12-63 mo)

CD: Celiac disease; AIH: Autoimmune hepatitis; GFD: Gluten-free diet; ESPGHAN: European Society for Paediatric Gastroenterology, Hepatology and Nutrition.