Frequency of Celiac Disease in Attention-deficit/Hyperactivity Disorder : Journal of Pediatric Gastroenterology and Nutrition

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Original Articles: Gastroenterology

Frequency of Celiac Disease in Attention-deficit/Hyperactivity Disorder

Güngör, Serdal*; Celiloğlu, Özgü Suna; Özcan, Özlem Özel; Raif, Sabiha Güngör*; Selimoğlu, Mukadder Ayşe§

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Journal of Pediatric Gastroenterology and Nutrition 56(2):p 211-214, February 2013. | DOI: 10.1097/MPG.0b013e318272b7bc
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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder of childhood characterized with attention deficit, hyperactivity, and impulsivity (1). It is reported that ADHD affects 5.29% of children all over the world (2). Although there is no agreement in the etiology of ADHD, complex interrelation of bio-physico-social factors is held responsible for the development of the disease (3).

Celiac disease (CD) is a multisystem disorder triggered by gluten in genetically susceptible individuals (4). The prevalence in European countries is reported between 1/99–133 (5,6). In recent years, it has been clear that CD presenting with nonclassical signs is more frequent than the classical form (4). Neurologic system complications, perception disorders, and psychiatric problems such as attention deficit have been reported in 6% to 11% of patients with CD (7–11); however, the pathophysiology of those neurological and psychiatric disorders developing in the course of CD is not clear (11,12). Moreover, response to gluten-free diet (GFD) is also controversial in patients with neurological disorders (13). There are some studies investigating neuropsychiatric problems and symptoms of ADHD (14) in patients with CD, but there are no clear data about the prevalence of CD in cases with ADHD (12,15). In our study, we aimed to determine the frequency of CD in children with the diagnosis of ADHD.

METHODS

In that prospective study, 362 children between the ages 5 and 15 years, who were diagnosed as having ADHD at child psychiatry outpatient clinic between 2007 and 2010, were included. The diagnosis of ADHD was made according to the criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)(1,2,16) by 2 independent psychiatrists. Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version ADHD module was also used. The patients with comorbid mental retardation were not included. All of the patients accepted participation and none of these patients left the study.

Sex- and age-matched 390 children, who were evaluated at pediatrics clinic for mild upper respiratory tract infection, were selected as control group. Demographic characteristics, diet and medication histories, and clinical findings of all of the cases were recorded. Both gastrointestinal and nongastrointestinal symptoms that may be related to CD were specifically questioned. None of the patients had a concurrent autoimmune disorder. Venous blood samples were stored at −20°C until the procedure. Tissue transglutaminase (tTg) immunoglobulin (Ig) A and IgG were studied with micro-enzyme-linked immunosorbent assay method (ImmuLisa, Immco Diagnostics Inc, Buffalo, NY). Cases with a value of tTg IgA >15 U/mL were considered positive. Serum IgA was studied in patients who have tTg IgG value >15 U/mL to rule out selective IgA deficiency. In tTg IgA–positive cases, with the permission of their families, upper gastrointestinal endoscopy with a flexible endoscope was performed and multiple biopsies (at least 1 from bulb and 4 from the second part of duodenum) were taken (17). The diagnosis of CD was established with pathologic examination using Marsh-Oberhuber classification (18).

Statistical analyses were performed by SPSS for Windows version 16.0 (SPSS, Inc, Chicago, IL). Student t test and χ2 test were used.

The ethics committee of the medical faculty approved the study, which has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Additionally, all of the parents gave informed consent before their inclusion in the study.

RESULTS

Cases of ADHD and control groups had no statistically significant difference in terms of mean age and sex (Table 1). Symptoms such as hyperactivity (82.9%), distractibility (82.9%), course failure (76.5%), and seizures (8.3%) were reported in the history of cases with ADHD. The frequency of symptoms such as course failure, attention deficit, and seizure was not statistically different in respect with sex (P = 0.670, P = 0.220, and P = 0.360, respectively). The patients had a history of recurrent abdominal pain (15.7%), constipation (13%), abdominal distention (3.3%), diarrhea (3%), rash (2.5%), and hair loss (2.2%) when they were evaluated for symptoms that may be associated with CD. Dental caries frequency was found as 35.4% in ADHD group and 19.3% in control group (P = 0.0001).

T1-21
TABLE 1:
Patient characteristics of ADHD and control group

tTg IgA was positive in 4 cases of ADHD (1.1%) and in 3 cases of control group (0.8%) (P = 0.716). Only in one of the patients, tTg IgA level was 10-fold higher than the cutoff level (210 U/mL). tTg IgG was positive in 14 cases of ADHD (3.9%) and in 2 of control group (0.5%) (P = 0.001). Both tTg IgA and tTg IgG were positive in one of the ADHD cases. Serum IgA levels were normal in all those with positive tTg IgG. tTg IgA and tTg IgG tests were repeated to rule out false positivity, owing to lower sensitivity and specificity of tTg IgG compared with tTg IgA, and all were found negative. Endoscopic duodenal biopsy was offered to patients who were seropositive for tTg IgA from ADHD and control groups. Findings compatible with Marsh-Oberhuber stage-1 were detected in 1 of the 4 patients who accepted biopsy from the ADHD group, whereas there was no finding in favor of CD in the remaining 3 patients. The patient who had histological finding was the one who had the highest tTg IgA level. Duodenal biopsy of the only patient from control group, who underwent upper gastrointestinal endoscopy, revealed normal intestinal mucosa. Biopsy-proven CD was found in only 1 child (0.27%) from the ADHD group. Other 2 patients, who had normal histology from the ADHD group, were considered as having potential CD (0.8%).

tTg IgA seropositivity in cases of ADHD compared with seronegative patients did not differ by sex and age (P = 0.536 and P = 0.069, respectively). The duration of breast-feeding and starting time of bakery foods were similar in seropositive and seronegative patients in ADHD group (P = 0.282 and P = 0.965, respectively). The relation between the history of both abdominal distention and seizures and seropositivity of tTg IgA was found statistically significant in cases with ADHD (P = 0.032 and P = 0.006, respectively) (Table 2). Furthermore, history of postnatal seizures showed a significant relation with tTg IgA seropositivity (50% vs 1.1%) (P = 0.001). When anthropometric measurements were evaluated in respect to the seropositivity, no difference was found.

T2-21
TABLE 2:
Symptoms of children with ADHD in respect to seropositivity of tTg IgA

DISCUSSION

ADHD, a developmental disorder of childhood, is one of the most common psychiatric problems seen in children and adolescents. ADHD, which shows similar prevalence all over the world, is reported to be more common between 6 and 12 years of age (19,20). ADHD has been reported with a rate of 6.5% in a study conducted among primary school children in an urban area (21). It is more common in men, and the male/female ratio can vary between 4/1 and 9/1 (2). We found a similar ratio of 5.9/1 in our study.

Hyperactivity, attention deficiency, and failure of course take part in the diagnostic criteria of ADHD (2,16). Hyperactivitiy (82.9%), attention deficiency (82.9%), and course failure (76.5%) were the most frequent complaints in patients with ADHD in our study. Mild neurological signs, learning disabilities, nonspecific electroencephalogram abnormalities, and probability of epilepsy development have been reported with a rate of 12% to 17% in that population (2,19). We detected the history of seizures in 8.3% of ADHD cases.

CD is an extremely common disease with a prevalence of 1.2% to 2% (5,6,22,23), although it was considered as a rare disease with a prevalence ranging from 0.01% to 0.1% in Europe until the 1980s (24). Seroprevalence of CD is 0.9% to 2.1%, and the prevalence of biopsy-proven CD is 0.5% to 0.6% in healthy children between 6 and 17 years of age in our country (25,26). The rate of seropositivity in our study was not as high as reported in literature and not statistically different from that of control group (1.1% vs 0.8%). Prevalence of biopsy-proven CD in patients with ADHD (0.27%) seemed not to be different from the normal population either. That means that CD is not more common in patients with ADHD, and thus there are not enough data to support screening of CD in cases with ADHD; however, larger study results may alter this reality in the future.

An interesting finding of our study is the higher portion of the patients with positive tTg IgA having the history of seizures compared with seronegative ones (50% vs 7.8%; P = 0.032). This result may lead to a conclusion that one should be more cautious about CD in ADHD patients with seizures. Relation between CD and seizures is well known. A study by Dalgıç et al (27) revealed seropositivity of CD as 4.7% and biopsy-proven CD as 1.17% in 170 epileptic children; however, the fact that the history of postnatal seizures was also more common in our seropositive ones suggests that the relation between CD and seizures in the ADHD population is coincidental because postnatal seizures are irrelevant to CD. Neurologic system complications were reported in 6% to 11% of celiac patients (7,8). Although pathophysiology of neuropsychiatric disorders in CD is not clear, deficiency of vitamin B12, E, D, and pyridoxine has been implicated (7,11,13). In patients with ataxia, Purkinje cells cross-reacting with anti-gliadin antibodies have been reported (28). Anti-ganglioside antibodies, which support the role of autoimmunity, were found in adult patients with CD who have neuropathy and other neurological symptoms (9,29–31).

Although data on psychological and/or psychiatric problems in celiac patients are not sufficient, rate of psychiatric illness in patients with untreated CD has been reported as high as 21% (32). The most common psychiatric disorders observed in CD are depression (33,34), personality disorders, schizophrenia (35), anorexia nervosa (36), anxiety (37), ADHD (12,15), and autism (38). Niederhofer et al (15) administered ADHD symptomatology score in 78 children and adult celiac patients just after the diagnosis and after 6 months of GFD. They found that ADHD-like symptomatology was common among untreated patients with CD and that GFD led to a significant reduction in ADHD score. As a conclusion of that study, they suggested screening of CD in patients who have ADHD symptoms. A study in 67 patients with ADHD, either children or adults, revealed a striking frequency of CD: 14.9% (39). Similar to the study mentioned above, they again reported a significant improvement in symptomatology related to ADHD after 6 months of GFD. As we could not find a statistically significant increased risk for CD in children with ADHD, it would be meaningless to recommend a GFD for that population.

Hernanz et al (40) identified behavioral disorders, irritability, and apathy in 9 of 15 children with newly diagnosed CD and reported an improvement with GFD. Zelnik et al (12) reported learning disabilities and ADHD with a ratio of 20.7% and developmental retardation as 15.5% in the course of CD. The answer of the following question is still unknown: “Is disruption of learning and attention in CD a result of nutritional, immunological, and inflammatory factors or a result of indirect and nonspecific outcome of chronic disease?” (12). Decreased tryptophan intake and impaired central serotonergic functions have been implicated in the mechanism of developing mental and behavioral disorders in CD (32,40,41).

There is a tendency of consuming GFD in some disorders including ADHD, which has been claimed to be affected by gluten exposure (42). A group of patients have been diagnosed as having gluten sensitivity, in which neither allergic nor autoimmune gluten reactions were thought to play a role (42). It is different from CD and is not accompanied by the concurrence of anti-tTG autoantibodies or other autoimmune comorbidities (42); however, there is still no evidence of the effectiveness of the diet (42).

In conclusion, we found the rates of seropositivity of CD as 1.1% and biopsy-proven CD as 0.27% in a quite large series of children with ADHD. Those figures were not higher than those of normal population. Moreover, lack of mucosal injury in the majority of seropositive patients and the low degree of damage, if exists, in patients with ADHD suggest that CD should not be a major concern in children with ADHD. Thus, neither routine screening of CD nor implementation of GFD in ADHD seems necessary; however, it should be kept in mind that CD may manifest at any age in life and those with potential CD may become symptomatic during follow-up. Gluten sensitivity is another aspect that should be evaluated in patients with ADHD via further randomized controlled studies.

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Keywords:

attention-deficit hyperactivity disorders; celiac disease; frequency

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