THE FREQUENCY OF THE CELIAC DISEASE AMONG CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER
Yasin Sahin1, Amra Adrovic2, Kenan Barut2, Tufan Kutlu1, Fugen Cullu-Cokugras1, Sezgin Sahin2, Ozgur Kasapcopur2, Tulay Erkan1
From the Department of Pediatric Gastroenterology1, Pediatric Rheumatology2, Cerrahpasa Medical School, Istanbul University, Turkey
Y. Sahin, Pediatrician; A. Adrovic, Pediatrician; K. Barut, Pediatrician; T. Kutlu, MD, Professor in Pediatric Gastroenterology; F. Cullu-Cokugras, MD, Professor in Pediatric Gastroenterology; S. Sahin, Pediatrician; O. Kasapcopur, MD, Professor in Pediatric Rheumatology; T. Erkan, MD, Professor in Pediatric Gastroenterology.
Author responsible for correspondence: Y. Sahin, Merkezefendi Mah. Mevlana Cad. Sedeftepe Sitesi A Blok No: 98, K: 11, D: 51, 34015 Zeytinburnu, Istanbul, Turkey
Telephone: 90-532-602 10 63
Fax: 90-212-6328633
e- Mail address: ysahin977@gmail.com
Running title: The frequency of the celiac disease in Familial Mediterranean Fever
Funding: This study was supported by the Turkish Pediatric Association.
Abstract:
Objectives: We aimed to assess the frequency of celiac disease (CD) in patients with Familial Mediterranean Fever (FMF).
Methods: This prospective study was carried out from October 2015 to March 2016 and included 303 patients with FMF. Ninety-eight sex- and age-matched healthy subjects we used as a control group. Levels of total IgA and tissue transglutaminase (tTG) IgA antibody were measured in both patients and control groups. Those with increased level of tTG IgA were tested for anti-endomysium IgA antibodies (EMA). Patients with positive EMA underwent gastroduodenoscopy and intestinal biopsy for a definite diagnosis of CD.
Results: Of the 303 patients in this study, 152 (50.2%) were male and 151 (49.8%) were female. In the control group: 50 subjects (51 %) were male and 48 of them (49%) were female. Only 9 of 303 patients (2.9%) were positive for tTG IgA. Patients positive for tTG IgA were then tested for EMA IgA antibodies and only one of them (0.3%) had a positive result. This patient underwent gastro-duodenoscopy. The pathological report was compatible with Marsh 0 classification score for the diagnosis of CD. Two subjects from the control group were positive for tTG IgA but none of them had positive EMA antibodies.
Conclusion: We did not find CD in the large cohort of childhood FMF patients. This study reports the lack of association between FMF and CD in childhood. It points out that screening for CD could be unnecessary for the patients with childhood FMF.
Keywords: celiac disease, Familial Mediterranean fever, intestinal biopsy
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Introduction
Familial Mediterranean fever is an autosomal recessive inherited autoinflammatory disease characterized by recurrent attacks of fever, severe abdominal pain and serositis (1). It is shown to be associated with MEFV gene mutation, localized on the short arm of the 16th chromosome, responsible for the synthesis of the protein called pyrin (2). Pyrin, an inflammatory response inhibitor, is a protein consisted of 781 amino acids. In the cases of MEFV gene mutations, inhibition of the inflammation is decreased so the inflammation attacks appear (3,4). Attacks of FMF are typically 1-3 days lasting periods of acute synovitis, pleuritis or peritonitis, characterized with spontaneous regression of symptoms. About 90% of patients are complaining of abdominal pain during the FMF attack. Arthritis of the lower extremities is the second commonly seen finding of the disease attack. The frequency of the attacks varies from once per week to once per month. It is important to accent that children remain completely healthy between attacks (1).
Celiac disease is an immune-mediated systemic disease seen among genetically susceptible individual, characterized by intestinal villous atrophy secondary to gluten intake (5). Although the disease is generally presented by different gastrointestinal and extra-intestinal symptoms, it can remain totally asymptomatic in some of the cases. Classical gastrointestinal presentations include malabsorption, weight loss, steatorrhea, and diarrhea. It is interesting that about half of patients have extraintestinal or atypical manifestations of the disease (6).
The disease presentation can vary according to the disease stage and patient's age at the disease onset. While the patients of an earlier age are complaining of diarrhea, growth retardation and abdominal pain; adolescents are more prone to have fatigue, osteoporosis, neurological signs, anemia, dermatitis herpetiformis and transaminase elevation (7,8). A study among celiac disease patients reported abdominal pain to be the most commonly seen complaint (seen in 52.7% of patients), similarly to patients with FMF (9). Previous studies showed the association between FMF and different clinical conditions, including vasculitis, spondyloarthropathies, Behcet disease, inflammatory bowel disease and psoriasis (10-14). Furthermore, FMF and celiac disease share many common clinical features; eg. diarrhea, abdominal pain, arthralgia, arthritis etc. (15). Both of the diseases are associated with many inflammatory and auto-immune conditions, as well (16). A diagnosis of celiac disease among FMF patients could be challenging due to many common clinical features.
Two previous studies showed no association between celiac disease and FMF but both of those studies had a small number of patients (16,17). This reason led us to try to investigate the association between these two clinical conditions in a large cohort of childhood FMF patients.
Materials and Methods
Study groups: This is a prospective, cross sectional study performed in the time period from October 2015 to March 2016. A total of 303 patients followed up with the diagnosis of Familial Mediterranean fever at Department of Pediatric Rheumatology at Istanbul University, Cerrahpasa Medical School were included in the study. Ninety-eight sex- and age-matched healthy subjects we used as a control group in the study.
Patients with coincidental disease and those with resistant FMF were excluded from the study. All patients were diagnosed according to pediatric diagnostic criteria for Familial Mediterranean fever 2009 (18). All included patients were followed up for at least 6 months at our clinic.
Study Design: A prospective study was performed in the time period from October 2015 to March 2016. A total of 303 patients with the diagnosis of FMF, followed up at Department of Pediatric Rheumatology at Cerrahpasa Medical School (Istanbul University), were randomized for the study. The study protocol was approved by the Institutional Review Board at the Istanbul University, Cerrahpasa Medical School (313606 / 06 October 2015).
An informed written consent has been obtained from the patients and their parents prior to initiation of the study. All included patients were under colchicine treatment (1.2 mg/m2/day). Ninety-eight sex- and age-matched subjects were used as a control group. All patients and controls were asses for the celiac disease. Venous blood samples were collected from the patients and controls. Each sample was divided into aliquots and samples were stored at -80”C until biochemical analysis.
Immunoturbidimetric method (Roche Diagnostics GmbH, Mannheim, Germany) was used for determination of total IgA and ELISA was performed in order to assess the tTG IgA (Catalog No. 3503, Aesku Diagnostics Gmbh, Wendelsheim, Germany).
The cut-off value for tTG IgA was 12 U/ml. Patients with positive tTG IgA results underwent investigation for EMA IgA, which was performed by IFA technique (Inova Diagnostics, Inc. L”beck, Germany) at the "Duzen Laboratory Group" in Istanbul, Turkey. Gastroduodenoscopy and small intestine biopsy were performed in patients with positive EMA antibodies for a definitive diagnosis of the celiac disease.
Biopsies: Patients and controls with positive both tTG and EMA antibodies underwent gastroduodenoscopy. Four duodenal biopsies and one biopsy from bulbus were taken. All biopsy specimens were evaluated by the same experienced pathologist according to Marsh classification criteria for celiac disease.
Statistical evaluation: Statistical analysis was performed using SPSS software version 13.0 (SPAA Inc, Chicago IL, USA). Categorical data were reported as percentages and continuous data a mean standard deviation (SD) or median (range). Independent-Samples t-test was used for nominal data. Categorical variables were compared using chi-square test. P value was considered statistically significant as a <0.05.
Results
A total of 303 FMF patients we included in the study. The mean age of patients was 12.06”4.2 years. One hundred fifty-two patients (50.2%) were male and 151 of them (49.8%) were female. In the control group: 50 subjects (51%) were male and 48 of them (49%) were female. The mean age of control group was 11.51”4.18 years. There was no statistically significant difference regarding age, sex, weight or height between patients and controls (p<0.05) (Table I).
Only 9 of 303 patients (2.9%) were positive for tTG IgA. Patients positive for tTG IgA were then tested for EMA IgA antibodies and only one of them (0.3%) had a positive result (Table II). These patients underwent gastro-duodenoscopy; 1 biopsy specimen was taken from the bulbus and 4 specimens were taken from the duodenum. The pathological report was compatible with Marsh 0 classification score. The HLA-DQ2/DQ8 analysis was negative, as well. Two subjects from the control group (2%) were positive for tTG IgA but none of them had positive EMA antibodies so the further assessment was unnecessary.
Discussion
Familial Mediterranean fever is an autosomal recessive inherited auto-inflammatory disease commonly seen in Mediterranean area among certain ethnical groups such as Turks, Jewry, Armenians and Arabs (1). Celiac disease is a chronical immune-mediated systemic disease secondary to gluten intake, seen among genetically susceptible persons and possibly associated with some auto-immune and inflammatory conditions (19). Its prevalence is thought to vary between 0.5-1% in the different parts of the World, including USA, Europe, Australia, North Africa, Middle East and India. Studies among adults reported co-existence of celiac disease and some other auto-immune condition in 30% of cases (20). Family members of patients with celiac disease that are sharing the same HLA antigens are shown to be more prone to different auto-immune disease and diabetes (21).
The general prevalence of the celiac disease seems to be increased in the last 2 decades, possible due to an availability of the serological tests. Since only 10% of patients are symptomatic, a majority of asymptomatic patients remains undiagnosed despite screening of the risk populations (22). Highly specific and sensitive tests have modified the approach to diagnosis of the celiac disease. Both EMA-IgA and tTG IgA are shown to have high sensitivity and high specificity for the diagnosis of the celiac disease (23).
ESPGHAN criteria for initial screening of the celiac disease include total IgA and tTG IgA as reliable tests. Anti-endomysium antibody tests and small intestine biopsy are suggested in cases with positive anti tTG IgA (5). In patients with IgA deficiency tTG IgG and EMA IgG are helpful in making a decision for the intestinal biopsy (24). When used in combination, EMA and tTG antibodies have a specificity and sensitivity of 95% (25).
Sometimes, the auto-inflammatory disease can mimic the clinical presentation of the auto-immune condition or they can be in co-existence, what makes the diagnosis more challenging (26). There are some case reports on the coexistence of FMF and celiac disease (27-29). Association between FMF and celiac disease was investigated in the two different studies (16,17). Although there were quite small patients' samples, none of the mentioned studies reported an association between those two conditions.
Kuloglu et al. explored the frequency of celiac disease among 50 FMF patients. They performed anti-gliadin antibodies (AGA) (IgA/IgG) and EMA antibodies (IgA/IgG) to all patients (16). One patient was positive for AGA IgA, the other one was positive for EMA-IgA and six patients were positive for AGA IgG. Only patients with positive EMA IgA underwent gastroduodenoscopy and small intestine biopsy but the result was not compatible with the diagnosis of the celiac disease. None of their patients was diagnosed with celiac disease and the authors reported no association between FMF and celiac disease.
In the other study by Isikay et al. among 112 FMF patients and 32 healthy controls, three patients from FMF group and one patient from the control group were positive for tTG IgA (17).
Unlike previously mentioned studies, those four patients underwent gastroscopy without testing for EMA IgA. Small intestinal biopsies revealed celiac disease in all of four patients.Two patients from the FMF group and one from the control group were HLA-DQ2 positive and one patient from FMF group was HLA-DQ8 positive. Again, this study did not show a relation between FMF and celiac disease, similarly to previously mentioned investigations.
There are some common limitations of those two studies: the number of patients was small and the ESPGHAN criteria were not used for the diagnosis of celiac disease.
Our study used the ESPGHAN criteria for the diagnosis of celiac disease. Only 9 of 303 patients (2.9%) were positive for tTG IgA. Patients positive for tTG IgA were then tested for EMA IgA antibodies and only one of them (0.3%) had a positive result. This patient underwent gastro-duodenoscopy; 1 biopsy specimen was taken from the bulbus and 4 specimens were taken from the duodenum. The pathological report was compatible with Marsh 0 classification score for diagnosis of celiac disease. The HLA-DQ2/DQ8 analysis was negative, as well. Two subjects from the control group (2%) were positive for tTG IgA but none of them had positive EMA antibodies so the further assessment was unnecessary.
Previous studies from Turkey among healthy children between 6-17 years reported a prevalence of celiac disease as a 1/212 (30). None of our 303 childhood FMF patients was diagnosed with celiac disease. We have not determined the association between childhood FMF and celiac disease.
As a conclusion, we did not find celiac disease in the large cohort of childhood FMF patients. This study reports the lack of association between FMF and celiac disease in childhood. It points out that screening for celiac disease could be unnecessary for the patients with childhood FMF.
Funding: This study was supported by the Turkish Pediatric Association.
Disclosure: None.
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Tables
Table I. Demographic and laboratory characteristics of patients and healthy controls
Patients Healthy controls
(n=303) (n=98)
Mean”SD Mean”SD p
Age (yrs) 12.06”4.23 11.51”4.18 0.26
Height (cm) 148.23”21.18 143.91”20.03 0.07
Weight (kg) 43.64”18.89 40.06”15.36 0.06
Hemoglobine (mg/dL) 12.70”1.37 12.97”1.32 0.07
MCV 81.06”6.07 80.33”3.80 0.15
Plt (/mm3) 299.95”427.21 271.90”76.52 0.27
tTG IgA (U/ml) 3.22”18.22 1.47”2.64 0.10
Total IgA (mg/dl) 140.72”69.49 131.42”60.06 0.20
Disease duration (yrs) 5.47”3.46 – –
Plt=thrombocytes, MCV= mean corpuscular volume, tTG=tissue transglutaminase
Table II. Patients with positive tissue transglutaminase (tTG) antibodies
Patient no tTG-IgA Total IgA EMA-IgA FMF gene mutation
(U/ml) (mg/dl)
1 300 140 + M694V/V726A compound het.
2 44 104 – Normal
3 32 245 – M680I homozygous
4 42 173 – Normal
5 59 182 – Normal
6 29.3 167 – M680I/M694V
7 27 178 – Normal
8 41.8 147 – M694V/M694V-R202Q/R202Q
9 15.1 223 – M694V homozygous
tTG=tissue transglutaminase, EMA= anti-endomysium antibodies