Functional dyspepsia (FD) is a common functional gastrointestinal disorder in clinical pratice [1,2]. The Rome III consensus proposed the subdivision of FD into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Diagnostic criteria for EPS include intermittent epigastric pain or burning of minimal to moderate severity at least once a week. This condition must have persisted for the last 3 months with the onset of symptoms occuring at least 6 months prior to diagnosis [3]. Functional dyspepsia is treated by two major categories of drug, acid inhibitors (H2-receptor antagonists and proton pump inhibitors) and prokinetic drugs, diet and life-style modification or helicobacter pylori (HP) eradication therapy [4,5]. However, all prescribed medications provide only limited or temporary improvement of dyspeptic symptoms. Thus, the healthy quality of life for patients with FD may deteriorate [1,6].
Familial Mediterranean fever (FMF) is an autosomal recessive inherited disorder, characterized by recurrent attacks of fever and polyserositis. The most frequent symptom is abdominal pain. Familial Mediterranean fever is especially common in Mediterranean populations such as Jews, Arabs, Turks, Greek and Armenians [7]. It is caused by mutations in the Mediterranean fever (
The clinical profile of FMF is wide related to
This study was performed at the Department of Gastroenterology, Kayseri Training and Research Hospital, Kayseri, Turkey, between January 2014 and December 2015. The study protocol was permitted by the local ethics committee of Cumhuriyet University, Sivas, Turkey. Written informed consent was obtained from all of the participants.
A total of 75 patients aged between 18 and 65 years, who were diagnosed with therapy-resistant EPS, were included in this study. Patients were diagnosed according to the Rome III criteria (Table 1) [3]. Therapy-resistant EPS was defined as persistent epigastric pain despite a minimum 4 weeks of acid suppression, procinetics and HP eradication therapy [5]. All examinations of patients, including upper gastrointestinal endoscopy, abdominal ultrasonography, whole blood count and biochemical analyses (renal and liver function), were normal within 3 months of the study. Exclusion criteria were as follows: presence of ulcer or erosion in the upper gastrointestinal system endoscopy, patients who had gastroesophageal reflux symptoms or irritable bowel syndrome, inflammatory bowel disease, pancreaticobiliary tract disease, use of non steroidal anti-inflammatory drugs or alcohol, presence of malignancy (stomach/pancreatic cancer), previous abdominal surgery, other severe systemic disease (
Diagnostic criteria of epigastric pain syndrome (Rome III criteria). Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.1 Pain or burning localized to the epigastrium of at least moderate severity, at least once per week 2 The pain is intermittent 3 Not generalized or localized to other abdnominal or chest regions 4 Not relieved by defecation or passage of flatus 5 Not fulfilling criteria for gallbladder or sphincter of Oddi disorders
The control group consisted of 20 healthy age- and sex-matched subjects without any systemic illness such as diabetes mellitus, renal failure, pulmonary/heart disease and chronic inflammatory diseases. All patients and healthy controls were Turkish residents of Central Anatolia. Table 2 shows demographic and clinical findings in the EPS patients and control group.
The demographic, clinical and laboratory characteristics of patients with epigastric pain syndrome and the control group. FMF: familial Mediterranean fever.Parameters Patient Group ( Control Group ( Gender F: 54; M: 21 F: 12; M: 8 Age (years) 38.9 ± 13.9 34.6 ± 7.6 Family history of FMF 18 (24.0%) 0 (0.0%) Consanguinity 10 (13.3%) 0 (0.0%) Homozygotes 3 (4.0%) 0 (0.0%) Heterozygotes 30 (40.0%) 8 (40.0%) Compound heterozygotes 10 (13.3%) 0 (0.0%) Fever 28 (37.3%) – Arthralgia 27 (36.0%) – Chest pain 11 (14.6%) – Oral ulcers 10 (13.3%) – Kidney stones 9 (12.0%) –
To investigate the diagnosis of FMF in patients with therapy-resistant EPS, Tel-Hashomer criteria (recurrent fever attacks, abdominal pain, chest pain, arth-ralgia and erysipelas-like erythema), familial history of FMF and the presence of other autoimmune diseases, were recorded [10]. All patients and healthy controls were referred for genetic testing. Other laboratory findings (complete blood count, biochemical and urinary analyses), sedimentation and C-reactive protein were obtained from hospital records.
For FMF gene mutation analysis, genomic DNA was extracted from peripheral blood leukocytes using the QIAamp blood kit (Qiagen GmbH, Hilden, Germany). A dideoxy sequencing method was used in this study. To perform mutational analysis, amplified polymerase chain reaction (PCR) products were purified by USB ExoSAP-IT (Affymetrix, Cleveland, OH, USA) and subjected to bidirectional sequencing (BigDye Terminator, version 3.1, Applied Biosystems Inc., Foster City, CA, USA) and further processed on Performa DTR Gel Filtration columns (Edge Biosystems, San Jose, CA, USA). The sequencing products were analyzed on an ABI PRISM™ 3500 genetic analyzer (Applied Biosystems Inc.). We performed sequencing in the forward and reverse directions.
Data were analyzed using the Statistical Package for the Social Sciences (SPSS) version 16.0) (SPSS Inc., Chicago, IL, USA). Descriptive statistics [
The EPS patients and controls had mean ages of 38.9 ± 13.9 and 34.6 ± 7.6, respectively. Seventy-two percent of EPS patients were female. Eighteen patients (24.0%) had a family history of FMF. The mean duration of abdominal pain was 10 ± 2.5 years (range from 5 to 22 years). Ten (13.3%) patients were the result of consanguineous parents. Episodic epigastric pain was the principal complaint reported by all patients. Other observed complaints consisted of several types: fever (28; 37.3%), arthralgia (27; 36.0%), chest pain (11; 14.6%), history of kidney stones (9; 12.0%) and oral ulcers (10; 13.3%). In the patients, the mean erythrocyte sedimentation rate was 21.4 ± 11.4 mm/h (normal value <15 mm/h), C-reactive protein was 8.0 ± 3.3 mg/dL (normal range: 0.0-6.0 mg/dL) and fibrinogen 311.8 ± 85.0 mg/dL (normal range: 180.0-400.0 mg/dL).
Of the 75 patients, 43 (57.3%) had
In the control group, eight subjects (40.0%) had
The frequency of Genotype Patient Group ( Control Group ( Mutation/– 32 12 Heterozygotes for one mutation: R202Q/– 15 2 R761H/– 5 0 E148Q/– 5 2 V726A/– 1 2 M680I/– 2 1 G304R/– 1 0 M694I/– 1 1 Homozygotes for one muation: R202Q/R202Q 3 0 Compound heterozygotes for two mutations: R202Q/R761H 2 0 K695R/V726A 1 0 P396S/R408Q 1 0 L110P/E148Q 1 0 M680I/V726A 1 0 Compound heterozygotes for three mutations: R202Q/M694V/V726A 2 0 R202Q/R408Q/E148Q 1 0 R202Q/R202Q/P369S 1 0 Total 75 20
No significant differences were observed in the frequencies of consanguinity, fever, arthralgia, chest pain and FMF family history in EPS patients with or without the
The genotype, clinical and demographic findings in familial Mediterranean fever patients.Patient Sex Age Family History Abdominal Pain Fever Arthalgia Chest Pain Microscopic Hematuria #1 G304R/– F–38 [+] [+] [+] [+] [–] [–] #2 R202Q/– F–27 [+] [+] [+] [+] [–] [–] #3 V726A/K695R F–28 [+] [+] [+] [+] [–] [–] #4 R202Q/R761H F–19 [+] [+] [+] [+] [–] [–] #5 R202Q/R202Q M–31 [–] [+] [+] [+] [+] [–] #6 V726A/M694V/R202Q M–29 [+] [+] [+] [+] [–] [–] #7 V726A/M694V/R202Q M–41 [–] [+] [+] [+] [+] [–] #8 R202Q/E148Q/R408Q F–37 [+] [+] [–] [+] [–] [–]
Comparison of clinical findings between epigastric pain syndrome patients with/without Negative ( Positive ( Family history 5 (5.8%) 12 (14.1%) 0.54 Positive consanguinity 3 (9.4%) 7 (16.3%) 0.38 Fever 10 (31.3%) 18 (41.9%) 0.35 Arthalgia 12 (37.5%) 19 (44.2%) 0.56 Chest pain 3 (9.4%) 8 (18.6%) 0.26 Oral ulcers 1 (3.1%) 9 (20.9%) 0.02 Kidney stones 0 (0.0%) 9 (20.9%) 0.01
Our study aimed to determined the frequency of
The most commonly seen mutations in FMF patients are M694V, M680I (G/C), E148Q, V726A, and frequency of the mutations change according to ethnicity [17,18]. Erden
The R202Q was another common mutation in the Turkish population. Some studies have also recently reported that frequency of R202Q was higher than the frequency of the M694V mutation in FMF patients [22,23]. In a study by Yigit
However, contrary to the above data, Comak
E148Q and V726A are other commonly observed mutations in Turkish FMF patients. The carrier frequencies of E148Q and V726A have been reported as 12.0 and 3.0-14.0%, respectively. The frequency of E148Q in Turks is similar with other ethnicities [25,28,29], while V726A is especially common in Arabs [30]. Ben-Chetrit
V726A is associated with a mild form of the disease. However, V726A homozygotes and compound heterozygotes for the V726A/E148Q variants are associated with severe disease, and patients can develop renal amyloidosis. Hence, the authors proposed that patients carrying this complex allele should have been given colchicine prophylaxis [9,34]. In the present study, V726A is the third most common mutation with a frequency of 9.3%. While two patients who had compound heterozygosities for two or three mutations (V726A/K695R and V726A/M694V/ R202Q), presented with FMF symptoms, one patient with heterozygous V726A/– and one patient with a compound heterozygosity for V726A/M680I, did not.
In this study, the rare
Familial Mediterranean fever can be divided into three clinical phenotypes: type 1 or typical FMF phenotype (attacks of abdominal pain, arthritis, fever); type 2 characterized by the presence of amyloidosis in asymptomatic subjects and (incidence of 7.0-25.0%); type 3 ‘silent type’ homozygous or compound heterozygous state and is estimated to occur in 1:300 Ashkenazi and 1:25 Iraqi Jews. In recent years, it has been observed that heterozygous mutation carriers can suffer also from a mild or incomplete form of FMF, named ‘FMF-like’ disease (a new phenotype) [9]. In recent years, a new phenotype termed ‘FMF-like disease,’ which is characterized as a mild or incomplete form of FMF in patients with heterozygous mutations has been defined. The reason why some carriers experience FMF clinical symptoms, while others present with only mild or no symptoms, is largely unknown, but it is assumed that the
Thus, we also speculated that the heterozygous state of the
Treatment for asymptomatic individuals with heterozygous mutations is unknown. Guidelines recommend that they should be followed with urine analyses [39]. Familial Mediterranean fever-like disease may initiate periodic follow-up, and administering colchicine should be considered. The patients with the ‘silent’ carrier status of two mutations (homozygous or compound heterozygous) could predispose to developing renal amyloidosis, and particularly patients with a family history of FMF should be administered colchicine prophylaxis [40]. In our study, we started colchicine therapy for FMF patients and patients who have an asymptomatic homozygous R202Q mutation and family history of FMF for increased risk of developing amyloidosis.
Our results demonstrated a high carrier rate of