International Journal of Rheumatic Diseases 2013
ORIGINAL ARTICLE
Functional gastrointestinal disorders in patients with familial Mediterranean fever 1 3 5 € € € Elif BOREKCI, Mehmet CELIKBILEK,2 M€ ujde SOYTURK, Servet AKAR,4 Hasan BOREKCI 6 € and Ilhan GUNAYDIN 1
Department of Internal Medicine, Bozok University Faculty of Medicine, 2Department of Gastroenterology, Bozok University Faculty of Medicine, Yozgat, 3Department of Gastroenterology, Dokuz Eyl€ ul University Faculty of Medicine, 4Department of Rheumatology, Dokuz Eyl€ ul University Faculty of Medicine, Izmir, 5Department of General Surgery, Bozok University Faculty of Medicine, and 6 Department of Rheumatology, Bozok University Faculty of Medicine, Yozgat, Turkey
Abstract Aim: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterised by recurrent episodes of fever and polyserositis. To date, insufficient data regarding the prevalence of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) and functional dyspepsia (FD) have been reported in patients with FMF. This study aimed to determine the prevalence of functional gastrointestinal disorders in patients with FMF. Methods: This study included 122 patients with FMF and a control group of 122 healthy volunteers who were similar with respect to age and sex. Clinical data were collected and gastrointestinal complaints were evaluated according to the Rome III criteria. Results: IBS was found in 18% of the patients and 10.7% of the controls (P > 0.05). Dyspepsia was reported in 37.7% of the patients and 35.2% of the controls. Constipation was significantly higher in the control group (15.6% vs. 7.4%, P = 0.045), whereas diarrhoea was reported significantly more often in patients with FMF (P = 0.001). Conclusions: IBS and dyspepsia were not increased in patients with FMF, whereas diarrhoea was more frequently reported. Key words: dyspepsia, familial Mediterranean fever, functional gastrointestinal disorders, irritable bowel syndrome, Rome criteria.
INTRODUCTION Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurrent episodes of fever and polyserositis.1 The most frequent symptom is abdominal pain. The current standard treatment for FMF is the lifelong use of colchicine;
€ Correspondence: Dr Mehmet Celikbilek, Bozok Universitesi Tıp Fak€ ultesi Hastanesi Gastroenteroloji Bilim Dalı, Yozgat 66200, Turkey. Email: [email protected]
however, the most common side effect of colchicine is diarrhoea and abdominal pain.2 Although digestive system complaints due to the disease and medicinal treatment are common, little is known regarding the prevalence of these symptoms in patients with FMF. Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common functional gastrointestinal disturbances that are encountered frequently in the general population. Several studies have reported low plasma serotonin levels in patients with FMF.3,4 Additionally, psychosocial factors and abnormalities in serotoninergic functions are common in patients with IBS
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
E. B€ orekci et al.
and dyspepsia pathogenesis.5 Gastrointestinal disturbances are the most common side-effects of colchicine, and histological alterations have been observed on gastric biopsies from patients treated with colchicine.6 Additionally, functional gastrointestinal complaints are seen more frequently in patients with chronic rheumatic diseases.7–9 However, few studies have investigated the prevalence of functional gastrointestinal disorders in patients with FMF. Familial Mediterranean fever is a chronic rheumatic disease and the frequency of digestive system disorders could increase in patients with FMF. This study aimed to estimate the prevalence of IBS and FD in patients with FMS.
MATERIALS AND METHODS Study groups This study was conducted between January 2007 and November 2010 at the Dokuz Eyl€ ul University Medical Facility in the Department of Internal Medicine, Izmir, Turkey. We retrospectively analyzed 152 patients diagnosed with FMF. All patients were asked to come to the hospital; however, a detailed interview was carried out by phone with those unable to come to the hospital. Individuals were briefed before participating in the survey, and those who did not agree to the interview were excluded from the study. Patients with one or more of the following complications were excluded.10 diabetes mellitus, hypothyroidism, colon cancer and patients on medication that could alter gastrointestinal motility. Three patients did not agree to be interviewed. One patient with a history of colectomy, nine patients with diabetes mellitus, 14 patients with hypothyroidism and two patients with alarm symptoms were excluded. In total, 122 patients and 122 healthy individuals who were similar in terms of age and sex participated in the study. Patients having clinical data within the normal range regarding blood count, erythrocyte sedimentation rate, and stool examination for occult blood, leukocytes, ova and parasites (examined in three stool specimens independently collected) were included to rule out organic diseases. All cases were evaluated for clinical and medical background and surveyed for gastrointestinal system complaints.11 To investigate the functional gastrointestinal disturbances, patients were asked to complete a modified version of the Rome III criteria questionnaire, which consisted of 24 questions. FD was defined as postprandial fullness, easy satiety, epigastric pain, and/or epigastric burning for the past 3 months with onset at least 6 months before
2
diagnosis. Patients were diagnosed with IBS if they had recurrent abdominal pain or discomfort for at least three of the previous 6 months and had two or more of the following symptoms: (i) relief with defecation; (ii) onset associated with a change in frequency of stool; and (iii) onset associated with a change in form of stool. Functional constipation and diarrhea were defined according to the Rome III criteria.12 This study was conducted in accordance with the principles of the Helsinki Declaration and approved by the local ethics committee.
Statistical analysis The Statistical Package for the Social Sciences for Windows 15.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analyses. Numerical data (quantitative) are reported as means SD. Categorical data (nominal) are reported as the numbers of people in a group (n) or percentages (%). Categorical variables in the patient and healthy control groups were compared using the chi-square test. The Mann–Whitney U-test was used for continuous variables. Results were considered significant at P < 0.05 at the 95% confidence interval (CI).
RESULTS This study included 122 patients with FMF and 122 healthy subjects with no systemic diseases. The demographic data of the patients and the control group are summarized in Table 1.
Table 1 Demographic characteristics of the patients with familial Mediterranean fever and controls
Age Gender (male/ female) Disease duration (years) Duration of symptoms (years) Delay in diagnosis (years)
Patient (n = 122)
Control (n = 122)
P
39 (31–49.25) 63/59
35 (28.75–43.25) 50/72
0.028 0.095
9.63 7.50
–
–
23.83 12.81
–
–
15.75 11.62
–
–
Values are expressed as n, mean SD or median (25–75 th percentiles).
International Journal of Rheumatic Diseases 2013
IBS and dyspepsia in FMF
Intra-abdominal operations were significantly more frequent in the patient group (P = 0.001). Appendectomy was the most frequent operation conducted, affecting 50 individuals in the patient group and 13 in the control group (41% vs. 10.6%, P < 0.001). All patient tests were within normal limits, including blood count, erythrocyte sedimentation rate and stool examination for occult blood, leukocytes, ova and parasites. Several patients with FMF had concomitant diseases: hypertension was observed in 13 patients, spondyloarthropathy in eight, rheumatoid arthritis in one and non-Hodgkin’s lymphoma in one patient. All patients received on-going colchicine treatment with an average dose of 1.5 mg/day. No difference was observed between the groups regarding the regular use of non-steroidal anti-inflammatory drugs, acetyl salicylic acid and corticosteroids. Proton pump inhibitors (PPI) or H2 receptor blocker (H2RB) usage was higher among patients with FMF (P < 0.05). Twenty-nine (23.8%) subjects in the patient group and 14 (11.5%) in the control group were taking antacid drugs. When PPI or H2RB usage were evaluated in the FD group, 19 of 46 patients with FMF (41.3%) and 12 of 43 controls (27.9%) were taking antacid drugs, without any significant differences. Functional gastrointestinal disease prevalences are summarized in Table 2. Although IBS was observed more often in the patient group than in the controls, the difference was not significant (18% vs. 10.7%, P = 0.100). Abdominal pain or discomfort was present in 34.4% of patients and 27.9% of controls without significant differences (P = 0.269). Improvement with defecation and change in frequency of stool were not different in patients and controls (23.0% vs. 15.6%, P = 0.144 and 26.2% vs. 18.0%, P = 0.123, respectively). Change in form of stool was more common in patients with FMF than in controls (21.1% vs. 11.5%, P = 0.026). IBS subtypes in the patient group were Table 2 Functional gastrointestinal diseases in patients with familial Mediterranean fever and control groups according to Rome III criteria
IBS FD Constipation Diarrhea
Patients (n = 122)
Controls (n = 122)
P
22 (18.0) 46 (37.7) 9 (7.4) 15 (12.3)
13 (10.7) 43 (35.2) 19 (15.6) –
0.100 0.045 0.001
Values are expressed as n (%); IBS, irritable bowel syndrome; FD, functional dyspepsia.
International Journal of Rheumatic Diseases 2013
diarrhoea-predominant in 63.6%, constipation-predominant in 27.3% of the cases, and 9.1% patients had the mixed type. According to the Rome III criteria, 19 out of 22 cases with IBS had the disease before being diagnosed with FMF. When dyspeptic complaints from patients with FMF and control groups were evaluated according to the Rome III criteria, FD was observed in 46 (37.7%) patients and 43 (35.2%) controls (P > 0.05). Postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which are subgroups of FD, were evaluated. PDS was found in 18% (22/122) of patients and 15.6% (19/122) of controls. EPS was observed in 27% (33/122) of patients and 29.5% (36/122) of controls (P > 0.05). Both PDS and EPS were found in nine patients (7.3%) and 12 (9.8%) controls. When all patients and controls were evaluated according to the Rome III criteria, functional constipation was observed more frequently in the control group (15.6% vs. 7.4%, P = 0.045). On the other hand, functional diarrhoea was present only in patients with FMF (P = 0.001).
DISCUSSION In this study, IBS was increased slightly in patients with FMF than in the controls, but this difference was not significant. FD was similar between both groups. While constipation was significantly more frequent in the control group, diarrhea was found more often in the patient group (P > 0.05). IBS is a functional disorder of the bowel characterized by abdominal pain and altered bowel habits. The prevalence of IBS is reported to be 7–10%.13 Although its etiopathogenesis is not fully understood, evidence suggests that a number of factors could play a role, including genetic, environmental, physiological and psychosocial factors. Little is known about IBS in patients with FMF. In our study, IBS was diagnosed in 18% of patients with FMF. Although this was somewhat higher than in the controls (10.7%) and previous reports (7–10%), the difference was not significant. The reason for this could be the low number of participants. A recent study from Turkey using the Rome III criteria classified IBS patients as 42.3% constipation-predominant.14 In our study, diarrhea-predominant was the most common subtype (63.6%), and colchicine use could be a contributing factor. A previous study showed a rise in antral gastric biopsies due to colchicine use, and histological alterations showed an increase in cell cycle events such as
3
E. B€ orekci et al.
apoptosis, mitosis in the metaphase and epithelial pseudoproliferation in patients with FMF.6 These data indicate that the prevalence of dyspepsia in FMF could differ compared to that in the normal population. However, dyspepsia did not differ significantly between the groups in our study. A greater percentage of our patients used PPI or H2RB; therefore, dyspeptic complaints might have been masked with these drugs. Colchicine is the most effective drug used for the treatment of FMF. The most common side effect is diarrhoea, and gastrointestinal side effects such as stomach pain, nausea and vomiting are rarely present. Chronic colchicine treatment may cause malabsorption by villous atrophy in small intestine mucosa,15 decrease the activities of digestive enzymes, such as lactase and maltase, in the jejunum and cause an increase in intestinal secretion and diarrhea by inhibiting Na-K adenosine triphosphatase.16 In our study, constipation was less common in the patients, whereas complaints of diarrhea and gas were more frequent. Diarrhea predominance could thus be associated with colchicine use. In our patients, the delay in FMF diagnosis was approximately 15.8 years. In a study carried out by the Turkish FMF study group involving 2838 patients, the delay in diagnosis was 6.9 years.17 Nineteen of 22 cases with IBS in our study had the disease before the FMF diagnosis. Although IBS is not a valid differential for FMF, abdominal pain may accompany both IBS and FMF; therefore, the delay in FMF diagnosis may be attributed to IBS diagnosis. In addition, because of the existence of acute abdomen during FMF attacks, the number of operations increases as diagnosis is delayed. Our patients also had a significantly greater history of surgery compared to controls. This retrospective study has several limitations, including the low number of patients and the crosssectional design. Due to the retrospective nature, we were unable to perform endoscopic examinations to exclude organic diseases. On the other hand, disease and symptom duration continued for years in our patients, which may assist in excluding malignant diseases. All of our patients with FMF received on-going colchicine treatment, and this drug has some gastrointestinal side effects, as mentioned previously. This may contribute to diagnostic bias when applying the Rome III criteria. In conclusion, the incidences of IBS and dyspepsia are not increased significantly in patients with FMF. Additional controlled and prospective studies are needed to clarify functional gastrointestinal disorders that occur in patients with FMF.
4
ACKNOWLEDGEMENTS We would like to thank Bahar Gunaydin for her technical assistance and linguistic and grammatical corrections of the manuscript.
FINANCIAL SUPPORT None.
CONFLICTS OF INTEREST None.
REFERENCES 1 Lachmann HJ, Sengul B, Yavuzsen TU et al. (2006) Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology 45 (6), 746–50. 2 Lidar M, Livneh A (2007) Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med 65 (9), 318–24. 3 Onat AM, Ozturk MA, Ozcakar L et al. (2007) Selective serotonin reuptake inhibitors reduce the attack frequency in familial mediterranean Fever. Tohoku J Exp Med 211 (1), 9–14. 4 Onat AM, Ozcakar L, Ozturk MA et al. (2007) Plasma and platelet serotonin levels in familial Mediterranean fever. Clin Exp Rheumatol 25 (4 Suppl. 45), S16–20. 5 Dunlop SP, Coleman NS, Blackshaw E et al. (2005) Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 3 (4), 349–57. 6 Al-Daraji WI, Al-Mahmoud RM, Ilyas M (2008) Gastric changes following colchicine therapy in patients with FMF. Dig Dis Sci 53 (8), 2079–82. 7 Ebert EC (2012) Gastrointestinal and hepatic manifestations of Sjogren syndrome. J Clin Gastroenterol 46 (1), 25–30. 8 Myasoedova E, Talley NJ, Manek NJ, Crowson CS (2011) Prevalence and risk factors of gastrointestinal disorders in patients with rheumatoid arthritis: results from a population-based survey in olmsted county, Minnesota. Gastroenterol Res Pract 2011, 745829. PubMed PMID: 22144996. Pubmed Central PMCID: 3226530. 9 Pamuk ON, Umit H, Harmandar O (2009) Increased frequency of gastrointestinal symptoms in patients with fibromyalgia and associated factors: a comparative study. J Rheumatol 36 (8), 1720–4. 10 Talley NJ, Vakil NB, Moayyedi P (2005) American gastroenterological association technical review on the evaluation of dyspepsia. Gastroenterology 129 (5), 1756–80.
International Journal of Rheumatic Diseases 2013
IBS and dyspepsia in FMF
11 Tack J, Talley NJ, Camilleri M et al. (2006) Functional gastroduodenal disorders. Gastroenterology 130 (5), 1466–79. 12 Rome Foundation. Rome III Disorders and Criteria: Rome Foundation. Available from: http://www.romecriteria.org/ assets/pdf/19_RomeIII_apA_885-898.pdf (accessed 20 October 2012). 13 College American of Gastroenterology Task Force on Irritable Bowel Syndrome, Brandt LJ, Chey WD et al. (2009) An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 104 (Suppl. 1), S1–35. 14 Karabulut GS, Beser OF, Erginoz E, Kutlu T, Cokugras FC, Erkan T (2013) The incidence of irritable bowel syndrome
International Journal of Rheumatic Diseases 2013
in children using the Rome III criteria and the effect of Trimebutine treatment. J Neurogastroenterol Motil 19(1), 90–3. PubMed PMID: 23350053. Pubmed Central PMCID: 3548133. 15 Verne GN, Eaker EY, Davis RH, Sninsky CA (1997) Colchicine is an effective treatment for patients with chronic constipation: an open-label trial. Dig Dis Sci 42 (9), 1959–63. 16 Mor A, Gal R, Livneh A (2003) Abdominal and digestive system associations of familial Mediterranean fever. Am J Gastroenterol 98 (12), 2594–604. 17 Tunca M, Akar S, Onen F et al. (2005) Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 84 (1), 1–11.
5
ORIGINAL ARTICLE
Functional gastrointestinal disorders in patients with familial Mediterranean fever 1 3 5 € € € Elif BOREKCI, Mehmet CELIKBILEK,2 M€ ujde SOYTURK, Servet AKAR,4 Hasan BOREKCI 6 € and Ilhan GUNAYDIN 1
Department of Internal Medicine, Bozok University Faculty of Medicine, 2Department of Gastroenterology, Bozok University Faculty of Medicine, Yozgat, 3Department of Gastroenterology, Dokuz Eyl€ ul University Faculty of Medicine, 4Department of Rheumatology, Dokuz Eyl€ ul University Faculty of Medicine, Izmir, 5Department of General Surgery, Bozok University Faculty of Medicine, and 6 Department of Rheumatology, Bozok University Faculty of Medicine, Yozgat, Turkey
Abstract Aim: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterised by recurrent episodes of fever and polyserositis. To date, insufficient data regarding the prevalence of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) and functional dyspepsia (FD) have been reported in patients with FMF. This study aimed to determine the prevalence of functional gastrointestinal disorders in patients with FMF. Methods: This study included 122 patients with FMF and a control group of 122 healthy volunteers who were similar with respect to age and sex. Clinical data were collected and gastrointestinal complaints were evaluated according to the Rome III criteria. Results: IBS was found in 18% of the patients and 10.7% of the controls (P > 0.05). Dyspepsia was reported in 37.7% of the patients and 35.2% of the controls. Constipation was significantly higher in the control group (15.6% vs. 7.4%, P = 0.045), whereas diarrhoea was reported significantly more often in patients with FMF (P = 0.001). Conclusions: IBS and dyspepsia were not increased in patients with FMF, whereas diarrhoea was more frequently reported. Key words: dyspepsia, familial Mediterranean fever, functional gastrointestinal disorders, irritable bowel syndrome, Rome criteria.
INTRODUCTION Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurrent episodes of fever and polyserositis.1 The most frequent symptom is abdominal pain. The current standard treatment for FMF is the lifelong use of colchicine;
€ Correspondence: Dr Mehmet Celikbilek, Bozok Universitesi Tıp Fak€ ultesi Hastanesi Gastroenteroloji Bilim Dalı, Yozgat 66200, Turkey. Email: [email protected]
however, the most common side effect of colchicine is diarrhoea and abdominal pain.2 Although digestive system complaints due to the disease and medicinal treatment are common, little is known regarding the prevalence of these symptoms in patients with FMF. Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common functional gastrointestinal disturbances that are encountered frequently in the general population. Several studies have reported low plasma serotonin levels in patients with FMF.3,4 Additionally, psychosocial factors and abnormalities in serotoninergic functions are common in patients with IBS
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
E. B€ orekci et al.
and dyspepsia pathogenesis.5 Gastrointestinal disturbances are the most common side-effects of colchicine, and histological alterations have been observed on gastric biopsies from patients treated with colchicine.6 Additionally, functional gastrointestinal complaints are seen more frequently in patients with chronic rheumatic diseases.7–9 However, few studies have investigated the prevalence of functional gastrointestinal disorders in patients with FMF. Familial Mediterranean fever is a chronic rheumatic disease and the frequency of digestive system disorders could increase in patients with FMF. This study aimed to estimate the prevalence of IBS and FD in patients with FMS.
MATERIALS AND METHODS Study groups This study was conducted between January 2007 and November 2010 at the Dokuz Eyl€ ul University Medical Facility in the Department of Internal Medicine, Izmir, Turkey. We retrospectively analyzed 152 patients diagnosed with FMF. All patients were asked to come to the hospital; however, a detailed interview was carried out by phone with those unable to come to the hospital. Individuals were briefed before participating in the survey, and those who did not agree to the interview were excluded from the study. Patients with one or more of the following complications were excluded.10 diabetes mellitus, hypothyroidism, colon cancer and patients on medication that could alter gastrointestinal motility. Three patients did not agree to be interviewed. One patient with a history of colectomy, nine patients with diabetes mellitus, 14 patients with hypothyroidism and two patients with alarm symptoms were excluded. In total, 122 patients and 122 healthy individuals who were similar in terms of age and sex participated in the study. Patients having clinical data within the normal range regarding blood count, erythrocyte sedimentation rate, and stool examination for occult blood, leukocytes, ova and parasites (examined in three stool specimens independently collected) were included to rule out organic diseases. All cases were evaluated for clinical and medical background and surveyed for gastrointestinal system complaints.11 To investigate the functional gastrointestinal disturbances, patients were asked to complete a modified version of the Rome III criteria questionnaire, which consisted of 24 questions. FD was defined as postprandial fullness, easy satiety, epigastric pain, and/or epigastric burning for the past 3 months with onset at least 6 months before
2
diagnosis. Patients were diagnosed with IBS if they had recurrent abdominal pain or discomfort for at least three of the previous 6 months and had two or more of the following symptoms: (i) relief with defecation; (ii) onset associated with a change in frequency of stool; and (iii) onset associated with a change in form of stool. Functional constipation and diarrhea were defined according to the Rome III criteria.12 This study was conducted in accordance with the principles of the Helsinki Declaration and approved by the local ethics committee.
Statistical analysis The Statistical Package for the Social Sciences for Windows 15.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analyses. Numerical data (quantitative) are reported as means SD. Categorical data (nominal) are reported as the numbers of people in a group (n) or percentages (%). Categorical variables in the patient and healthy control groups were compared using the chi-square test. The Mann–Whitney U-test was used for continuous variables. Results were considered significant at P < 0.05 at the 95% confidence interval (CI).
RESULTS This study included 122 patients with FMF and 122 healthy subjects with no systemic diseases. The demographic data of the patients and the control group are summarized in Table 1.
Table 1 Demographic characteristics of the patients with familial Mediterranean fever and controls
Age Gender (male/ female) Disease duration (years) Duration of symptoms (years) Delay in diagnosis (years)
Patient (n = 122)
Control (n = 122)
P
39 (31–49.25) 63/59
35 (28.75–43.25) 50/72
0.028 0.095
9.63 7.50
–
–
23.83 12.81
–
–
15.75 11.62
–
–
Values are expressed as n, mean SD or median (25–75 th percentiles).
International Journal of Rheumatic Diseases 2013
IBS and dyspepsia in FMF
Intra-abdominal operations were significantly more frequent in the patient group (P = 0.001). Appendectomy was the most frequent operation conducted, affecting 50 individuals in the patient group and 13 in the control group (41% vs. 10.6%, P < 0.001). All patient tests were within normal limits, including blood count, erythrocyte sedimentation rate and stool examination for occult blood, leukocytes, ova and parasites. Several patients with FMF had concomitant diseases: hypertension was observed in 13 patients, spondyloarthropathy in eight, rheumatoid arthritis in one and non-Hodgkin’s lymphoma in one patient. All patients received on-going colchicine treatment with an average dose of 1.5 mg/day. No difference was observed between the groups regarding the regular use of non-steroidal anti-inflammatory drugs, acetyl salicylic acid and corticosteroids. Proton pump inhibitors (PPI) or H2 receptor blocker (H2RB) usage was higher among patients with FMF (P < 0.05). Twenty-nine (23.8%) subjects in the patient group and 14 (11.5%) in the control group were taking antacid drugs. When PPI or H2RB usage were evaluated in the FD group, 19 of 46 patients with FMF (41.3%) and 12 of 43 controls (27.9%) were taking antacid drugs, without any significant differences. Functional gastrointestinal disease prevalences are summarized in Table 2. Although IBS was observed more often in the patient group than in the controls, the difference was not significant (18% vs. 10.7%, P = 0.100). Abdominal pain or discomfort was present in 34.4% of patients and 27.9% of controls without significant differences (P = 0.269). Improvement with defecation and change in frequency of stool were not different in patients and controls (23.0% vs. 15.6%, P = 0.144 and 26.2% vs. 18.0%, P = 0.123, respectively). Change in form of stool was more common in patients with FMF than in controls (21.1% vs. 11.5%, P = 0.026). IBS subtypes in the patient group were Table 2 Functional gastrointestinal diseases in patients with familial Mediterranean fever and control groups according to Rome III criteria
IBS FD Constipation Diarrhea
Patients (n = 122)
Controls (n = 122)
P
22 (18.0) 46 (37.7) 9 (7.4) 15 (12.3)
13 (10.7) 43 (35.2) 19 (15.6) –
0.100 0.045 0.001
Values are expressed as n (%); IBS, irritable bowel syndrome; FD, functional dyspepsia.
International Journal of Rheumatic Diseases 2013
diarrhoea-predominant in 63.6%, constipation-predominant in 27.3% of the cases, and 9.1% patients had the mixed type. According to the Rome III criteria, 19 out of 22 cases with IBS had the disease before being diagnosed with FMF. When dyspeptic complaints from patients with FMF and control groups were evaluated according to the Rome III criteria, FD was observed in 46 (37.7%) patients and 43 (35.2%) controls (P > 0.05). Postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which are subgroups of FD, were evaluated. PDS was found in 18% (22/122) of patients and 15.6% (19/122) of controls. EPS was observed in 27% (33/122) of patients and 29.5% (36/122) of controls (P > 0.05). Both PDS and EPS were found in nine patients (7.3%) and 12 (9.8%) controls. When all patients and controls were evaluated according to the Rome III criteria, functional constipation was observed more frequently in the control group (15.6% vs. 7.4%, P = 0.045). On the other hand, functional diarrhoea was present only in patients with FMF (P = 0.001).
DISCUSSION In this study, IBS was increased slightly in patients with FMF than in the controls, but this difference was not significant. FD was similar between both groups. While constipation was significantly more frequent in the control group, diarrhea was found more often in the patient group (P > 0.05). IBS is a functional disorder of the bowel characterized by abdominal pain and altered bowel habits. The prevalence of IBS is reported to be 7–10%.13 Although its etiopathogenesis is not fully understood, evidence suggests that a number of factors could play a role, including genetic, environmental, physiological and psychosocial factors. Little is known about IBS in patients with FMF. In our study, IBS was diagnosed in 18% of patients with FMF. Although this was somewhat higher than in the controls (10.7%) and previous reports (7–10%), the difference was not significant. The reason for this could be the low number of participants. A recent study from Turkey using the Rome III criteria classified IBS patients as 42.3% constipation-predominant.14 In our study, diarrhea-predominant was the most common subtype (63.6%), and colchicine use could be a contributing factor. A previous study showed a rise in antral gastric biopsies due to colchicine use, and histological alterations showed an increase in cell cycle events such as
3
E. B€ orekci et al.
apoptosis, mitosis in the metaphase and epithelial pseudoproliferation in patients with FMF.6 These data indicate that the prevalence of dyspepsia in FMF could differ compared to that in the normal population. However, dyspepsia did not differ significantly between the groups in our study. A greater percentage of our patients used PPI or H2RB; therefore, dyspeptic complaints might have been masked with these drugs. Colchicine is the most effective drug used for the treatment of FMF. The most common side effect is diarrhoea, and gastrointestinal side effects such as stomach pain, nausea and vomiting are rarely present. Chronic colchicine treatment may cause malabsorption by villous atrophy in small intestine mucosa,15 decrease the activities of digestive enzymes, such as lactase and maltase, in the jejunum and cause an increase in intestinal secretion and diarrhea by inhibiting Na-K adenosine triphosphatase.16 In our study, constipation was less common in the patients, whereas complaints of diarrhea and gas were more frequent. Diarrhea predominance could thus be associated with colchicine use. In our patients, the delay in FMF diagnosis was approximately 15.8 years. In a study carried out by the Turkish FMF study group involving 2838 patients, the delay in diagnosis was 6.9 years.17 Nineteen of 22 cases with IBS in our study had the disease before the FMF diagnosis. Although IBS is not a valid differential for FMF, abdominal pain may accompany both IBS and FMF; therefore, the delay in FMF diagnosis may be attributed to IBS diagnosis. In addition, because of the existence of acute abdomen during FMF attacks, the number of operations increases as diagnosis is delayed. Our patients also had a significantly greater history of surgery compared to controls. This retrospective study has several limitations, including the low number of patients and the crosssectional design. Due to the retrospective nature, we were unable to perform endoscopic examinations to exclude organic diseases. On the other hand, disease and symptom duration continued for years in our patients, which may assist in excluding malignant diseases. All of our patients with FMF received on-going colchicine treatment, and this drug has some gastrointestinal side effects, as mentioned previously. This may contribute to diagnostic bias when applying the Rome III criteria. In conclusion, the incidences of IBS and dyspepsia are not increased significantly in patients with FMF. Additional controlled and prospective studies are needed to clarify functional gastrointestinal disorders that occur in patients with FMF.
4
ACKNOWLEDGEMENTS We would like to thank Bahar Gunaydin for her technical assistance and linguistic and grammatical corrections of the manuscript.
FINANCIAL SUPPORT None.
CONFLICTS OF INTEREST None.
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IBS and dyspepsia in FMF
11 Tack J, Talley NJ, Camilleri M et al. (2006) Functional gastroduodenal disorders. Gastroenterology 130 (5), 1466–79. 12 Rome Foundation. Rome III Disorders and Criteria: Rome Foundation. Available from: http://www.romecriteria.org/ assets/pdf/19_RomeIII_apA_885-898.pdf (accessed 20 October 2012). 13 College American of Gastroenterology Task Force on Irritable Bowel Syndrome, Brandt LJ, Chey WD et al. (2009) An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 104 (Suppl. 1), S1–35. 14 Karabulut GS, Beser OF, Erginoz E, Kutlu T, Cokugras FC, Erkan T (2013) The incidence of irritable bowel syndrome
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