Arthritis Res Ther. 2013;15(6):R201.

Remarkable prevalence of coeliac disease in patients with irritable bowel syndrome plus fibromyalgia in comparison with those with isolated irritable bowel syndrome: a case-finding study.

Rodrigo L, Blanco I, Bobes J, de Serres FJ.

Gastroenterology, Central University Hospital of Asturias (HUCA), Celestino Villamil, s/n. ES-33006 Oviedo, Principality of Asturias, Spain

 

Abstract

INTRODUCTION: Irritable bowel syndrome (IBS) and fibromyalgia syndrome (FMS) are two common central sensitization disorders frequently associated in the same patient, and some of these patients with IBS plus FMS (IBS/FMS) could actually be undiagnosed of coeliac disease (CD). The present study was an active case finding for CD in two IBS cohorts, one constituted by IBS/FMS subjects and the other by people with isolated IBS.

METHODS: A total of 104 patients (89.4% females) fulfilling the 1990 ACR criteria for FMS and the Rome III criteria for IBS classification and 125 unrelated age- and sex-matched IBS patients without FMS underwent the following studies: haematological, coagulation and biochemistry tests, serological and genetic markers for CD (i.e., tissue transglutaminase 2 (tTG-2) and major histocompatibility complex HLA-DQ2/HLA-DQ8), multiple gastric and duodenal biopsies, FMS tender points (TPs), Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ), 36-Item Short Form Health Survey (SF-36) and Visual Analogue Scales (VASs) for tiredness and gastrointestinal complaints.

RESULTS: As a whole, IBS/FMS patients scored much worse in quality of life and VAS scores than those with isolated IBS (P < 0.001). Seven subjects (6.7%) from the IBS/FMS group displayed HLA-DQ2/HLA-DQ8 positivity, high tTG-2 serum levels and duodenal villous atrophy, concordant with CD. Interestingly enough, these seven patients were started on a gluten-free diet (GFD), showing a remarkable improvement in their digestive and systemic symptoms on follow-up.

CONCLUSIONS: The findings of this screening indicate that a non-negligible percentage of IBS/FMS patients are CD patients, whose symptoms can improve and in whom long-term CD-related complications might possibly be prevented with a strict lifelong GFD.

PMID: 24283458

 

SUPPLEMENTS:

Irritable bowel syndrome (IBS) is a common gastrointestinal functional disease characterized by the presence of chronic abdominal pain, associated with changes in bowel habits, defecation urgency; tenesmus; bloating and abdominal distension. Diagnosis of IBS was based on a positive history of gastrointestinal symptoms according to the Rome III criteria in the absence of obvious alarm signs. Several comorbidities which may occur more often than expected by chance in IBS patients, including fibromyalgia syndrome (FMS), chronic fatigue syndrome (CFS), gastro-oesophageal reflux disease, headache, backache, genitourinary symptoms, temporomandibular joint disorder, anxiety and depression. Specifically, FMS, a prevalent, chronic, widespread pain disorder affecting mainly females, classified according to the 1990 American College of Rheumatology (ACR) criteria [6], occurs in 20% to 32% of people with IBS, and, in turn, 32% to 70% of people with FMS also meet the criteria for IBS. It has been reported that the incidence of coeliac disease (CD) in patients with IBS, is much higher than that expected to be found in the general population . In spite of the fact that IBS, FMS and CD are three prevalent disorders in all over the world, no study has been carried out to date, to assess their association rate to our knowledge.

Therefore, with the aim of estimating the prevalence of CD masquerading as IBS and/or FMS, a specific protocol for active case-finding of coeliac disease, was applied to an IBS/FMS population from Asturias (Northern Spain) and to a sex, age and size-matched cohort of IBS patients without FMS to establish comparations.

During the 6-year period study, from 2007 through 2012, the Rome III criteria for IBS diagnosis and the 1990 ACR criteria for FMS classification  were prospectively applied to 442 consecutive patients upon their first visit to an outpatient gastroenterology clinic at the Central University Hospital of Asturias (HUCA, Oviedo, Spain).

Most patients were referred from the rheumatology and internal medicine departments of the same hospital for the study of a variety of long-standing gastrointestinal symptoms. A total of 213 patients were not included by several reasons, before starting.

These 229 participants were invited to participate, on a voluntary basis, after signing a specific informed consent form. The study was approved by the HUCA research and Ethics Committee according to the principles included in the modified Declaration of Helsinki.

Initially, every selected participant underwent an updated medical history, a quality of life (QoL) battery of tests and a thorough physical examination. Each participant filled out the self-administered Spanish version form of the Fibromyalgia Impact Questionnaire (FIQ) , the Stanford Health Assessment Questionnaire (HAQ)  and the 36-Item Short Form Health Survey (SF-36) at the entrance into the study. Complete blood cell counts were performed . Several coagulation studies. Analytical biochemistry tests, including urea, glucose, total proteins, albumin, C-reactive protein, calcium, folate, vitamin B12 , creatinine, creatine kinase, lipid profile, liver function tests (LFTs), iron metabolism tests, immunoglobulin G (IgG), IgA and IgM, rheumatoid factor, thyroid function test and urinalysis with microscopic examination of sediment.

Anti-IgA tissue transglutaminase subtype 2 (tTG-2) was measured by a commercial Elisa technique. To assess the participants’genetic susceptibility to CD, the major histocompatibility complex class II human leucocyte antigen (HLA) markers HLA-DQ2 and DQ8 were characterized by PCR. An upper gastrointestinal endoscopy with at least four duodenal biopsies was performed in all patients for CD diagnosis and thy were classified according to Marsh criteria. Only those patients showing villous atrophy in the duodenal biopsy were considered as celiacs.

Demographic data of all participants into the study were described. Only the comparison of putting together the patients with  Marsh stages 1 and 3vs. Marsh stage 0,  in their duodenal biopsies, showed significant difference (p<0.001 (Table 1). 

Table 1. Demographic data.

  IBS IBS/FMS P value(IBS vs FMS) IBS/FMS casesClassified by Marsh’s stages P value(Marsh-1/3 vs. Marsh-0)
        Marsh-0 Marsh-1 Marsh-3  
Sample size 125 104 NA 39 58 7 <0.001
Females 104 (84) 93 (89) 0.122 34 (87) 52 (90) 7 (100) 0.595
Age, years 51 (8) 50 (8) 0.668 49 (7) 51 (9) 49 (12) 0.146
BMI, Kg/m2 27 (4) 26 (4) 0.388 25 (3) 28 (5) 24 (3) 0.003
Marital status              
   Single 3 (2) 2 (2) 0.748 1 (3) 2 (3) 1 (14) 0.892
   Married 103 (82) 92 (89) 0.272 33 (85) 52 (90) 4 (57) 1.000
   Domestic partnership 10 (8) 5 (5) 0.481 4 (10) 1 (0) 1 (14) 0.123
   Separated/ divorced 10 (8) 5 (5) 0.481 1 (3) 3 (5) 1 (14) 0.722
Education level              
   None 2 (2) 2 (2) 0.748 2 (5) 2 (3) 1 (14) 0.834
   Primary school 92 (73) 75 (72) 0.918 29 (74) 42 (72) 2 (28) 0.865
   Secondary education 27 (22) 24 (23) 0.914 10 (26) 11 (19) 3 (42) 0.810
   Higher education 4 (3) 3 (3) 0.804     3 (8) 3 (5) 1 (14) 0.449
Labour status              
   Employed 59 (47) 47 (45) 0.864 21 (54) 24 (41) 2 (29) 0.242
   Unemployed 26 (21) 22 (21) 0.922 7 (18) 13 (22) 2 (29) 0.844
   Householder chores 23 (18) 19 (18) 0.883 8 (20) 9 (15) 2 (29) 0.709
   Retired/pensioner 17 (14) 16 (15) 0.846 3 (8) 12 (21) 1 (14) 0.160
Subjects with relatives diagnosed of CD —– 12 (11) NA 2 (5) 10 (17) 2 (29) 0.161
Subjects with relatives diagnosed of FMS 4 (3) 5 (5) 0.389 1 (2) 4 (7) 1 (14) 0.619

Data are expressed as total and percentage of the total value, or mean and standard deviation. BMI= Body Mass Index. NA=Not Applicable.

 

All the histological findings, genetic and serological markers for the IBS and IBS/FMS showed significant  comparative differences (Table 2). The IELs count, HLA-DQ2 status and tTG2 serological levels, were different according to Marsh state, but the prevalence of Helicobacter pylori didn´t show any difference between analyzed groups (Table 3). Main symptoms, associated diseases, tender points and test scores were shown (Table 4). Fibromyalgic patients receive a lot of prescription drugs for relieve of their symptoms, specially for the pain. The labels of these products and the percentage of consumers of each one, are described (Table 5). The haematological and biochemical laboratory findings are included (Tabe 6)

 

Table 2. Gastroduodenal histological findings, genetic and serological markers of Celiac Disease in two cohorts of Irritable Bowel Syndrome and Irritable Bowel Syndrome plus Fibromyalgia Syndrome patients.

Cohorts IBS(N= 125) IBS/FMS(n= 104) P value  
 
Gastroduodenal biopsy    
  IELs count x 100        epithelial cells 15 (10) 27 (26) <0.001 
  Marsh-0 105 (84) 39 (37) <0.001 
  Marsh-1 20 (16) 58 (56) <0.001 
  Marsh-3 2 (2) 7 (7) <0.001 
  Helicobacter Pylori (+) 58 (46) 44 (42) 0.080 
CD Lab biomarkers    
  HLA-DQ2 A1/B1 (+) 30 (24) 52 (50) <0.001 
  IgA anti tTG-2 serum     levels, U/ml 0.4 (0.1) 4.7 (20) <0.001 

Data expressed as total and percentage of the total value, or mean and standard deviation.  IBS= Irritable Bowel Syndrome. IBS/FMS= Irritable Bowel Syndrome plus Fibromyalgia Syndrome. CD= Celiac Disease. IELs= Intraepithelial lymphocytes count x 100 epithelial cells in duodenal biopsy samples. HLA= Major Histocompatibility Complex Class II. IgA= immunoglobulin A. tTG= tissue Transglutaminase.

 

Table 3. Distribution of ILEs count, Helicobacter Pylori positive biopsies, HLAQ2 A1/B1 haplotypes, and tGT-2 serum levels in IBS and FMS subgroups.

  IBS(n= 125) IBS/FMS cases  (n= 104),Classified by Marsh’s stages P value(Marsh-1/3 vs. Marsh-0)
Normal mucosa[Marsh-0](n= 39) Lymphocytic enteritis[Marsh-1](n= 58) Villous atrophy[Marsh-3](n= 7)
IELs count x 100 epithelial cells 15 (10) 14 (2) 35 (5) 37 (5) <0.001
Helicobacter Pylori (+) 58 (46) 17 (43) 24 (41) 3 (43) 0.159
HLA-DQ2 A1/B1 (+) 30 (24) 15 (38) 31 (53) 6 (86) 0.052
IgA anti tTG-2, U/ml 0.4 (0.1) 0.5 (0.1) 0.9 (0.7) 60.4 (52) 0.001

Data expressed as mean and standard deviation, or total and percentage of the total value.

 

The results of this study clearly show that as a whole, IBS/FMS patients scored much worse in quality of life and VAS scores than those with isolated IBS (p < 0.001). Seven subjects (6.7%) from the IBS/FMS group displayed HLA-DQ2/HLA-DQ8 positivity, high tTG-2 serum levels and duodenal villous atrophy, concordant with CD. Interestingly enough, these seven patients were started on a gluten-free diet (GFD), showing a remarkable improvement in their digestive and systemic symptoms on follow-up.

 

Table 4. Main symptoms, associated diseases, tender points, FIQ, HAQ, SF-36 and VAS scores.

  IBS(n= 125) IBS/FMS(n= 104) P value(IBS Vs FMS) IBS/FMS casesClassified by Marsh’s stages P value(Marsh-1/3Vs. Marsh-0)
Marsh-0(n= 39) Marsh-1(n= 58) Marsh-3(n= 7)
Widespread pain —- 104 (100) NA 39 (100) 58 (100) 7 (100) 1.000
Digestive complaints 125 (100) 104 (100) 1.000 39 (100) 58 (100) 7 (100) 1.000
Fatigue 31 (25) 94 (90) <0.001 35 (90) 53 (91) 6 (86) 0.878
Sleep disturbances 28 (22) 87 (84) <0.001 29 (74) 52 (89) 6 (86) 0.134
Anxiety/depression 77 (62) 69 (66) 0.273 22 (56) 42 (72) 5 (71) 0.251
Skin problems ^ 31 (25) 52 (50) <0.001 20 (51) 28 (48) 4 (57) 0.888
Cognitive dysfunction 5 (4) 37 (36) <0.001 14 (36) 20 (34) 3 (43) 0.908
Urinary urgency 6 (5) 30 (29) <0.001 10 (26) 18 (31) 2 (29) 0.848
Headaches 24 (19) 29 (28) 0.082 5 (13) 21 (36) 3 (43) 0.028
Balance problems/dizziness 9 (7) 29 (28) <0.001 10 (26) 17 (29) 2 (29) 0.924
Joint stiffness 2(2) 27 (26) <0.001 9 (23) 16 (28) 2 (29) 0.872
Paresthesias 4 (3) 25 (24) <0.001 9 (23) 14 (24) 2 (29) 0.952
Osteoporosis 7 (6) 14 (13) 0.034 2 (5) 10 (17) 2 (29) 0.110
TMJ disorder       —– 13 (12) NA 5 (13) 6 (10) 2 (29) 0.520
Restless legs —– 13 (12) NA 3 (8) 8 (14) 1 (14) 0.277
Sjögren Syndrome —– 8 (8) NA —– 7 (12) 1 (14) NA
Raynaud Syndrome 1 (1) 5 (5) 0.069 —– 5 (9) 1 (14)  NA
Tender Points(scale 0-18)      —— 16.1 (1.9) NA 14.8 (1.2) 16.9 (1.8) 16.3 (2.4) <0.001
FIQ(scale 0-80) —— 68 (9) NA 63 (7) 70 (9) 74 (3) <0.001
HAQ(scale 0-3)      —— 1.5 (0.6) NA 1.4 (0.5) 1.6 (0.6) 1.7 (0.6) 0.298
SF-36 physical (scale 0-100) 44 (13) 29 (5) <0.001 30 (7) 29 (1) 27 (4) 0.380
SF-36 mental(scale 0-100) 41 (13) 29 (14) <0.001 35 (10) 25 (13) 17 (4) <0.001
VAS fatigue(scale 0-10) 3 (1) 7 (2) <0.001 7 (0.8) 8 (1.5) 8 (0.3) 0.006
VAS digestive(scale 0-100) 31 (12) 47 (8) <0.001 46 (9) 47 (9) 48 (2) 0.516
Gastrointestinal symptoms  duration, years 29 (5) 29 (7) 0.917 29 (5) 29 (8) 28 (9) 0.905
Extra-intestinal systemic symptoms duration, years     —— 9 (2) NA 9 (2) 9 (2) 7 (4) 0.813

Data expressed as total and percentage of the total values, or mean and standard deviation. ^ Skin problems included: itchy/dry/burning skin,  chronic urticaria, and 1 case of herpetiformis dermatitis classified as Marsh-3. Headaches included migraine, tension and mixed headache syndrome. TMJ= Temporo-Mandibular Joint disorder. FIQ= Fibromyalgia Impact Questionnaire. HAQ= Health Assessment Questionnaire. SF-36= Short Form Health Survey. VAS= Visual Analogue Scale. NA=Not Applicable.

 

The findings of this case-finding study indicate that some misdiagnosed IBS/FMS patients could have underlying CD, which could contribute to IBS/FMS symptom development and maintenance. If they were replicated in the future with more potent studies, our observations could have pivotal therapeutic connotations, because one of the most disappointing aspects of FMS therapy is that only a small number of patients experience substantial relief when treated with the available US Food and Drug Administration [FDA], approved medications (that is, pregabalin, duloxetine and milnacipran), but a great number of patients discontinue their treatment because of drug-related adverse effects or its low effectiveness.

 

Table 5. Most frequently prescribed drugs.

  IBS(n= 125) IBS/FMS(n= 104) P value(BIS Vs. FMS) IBS/FMS casesclassified by Marsh’s stages P value(Marsh-1/3Vs. Marsh-0)
Marsh-0(n= 39) Marsh-1(n= 58) Marsh-3(n= 7)
Analgesics* 22 (18) 85 (82) <0.001 34 (87) 45 (78) 6 (86) 0.468
Omeprazole 102 (82) 82 (79) 0.360 29 (74) 47 (81) 6 (86) 0.659
Antidepressants^ 30 (24) 70 (67) <0.001 25 (64) 40 (69) 5 (71) 0.857
Pregabalin 4 (3) 60 (58) <0.001 19 (49) 36 (62) 5 (71) 0.319
Benzodiazepines/Hypnotics 55 (44) 59 (57) 0.037 20 (51) 35 (60) 4 (57) 0.677
Antispasmodic/Antidiarrheal 58 (46) 52 (50) 0.341 17 (38) 33 (57) 2 (29) 0.220
Laxatives 14 (11) 42 (40) <0.001 10 (26) 27 (47) 5 (71) 0.027
Opiate patches —– 17 (16) NA    1 (2) 12 (21) 4 (57) <0.001
Number of drugs prescribed per patient/day 1.8 (1.1) 4.6 (2.2) <0.001 3.9 (1.9) 4.9 (2.2) 6.6 (1.5) 0.003

Data expressed as total value and percentage of the total value, or mean and standard deviation. *Analgesics were usually used on irregular basis (on demand), and generally consisted on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Paracetamol, Tramadol, Metamizol and Codeine. ^Antidepressants: Tricylcic Antidepressant (TCA), Selective Serotonin Reuptake Inhibitors (SSRIs), other antidepressant. Antispasmodics: Mebeverine and/or Octilonium bromide; Antidiarrheal: Loperamide, Diphenoxylate/Atropine.  NA= Not Applicable.

 

The detection of CD-IBS/FMS-like index cases implies that decisive therapeutic and preventative actions be taken for these patients and their relatives with silent or symptomatic, but not yet diagnosed, CD. These measures would include the implementation of a gluten-free diet (GFD), which can potentially improve symptoms, reverse the intestinal mucosal pathological changes and prevent longterm CD-related complications.

 

Table 6. Laboratory Hematological and Biochemical findings.

  IBS(n= 125) IBS/FMS(n= 104) P value(IBS Vs. FMS) IBS/FMS casesClassified by Marsh’s stages P value(Marsh-1/3Vs. Marsh-0)
Marsh-0(n= 39) Marsh-1(n= 58) Marsh-3(n= 7)
Haemoglobin, g/dl 13 ( 1) 13 (1)    1.000 13 (1) 14 (1) 13 (1) 0.271
WBC count, n x 103 7.6 (1) 7.0 (2) 0.002 7.6 (1) 6.7 (2) 5.8 (2) 0.002
Platelets count, n x 103 272 (37) 257 (54) 0.021 274 (37) 248 (60) 232 (57) 0.010
Prothrombin activity % 98 (5) 98 (9) 0.777 98.2 (8) 98 (10) 98 (4) 0.741
aPTT, seconds 34 (2) 35  (2) 0.024 35 (2) 33 (2) 33  (1) 0.019
Fibrinogen, mg/dL 261 (111) 349 (152) <0.001 259 (113) 385 (128) 552 (218) <0.001
Glucose, mg/dL 108 (27) 101 (20) 0.018 109 (27) 96 (13) 99 (9) 0.020
Urea, mg/dL 44 (23) 40 (14) 0.022 43 (21) 38 (7) 38 (8) 0.017
CK, IU/L 59 (7) 60 (9) 0.985 58 (7) 61 (10) 62 (12) 0.276
CRP, mg/L 0.6 (0.6) 0.5 (0.6) 0.211 0.6 (0.7) 0.5 (0.7) 0.3 (0.2) 0.466
IgG, g/L 9.7 (0.5) 9.9 (1.0) 0.098 9.6 (0.5) 10.2 (1.2) 9.6 (1.0) 0.107
IgA, g/L 2.4 (0.5) 2.6 (0.6) 0.126 2.4 (0.6) 2.7 (0.6) 2.4 (0.5) 0.008
IgM, g/L 1.8 (0.4) 1.9 (0.5 ) 0.126 1.9 (0.3) 1.9 (0.6) 1.6 (0.5) 0.722
Iron, mcg/ml 68 (19) 80 (29) 0.001 66 (20) 89 (32) 91 (21) <0.001
Ferritin, ng/ml 56 (23) 88 (164) 0.821 48 (28) 114 (214) 90 (70) 0.064
TSI, mcg/dl 20 (11) 24 (9) 0.001 20(11) 25 (8) 25 (6) 0.001
Cholesterol , g/dl 176 (24) 174 (39) 0.293 192 (18) 166 (42) 144 (52) 0.001
AST, IU /L 20 (9) 23 (9) <0.001 21 (5) 25 (11) 30 (20) 0.269
ALT, IU/L 21 (6) 25 (13) 0.803 21 (7) 27 (17) 19 (10) 0.765
GGT, IU/L 23 (20) 28 (23) 0.074 24 (20) 31 (22) 23 (33) 0.060
ALP, IU/L 70 (23) 76 (26) 0.012 74 (30) 78 (23) 77 (22) 0.066
Bilirubin, mg/dL 0.7 (0.2) 0.8 (0.2) 0.639 0.7 (0.1) 0.7 (0.2) 0.9 (0.24) 0.591
TSH, µU/mL   1.8 (0.6) 3.1 (5.9) 0.209 1.9 (0.7) 4.1 (7.8) 1.2 (0.8) 0.157
Folate, ng/dl 10 (4) 9 (3) 0.019 10 (3) 8 (3) 10 (5) 0.019
B12 vitamin, pg/ml 451 (168) 521 (206) 0.002 450 (170) 555 (213) 636 (238) 0.001
RF, IU/ml. 13 (1) 13 (2) 0.858 13 (1) 13 (2) 14 (2) 0.775
ANAs (+) 4 (3) 29 (28) <0.001 3 (8) 23 (40) 3 (43) 0.002
   Titre              
   1/160 4 (3) 23 (22) <0.001 4 (10) 18 (31) 1 (14) 0.004
   1/320 —– 3 (3) NA —– 2 (3) 1 (14) NA
   1/640 —– 3 (3) NA —– 2 (3) 1 (14) NA
   Staining pattern              
   Speckled 4 (3) 25 (24) <0.001 4 (10) 21 (34) —– NA
   Homogenous —– 2 (2) NA —– 1 (2) 1 (14) NA
   Nucleolar —– 2 (2) NA —– —– 2 (29) NA
Anti-TPO (+) —– 12 (11) NA —– 10 (17) 2 (29) 0.011
Serum levels, IU/mL —– 31 (108) NA —– 51 (140) 40 (72) NA
AMAS (+) —– 5 (4) NA —– 4 (7) 1 (0) NA
    Titre              
    1/160 —– 1 (1) NA —– 1 (2) —– NA
    1/320 —– 2 (2) NA —– 1 (3) 1 (14) NA
    1/640 —– 2 (2) NA —– 2 (3) —–  NA

Values expressed as mean, and standard deviation, or total value and percentage.  WBC= White Blood Cell count. aPTT= Activated Partial Thromboplastin time. CK= Creatine Kinase. CRP= C-Reactive Protein. Ig= Immunoglobulin. TSI= Transferrin Saturation Index. AST= Aspartate Amino-Transferase. ALT= Alanine Amino-Transferase. GGT= Gamma Glutamyl Transpeptidase. ALP= Alkaline Phosphatase. TSH= Thyroid-Stimulating Hormone. RF= Rheumatoid Factor. ANAs= Anti-Nuclear antibodies. Anti-TPO= Anti-Thyroid Peroxidase antibodies. AMAs= Anti-Mitochondrial antibodies. NA=Not Applicable.

 

In addition, it is important to provide genetic counselling to patients and their families to help them understand the medical, psychological and familial implications of this disease; educate them about management, inheritance, prevention,testing and identification of reliable sources of information and products; and support adherence to a lifelong GFD regimen.

 

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