Prevalence of Coeliac Disease in Adult Saudi Patients with Symptoms of Irritable Bowel

Syndrome; pilot study.

Shendy M. Shendy* and Nihal Al-Assaly** , Naema I. El-Ashry**.

*Tropical, Hepatology and gastroenterology department, **Clinical biochemistry dep, Theodor Bilharz research Institute.

-Accepted for publication in Journal of Arab Society for Medical Research (JASMR), 29- 12- 2006

Abstract

Few recent studies have found higher prevalence of coeliac disease among patients with diagnosis of irritable bowel syndrome (IBS) than general population (3-11% vs. 0.2-0.6%). Similar studies showed that coeliac disease is as common in Middle Eastern countries as in Europe; in both the general population and at-risk groups. The aim of this work is to estimate the prevalence and the potential clinical consequences of coeliac disease testing in adult Saudi patients with IBS. Materials and methods: This is a prospective pilot study including 320 Arab patients with features compatible with IBS as defined by Rome III criteria without any other co-morbidity. The age of patients ranged between18-70 years. All patients were subjected to good history taking, clinical examination, and some investigations if needed such as stool, urine, CBC, liver enzymes, kidney function tests, ECG, electrolytes, H pylori serology, upper and lower endoscopy when indicated. Those diagnosed as having persistent criteria of IBS were tested for coeliac disease by IgA and IgG anti-gliadin antibodies, anti endomysial antibodies (EMA) IgA and anti-TG2 (IgA and IgG). Upper endoscopy and duodenal biopsies were done and gluten free diet was implemented for only those with positive serological test. The same tests were repeated after period of about 6 months. Results: Anti-gliadin antibodies were found positive in 15/320(4.69%) patients (14 with IgA and 13 IgG), EMA IgA in 13/320 (4.06%), anti-TG2 IgA in 12/320 (3.76%) and anti- TG2 IgG in 13/320 (4.06%). Abdominal pain, diarrhea, dyspepsia, postprandial distress, epigastric pain, distension and chronic diarrhea were significantly higher and more common in combinations in those with positive serology in comparison to serologically negative patients (P < 0.05). Haemoglobin level, serum iron, albumin and calcium were found to be significantly lower in those with positive serology in comparison to serologically negative patients (P < 0.05). All these parameters improved significantly after gluten free died (GFD) for about 6 months (P< 0.05). Only 11 patients (74.44% of those with positive serology and 3.49% of total patients) were diagnosed by biopsies as compatible with coeliac disease of which, two patients

have family history of coeliac disease in first degree relatives. After gluten free died (GFD) for about 6 months, seroconversion to negative tests occurred in 6 patients for AGA-IgA, 4 for AGA- IgG, 3 for EMA IgA, 5 for Anti-TG2 IgA and 5 for Anti-TG2 IgG. Also, the grade of histopathology showed complete healing in 4 patients and improvement to lower grades in 4 patients after GFD. Worsening occurred in one case and still 7 cases showed the same grade of the disease. Conclusion: It is concluded from this study that minimally symptomatic coeliac disease can easily be mistaken for IBS. The presence of many persistent gastrointestinal symptoms in addition to the lower serum levels of some nutritional parameters must alert the physicians to screen for coeliac disease. Any serological test can be used for the screening but this must be confirmed by tissue diagnosis which is the gold standard for diagnosis. Finally, screening for coeliac disease among patients with IBS must be considered to offer better prognosis to these patients simply by gluten free diet.

Introduction:

Irritable bowel syndrome (IBS) is a highly prevalent, multi-symptomatic, gastrointestinal motility disorder that has a wide clinical spectrum. This disease is associated with gastrointestinal dysmotility and/or visceral hypersensitivity.

Recent studies suggest that the prevalence of coeliac disease, a gluten-sensitive enteropathy characterized by intestinal villous blunting and malabsorption, is 3-11% among patients diagnosed with IBS, compared with 0.02-0.65% in the general population. Coeliac disease may be present in patients with IBS-like symptoms with diarrhoea or constipation predominance, or alternating bowel habit. Recent studies showed that coeliac disease is as common in Middle Eastern countries as in Europe; in both the general population and at-risk groups, e.g. patients with irritable bowel syndrome or type 1 diabetes. Also, these studies showed that presentation with non-specific symptoms or no symptoms is as common in the Middle East as in Europe

Measurement of IgA antibody to human recombinant tissue transglutaminase (TTG) is recommended for initial testing for CD. Although as accurate as TTG, measurement of IgA antibody to endomysium (EMA) is observer dependent and therefore more subject to interpretation error. It is recommended that confirmation of the diagnosis of CD require an intestinal biopsy in all cases. Because the histologic changes in CD may be patchy, it is recommended that multiple biopsy specimens be obtained from the second or more distal part of the duodenum. There is good evidence that villous atrophy (Marsh type 3) is a characteristic histopathological feature of CD (34). The presence of infiltrative changes with crypt hyperplasia (Marsh type 2) on intestinal biopsy is compatible with CD but with less clear evidence. The presence of infiltrative changes alone (Marsh type 1) on intestinal biopsy is not specific for CD in

children. Concomitant positive serological tests for CD (TTG or EMA) increases the likelihood such an individual has CD. In circumstances where the diagnosis is uncertain additional strategies can be considered, including determination of the HLA type, repeat biopsy or a trial of treatment with a gluten-free diet (GFD) and repeat serology and biopsy. The diagnosis of CD is considered definitive when there is complete symptom resolution after treatment with a strict GFD in a previously symptomatic individual with characteristic histologic changes on small intestinal biopsy. A positive serological test that reverts to negative after treatment with a strict GFD in such cases is further supportive evidence for the diagnosis of CD.

Our aims were to estimate the prevalence and the potential clinical consequences of coeliac disease testing in adult Saudi patients with IBS.

Materials and methods:

This is a prospective pilot study evaluating adult patients attending GIT outpatient clinic in Riyadh city in SA. Those patients with symptoms suggestive of IBS and those also diagnosed after exclusion as IBS were included in the study. The study included 320 patients. All patients were Arabs. They were 184 males and 136 females. Their age ranged from 18-67 years. They were chronic patients attending the clinic for more than 6 months complaining of abdominal pain with features compatible with IBS as defined by Rome III criteria.

Exclusion criteria:1- Those with age below 18 years or above 70 years2- Presence of red flag signs or alarm features as severe unrelenting

diarrhoea, nocturnal symptoms, unintentional weight loss, haematochezia, a family history of organic gastrointestinal diseases such as IBD, celiac sprue or malignancy

3- Symptoms or signs of coeliac disease or those already on gluten free diet being diagnosed already as coeliac disease.

4- Those with other medical illnesses or on chronic medications for organic disease.

5- Those who did not agree to continue follow up and giving consent to study.

6- Females during pregnancy or breast feeding

All patients were subjected to good history taking, clinical examination, and some investigations if needed such as stool, urine, CBC, liver enzymes, kidney function tests, ECG, electrolytes, H pylori serology, upper and lower endoscopy when indicated. Those with mixed or atypical presentation were investigated properly for other diagnoses and then managed accordingly. Those diagnosed as having persistent criteria of IBS were included in the study. As serological

tests and small bowel biopsy remain the cornerstones of diagnosis of coeliac disease (23), these patients were subjected to:1- Serum IgA and IgG anti-gliadin antibodies (AGA), Anti endomysial

antibodies (EMA) IgA (The test result is reported simply as positive or negative, since even low titers of serum IgA endomysial antibodies are specific for CD) and Anti-TG2 (IgA and IgG).

2- Upper endoscopy for those with positive serology and histopathology of duodenal biopsy.

3- Gluten free diet for those with positive serology. 4- All the above tests were repeated after period of 6-12 months.

During endoscopy of patients with any positive serological tests, 4 to 6 duodenal biopsies were obtained. An experienced pathologist who was blinded to the patient’s history and antibody assay results assessed the mucosal biopsy sections for pathologic features of CD. Diagnosis of CD was made when there were an increased number of intraepithelial lymphocytes with associated subtotal or total villous atrophy (32). Histological grading was done according the conventional system which grades the mucosal findings as normal, slight partial villous atrophy, marked partial villous atrophy, subtotal and total villous atrophy and Marsh system (34) which classified the histological changes of CD as Type 0 or preinfiltrative stage (normal), Type 1 or infiltrative lesion (increased intraepithelial lymphocytes), Type 2 or hyperplastic lesion (Type 1+ hyperplastic crypts), Type 3 or destructive lesion (Type 2 + variable degree of villous atrophy) and Type 4 or hypoplastic lesion (total villous atrophy with crypt hypoplasia). Type 3 has been modified to include Type 3a (partial villous atrophy), Type 3b (subtotal villous atrophy) and Type 3c (total villous atrophy) (35).

Patients can be considered as one of two groups - 'silent' celiac disease when the patients are symptom free and serologically negative but bear the hallmarks of the disease on histological grounds, and 'latent' celiac disease when serological tests are positive but there are no or minimal histological changes, such as increased density of intraepithelial lymphocytes (IELs) (25).Statistical analysisResults were analysed using SPSS 12 for windows software.This study included 320 patients; 184 males and 136 females. Age ranged from 18-56 years

Table 1: clinical presentation in all patients. Complaints Males

N=184FemalesN=136

TotalN=320

Complaints MalesN=184

FemalesN=136

TotalN=320

Abdominal painFrequent or loose stoolHard or infrequent stoolAltered stool habitsOther stool abnormalities*

7835212632

9816462027

17651674695

Dyspepsia Postprandial distress. Epigastric painAbdominal distension Eructation.

5238644118

2218474521

74561018639

Chronic Anorexia 4 11 15

Other stool abnormalities*: straining during a bowel movement ,urgency (having to rush to have a bowel movement) , feeling of incomplete bowel movement or anorectal obstruction, passing mucus (white material) during bowel movement , abdominal fullness, bloating or swelling.

Table 2: clinical presentation in all patients according sero-positivity.Complaints Serologically

negative (n=305)

Serologically positive (n=15)

Complaints Serologically negative (n=305)

Serologically positive(n=15)

Abdominal painFrequent or loose stoolHard or infrequent stoolAltered stool habitsOther stool abnormalities

164 (53.8%)43(14.1%)66(21.6%)45(14.8%)

93(30.5%)+

12 (80.0%)*8 (53.3%)*1 (6.7%)1 (6.7%)2 (13.3%)

Dyspepsia Postprandial distress. Epigastric painAbdominal distensionEructation. Chronic Anorexia

64(21.0%)55(18.0%)91(29.8%)87(28.5%)34(14.1%)11(3.6%)

10 (66.7%)*11 (73.3%)*10 (66.7%)*9 (60.0%)*5 (33.3%)*4 (26.7%)*

Significantly higher in comparison to serologically negative (P < 0.05).

Table 3: clinical presentation in sero-positive patients before and after Gluten Free Diet (GFD):

ComplaintsSerologically positive (n=15)

ComplaintsSerologically positive (n=15)

Before GFD After GFD Before GFD After GFDAbdominal painFrequent or loose stoolHard or infrequent stoolAltered stool habitsOther stool abnormalities

12 (80.0%)8 (53.3%)1 (6.7%)1 (6.7%)2 (13.3%)

3(20.0%) *2(13.3%) *2 (13.3%)3 (20.0%)4 (26.7%)

Dyspepsia Postprandial distress. Epigastric painAbdominal distensionEructation. Chronic Anorexia

10 (66.7%)11 (73.3%)10 (66.7%)9 (60.0%)5 (33.3%)4 (26.7%)

4 (26.7%) * 2 (13.3%) *3 (30.0%) *2 (13.3%) *

1 (6.7%)1 (6.7%)

* Significant decrease in the number of patients after GFD in comparison to before GFD (P < 0.05).

Table 4: Haemoglobin, serum iron, and liver enzymes in serologically negative and serologically positive patients before and after gluten free diet.

Factor Serologically negative patients

Serologically Positive patients

At diagnosis At diagnosis After GFDHb (g/dl) 14.53 ± 03.45 13.21 ± 3.72* 14.25 ± 3.25+S. iron (μg/dl) 72.63 ± 29.32 55.65 ±23.72* 65.34 ±20.76+ALT (units/dl) 25.61 ± 11.34 27.23 ± 13.52 26.53 ± 13.84AST (units/dl) 22.16 ± 10.35 26.35 ± 11.72 24.73 ± 11.51Alk. Phosphatase (U/dl)

* Significant differences in comparison with serologically negative patients at diagnosis (P< 0.05).+ Significant differences in comparison with serologically positive patients at diagnosis (P< 0.05).

Table 5: Blood levels of albumin, calcium, cholesterol and triglycerides in serologically negative and serologically positive patients before and after gluten free diet.Factor Serologically negative

patientsSerologically Positive patients

At diagnosis At diagnosis After GFDS. albumin (g/dl) 4.30 ± 00.65 3.51 ± 00.71* 4.22 ± 0.51+S calcium (mg/dl) 10.13 ± 1.20 8.35 ± 1.41* 9.02 ± 4.52+Blood Cholesterol (mg/dl)

169.50 ±21.37 151.28±23.56 158.40±22.64

Triglycerides (mg/dl) 153.28 ± 32.62 146.53±28.35 150.24 ±23.52* Significant differences in comparison with serologically negative patients at diagnosis (P< 0.05).+ Significant differences in comparison with serologically positive patients at diagnosis (P< 0.05).

Table 6: the results of serology in all patientsSerological tests total Positivity Positivity (males) Positivity (female)Anti-gliadin antibodies (IgA/G) 15/320 (4.69% 7 (2.19%) 8 (2.50%)EMA IgA 13/320 (4.06%) 6 (1.88%) 7 (2.19%)Anti-TG2 IgA 12/320 (3.76%) 5 (1.57%) 7(2.19%)Anti- TG2 IgG 13/320 (4.06%) 6 (1.88%) 7 (2.19%)

Table 7: IgA and IgG anti-gliadin antibody titres in those with positive tests (15 patients):IgA anti-gliadin titre IgG anti-gliadin titre

Optical densityNumber of patients Optical

densityNumber of patients

At the diagnosis After GFD At the diagnosis After GFD>0.8750.75-0.8750.625–0.750.5–0.6250.375–0.50.25–0.3750.125–0.250.0–0.125 (-)*

52133001

01122125

>1.00.9-1.00.8–0.90.7–0.80.6–0.70.5–0.60.4–0.50.3–0.40.1-0.3

0.0-0.1 (-)*

3221121102

0011013117

Titre is expressed as optical density. GFD: gluten free diet. 14 patients were positive for IgA, and 13 were positive for IgG. Those who were negative for any of them are positive for the other. * = negative values

Table 8: Serology and histopathology in all positive cases (Before/After GFD):

AGA EMA IgA

Anti-TG2Histopathology (Marsh

classification)**

IgA IgG IgA IgGAt

diagnosisAfter GFD*

12

3 +45678910

11+12131415

Total

+/++/-+/++/-+/-+/++/++/-+/--/-

+/++/++/++/++/-

14/8

+/++/++/++/+-/-+/++/++/-+/-+/-+/++/+-/-+/++/-13/9

+/++/++/++/-+/-+/++/++/-+/+-/-+/++/+-/-+/++/+13/10

+/-+/++/-+/+-/-+/-+/++/++/+-/++/-+/--/-+/++/-12/7

+/-+/++/++/++/-+/++/++/-+/--/++/-+/+-/-+/++/-13/8

Type 1Type2Type3aType 1NormalType3bType2Type2 Type 1NormalType1Type2NormalType2Normal

11

NormalType 2NormalNormalNormalType 2Type 2Type 1Type2NormalNormalType 1NormalType1Normal

7

positivity

After gluten free died for about 6 months, seroconversion to negative tests occurred in 6 patients for AGA-IgA, 4 for AGA- IgG, 3 for EMA IgA, 5 for Anti-TG2 IgA and 5 for Anti-TG2 IgG. * GFD: gluten-free diet. + these patients have family history of coeliac disease in first degree relatives.

It is clear from these results that patients number 10, and 13 were only positive for one test (IgG-AGA and IgA-AGA respectively) and patient number 5 is positive for three of the five tests; IgA AGA, EMA and IgG anti-TG2. The three patients showed normal histopathology in addition to patient number15. Thus, only 11 patients (74.44% of those with positive serology and 3.49% of total patients) were diagnosed by biopsies as compatible with coeliac disease. Two patients have family history of coeliac disease in first degree relatives. One of them; patient number 3 was found to have positive serology for all tests and type 3a histopathology. The other patient had similar serology but type 1 histopathology. All patients with positive serology were subjected to GFD for at least 6 months. Then all serological tests and tissue biopsies were repeated and showed some improvement.

Table 9: Summery of histopathological findings in the 15 AGA positive patients:

Normal Positive histopathologyType 1 Type 2 Type 3 Type 4 Total

At diagnosis 4 4 5 2 0 11 (74.44%)After GFD 8 3 4 0 0 7 (46.67%)

The grade of histopathology showed complete healing in 4 patients and

improvement to lower grades in 4 patients (one type 3 changed to type 1 and 3 cases of type 2 changed to type 1). Worsening occurred in one case from type 1 to type 2. 7 cases still showed type 1 or type 2 diseases.

It is concluded from this study that minimally symptomatic coeliac disease can easily be mistaken for IBS. The presence of many persistent gastrointestinal symptoms in addition to signs and lower serum levels of some nutritional parameters must alert the physicians to screen for coeliac disease. Any serological test can be used for the screening but this must be confirmed by tissue diagnosis which is the gold standard for diagnosis of this disease. Finally, screening for this disease among patients with IBS must be considered to offer better prognosis to these patients simply by gluten free diet.