CELIAC DISEASE AMONG GASTROINTESTINAL PATIENTS IN YEMEN: ITS PREVALENCE, SYMPTOMS AND ACCOMPANYING SIGNS, AND ITS ASSOCIATION WITH AGE AND GENDER

Omar Ahmed Ismael Al-dossary1image, Redhwan A. Ahmed1,2image, Khaled Abdulkareem A Al-Moyed1image,  Azhar Azher Mohammed Al-Ankoshy3image, Mohammed Mohammed Ali Al-Najhi4image, 

Hassan Abdulwahab Al-Shamahy1,5image

1Medical Microbiology and Clinical Immunology Department, Faculty of Medicine and Health Sciences, Sana’a University, Republic of Yemen.

2Laboratory Department, University of Science and Technology Hospital, Sana'a, Yemen.

3Jabir ibnHayyan Medical University, Faculty of Medicine/Iraq 

4Orthodontics, Pedodontics and Prevention Department Faculty of Dentistry, Genius University for Sciences & Technology, Dhamar city, Republic of Yemen. 

5Medical Microbiology department, Faculty of Medicine, Genius University for Sciences & Technology, Dhamar city, Republic of Yemen.

ABSTRACT 

Background and objectives: Celiac disease is a long-standing autoimmune illness that principally affects the small intestine. Typical symptoms comprise digestive problems such as chronic diarrhea, flatulence, malabsorption, loss of appetite, and failure of children to grow normally. The prevalence of celiac disease has not been established in Yemen, either in the general population or in symptomatic patients. Therefore, the current study aimed to assess the prevalence of disease in symptomatic patients and to investigate associated symptoms and signs; and whether prevalence of CD varies greatly between different ages and genders in a hospital in Sana'a.  

Methods: A cross sectional study based on the results of serological markers; IgA anti-tissue glutaminase and small bowel biopsies of 600 patients with gastrointestinal symptoms who were all patients who attended in the research period. Data were collected from hospital records during the period from March 2014 to December 2018. Total 600 suspected patients (245 males and 355 females) were subjects and the mean age of ±SD patients was 30.6±14.5 years (range 2-92 years). 

Results: The prevalence of CD among patients with gastrointestinal symptoms was 9.2%. There was a significant association between CD with females (rate being 11.3%, OR=1.9, p=0.03), and  2-19 years age group (21.4% , OR=4.3, p<0.001), considering the clinical signs and symptoms there was a significant association between celiac disease and chronic diarrhea (OR=18.4), steatorrhea (OR=9.6), foul odor (OR=8.3), weight loss (OR=5.7), anemia (OR=10.2), abdominal distension (OR=3.1), mouth ulcers (OR=7.2), abdominal bleeding (OR=13.5), diabetes mellitus I (OR=18), and hypothyroidism (OR=79.3).

Conclusion: A high rate of CD was identified among gastrointestinal symptoms patients arriving at the general hospital in Sana’a, Yemen, and this demonstrates the importance of general practitioners in identifying patients with CD, especially in the absence of a medical facility for CD, and this was facilitated through the serological markers test. 

Keywords: Celiac disease (CD), prevalence, signs, symptoms, Yemen.

 

INTRODUCTION

 

Celiac disease or Coeliac disease (CD), is a continuing autoimmune illness that mainly involves the small intestine. Typical symptoms comprise digestive problems for instance chronic diarrhea, flatulence, loss of appetite, malabsorption, and failure of children to grow normally. This regularly begins between six months and two years of age. Non-classical symptoms are more frequent, in particular in people older than two years. Moderate or absent gastrointestinal symptoms may be present, a large number of symptoms relating any part of the body, or no apparent symptoms. CD was first illustrated in childhood; nevertheless, it may arise at all ages. It is also linked with autoimmune diseases, for instance Hashimoto's thyroiditis and type 1 diabetes1.  CD results from a reaction with gluten, which is a group of different proteins found in wheat and other grains such as barley and rye. Moderate amounts of oats, free from pollution with further gluten-containing grains, are regularly tolerated2. The incidence of harms may depend on the type of oats. CD appears in people with a genetic predisposition. When exposed to gluten, the abnormal immune response may result in the production of many different auto-antibodies that can involve a number of distinct organs. In the small intestine, this causes an inflammatory reaction and may lead to villous atrophy. This affects the absorption of nutrients, often leading to anemia3. The gold standards in diagnosing CD are bowel biopsy and positive serological markers (anti-tissue IgA (Ttg IgA) antibody and anti-endomysial)1. HLA class II DQ2 and DQ8 haplotypes are found in nearly all patients with sensitivity of nearly 100% and also in 30% to 40% of the population. On account of a very high negative predictive value, HLA typing can assist and support the exclusion of the diagnosis of CD in ambiguous cases in which the patient not has HLA-DQ2 and DQ84. On the other hand, making the diagnosis is not continuously simple5. Often, serum autoantibodies are negative4,6, and many people have only minor changes in the intestine with normal villi.  It is reported that many people may have severe symptoms and can be explored for years before a diagnosis is made7. Currently, the diagnosis is increasingly being made in people who have no symptoms as a result of screening. However, the evidence regarding the effects of screening is not sufficient to determine its usefulness. While this disease is caused by a persistent intolerance to gluten proteins3, it differs from wheat allergy which is known to be very rare.

Epidemiologically, CD affects about 1 in 100 to 1 in 300 of the world's population1. This rate may be increased among those at risk; Like first-degree relatives: 1 in 10, or like second-degree relatives: 1 in 39 and 1 in 56 in asymptomatic patients1. Moreover, the prevalence of CD among unexplained iron deficiency anemia’s is 3% to 15%, 2% to 15% among type 1 diabetes, 2% to 7% among hypothyroidism, 3% to 6% among Addison's disease , and autoimmune hepatitis, 3% among irritable bowel syndrome, ataxia, and idiopathic neuropathy1. Studies in gastroenterology and/or autoimmune diseases are still limited in Yemen and only a few studies have been conducted on autoimmune hepatitis9,10 and the relationship between CD and infertility by measuring sex hormones in CD compared to controls healthy11, anti-mannose auto-antibodies in patients with rheumatoid arthritis12, and intestinal infection among adults and children13-15.  At present, the only effective treatment is to follow a gluten-free diet for life. There is no medicine that prevents damage or prevents the body from attacking the intestines when gluten is present. Strict adherence to the diet helps to heal the intestines, which in most cases resolves all symptoms, and depending on when the diet is started, the risk of osteoporosis, bowel cancer and, in some cases, infertility can also be eliminated. Diet can be stressful; failure to comply with the diet may lead to relapse16.  The prevalence of CD has not been established in Yemen, either in the general population or in symptomatic patients. Therefore, the current study aimed to assess the prevalence of disease in symptomatic patients and to investigate associated symptoms and signs; and whether prevalence of CD varies greatly between different ages and genders. 

 

SUBJECTS AND METHODS 

 

Study design and setting

This cross sectional study was conducted at the University of Science and Technology Hospital (USTH) in Sana'a, Yemen. USTH is one of the main hospitals in Yemen, which receives patients from all over the country and also the city of Sana'a is the capital of Yemen. For these factors, the results of this study may represent the whole country.

Data collection

600 symptomatic patients were enrolled in this study. Among them, 245 (40.8%) males and 355 (59.2%) females attended pediatric clinics, internal medicine clinics, and gastroenterology units for medical care in USTH from March 2014 to December 2018. Data were obtained from electronic patient records after approval of the hospital ethics committee. By enzyme-linked immunosorbent assay (ELISA), positive ATtg IgA criteria greater than 10 times the  upper  limit of  normal (ULN) in children or less than 10 times the ULN but confirmed by small bowel biopsy, were the criteria used to measure the prevalence of celiac disease. Hemoglobin levels (to define anemia based on a hemoglobin concentration less than 11 g/dL) were also included. The subjects were divided into categories based on gender and age. Clinical signs, symptoms and other diseases associated with celiac disease were also collected and analyzed.

Data analysis

The whole data were analyzed by IBM SPSS Statistics 22. Ink (International Business Machines Corporation, New York, USA). The outcomes for variables were given in the form of rates (%). Chi Square was used for categorical variables that measured association among categorical variables. P-values less than 0.05 were considered significant. Odds of celiac disease (odds ratio, OR) were also analyzed by sex, age groups, symptoms, signs and other syndromes, with 95% CI, X2 and p to test for significance of association with the above factors.

 

RESULTS

 

Table 1 shows the age and gender distribution of patients with gastrointestinal symptoms admitted to the University of Science and Technology Hospital, Sana'a, Yemen - during the period from March 2014 to December 2018 who underwent examination for serological markers; Anti-tissue IgA glutaminase and small intestine biopsies for CD. The percentage of females was 59.2% compared to 40.8% for males. Looking at the age groups, most patients were in the age group 20-40 years (58.2%), followed by 2-19 years (21%) and 41-60 years (18%), while the >60 years group was only 2.8%. 

Table 2 shows the prevalence of serological markers. Anti-tissue IgA glutaminase and small bowel biopsies for CD among different sex and age groups of patients with gastrointestinal symptoms. The prevalence of CD among patients with gastrointestinal symptoms was 9.2%. 

 

Table 2: Serological Markers; Anti-tissue IgA glutaminase and small bowel biopsies for celiac disease among different patients with intestinal symptoms.

Considering gender, there was a significant association between celiac disease and females with the rate being 11.3% with an odds ratio equal to 1.9, CI equal to 1.1–3.9 (p=0.03). Considering ages, there was a significant association between celiac disease with 2-19 years as the rate was 21.4% with an odds ratio equal to 4.3, CI equal to 2.4-7.6 (p<0.001), while there was no association between CD and age groups other. Considering the clinical signs and symptoms associated with intestinal symptoms compared to CD (Table 3), there was a significant association between celiac disease and chronic diarrhea (odds ratio=18.4 times), steatorrhea ( OR=9.6), foul odor (odds ratio=8.3 times), weight loss (Odds ratio=5.7 times), anemia (odds ratio=10.2 times), abdominal distension (odds ratio=3.1 times), mouth ulcers (odds ratio=7.2 times), abdominal bleeding (odds ratio=13.5 times), diabetes mellitus I  (odds ratio=18 times), and hypothyroidism (odds ratio=79.3 times). 

Table 3: Clinical signs and symptoms associated with intestinal symptoms compared to celiac disease patients.

 

DISCUSSION

 

CD is an immune condition mediated by systemic disease of the small intestine.  Symptoms interrelated to mal-absorption and/or activation of immunity and auto-antibodies to tissue transglutaminase (TTG). CD is distinctive amongst autoimmune diseases in that a generate, dietary gluten, has been recognized, and its removal resolves symptoms and enteropathy in the greater part of patients. Increased knowledge and development of serological tests have led to an increased incidence of disease and a change in the distribution of clinical features1 . In Yemen, its prevalence has not yet been estimated, and current work is an attempt to determine the rate of CD among clinically suspected patients. The prevalence of celiac disease among patients with gastrointestinal symptoms in the current study was 9.2%. Compared with current observations, the prevalence of CD in Yemen exceeds the rate of CD among suspected Finns 5.33% among patients with gastrointestinal symptoms17 and other previous rates of disease as in Saudi Arabia, South Yorkshire, Amsterdam, the Netherlands and in North America are among the symptoms gastrointestinal representing; 7.6%, 4.7%, 3.0% and 2.0%, respectively18-21. On the other hand, results similar to ours were presented by Dickey et al., and Hopper et al.,22, 23 where the incidence of CD among patients with undiagnosed gastrointestinal symptoms was about 9%. In contrast to the average (9.2%), the prevalence of CD among Iranian patients with irritable bowel syndrome was about 12% and among patients with gastrointestinal symptoms in Italy was about 13% as reported by Shahbazkhani et al., and Carroccio et al., respectively24,25. Considering gender, there was a significant association between CD and females with a rate of 11.3% (OR=1.9 (CI=1.1-3.9, p=0.03) (Table 2). 

This result is similar to that reported where the incidence of CD is higher in females than in males (17.0 versus 7.8 per 100,000 person-years) in collective analysis26 , but this may be for the reason that men are more possible to remain undiagnosed. A systematic review and meta-analysis found a slight increase in seropositivity among women participating in screening studies27  although some studies in adults have found that men and women have the same seroprevalence rates28,29. Men are less likely to undergo duodenal biopsy during upper endoscopy for indications such as diarrhea and weight loss, which may contribute to underdiagnosis30. CD can develop at any age, including the elderly31. Considering age in the current study, there was a significant association between celiac disease and age group 2-19 years where the rate was 21.4% with an OR equal to 4.3, CI equal to 2.4-7.6 (p< 0.001) (Table 2). This is similar to what has been previously reported where the incidence of CD was higher in the younger age group. This rise in CD at a young age can be explained by the fact that such diagnoses do not necessarily indicate the late detection of CD long ago - it may result from a de novo loss of gluten tolerance. Studies of serial serum samples have reported loss of gluten tolerance in adulthood32. However, recent prospective cohort studies have found that most patients develop CD before the age of 10 years33,34. Moreover, in the current study, the prevalence of anemia was widespread (71.4%, OR=40.4 times, p<0.001) (Table 3) among ATtg IgA-positive patients in agreement with several studies35,36. These patients are more likely to have acute disease compared to non-anemic CD patients according to Daya, et al.,37. 

Once serological testing began in the 1990s, there was an expansion of clinical offerings leading to a diagnosis of celiac disease. The proportion of patients with CD who had diarrhea decreased from 73% before 1993 (the year in which serological testing became available at the study site) to 43% thereafter38. Although diarrhea continued to be the most common symptom at presentation, most patients received the diagnosis based on this on other signs or symptoms, such as osteoporosis, anemia, bloating, or irregular bowel habits; some had less common symptoms, including infertility9, migraine headaches39 neuro-psychiatric symptoms40 and abnormal liver enzyme levels41.

In the current study considering the clinical signs and symptoms associated with intestinal symptoms compared to celiac disease, there was a significant association between celiac disease and chronic diarrhea (OR=18.4), steatorrhea (OR=9.6), foul odor (OR=8.3), weight loss (OR=5.7), anemia (OR=40.4), abdominal distension (OR=3.1), mouth ulcers (OR=7.2), abdominal bleeding (OR=13.5), diabetes mellitus I  (OR=18), and hypothyroidism (OR=79.3).  These signs and symptoms combined outnumber diarrhea, so diarrhea can no longer be referred to as typical and presentation without diarrhea as atypical. As such, a 2013 consensus statement renamed diarrhea and non-diarrhea presentations as classic and non-classical celiac disease, respectively42. Regardless of the type of symptoms, there is often a long-term delay between the onset of symptoms and a diagnosis of celiac disease. A national survey of patients with celiac disease in the US found the median duration of symptoms to be 11 years before diagnosis43 and a UK study found the median duration to be 4.9 years44. In the current study, abnormal LFT occurred in 20% of CD patients, and this is lower than that performed by Castillo et al., as liver biochemical abnormalities were presented in 40% of patients newly diagnosed with celiac disease, according to Castillo et al., series the slight increases observed in aspartate and alanine transaminases are the most common abnormalities41. The incidence of CD is increasing with its worldwide spread. There is a trend towards an increased diagnosis of non-classical presentations, and there is emerging evidence for accurate non-biopsy diagnosis in selected children33. Newly developed diagnostic tools, such as the HLA-DQ-based blood test - gluten tetramer, may change the way we diagnose CD in the near upcoming, impending validation and scalability. This technology, combined with validation of serology-based diagnostic algorithms, may bring about an alteration in diagnostic criteria as small bowel biopsy is no longer essential while patients persist to follow a gluten-containing diet. These changes may convert the roles of gastroenterologists, from diagnosis to management and follow-up45. If an evidence-based, biopsy-free strategy is developed for diagnosis, the incidence of celiac disease may increase further and stimulate interventional studies for the prevention of celiac disease in individuals at risk1.

 

CONCLUSION

 

The prevalence of CD among Yemeni patients with gastrointestinal disorders was as high as 9.2%, especially among children and adolescents compared to primary care groups elsewhere in the world who reported gastrointestinal symptoms, and the incidence of celiac disease was around 3%. The disease was prevalent among females. On the other hand diagnosis by serological markers is useful in detecting CD in these patients. However, more studies are needed to support and confirm current findings and conclusions. According to this high prevalence, clinicians should pay more attention to CD when examining huge different symptoms especially among women, children and teens to avoid misdiagnosis or long-term delay diagnosis.

 

ACKNOWLEDGMENTS

 

The authors acknowledge the administration of University of Science and Technology Hospital for data supply. 

 

AUTHORS’ CONTRIBUTIONS

 

All authors contributed to the study design, analysis and manuscript writing. 

 

ETHICAL APPROVAL

 

Ethical approval was obtained from the Ethics Committee from the USTH Sana'a, Yemen.

 

CONFLICT OF INTEREST 

 

No conflict of interest associated with this work.

 

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