Document Type : Original Article
Authors
1 Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
2 Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
3 Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
4 Cancer Epidemiology Research and Treatment Center, Emam reza hospital, Tehran, Iran
5 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
6 Colorectal research center, Shiraz University of Medical Sciences, Shiraz, Iran
7 Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran
Abstract
Graphical Abstract
Keywords
Celiac disease (CD) is an immune-related condition of the small bowel followed by over sensitivity and immune reaction to the gluten's dietary protein. [1] likewise, CD is increasingly associated with other endocrinological diseases, including hypothyroidism. [2] Its prevalence varies from less than 1% in the normal population to approximately 5% in patients with autoimmune thyroidal disease (ATD). Likewise, CD and thyroid disease's coincidence was associated with genetically determined due to the common detection of human lymphocyte antigen (HLA) in some reports. [3-6]
Clinical manifestations extend from a classic malabsorption syndrome to atypical presentation such as anemia, osteoporosis, and phycological disorders. Likewise, several involved patients never indicate any disease symptoms, and only 10–20% of the histologically diagnosed CD are identified through clinical findings. [7] Furthermore, previous studies reported several cases presenting with persistent hypothyroidism who did not respond to a determinate levothyroxine dose that CD was diagnosed for them eventually. Since the management of the mentioned patients with gluten-free diet followed by subclinical CD recognition in hypothyroidism patients not only helps prevent the long-term complication of the CD but also economically viable by reducing the needed dose of levothyroxine. Moreover, autoimmune thyroiditis frequently ensues in patients medicated with alpha interferons, such as hepatitis C, and reports of interferon-alpha therapy inducing CD suggesting the interpretation of mutual etiological mechanisms between CD and autoimmune thyroiditis. [8-10]
Although, small bowel biopsy and villous atrophy observation considering as accurate and gold diagnostic methods. Given the cost and invasive nature of the biopsy, genetic and serologic laboratory tests may be used to identify individuals with a high possibility of having celiac disease. [11] In terms of serology, celiac disease is associated with various autoantibodies, including tissue transglutaminase (tTG), deamidated gliadin antibodies, and endomysial. Anti-tTG is the first diagnostic step in suspected individuals. [12]
Previous studies usually reported the prevalence of CD in autoimmune thyroiditis. We designed a study to determine the relationship between the two diseases in autoimmune and non-autoimmune and clinical and subclinical hypothyroidism.
Table 1: The baseline characteristics of patients |
||||
Variable |
Case group n=100 |
Control group n=150 |
P-value |
|
Gender
|
Male |
33 (33%)
|
30 (20%)
|
0.39a |
Female |
67 (67%) |
120 (80 %) |
|
|
Age |
|
36.8 ± 11.2 |
38.4 ± 9.6 |
0.43b |
Type of Thyrothyroidism |
Autoimmune hypothyroidism |
60 (60%) |
- |
|
non-autoimmune hypothyroidism |
40 (40%) |
- |
- |
|
Clinical hypothyroidism |
22 (22%) |
- |
|
|
Sub-clinical hypothyroidism |
78 (78%) |
- |
|
|
a chi-square test , b independent sample t-test |
|
Table 2: The prevalence of positive celiac serology in patients with hypothyroidism |
||||
Group |
Celiac status; n (%) |
P-value* |
||
Negative |
Positive |
|||
Case group |
Clinical hypothyroidism |
80 (95.2%) |
4 (4.8%) |
< 0.001 |
Sub-clinical hypothyroidism |
15 (93.7%) |
1 (6.3%) |
||
Autoimmune hypothyroidism |
61 (93.8%) |
4 (6.2%) |
< 0.001 |
|
non-autoimmune hypothyroidism |
34 (97.1) |
1 (2.9%) |
Table3: The relation between hypothyroidism and celiac serology |
|||
Celiac serology |
Study group |
P-value* |
|
Case group n=100 |
Control group n=150 |
||
Positive |
5 (5%) |
2 (1.3%) |
< 0.001 |
Negative |
95 (95%) |
148 (98.7%) |
As seen in Table 2, positive celiac prevalence is significantly higher in autoimmune and clinical hypothyroidism than in subclinical and non-autoimmune patients (P < 0.05).
The prevalence of positive serology for celiac disease in case groups and control groups is presented in table 3.
As seen in Table 3, positive serology for celiacs is significantly higher in the case group than the control group (P < 0.05). It is worth mentioning that among the case group patients with celiac disease, 4 (80%) used a daily dose of 1 mcg/day levothyroxine or higher, while 1 (20%) used a daily dose of lower than 1 mcg/day; However, there was no statistical difference among the two groups (P=0.847)
The association between CD and thyroid disorders such as hypothyroidism has been the subject of several studies. [15] Furthermore, although minor conflicts may exist in the results [16], most of these studies have focused on the relation between CD and autoimmune thyroid disease since they both have an autoimmune basis;[9] But CD can also be seen in other types of thyroid disease. This issue is especially of significance in the case of undiagnosed or subclinical celiac disease. In this study, we evaluated the prevalence of CD among specifically hypothyroid patients -and not only autoimmune thyroid disease - based on serological markers to address the question of whether it is necessary to rule out CD in hypothyroid patients.
As mentioned earlier, our results revealed that 5% of hypothyroid cases had positive serology for CD, yet the prevalence was only 1.3% in the control group, which was significantly lower than the case group hypothyroidism patients. Some variations may exist among studies regarding this issue; some reported that the prevalence of CD in hypothyroid patients is between 4-8%. [17,18] while others reported a lower incidence of this issue (1.5% to 2.5%). [14,19] These variations may have arisen from differences in the study subjects since some studies have chosen their subjects from clinical hypothyroid patients while others have restricted their research to autoimmune-hypothyroidism, congenital hypothyroidism, or those patients with only serological hypothyroidism. [20] Our study results alongside other studies show that celiac is more prevalent in all type of hypothyroid patients.
One of the important concern which follows is the higher dose requirements of levothyroxine in these patients, as our study demonstrated that 80% of celiac patients with hypothyroidism required a daily dose of 1mcg/day or more, however statistically insignificant, which may be due to the low sample size of celiac patients in our study. Different hypotheses exist, but the most important one is that celiac disease, as a gastrointestinal disease that is thought to present mainly in jejunum and ileum [18], reduces jejunal absorption of levothyroxine. [13] Therefore, an important matter to keep in mind is that in the co-existence of CD and hypothyroidism, the needed dose of levothyroxine has been shown to increase, and therefore further dose adjustments will be needed. Likewise, the subclinical and undiagnosed CD can play a role in wasting resources and increasing costs and drug-related side effects, which is problematic both for patients and the health care system. Since promising data exists about the positive effects of dietary treatment (gluten-free diet) on reducing levothyroxine dosing [7], it is critical to consider CD in hypothyroid patients, especially those resistant to the usual doses of levothyroxine. Our study results further highlight the importance of celiac screening in hypothyroid patients, although more studies with a larger sample size are required to assess the cost efficiency of this screening for all hypothyroid patients.
Additional evaluations and outcomes showed that a statistical relationship could be assumed between CD and clinical hypothyroidism in that only 20% of patients with positive celiac serology had subclinical hypothyroidism, and the rest (80%) were the cases diagnosed with clinical hypothyroidism. This means that the prevalence of CD is 4 folds higher in cases with clinical hypothyroidism. In a similar study, Mehrdad et al. [14] reported that 54.5% of patients detected with positive results of celiac serology were overt hypothyroidism. This result prompts us to consider CD more thoroughly in clinical hypothyroidism, even with atypical presentation. However, existing data about this issue is insufficient, and more information is needed to support this idea.
Our results showed that positive serology in ATD is 4 times greater than this prevalence in non-ATD (prevalence: 4.69%). Results resemblance 0f 2-5% CD in ATD were found in other studies. [19] Roy et al. [9] also concluded that CD exists in 1.6% of the total number of ATD patients. The exact pathogenesis behind this co-occurrence is unknown, but evidence suggests that genetics may play a role, and HLA antigens are the possible culprits. [19,21] Therefore, further immunopathological studies are required to assess this correlation and establish a clearer explanation because a better explanation paves the way for the development of new treatments and reduces the comorbidities in these people.
. Our study results showed that neither age nor gender has a statistical relation with celiac disease prevalence. This is in accordance with other studies. [14,19] Also, Collins et al. [13], in an attempt to compare the required dose of levothyroxine in cases suffering from CD and hypothyroid disease compared to controls with hypothyroidism, found no significant difference in age and gender between cases and controls. This cannot be applied in the case of ATD since studies have shown that younger age is related to the higher prevalence of CD in ATD patients. [9] Demographic data about hypothyroid patients with concomitant CD is not yet satisfying and more researches can help to find an answer to this question that if screening for CD would be more critical in a defined group of hypothyroid patients
Our study is one of the few case-control studies conducted in Iran about this topic. Controls were matched with cases in age and gender, therefore minimizing bias. Selection and sample bias was the major issue since our subjects included the patients referred to our clinic, so many sub clinical hypothyroid individuals remain unrecognized; therefore, they may not represent the society. Although our sample size was determined by sample size analysis, the risk assessment required a much greater sample size, and a prospective cohort study with large sample size is suggested to overcome the insufficiencies and assess risks precisely.
While undiagnosed and untreated CD causes comorbidities in hypothyroid patients, timely CD diagnosis and treatment diminishes the complications that were caused. Considering the significant relation and growing prevalence, it seems logical to design a screening program to detect CD in hypothyroid patients, especially the clinical ones with autoimmune hypothyroidism, especially those who require higher doses of levothyroxine.
Data Availability
SPSS data of the participant can be requested from the authors. Please write to the corresponding author if you are interested in such data.
Conflict Of Interest
The authors declare that they have no competing interests.
Funding Statement
No financial support was received for this study.
Acknowledgments
This article is extracted from a thesis by Ayoub Ghazi from Sanandaj Medical School.