Association between subclinical hypothyroidism and metabolic disorders: A retrospective chart review study in an emerging university hospital

Abstract Background Subclinical hypothyroidism is defined as an increase in serum levels of Thyroid Stimulating Hormone (TSH) above the normal range, without alteration of total T4 concentrations that is reported to have association with various metabolic conditions. The study aimed to investigate any association between subclinical hypothyroidism and metabolic disorders in Al Kharj city. Methods This is a cross‐sectional study that included review of patients’ charts from prince Sattam bin Abdul‐Aziz University, Al Kharj, Saudi Arabia, from August 1 to November 30, 2016. Data were analyzed with SPSS version 21. Descriptive statistics were obtained as frequencies. Pearson chi‐square analysis was used to assess any differences between disease status and study variables. P‐value < 0.05 was considered significant. Results The mean age was 30.65 ± 13.3 with a female predominance. The average BMI was 29.5 ± 7.71; 46 (11.5%) had hypertension, 52 (46.8%) had diabetes, 173 (44%) had anemia, and 192 (56%) had vitamin D deficiency. Due to increased TSH levels, male gender had higher prevalence of subclinical hypothyroidism with P‐value < 0.001 and 0.011, respectively. Conclusion Subclinical hypothyroidism is a significant topic worldwide whose prevalence is rising. In this study, we could not find any significant association between subclinical hypothyroidism and metabolic disorder. Further longitudinal studies with large sample size are needed to study this association.

a disease without obvious symptoms, which means that evolution of the disease might be at an early stage. Subclinical hypothyroidism is classified into a mild subclinical hypothyroidism with TSH levels between 4.0 and 10.0 mIU/L and a severe subclinical hypothyroidism with TSH > 10.0 mIU/L. Subclinical hypothyroidism affects women more than men. Even though there is high risk in patients with severe subclinical hypothyroidism to develop into hypothyroidism, the risk is also great in patients with mild subclinical hypothyroidism. 1 Numerous studies have been conducted to investigate the correlation between subclinical hypothyroidism, metabolic syndrome, and cardiovascular risk factors. Risk of clinical manifestations is 2-3 times greater than individuals with normal TSH levels. 2 In 2011, a study was carried out in Korea demonstrated that high normal TSH level is significantly associated with an increased prevalence of metabolic syndrome. 3 In Japan, cross-sectional and longitudinal follow-up studies were published in 2013 observed strong correlation between subclinical hypothyroidism and metabolic syndrome. 4 A study carried out in 2014 in Serbia revealed that traditional cardiovascular risk factors were more frequent in subclinical hypothyroidism patients compared with euthyroid patients. 5 However, a systematic review that was done in 2015 in China showed that patients with type 2 DM are more likely to have subclinical hypothyroidism compared with healthy population. 6 Significant risk factors for subclinical thyroid dysfunction in Nepal included family history of thyroid illness having relative risk (RR) of 2.57, smoking with RR of 2.56, and female gender with RR of 1.44. 7 Various studies showed the association of its increased incidence with increasing age. In India, a population-based study found high occurrence of subclinical hypothyroidism in women (11.4%) compared with men (6.2%). The same study found that increasing age has a significant association with it. 8 Likewise, other studies also found increased prevalence of subclinical hypothyroidism with advancing age of women and those having higher BMI; however, a study conducted in Saudi Arabia did not find any significant variance between BMI groups. Moreover, unidentified thyroid dysfunction could create a negative impact on diabetes as well as its complications along with a high frequency of nephropathy and retinopathy in patients with diabetes having subclinical hypothyroidism. 9 Therefore, managing subclinical hypothyroidism in patients with diabetes may prove extremely beneficial.
As far as the studies that were done in Saudi Arabia, we found a literature review on a cohort study done in 2015 revealed that the prevalence of subclinical hypothyroidism in heart failure patients was 14.4%, 6 while it was 14.9% in pregnant women in a prospective study done in 2011. 10 Another study from Saudi Arabia reported 28.5% of patients with type 2 diabetes have thyroid dysfunction, 9 while a non-significant trend was noted in TSH levels with high blood pressure and hyperlipidemia. 11 Unfortunately, there are no studies done in Saudi Arabia or even in Arab countries to determine the correlation between subclinical hypothyroidism and metabolic diseases. The study aimed to investigate any association between subclinical hypothyroidism and metabolic disorders in Al Kharj city. Given that the prevalence of subclinical hypothyroidism in Saudi Arabia is 7% according to study done in Jeddah and the total population of Al kharj governorate is 376 325, 12 by using Raosoft.com website, the sample size was calculated by keeping the confidence level at 95% and margin of error at 5%; the total sample was determined as 379, which was adjusted to 420 by keeping response rate in consideration. According to the World Health Organization, overweight was defined as a BMI greater than or equal to 25, whereas obesity was a BMI greater than or equal to 30. 13 A trained research assistant constructed a chart review of patient files. We have taken TSH test to know whether the patient has subclinical hypothyroidism; the normal range of TSH was from 0.40 to 4.70 ulU/mL and T4 was from 12 to 22 Pmol/L according to the University Hospital Lab, 14 so any patient with high TSH and normal T4 was diagnosed as subclinical hypothyroidism; we have taken the following tests to study metabolic disorders: levels of hemoglobin, ferritin, vitamin D, hemoglobin A1C, albumin, Alkaline phosphatase (ALP), Alanine transaminase (ALT), Aspartate aminotransferase (AST), creatinine, urea/blood urea nitrogen, High-density lipoprotein (HDL), Low-density lipoproteins (LDL), and triglyceride. The normal range for those tests is given in Table 1.

| ME THODOLOGY
Patients from 2 to 70 years old were included in the study, whereas patients who were already diagnosed with hypothyroidism and were on the treatment, or any patient treated surgically for thyroid gland disorders, pregnant patients and admitted patients with other medical illnesses were not included in this study.   Data showed that the prevalence of subclinical hypothyroidism in other Arab countries was 2.3% in Libya, 15 while in Saudi Arabia, the newly diagnosed subclinical hypothyroidism was 11.1% in obstructive sleep apnea (OSA) patients and 4% in non-OSA patients. 16 In Korea, it was reported between 0.2% and 9.7% in adult population, generally about 2%-3%. 17 According to a review done by Al Shahrani, the prevalence of subclinical hypothyroidism in Arab region is comparatively low, which could possibly be the result of small sample size used for these studies. 18 Another study from Jeddah having female predominance in the sample (82%)

| D ISCUSS I ON
showed that 71.9% of the patients with clinically evident hypothyroidism had metabolic syndrome. 19 In the western world, in the US adult population subclinical hypothyroidism was found to be around 0.7% being more common in women than in men. 20 The significant association between TSH and gender in our study was also confirmed by various other studies, being evident in females. [7][8][9] Subclinical hypothyroidism was also found to be associated with adverse cardiovascular consequences in women aged 55 years and older. Likewise, its simultaneous occurrence with Antithyroid antibodies may reflect ultimate progression to more severe form of hypothyroidism. A subgroup investigation on individuals aged 65 and more found that the maximum risk of cardiovascular or all-cause mortality was found in this subgroup. 21 In a cross-sectional study, which was a population-based Nord-Trøndelag Health Study, the risk of mortality due to coronary heart disease was significantly higher in people with an average age of about 60.1. 22

| CON CLUS ION
Subclinical hypothyroidism is recognized greatly as a probable cardiovascular risk factor that might interfere with total morbidity and mortality. Data supporting such findings as well as any other adverse clinical outcomes or treatment benefits are also limited. Since subclinical hypothyroidism is associated with augmented cardiovascular risk, a systematic review indicated that benefits of thyroid hormone replacement are reported to avoid its progression to overt hypothyroidism and specifically when the focus is to improve lipid profile, reduce LDL, and overall better cardiac function. Therefore, a costeffective strategy of screening the patients for thyroid dysfunction can be a favorable strategy. affiliations. Our study added some more information into the existing data about this topic. Another strength of this study is the use of WHO-approved definitions and laboratory sample cutoffs. However, this study is a cross-sectional study and so causal inferences were not achieved. Secondly, the proportion of women was higher in the sample so the real gender distribution could not be appreciated. Almost all the participants had subclinical hypothyroidism, there was no control group, that is the comparison group, and association was not appropriately evaluated with small sample size.

| RECOMMENDATIONS
It is essential to carry out clinical trials in order to generate newer insights to guide clinical practitioners to screen, diagnose, and treat all the suspected cases of subclinical hypothyroidism. Additionally, population-level screening as a part of a routine workup should also be considered. It is equally important to revise the normal reference ranges for TSH according to the population and a standardized value to be followed in order to ensure that the results are reproducible and accurate and so unnecessary usage of thyroid hormones would be prevented.

ACK N OWLED G M ENTS
The authors thank the laboratory technicians for their help in conducting the study.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

AUTH O R S ' CO NTR I B UTI O N S
This work was performed as collaboration among all the authors.
KAD and SAG participated in the study design and wrote the first draft of the manuscript. JAZ and AAJ collected and processed the samples. BAA, AAB, and MAA participated in the study design and performed the statistical analyses. All of the authors read and approved the final manuscript.

E TH I C A L A PPROVA L
The study was approved by the Ethics Committee of Prince Sattam bin Abdulaziz University Institutional Review Board.

DATA AVA I L A B I L I T Y
Data are available upon request from the authors.

CO N S E NT FO R PU B LI C ATI O N
Not applicable.