This section describes the types of hypothyroidism causing the most concern in Saudi Arabia and GCC countries.
Congenital Hypothyroidism
The main cause of CH is insufficient production of thyroid hormone in newborns, which can lead to failure to grow and mental retardation [
48]. CH is classified into two types: (1) thyroid dysgenesis, in which defective thyroid gland development leads to athyreosis, thyroid ectopy and hypoplasia [
49], and (2) thyroid dyshormonogenesis, which is a defect in thyroid hormone synthesis [
50].
The estimated incidence of CH was 1 in 3450 (0.03%) live births in Saudi Arabia from 1988 to 1995 [
51,
52]. This is comparable with other countries in the Middle East-North Africa region. In a pilot screening programme for CH in Oman, 36,000 infants were screened and the estimated prevalence of CH was 1:2200 (0.05%) from 1995 to 2000 [
53]. In a pilot cord blood screening study of 35,067 newborns in Iran from 1998 to 2002, the estimated prevalence of CH was 1:1403, with a positive correlation between disease and parental consanguinity [
54].
In a comprehensive mutation screening of Saudi patients with CH using next generation sequencing, the overall mutation rate was 52.7%. The most frequent genetic defects in thyroid dyshormonogenesis and dysgenesis were
TG and
TSHR mutations, respectively. The proportion of patients with
TSHR mutations was 10.9% [
48], which was significantly higher than that previously reported in Chinese patients (1.6%) [
55]. Furthermore,
TSHR mutations in Saudi patients were biallelic, whereas all
TSHR mutations in Chinese patients were monoallelic, which may not cause symptomatic CH [
55].
The mutation spectrum in Saudi patients with CH is narrow and specific, and mainly concentrated in the
TG and
TSHR gene loci, which may reflect the consanguineous nature of the disease. Other gene mutations include
TPO,
DUOX2,
SLC26A4,
TSHB,
TSHR,
NKX2-
1,
PAX8,
CDCA8 and
HOXB3 [
48].
There may be regional differences in the prevalence of CH in Saudi Arabia. A retrospective study found that the prevalence of CH among children born in the Arar Central Hospital in Arar City, a Northern Borders Province in Saudi Arabia, was 2.6 per 10,000 (0.03%) between 2008 and 2014 [
56]. In contrast, the prevalence of CH in Najran, a southern province of Saudi Arabia, was reported to be 1 per 1400 (0.07%) between 1990 and 1995 [
57]. Of note, the time period of screening was different for the two regions, which may affect the comparability of CH prevalence in these two Saudi Arabian studies.
Given the high prevalence of CH in Saudi Arabia, newborn screening has been suggested in the Middle East and North Africa as a preventative health measure [
58].
Subclinical Hypothyroidism
The estimated prevalence of SH in adults in the primary care setting in Saudi Arabia is 10.3% [
14].
In cross-sectional studies in Saudi Arabia that included only women, the prevalence of SH was high again, being 35% in a study exclusively in those aged > 50 years [
59] and 14.9% (data available only as an abstract) [
60] and 13% (95% CI 9.8–16.8%) [
61] in studies in pregnant women. The study of 257 women aged > 50 years (mean age 55.8 ± 7.2 years) was conducted at the King Abdulaziz University outpatient clinic in Jeddah and defined SH as a TSH level of > 4.2 mIU/l and normal levels of free T
4 (12–22 pmol/l) and free T
3 (0.27–7.1 pmol/l) [
59]. Fatigability was the most common symptom (20%), followed by constipation (16%), infertility (12%), cold intolerance (7%) and weight gain (4%). This high SH prevalence was likely due to environmental or genetic factors, although verification in further studies is required. The fully published study in pregnant women used slightly different criteria for SH: in this multicentre, cross-sectional study conducted in Riyadh [
61], the 2011 ATA criteria for SH were used (TSH 2.5–10 mIU/l and trimester-specific normal range of T
4 [
62]). This study also found that pregnant women were three times more likely to be diagnosed with SH if they were screened randomly compared with screening based on their physician’s judgement [
61]. As previously mentioned, screening for SH is warranted in pregnant women.
The prevalence of SH was investigated in Saudi Arabian patients with obstructive sleep apnoea (OSA) in a cross-sectional study of patients referred to a sleep disorder centre [
63]. SH was defined as a serum TSH level of > 5.0 mIU/ml with serum T
3 level within normal levels. Newly diagnosed SH was found in more of the 271 subjects diagnosed with OSA (11.1%) than in the 76 subjects without a diagnosis of OSA (4%). Although authors concluded that routine thyroid function testing in OSA patients was probably not warranted unless signs and symptoms were present [
63], sleep apnoea itself is considered to be one of the clinical signs of hypothyroidism, at least according to US guidelines [
26].
As expected, the prevalence of SH in Saudi Arabia may be explained in part by the role of iodine intake in the development of hypothyroidism. In one Saudi Arabian study, TSH levels were high in 13.3% of patients who did not use iodised salt in their diet compared with 8.9% in those who used iodised salt [
14]. Another study of patients with thyroid diseases attending clinics at three hospitals in Makkah (
n = 391) found that iodine deficiency and poor nutrition were significantly more common in women (
n = 142) with hypothyroidism than men (
n = 54) with hypothyroidism [
64].
Other clinical characteristics of hypothyroidism and comorbidities differing between women and men in the Makkah study included a greater incidence of autoimmune thyroiditis (Hashimoto thyroiditis, Graves’ disease), congenital hypothyroidism, thyroid malignancy, psychiatric disorders and diabetes mellitus among male than female patients and a lower incidence of iodine deficiency, goitre, poor nutrition and benign thyroid cancer [
64]. Further study of the clinical characteristics of patients with hypothyroidism and risk factors for hypothyroidism in Saudi Arabia is required.
Patient age may also be a contributing factor to SH, as in one study TSH levels were higher in elderly patients [
14]. Therefore, thyroid screening in primary care settings among adults, particularly those aged > 60 years, may be warranted for early detection of SH [
14].
Consequences of Hypothyroidism
There is insufficient evidence to support hypothyroidism as a causative factor in clinical heart disease; however, mild thyroid gland failure and elevated TSH levels may be associated with cardiovascular disease [
65]. A study of 1149 elderly women from Rotterdam, The Netherlands, showed that SH was associated with an increased risk of atherosclerotic vascular disease and myocardial infarction [
11].
In a cross-sectional study of the prevalence of thyroid disease in Colorado, USA, significantly elevated LDL cholesterol was observed in patients with SH [
66]. Furthermore, a longitudinal follow-up study showed that patients with symptomatic improvement of hypothyroidism had improved left ventricular contractility and cardiorespiratory exercise capacity and reported increased energy and decreased skin dryness and constipation [
65].
In a primary care study of Saudi patients with SH, there was a non-significant trend of increasing blood pressure and hyperlipidaemia in patients with high TSH levels [
14].
A study of 111 Saudi women with heart failure found that 33.3% had hypothyroidism and 14.4% had SH. There was a significant negative correlation between TSH levels and ejection fraction, indicating a close association between hypothyroidism and heart failure in this population [
67].
Thyroid disorders are also associated with an increased prevalence of anaemia and iron deficiency. In a study of non-pregnant Saudi women, the prevalence of anaemia was significantly higher in participants with thyroid abnormalities (44%) compared with euthyroid participants (14.3%,
p = 0.00002) [
68].
An association between diabetes and thyroid disorders has also been postulated, as both diseases are caused by endocrine dysfunction and both insulin and thyroid hormones contribute to body metabolism; disruption in either hormone can impair the function of the other [
69]. In a case-control study of 100 Saudi patients with type 2 diabetes at King Abdulaziz University Hospital, thyroid autoimmunity was detected in 10% of patients with diabetes versus 5% of controls (
p = 0.05), and thyroid dysfunction was detected in 16% of patients with diabetes versus 7% of controls (
p = 0.03) [
70]. A subsequent study of patients with type 2 diabetes at a Golestan Hospital Diabetes Clinic in Ahvaz, Iran, showed high levels of TPO antibodies in 33.9% of patients and high levels of anti-thyroglobulin antibodies in 32.7% [
71]. Therefore, due to the relationship between thyroid dysfunction and diabetes, patients with type 2 diabetes should undergo annual screening of serum TSH levels.