In recent times, there seems to be an explosion in the number of patients with thyroid dysfunction seen in the clinical outpatient practice, especially in the subclinical hypothyroidism. A recent population-based survey from Cochin [1] found a high prevalence of the subclinical hypothyroidism in females (11.4%) and males (6.2%) with an overall prevalence of 9.4%. The prevalence increased with age, and 53% of the subclinical hypothyroid subjects were positive for anti-thyroid peroxidase antibodies.

What is the reason for this increase?

As with all the clinical quandaries, several hypotheses exist. First, there is a huge increase in the number of people being screened for a thyroid disorder. Though universal screening is strongly recommended for pregnant women and newborn children, the utility of routine screening of nonpregnant adults is doubtful. When this screening is done by ultrasensitive thyroid-stimulating hormone (TSH) methods, more and more asymptomatic people are found to have subclinical hypothyroidism.

Our populations are ageing. The average life expectancy increased from 58.5 years in 1990 to 66.4 years in 2013. [2] As is clear from the recent literature, there is an age-related increase in TSH levels, [3],[4] which is associated with increased longevity. [5] As Indians are living longer, are we diagnosing this age-related TSH increase as subclinical hypothyroidism? The prevalence of subclinical hypothyroidism showed a positive correlation with age in data from both South as well as North India. [1],[6]

The whole iodine conundrum has been bandied about. Iodine deficiency is known to increase goitre prevalence and hypothyroidism. However, when a previously iodine-deficient population is exposed to iodine, there is found to be an increase in the incidence of the subclinical hypothyroidism in the postiodization phase. Marwaha et al. [6] showed a 19.3% prevalence of the subclinical hypothyroidism 20 years after universal salt iodization in Indian adults. The possible reason is the ability of iodine to render thyroglobulin more immunogenic, generate reactive oxygen intermediates, and directly activate the immune system. [7] In this study by Marwaha et al.; [6] however, there was no correlation of subclinical hypothyroidism with either thyroid autoimmunity or iodine intake, further confusing the issue.

Is the rise in autoimmune diseases per se leading to the rise in autoimmune subclinical hypothyroidism? As is known, when developed countries overcome infectious diseases, autoimmune diseases emerge which is known as the ‚Äúhygiene hypothesis.‚ÄĚ [8]¬†Within Europe, the highest rates of childhood diabetes are found in Scandinavia and North-west Europe, with an incidence range from 57.4 cases/100,000/year in Finland to 3.9/100,000 in Macedonia for children aged 0-14 years.¬†[9]¬†These are the countries where infectious diseases have been largely vanquished. Is an emerging economy like India now faced with a two-edged sword death due to infectious diseases still rampant on one hand with the emergence of autoimmune diseases on the other hand?

The last hypothesis is probably as important as the iodine hypothesis if not more is the relation of rising TSH with rising obesity. Our young children are rapidly gaining weight [10] as are the adults [11] due to the increasing consumption of calorie-dense food and sedentary lifestyles. Because T3 (triiodothyronine) regulates the energy metabolism and thermogenesis, thus, the obesity and thyroid function TSH levels are at the upper limit of the normal range or slightly increased in obese children, adolescents, and adults and are positively correlated with body mass index (BMI). [12],[13] A positive correlation has been identified between serum leptin and serum TSH levels in obese individuals. Leptin, adjusted for BMI, was found to correlate with TSH, which suggests that the increase in TSH and leptin levels in severe obesity could result from the increased amount of fat. [13] Despite the higher plasma TSH levels, TSH receptors are lesser expressed on adipocytes of obese versus lean individuals. [14] This reduced TSH receptor expression might induce down-regulation of thyroid hormone receptors and thyroid hormone action, thereby further increasing plasma TSH and FT3 concentrations and constituting a condition of peripheral thyroid hormone resistance. This sequence of events would be reversed by weight loss, which restores the size and function of mature adipocytes. [14]Aberrant thyroid function and TSH level usually normalize after weight loss whether consequent to diet or to bariatric surgery. [14],[15]

There is some debate about the link between obesity and the risk of autoimmune thyroid disease (AITD), which is the main cause of hypothyroidism in adults. Marzullo et al. [16] address the intriguing hypothesis of a link between obesity, leptin, autoimmunity, and hypothyroidism. In their study, almost 70% of their patients had severe obesity (BMI >40 kg/m 2 ) and the prevalence of hypothyroidism was higher in obese patients than in a control group of age- and sex-matched subjects with normal BMI (P < 0.05). AITD patients (with positive thyroid peroxidase antibodies) were most severely obese. Leptin levels were higher in AITD-positive obese patients than in AITD-negative patients, and the prevalence of AITD was higher in patients with a leptin level >33.8 mcg/litre (24 vs. 8.6%, P < 0.01). Logistic regression analysis revealed an association between AITD and leptin (r = 0.26, P < 0.001) that was unrelated to either fat body mass or BMI (P < 0.001). Multiple logistic regression analysis in pooled groups identified female sex and leptin as significant predictors of AITD. [16]

This hypothesis to my mind is the most attractive. Most of our newly detected subclinical hypothyroid patients are middle-aged perimenopausal women with a recent increase in weight over the past decade. They usually do not have antibody positivity or goitre and have always lived in an era of iodine sufficiency. Is this a disease or a simple change in the set point of TSH consequent to peripheral thyroid hormone resistance ‚Äď the so-called obesity set point? Are we medicalizing, what is essentially a consequence of the epidemic of obesity?

To my mind, once the treatment is initiated for the subclinical hypothyroidism, the patient now has a medical illness and will have to continue to take levothyroxine supplementation for the rest of their lives. The careful explanation attempts to lose weight must precede the initiation of treatment. The frequent iatrogenic thyrotoxicosis with levothyroxine supplementation that we see in practice is detrimental to a patient’s bone health. There is an acceleration of bone loss/osteoporosis in these already vulnerable perimenopausal women as a result of iatrogenic osteoporosis. [17] Thus, the treatment initiation must follow careful risk-benefit assessment, especially in older individuals.

Thus to summarize, there are numerous theories for the recent increase in thyroid diseases with iodine exposure and obesity set-point theories being the most likely. Further research and time will hopefully reveal the real reason.