Causes of Hypothyroidism
As described earlier, hypothyroidism is characterised by deficiency in the T4 and T3 hormones [1, 2]. T4 is the main hormone produced by the thyroid gland, which only produces a small amount of T3. Only 20% or less of T3 in peripheral tissue originates in the thyroid gland [23, 24]; the rest is derived from the enzymatic conversion of T4 to T3 within the target tissues . Failure of the thyroid to produce T4 and T3 stimulates the pituitary to increase production of a thyroid-stimulating hormone (TSH) through a negative feedback mechanism .
In over 99% of cases, hypothyroidism is caused by a failure of the thyroid gland to produce thyroid hormones (primary hypothyroidism) [2, 25]. The remaining 5% of patients have hypothyroidism from other causes, including secondary hypothyroidism, caused by underproduction of TSH by the pituitary gland, tertiary hypothyroidism, caused by deficiency of thyrotropin-releasing hormone, and peripheral (extra-thyroidal) hypothyroidism [2, 3]. Central hypothyroidism, which includes both secondary and tertiary hypothyroidism, and peripheral hypothyroidism account for less than < 1% of cases [3, 26].
A large population study in Denmark reported that the most common subtype (present in 84.4% of patients) was spontaneous (presumably autoimmune) hypothyroidism, followed by post-partum (4.7%) and amiodarone-induced hypothyroidism(4.0%). Less common causes were subacute thyroiditis (1.8%), previous radiation or surgery (1.8%) to the thyroid gland, congenital hypothyroidism (1.6%) and lithium-associated (1.6%) thyroid failure . Nowadays, iatrogenic causes have become more frequent due to various immunotherapies.
Prevalence and Incidence
The reported prevalence of hypothyroidism varies geographically, in part due to differences in disease definitions, poorly defined and diverse populations studied, variability in the sensitivity of measures of thyroid function used in the past, and iodine intake . In Europe, the estimated prevalence of overt (i.e. symptomatic) hypothyroidism in the general population is 0.2–5.3% [8,9,10,11, 28]. Across nine European countries, the prevalence of undiagnosed hypothyroidism, including both overt and subclinical hypothyroidism, has been estimated at approximately 5% in a meta-analysis of seven studies ; the same meta-analysis calculated the incidence rate at 226.2 (222.26–230.17) per 100,000 per year. Similarly, the prevalence of overt and subclinical hypothyroidism in the US has been estimated at 0.3% and 4.3%, respectively .
Primary hypothyroidism is up to 8–9 times more common in women than in men, and the prevalence increases with age, with a peak incidence between the ages of 30 and 50 years [2, 30]. In the US, hypothyroidism affects an estimated 4% of women aged 18–24 years and 21% of women older than 74 years ; respective values in men are 3% and 16% . A UK survey determined that approximately 7.5% of women and 2.8% of men have elevated serum levels of TSH , while a Danish population study found that the lifetime risk of overt hypothyroidism was 4.1% in women and 1.3% in men .
Hypothyroidism also appears to be more prevalent in white people than in black or Hispanic people [29,30,31,32].
Impact of Iodine
Worldwide, environmental iodine deficiency is the most common cause of thyroid disorders, including hypothyroidism . Iodine is an essential component of thyroid hormones, but is also thought to make the thyroid gland more antigenic [2, 3, 33]. Despite the implementation of iodine supplementation programmes (e.g. salt iodization), iodine intake remains suboptimal in large parts of Europe, Africa and Asia , while it can affect specific subpopulations in developed countries, such as pregnant women in some areas of Italy, the US and UK [3, 33,34,35,36]. Socioeconomic factors may play a role in the lack of adherence to iodine supplementation programmes. A recently published Italian study showed that poverty and lack of access to public health services were barriers to the use of iodized salt and maternal iodine supplements among poor or immigrant women . Iodine intake and hypothyroidism demonstrate a “U-shaped” relationship: hypothyroidism prevalence decreases in populations with mild iodine deficiency as compared to those with severe deficiency, while autoimmune hypothyroidism increases in prevalence as population iodine intake increases to sufficiency or excess .
In areas of iodine sufficiency, the most common cause of primary hypothyroidism is chronic autoimmune thyroiditis (Hashimoto’s disease) [2, 6]. Hashimoto’s disease is characterised by diffuse infiltration of the thyroid by lymphocytes and the presence of thyroid auto-antibodies, such as anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin antibodies (TgAb) [2, 38]. One study found that the prevalence of overt hypothyroidism was strongly correlated with the presence of the former, with no hypothyroid individuals having positive TgAb in the absence of positive TPOAb . Thyroid antibody positivity is almost universal (> 95%) among patients with overt hypothyroidism  and present in ~ 50% with subclinical hypothyroidism , while 10–20% of the background population have thyroid antibodies .
While this disease entity is often named Hashimoto’s hypothyroidism, all cases in the original study by Hashimoto had large goitres . Therefore, autoimmune hypothyroidism is often referred to as Ord’s hypothyroidism in those with small thyroid glands, and Hashimoto’s disease in those with goitres . However, this distinction is not clear-cut since thyroid size in hypothyroidism shows a normal distribution, with cases of thyroid atrophy or goitre representing extremes within this distribution .
The prevalence of autoimmune thyroiditis is increased in populations with high dietary iodine, as well as in severely iodine-deficient populations, likely as a result of prolonged thyroid adaptation to iodine intake in both cases [2, 3, 44, 45]. Other environmental factors that have been implicated in autoimmune thyroiditis are deficiencies in vitamin D  and selenium , whereas moderate alcohol consumption has been found to reduce the risk . Immune changes during pregnancy can also provoke the onset of autoimmune hypothyroidism, which occurs at a rate of 92.3 per 100,000 women per year according to a nationwide Danish study .
Primary hypothyroidism can also be caused by damage to, or destruction of, the thyroid gland caused by treatment or conditions, such as thyroidectomy, radioactive iodine therapy for Graves’ disease or nodular goitre, radiotherapy for head and neck cancer, or toxic exposure to some chemicals or drugs [2, 3]. Drugs that may cause hypothyroidism include amiodarone, interleukin-2, kinase inhibitors, and lithium . Rarely, primary hypothyroidism may be congenital, caused by failed embryologic development of the thyroid gland (thyroid dysgenesis) or inherited defects of the genes responsible for the thyroid hormone synthesis (thyroid dyshormonogenesys) [3, 7].
Burden of Hypothyroidism
The economic impact of undiagnosed/untreated hypothyroidism may be significant, especially with regard to costs associated with maternal and congenital hypothyroidism [14, 15], or with hypothyroid patients having comorbid conditions such as diabetes mellitus .
Hypothyroidism is also associated with decreased quality of life, most likely related to symptoms such as changes in body weight, fatigue, weakness and depression [1, 12, 17,18,19]. Physicians and patients themselves rate fatigue and emotional susceptibility as being particularly relevant to the impact of hypothyroidism .
Hypothyroidism is implicated in many other diseases, involving most organs of the body, but is most extensively studied in terms of cardiovascular disease. Specifically, hypothyroidism is associated with reduced cardiovascular contractility, and its association with coronary artery disease has long been recognised . Hypothyroidism also contributes to infertility [3, 4], and can cause reversible dementia, as well as neurosensory, musculoskeletal and gastrointestinal symptoms . A considerable number of untreated patients with either overt or subclinical hypothyroidism show evidence of asymptomatic small fibre sensory neuropathy .
Diagnosis of Hypothyroidism
Hypothyroidism has a varied clinical presentation and non-specific symptoms, including weight gain, fatigue, poor concentration, depression, diffuse muscle pain, menstrual irregularities, and constipation , with no particular symptom definitively predicting the presence of hypothyroidism . Furthermore, symptoms generally become apparent by the time (and even long-term after) circulating thyroxine levels have decreased . As a result, patients with overt hypothyroidism exhibit a greater number of symptoms , but only some of them, such as constipation, dry skin, hair loss and proximal weakness, are more characteristic of thyroid failure . While not definitive, use of symptoms to diagnose hypothyroidism is more successful in some population groups than in others. Symptoms more accurately predict overt hypothyroidism in men than in women , and in younger than older people, particularly in younger men compared with older women .
The diagnosis of hypothyroidism is therefore entirely based on repeated biochemical findings [3, 4, 26, 53, 55, 56].
An imbalance between reactive oxygen species and the anti-oxidant defence system, leading to an increased oxidative stress, has been described in humans and in animal models of hypothyroidism . The pro-oxidant environment induced by hypothyroidism could promote the atherosclerotic processes frequently described in this condition. In an experimental model of hypothyroidism, the total nitric oxide synthase (NOS) activity increased and significant changes in the mRNA and protein expression of all three NOS isoforms were observed . However, serum assays of pro-oxidant and anti-oxidant species are currently not included in the diagnostic work-up of hypothyroid patients.
Overt primary hypothyroidism is defined as serum TSH concentrations above, and free thyroxine concentrations below, the normal reference range [3, 53]. It is also important to note that reference ranges are a subject of ongoing debate and differ with the assay used, as well as by patient age, sex, and ethnic origin . The upper limit of the TSH reference range generally increases with age in adults . Furthermore, individuals have their own TSH reference range, which effectively covers only 25% of the reference range for the entire population .