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Hypothyroidism in Context: Where We’ve Been and Where We’re Going


Hypothyroidism affects up to 5% of the general population, with a further estimated 5% being undiagnosed. Over 99% of affected patients suffer from primary hypothyroidism. Worldwide, environmental iodine deficiency is the most common cause of all thyroid disorders, including hypothyroidism, but in areas of iodine sufficiency, Hashimoto’s disease (chronic autoimmune thyroiditis) is the most common cause of thyroid failure. Hypothyroidism is diagnosed biochemically, being overt primary hypothyroidism defined as serum thyroid-stimulating hormone (TSH) concentrations above and thyroxine concentrations below the normal reference range. Symptoms of hypothyroidism are non-specific and include mild to moderate weight gain, fatigue, poor concentration, depression, and menstrual irregularities, while the consequences of untreated or under-treated hypothyroidism include cardiovascular disease and increased mortality. Levothyroxine has long been the main tool for treating hypothyroidism and is one of the world’s most widely prescribed medicines. In adults with overt hypothyroidism, levothyroxine is usually prescribed at a starting dose of 1.6 µg/kg/day, which is then titrated to achieve optimal TSH levels (0.4–4.0 mIU/L), according to the therapeutic target. We here summarise the history of levothyroxine and discuss future issues regarding the optimal treatment of hypothyroidism. Because nearly one-third of patients with treated hypothyroidism still exhibit symptoms, it is important that levothyroxine is used more appropriately to achieve maximum benefit for patients. In order to ensure this, further research should include more accurate assessments of the true prevalence of hypothyroidism in the community, optimisation of the levothyroxine substitution dose, proper duration of treatment, and identification of patients who may benefit from combination therapy with levothyroxine plus levotriiodothyronine.

Funding: Merck.

Plain Language Summary: Plain language summary available for this article.

Plain Language Summary

Hypothyroidism is one of the most common diseases worldwide, and levothyroxine is the usual medication prescribed to manage it. Hypothyroidism occurs when the thyroid gland, located in the neck, does not produce enough thyroid hormone for the body’s requirements. This can result in heart disease, infertility, and poor brain development in children. People with hypothyroidism may have changes in body weight, and feel tired, weak or unhappy, all of which can reduce their quality of life. In underdeveloped parts of the world, the main reason why people develop hypothyroidism is that they not getting enough iodine from food. Thus, many countries try to increase iodine intake by adding iodine to salt. In areas of the world where people ingest enough iodine, the most common cause of hypothyroidism is Hashimoto’s disease. This is an autoimmune disease in which the person’s immune system produces cells and antibodies that attack the thyroid gland. Most people with hypothyroidism will need to take levothyroxine for a long time, perhaps even for the rest of their lives. Levothyroxine replaces the person’s levels of thyroid hormone and makes them feel better, but the dose often needs to be adjusted for the best effect. In addition, many people with hypothyroidism do not know they have it. Research is ongoing to ensure that more people with hypothyroidism are diagnosed and are given effective treatment, and to work out the best way to use levothyroxine so that patients get the best results.


Hypothyroidism is a chronic disease associated with deficiency in the thyroid hormones, thyroxine (T4) and triiodothyronine (T3) [1, 2]. The consequences of untreated or inadequately treated hypothyroidism include infertility, cardiovascular disease, and neurological and musculoskeletal symptoms [3,4,5]. Environmental iodine deficiency is the most common cause of thyroid disorders, including hypothyroidism, worldwide [6], while in areas of iodine sufficiency, the most common cause of primary hypothyroidism is autoimmune thyroiditis (Hashimoto’s disease) [2, 6, 7].

The full implications of hypothyroidism in the population are not completely appreciated or defined. Hypothyroidism affects up to 5% of the population according to European prevalence estimates [8,9,10,11], while as many as 5% of the population may have undiagnosed thyroid failure [9]. Of patients who are treated, up to one-third are not receiving adequate treatment [12, 13]. The economic impact of undiagnosed, untreated or undertreated hypothyroidism is therefore not inconsequential, especially with regard to costs associated with maternal and congenital hypothyroidism [14, 15], or with hypothyroid patients having comorbid conditions such as diabetes mellitus [16]. Hypothyroidism is also associated with decreased quality of life [1, 12, 17,18,19], increased number of sick leave days [20], and even increased mortality [21].

Levothyroxine is the mainstay of treatment for hypothyroidism, and is one of the World Health Organization’s essential medicines required for basic health care [22]. Here, we review the background of hypothyroidism, including aetiology, prevalence, and symptoms, with a focus on the use of levothyroxine in the management of hypothyroidism. In particular, we review advances to date and unresolved issues in the treatment of hypothyroidism.


A search of the literature was conducted using PubMed and general search terms such as primary hypothyroidism, levothyroxine, aetiology, economic impact, quality of life and treatment guidelines. Potential articles of interest were identified by title and abstract, and citation lists of articles of interest were used to identify additional literature. This article is based on previously conducted studies and does not contain any studies with animals performed by any of the authors. Some of the cited studies include analyses, or studies with human participants, performed by the authors and completed prior to the initiation of this manuscript.

Hypothyroidism in Context

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 [2]. 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 [2].

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 [7]. 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 [27]. 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 [9]; 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 [29].

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 [27]; respective values in men are 3% and 16% [27]. A UK survey determined that approximately 7.5% of women and 2.8% of men have elevated serum levels of TSH [10], while a Danish population study found that the lifetime risk of overt hypothyroidism was 4.1% in women and 1.3% in men [7].

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 [6]. 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 [34], 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 [37]. 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 [3].

Autoimmune Hypothyroidism

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 [29]. Thyroid antibody positivity is almost universal (> 95%) among patients with overt hypothyroidism [39] and present in ~ 50% with subclinical hypothyroidism [40], while 10–20% of the background population have thyroid antibodies [41].

While this disease entity is often named Hashimoto’s hypothyroidism, all cases in the original study by Hashimoto had large goitres [42]. 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 [43]. 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 [43].

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 [46] and selenium [47], whereas moderate alcohol consumption has been found to reduce the risk [48]. 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 [49].

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 [50]. 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 [16].

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 [51].

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 [3]. Hypothyroidism also contributes to infertility [3, 4], and can cause reversible dementia, as well as neurosensory, musculoskeletal and gastrointestinal symptoms [3]. A considerable number of untreated patients with either overt or subclinical hypothyroidism show evidence of asymptomatic small fibre sensory neuropathy [5].

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 [4], with no particular symptom definitively predicting the presence of hypothyroidism [52]. Furthermore, symptoms generally become apparent by the time (and even long-term after) circulating thyroxine levels have decreased [53]. As a result, patients with overt hypothyroidism exhibit a greater number of symptoms [27], but only some of them, such as constipation, dry skin, hair loss and proximal weakness, are more characteristic of thyroid failure [4]. 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 [54], and in younger than older people, particularly in younger men compared with older women [55].

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 [57]. 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 [58]. 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 [3]. The upper limit of the TSH reference range generally increases with age in adults [3]. Furthermore, individuals have their own TSH reference range, which effectively covers only 25% of the reference range for the entire population [59].


Thyroid hormone replacement therapy with levothyroxine, the exogenous form of T4, has been the “gold standard” for the treatment of primary hypothyroidism for more than 60 years [60]. The first use of thyroid hormone to treat hypothyroidism was documented in the 1890s, when an ovine thyroid gland was grafted into a patient with myxoedema (severe hypothyroidism) [61]. Subsequently, sheep thyroid extract was injected into two patients with myxoedema [61, 62], with both showing an improvement in their condition. Extraction of the vital ingredient, thyroxine, followed in 1914, with its structure finally established a decade later [63, 64]. Synthetic formulations of thyroxine have been available for use since the 1950s. However, desiccated animal thyroid gland remained the mainstay of therapy until the 1970s [63, 64].

Thyroxine occurs naturally as a racemic mixture of levo (sodium l-thyroxine) and dextro forms [64]. Levothyroxine was introduced in 1962 with the realization that the levo form was better absorbed and had greater physiological activity compared with the dextro form [63, 64]. In the 1970s, it was also noted that administration of both LT4 and LT3 was not required for successful treatment of hypothyroidism [65]. Because the T3 preparations have a short biological half-life, the treatment approach transitioned to LT4 monotherapy, such that today almost all patients with hypothyroidism receive once-daily synthetic thyroxine preparations [4].

Levothyroxine is available as tablets and soft-gel caps, intravenously, and, more recently, in liquid formulations (Table 1) [60, 65]. The liquid formulations demonstrate improved absorption when ingested with food, and have been developed with the aim of improving adherence [1, 65].

Table 1 Available formulations of levothyroxine

Because levothyroxine is classified as a narrow therapeutic index medication, indicating that small differences in dose or blood concentration may lead to therapeutic failure or adverse drug reactions [66], the American Association of Clinical Endocrinologists, American Thyroid Association (ATA) and the Endocrine Society recommended the consistent use of a single preparation of brand-name levothyroxine over generic preparations, which can vary in potency (Table 1) [2, 60, 63, 67, 68].

Levothyroxine is among the most widely prescribed medications in the world, and is one of the two most frequently prescribed medications in the US [60, 69, 70]. It is considered by the World Health Organization as an essential medicine for basic health care [22].

The Use of Levothyroxine to Treat Hypothyroidism

Upon diagnosis of hypothyroidism, lifelong treatment with levothyroxine is often initiated [4, 53, 67, 68, 71,72,73], except in cases where hypothyroidism is caused by transient forms of thyroiditis or by drugs which can be discontinued [50].

The starting dose of levothyroxine depends on patient age, the presence of co-existing cardiac disease, and the aetiology and the severity of the patient’s biochemical hypothyroidism [2]. The levothyroxine dose is titrated until TSH levels are normalised [53, 71, 73] at between 0.4 and 4.0 mIU/L [68]. Healthy adult patients diagnosed with overt hypothyroidism aged less than 50 years usually receive the full replacement dose of levothyroxine (1.6 µg/kg/day) orally, while those with coronary artery disease or aged 50–60 years receive a lower starting dose (25–50 µg once daily) [71]. In pregnancy, dose adjustment of levothyroxine should aim to achieve TSH in the lower half of the trimester-specific range, when available, or below 2.5 mIU/L [74]. In subclinical hypothyroidism, doses around 50–75 µg may be sufficient for normalising the serum TSH.

Due to the long half-life of levothyroxine (1 week), TSH should be measured 4–6 weeks after initiation of therapy or dosage change. Thereafter, patients with stable normal serum TSH levels should be monitored every 12 months [67, 71, 73].

The goal of levothyroxine treatment is to reduce symptoms and prevent long-term complications [2, 53, 68, 71, 72]. Generally, disease control is easily accomplished, with full recovery upon adequate replacement of thyroid hormones [2]. Over a period of years, levothyroxine replacement dose may require adjustment as the disease progresses or if the patient develops other conditions that affect thyroid hormone metabolism [2]. Other factors that can lead to, or necessitate, an adjustment in levothyroxine dose include a lack of medication adherence, use of concomitant medications or dietary supplements such as calcium or iron, and changes in body mass and dietary habits [60].

Unresolved Issues in Hypothyroidism Management

Despite the switch to levothyroxine monotherapy in the 1970s [65], the need for combination therapy with levothyroxine + LT3 has been recently readdressed in several clinical guidelines [13, 75, 76]. More than a third of patients remain inadequately treated despite levothyroxine therapy, with evidently elevated TSH levels and/or persistent symptoms [12, 13]. Even when TSH levels are controlled on levothyroxine, about 5–10% of treated hypothyroid patients have persistent symptoms for various reasons [76], including differences in individual set-points, coexistence of other autoimmune diseases, and failure to appropriately convert T4 to T3 with a low T3/T4 ratio, on levothyroxine monotherapy.

It has been argued that, in such patients, the addition of synthetic LT3 to standard LT4 therapy would create a more natural treatment plan [13]. The majority of Clinical Guidelines have addressed this issue and recommend against the routine use of combination therapy, but European, UK and ATA guidelines recommend combination therapy as an individual experimental approach, but only in some circumstances [13, 65, 68, 76]. The 2012 European Thyroid Association guidelines only recommend combination therapy as an experimental approach in patients with ongoing symptoms despite good adherence to LT4 therapy, and a serum TSH within the normal reference range for longer than 6 months [76]. The Italian Society of Endocrinology and the Italian Thyroid Association endorsed this instance in a 2016 paper [77]. Prior to commencing combined therapy, other autoimmune conditions (e.g. type 1 diabetes mellitus, autoimmune B12 deficiency, adrenal insufficiency, coeliac disease) must be ruled out and, if symptoms do not improve after 3 months, the patient should be shifted back to T4 monotherapy [76].

Another matter of debate is the treatment of subclinical hypothyroidism with levothyroxine. While there is consensus on the need to treat subclinical hypothyroidism with levothyroxine in pregnant women and in those contemplating pregnancy, in order to decrease the risk of pregnancy complications and effects on infant cognitive development, treatment of non-pregnant adults remains controversial [78]. Subclinical hypothyroidism is considered a sign of early thyroid failure [3, 79,80,81] and is defined as serum TSH concentrations above the reference range associated with a normal concentrations of free thyroxine. However, there is debate about which upper reference range of serum TSH should be used as a threshold for treatment [3, 80, 81]. It is believed that treatment of subclinical hypothyroidism with levothyroxine may prevent progression to overt hypothyroidism, as well as reduce the occurrence of coronary artery disease and improve neuropsychiatric and musculoskeletal symptoms associated with hypothyroidism [82, 83]. However, these benefits must be balanced against the risk of cardiovascular, neuropsychiatric and musculoskeletal side effects associated with the administration not only of excess levothyroxine but also of a normal substitution dose [82]. Indeed, there is evidence to suggest that, at least in very old patients, subclinical hypothyroidism may confer a longevity benefit over euthyroidism, with patients with lower levels of circulating T4 living longer [84]. Since there is currently a lack of data regarding the benefits/risks of treatment of subclinical hypothyroidism [80, 81, 83, 85], the decision on whether or not to treat should be individualised [79, 80].

Further studies are clearly warranted in the areas of subclinical hypothyroidism and regarding the use of levothyroxine monotherapy versus combination therapy with LT3. The rates of underdiagnosis and undertreatment of hypothyroidism and the issue of iodine insufficiency must also be addressed. However, lifelong treatment with levothyroxine has successfully treated many people with hypothyroidism over the last 60 years, and will continue to benefit many others in the future.


  1. Guglielmi R, Grimaldi F, Negro R, et al. Shift from levothyroxine tablets to liquid formulation at breakfast improves quality of life of hypothyroid patients. Endocr Metab Immune Disord Drug Targets. 2018;18:235–40.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Malaty W. Primary hypothyroidism. 2017. Accessed 4 Jan 2017.

  3. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet. 2017;390:1550–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Gaitonde DY, Rowley KD, Sweeney LB. Hypothyroidism: an update. Am Fam Physician. 2012;86:244–51.

    PubMed  Google Scholar 

  5. Magri F, Buonocore M, Oliviero A, et al. Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients. Eur J Endocrinol. 2010;163:279–84.

    CAS  Article  PubMed  Google Scholar 

  6. Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull. 2011;99:39–51.

    Article  PubMed  Google Scholar 

  7. Carle A, Laurberg P, Pedersen IB, et al. Epidemiology of subtypes of hypothyroidism in Denmark. Eur J Endocrinol. 2006;154:21–8.

    CAS  Article  PubMed  Google Scholar 

  8. Asvold BO, Vatten LJ, Bjoro T. Changes in the prevalence of hypothyroidism: the HUNT Study in Norway. Eur J Endocrinol. 2013;169:613–20.

    CAS  Article  PubMed  Google Scholar 

  9. Garmendia Madariaga A, Santos Palacios S, Guillen-Grima F, Galofre JC. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab. 2014;99:923–31.

    Article  CAS  Google Scholar 

  10. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977;7:481–93.

    CAS  Article  Google Scholar 

  11. Knudsen N, Bulow I, Jorgensen T, et al. Comparative study of thyroid function and types of thyroid dysfunction in two areas in Denmark with slightly different iodine status. Eur J Endocrinol. 2000;143:485–91.

    CAS  Article  PubMed  Google Scholar 

  12. Dew R, Okosieme O, Dayan C, et al. Clinical, behavioural and pharmacogenomic factors influencing the response to levothyroxine therapy in patients with primary hypothyroidism-protocol for a systematic review. Syst Rev. 2017;6:60.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kraut E, Farahani P. A systematic review of clinical practice guidelines’ recommendations on levothyroxine therapy alone versus combination therapy (LT4 plus LT3) for hypothyroidism. Clin Invest Med. 2015;38:E305–13.

    CAS  Article  PubMed  Google Scholar 

  14. Malik BA, Butt MA. Is delayed diagnosis of hypothyroidism still a problem in Faisalabad, Pakistan. J Pak Med Assoc. 2008;58:545–9.

    PubMed  Google Scholar 

  15. Smallridge RC, Ladenson PW. Hypothyroidism in pregnancy: consequences to neonatal health. J Clin Endocrinol Metab. 2001;86:2349–53.

    CAS  Article  PubMed  Google Scholar 

  16. Raval AD, Sambamoorthi U. Incremental healthcare expenditures associated with thyroid disorders among individuals with diabetes. J Thyroid Res. 2012;2012:418345.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ott J, Promberger R, Kober F, et al. Hashimoto’s thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter. Thyroid. 2011;21:161–7.

    Article  PubMed  Google Scholar 

  18. Shin YW, Choi YM, Kim HS, et al. Diminished quality of life and increased brain functional connectivity in patients with hypothyroidism after total thyroidectomy. Thyroid. 2016;26:641–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Vigario Pdos S, Vaisman F, Coeli CM, et al. Inadequate levothyroxine replacement for primary hypothyroidism is associated with poor health-related quality of life-a Brazilian multicentre study. Endocrine. 2013;44:434–40.

    Article  CAS  PubMed  Google Scholar 

  20. Thvilum M, Brandt F, Brix TH, Hegedus L. Hypothyroidism is a predictor of disability pension and loss of labor market income: a Danish register-based study. J Clin Endocrinol Metabol. 2014;99:3129–35.

    CAS  Article  Google Scholar 

  21. Thvilum M, Brandt F, Almind D, et al. Excess mortality in patients diagnosed with hypothyroidism: a nationwide cohort study of singletons and twins. J Clin Endocrinol Metabol. 2013;98:1069–75.

    CAS  Article  Google Scholar 

  22. World Health Organization. WHO model list of essential medicines. 2017. Accessed 4 Jan 2019.

  23. Abdalla SM, Bianco AC. Defending plasma T3 is a biological priority. Clin Endocrinol. 2014;81:633–41.

    CAS  Article  Google Scholar 

  24. Larsen PR, Silva JE, Kaplan MM. Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications. Endocr Rev. 1981;2:87–102.

    CAS  Article  PubMed  Google Scholar 

  25. Kronenberg H, Melmed S, Polonsky K, Larsen PR. Principles of endocrinology. In: Kronenberg H, Melmed S, Polonsky K, Larsen PR, editors. Williams textbook of endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2007. p. 3–11.

    Google Scholar 

  26. Persani L. Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97:3068–78.

    CAS  Article  PubMed  Google Scholar 

  27. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34.

    CAS  Article  PubMed  Google Scholar 

  28. Knudsen N, Jorgensen T, Rasmussen S, Christiansen E, Perrild H. The prevalence of thyroid dysfunction in a population with borderline iodine deficiency. Clin Endocrinol. 1999;51:361–7.

    CAS  Article  Google Scholar 

  29. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489–99.

    CAS  Article  PubMed  Google Scholar 

  30. Aoki Y, Belin RM, Clickner R, et al. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999–2002). Thyroid. 2007;17:1211–23.

    Article  PubMed  Google Scholar 

  31. McLeod DS, Caturegli P, Cooper DS, Matos PG, Hutfless S. Variation in rates of autoimmune thyroid disease by race/ethnicity in US military personnel. JAMA. 2014;311:1563–5.

    CAS  Article  PubMed  Google Scholar 

  32. Sichieri R, Baima J, Marante T, et al. Low prevalence of hypothyroidism among Black and Mulatto people in a population-based study of Brazilian women. Clin Endocrinol (Oxf). 2007;66:803–7.

    Article  Google Scholar 

  33. Bougma K, Aboud FE, Harding KB, Marquis GS. Iodine and mental development of children 5 years old and under: a systematic review and meta-analysis. Nutrients. 2013;5:1384–416.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. World Health Organization. Assessment of iodine deficiency disorders and monitoring their elimination. A guide for programme managers. 2007. Accessed 4 Jan 2019.

  35. Bath SC, Steer CD, Golding J, Emmett P, Rayman MP. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet. 2013;382:331–7.

    CAS  Article  PubMed  Google Scholar 

  36. Caldwell KL, Pan Y, Mortensen ME, et al. Iodine status in pregnant women in the National Children’s Study and in U.S. women (15–44 years), National Health and Nutrition Examination Survey 2005–2010. Thyroid. 2013;23:927–37.

  37. Magri F, Zerbini F, Gaiti M, et al. Poverty and immigration as a barrier to iodine intake and maternal adherence to iodine supplementation. J Endocrinol Invest. 2019;42:435–42.

    CAS  Article  PubMed  Google Scholar 

  38. Tomer Y. Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics. Annu Rev Pathol. 2014;9:147–56.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Carle A, Laurberg P, Knudsen N, et al. Thyroid peroxidase and thyroglobulin auto-antibodies in patients with newly diagnosed overt hypothyroidism. Autoimmunity. 2006;39:497–503.

    CAS  Article  PubMed  Google Scholar 

  40. Collet TH, Bauer DC, Cappola AR, et al. Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis. J Clin Endocrinol Metabol. 2014;99:3353–62.

    CAS  Article  Google Scholar 

  41. Pedersen IB, Knudsen N, Jorgensen T, et al. Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin Endocrinol. 2003;58:36–42.

    Article  Google Scholar 

  42. Hashimoto H. Zur Kenntniss der lymphomatösen Veränderung der Schilddrüse (Struma lymphomatosa). Archiv Klin Chir. 1912;97:219–48.

    Google Scholar 

  43. Carle A, Pedersen IB, Knudsen N, et al. Thyroid volume in hypothyroidism due to autoimmune disease follows a unimodal distribution: evidence against primary thyroid atrophy and autoimmune thyroiditis being distinct diseases. J Clin Endocrinol Metabol. 2009;94:833–9.

    CAS  Article  Google Scholar 

  44. Laurberg P, Cerqueira C, Ovesen L, et al. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab. 2010;24:13–27.

    CAS  Article  PubMed  Google Scholar 

  45. Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med. 2006;354:2783–93.

    CAS  Article  PubMed  Google Scholar 

  46. Kim D. The role of vitamin D in thyroid diseases. Int J Mol Sci. 2017;18:1949.

    Article  CAS  PubMed Central  Google Scholar 

  47. Wu Q, Rayman MP, Lv H, et al. Low population selenium status is associated with increased prevalence of thyroid disease. J Clin Endocrinol Metabol. 2015;100:4037–47.

    CAS  Article  Google Scholar 

  48. Carle A, Pedersen IB, Knudsen N, et al. Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case-control study. Eur J Endocrinol. 2012;167:483–90.

    CAS  Article  PubMed  Google Scholar 

  49. Andersen SL, Carle A, Olsen J, Laurberg P. Hypothyroidism incidence in and around pregnancy: a Danish nationwide study. Eur J Endocrinol. 2016;175:387–93.

    CAS  Article  PubMed  Google Scholar 

  50. Sweeney LB, Stewart C, Gaitonde DY. Thyroiditis: an integrated approach. Am Fam Physician. 2014;90:389–96.

    PubMed  Google Scholar 

  51. Watt T, Hegedus L, Rasmussen AK, et al. Which domains of thyroid-related quality of life are most relevant? Patients and clinicians provide complementary perspectives. Thyroid. 2007;17:647–54.

    Article  PubMed  Google Scholar 

  52. Canaris GJ, Tape TG, Wigton RS. Thyroid disease awareness is associated with high rates of identifying subjects with previously undiagnosed thyroid dysfunction. BMC Public Health. 2013;13:351.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Okosieme O, Gilbert J, Abraham P, et al. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol (Oxf). 2016;84:799–808.

    Article  Google Scholar 

  54. Carle A, Pedersen IB, Knudsen N, et al. Gender differences in symptoms of hypothyroidism: a population-based DanThyr study. Clin Endocrinol (Oxf). 2015;83:717–25.

    CAS  Article  Google Scholar 

  55. Carle A, Pedersen IB, Knudsen N, et al. Hypothyroid symptoms fail to predict thyroid insufficiency in old people: a population-based case-control study. Am J Med. 2016;129:1082–92.

    Article  PubMed  Google Scholar 

  56. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med. 1997;12:544–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Mancini A, Di Segni C, Raimondo S, Olivieri G, Silvestrini A, Meucci E, Currò D. Thyroid hormones, oxidative stress, and inflammation. Mediat Inflamm. 2016.

  58. Zhou J, Cheng G, Pang H, Liu Q, Liu Y. The effect of 131I-induced hypothyroidism on the levels of nitric oxide NO), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), total nitric oxide synthase (NOS) activity, and expression of NOS isoforms in rats. Bosn J Basic Med Sci. 2018;18(4):305–12.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metabol. 2002;87:1068–72.

    CAS  Article  Google Scholar 

  60. Elmor R, Sandulli W, Carter CA. The economic impact of changing levothyroxine formulations in difficult-to-treat hypothyroid patients: an evidence-based model. Pharmacoeconomics. 2017;2:1–10.

    Google Scholar 

  61. Bettencourt A-M, Serrano J-A. Un cas de myxoedème (cachexie pachydermique) traité par la greffe hypodermique du corps thyoïde d’un mouton. Congres de l’Association Francaise pour l’Avancement des Sciences; 1890; Limoges, France.

  62. Murray GR. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. Br Med J. 1891;2:796–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. American Association of Clinical Endocrinologists. AACE, TES, and ATA joint position statement on the use and interchangeability of thyroxine products. 2004. Accessed 3 Jan 2019.

  64. Bryan J. Levothyroxine: from sheep thyroid injections to synthetic formulations. Pharm J. 2013;291:90.

    Google Scholar 

  65. Hennessey JV. The emergence of levothyroxine as a treatment for hypothyroidism. Endocrine. 2017;55:6–18.

    CAS  Article  PubMed  Google Scholar 

  66. Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015;71:549–67.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18:988–1028.

    Article  PubMed  Google Scholar 

  68. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670–751.

    Article  PubMed  PubMed Central  Google Scholar 

  69. IMS Institute for Healthcare Informatics. Medicine use and shifting costs of healthcare. IMS Health. 2014;46.

  70. Fuentes AV, Pineda MD, Venkata KCN. Comprehension of top 200 prescribed drugs in the US as a resource for pharmacy teaching, training and practice. Pharmacy (Basel). 2018;6.

  71. Brenta G, Vaisman M, Sgarbi JA, et al. Clinical practice guidelines for the management of hypothyroidism. Arq Bras Endocrinol Metabol. 2013;57:265–91.

    Article  PubMed  Google Scholar 

  72. Jonklaas J. Update on the treatment of hypothyroidism. Curr Opin Oncol. 2016;28:18–25.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Toward Optimized Practice (TOP) Endocrine Working Group. Investigation and management of primary thyroid dysfunction clinical practice guideline. Edmonton, AB: Toward Optimized Practice. 2014. Accessed 3 Jan 2019.

  74. Alexander EK, Pearce EN, Brent GA, et al. 2017 guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27:315–89.

    Article  PubMed  Google Scholar 

  75. Perros P. European Thyroid Association guidelines on L-T4 + L-T3 combination for hypothyroidism: a weary step in the right direction. Eur Thyroid J. 2012;1:51–4.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1:55–71.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Biondi B, Bartalena L, Chiovato L, et al. Recommendations for treatment of hypothyroidism with levothyroxine and levotriiodothyronine: a 2016 position statement of the Italian Society of Endocrinology and the Italian Thyroid Association. J Endocrinol Invest. 2016;39:1465–74.

    CAS  Article  PubMed  Google Scholar 

  78. Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat and how. Drugs. 2012;72:17–33.

    CAS  Article  PubMed  Google Scholar 

  79. Delitala AP, Fanciulli G, Maioli M, Delitala G. Subclinical hypothyroidism, lipid metabolism and cardiovascular disease. Eur J Intern Med. 2017;38:17–24.

    CAS  Article  PubMed  Google Scholar 

  80. Javed Z, Sathyapalan T. Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab. 2016;7:12–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Redford C, Vaidya B. Subclinical hypothyroidism: should we treat? Post Reprod Health. 2017;23:55–62.

    Article  PubMed  Google Scholar 

  82. Tng EL. The debate on treating subclinical hypothyroidism. Singapore Med J. 2016;57:539–45.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Udovcic M, Pena RH, Patham B, Tabatabai L, Kansara A. Hypothyroidism and the heart. Methodist Debakey Cardiovasc J. 2017;13:55–9.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004;292:2591–9.

    CAS  Article  PubMed  Google Scholar 

  85. Peeters RP. Subclinical hypothyroidism. N Engl J Med. 2017;376:2556–65.

    Article  PubMed  Google Scholar 

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This supplement has been sponsored by Merck.


Sponsorship for this manuscript, the Rapid Service and Open Access Fees were funded by Merck.

Medical Writing, Editorial, and Other Assistance

We would like to thank Andrea Bothwell and Marion Barnett who drafted an outline and early version of this manuscript on behalf of Springer Healthcare. This medical writing assistance was funded by Merck.


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Luca Chiovato, Flavia Magri and Allan Carlé have nothing to disclose.

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Chiovato, L., Magri, F. & Carlé, A. Hypothyroidism in Context: Where We’ve Been and Where We’re Going. Adv Ther 36, 47–58 (2019).

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  • Chronic patient
  • Endocrinology
  • Hypothyroidism
  • Levothyroxine
  • Management
  • Treatment