Hypothyroidism

doi:10.1016/S0140-6736(17)30703-1

The Lancet

Volume 390, Issue 10101, 23–29 September 2017, Pages 1550-1562

https://doi.org/10.1016/S0140-6736(17)30703-1 Get rights and content

Summary

Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.

Introduction

Hypothyroidism refers to the common pathological condition of thyroid hormone deficiency. If untreated, it can lead to serious adverse health effects and ultimately death. Because of the large variation in clinical presentation and general absence of symptom specificity, the definition of hypothyroidism is predominantly biochemical. Overt or clinical primary hypothyroidism is defined as thyroid-stimulating hormone (TSH) concentrations above the reference range and free thyroxine concentrations below the reference range. Mild or subclinical hypothyroidism, which is commonly regarded as a sign of early thyroid failure, is defined by TSH concentrations above the reference range and free thyroxine concentrations within the normal range. Subclinical hypothyroidism has been reviewed in a previous Lancet Seminar¹ and is therefore not the focus here.

Whether the existing reference ranges of TSH and free thyroxine should be used to define thyroid dysfunction is a matter of debate. This issue is of clinical importance because the reference ranges are generally used as a threshold for treatment. Thyroid hormone replacement with levothyroxine is the standard treatment for patients with hypothyroidism. However, a substantial proportion of patients treated with levothyroxine have persistent complaints despite reaching the biochemical therapy targets, which has prompted the question of whether levothyroxine treatment is sufficient for all patients or whether alternative therapies (eg, combination with liothyronine preparations) could be adopted. Hypothyroidism in children and pregnant women are considered separate topics and have been discussed elsewhere.2, 3

Section snippets

Prevalence and risk factors

The prevalence of overt hypothyroidism in the general population varies between 0·3% and 3·7% in the USA and between 0·2% and 5·3% in Europe,4, 5, 6, 7, 8 depending on the definition used. A meta-analysis⁷ of studies across nine European countries estimated the prevalence of undiagnosed hypothyroidism, including both overt and mild cases, at around 5%. Differences in iodine status affect the prevalence of hypothyroidism, which occurs more frequently both in populations with a relatively high

Causes

Hypothyroidism can be classified as primary (due to thyroid hormone deficiency), secondary (due to TSH deficiency), tertiary (due to thyrotropin-releasing hormone deficiency), and peripheral (extra-thyroidal; panel). Central hypothyroidism (including both secondary and tertiary) and peripheral hypothyroidism are rare and account for less than 1% of cases.²²

Myxedema coma and severe hypothyroidism

The clinical manifestations of hypothyroidism range from life threatening—in the case of myxedema coma—to no signs or symptoms. Myxedema coma, which was first described in the late 1900s as an outcome of long-standing untreated and severe hypothyroidism, has become a rare condition. Nevertheless, because the disease course is striking, with mortality of 40% despite treatment, early recognition is vital.⁵¹ Myxedema coma leads to an altered mental status, hypothermia, progressive lethargy, and

Diagnosis

Primary hypothyroidism is defined by TSH concentrations above the reference range (most commonly used 0·4–4·0 mIU/L) and free thyroxine concentrations below the reference range, which is dependent on the type of assay used and the population studied (figure 1). The US Preventive Service Task Force⁸³ has suggested reserving the term overt hypothyroidism for cases in which patients present with symptoms. However, such a definition is challenging in practice because of the large variability in

Treatment

Levothyroxine monotherapy in solid formulation, taken on an empty stomach, is the treatment of choice. The presence of clinical features of hypothyroidism, with biochemical confirmation of overt hypothyroidism, is the indication for treatment initiation. No rationale exists for avoiding the prescription of generic preparations, but switches between levothyroxine products in patients who are stable are not recommended.¹⁰¹ The optimal daily dose in overt hypothyroidism is 1·5–1·8 μg per kg of

Directions for future research

Although great advances have been made in the identification of causes, knowledge of clinical implications, diagnosis, and treatment of hypothyroidism, several unanswered questions remain, especially regarding diagnosis and treatment.

Many risk factors have been identified for abnormal TSH concentrations, free thyroxine concentrations, and thyroid disease, but only a small proportion of the variability is explained.¹³⁹ Therefore, identification of risk factors is important. Increasing evidence

Search strategy and selection criteria

We searched Embase, MEDLINE, and the Cochrane database between Jan 1, 2000 and Sept 22, 2016, for articles published in or translated into English. The full search and search terms are provided in the appendix. We mainly selected publications from the past 3 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search and selected those we judged relevant. We supplemented the search with mainly

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Are resting metabolic rate and clinical symptoms affected by variation of serum thyroid stimulating hormone levels within the normal range in healthy and women with hypothyroidism? A case–control study
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It is unclear whether variation in thyroid stimulating hormone (TSH) levels within the reference range affect energy expenditure and clinical symptoms and even within the normal range of TSH levels, resting energy expenditure may alter. The aim of the present study was to determine whether treated hypothyroid subjects and healthy subjects with a low-normal TSH range (0.3–2.3 mIU/L) have better clinical outcomes and increased energy expenditure than those with a high-normal TSH range (2.3–4.3 mIU/L).
This was a case–control study of 160 overweight/obese women with TSH levels across the reference range of 0.3–4.3 mU/l. Subjects were paired in four groups: healthy subjects with low-normal target TSH (n = 40), healthy subjects with high-normal target TSH (n = 40), subjects with treated hypothyroidism with low-normal target TSH (n = 40), and subjects with treated hypothyroidism with high-normal target TSH (n = 40). Resting energy expenditure (RMR), dietary intake, body composition, physical activity, and biochemical markers were assessed.
Subjects with low-normal (≤2.3 mU/L) and high-normal (>2.3 mU/L) TSH levels did not differ in terms of RMR, serum T3 levels, and clinical symptoms except fatigue (P = 0.013). However, serum fT4 levels were found to be significantly different between the study groups (P = 0.002). Serum fT4 concentration was the highest in subjects with treated hypothyroidism with low-normal target TSH.
Variation in serum TSH levels within the reference range did not significantly affect REE and clinical symptoms except fatigue in healthy and women with hypothyroidism.
Sex differences in effectiveness and adverse effects of mood stabilizers and antipsychotics: A systematic review
2024, Journal of Affective Disorders
Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically.
We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk.
Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies.
Substantial heterogeneity among the studies precluded performing a meta-analysis.
Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention.
Association between hypothyroidism subtypes and major depression: A two-sample Mendelian randomization study
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The causal relationship between different hypothyroidism subtypes and the risk of major depression (MD) is yet to be fully elucidated. This study aimed to determine if there's a causal relationship between various hypothyroidism subtypes (and related factors) and the risk of MD.
This genetic association study utilized a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between various hypothyroidism subtypes and MD risk. Genome-Wide Association Study (GWAS) summary statistics were obtained from the FinnGen and the UK Biobank. Instrumental variables (IVs) were chosen based on single nucleotide polymorphisms (SNPs).
Among the analyzed hypothyroidism subtypes and related factors, “Hypothyroidism, strict autoimmune” (HTCBSA) and “Hypothyroidism, levothyroxin purchases” (HT/LP) demonstrated a statistically significant positive causal relationship with MD, with odds ratios of 1.020 (95 % CI: 1.004–1.037) and 1.022 (95 % CI: 1.005–1.040), respectively. The sensitivity analysis supported the robustness of these findings, showing no significant horizontal pleiotropy and confirming the stability of results when individual SNPs were removed. “Congenital iodine-deficiency syndrome/hypothyroidism” (CIDS/HT), “Postinfectious hypothyroidism” (PHT), “Hypothyroidism due to medicaments and other exogenous substances” (HDTDM and OES), “Thyroid Stimulating Hormone” (TSH), “Thyrotropin-releasing hormone” (THRH), and “Hypothyroidism, strict autoimmune, 3 medication purchases required” (HTCBSA/3MPR) showed no significant causal relationship with MD.
The study population was limited to individuals of European ancestry, and there may be certain genetic differences between different ethnic groups.
This MR study suggests a potential causal relationship between certain hypothyroidism subtypes (specifically HTCBSA and HT/LP) and an increased risk of MD.
Association between per- and polyfluoroalkyl substances exposure and thyroid function biomarkers among females attending a fertility clinic
2024, Environmental Pollution
Per- and polyfluoroalkyl substances (PFAS) exposure was associated with changes in thyroid function in pregnant mothers and the general population. Limited such evidence exists in other susceptible populations such as females with fertility problems. This cross-sectional study included 287 females seeking medically assisted reproduction at a fertility clinic in Massachusetts, United States, between 2005 and 2019. Six long-alkyl chain PFAS, thyroid hormones, and autoimmune antibodies were quantified in baseline serum samples. We used generalized linear models and quantile g-computation to evaluate associations of individual PFAS and their total mixture with thyroid biomarkers. Most females were White individuals (82.7%), had graduate degrees (57.8%), and nearly half had unexplained subfertility (45.9%). Serum concentrations of all examined PFAS and their mixture were significantly associated with 2.6%–5.6% lower total triiodothyronine (TT3) concentrations. Serum concentrations of perfluorononanoate (PFNA), perfluorodecanoate (PFDA), and perfluoroundecanoate (PFUnDA), and of the total mixture were associated with higher ratios of free thyroxine (FT4) to free triiodothyronine (FT3). No associations were found for PFAS and TSH or autoimmune antibodies. Our findings support the thyroid-disrupting effect of long alkyl-chain PFAS among a vulnerable population of subfertile females.
Thyroid allostasis in drug-free affective disorder patients
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To assess the thyroid allostasis in drug-free patients with affective disorder.
Patients with major depressive disorder or bipolar disorder as drug-free, defined as those without psychiatric drugs exposure for at least 4 months before admission, from a tertiary hospital were recruited in this cross-sectional study. The primary outcomes were “structure parameters of thyroid homeostasis”, which include “thyroid's secretory capacity” (SPINA-GT), “sum step-up activity of deiodinases” (SPINA-GD), the ratio of total to free thyroxine and “thyroid homeostasis central set point” (TSH index and “thyroid feedback quantile-based index” [TFQI]), calculated by TSH and thyroid hormones measured at admission. A healthy population and non-affective psychiatric disorder (schizophrenia) from the same catchment area were recruited as two comparison groups.
A total of 1263 cases of major depressive disorder, 1619 cases of bipolar disorder, 1186 cases of schizophrenia, and 162 healthy controls were included in the study. Compared to healthy control, GD and ratio of total to free thyroxine were lower in affective disorders. Bipolar with mania episode had higher GT than bipolar with depressive episode and major depressive disorder (median level at 3.70 vs. 3.04 and 3.03, respectively). Compared with healthy control, schizophrenia had higher TSH index and TFQI, but no increase in these parameters in major depressive disorder and bipolar disorder.
Affective disorders have a unique profile of thyroid allostasis with impaired step-up deiodinase activity and reduced serum protein binding of thyroid hormones, but no change in thyroid homeostasis central set point. Mania episode may be associated with higher thyroid secretory capacity.
Association between short-term air pollution exposure and perturbation in thyrotropin levels in 1.38 million Chinese women: A national longitudinal analysis, 2014–2019
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Prevalence of subclinical hypothyroidism substantially increased during the last decade in China, which has been commonly/clinically diagnosed as elevation in thyrotropin (thyroid-stimulating hormone [TSH]). Tobacco smoke containing toxic substances has been linked to thyroid dysfunction; however, data on perturbation of TSH following air pollution exposure in human has not been assessed at nationwide population level. We investigated the longitudinal impact of daily ambient air pollution estimated at residential level on serum TSH in 1.38 million women from China’s 29 mainland provinces between 2014 and 2019. We observed that particulate matter with aerodynamic diameter ≤ 10 and ≤ 2.5 µm (PM_10, PM_2.5) and nitrogen dioxide (NO₂) at cumulative lag 0–7 days of exposure were associated with percent elevations in TSH (0.88% [95% CI: 0.71, 1.05] per [interquartile range, IQR: 54.8 μg/m³] of PM₁₀; 0.89% [95% CI, 0.71, 1.07] per IQR [40.3 μg/m³] of PM_2.5; 2.01% [95% CI: 1.81, 2.22] per IQR [27.4 μg/m³] of NO₂). Greater associations were observed in participants living in areas with ≥adequate iodine intake and those with low BMI levels and high inflammation status. Our results suggest that increased concentrations of recent ambient air pollutants at exposure ranges commonly encountered in Asia were associated with increases in TSH, supporting disturbing role of short-term air pollution exposure on the regulation of thyroid hormone homeostasis.

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View full text

SeminarHypothyroidism

Summary

Introduction

Section snippets

Prevalence and risk factors

Causes

Myxedema coma and severe hypothyroidism

Diagnosis

Treatment

Directions for future research

Search strategy and selection criteria

Lancet

Lancet Diabetes Endocrinol

Best Pract Res Clin Endocrinol Metab

Am J Hum Genet

Lancet

Lancet Diabetes Endocrinol

Lancet

Am J Geriatr Psychiatry

Clin Oncol (R Coll Radiol)

Biochim Biophys Acta

Endocr Pract

Am J Med

J Clin Lipidol

Am J Med

Lancet

Endocr Pract

Lancet Diabetes Endocrinol

Endocr Pract

Subclinical hypothyroidism in childhood—current knowledge and open issues

Nat Rev Endocrinol

Changes in the prevalence of hypothyroidism: the HUNT Study in Norway

Eur J Endocrinol

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

The Colorado thyroid disease prevalence study

Arch Intern Med

The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis

J Clin Endocrinol Metab

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

Effect of iodine intake on thyroid diseases in China

N Engl J Med

Low prevalence of hypothyroidism among black and Mulatto people in a population-based study of Brazilian women

Clin Endocrinol

Variation in rates of autoimmune thyroid disease by race/ethnicity in US military personnel

JAMA

Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case-control study

Eur J Endocrinol

Tobacco smoking and thyroid function: a population-based study

Arch Intern Med

Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins

J Clin Endocrinol Metab

Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort

Clin Endocrinol

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function

PLoS Genet

Novel associations for hypothyroidism include known autoimmune risk loci

PLoS One

Detection and interpretation of shared genetic influences on 42 human traits

Nat Genet

Genetic determination of the hypothalamic-pituitary-thyroid axis: where do we stand?

Endocr Rev

Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges

J Clin Endocrinol Metab

Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study

Eur J Endocrinol

Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques

J Clin Endocrinol Metab

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease

PLoS Genet

A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations

J Clin Endocrinol Metab

Discontinuation of smoking increases the risk for developing thyroid peroxidase antibodies and/or thyroglobulin antibodies: a prospective study

J Clin Endocrinol Metab

Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III)

J Clin Endocrinol Metab

Low population selenium status is associated with increased prevalence of thyroid disease

J Clin Endocrinol Metab

Iodine and mental development of children 5 years old and under: a systematic review and meta-analysis

Seminar
Hypothyroidism