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
SeminarHypothyroidism
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
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