Clinical presentation and implications on the hypothyroidism
April 7, 2024 | by hypothyroidism.blog
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 bradycardia and can eventually result in multiple organ dysfunction syndrome and death. Therefore, early initiation of thyroid hormone therapy and other supportive measures is crucial.52
Although very rare, severe primary hypothyroidism can lead to pituitary hyperplasia with concomitant pituitary pathology (eg, secondary adrenal insufficiency) and symptoms (eg, amenorrhoea).53
Signs and symptoms
The most common symptoms of hypothyroidism in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but the clinical presentation can include a wide variety of symptoms that differ with age, sex, and time between onset and diagnosis (table 1).54,55 The symptoms for the diagnosis of hypothyroidism are non-specific, especially in elderly patients who present with fewer and less classic signs and symptoms than younger individuals.55 An increase in the severity of symptoms might predict hypothyroidism, since a change in seven or more symptoms in the past year increases the likelihood of hypothyroidism (likelihood ratio 8–7).56 However, in a case-control study,57 none of 34 hypothyroidism-related symptoms could be used to identify patients with hypothyroidism. Furthermore, 15% of patients with autoimmune hypothyroidism are asymptomatic or report only one hypothyroidism-associated symptom, whereas 70% of euthyroid controls have one or more thyroid- associated complaints.57
Table 1:
Clinical presentation and implications of hypothyroidism
| Presentation | Signs and implications | |
|---|---|---|
| General metabolism | Weight gain, cold intolerance, fatigue | Increase in body-mass index, low metabolic rate, myxedema*, hypothermia* |
| Cardiovascular | Fatigue on exertion, shortness of breath | Dyslipidaemia, bradycardia, hypertension, endothelial dysfunction or increased intima-media thickness*, diastolic dysfunction*, pericardial effusion*, hyperhomocysteinemia*, electrocardiogram changes* |
| Neurosensory | Hoarseness of voice, decreased taste, vision, or hearing | Neuropathy, cochlear dysfunction, decreased olfactory and gustatory sensitivity |
| Neurological and psychiatric | Impaired memory, paresthesia, mood impairment | Impaired cognitive function, delayed relaxation of tendon reflexes, depression*, dementia*, ataxia*, Carpal tunnel syndrome and other nerve entrapment syndromes*, myxedema coma* |
| Gastrointestinal | Constipation | Reduced oesophageal motility, non-alcoholic fatty liver disease*, ascites (very rare) |
| Endocrinological | Infertility and subfertility, menstrual disturbance, galactorrhoea | Goiter, glucose metabolism dysregulation, infertility, sexual dysfunction, increased prolactin, pituitary hyperplasia* |
| Musculoskeletal | Muscle weakness, muscle cramps, arthralgia | Creatine phosphokinase elevation, Hoffman’s syndrome*, osteoporotic fracture* (most probably caused by overtreatment) |
| Haemostasis and haematological | Bleeding, fatigue | Mild anaemia, acquired von Willebrand disease*, decreased protein C and S*, increased red cell distribution width*, increased mean platelet volume* |
| Skin and hair | Dry skin, hair loss | Coarse skin, loss of lateral eyebrows*, yellow palms of the hand*, alopecia areata* |
| Electrolytes and kidney function | Deterioration of kidney function | Decreased estimated glomerular filtration rate, hyponatraemia* |
Hypothyroidism has clinical implications related to nearly all major organs (table 1), but the cardiovascular system is the most robustly studied. Hypothyroidism results in increased vascular resistance, decreased cardiac output, decreased left ventricular function, and changes in several other markers of cardiovascular contractility. Myocardial injuries and pericardial effusions are more common in patients with hypothyroidism than in matched euthyroid controls.58 Furthermore, patients with hypothyroidism have a higher prevalence of cardiovascular risk factors and often have features of metabolic syndrome, including hypertension, increased waist circumference, and dyslipidaemia.59 Hypothyroidism also increases total cholesterol, low-density lipoprotein, and homocysteine concentrations.
Patients with acute hypothyroidism, in the context of thyroid cancer treatment, show a decline in mood and quality of life.60 Hypothyroidism is considered a cause of reversible dementia; however, how often this occurs and in what proportion of patients dementia is truly reversible is unclear.61 Other manifestations include neurosensory, musculoskeletal, and gastrointestinal signs and symptoms (table 1). Because of the pleiotropic effects of thyroid hormone, hypothyroidism can also affect the course of other disorders. For example, statin intolerance is more prevalent in individuals with hypothyroidism than in controls without hypothyroidism.62
Long-term outcomes
Most long-term consequences of hypothyroidism have been studied in the context of subclinical hypothyroidism, because overt hypothyroidism is generally treated. Few studies63–65 have investigated the association of hypothyroidism with all-cause mortality and results are mainly available for subclinical hypothyroidism. Results from a population-based follow-up study65 of 599 participants aged 85 years suggested that, in elderly populations, subclinical hypothyroidism might be associated with better survival than euthyroidism or suppressed TSH. However, this finding was not confirmed in a large individual participant-based meta-analysis63 that included more than 2500 participants (aged >80 years). This meta-analysis63 showed an increased risk of coronary heart disease events and mortality in those with higher TSH concentrations, particularly those with TSH concentrations above 10 mIU/L. However, the association between hypothyroidism and coronary artery disease has been recognised for a long time.66 Subclinical hypothyroidism with TSH concentrations above 10 mIU/L has also been associated with an increased risk of heart failure.63,67 Patients with hypothyroidism undergoing percutaneous coronary intervention have more major adverse cardiovascular and cerebral events than those with normal thyroid function and those with adequately treated hypothyroidism.68 By contrast, the association with stroke is less evident and might be apparent only in younger individuals (<65 years).69 Patients with hypothyroidism have fewer neurological deficits post-stroke than controls without elevated TSH concentrations;70 normally after a stroke localised hypothyroidism is observed as a result of deiodinase 3 induction in the ischaemic brain area.71,72 The risk of coronary heart disease in patients with subclinical hypothyroidism does not differ by thyroid peroxidase antibody concentrations, suggesting that autoimmunity per se is not a contributing factor to the association.73 Hypothyroidism can present with cognitive impairments and dementia but the association is controversial, because results from several population-based cohort studies74–77 showed a protective effect of elevated TSH concentrations on the risk of dementia.
Hypothyroidism has also been associated with nonalcoholic fatty liver disease, cancer mortality, arthritis, kidney dysfunction, and diabetes; however, in most cases causality is suggested but not proven.78–82
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 presentation of even severe hypothyroidism. Additionally, patients might recognise previous symptoms only after the initiation of levothyroxine treatment.
TSH=thryoid-stimulating hormone.
TSH has circadian fluctuations, with higher concentrations towards the evening. Patients with severe hypothyroidism show irregularity of TSH secretion.84 Seasonal variations have also been described, with higher TSH concentrations in winter and spring than in autumn and summer.85 No indications exist for routine measurement of total tri-iodothyronine, total thyroxine, or free tri-iodothyronine. Measurement of thyroid peroxidase antibody is not strictly necessary to diagnose hypothyroidism but is useful to affirm the diagnosis of autoimmune primary hypothyroidism. Hypothyroidism is often characterised by a hypoechogenic pattern on thyroid sonography, even in the absence of raised thyroid peroxidase antibody concentrations. However, in the absence of additional clinical indications, such as abnormal thyroid palpation, an ultrasound is not required.
Reference ranges of thyroid function tests
Most commercially available TSH and free thyroxine assays are immunoassays, and their reference ranges are statistically defined as between the 2 · 5th and 97 · 5th percentile in an apparently healthy population. Therefore, the reference ranges do not consider symptoms or the risk of adverse events or disease, which is demonstrated by studies showing an increased risk of adverse events with variations in thyroid function even within these reference ranges.76,86–89 Furthermore, the reference ranges differ with age, sex, and ethnic origin.90 The applied reference ranges for thyroid function have been a matter of debate in recent years.91,92 The upper limit of TSH reference ranges typically increases with age in adults, and age-specific reference ranges gave conflicting results in younger individuals in studies from the UK and Australia.93,94 Nevertheless, in both studies,93,94 the use of age-specific reference ranges led to a reclassification from abnormal to normal thyroid function predominantly in older individuals. Little information exists about the consequences of treatment and thus no convincing arguments have been put forward to change the applied reference ranges.
Conditions that interfere with diagnosis
Several conditions can interfere with the laboratory measurements of thyroid analytes. Interference should be suspected when thyroid function tests do not match the clinical presentation (figure 2). Human anti-animal antibodies in patient’s serum can cause falsely high TSH concentrations and can interfere with free thyroxine equilibrium dialysis platform assays. Heparin, including low-molecular-weight heparin, can lead to falsely elevated concentrations of free thyroxine.95 High intake of biotin, a popular over-the-counter supplement, can interfere with biotin-based hormone assays, leading to false results of thyroid function tests.
TSH=thryoid-stimulating hormone. TRH=thyrotropin-releasing hormone. *TSH can also be suppressed.
Free thyroxine measurement is important to the diagnosis of hypothyroidism (eg, central hypothyroidism) and during follow-up and treatment. The accuracy of free thyroxine immunoassays has been questioned in conditions that affect binding protein concentrations (ie, albumin or thyroxine-binding globulin), such as pregnancy or acute illness. However, free thyroxine assays generally perform well in daily clinical practice. Free thyroxine measured by liquid chromatography-tandem mass spectrometry seems to perform better than immunoassays in certain clinical conditions, such as acute illness and pregnancy,96 but is not available in most health-care facilities.
Independent of measurement artifacts, severe illness is characterised by low thyroid hormone status, but TSH concentration is generally within the normal range, although it can be transiently increased during recovery from a non-thyroidal illness.97 Changes in thyroid hormone metabolism, thyroid hormone transporters, and thyroid hormone receptors all have a role in the pathophysiology of non-thyroidal illness. Non-thyroidal illness occurs in different disease states, but is present in almost all critically ill patients.97 Thyroid function testing should therefore not be done in these patients, unless thyroid disease or central hypothyroidism is suspected. No evidence exists that thyroid hormone replacement therapy is beneficial in critically ill patients.
Screening
Despite the high prevalence of hypothyroidism, easy diagnostics, and cheap treatment, no consensus has been reached about TSH screening in specific subgroups of the general population. Several organisations—including the American Thyroid Association, American Association of Clinical Endocrinologists, and the Latin American Thyroid Society—recommend screening above a particular age (ranging from every 5 years for individuals aged >35 years to periodically for those aged ≥60 years), especially in women.98,99 The US Preventive Services Task Force83 found no evidence for or against screening, whereas the UK Royal College of Physicians100 suggests that screening of the general population is unjustified. However, evidence98 does support case finding in patients with dementia, infertility, autoimmune diseases, hypercholesterolaemia, dysmenorrhoea, or a family history of autoimmune hypothyroidism, in patients taking amiodarone or lithium, or in those at risk of iatrogenic hypothyroidism (eg, after neck radiation).
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 bodyweight.101–103 In patients with coronary artery disease, the starting dose is generally 12·5—25·0 μg per day and should be gradually increased on the basis of symptoms and TSH concentrations.101 This regimen is often preferred in the elderly, especially in patients with many co-morbidities.101,102 In younger patients without comorbidities, the full dose can usually be given from the start with adequate monitoring to avoid overtreatment. After the initiation of therapy, TSH measurement is repeated after 4–12 weeks and then every 6 months and, once stabilised, annually. Adjustments should be made according to laboratory findings, keeping in mind that in some patients (ie, those with low bodyweight or older patients) small changes in dose can have substantial effects on serum TSH concentrations. The clinical significance of low tri-iodothyronine concentrations in some patients despite reaching normal TSH concentrations is unknown. Routine measurement of tri-iodothyronine should not be used to assess treatment effectiveness.104
Women of childbearing age
Because of physiological changes during pregnancy, an increase in levothyroxine dose is required to maintain euthyroidism.105 Therefore, women of childbearing age with levothyroxine-treated hypothyroidism should be informed to increase their dose by 30% once pregnant and directly contact their physician for further guidance.106 Screening, the definition of subclinical hypothyroidism, and potential treatment during pregnancy are beyond the scope of this Seminar.107,108
Treatment targets
Treatment targets include normalisation of TSH concentrations and resolution of physical and mental complaints, while avoiding undertreatment or overtreatment.101 Nevertheless, an estimated 35—60% of patients treated with levothyroxine do not reach the target range of TSH (either overtreated or undertreated).109,110 Results from a retrospective cohort study in the UK109 showed that, after 5 years of levothyroxine therapy, almost 6% of patients have TSH concentrations below 0–1 mIU/L and more than 10% have TSH concentrations above 10–0 mIU/L. Overtreatment (ie, iatrogenic subclinical or overt hyperthyroidism) can have deleterious health effects, such as atrial fibrillation and osteoporosis, and should always be avoided, especially in the elderly and postmenopausal women. Undertreatment (ie, persistent thyroid hormone deficiency) can result in an increased risk of cardiovascular disease and persistent signs and symptoms. Treatment targets for central hypothyroidism are different from primary hypothyroidism because clinicians cannot rely on the so- called reflex TSH strategy. Further information on the treatment of central hypothyroidism can be found elsewhere.22
Failure to reach treatment targets
Factors that prevent patients from reaching therapy targets include prescription or intake of inadequate doses, interaction with supplements or medication, concurrent medical conditions, and non-adherence to therapy (table (table2).2). Lower levothyroxine doses are needed to suppress TSH secretion in the elderly and higher doses are needed after thyroidectomy. Levothyroxine treatment and therapy targets in the context of thyroid malignancy are beyond the scope of this Seminar.
Table 2:
Reasons for failure to reach levothyroxine treatment goals and recommendations
| Recommendations | |
|---|---|
| Elevated TSH with or without (persistent) symptoms | |
| Inadequate dose | Consider higher doses, especially in patients with no remaining functional thyroid capacity (eg, after total thyroidectomy or radioablation therapy for Graves’ disease) |
| Simultaneous intake of levothyroxine with food can impair absorption | Intake 30–60 min before breakfast or at bedtime (2–3 h after evening meal); discuss patient preference |
| Some drugs can affect levothyroxine absorption—eg, calcium carbonate*, ferrous sulfate*, proton pump inhibitors, aluminium containing antacid, sucralfate, and orlistat | Separate intake of levothyroxine from interfering medications and supplements (eg,4 h) |
| Some drugs can affect levothyroxine availability and requirement— eg, oestrogens, androgens, sertraline, phenobartbital†, carbamazepine, phenytoin, and rifampicin | Monitor TSH at initiation and adjust levothyroxine dose if required |
| Malabsorption due to gastrointestinal disease and conditions | Helicobacter pylori gastritis, coeliac disease, autoimmune atrophic gastritis, and diabetic gastropathy should be considered and treated if possible |
| Non-adherence | Common cause, but should be suspected after other causes have been excluded; consider thyroxine absorption test |
| Normal TSH and (persistent) symptoms | |
| Concurrent (autoimmune) disease or causes | Autoimmune atrophic gastritis with pernicious anaemia, Addison’s disease, diabetes, and rheumatoid arthritis could be considered |
| Inadequate thyroid hormone concentrations at the tissue level | Acknowledgment of the patient’s symptoms; check if the patient feels better at a different TSH concentration in the normal range (ie, an individual set-point); a trial of levothyroxine–liothyronine combination therapy can be considered in adherent patients with long-lasting steady state of TSH in serum |
| Low TSH with or without (persistent) symptoms | |
| Overtreatment due to high doses | Consider lower doses in elderly individuals and patients with subclinical hypothyroidism; ask if the patient takes any over-the-counter preparations that might contain thyroid hormone |
| Medical conditions—certain drugs (eg, metformin) and weight loss can decrease TSH concentrations | Consider lower doses |
TSH= thyroid-stimulating hormone.
Levothyroxine is absorbed in the small intestine and intake is advised in the morning 30–60 min before breakfast. Intake before bedtime (2–3 h after last meal) might improve absorption and can be considered to increase compliance.111 Several drugs can interfere with the absorption, availability, or metabolism of levothyroxine, although evidence for some of these preparations comes from n-of-1 trials. Gastrointestinal conditions that reduce levothyroxine absorption include Helicobacter pylori gastritis, coeliac disease, and autoimmune atrophic gastritis. Results from some studies112,113 suggest that liquid and soft gel formulations of levothyroxine do not depend on gastric pH for absorption, and could provide a solution for patients with difficulties ingesting levothyroxine 30–60 min before breakfast. In a double-blind randomised crossover trial114of liquid thyroxine in 77 treatment-naive patients with hypothyroidism, no significant differences in thyroid function tests were seen when the liquid preparation was ingested at breakfast or 30 min before breakfast. However, no studies have compared liquid gel formulations of levothyroxine with solid formulations in relation to clinical outcomes.
For individuals in whom high TSH concentrations persist and other causes have been excluded, the possibility of non-adherence, a common cause of therapy failure, should be considered and discussed with the patient. High TSH concentrations with normal or highnormal free thyroxine concentrations can be a result of levothyroxine tablets taken shortly before blood sampling. A supervised thyroxine absorption test to distinguish non-adherence from other reasons for undertreatment should be considered. Figure 3 shows a suggested protocol that combines both acute and long-term supervised administration.115,116
Protocol for supervised thyroxine absorption test, followed by weekly supervised thyroxine administration. Adapted from reference 115, by permission of Elsevier. TSH=thryoid-stimulating hormone. *Laboratory test values, especially an increase in free thyroxine, can be interpreted already at this stage. †Adequate free thyroxine rise is estimated to be roughly 50% from baseline at 120 min.116
Persistent complaints despite biochemical normalisation of TSH
About 5–10% of biochemically well controlled patients with levothyroxine-treated hypothyroidism have persistent symptoms, such as depression and impaired mental wellbeing.117 Concurrent diseases or perimenopausal status might cause these complaints and should be excluded. Patients with hypothyroidism have a higher prevalence of autoimmune diseases than the general population, which could give rise to similar symptoms. Autoimmunity per se has been suggested to lead to persistent symptoms.118
Circulating thyroid hormone concentrations are regulated by the hypothalamic–pituitary–thyroid axis with an individually determined set-point, reflected by a smaller intraindividual variability than interindividual variability.119 Therefore, the TSH concentration needed to achieve similar concentrations of circulating thyroid hormones differs between individuals. Differences in individual set-point could explain why patients with similar TSH concentrations under treatment respond differently. However, the individual set-point before hypothyroidism is rarely known. Also, studies120,121 that target different TSH goals generally do not show alterations in wellbeing or other clinical parameters.
An alternative explanation for persistent complaints in specific patients might be the imperfections oflevothyroxine monotherapy itself. Generally, levothyroxine can ensure adequate concentrations of circulating thyroxine that can then be converted into tri-iodothyronine by deiodination via deiodinase 1 and deiodinase 2. However, in euthyroid patients, about 20% of circulating tri-iodothyronine is derived from direct thyroidal secretion, whereas in patients on levothyroxine monotherapy all tri-iodothyronine is derived from the conversion of peripheral thyroxine to triiodothyronine. Consequently, patients on levothyroxine monotherapy have higher free thyroxine to triiodothyronine ratios than euthyroid individuals. Some patients with normalised TSH have serum tri-iodothyronine concentrations below the reference range, while free thyroxine serum concentrations are high.122–124 The clinical significance of this occurrence is unknown. However, levothyroxine monotherapy cannot restore physiological tri-iodothyronine concentrations or thyroid hormone-dependent biological effects in all tissues of hypothyroid rats.125,126 Although a normal TSH concentration reflects euthyroidism at the level of the pituitary, this might not necessarily reflect euthyroidism in all tissues. Tissue-specific differences in the inactivation of deiodinase 2 could play a part, resulting in the normalisation of triiodothyronine concentrations in the hypothalamus before tri-iodothyronine concentrations have fully normalised in the rest of the body.125
Levothyroxine–liothyronine combination therapy
Several trials using combined levothyroxine–liothyronine therapy have been done in the past 15 years.127 Although some studies128–131 show a beneficial effect, such as patient preference for combination therapy or an improved metabolic profile, patients on combination therapy generally do not have improved outcomes compared with those on levothyroxine monotherapy.132 Possible explanations include inadequate levothyroxine and liothyronine doses or frequency of administration.133 Liothyronine has a short half-life and no previous studies used a slow-release tri-iodothyronine. Additionally, most trials were of short duration (<4 months) and used questionnaires to record patients’ symptoms, which might not have been targeted or sensitive enough.
Alternatively, trials might have failed to identify the appropriate subgroups that would benefit from combination therapy. Most trials did not specifically recruit patients who feel unwell on levothyroxine or those with particularly low serum tri-iodothyronine concentrations. Individuals with genetic variations in thyroid hormone metabolism have not been specifically targeted.133 A subgroup that could be targeted is individuals with common genetic variations in DIO2, which encodes the deiodinase 2 enzyme that converts thyroxine to tri-iodothyronine locally in several tissues, including the brain.134 The Thr92Ala polymorphism in DIO2 gives rise to deiodinase 2 with a longer half-life than the wild-type enzyme and ectopic localisation in the Golgi apparatus. It was shown to alter expression profiles in the cerebral cortex in a similar pattern as seen in neurodegenerative disease, without evidence of altered thyroid hormone signalling.135 In a study136 of 552 people, the Thr92Ala polymorphism in DIO2 was associated with lower baseline psychological wellbeing in patients on levothyroxine replacement therapy and with better response to combination therapy, compared with patients without the polymorphism on levothyroxine replacement therapy. However, after appropriate multiple testing correction, the results were not significant. Results from a population-based cohort study137 showed no effect of the Thr92Ala polymorphism on quality of life or cognitive function measures. Sufficiently powered prospective randomised controlled trials are therefore needed before conclusions can be drawn.
Although the American Thyroid Association101 and European Thyroid Association138 guidelines generally recommend against the routine use of combination therapy in patients with hypothyroidism, the recommendations concerning trials in patients with persistent symptoms differ slightly. The European Thyroid Association states that a 3 month trial of levothyroxine–liothyronine combination might be considered experimentally in adherent, biochemically well controlled patients who have persistent complaints despite levothyroxine treatment138 and provides methods for calculating levothyroxine and liothyronine doses.138 However, treatment should be initiated only by accredited doctors of internal medicine or endocrinologists, closely monitored, and discontinued if no improvement is seen. By contrast, the American Thyroid Association recommends against any routine use of such trials outside of formal research and clinical trials, mainly because of uncertainty regarding benefit and long-term safety.101 Both the European Thyroid Association and American Thyroid Association agree on the need for long-term randomised controlled trials to assess risk-benefit ratios. Such trials would need to incorporate investigation of the ideal thyroid parameters to monitor during combination therapy, and whether tri-iodothyronine concentrations would be an important parameter. The timing of phlebotomy is also important, particularly if liothyronine is being administered more than once daily.
Little evidence exists to support other therapies for hypothyroidism. The use of thyroid extracts or liothyronine monotherapy is generally not recommended because of potential safety concerns associated with the presence of supraphysiological serum tri-iodothyronine concentrations and a paucity of long-term safety outcome data. The use of compounded thyroid hormones, dietary supplements, and any over-the-counter drug for the treatment of hypothyroidism is discouraged.
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 shows that endocrine-disrupting chemicals might be casual factors for endocrine diseases. Thyroid-disrupting chemical exposure can come from sources ranging from environmental (eg, flame retardants) to dietary (eg, food packaging material).140 A transatlantic call for action has been made to answer these questions in a collaborative effort.141
The association of hypothyroidism with cardiovascular disease has been established and replicated in several studies.63,67 However, the mechanisms behind this association remain unclear. The link between hypothyroidism and several cardiovascular diseases seems independent of traditional cardiovascular risk factors.63,67,69 Further research focused on novel cardiovascular risk factors or other pathways could shed light on the exact mechanisms, which would be crucial to support treatment decisions and monitor strategies in patients with asymptomatic hypothyroidism.
The diagnosis of hypothyroidism is currently based on statistically defined reference ranges for TSH and free thyroxine, which do not consider whether patients are at risk to develop disease. Because of the arbitrary nature of the cutoffs that define mild and overt hypothyroidism, an alternative grading system based on thyroid function tests has been proposed. The arbitrary nature of these cutoffs was also highlighted by the US Preventive Service Task Force83 as one of the important factors hampering decision making for screening of thyroid dysfunction in asymptomatic patients. These cutoffs also affect treatment decisions in asymptomatic patients with hypothyroidism. More research is needed to identify which adverse health events occur after long-term thyroid dysfunction. Furthermore, which concentrations of TSH and free thyroxine are accompanied by an increased risk of disease needs to be established. This information can be obtained from collaborative observational cohort studies with sufficiently long follow-up. Once this information is available, randomised controlled trials can assess whether treatment of thyroid function beyond these cutoffs for thyroid function test concentrations reduces excess risk and also the risk–benefit ratio of treatment.
Levothyroxine monotherapy is the standard treatment for hypothyroidism. However, several unresolved issues exist concerning patients who are biochemically well controlled but unsatisfied with their treatment outcome. Future studies should address whether alternative regimens could provide a solution for at least a proportion of patients with residual symptoms. Research areas most urgently in need of progress include: identification of the causes of persistent symptoms in biochemically well controlled patients, assessment of whether a more adequate dose (eg, tailored to patient serum triiodothyronine or to a patient’s own particular TSH set-point) produces more satisfactory outcomes, investigation of whether new formulations (eg, slow-release liothyronine) or increased administration frequency of levothyroxine–liothyronine combination therapy (eg, liothyronine three times daily) can ameliorate patient symptoms, and identification of patient subgroups that could benefit from therapies other than levothyroxine monotherapy (eg, by identifying additional genetic polymorphisms that could provide information on the individual thyroid set-point). Genome-wide association studies that include a large number of individuals with detailed genotyping could provide such information.
source:www.ncbi.nlm.nih.gov
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