Hypothyroidism

• Hypothyroidism is a state of too little thyroid hormone acting on the body's tissues, leading to a slowed metabolism.
• It is most often caused by autoimmune destruction of the thyroid (Hashimoto thyroiditis), but it can follow surgery or radioiodine, iodine deficiency, drugs such as amiodarone and lithium, pituitary or hypothalamic disease, and congenital problems.
• Typical features are tiredness, weight gain, cold intolerance, dry skin, constipation, slowed thinking, a low pulse and a hoarse voice; severe disease can depress breathing, circulation and consciousness.
• Diagnosis is usually simple: a high thyroid stimulating hormone (TSH) with a low free thyroxine (free T4) confirms primary hypothyroidism; free T3 and antibody tests help with cause.
• Treatment is daily oral levothyroxine, usually about 1.6 micrograms per kilogram of body weight, with the TSH rechecked 4 to 6 weeks after a dose change and the dose titrated to a normal TSH.

By the end of this page you should be able to:

1. Define hypothyroidism and distinguish primary from central (secondary and tertiary) hypothyroidism.
2. List the principal causes of hypothyroidism and link each to its mechanism.
3. Recognise the clinical features of mild, overt and severe hypothyroidism, including myxoedema coma.
4. Plan the investigation of suspected hypothyroidism, including antibody testing and when to scan.
5. Explain and apply the treatment approach: starting dose, titration, timing, drug interactions and monitoring.
6. Describe subclinical hypothyroidism and state when treatment is recommended.
7. Adjust levothyroxine in special groups, especially pregnancy, older adults and children.
8. Recognise why newborn screening for congenital hypothyroidism exists and what early treatment achieves.

Primary hypothyroidism accounts for the large majority of cases. In it the thyroid secretes too little thyroxine (T4) and triiodothyronine (T3); the pituitary responds by secreting more TSH, so the TSH is raised. In central hypothyroidism the gland is intrinsically normal but is not stimulated, because of pituitary or hypothalamic disease; the TSH may be low, normal or inappropriately normal, and the free T4 is low.

Hypothyroidism is a graded condition rather than an all-or-nothing state. A mildly raised TSH with a normal free T4 is called subclinical hypothyroidism. As thyroid hormone falls further, free T4 becomes low while T3 is still maintained; in the final stage both T4 and T3 are low with a markedly raised TSH. The extreme end of the spectrum, with life-threatening depression of consciousness, breathing and circulation, is myxoedema coma.

Hypothyroidism is one of the most common endocrine disorders seen in primary care. Prevalence rises steeply with age and is higher in women than in men, mainly because autoimmune thyroiditis becomes more common as people age. It is more prevalent in iodine-deficient populations, where goitrous hypothyroidism is common, and in people previously treated for hyperthyroidism with surgery or radioiodine. Congenital hypothyroidism affects roughly 1 in 2,000 to 1 in 4,000 newborns in most screened populations ^[3]. ^[1]

The causes of hypothyroidism can be grouped by where the problem starts. The table summarises the common causes, the mechanism and the clue that points to each ^[1][4].

Hashimoto thyroiditis is the commonest cause in iodine-adequate areas. It is an autoimmune process in which thyroid antigens, especially thyroid peroxidase, are targeted. It often clusters with other autoimmune disease and runs in families. The gland may be normal in size, enlarged or eventually atrophic.

Iodine deficiency remains an important cause worldwide, particularly in regions where salt is not iodised. In severe deficiency the thyroid cannot synthesise hormone despite a working gland, and a goitre develops. Treating severe hypothyroidism in an iodine-deficient person requires care, and iodised salt programmes prevent it.

Drugs matter because they are often overlooked. Amiodarone contains a large iodine load and can cause hypothyroidism as well as hyperthyroidism, particularly where iodine intake is adequate. Lithium blocks hormone release and is a frequent cause of raised TSH in people taking it long term. Methimazole, carbimazole and propylthiouracil used for hyperthyroidism commonly lead to hypothyroidism if the dose is not reduced. Interferon, sunitinib and other targeted agents can damage the thyroid. Always review the drug list in someone with unexpected hypothyroidism.

Central hypothyroidism is uncommon but important to recognise, because the TSH is misleading. It accompanies other evidence of hypothalamic-pituitary disease, such as headache, visual field defects, other hormone deficiencies, or a known pituitary tumour. Measuring the other pituitary hormones and imaging the pituitary is part of the work-up.

Congenital hypothyroidism is discussed in Prevention and screening, below.

Thyroid hormone (T4 and, more importantly, its active metabolite T3) sets the basal metabolic rate of most tissues. It stimulates thermogenesis, heart rate and contractility, gut motility, skin turnover and central nervous system function, and it is needed for normal bone and brain development. When levels fall, every organ slows.

The symptoms and signs of hypothyroidism follow directly from slowed metabolism and from the tissue changes of hypothyroidism. Myxoedema is the term for the non-pitting oedema caused by accumulation of hydrophilic mucopolysaccharides in the skin and other tissues; it produces the puffy face, periorbital swelling and thick skin of severe disease.

TSH is a sensitive marker because of the log-linear relationship between free T4 and TSH: even a modest fall in free T4 raises the TSH several-fold. This is why TSH is the first screening test for thyroid dysfunction.

The symptoms develop slowly and are nonspecific, which is why hypothyroidism is often missed. Patients describe fatigue and a feeling of being slowed down; cold intolerance; weight gain despite no change in appetite; dry skin and hair; constipation; hoarseness; heavy, irregular or absent periods; muscle aches; carpal tunnel symptoms; low mood and slowed thinking. Older adults may present with confusion, falls or depression rather than classic symptoms.

Symptoms are worse with severe or long-standing disease, and they improve, sometimes slowly, once treatment starts. Many symptoms overlap with depression, sleep apnoea, perimenopause and drug effects, so thyroid testing is sensible in anyone with this cluster.

On examination look for bradycardia, cool and dry skin with coarse hair, periorbital puffiness, facial puffiness, macroglossia, a goitre, delayed relaxation of deep tendon reflexes (especially the ankle jerk), a pericardial or pleural effusion, and myxoedema. Blood pressure may be raised with a narrow pulse pressure, and serum cholesterol is often high. In severe disease there may be hypothermia.

Hypothyroidism must be distinguished from conditions that mimic it. Depression, anaemia, chronic fatigue, sleep apnoea, perimenopause, renal failure, nephrotic syndrome, liver disease and drug effects (sedatives, amiodarone, lithium, high-dose glucocorticoids) can all produce a similar picture. Raised TSH also occurs in recovery from non-thyroidal illness and with drugs such as amiodarone and lithium, so biochemical confirmation is essential. If the TSH is raised but free T4 is normal, think subclinical hypothyroidism or a transient rise; if free T4 is low without a raised TSH, think central hypothyroidism and search for pituitary disease.

A serum TSH is the single best screening test for primary thyroid dysfunction in most outpatient situations ^[4]. Measuring TSH and free T4 together is sensible when the diagnosis is likely or when results are confusing. The standard interpretation:

• Raised TSH, low free T4: overt primary hypothyroidism.
• Raised TSH, normal free T4: subclinical hypothyroidism (confirm on a repeat sample).
• Low or normal TSH, low free T4: central hypothyroidism.
• Raised TSH with a high free T4 is unusual and suggests analytical interference, assay problems, or antibody interference.

Free T3 is not usually needed to diagnose hypothyroidism, but it may be low in advanced disease. It can be useful in selected cases and is essential in hyperthyroidism.

Thyroid peroxidase (TPO) antibodies confirm an autoimmune cause such as Hashimoto thyroiditis and predict progression of subclinical to overt disease. Thyroglobulin antibodies can also be measured. A thyroid ultrasound is not needed to diagnose hypothyroidism, but it helps if there is a goitre, nodules or doubt about gland structure, and it detects structural disease.

Other useful tests depend on the situation: a lipid profile (cholesterol is often high), full blood count, creatine kinase, renal and liver tests, and an ECG in older adults or those with cardiac symptoms. In myxoedema, check cortisol because coexistent adrenal insufficiency can be unmasked by thyroid replacement.

There is no formal scoring system for hypothyroidism in adults. The diagnosis rests on TSH and free T4. Subclinical hypothyroidism deserves its own clear definition, because it is the situation where treatment decisions are hardest ^[2].

Subclinical hypothyroidism is a raised serum TSH with free T4 and (when measured) free T3 within the reference range, confirmed on a repeat test. It is commoner with older age, antibody positivity and female sex. The 2013 ETA guideline separates it into mild elevation (TSH 4.0 to 10.0 mIU/L) and more severe elevation (TSH over 10 mIU/L). Treatment recommendations: ^[2]

• In younger patients, under about 65 to 70 years, with TSH above 10 mIU/L, levothyroxine is recommended even without symptoms. ^[2]
• In younger patients with TSH under 10 mIU/L and symptoms suggestive of hypothyroidism, a trial of levothyroxine is reasonable. ^[2]
• In the oldest old, over 80 to 85 years, with TSH of 10 or under, a watch-and-see approach is preferred and treatment is generally avoided. ^[2]
• In general the TSH should be rechecked after 2 months, and the aim is a stable TSH in the lower half of the reference range (0.4 to 2.5 mIU/L) in most adults. ^[2]
• If treatment was started for symptoms, reassess 3 to 4 months after the TSH normalises; if symptoms do not improve, treatment should usually be stopped. ^[2]

The ATA 2014 guideline supports individualised treatment and notes that a TSH target in the lower half or in the lower tertile of the reference range has been proposed for some patients, but it is not universally endorsed, and that for people over 70 to 80 years a higher target of 4 to 6 mIU/L may be reasonable ^[1]. The 2012 AACE/ATA guideline adds that the decision to treat subclinical hypothyroidism with TSH under 10 mIU/L should be tailored to the patient ^[4].

The goal of treatment is to restore tissue euthyroidism: symptoms resolve, TSH normalises and iatrogenic thyrotoxicosis, with its risks of atrial fibrillation and osteoporosis, is avoided. Levothyroxine remains the standard of care; combination preparations with triiodothyronine have not been shown to be superior ^[1]. ^[4]

For overt primary hypothyroidism the full replacement dose is usually about 1.6 to 1.8 micrograms per kilogram of body weight per day ^[1]. The dose depends on lean body mass, the cause of the hypothyroidism, the degree of TSH elevation, age, pregnancy status and other medicines. People with thyroid cancer needing TSH suppression need more, around 2.1 to 2.7 micrograms per kilogram.

Practical approach:

• If TSH is markedly elevated, start the full weight-based dose.
• If the degree of hypothyroidism is mild (TSH 10 or less, or subclinical), start 25 to 50 micrograms daily and titrate. ^[1]
• If the patient is older, taking several other medicines, or has significant comorbidity, start low and increase slowly. For subclinical hypothyroidism without cardiac disease, about 1.5 micrograms per kilogram per day is a suitable starting dose ^[2].
• For patients with cardiac disease, and for elderly patients, start 25 or 50 micrograms daily in subclinical hypothyroidism and increase by about 25 micrograms every 14 to 21 days until the full dose is reached ^[2].

Levothyroxine should be taken once daily, and timing affects absorption. The best absorption, ranked from most to least consistent, comes from taking it about 60 minutes before breakfast, at bedtime, 30 minutes before breakfast and with breakfast ^[1]. The commonest advice, take it 30 to 60 minutes before breakfast with water and an empty stomach, is a convenient compromise. A consistent daily routine matters more than the exact time, and the absorption steady state is reached in about 6 weeks.

Levothyroxine binds to several orally taken agents in the gut and its absorption is impaired. The standard approach is to separate it by at least 4 hours from calcium carbonate, ferrous sulfate, aluminium-containing antacids, sucralfate, cholestyramine, colesevelam and phosphate binders, and from multivitamins containing calcium or iron ^[1]. Proton pump inhibitors, soy, coffee and malabsorptive conditions such as coeliac disease and atrophic gastritis also reduce absorption and can require higher doses. Gastritis in particular can raise the daily requirement substantially.

Some drugs increase the clearance of levothyroxine and raise the dose needed: phenytoin, phenobarbital, carbamazepine and rifampicin. Oestrogen started in menopause raises the requirement by increasing thyroxine-binding globulin.

After starting or changing a dose, recheck the TSH in 4 to 6 weeks (which is five to six half-lives, the time to steady state) ^[1]. Once stable, check every 6 to 12 months. The monitoring interval should be shorter in pregnancy (every 4 weeks in the first half), after a large weight change, in older adults and in anyone with erratic absorption or adherence.

If the TSH is high, increase the dose by 12.5 to 25 micrograms and retest in 4 to 6 weeks. If it is low but above 0.1, reduce slightly; if it is below 0.1, reduce more firmly. Small unexpected swings in TSH usually reflect adherence problems, formulation issues or a change in absorption, so ask about pills missed, new medicines, supplements or gastrointestinal symptoms before assuming the dose is wrong.

Here TSH cannot be used to titrate treatment. The goal is to keep free T4 in the upper half of the reference range, while recognising that older patients and those with comorbidity may need a lower target ^[1]. Thyroid replacement should not be started until coexistent adrenal insufficiency has been excluded or covered, because unmasking adrenal failure can be dangerous. In the intensive care setting levothyroxine may need to be given intravenously at about 75 percent of the oral dose that achieved euthyroidism.

Women already taking levothyroxine usually need more as soon as pregnancy is confirmed: increasing the current dose by about two tablets per week (one extra dose twice weekly on separate days) is a simple, effective manoeuvre ^[1][4]. Up to 70 percent of women will need adjustments of 30 percent or more from the preconception dose. The aim is a trimester-specific TSH from the local laboratory's pregnancy range (older guidance used about 0.1 to 2.5 mIU/L in the first trimester; newer guidance allows an upper limit near 4.0 mIU/L where no local range exists) and free T4 at the appropriate level, with TSH rechecked every 4 weeks at least during the first half of pregnancy and again in the second half. Ideally the TSH is below 2.5 mIU/L before conception, and very close control is needed in the first trimester because the fetal brain depends on maternal T4 before the fetal thyroid starts to function.

Newly diagnosed overt hypothyroidism in pregnancy should be treated with full replacement immediately. For more detail on pregnancy-specific management and on women with Hashimoto thyroiditis who are not yet hypothyroid, see the ATA pregnancy guidelines ^[4].

Hypothyroidism is more common and more easily missed in older adults, in whom symptoms are muted and may look like ageing or depression. Start with a low dose and titrate slowly in anyone with known or suspected heart disease, and in many clinicians' practice in the oldest adults: ATA 2014 notes that for those over 70 to 80 years a higher TSH target of 4 to 6 mIU/L may be reasonable, and subnormal TSH should be avoided because of arrhythmia and bone loss risk ^[1].

Children are treated per kilogram of body weight, at doses higher than adults on a microgram-per-kilogram basis, supervised by paediatric endocrinology. Treatment should not be delayed once confirmed hypothyroidism is present, because brain development in early life is thyroid-hormone dependent. Congenital hypothyroidism is covered below.

Myxoedema coma is the decompensated end stage of severe hypothyroidism. It is rare but has a high mortality. It usually presents in winter with altered consciousness ranging from lethargy to coma, hypothermia, hypoventilation and carbon dioxide retention, hypotension, bradycardia and hyponatraemia. Precipitants include infection, cold exposure, trauma, myocardial infarction, stroke, surgery, drugs with central nervous system depressant effects, and the withdrawal or underdosing of levothyroxine. The TSH may be only modestly raised because severe illness suppresses the hypothalamic-pituitary axis, so the diagnosis rests on the clinical picture and a low free T4.

Management is supportive and specific, usually in an intensive care or high-dependency setting:

• Airway and ventilation: anticipate carbon dioxide retention; many patients need ventilatory support.
• Temperature: blanket warming only; do not use active rewarming, which can precipitate arrhythmia or hypotension.
• Circulation: careful fluid resuscitation; vasopressors if needed.
• Glucose, sodium and infection: treat hypoglycaemia, review sodium, look hard for infection and treat it.
• Steroids: give empiric stress-dose glucocorticoid (for example hydrocortisone 100 mg intravenously then 50 mg four times daily) before or with thyroid hormone, because coexistent adrenal insufficiency is not uncommon; ideally measure cortisol first if it does not delay treatment.
• Thyroid hormone: levothyroxine intravenously, with a loading dose of about 200 to 500 micrograms (guidelines give 200 to 400, product labels 300 to 500; smaller or older patients and those with coronary disease or arrhythmia are kept at the lower end), then a daily dose that guidelines give as about 1.6 micrograms per kilogram reduced to roughly 75 percent while intravenous, and product labels give as 50 to 100 micrograms intravenously, with the exact conversion not established ^[1].
• Adjunctive triiodothyronine: intravenous liothyronine 5 to 20 micrograms as a loading dose, then 2.5 to 10 micrograms every 8 hours, may be added, with lower doses for smaller or older patients or those with coronary artery disease or arrhythmia ^[1]. High doses should be avoided because high serum T3 during treatment is associated with higher mortality.

Monitor mental status, cardiorespiratory parameters, temperature and renal function, and recheck thyroid hormones every 1 to 2 days to ensure a favourable trend. Therapy should be aggressive: if the clinical picture is not improving, increase levothyroxine or add liothyronine. Once the patient improves, switch to oral levothyroxine at the usual replacement dose.

Covered in Management above. Pre-pregnancy optimisation, early dose increase and close monitoring are the key messages.

Covered above and in Prevention and screening. Start treatment promptly on confirmed disease.

Covered above: start low, titrate slowly, and consider a higher TSH target with avoidance of over-treatment.

If amiodarone causes hypothyroidism it is usually managed with levothyroxine while the drug is continued when amiodarone is essential, and the dose requirement may be higher. If amiodarone is stopped and hypothyroidism persists, treat as usual.

Hypothyroidism itself, untreated, leads to hyperlipidaemia, hypertension, diastolic dysfunction and heart failure, pericardial effusion, macrocytic anaemia, infertility, depression, and in extreme cases myxoedema coma. Over-treatment is not harmless either: a suppressed TSH, especially below 0.1 mIU/L, in older adults and postmenopausal women increases the risk of atrial fibrillation and osteoporotic fracture ^[1].

With appropriate replacement and monitoring, life expectancy is normal and symptoms resolve. Compliance and monitoring are the main variables. Congenital hypothyroidism treated before about 2 weeks of age has an excellent neurodevelopmental outcome; delay risks irreversible cognitive impairment.

Congenital hypothyroidism is the commonest preventable cause of intellectual disability in countries where screening exists. The incidence of primary congenital hypothyroidism is roughly 1 in 2,000 to 1 in 3,000 newborns, and the highest reported incidence of central (secondary or tertiary) congenital hypothyroidism is around 1 in 16,000 ^[3]. The leading cause is thyroid dysgenesis, affecting roughly 1 in 2,000 to 1 in 4,000 newborns, depending on the series ^[1].

Screening is done on a dried blood spot obtained from a heel prick, typically between 24 and 72 hours of age and before hospital discharge. Strategies include primary TSH with reflex free T4, primary free T4 with reflex TSH, or combined TSH and free T4. The most sensitive test for primary disease is the TSH. Where resources allow, adding T4 to TSH detects central hypothyroidism ^[3]. A second sample is needed for high-risk groups such as preterm, low-birth-weight and sick infants, twins, infants with Down syndrome and those transfused before screening. A normal or near-normal screen does not replace clinical judgement: an infant with suggestive signs (prolonged jaundice, large posterior fontanelle, macroglossia, umbilical hernia, constipation, lethargy, hypothermia) should have serum TSH and free T4 measured regardless of the screening result.

Treatment should start early, using levothyroxine at 10 to 15 micrograms per kilogram per day, higher doses for severe biochemical disease ^[1]. The aim is to normalise free T4 within 2 to 3 weeks. Stopping or skipping doses in infancy risks permanent neurodevelopmental harm. Many programmes recommend lifelong follow-up.

In iodine-deficient regions the prevention is public health iodisation of salt and monitoring of iodine status, not individual treatment. Severe deficiency can produce goitrous hypothyroidism and, in pregnancy, impaired fetal brain development.

• A serum TSH, the single best screen for primary thyroid dysfunction, is widely available even where specialist care is not. If only TSH is available, a low free T4 with an inappropriately normal TSH should prompt referral for central hypothyroidism.
• When confirmatory testing is delayed, clinically obvious myxoedema with supporting features can be treated, while always looking for treatable precipitants and cardiac disease.
• Levothyroxine is inexpensive and heat stable, but it is sensitive to moisture and poor logistics. Store it cool and dry, dispense in original packaging and date the box.
• Separate the daily dose from calcium, iron and traditional remedies or antacids that chelate it by several hours, and explain this in the patient's language and script.
• Cognitive and clinical follow-up can guide therapy where regular laboratory testing is unaffordable: pulse, weight, energy, reflexes and ankle jerk all track response.
• Radioiodine and thyroid cancer follow-up are usually absent; refer to the nearest endocrine service.
• In iodine-deficient regions, report suspected clusters and support iodised salt programmes; individual iodine supplementation should follow national guidance to avoid triggering hyperthyroidism in long-standing goitre.
• Special groups such as pregnancy still need TSH and free T4 follow-up; if tests are scarce, plan around the antenatal schedule and contact the nearest specialist.

• Hypothyroidism is tissue deficiency of thyroid hormone and is usually primary, marked by a high TSH and low free T4.
• Hashimoto thyroiditis is the commonest cause in iodine-adequate areas; iodine deficiency remains important worldwide.
• Always check the drug list, including amiodarone and lithium.
• Central hypothyroidism is suspected when free T4 is low without a raised TSH, and needs pituitary assessment.
• Subclinical hypothyroidism is defined by a raised TSH with normal free T4; treat younger patients with TSH above 10 mIU/L, and consider a trial for younger patients with symptoms at lower TSH values.
• Levothyroxine at about 1.6 micrograms per kilogram is the standard replacement; start lower in older adults and cardiac disease and titrate.
• Take the dose consistently on an empty stomach, separated from calcium and iron by about 4 hours; absorption reaches steady state in about 6 weeks.
• Recheck TSH 4 to 6 weeks after a dose change, then periodically, and every 4 weeks in early pregnancy.
• In pregnancy, increase the dose by about two tablets per week as soon as pregnancy is confirmed; most women need a 30 percent or greater increase. ^[1]
• Myxoedema coma is an emergency treated with intravenous levothyroxine, possible adjunctive liothyronine, empiric steroids, ventilation and careful warming.
• Newborn screening aims to detect congenital hypothyroidism and treatment within the first 2 weeks protects brain development.
• Avoid over-treatment in older adults because of atrial fibrillation and osteoporosis risk.

• Hyperthyroidism and thyrotoxicosis
• Thyroid function tests
• Thyroiditis
• Thyroid neoplasms
• Type 1 diabetes mellitus (commonly associated autoimmune disease)
• Hyperlipidaemia

Measured or claimed numbers above are taken from the sources listed in the front matter and saved in the accompanying claims ledger.