Hypothyroidism results from inadequate thyroxine (T4) from the thyroid gland.
T4 production is stimulated by a feedback-controlled cascade of thyroid-stimulating hormone (TSH) from the anterior pituitary in response to thyrotropin-releasing hormone (TRH) from the hypothalamus.
The enzyme thyroperoxidase (TPO) iodinates locally-stored thyroglobulin (Tg) to produce T4. This is then released as required.
T4 is highly protein bound, the unbound or freeT4 (fT4) is relatively constant and undergoes peripheral conversion to tri-iodothyronine (T3), the biologically active form.
Primary disease is more common in women than in men (19 per 1,000 compared with 1 per 1,000), and increases in prevalence with age.
Hypothyroidism occurs when TSH levels are above normal and T4 is either low (overt disease) or normal (subclinical).
If T4 is low and TSH is not raised or slightly raised, higher order hypothyroidism should be suspected. The clinical presentation is usually nonspecific and includes symptoms secondary to the lowered metabolic rate such as fatigue, cold intolerance, decreased sweating, periorbital puffiness, coarse skin, weight gain, depression, loss of scalp hair and hyporeflexia.
The increased stimulatory effect of TSH can cause a goitre. The rare sign of pretibial myx-oedema is due to the accumulation of lucosoaminoglycans in tissue. These signs are more common in the elderly and may be absent in the young.
In the presence of physiological stress undiagnosed hypothyroidism can present with coma, hypothermia, bradycardia and cardiogenic shock.
The most common cause worldwide is iodine deficiency. In the UK it is autoimmune thyroiditis, known as Hashimoto's disease if goitre is present. Risk factors include a family history of autoimmune disorders, Graves' disease or associated autoimmune disorders such as vitiligo, pernicious anaemia and type-1 diabetes.
Antithyroid antibodies are detectable in 95 per cent of cases, usually against TPO and sometimes Tg. The destruction of functional tissue leads to hypothyroidism.
The presence of a goitre requires an ultrasound and possible fine needle aspiration biopsy to rule out the 5 per cent of malignant nodules.
The acute self-limiting viral inflammation, de Quervain's thyroiditis, has a pattern of initial hyperthyroidism followed by hypothyroidism. It is typically marked by neck pain and tenderness over the thyroid area and fever - 90 per cent of cases resolve by four to 12 weeks.
Other causes include drugs such as amiodarone, lithium and interferon. Patients who have had radioactive treatment for Graves' usually become hypothyroid within a year.
Less common causes include thyroidectomy, radiation therapy to the neck as treatment for neoplasms, agenesis of the thyroid gland and inborn errors of thyroxine production. T4 can be temporarily depressed by illness, low energy intake and psychiatric disorders.
Treatment of primary hypothyroidism is to give replacement synthetic T4, known as levothyroxine or LT4.
The aim is to normalise TSH, primarily, and T4, secondarily, through a process of titration. Sometimes achieving a normal TSH requires a slightly above reference range of fT4.
This is acceptable in the absence of clinical hyperthyroidism as the T4:T3 ratio is altered and the T3 levels more accurately reflect a euthyroid state.
Subclinical hyperthyroidism (treatment with LT4 until TSH is below the normal range) should be avoided as it is associated with osteoporosis and fracture in postmenopausal women and possible adverse cardiac events. This does not apply to patients with a history of thyroid cancer who are treated to lower TSH levels (<0.1mU/l).
In pregnant women, treatment is slightly supratherapeutic, on average an increase of at least 50 microgram of LT4 is recommended to maintain the TSH in the lower half of the normal range (<2.5mU/l).
These patients require frequent assessment of TSH and T4 (three to four weekly) and this is best managed by referral to an endocrinologist.
Clinical benefits are seen within a week and level off at six weeks. Hence, adjustments to dosage should be made at six-weekly intervals.
In the elderly, or those with severe COPD or cardiovascular disease the maxim is start low and go slow. Initial dosages should be subtherapeutic and increased in small steps to the desired level. Contraindications include acute MI and uncorrected adrenal insufficiency.
Levothyroxine should ideally be taken early in the morning to avoid insomnia and on an empty stomach to prevent impaired absorption. Absorption can be impaired by concomitant iron, calcium carbonate, aluminium hydroxide and sucralfate.
Once patients are stabilised, monitoring of TSH can occur on a six-monthly to yearly basis to assess for any signs of hyper-thyroidism.
The evidence base for the treatment of subclinical hypothyroidism is inconclusive. Treatment in patients with a TSH >10mU/l and TPOAb-positive has been shown to reduce LDL, non-HDL and total cholesterol but, while some studies show benefit in early treatment, others show a protective effect of a subclinical state, especially in the elderly.
Guidelines recommend treatment if the TSH levels are >10mU/l or between 5-10mU/l in combination with anti-TPO antibodies or goitre as they have the highest rate of progression to overt hypothyroidism, or patients seeking pregnancy.
There are no evidence-based guidelines to recommend screening apart from in neonates. General screening of the not-at-risk population is not recommended.
Targeted screening has been promoted by experts in pregnant women, patients with a history of postpartum thyroiditis, women older than 60 years, patients with type-1 diabetes or history of neck irradiation.
Other at-risk patients, apart from drug and autoimmune associated conditions, include those with a diffuse goitre, chronic hepatitis C virus (secondary to interferon therapy), HIV, Down's and Turner's syndrome.
Other diseases where thyroid function should be tested include subfertility, dyslipidaemia and type-2 diabetes, at diagnosis only.
- Dr Hashmi is a former GP in London working as a consultant in family medicine in Jeddah, Saudi Arabia
- Clinical Knowledge Summaries - Hypothyroidism
- UK Guidelines for the Use of Thyroid Function Tests, July 2006