Introduction

Hypothyroidism (aka myxoedema) is a common disorder which presents most frequently in women and the elderly. It can usually be managed in primary care without the need for specialist involvement (unlike hyperthyroidism) and is typically straight-forward to treat, although it does require ongoing monitoring. As the symptoms can be non-specific, be on the lookout, particularly in women over 40.
The two main causes are:
  • Primary disease of the thyroid – In the developed world, this can often be autoimmune thyroid disease (several types of this exist, the most common type is Hashimoto’s thyroiditis).
    • It can can also be due to damage caused by radioiodine that has been used to treat hyperthyroidism.
  • In the developing world iodine deficiency is the major cause
  • Very occasionally, the disease may be secondary to pituitary or hypothalamic disorders.
The onset of the disease is gradual, and will be associated with a rise in TSH levels – as the hypothalamic-pituitary-thyroid axis tries to combat decreasing thyroid hormone (T4/T3) output.
  • TSH levels are typically used as a screening test for hypothyroidism. If an abnormality is detected, then T4 levels can be used to confirm the diagnosis
  • The point where TSH levels are above normal, but T4 remains normal is known as sub-clinical hypothyroidism.
  • As the damage continues, TSH levels will rise higher, and free T4 levels will fall.
  • Once levels of TSH are greater than 10u/L then symptoms will usually be apparent, and T4 levels will be low. At this stage, we say the patient has overt or clinical hypothyroidism
  • There is some debate as to the benefit of treating those with “sub-clinical hypothyroidism” – in symptomatic patients with a high TSH, but normal T4 – a trial of treatment may be suitable

Hypothyroidism is typically treated with a daily dose of thyroxine – 1.6 μg/kg lean body weight daily. This is usually a dose of 100 – 150mcg daily.

  • Doses should be titrated up or down by 12.5 – 25mcg per day, every 6-8 weeks according to effect
  • TSH is the main marker used to monitor the effectiveness of treatment. T4 levels areon ly a secondary marker
Most cases are managed in general practice and do not require specialist involvement.
Unless there is an obvious goitre or neck mass, imaging is not usually required.
There has been considerable research into the benefits of screening and managing thyroid dysfunction in pregnancy, but the general consensus at present is that screening is not beneficial, and other than recommending routine iodine supplementation, the diagnosis of hypothyroidism is not different than in non-pregnant patients.
  • If hypothyroidism is diagnosed in pregnancy then specialist management should be sought

Epidemiology

  • Prevalence in the UK is about 1% in women, but only 0.1% in men.
  • Lifetime risk is actually higher – about 9% for women and 1% for men.
  • The mean age of diagnosis is about 60.
  • Prevalence of subclinical hypothyroidism is about 7% of women and 3% of men. About 4% of these people will progress to clinical hyperthyroidism annually.
  • Congenital hypothyroidism is present in about 1 in 4000 babies, and this has lead to screening programs of neonates.

Normal Thyroid Physiology

The functioning of the thyroid gland is dependent on the hypothalamic-pituitary-thyroid axis. 

  • The hypothalamus first releases thyrotropin releasing hormone
  • The pituitary produces thyroid stimulating hormone (TSH) in response to this, and in response to feedback loops from T4 and T3
  • TSH acts upon the thyroid gland to stimulate it to produce thyroid hormones
    • T4
    • T3 – only about 25% of the circulating T3 is produce by the thyroid gland. The rest is produced in the tissues by converting T4 to T3
    • This is why when we replace thyroid hormone we only need to give T4 – as T3 is subsequently produced by the metabolism of T4 to T3
  • These thyroid hormones circulate in the blood, and act on the peripheral tissue to cause a wide variety of effects – mainly related to metabolism
  • They also act as a feedback loop to the hypothalamus – which can then adjust the amount of TSH that is produced in response to this
    • Under normal control, the thyroid gland responds to the ‘signal’ of the TSH, to alter its production of T3 and T4 relative to the bodies needs
    • In thyroid disease, the production of T3 and T4 becomes “uncoupled” from the production of TSH
    • In primary hypothyroidism
      • The thyroid gland is unable to produce sufficient amounts of T4 and T3, despite a ‘strong signal” (high TSH) from the pituitary gland.
    • In secondary hypothyroidism
      • Either, insufficient TSH is produced, and thus the thyroid gland does not produce sufficient T3 and T4
      • Or, the thyroid gland has been removed or damaged surgically, or by radiotherapy or another process, and thus is unable to produce sufficient T3 and T4

It is crucial to understand this process to be able to interpret thyroid function test blood results.

Hypothalamic-thyroid-pituitary axis

Hypothalamic-thyroid-pituitary axis. This file is taken from wikimedia commons and is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Causes

There are several different pathologies that can lead to hypothyroidism, and several ways of classifying these. The simplest method is to separate the causes into autoimmune (Hashimoto’s and atrophic hypothyroidism) and non-autoimmune (everything else!).

  • Primary
    • Autoimmune
      • These are by far the most common causes in the developed world
      • Autoimmune lymphocytic thyroiditis of which there are two man types:
      • Hashimoto thyroiditis
      • Atrophic thyroiditis
    • Congenital
    • Defects in hormone synthesis – usually be due to: Iodine deficiency, Antithyroid drugs (e.g. lithium, amiodarone, interferon)
    • Infective
  • Secondary
    • Hypopituitarism (which produces isolated TSH deficiency)
    • Post Surgery – Post irradiation (e.g. radioactive iodine therapy, external neck irradiation)
  • Other – peripheral resistance to thyroid hormone
Atrophic hypothyroidism
Do NOT confuse this with auto-immune hyperthyroisidm (Grave’s disease)!
  • This is the most common type of hypothyroidism in the developed world
  • It is the result of T-cell mediated auto-reactive cytotoxicity against follicular cells.
  • Cytotoxicity just means ‘toxic to cells’ – so in this case, it just means that T-cells are toxic to follicular cells – i.e. they kill them!
  • This condition is 6x more common in females, and incidence increases with age. It is also often associated with other autoimmune diseases such as pernicious anaemia and other endocrine disorders.
  • Aetiology is unclear, but it is thought that the antibodies may block TSH receptors and that this results in the hypothyroidism. As with most auto-immune diseases, the exact causes are complex and unknown, but it will involve a combination of genetic and environmental factors. In some instances, development of this condition has been associated with a high iodine intake.

Hashimoto’s Thyroiditis

  • This is also an autoimmune disease. It was the first ever autoimmune disease to be recognised as such.
  • Hashimoto’s disease may initially cause a transient hyperthyroidism which later becomes hypothyroid.
  • In this disease, the thyroid is again attacked by T-cells. The main difference between this and atrophic hypothyroidism, is that atrophic hypothyroidism does not cause goitre, but that Hashimoto’s can do. 
  • The condition causes an enlarged thyroid (goitre). The enlargement is due to infiltration of the thyroid with lymphocytes, and resultant fibrosis.
    • Goitre is often associated with hyperthyroidism, but in these circumstances, this is not the case.
  • The thyroid usually becomes firm and rubbery but this is not always the case – it can be anywhere from soft to hard.
  • It is approximately 15x more common in women, and onset occurs usually in middle age (about 50)
  • You will find very high levels of TPO antibody in the blood. TPO (Thyroid peroxidase) is the enzyme that ionises iodine to I+, ready for release into the colloid. Without this enzyme, there will not be enough I+ released into the colloid to produce sufficient amounts of T3 and T4. Patients with this condition will often have TPO levels of > 1000 U/L.
  • Patients with the condition may be hypothyroid or euthyroid (normal thyroid function). If they are euthyroid, you will only detect the condition with TPO tests and neck examination.
    • Treating patients with positive antibodies who have otherwise normal thyroid function has NOT been proven to be of benefit
  • Initially, the disease will cause toxicity (Hashi-toxicity) – i.e. it will cause a lot of initial damage, and then after this the patient may become hypothyroid or euthyroid.
  • Pathology There will be massive lymphocytic infiltrate into the thyroid, and there will be varying destruction of tissue. Often there will be no colloid. The remaining cells will have an increased concentration of mitochondria. There will be varying degrees of fibrosis. With thyroxine replacement, the goitre will usually disappear
  • Some people believe that Hashimoto’s disease progresses to atrophic hypothyroidism and as such – they are the same disease. 
Thyroid gland

Image modified from original images taken from SMART by Servier Medical Art by Servier and is licensed under a Thyroid gland. Creative Commons Attribution 3.0 Unported License

Autoimmune thyroid conditions are associated with other autoimmune diseases. Both autoimmune hypothyroidism and Grave’s disease are associated with type I diabetes and Addison’s disease. Other associations include SLE, pernicious anaemia, Crohn’s disease and many more!

Pernicious anaemia – in this disease, lymphocytes attack the parietal cells of the stomach and destroy them. This results in lack of intrinsic factor being produced, and thus vitamin B12 is not absorbed (in the terminal ileum). This produces a macrocytic anaemia. This skin and mucosa will become pale and the tongue becomes smooth. There may also often be peripheral neuropathy which causes parasthesaie, numbness, and possibly even ataxia. All that you need to keep the patient healthy is a monthly injection of vitamin B12. Before the discovery of B12, this condition was fatal.

Infiltrative

There may be massive fibrosis, but not much evidence of lymphocytic infiltrate. (This is different to Hashimoto’s thyroiditis, where the infiltrate is much greater). By the time of diagnosis, often there will be few thyroid follicles remaining.   

Post-partum thyroiditis

  • This is a condition usually seen transiently after pregnancy, and it may involve hypothyroidism, hyperthyroidism or both.
  • In pregnancy, hyperthyroidism may occurs because Beta-HCG can act on TSH receptors, producing more thyroid hormone.
  • It is thought to arise from modifications to the immune system that occur during pregnancy, and histologically it can be seen as a lymphocytic thyroiditis.
  • Often the disease is self-limiting, but in some instances, there may be conventional antibodies present – in which case the disease has a high chance of progressing to permanent hypothyroidism.

Iodine deficiency

  • This is particularly common in mountainous areas such as the Alps, Himalayas, south America and Central Africa. In such regions, there may be endemic goitre where large proportions of the population suffer from goitre.
  • Patients will either by euthyroid or hypothyroid depending on the severity of the deficiency.
  • The goitre is caused by a continuing underlying iodine deficiency, that will ultimately stimulate TSH production, and thus result in thyroid enlargement to compensate for the low levels of iodine.

Congenital Hypothyroidism

  • 60% of cases are due to thyroid aplasia or hypoplasia
  • 30% of cases are due to ectopic tissue
  • 10% of cases are due to dyshormonogenesis. In this condition, there are genetic defects that prevent the proper formation of thyroid hormones. The patients will develop lymphcytosis with goitre. One particular form of the disease is associated with sensori-neuro deafnessPendred’s Syndrome – in this condition, there is a defect in the chloride / iodide transporter.

Myxoedema

This is a skin and tissue disorder associated with prolonged hypothyroidism (of any cause). The skin and subcutaneous tissues will thicken resulting in an unusual looking ‘coarse’ appearance. The thickening is caused by the accumulation of mucopolysaccharide in the subcutaneous tissues. The term ‘myxoedema’ is often used inter-changeably with ‘hypothyroidism’.

Clinical features

The availability of tests for TSH has meant that hypothyroidism is now often noticed before it causes significant clinical signs and symptoms.
The differential diagnosis is vast due to the vague symptoms, but hypothyroidism should always be excluded as one of the first possibilities. It often presents in middle aged women – and in such patients, chronic fatigue syndrome and depression are common differential diagnoses.
The onset of symptoms can give a clue as to the cause:
  • Autoimmune thyroid disease tends to present slowly over many years and symptoms are often much more vague
Appearance
  • Ask about or look for a change in appearance from the patients baseline
  • Puffy eyes
  • Dry skin
  • Dry, brittle, unmanageable hair
  • Very thin hair, loss of eyebrows
  • Overweight / obesity
  • ‘Peaches and cream’ complexion
  • Deep voice
Metabolism
  • Cold intolerance
  • Fatigue
  • Tiredness / malaise
Nervous system
Cognitive
  • Poor memory / mental slowness
  • Depression
  • Reduced attention span
Cardiovascular
  • Bradycardia – slow heart beat (<60bpm)
  • Peripheral oedema
  • Decreased exercise tolerance
  • Hypertension
Gastrointestinal
  • Poor appetite – especially when in combination with weight gain
  • Constipation
Reproductive system
  • Poor libido
  • Menorrhagia or oligomenorrhoea
  • Infertility

Goitre

  • This is most common with auto-immune hypothyroidism The goitre will often be firm and nodular raising the suspicion of thyroid malignancy. This should be investigated by biopsy to exclude this possibility. In hashimoto’s disease, goitre may be noticeable before other symptoms. Pain is a rare complication of auto-immune hypothyroidism (i.e. most patients don’t have pain!)

Myxoedema coma

  • This is rare. It may present with hypothermia (sometimes as low as 23’C), coma and possibly seizures. Mortality for this presentation is about 50%. Patients are usually old, and there is often an additional condition on presentation such as heart failure, pneumonia, stroke, anaemia.
  • Often patients will be undiagnosed (with hypothyroidism), but sometimes it occurs in diagnosed patients who have been un-compliant with treatment
The ‘classical’ patient will have dry hair, thick skin, a deep voice, cold intolerance, have weight gain, bradycardia and constipation, and will be generally slowed in their thoughts and actions. The diagnosis for these patients is fairly easy.
Patients with more mild symptoms are harder to diagnose as their symptoms may be so vague as to sound like just general tiredness.
Particularly difficult to diagnose, due to lack of classic symptoms are:
  • Children – hypothyroidism is generally rare. They may have retarded growth (both physical and mental) and have an infantile looking face. Puberty may be delayed, and there may also be muscle enlargement.
  • Neonates – this is also very rare, and will probably present with failure to thrive, prolonged jaundice, feeding difficulties ad constipation. If left untreated for the first couple of weeks after birth it may cause permanent neurological damage.
  • Young women – hypothyroidism should be excluded in all cases of oligomenorrhoea and amenhorroea
  • The elderly – may show many signs that are difficult to distinguish from ‘signs of ageing’

Investigations

Thyroid stimulating hormone (TSH) is the main diagnostic test. A low TSH suggests hypothyroidism – which is then usually confirmed with a T4 level. Together, TSH and T4 are often referred to as Thyroid function tests (TFTs). 

  • TSH raised on two separate occasions = overt hypothyroidism
  • TSH >2.5 AND T4 low = overt hypothyroidism
  • TSH 2.5 – 10 with normal T4 – subclinical hypothyroidism – see below

Interpreting TFTs is an important clinical skill and takes a little bit of practice.

  •  If TSH is normal or low, and T4 is also low, then we can deduce that there is a TSH deficiency (i.e. a hypothalamic/pituitary cause). This is rare.
    • In normal physiology, a low T4, will feedback to the hypothalamus and result in a production of more TSH. So – high TSH alone will confirm a suspected diagnosis of primary hypothyroidism but if you suspect secondary hypothyroidism, then you should check T4 as well – if they are both low, then this will confirm a suspected diagnosis of hypothyroidism. You need a TSH of above 10U/L consistently to be able to diagnose hypothyroidism.
    • After surgery and radiotherapy, TSH and T4 levels may give the impression of hypothyroidism, but this is usually just compensatory, and levels will return to normal after a while.
  • Measuring T3 is not very useful as in ¼ of patients T3 levels will be normal anyway due to the fact that T4 is converted to T3 in the bloodstream.
  • In suspected cases of myxoedema then you need to start treatment straight away without waiting for confirmation of diagnosis
Interpreting TFTs

Interpreting TFTs. Adapted from a diagram in Thyroid – afp

Additional Investigations

  • TPO antibodies – confirm an autoimmune cause
  • Cholesterol – patients often have hypercholesterolaemia
  • FBC – for anaemia
    • Typically normocytic, although it may be macrocytic when pernicious anaemia is also present, and may even be microcytic in the presence of menorrhagia.
  • U+Es – for hyponatraemia
  • CK – may be raised – especially in cases which present with myopathy (muscle pain)
  • AST levels may be increased due to muscle and liver problems (mainly myopathy

Congenital hypothyroidism

Congenital hypothyroidism is important as failure to treat can lead to permanent neurological deficit. Once the diagnosis is established, you should commence treatment on thyroxine immediately to reduce the risk of permanent neurological deficit. After 3-4 years, you can re-assess the situation to see if life-long thyroxine is necessary. By this age, there will be no permanent neurological consequences of stopping treatment.

Treatment

The only effective treatment is oral T4 – usually referred to as levothyroxine and occasionally thyroxine. 

  • Treatment with triiodothyronine (T3) has been used in combination with levothyroxine previously but has not been shown to be of benefit
  • It may be considered in specialist cases

Usually treatment is lifelong – except in cases where transient disease is caused by severe illness or drugs.

Principles of treatment

  • The aim of treatment is to achieve a T4 level in the normal range AND a TSH level in the normal range
    • The doses is primarily titrated to the TSH level
  • The typical dose is 1.6µg/Kg, but the dose should be started low and titrated up to this
    • Typically this means doses are in the 100-200µg per day range
  • Initially give 25-50µg, and review after 6 weeks
    • Start at the lower end for frail and elderly patients
  • Adjust the dose every 6 weeks so that TSH levels are in the normal range (not suppressed)
    • Low TSH suggests over-replacement of T4 (even if T4 is not elevated) – titrate the dose down until TSH returns to the normal range
    • High TSH suggests under-replacement – increase the dose of levothyroxine
  • The half life of T4 is about 7 days, so any change in the dose will not be clinically noticeable for about 4 weeks. You should adjust the dose in 12.5-25µg/day increments. Once you have got the TSH to normal and relieved symptoms, then check every year.
  • If levels fluctuate on follow-up it is probably a compliance issue. Because of the long half life of thyroxine, it is safe for patients to take missed tablets at a later time, and you should inform them of this.
  • In secondary hypothyroidism the TSH is unreliable, and doses should be titrated to the T4 level
  • Advise patients:
    • Treatment is usually lifelong
    • There is an association with other autoimmune diseases, particularly:
      • Pernicious anaemia
      • Addison’s disease
    • About the risk of side effects
      • Typically few, and usually dose related – due to too much thyroxine causing signs of hyperthyroidism:
        • Palpitations and atrial fibrillation
        • Diarrhoea
        • Increase appetite
        • Anxiety
        • Insomnia
        • Tremors

Subclinical hypothyroidism

  • Historically, a contentious issue
  • Defined as elevated TSH, with normal T4. It is seen in:
    • 4-8% of general population
    • 15% of women over 60
  • About 10-15% of these patients will progress to overt hypothyroidism within 12 months
  • A Cochrane review suggested no benefit in life-expectancy or other long-term measurable outcomes for cardiovascular health or other consequences of hypothyroidism, but did find an improvement in quality of life in patients treated with levothyroxine
  • A practical approach would be to treat:
    • Those with positive TPO antibodies, who are symptomatic with a TSH >5
    • Those with a TSH >10
  • Those who do not fit these criteria should be offered TSH testing every 3 years

Pregnancy – in pregnant patients you should increase the thyroxine dose by 25-50µg to ensure normal TSH levels and up until 20 weeks gestation, levees should be checked every 4 weeks. This is particularly important, because babies born in mothers with raised TSH have an increased risk of impaired cognitive function.

Depression – patients with hypothyroidism are at increased risk of depression, but in the elderly patient, sometimes a severe psychosis may develop – often shortly after commencing treatment. This will subside with prolonged treatment. Treatment is lifelong and patients have a normal life-expectancy. Occasionally patients may stop treatment and remain euthyroid.

Indications for specialist involvement

  • Patients <18 yo
  • Patients not responding to standard therapy
  • Hypothyroidism in pregnancy
  • Hypothyroidism in the presence of cardiac disease
  • Hypothyroidism with goitre, thyroid nodules or other anatomical thyroid abnormalities

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