Introduction

Hypothyroidism (aka myxoedema)

This is quite common, and easy to treat. 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, or due to damage caused by radioiodine that has been used to treat hyperthyroidism.
  • Iodine deficiency
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 body tries to combat decreasing thyroid hormone output.
The point where TSH levels are above normal, but there are no symptoms yet apparent is known as subclinical 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.At this stage, we say the patient has overt or clinical hypothyroidism.
 

Causes

Primary

  • Congenital
  • Defects in hormone synthesis can be due to: Iodine deficiency, Antithyroid drugs (e.g. lithium, amiodarone, interferon)

Autoimmune – these are by far the largest cause -Infective
Secondary – Hypopituitarism (which produces isolated TSH deficiency)
Post Surgery – Post irradiation Radioactive iodine therapy External neck irradiation
Other – peripheral resistance to thyroid hormone

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.
Autoimmune hypothyroidism (atrophic hypothyroidism)
Do NOT confuse this with auto-immune hyperthyroisidm (Grave’s disease)!
  • This is the most common type of hypothyroidism.
  • 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.

Pathology

There will usually 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. o    

Hashimoto’s Thyroiditis

  • This is also an autoimmune disease. It was the first ever autoimmune disease to be recognised as such.
  • 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.
  • The condition causes an enlarged thyroid (goitre). The enlargement is due to infiltration of the thyroid with lymphocytes, and resultant fibrosis.
  • 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) –Goitre is often associated with hyperthyroidism, but in these circumstances, this is not the case.
  • 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. Both types of the disease can be treated with thyroxine (T4) therapy, and this will usually shrink the goitre. -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.
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.

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 any 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.
  • Tiredness / malaise
  • Weight gain and poor appetite.
  • Cold intolerance
  • Poor memory / mental slowness
  • Change in appearance
  • Depression
  • Poor libido
  • 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!)
  • Puffy eyes
  • Dry, brittle, unmanageable hair. Very thin hair, loss of eyebrows.
  • Constipation
  • Menorrhagia (over-abundance of menstrual discharge) or oligomenorrhoea(infrequent menstruation)
  • Overweight / obesity
  • Dry skin
  • ‘Peaches and cream’ complexion
  • Hypertension
  • Hypothermia
  • Peripheral oedema
  • Deep voice
  • Cold peripheries
  • Carpal tunnel syndrome
  • Bradycardia – slow heart beat (<60bpm)
  • Myxoedema comathis is rare. It will present with all the usual features, plus hypothermia (sometimes as low as 23’), 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, chest infection, stroke, blood loss etc. Often patients will be undiagnosed, but sometimes it occurs in diagnosed patients who have been incompliant 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 slow The diagnosis for these patients is fairly easy.
Patients with more mild symptoms are harder to diagnose as their symptoms will probably sound like just general tiredness.
Particularly difficult to diagnose, due to lack of classic symptoms are:
  • Children – this is generally rare. They may have retarded growth (both physical and mental) and have an infantile looking face. In the past, this condition may have been called a form of cretinism. 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

The main test is for TSH. High TSH confirms hypothyroidism – but cannot confirm a hypothyroid state. You usually perform this test in conjunction with a test for free T4. A low level of this will confirm a hypothyroid state. -If TSH is normal or low, and T4 is also low, then we can deduce that there is a TSH deficiency (i.e. autoimmune hypothyroidism is not the cause). Normally, a low T4, will feedback to the hypothalamus and result in a production of more TSH. –So! – highTSH 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.
  • Anaemia is also a common finding on investigation. In will usually be normocytic, although it may be macrocytic when pernicious anaemia is also present, and may even be microcytic in the presence of menorrhagia.
  • The diagnosis of auto-immune hypothyroidism can be further confirmed by high levels TPO antibodies, although sometimes these are absent. In iodine sufficient countries, this is the most common cause of hypothyroidism.
  • AST levels may e increased due to muscle and liver problems(mainly myopathy). Myopathy will also be associated with high creatine kinase levels. Hypercholesterolaemia and hyponatraemia may also be present. Hyponatraemia is a low serum sodium level. Common causes include:

Excessive ADH secretion causing water retention (this is usually the cause if it present in association with hypothyroidism)

  • Dilution of blood – ie if fluids are given that have a poor salt balance.
  • Excessive sodium loss
  • Inadequate sodium intake (rare)

Congential hypothyroidism Once you have established this, you should commence treatment on thyroxine immediately. 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
This varies on whether or not the patient is ‘fit and healthy’

Young fit patient (no heart disease)

  • Levothyroxine – this is T4. Treatment will be for life. Initially you will give 50-100µg, and get the patient to come back after 12 weeks. Adjust the dose every 6 weeks so that TSH levels are normal (not suppressed). 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 25-50µg 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 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.

Older patient – possibly with heart disease

  • Same as above, except if they are older /small / frail you will want to start on a low dose (~50). If they have heart disease, you should start on an even lower dose (~25) and then gradually increase it.
  • With not functioning thyroid tissue at all, a normal person needs about 150µg a day of T4. If you give more than this you increase the risk of atrial fibrillation particularly in those over 60. -Full resolution of symptoms may take 6 months.
  • Advise the patient that their treatment is lifelong, and there is a possibility of other autoimmune disease developing, particularly Addison’s disease and pernicious anaemia. Addison’s disease – this is a deficiency in the adrenal hormones – cortisol, aldosterone and androgens due to destruction of the adrenal cortex. 70% of cases are autoimmune, 30% are due to TB. In the past, a far greater number were due to TB. Carcinoma is also a very rare cause. Symptoms include loss of appetite, weight loss, fatigue and nausea. The skin will become pigmented as a result of increased production of ACTH. The patient may also feel faint, particularly on standing due to postural hypotension. Women will lose their axillary hair, and both sexes are likely to develop depression. It is treated with hormone replacement therapy, which is usually in the form of hydrocortisone tablets. After treatment, patients are able to lead a perfectly normal life, and have a normal life expectancy.

Pregnancy – in pregnant patients you should increase the thyroxine dose by 25-50µg to ensure normal TSH levels. This is particularly important, because babies born in mothers with raised TSH tend to have impaired cognitive function.

Depressionit is normal for patients to become depressed, but in the elderly patient, sometimes a severe psychosis may develop – sometimes just 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.

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