Myxoedema coma

Synonym: myxoedema crisis

What is a myxoedema coma?

Myxoedema coma is the extreme manifestation of (usually untreated) hypothyroidism. It is one of a relatively small number of endocrine emergencies, and it is a rare, but potentially fatal disorder. It does not necessarily involve the presence of pretibial oedema or of coma.

Myxoedema coma can be difficult to diagnose and successfully treat. Even if promptly treated it has a high mortality rate.¹

In a patient who has untreated or undertreated hypothyroidism several physiological changes take place to compensate for the lack of thyroid activity.² This ability of the body to compensate for deficiency of T4 and T3 may, however, be overwhelmed - for example, by infection, drugs, other diseases or hypothermia. The resulting state is referred to as 'myxoedema coma' despite the fact that the patient may not be comatose or display the skin changes of myxoedema (hence the alternative term 'myxoedema crisis').

Pathophysiology³

Myxoedema coma can be regarded as a form of decompensated hypothyroidism in which the adaptations of the body to untreated hypothyroidism fail to maintain homoeostasis and become overwhelmed by hypothermia, infection or other precipitating factors. These adaptations include peripheral vasoconstriction to maintain core body temperature.

This process of adaptation and eventually failing function, affects all organs, including the brain, heart, lungs, kidney and gastrointestinal tract (see 'Clinical features found in myxoedema coma', below).

Factors which may precipitate myxoedema coma⁴

• Hypothermia (common precipitant).

• Infections:
  

  • Influenza.

  • Pneumonia.

  • Urinary tract infections.

• Medication:
  

  • Amiodarone.⁵

  • Anaesthesia.

  • Beta-blockers.

  • Diuretics.

  • Drugs acting on the central nervous system.

  • Lithium.

  • Phenytoin.

  • Rifampicin.

• Other significant physiological challenges:
  

  • Hypoglycaemia.

  • Gastrointestinal haemorrhage.

  • Cerebrovascular disease.

  • Surgery, anaesthetics or trauma.

  • Accidents, burns.

  • Respiratory depression and retention of carbon dioxide.

How common is myxoedema coma? (Epidemiology)

• Myxoedema coma is relatively rare; incidence of 1.08 per million people per year in Japan.⁶ Estimates for Western countries are 0.22 cases per million people per year.⁴

• Myxoedema coma is around four times more common in women than in men (reflecting the higher incidence of hypothyroidism in women, which has a prevalence of 8% in women aged over 50).

• Myxoedema coma occurs almost exclusively in patients over 60 years of age.

• In communities with iodine deficiency (mountain regions of Asia, Africa and South America) the prevalence of hypothyroidism is higher. It is therefore likely that the incidence of myxoedema coma is also higher in these populations.

• The condition presents more often in the winter months (90% of cases present in the winter). This seasonal variation probably relates to age-related loss of temperature sense, combined with lower heat production secondary to hypothyroidism.

• It usually presents in patients with long-standing hypothyroidism, which may be undiagnosed or inadequately treated due to lack of monitoring or poor compliance.

• Other factors known to precipitate myxoedema coma include hypoglycaemia, infection, trauma, haemorrhage and change of medication.

Myxoedema coma symptoms⁷

• Most patients present with neither coma nor non-pitting oedema and the term 'myxoedema coma' is hence something of a misnomer. However, patients can present in a comatose state.

• Patients who develop myxoedema coma usually have long-standing hypothyroidism.

• Typically patients will have classic features of weight gain, fatigue, constipation and cold intolerance. They may also show coarsened hair, deepened voice and dry, pale, cool skin. However, elderly patients with hypothyroidism may have atypical symptoms. They may just present with reduced mobility, and some patients with compensated hypothyroidism are asymptomatic. Hypothyroidism of long standing can therefore easily be missed.

• Myxoedema coma usually affects the mental state: patients may present with apathy, low mood, cognitive decline, confusion and even coma. The changes can be subtle and may be misdiagnosed as dementia or depression.

• Patients with myxoedema coma are commonly hypothermic with core temperatures less than 35.5°C

• Patients with myxoedema coma are commonly hypotensive and bradycardic.

• Hypoventilation due to diaphragmatic weakness and altered ventilatory response can lead to sleep apnoea.

Clinical features found in myxoedema coma⁶

The effects are widespread:

Central nervous system

• Deterioration in mental state is the cardinal symptom.

• A largely unknown mechanism disrupts brain function.

• Reduced cerebral blood flow, reduced oxygen and glucose consumption are all involved.

• Confusion.

• Apathy.

• Psychosis - may be present but is relatively rare.⁴

• It may also produce lethargy, stupor or (very rarely) coma.

• Reflexes will show a slow relaxation phase.

• Other metabolic effects may compound these effects (for example, hyponatraemia).

Metabolic

• Reduced metabolic rate causes weight gain, growth reduction, lower energy production and many other effects.

• Significantly, the metabolic effects impair drug metabolism (see the triggers listed under 'Factors which may precipitate myxoedema coma', above).

• Hypothermia (core temperature <35.5°C is common, although temperature may be normal).

• Respiratory acidosis, hypoxia and hypercapnia are common.

Classic myxoedematous facial appearance

• Generalised swelling and puffiness.

• Macroglossia.

• Ptosis.

• Periorbital oedema.

• Coarse, sparse hair.

Skin

• Dry, cool and doughy skin.

• Non-pitting oedema of the hands and feet.

• Hair loss (alopecia).

Cardiovascular

• Bradycardia and reduced cardiac output resulting from profound effects on the heart muscle.

• Pericardial effusions may occur and lead to cardiomegaly on X-ray.

• There is increased peripheral vascular resistance.

• Reduced heart sounds and reduced apical impulse are typically found.

• Blood pressure may be raised in the early stages. Raised diastolic and normal systolic pressures occur. Hypotension can occur in the later stages.

• Blood counts may show normocytic or macrocytic anaemia. Pernicious anaemia may co-exist.

Gastrointestinal

• Constipation (may present with faecal impaction).

• The most dramatic manifestations of reduced motility are myxoedema megacolon and paralytic ileus.

• Gastric atony can occur.

• Ascites can occur by a variety of mechanisms.

Renal and bladder

• Renal impairment may be severe.

• Low cardiac output and other metabolic changes contribute to low glomerular filtration rate.

• Bladder distention may occur.

Respiratory

• Depressed function of the respiratory muscles, reduced ventilatory drive and reduced oxygen consumption all contribute to hypoventilation.

• Hypoventilation, hypoxia, and hypercarbia result.

• The associated weight gain and obesity may be further complicated by sleep apnoea.

Differential diagnosis⁴

The differential diagnosis of myxoedema coma will includes other causes of a deterioration in mental state:

• Hypothermia.

• Septic shock.

• Psychiatric disorders:
  

  • Dementia (including Alzheimer's disease).

  • Depression.

• Changes in mental state secondary to other medical conditions and drugs:
  

  • Hypoglycaemia (may co-exist).

  • Encephalitis and meningitis.

  • Hepatic encephalopathy.

  • Cerebrovascular disease

  • Other infections (urinary tract, pneumonia, influenza, amongst others)

  • Drugs

• Respiratory depression and hypoventilation syndromes.

• Stroke.⁸

Investigations⁴

A patient in whom a diagnosis of myxoedema coma is suspected should have the following investigations performed:

• TFTs:
  

  • TSH level: almost always raised, but may be normal if the hypothyroidism is a result of pituitary disease.

  • T4 levels (and T3 level) are always reduced.

• Routine biochemistry:
  

  • U&Es show reduced sodium level (hyponatraemia): sodium reabsorption is reduced by enzyme deficiencies. Osmolality is reduced, creatinine is usually raised and hypoglycaemia can result from the reduced metabolic activity.

  • Blood sugar is frequently reduced, usually because of the reduced metabolic rate. However, co-existing diabetes or adrenal insufficiency may contribute to this.

  • FBC often reveals normocytic anaemia and mild leukopenia. There may be signs of infection.

  • Blood and urine cultures should be performed as infection is a common precipitant.

  • Oxygen saturation is frequently reduced.

  • Blood gases reveal hypoxia, hypercapnia and respiratory acidosis.

• Serum enzymes:
  

  • Raised creatine kinase (usually of skeletal muscle origin unless myocardial infarction is involved) is often found.

  • Raised transaminases are often present.

• Lipid profile reveals hyperlipidaemia.

• ECG. Possible changes include:
  

  • Bradycardia.

  • Other nonspecific ST and T-wave changes.

  • Reduced voltages.

  • Varying degrees of heart block and prolonged QT interval.

  • Myocardial infarction - beware of the possibility.

• CXR can reveal:
  

  • Pleural effusions with or without cardiomegaly.

  • Pericardial effusion.

• Serum cortisol levels:
  

  • This is done to rule out the possibility of adrenal insufficiency as a result of hypopituitarism.

• Infection screening:
  

  • This may identify the trigger to the myxoedema coma. Examples include urine culture and blood culture.

Myxoedema coma treatment⁹

General measures

• Patients with myxoedema coma require admission to an intensive care or high-dependency unit for careful monitoring and treatment.

• Mechanical ventilation will be required if there is significant hypercapnia or hypoxia. Non-invasive ventilation such as continuous positive airway pressure (CPAP) may used.

• Hypovolaemia, hypoglycaemia and electrolyte disturbances should be corrected.

• Cardiovascular status should be carefully monitored:

• • ECG monitoring is essential.

  • Myocardial infarction should be excluded.

  • Blood pressure should be carefully monitored.

  • Pressor agents and inotropes should be avoided, as they provoke arrhythmias.

• Hypothermic patients should be warmed slowly without the use of warming blankets, as peripheral vasodilatation may aggravate or induce hypotension.

Specific measures

• As the numbers of patients with myxoedema coma are relatively small, there are few clinical trials regarding the treatment of these patients.

Thyroid replacement therapy

• Immediate intravenous thyroid replacement is mandatory. Gastrointestinal absorption is compromised.

• There is controversy as to whether this should be T4 alone, combined with T3, or T3 alone.

• It is most common in adults to use T4 alone, with an initial loading dose of intravenous T4 of 100-500 micrograms. This is followed by a dose of 75-100 micrograms per day until the patient is able to take oral replacement.

• It may be combined with T3 in younger patients with lower cardiovascular risk.

Antibiotics

• In view of the fact that many patients will have had their condition precipitated by infection, many advocate adding a broad-spectrum antibiotic to the treatment regime.

Corticosteroids

• It should be assumed that all patients have adrenal insufficiency secondary to hypopituitarism until this can be ruled out, and all patients should receive intravenous hydrocortisone at a dose of 100 mg every eight hours until the results of the random cortisol level prior to treatment are available.

Complications⁴

• Adrenal crisis.

• Myocardial infarction.

• Cardiac arrhythmias.

Prognosis

The prognosis for any patient will depend on their general condition at the time of presentation, and other comorbidities. The mortality rate can be high even with treatment. The risk is highest in elderly, hypothermic and bradycardic patients. A 2017 review of 149 cases in Japan showed an average mortality of 29.5%.⁶

The most important factors in the prevention of fatality in cases of myxoedema coma are early recognition, presumptive thyroid hormone replacement, hydrocortisone and supportive care.

How to prevent myxoedema coma

It is important, particularly in general practice, to be vigilant and diagnose hypothyroidism early. There should be a low threshold for initiating thyroid function testing in the elderly, especially elderly women presenting in the winter months with changes in mental state.