Pathophysiology

Longstanding hypothyroidism brings about physiological adaptations. These adaptations, for example, include peripheral vasoconstriction to maintain core body temperature. Myxoedema coma can be regarded as a form of decompensated hypothyroidism in which the adaptations fail to maintain homoeostasis and become overwhelmed by hypothermia, infection or other precipitating factors (see below). This process of adaptation and eventually failing function, affects all organs, including the brain, heart, lungs, kidney and gastrointestinal tract (see features of myxoedema under Presentation below).

Epidemiology

• Hypothyroidism is common especially in the elderly (prevalence 8% of women over 50). In communities with iodine deficiency (mountain regions of Asia, Africa and South America) the prevalence of hypothyroidism is higher. It is likely that the incidence of myxoedema coma is higher.
• Myxoedema coma is between 4 and 8 times more common in women than men (reflecting the higher incidence of hypothyroidism in women).
• It presents more often in the winter months (90% of cases present in the winter).^[3][4]
• The average age of patients with myxoedema coma is over 70. It is rarely seen in patients aged less than 60.^[5]
• It presents more frequently in the winter months, precipitated by hypothermia. Other factors known to precipitate myxoedema coma include, hypoglycaemia, infection, trauma, haemorrhage and change of medication.

Presentation^[4]

• Patients who develop myxoedema coma usually have long-standing hypothyroidism. Typically they will have a long history of weight gain, fatigue, constipation and cold intolerance.
• However this may not yet have been diagnosed and myoedema coma is the most severe presentation of profound hypothyroidism.
• At presentation they will usually demonstrate some of the typical features of hypothyroidism, but may also present with more atypical features such as impaired mobility.
• The cardinal feature of myxoedema coma is a deterioration in mental state although this may be subtle in some cases and misdiagnosed as dementia or depression.
• Most patients present with neither coma nor non-pitting oedema and the term 'myoedema coma' is hence something of a misnomer. However, patients can rarely present in a comatose state.

Differential diagnosis

The differential diagnosis of myxoedema coma will include particularly 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 coexist)
  • Encephalitis and meningitis
  • Hepatic encephalopathy^[6][7]
  • Cerebrovascular disease
  • Other infections (urinary tract, pneumonia, influenza, amongst others)
  • Drugs
• Respiratory depression and hypoventilation syndromes
• Stroke

Investigations

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

• Thyroid function tests:
  • 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:
  • Urea and electrolytes show reduced sodium level (hyponatraemia).
  • Creatinine is likely to be raised.
  • Blood sugar is frequently reduced, usually because of the reduced metabolic rate. However, coexisting diabetes or adrenal insufficiency may contribute to this.
• Full blood count often reveals normocytic anaemia and mild leucopenia. There may be signs of infection.
• Oxygen saturation is frequently reduced.
• Blood gases reveal hypoxia, hypercapnoea and respiratory acidosis.
• Serum enzymes:
  • Raised creatine kinase (usually 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.
  • Beware of the possibility of myocardial infarction.
• 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.

Management

• 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 hypercapnoea or hypoxia. Noninvasive 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.^[8][9]
    • 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 8 hours until the results of the random cortisol level prior to treatment are available.

Complications

• 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 usually reported to be highest in the elderly, hypothermic and bradycardic patients.^[10] However another study of 11 patients listed coma on admission, Glasgow Coma Scale score and Apache II scores as better indicators of survival.^[11]

Prevention

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 with changes in mental state but also with weight gain, constipation and other relevant symptoms.^[4]