OVERVIEW: What every practitioner needs to know
Are you sure your patient has myxedema coma? What are the typical findings for this disease?
Myxedema coma occurs in patients with long-standing hypothyroidism and a precipitating stressful event. It is rare in children. The most common precipitating event is an infection, but it can occur following trauma, exposure to the cold, exposure to certain drugs (sedatives, narcotics, or iodine-containing medications), with anesthesia, or worsening of an underlying medical condition.
Patients present with altered mental status, hypothermia, and symptoms and signs of cardiac, pulmonary, and hepatic hypofunction. (Table I) Hypothyroidism should be confirmed by measurement of serum free T4 and TSH levels. Other organ systems should be evaluated as indicated, e.g, with comprehensive metabolic panel, capillary blood gas, an EKG, and sepsis work-up.
Signs of hypothyroidism may be insidious or non-specific. In addition, myxedema coma is rare in children (most common in elderly women). When patients present with altered mental status and these non-specific features, hypothyroidism often is not an initial consideration. For all these reasons, diagnosis and treatment are delayed.
Initial treatment includes supportive measures to treat hypothermia, hypotension, hypoventilation, and possible infection. Once the diagnosis of myxedema coma and hypothyroidism is confirmed, thyroid hormone treatment should be started. While there is controversy on the optimal thyroid hormone regimen, most experts recommend a combination of T4 and T3 administered intravenously. Stress dosing of glucocorticoids is recommended; pituitary-adrenal function should be evaluated first. The prognosis is variable, with some studies reporting up to a 50% mortality in elderly adults; likely the prognosis is better in children.
What other disease/condition shares some of these symptoms?
Sepsis, cardiac disease with congestive heart failure, pneumonia with pulmonary decompensation, intracerebral vascular accident (stroke). Seizure disorder (resulting from hypoglycemia or hyponatremia).
What caused this disease to develop at this time?
Long-standing hypothyroidism with a precipitating event, such as infection, trauma, exposure to cold, exposure to certain drugs (e.g., sedatives, tranquilizers, narcotics, lithium, or iodine-containing medications), anesthesia, or deterioration of another medical condition. Sedatives, tranquilizers, or narcotics will exacerbate central hypoventilation.
Acquired hypothyroidism in children is most commonly caused by autoimmune thyroiditis (Hashimoto’s thyroiditis), but it can also occur in children after radiation for head and neck tumors, post thyroid ablation or thyroidectomy for Graves’ disease or thyroid cancer, or with excess iodine ingestion. Most cases of myxedema are associated with primary hypothyroidism, but it can occur with secondary (central) hypothyroidism.
Hypothyroidism in children is usually discovered by parental history or a review of previous thyroid function testing, though it is possible that long-standing autoimmune thyroiditis may be occult and features of hypothyroidism may develop slowly over time. Physical examination findings include short stature, low HR, RR, and BP, decreased body temperature (often profound), puffy facies and non-pitting edema (all resulting in appearing overweight for height; true obesity not a feature), dry skin, coarse, sparse hair, macroglossia, hoarse voice, goiter, and hypotonia with slow return of deep tendon reflexes.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Serum TSH and free T4: Serum TSH is elevated and the free T4 level is low. Bear in mind that patients with myxedema coma also may manifest features of “sick-euthyroid syndrome” (non-thyroidal illness syndrome). In non-thyroidal illness, the serum TSH may be lowered, though it would be unlikely to normalize in patients with long-standing hypothyroidism. As myxedema coma occurs with long-standing hypothyroidism, likely the free T4 will be significantly below the lower end of the reference range and TSH will be significantly elevated, usually >100 mU/L. Measurement of antithyroid antibodies will be positive with autoimmune thyroid disease.
Less commonly, myxedema coma is associated with central hypothyroidism; in such cases, serum free T4 levels are low and serum TSH levels are either low or “inappropriately normal”. Bear in mind that these findings are identical to those seen with non-thyroidal illness. As such, it may be impossible to separate central hypothyroidism from non-thyroidal illness. Ordinarily, measurement of a serum reverse T3 (rT3) level would help to separate these two possibilities.
Serum rT3 will be low or normal in patients with central hypothyroidism, whereas it is elevated in patients with non-thyroidal illness. However, as patients with true central hypothyroidism complicated by myxedema coma are acutely ill, serum rT3 levels may be elevated. Thus, a low, normal, or elevated serum rT3 level may be seen in patients with central hypothyroidism and myxedema coma. (In addition, most routine “analogue” free T4 assay levels are low with non-thyroidal illness. Free T4 is best measured by equilibrium dialysis, though this is performed in “reference labs” with a delay in getting the result.)
A metabolic panel may show hypoglycemia and hyponatremia, along with elevation of muscle enzymes (creatine phosphokinase [CPK] and lactic dehydrogenase [LDH]).
Blood gas analysis will show respiratory acidosis and hypoxia (low pH, high pCO2, low pO2).(Table I).
An EKG may show sinus bradycardia with non-specific changes. Echocardiography may show a large heart, pericardial effusion, and decreased ventricular function.
Serum cortisol, ideally before and after ACTH stimulation – (using high dose cortrosyn, 250 mcg) to evaluate for adrenal insufficiency, as the most common cause of acquired hypothyroidism is autoimmune thyroid disease, patients may have associated autoimmune adrenal disease (Addison’s disease).
If seizures are present (from hypoglycemia or hyponatremia), CSF analysis via LP will be normal except for slight elevation of CSF protein. An EEG will show nonspecific slowing with low voltage.
Other diagnostic tests may be indicated to evaluate the precipitating event, such as blood or urine culture.
Would imaging studies be helpful? If so, which ones?
Imaging studies are generally not indicated or helpful, except for evaluation of precipitating event, e.g., chest X-ray for suspected pneumonia, computed tomography (CT) or magnetic resonance imaging (MRI) of brain to evaluate head trauma or suspected intracerebral vascular accident.
If you are able to confirm that the patient has myxedema coma, what treatment should be initiated?
Initial treatment involves supportive measures, as the diagnosis of hypothyroidism may not be considered initially. Supportive measures include treatment of hypothermia, hypotension, hypoventilation, and possible infection. A rewarming blanket is used to raise body temperature slowly. Most patients require intubation and mechanical ventilation. Vasopressors are used to treat hypotension, along with IV fluids containing glucose to correct hypoglycemia. Hypotonic IV fluids should be avoided if hyponatremia is present. Broad spectrum antibiotics may be appropriate until culture results are known.
Stress dosing with glucocorticoids is recommended, as primary hypothyroidism may be associated with adrenal insufficiency and central hypothyroidism may be associated with hypopituitarism and central adrenal insufficiency. Hydrocortisone, 25 mg/m2, is administered IV every 8 hrs. If serum cortisol levels rule out adrenal insufficiency, hydrocortisone treatment can be discontinued.
Once hypothyroidism is suspected and a clinical diagnosis of myxedema coma is made, thyroid hormone treatment should be started (pending thyroid test results, if not available). Treatment with both levothyroxine (T4) and triiodothyronine (T3) is recommended initially. T3 is the biologically active form of thyroid hormone; there is decreased conversion of T4 to T3 in acutely ill patients (non-thyroidal illness syndrome in the past has been referred to as the “low T3 syndrome”). T3 has a more rapid onset of action than T4. It is recommended to administer T4 and T3 intravenously, as gastrointestinal absorption may be impaired.
There is some evidence to support giving a loading dose of T4 and T3. The initial dose of T4 is 200-400 mcg/1.73 m2 (~4-8 mcg/kg) IV and T3 5-20 mcg/1.73 m2 (~0.1-0.4 mcg/kg) IV (an IV preparation of levothyroxine is available in 100 mcg and 500 mcg vials; T3 is available in 10 mcg vials). Maintenance T4 dosing is 2 mcg/kg daily and T3 0.1 mcg/kg every 8 – 12 hrs. With clinical improvement, T3 treatment can be discontinued and T4 can be administered orally. It should be noted that the above advice is based on expert clinical opinion; there are no randomized clinical trials in the treatment of myxedema coma in children (Table II).
What are the adverse effects associated with each treatment option?
Too active rewarming risks vasodilation and worsening of hypotension.
Resuscitation with hypotonic fluids risks worsening of hyponatremia and cerebral edema.
Administration of too high a T4 or T3 dose risks a cardiac arrhythmia and/or worsening of cardiac function, especially if there is underlying heart disease.
Administration of high glucocorticoid dosing risks reduced inflammatory response to an infection, hyperglycemia, and hypertension.
What are the possible outcomes of myxedema coma?
Mortality approaches 50% with undiagnosed and untreated myxedema coma in adults, in particular the elderly with significant co-morbid disease. Myxedema coma may be fatal despite treatment. There are no series of myxedema coma in children, only case reports. One would expect the prognosis to be better than in elderly adults.
Myxedema coma is an endocrine emergency and should be treated aggressively. As such, most experts believe that the benefits of appropriate supportive care, thyroid hormone and glucocorticoid treatment outweigh the risks of no treatment.
What causes this disease and how frequent is it?
Myxedema coma is rare in children (incidence unknown); myxedema coma is most common in elderly women. There is a higher incidence in winter, with exposure to cold weather precipitating hypothermia.
Children may inherit a genetic predisposition to autoimmune thyroid disease (exact genes not identified, but likely they affect immune function); autoimmune thyroid disease is the most common cause of acquired hypothyroidism. The most common cause of congenital hypothyroidism is thyroid dysgenesis, a sporadic (non-genetic) disorder. Approximately 10-15% of cases of congenital hypothyroidism are due to one of the inborn errors of thyroid hormone biosynthesis (the dsyhormonogeneses). These inborn errors are inherited in an autosomal recessive fashion and include mutations in the sodium-iodide symporter, thyroid peroxidase, thyroglobulin, and the dehalogenase gene.
Other clinical manifestations that might help with diagnosis and management
Myxedema coma is associated with hypofunction of multiple organ systems, including the kidney and liver. Altered renal function resulting in an inability to excrete a water load leads to hyponatremia and “myxedema” (there also may be a component of inappropriate antidiuretic hormone secretion). Altered hepatic gluconeogenesis leads to hypoglycemia. Both hyponatremia and hypoglycemia may result in seizures.
What complications might you expect from the disease or treatment of the disease?
Details about complications (prognosis) come from reports in adults; in this population, mortality may approach 50%. As myxedema coma is rare in children, similar statistics are not available. With a high index of suspicion and early diagnosis, all the pathologic changes of myxedema coma are reversible with thyroid hormone treatment. Care must be taken with supportive treatment. Active rewarming risks vasodilatation and worsening hypotension. Use of hypotonic IV fluids risks fluid retention, cerebral edema, and convulsions, particularly if hyponatremia is already present. High dose glucocorticoids risks suppression of the inflammatory response to infection, hyperglycemia, and hypertension. Overtreatment with thyroid hormone risks cardiac arrhythmia and worsening cardiac function.
How can myxedema coma be prevented?
Diagnosis of hypothyroidism and treatment with thyroid hormone will prevent myxedema coma.
Myxedema coma is not hereditary, except in the sense that there is a genetic predisposition to some of the causes of both congenital and acquired hypothyroidism.
Ongoing controversies regarding etiology, diagnosis, treatment
Most experts agree on the underlying etiology and diagnosis of myxedema coma, but some controversy exists on the optimal thyroid hormone treatment regimen and dosing. Some experts recommend T3 only or T4 only, while others recommend combination T4 and T3 therapy. Too low a dose of thyroid hormone may not correct the untoward effects of myxedema coma quickly enough, while too high a dose risks adverse effects of hyperthyroxinemia. Not all experts agree on the administration of high-dose glucocorticoids. It seems reasonable to administer glucocorticoids pending serum cortisol results before and after ACTH stimulation.
What is the evidence?
Buhler, UK, Savary, A, Krauer, B, Stalder, GR. “Water intoxication in a cretinoid infant”. J Clin Endocr. vol. 26. 1966. pp. 111-116. (Pediatric case report of myxedema coma in a 4 mo old infant with undiagnosed congenital hypothyroidism.)
Kwaku, MP, Burman, KD. “Myxedema coma”. J Intensive Care Med. vol. 22. 2007. pp. 224
Dutta, P, Bhansali, A, Masoodi, SR. “Predictors of outcome in myxoedema coma: a study from a tertiary care centre”. Crit Care. vol. 12. 2008. pp. R1(Adult study, but with relevance to pediatrics.)
Beynon, J, Akhtar, S, Kearney, T. “Predictors of outcome in myxoedema coma”. Crit Care. vol. 12. 2008. pp. 111
Yamamoto, T, Fukuyama, J, Fujihoshi, A. “Factors associated with mortality of myxedema coma: report of eight cases and literature survey”. Thyroid. vol. 9. 1999. pp. 1167
Rodriguez, I, Fluiters, E, Perez-Mendez, LF. “Factors associated with mortality of patients with myxoedema coma: prospective study in 11 cases treated in a single institution”. J Endocrinol. vol. 180. 2004. pp. 347(Adult study, but with relevance to pediatrics.)
Wartofsky, L. “Myxedema Coma”. Endocrinol Metab Clin N Am. vol. 35. 2006. pp. 687-698. (Excellent review of precipitating causes, diagnosis and treatment.)
Popoveniuc, G, Chandra, T, Sud, A. “A diagnostic scoring system for myxedema coma”. Endocr Pract. vol. 11. 2014. pp. 1-36. (Based on experience with 14 patients with myxedema coma [adults, ages 41-89 years], the authors developed a diagnostic scoring system for myxedema coma; they then validated it on 22 patients reported in the literature with myxedema coma. This scoring system likely can be adapted to children suspected to have myxedema coma.)
Wiersinga, WM, De Groot, LJ, Beck-Peccoz, P, Chrousos, G, Dungan, K, Grossman, A, Hershman, JM, Koch, C, McLachlan, R, New, M, Rebar, R, Singer, F, Vinik, A, Weickert, MO. “Myxedema and Coma (Severe Hypothyroidism)”. 2000-2015 Apr 12.
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