Introduction
Myxedema coma is an important endocrine emergency caused by untreated or prolonged hypothyroidism that culminates in a comatose state. It is seen more commonly in elderly women during the winter months, typically having been triggered by exposure to cold weather, an infectious process, trauma, gastrointestinal (GI) bleeding, or other nonthyroidal illness superimposed on preexisting severe hypothyroidism. The estimated incidence of myxedema coma varies from 0.2 to 1.08 per million people per year, , and despite the high mortality rate of 29% to 60%, timely diagnosis and immediate treatment will increase the chance for survival. , ,
Pathophysiology
Myxedema coma always presents in the setting of a patient with a diagnosis of hypothyroidism that either is long-standing and not being treated or is recently established. The hypothyroidism may be due to any cause, for example, post-radioiodine ablation or thyroidectomy, but the most common cause will be underlying Hashimoto’s thyroiditis. Patients often have a known history of Hashimoto’s disease treated with levothyroxine but for various or uncertain reasons had interrupted or discontinued the treatment. Another relatively less frequent setting for myxedema coma is when it is due to secondary or tertiary hypothyroidism on a pituitary or hypothalamic basis. These patients are encountered in less than 5% of reported cases of myxedema coma.
In almost all instances, the clinical state of an otherwise stable hypothyroid patient is overcome by a precipitating event such as a pulmonary infection, congestive heart failure, or a cerebrovascular accident ( Box 4.1 ). Less frequent causes have included subclinical thyroiditis, diabetic ketoacidosis, and consumption of large amounts of raw bok choy ( Box 4.1 ). Why some superimposed nonthyroidal illness or event might lead to coma is unclear, but could be related to inhibition of conversion of thyroxine (T4) to triiodothyronine (T3) as occurs in the “euthyroid sick syndrome,” thereby worsening the hypothyroidism. Related to this possible mechanism, particular attention should be paid to the patient’s medications, as drugs such as amiodarone, lithium carbonate, or tyrosine kinase inhibitors may affect thyroid function. , Amiodarone, for example, also causes inhibition of T4 to T3 conversion, and lithium would inhibit any residual thyroid function in an already compromised thyroid gland. Other mechanisms that might underly decompensation are common in hospitalized patients and include the use of drugs such as opioids, anesthetics, and sedatives that suppress respiratory drive, facilitating the deterioration into coma. As is the case with most drugs administered to a hypothyroid subject, blood levels of these agents are higher and more prolonged due to the reduced distribution space and slowed metabolic turnover in these patients.
| Causes of Hypothyroidism | Precipitating Factors to Myxedema Coma |
|---|---|
|
|
Clinical Presentation
As noted earlier, the syndrome will typically present in a patient who develops an infection or other systemic disease superimposed upon previously undiagnosed, untreated, or inadequately treated hypothyroidism. Reported cases in the literature and designated as myxedema coma have included patients who were not frankly comatose, but rather presented in a lethargic, disoriented, and obtunded state; such patients, if not properly diagnosed and treated, are highly likely to progress into a comatose state. The physician first examining a lethargic subject may not have the benefit of a history of hypothyroidism, but slow speech and a hoarse voice can be important clues. On physical examination, a scar present in the anterior part of the neck should suggest prior thyroidectomy as the cause of the hypothyroidism. Other clues include dry, scaly skin, non-pitting edema of the face, hands, and feet, macroglossia, delayed deep tendon reflexes, and thinning or sparse body hair. In two series that identified 12 and 14 patients, respectively, with myxedema coma, the findings on presentation included hypoxemia in 36% to 80%, hypotension in 50%, hypercapnia in 36% to 54%, bradycardia in 36%, and hypothermia with a temperature below 94°F (34.4°C) in 50% to 88%. , The belief that early and aggressive therapeutic intervention is required is supported by the observed mortality of 50% of patients who died despite subsequent treatment with thyroid hormone. Patients with myxedema coma may manifest hypoglycemia, hypercalcemia, hyponatremia, hypercapnia, and hypoxemia as either precipitating factors or secondary consequences of the condition. Hypoventilation with hypercapnia and hypoxemia are particularly dreaded prognostic indicators, as they herald further CO 2 retention and progression into worsening respiratory failure, lethargy, stupor, and coma.
MANIFESTATIONS IN THE RESPIRATORY SYSTEM
An appreciation of the pathologic mechanisms threatening the integrity of the respiratory system in the myxedema coma patient is crucial to understanding both the cause of a patient’s deterioration and the intervention necessary to reduce the risk of their demise. In overtly hypothyroid patients, decreases in the respiratory response to hypercapnia are observed in combination with a decrease in respiratory drive. Hypothyroid patients retain fluid and may present with generalized edema, pleural or pericardial effusions, or ascites. The presence of pleural or pericardial effusion may compromise normal respiratory function with further deterioration provided by concomitant bronchopulmonary infection. Edema and swelling of the tongue occur in profound hypothyroidism and, together with the marked edema of the vocal cords, contribute to mechanical narrowing of the upper respiratory airways. After initiation of T4 therapy, the respiratory response to CO 2 has been reported to improve in most but not all cases.
CARDIOVASCULAR MANIFESTATIONS
In a patient with myxedema coma, bradycardia is often present, as it often is in uncomplicated hypothyroidism. Other electrocardiogram (ECG) findings may include low voltage, inverted T waves, and a prolonged QT interval, the latter exposing patients to risk of torsades de pointes and potentially dangerous arrhythmias. Cardiac ultrasound will reveal an enlarged cardiac silhouette due either to ventricular dilatation or pericardial effusion. When present, pericardial effusions are likely to have slowly accumulated over time, and only rarely cause cardiac tamponade.
Bradycardia with ventricular dilatation and reduced contractility results in reduced stroke volume and cardiac output. Whereas administration of cardioactive drugs may be considered, it requires only the initiation of treatment with T4 to reverse the above-mentioned abnormalities. However, overly aggressive or injudicious T4 replacement may increase the risk of myocardial infarction, especially when T3 is combined with T4 therapy. Hypotension may be present in spite of the increased retention of total body water, as fluids primarily accumulate in the extravascular compartments and intravascular volume is reduced. With initiation of T4 replacement, blood pressure should normalize, but the use of vasopressor agents may be required prior to onset of the vascular effects of T4 in order to avoid progression to severe hypotension or shock (see Management later). In view of the potential for shock, fatal arrhythmia, and mortality, myxedema coma patients should be admitted to, and managed in, an intensive care unit.
GASTROINTESTINAL MANIFESTATIONS
One of the first signs of altered GI physiology in myxedema is often slowed peristalsis, due mainly to impairment of GI innervation and edematous infiltration of the muscularis mucosae. Constipation is common, and the more severe cases can evolve into a paralytic ileus. Given the risks of anesthesia in the profoundly hypothyroid patient, surgical intervention should be temporized for suspected obstruction by conservative management with decompression until the therapeutic response to thyroid hormone might occur. Because absorption may be impaired due to intestinal edema and gastric atony, the initial therapy with T4 or T3 should be administered parenterally in preference to oral administration. Ascites has been documented in 51 cases, and GI bleeding can occur secondary to a coagulopathy.
RENAL AND ELECTROLYTE MANIFESTATIONS
Renal function is impaired in profound hypothyroidism, with decreases in glomerular filtration rate, renal clearance, renal plasma flow, and plasma osmolarity. As a consequence, total body water, urine sodium, and urine osmolarity are increased. Hypoperfusion of the distal nephron will trigger an increase of antidiuretic hormone (ADH) secretion leading to water retention and worsening of hyponatremia. Hyponatremia per se may cause altered mental status and, when severe, may be largely responsible for precipitating the comatose state.
HYPOTHERMIA
One of the cardinal signs of myxedema coma is hypothermia, which occurs in 50% to 75% of patients with myxedema, and its presence should prompt timely diagnosis of the syndrome. In some cases, it may reach dramatic levels (below 80°F [26.7°C]), and temperatures below 90°F (32.2°C) are associated with poorer prognosis. Because the presence of hypothermia may mask an underlying infection, a diagnosis of overt hypothyroidism or myxedema coma should be considered in any patient with a known infection but absent fever. Broad-spectrum empiric antibiotic therapy also should be considered in such patients. Infectious diseases, and pneumonia in particular, often serve as the triggering events to drive a patient with hypothyroidism into myxedema coma. Absent early diagnosis and treatment, the infection can lead to sepsis with vascular collapse and possible death. The presence of underlying hypoglycemia may further compound the observed decrement in body temperature.
NEUROPSYCHIATRIC MANIFESTATIONS
Although coma is the predominant and most dramatic clinical presentation in myxedema coma, an earlier history of disorientation, depression, paranoia, or hallucinations (“myxedema madness”) may often be elicited. Other neurologic findings that may have been present either just before entering the comatose state or which appear early during recovery include cerebellar signs, such as poorly coordinated purposeful movements of the hands and feet, ataxia, diadochokinesis, poor memory and recall, or even frank amnesia. Abnormal findings on electroencephalography are few and include low amplitude and a decreased rate of α-wave activity. Status epilepticus has been described, and up to 25% of patients with myxedema coma may experience minor to major seizures, possibly related to hyponatremia, hypoglycemia, and/or hypoxemia (due to reduced cerebrovascular perfusion from low cardiac output and atherosclerotic vessels in elderly patients). T4 treatment will generally lead to demonstrable clinical improvement of the condition.
HEMATOLOGIC MANIFESTATIONS
A microcytic anemia may be seen secondary to GI hemorrhage, or there may be a macrocytic anemia due to vitamin B12 deficiency, which, if present, may also be associated with a worsening of the neurologic state. Granulocytopenia with a decreased cell-mediated immunologic response may contribute to a higher risk of severe infection. In contrast to the tendency to thrombosis seen in mild hypothyroidism, severe hypothyroidism is associated with a higher risk of bleeding due to coagulopathy related to an acquired von Willebrand syndrome (type 1) and decreases in factors V, VII, VIII, IX, and X. The von Willebrand syndrome is reversible with T4 therapy. Another potential cause of bleeding in these patients may be disseminated intravascular coagulation when there is associated sepsis.
Diagnosis
Myxedema coma is fortunately a rare event, and its rarity suggests that physicians will generally have had little prior experience in making a proper and timely diagnosis. Diagnosis is indeed a clinical one and should be based on the concomitant presence of the abovementioned signs and symptoms (see Clinical Presentation) in the setting of a patient with either a history of or suspected hypothyroidism. Because the diagnosis is not achieved on the basis of laboratory tests or imaging results, some authors have proposed a scoring system based on the presence of some of the most crucial aspects of the myxedema presentation (e.g., personal medical history, precipitating event, hypothermia, cardiovascular dysfunction, nervous system manifestations, metabolic disorders, and GI findings). The Popoveniuc et al. scoring system has a sensitivity of 100% and specificity of 80%. According to the score achieved, the diagnosis of myxedema coma in a patient would be classified as either highly suggestive or unlikely ( Box 4.2 ). Another objective screening tool has been proposed based on heart rate, temperature, Glasgow coma scale, TSH, free thyroxine, and history of a precipitating event, and was associated with a sensitivity and specificity of approximately 80%. Even though these scoring systems may have some utility for rapid diagnosis of myxedema coma, it should be acknowledged that the scores were proposed based on data obtained from a limited sample of patients, and thus, further external validation may be needed.
| Thermoregulatory Dysfunction (Temperature °C) | Cardiovascular Dysfunction | ||
|---|---|---|---|
| >35 | 0 | Bradycardia | |
| 32–35 | 10 | Absent | 0 |
| <32 | 20 | 50–59 | 10 |
| Central Nervous System Effects | 40–49 | 20 | |
| Absent | 0 | <40 | 30 |
| Somnolent/lethargic | 10 | Other ECG changes a | 10 |
| Obtunded | 15 | Pericardial/pleural effusions | 10 |
| Stupor | 20 | Pulmonary edema | 15 |
| Coma/seizures | 30 | Cardiomegaly | 15 |
| Gastrointestinal Findings | Hypotension | 20 | |
| Anorexia/abdominal pain/constipation | 5 | Metabolic Disturbances | |
| Decreased intestinal motility | 15 | Hyponatremia | 10 |
| Paralytic ileus | 20 | Hypoglycemia | 10 |
| Precipitating Event | Hypoxemia | 10 | |
| Absent | 0 | Hypercarbia | 10 |
| Present | 10 | Decrease in GFR | 10 |
| A score of 60 or higher is highly suggestive/diagnostic of myxedema coma; a score of 25 to 59 is suggestive of risk for myxedema coma, and a score below 25 is unlikely to indicate myxedema coma. | |||
Related posts:
Severe Thyrotoxicosis and Thyroid Storm
Amiodarone-Induced Thyrotoxicosis
Ocular Emergencies in Graves’ Ophthalmopathy
Thyrotoxic Periodic Paralysis: A Review and Suggestions for Treatment
Post-Thyroidectomy Emergencies: Management of Tracheal and Esophageal Injuries
Recurrent Laryngeal Nerve Paralysis – Management of Recurrent Laryngeal Nerve Injuries
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
