50: Nondiabetic Endocrine Disease

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Chapter 50 Nondiabetic Endocrine Disease

Joel E. Wilson, MD

1 Describe four steps involved in thyroid hormone synthesis

1. Uptake of iodide: Iodide from the bloodstream is concentrated in thyroid cells by an active transport mechanism.
2. Iodination of thyroglobulin: Thyroglobulin, a large glycoprotein rich in tyrosine, is enzymatically iodinated and stored in the thyroid follicles.
3. Coupling reactions: The monoiodotyrosine and di-iodotyrosine moieties within the thyroglobulin molecule are coupled to one another to form tri-iodothyronine (T3) and thyroxine (T4).
4. Release of hormones: T3 and T4 are enzymatically cleaved from thyroglobulin within the follicular cell and released into the bloodstream.

2 How much tri-iodothyronine and thyroxine are produced? What regulates their production?

Approximately 8 mcg of T3 and 90 mcg of T4 are produced daily. Additional T3 is formed from the peripheral conversion of T4 to T3. T3 is approximately four times more potent than T4 but has a much shorter half-life; therefore the contribution of each to total thyroid activity is approximately equal. Thyroid-stimulating hormone (TSH) (produced by the anterior pituitary gland) acts on thyroid tissue to increase the rates of all steps involved in thyroid hormone synthesis and release. Thyrotropin-releasing hormone (TRH) (produced by the hypothalamus) in turn regulates the amount of TSH produced by the pituitary. T3 and T4 inhibit release of TSH and to a much smaller degree the release of TRH, thus establishing a negative feedback control mechanism.

3 List the common thyroid function tests and their use in assessment of thyroid disorders

Thyroid function tests include total T4 level, total T3 level, TSH level, and resin T3 uptake (T3RU). The T3RU is useful in conditions that alter levels of thyroid-binding globulin, which would alter total T4 results (Table 50-1).

Table 50-1 Usefulness of Thyroid Function Tests in the Diagnosis of Hypothyroid or Hyperthyroid States

image

4 List common signs, symptoms, and causes of hypothyroidism

Symptoms Signs
Fatigue Bradycardia
Cold intolerance Hypothermia
Constipation Deep tendon reflex relaxation phase prolongation
Dry skin Hoarseness
Hair loss Periorbital edema
Weight gain  

The most common cause of hypothyroidism is surgical or radioiodine ablation of thyroid tissue in the treatment of hyperthyroidism, most commonly Graves’ disease. Other causes of hypothyroidism include chronic thyroiditis (Hashimoto’s thyroiditis), drug effects, iodine deficiency, and pituitary or hypothalamic dysfunction.

The signs and symptoms observed in patients with mild hypothyroidism are nonspecific, and clinical detection is extremely difficult. Patients with severe long-term untreated hypothyroidism may progress to myxedema coma, which is frequently fatal. Factors that may lead to myxedema coma in hypothyroid patients include cold exposure, infection, trauma, and administration of central nervous system depressants. Myxedema coma is characterized by hypoventilation, hypothermia, hypotension, hyponatremia, hypoglycemia, obtundation, and adrenal insufficiency.

5 Of the numerous manifestations of hypothyroidism, which are most important in relation to anesthesia?

Hypothyroidism causes depression of myocardial function caused by protein and mucopolysaccharide deposition within the myocardium and depression of intracellular myocardial metabolism. Cardiac output declines as a result of decreased heart rate and stroke volume. Decreased blood volume, baroreceptor reflex dysfunction, and pericardial effusion may also accompany hypothyroidism. All of these effects make the hypothyroid patient sensitive to the hypotensive effects of anesthetics.

Hypoventilation may be a feature of hypothyroidism. The ventilatory responses to both hypoxia and hypercarbia are significantly impaired, making the hypothyroid patient sensitive to drugs that cause respiratory depression. Hypothyroidism also decreases the hepatic and renal clearance of drugs. In addition, patients are prone to hypothermia because of lowered metabolic rate and consequent lowered heat production.

6 How does hypothyroidism affect minimum alveolar concentration of anesthetic agents?

Animal studies show that minimum alveolar concentration (MAC) is not affected by hypothyroidism. Clinically it has been noted that hypothyroid patients have increased sensitivity to anesthetic agents. This is caused not by a decrease in MAC per se but by the patient’s metabolically depressed condition.

7 How is hypothyroidism treated?

Treatment consists of supplementation with exogenous thyroid hormones, most frequently levothyroxine (T4), because its long half-life, 6 to 7 days, results in a more constant serum level. Levothyroxine is available for intravenous use with the intravenous dose being one half the oral dose. The principal risk with treatment is in patients with coronary artery disease (CAD). An increase in the basal metabolic rate may result in myocardial ischemia. A suggested thyroid supplementation protocol for hypothyroid patients is summarized below:

image Patients without CAD: T4 50 mcg/day increasing monthly by 50-mcg/day increments until a euthyroid state is reached.
image Patients with CAD: T4 25 mcg/day increasing monthly by 25-mcg/day increments until a euthyroid state is achieved.
image In urgent situations thyroid supplementation may be given with caution intravenously. The recommended dose is T4 300 mcg/m2 by slow infusion. Hypothyroid patients receiving intravenous supplementation must be monitored closely for signs and symptoms of cardiac ischemia and adrenal insufficiency.
image When treating severe hypothyroidism, glucocorticoids should also be administered.

8 Under what circumstances should elective surgery be delayed for a hypothyroid patient?

Patients with mild to moderate hypothyroidism are not at increased risk when undergoing elective surgical procedures. Some authorities suggest that elective surgery in patients who are symptomatic should be delayed until the patient is rendered euthyroid. Other authorities recommend against delaying surgery if thyroid replacement can begin before surgery (in patients without CAD). In patients with severe hypothyroidism, elective surgery should be delayed until they have been rendered euthyroid. This may require 2 to 4 months of replacement therapy for complete reversal of cardiopulmonary effects. Normalization of the patient’s TSH level reflects reversal of hypothyroid-induced changes.

9 List common signs, symptoms, and causes of hyperthyroidism

Signs Symptoms Causes
Goiter Anxiety Graves’ disease
Tachycardia Tremor Toxic multinodular goiter
Proptosis Heat intolerance
Atrial fibrillation Fatigue
Weight loss
Muscle weakness

10 How is hyperthyroidism treated?

There are three approaches to treatment:

1. Antithyroid drugs such as propylthiouracil (PTU) inhibit iodination and coupling reactions in the thyroid gland, thus reducing production of T3 and T4. PTU also inhibits peripheral conversion of T4 to T3. Iodine in large doses not only blocks hormone production, but it also decreases the vascularity and size of the thyroid gland, making iodine useful in preparing hyperthyroid patients for thyroid surgery.
2. Radioactive iodine, 131I, is actively concentrated by the thyroid gland, resulting in destruction of thyroid cells and a decrease in the production of hormone.
3. Surgical subtotal thyroidectomy

All of these approaches may render the patient hypothyroid.

11 Which effects of hyperthyroidism are the most important with regard to anesthesia?

In hyperthyroidism the metabolic rate of the body is increased, causing significant changes in the cardiovascular system, the magnitude of which is proportional to the severity of the thyroid dysfunction. Because of the elevated oxygen consumption, the cardiovascular system is hyperdynamic. Tachycardia and elevated cardiac output are present, and tachyarrhythmias, atrial fibrillation, left ventricular hypertrophy, and congestive heart failure may develop. Hyperthyroid patients with proptosis are more susceptible to ocular damage during surgery because of difficulty with taping their eyelids closed.

12 How is minimum alveolar concentration affected by hyperthyroidism?

As in hypothyroidism, MAC is not affected by hyperthyroidism, although clinically hyperthyroid patients appear to be resistant to the effects of anesthetic agents. Inhalation induction is slowed by the increased cardiac output. The rate of drug metabolism is increased, giving the appearance of resistance. Hyperthyroidism-induced hyperthermia may indirectly elevate MAC.

13 Define thyrotoxicosis

Also known as thyroid storm, this is an acute exacerbation of hyperthyroidism usually caused by a stress such as surgery or infection. It is characterized by extreme tachycardia, hyperthermia, and possibly severe hypotension. Perioperatively it usually occurs 6 to 18 hours after surgery but can occur intraoperatively and be confused with malignant hyperthermia.

14 How is thyrotoxicosis treated?

Intraoperative treatment must be immediate, consisting of careful β-adrenergic blockade, infusion of intravenous fluids, and temperature control if hyperthermia is present. Corticosteroids should be considered for refractory hypotension because hyperthyroid patients may have a relative cortisol deficiency. Antithyroid drugs should be added after surgery.

15 What complications may occur after a surgical procedure involving the thyroid gland?

Because of the close proximity of the thyroid gland to the trachea and larynx, many of the complications that occur (such as cervical hematoma) can cause airway obstruction. For example, chronic pressure on the trachea from a goiter can lead to tracheomalacia, rendering the patient prone to tracheal collapse and airway obstruction following extubation. Inadvertent resection of the parathyroid glands in turn can lead to hypocalcemia, which may produce laryngospasm. Innervation to the vocal cord musculature may be compromised by surgical damage to the recurrent laryngeal nerves (RLNs). Bilateral partial RLN injury can result in the vocal cords being passively drawn together during inspiration, leading to severe obstruction that necessitates emergent tracheostomy. Destruction of the bilateral RLNs results in the vocal cords being in a midposition and usually does not result in total airway obstruction.

Unilateral injury results in dysfunction of the ipsilateral vocal cord. Damage to the nerve fibers innervating the vocal cord adductors results in unopposed abduction of the ipsilateral vocal cord, increasing the risk of aspiration. Damage to the innervation of the abductor muscles results in an abnormally adducted vocal cord, which can cause hoarseness. Vocal cord function may be assessed following surgery with direct or fiber-optic laryngoscopy.

16 Describe the functions and regulation of the adrenal gland

The adrenal gland can be functionally divided into the adrenal cortex and the adrenal medulla. The adrenal cortex principally produces the steroid hormones cortisol (the main glucocorticoid) and aldosterone (the main mineralocorticoid). Production of cortisol is regulated by adrenocorticotropic hormone (ACTH) produced by the anterior pituitary. The release of ACTH is promoted by corticotropin-releasing hormone (CRH) derived from the hypothalamus, completing the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol inhibits release of both CRH and ACTH, establishing negative feedback control. Ectopic ACTH can be produced by various neoplasms such as small-cell lung carcinomas. Aldosterone secretion is regulated by the renin-angiotensin system. The adrenal medulla secretes epinephrine and norepinephrine. Their release is governed by the sympathetic nervous system.

17 What is a pheochromocytoma?

A pheochromocytoma is a neoplasm arising from the adrenal medulla or paravertebral chromaffin tissue and is discussed in greater detail in Chapter 1.

18 How much cortisol is produced by the adrenal cortex?

Normally approximately 20 to 30 mg of cortisol per day is produced. This amount increases dramatically as a response to a stress such as infection or surgery. Under stressful conditions 75 to 150 mg/day may be produced, with the increase in production being generally proportional to the severity of the stress.

19 What is the most common cause of hypothalamic-pituitary-adrenal axis disruption?

Exogenous steroids (glucocorticoids) result in HPA axis suppression. Short-term steroid administration—no longer than 7 to 10 days—results in suppression of CRH and ACTH release, which usually returns to normal about 5 days after discontinuation of steroid therapy. Long-term administration of exogenous steroids results in adrenocortical atrophy secondary to a lack of ACTH. This results in prolonged adrenocortical insufficiency, which can last a year or more following steroid discontinuation. Therefore long-term steroid administration should not be terminated abruptly; rather it should be gradually tapered off over a period of 1 to 4 weeks. Other less common causes of HPA axis disruption include CNS mass lesions (tumor or abscess), head injury or subarachnoid hemorrhage, vascular injury, and adrenal causes (etomidate, ketoconazole, hemorrhage, infection [including human immunodeficiency virus], and bilateral adrenal metastases)

20 What is an addisonian crisis?

Also referred to as acute adrenocortical insufficiency, an Addisonian crisis is caused by a relative lack of cortisol or other glucocorticoid in relation to a physiologic stress such as surgery. It is a shock state characterized by refractory hypotension, hypovolemia, and electrolyte disturbances. Causes of adrenocortical insufficiency include the following:

image HPA axis suppression by exogenous corticosteroid administration
image Autoimmune adrenalitis
image Adrenal hemorrhage
image Adrenal tuberculosis
image Septic shock

21 How is an addisonian crisis treated?

Treatment must be immediate and consists of intravenous glucocorticoid, fluid replacement, physiologic monitoring, and correction of electrolyte abnormalities.

22 How do exogenous steroids compare to cortisol?

See Table 50-2.

Table 50-2 Relative Potency of Cortisol and Exogenous Steroids

image

KEY POINTS: Nondiabetic Endocrine Diseaseimage

1. Perioperatively mild to moderate hypothyroidism is of little concern even for elective surgery. Patients with severe, symptomatic hypothyroidism should be treated before surgery.
2. MAC of volatile anesthetics is unchanged in both hypothyroid and hyperthyroid states.
3. Thyroid storm may mimic malignant hyperthermia. It is detected by an increased serum T4 level and treated initially with β-blockade followed by antithyroid therapy.
4. Perioperative glucocorticoid supplementation should be considered for patients receiving exogenous steroids.
5. Chronic exogenous glucocorticoid therapy should not be discontinued abruptly. Doing so may precipitate acute adrenocortical insufficiency.

23 Is perioperative stress steroid supplementation for patients on steroid therapy necessary?

Few documented cases of acute perioperative adrenal insufficiency (i.e., addisonian crisis) exist. Studies have shown that patients who have been on long-term steroid therapy undergoing even major surgery rarely become hypotensive because of glucocorticoid deficiency. If observed, hypotension is usually the result of hypovolemia or cardiac dysfunction. The possible side effects of perioperative steroid supplementation include the following:

image Hyperglycemia
image Gastric ulceration
image Fluid retention
image Impaired wound healing
image Aggravation of hypertension
image Immunosuppression

One approach to this issue might be that no supplementation is required unless hypotension refractory to standard treatment occurs. However, although considerable data exist regarding the problems associated with long-term steroid therapy, few data indicate any significant problems related to short-term perioperative steroid supplementation. Despite its rarity, acute adrenal insufficiency is associated with significant morbidity and mortality. Therefore, because perioperative steroid supplementation is associated with few risks in itself and because acute adrenal insufficiency can potentially lead to death, supplemental steroids should be given. Currently this seems to be the view of most authorities.

24 If supplemental corticosteroids are to be administered perioperatively, how much should be given?

The optimal dosing, frequency, and duration continue to be debated, but more recent guidelines suggest lower doses and shorter durations than those recommended in the past. The recommended dosage is also highly dependent on the amount of stress that the surgery is likely to cause. Patients receiving 5 mg/day or less of prednisone should receive their normal daily replacement but do not require supplementation. For minor surgery no supplementation or minimal supplementation such as hydrocortisone, 25 mg, may suffice. For moderate surgery give 50 to 75 mg of hydrocortisone on the day of procedure and taper the dose quickly over 1 to 2 days. For major surgery a variety of dosages have been suggested, with none being shown to be superior to the rest. A suggested regimen would be 100 to 150 mg of hydrocortisone on the day of procedure with a quick 1- to 2-day taper. The goal of these regimens is to give the lowest dose that provides sufficient supplementation while avoiding potential side effects.

25 Review calcium homeostasis

Because of the importance of calcium in nearly all cellular functions, its intracellular and extracellular concentrations are tightly controlled through the action of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25[OH]2D). Changes in the serum calcium concentration are detected by extracellular calcium-sensing receptors expressed on parathyroid cells. When calcium levels decrease, PTH is released (or conversely suppressed with increasing calcium levels). PTH stimulates bone resorption, which delivers calcium and phosphorus into the bloodstream and increases the resorption of calcium in the kidney. PTH also enhances the conversion of 25-hydroxyvitamin D (25[OH]D) to the active 1,25[OH]2D, which increases the transepithelial transport of calcium and phosphorus in the gastrointestinal tract. It is estimated that one normal parathyroid gland is sufficient for maintaining PTH levels and calcium homeostasis. Magnesium depletion or excess may cause hypocalcemia by inducing functional hypoparathyroidism.

Suggested Readings

1. Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin North Am. 2003;32:367-383.

2. Connery L.E., Coursin D.B. Assessment and therapy of selected endocrine disorders. Anesthesiol Clin North Am. 2004;22:93-123.

3. Cooper M.S., Stewart P.M. Adrenal insufficiency in critical illness. J Intensive Care Med. 2007;22:348-362.

4. Shoback D. Hypoparathyroidism. N Engl J Med. 2008;359:391-403.

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Chapter 50 Nondiabetic Endocrine Disease

Joel E. Wilson, MD

1 Describe four steps involved in thyroid hormone synthesis

1. Uptake of iodide: Iodide from the bloodstream is concentrated in thyroid cells by an active transport mechanism.
2. Iodination of thyroglobulin: Thyroglobulin, a large glycoprotein rich in tyrosine, is enzymatically iodinated and stored in the thyroid follicles.
3. Coupling reactions: The monoiodotyrosine and di-iodotyrosine moieties within the thyroglobulin molecule are coupled to one another to form tri-iodothyronine (T3) and thyroxine (T4).
4. Release of hormones: T3 and T4 are enzymatically cleaved from thyroglobulin within the follicular cell and released into the bloodstream.

2 How much tri-iodothyronine and thyroxine are produced? What regulates their production?

Approximately 8 mcg of T3 and 90 mcg of T4 are produced daily. Additional T3 is formed from the peripheral conversion of T4 to T3. T3 is approximately four times more potent than T4 but has a much shorter half-life; therefore the contribution of each to total thyroid activity is approximately equal. Thyroid-stimulating hormone (TSH) (produced by the anterior pituitary gland) acts on thyroid tissue to increase the rates of all steps involved in thyroid hormone synthesis and release. Thyrotropin-releasing hormone (TRH) (produced by the hypothalamus) in turn regulates the amount of TSH produced by the pituitary. T3 and T4 inhibit release of TSH and to a much smaller degree the release of TRH, thus establishing a negative feedback control mechanism.

3 List the common thyroid function tests and their use in assessment of thyroid disorders

Thyroid function tests include total T4 level, total T3 level, TSH level, and resin T3 uptake (T3RU). The T3RU is useful in conditions that alter levels of thyroid-binding globulin, which would alter total T4 results (Table 50-1).

Table 50-1 Usefulness of Thyroid Function Tests in the Diagnosis of Hypothyroid or Hyperthyroid States

image

4 List common signs, symptoms, and causes of hypothyroidism

Symptoms Signs
Fatigue Bradycardia
Cold intolerance Hypothermia
Constipation Deep tendon reflex relaxation phase prolongation
Dry skin Hoarseness
Hair loss Periorbital edema
Weight gain  

The most common cause of hypothyroidism is surgical or radioiodine ablation of thyroid tissue in the treatment of hyperthyroidism, most commonly Graves’ disease. Other causes of hypothyroidism include chronic thyroiditis (Hashimoto’s thyroiditis), drug effects, iodine deficiency, and pituitary or hypothalamic dysfunction.

The signs and symptoms observed in patients with mild hypothyroidism are nonspecific, and clinical detection is extremely difficult. Patients with severe long-term untreated hypothyroidism may progress to myxedema coma, which is frequently fatal. Factors that may lead to myxedema coma in hypothyroid patients include cold exposure, infection, trauma, and administration of central nervous system depressants. Myxedema coma is characterized by hypoventilation, hypothermia, hypotension, hyponatremia, hypoglycemia, obtundation, and adrenal insufficiency.

5 Of the numerous manifestations of hypothyroidism, which are most important in relation to anesthesia?

Hypothyroidism causes depression of myocardial function caused by protein and mucopolysaccharide deposition within the myocardium and depression of intracellular myocardial metabolism. Cardiac output declines as a result of decreased heart rate and stroke volume. Decreased blood volume, baroreceptor reflex dysfunction, and pericardial effusion may also accompany hypothyroidism. All of these effects make the hypothyroid patient sensitive to the hypotensive effects of anesthetics.

Hypoventilation may be a feature of hypothyroidism. The ventilatory responses to both hypoxia and hypercarbia are significantly impaired, making the hypothyroid patient sensitive to drugs that cause respiratory depression. Hypothyroidism also decreases the hepatic and renal clearance of drugs. In addition, patients are prone to hypothermia because of lowered metabolic rate and consequent lowered heat production.

6 How does hypothyroidism affect minimum alveolar concentration of anesthetic agents?

Animal studies show that minimum alveolar concentration (MAC) is not affected by hypothyroidism. Clinically it has been noted that hypothyroid patients have increased sensitivity to anesthetic agents. This is caused not by a decrease in MAC per se but by the patient’s metabolically depressed condition.

7 How is hypothyroidism treated?

Treatment consists of supplementation with exogenous thyroid hormones, most frequently levothyroxine (T4), because its long half-life, 6 to 7 days, results in a more constant serum level. Levothyroxine is available for intravenous use with the intravenous dose being one half the oral dose. The principal risk with treatment is in patients with coronary artery disease (CAD). An increase in the basal metabolic rate may result in myocardial ischemia. A suggested thyroid supplementation protocol for hypothyroid patients is summarized below:

image Patients without CAD: T4 50 mcg/day increasing monthly by 50-mcg/day increments until a euthyroid state is reached.
image Patients with CAD: T4 25 mcg/day increasing monthly by 25-mcg/day increments until a euthyroid state is achieved.
image In urgent situations thyroid supplementation may be given with caution intravenously. The recommended dose is T4 300 mcg/m2 by slow infusion. Hypothyroid patients receiving intravenous supplementation must be monitored closely for signs and symptoms of cardiac ischemia and adrenal insufficiency.
image When treating severe hypothyroidism, glucocorticoids should also be administered.

8 Under what circumstances should elective surgery be delayed for a hypothyroid patient?

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