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Endocrine Disease 

Endocrine Disease
Chapter:
Endocrine Disease
Author(s):

William D. Freeman

DOI:
10.1093/med/9780190244927.003.0091
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Introduction

The endocrine system is involved in creating and distributing hormones that have wide-ranging organ effects and a potential for neurologic complications. Basic pathophysiology is covered in Volume 1, Chapter 15, “Principles of Neuroendocrinology and Hypothalamic Function.” Neurologic manifestations related to dysfunction of the thyroid, parathyroid, and adrenal glands are discussed in the present chapter.

Pituitary Disorders

Pathophysiology

The pituitary gland is subdivided into anterior and posterior lobes. The posterior pituitary (neurohypophysis) receives direct neuronal transmission from the hypothalamus (supraoptic and paraventricular nuclei) and secretes prolactin, oxytocin, and vasopressin (antidiuretic hormone [ADH]) (Figure 79.1). Prolactin release is regulated by a negative feedback inhibition mechanism involving dopamine. Lesions of the posterior hypothalamus or other factors that impair the dopaminergic inhibition can lead to release of prolactin, resulting in galactorrhea.

Figure 79.1 Neuroendocrine Systems of the Hypothalamus and Pituitary Gland. A, Magnicellular system. Neurons of the supraoptic and paraventricular nuclei synthesize arginine-vasopressin or oxytocin and send axons through the pituitary stalk to secrete these hormones into capillaries in the posterior pituitary. B, Parvicellular system. Neurons of the periventricular preoptic, paraventricular, and arcuate nuclei synthesize releasing or inhibitory factors, and their axons deliver these factors to the portal circulation at the level of the median eminence. The portal circulation delivers these factors to the anterior pituitary to control hormonal secretion by the pituitary endocrine cells.
Figure 79.1 Neuroendocrine Systems of the Hypothalamus and Pituitary Gland. A, Magnicellular system. Neurons of the supraoptic and paraventricular nuclei synthesize arginine-vasopressin or oxytocin and send axons through the pituitary stalk to secrete these hormones into capillaries in the posterior pituitary. B, Parvicellular system. Neurons of the periventricular preoptic, paraventricular, and arcuate nuclei synthesize releasing or inhibitory factors, and their axons deliver these factors to the portal circulation at the level of the median eminence. The portal circulation delivers these factors to the anterior pituitary to control hormonal secretion by the pituitary endocrine cells.

Figure 79.1 Neuroendocrine Systems of the Hypothalamus and Pituitary Gland. A, Magnicellular system. Neurons of the supraoptic and paraventricular nuclei synthesize arginine-vasopressin or oxytocin and send axons through the pituitary stalk to secrete these hormones into capillaries in the posterior pituitary. B, Parvicellular system. Neurons of the periventricular preoptic, paraventricular, and arcuate nuclei synthesize releasing or inhibitory factors, and their axons deliver these factors to the portal circulation at the level of the median eminence. The portal circulation delivers these factors to the anterior pituitary to control hormonal secretion by the pituitary endocrine cells.

(Adapted from Benarroch EE, Daube JR, Flemming KD, Westmoreland BF. Mayo Clinic medical neurosciences: organized by neurologic systems and levels. 5th ed. Rochester [MN]: Mayo Clinic Scientific Press and Florence [KY]: Informa Healthcare USA; c2008. Chapter 16, Part A, The supratentorial level: thalamus, hypothalamus, and visual system; p. 669-99. Used with permission of Mayo Foundation for Medical Education and Research.)

The anterior pituitary (adenohypophysis) makes follicle-stimulating hormone and luteinizing hormone (which are important in the female hypothalamo- ovarian-uterine menstrual cycle), growthhormone, corticotropin (which stimulates cortisol secretion from the adrenal glands), and thyrotropin (which stimulates the thyroid gland). Further details of pituitary pathophysiology are covered in Volume 1, Chapter 15, “Principles of Neuroendocrinology and Hypothalamic Function.”

Causes and General Manifestations of Pituitary Dysfunction

Pituitary disorders may result from traumatic, surgical, inflammatory, structural (eg, tumor), and sometimes vascular processes that impair normal function. Symptoms may depend on whether hormone production is disrupted (excess or deficiency) and whether surrounding structures are compromised (eg, third cranial nerve and optic chiasm).

Selected Disorders

Acromegaly

Acromegaly is a condition of excessive growth hormone production from a growth-hormone–producing tumor, which leads to large stature (gigantism) and coarse facial features. These pituitary tumors may grow larger and cause structural compression of the optic chiasm and the surrounding cavernous sinus, resulting in headache and, classically, bitemporal hemianopic visual field loss.

Pituitary Apoplexy

Progressive growth of a pituitary tumor can lead to vascular infarction or hemorrhage of the tumor, which is termed pituitary apoplexy. When it occurs postpartum, it is referred to as Sheehan syndrome. Pituitary apoplexy is a medical emergency that can result in a neuroendocrine crisis from a lack of pituitary hormone production, profound vasopressor-refractory hypotension due to the lack of stress hormones, blindness from optic nerve or chiasm compression, coma, and death. Emergent neuroimaging, such as computed tomography and magnetic resonance imaging, typically shows pituitary apoplexy (Figure 79.2), which can also cause cranial neuropathies within the cavernous sinus (ie, cranial nerves III, IV, or VI). Pituitary apoplexy requires emergency neurosurgical consultation for possible transsphenoidal surgery to debulk the lesion, stress-dose corticosteroid support because of the lack of corticotropin and cortisol, thyroxine intravenously if thyrotropin is lacking, and desmopressin administration if diabetes insipidus develops.

Figure 79.2 Pituitary Apoplexy.
Magnetic resonance imaging from a patient with pituitary apoplexy shows heterogeneous signal within a large pituitary adenoma indicative of hemorrhage (arrow in B). A, Axial fluid-attenuated inversion recovery image. B, T1-weighted with gadolinium contrast image.
Figure 79.2 Pituitary Apoplexy.
Magnetic resonance imaging from a patient with pituitary apoplexy shows heterogeneous signal within a large pituitary adenoma indicative of hemorrhage (arrow in B). A, Axial fluid-attenuated inversion recovery image. B, T1-weighted with gadolinium contrast image.

Figure 79.2 Pituitary Apoplexy.

Magnetic resonance imaging from a patient with pituitary apoplexy shows heterogeneous signal within a large pituitary adenoma indicative of hemorrhage (arrow in B). A, Axial fluid-attenuated inversion recovery image. B, T1-weighted with gadolinium contrast image.

Syndrome of Inappropriate Secretion of ADH

The overproduction of ADH can lead to the syndrome of inappropriate secretion of ADH (SIADH) with hyponatremia from excessive water absorption in the kidney. SIADH typically causes fluid retention, concentrated, dark urine (with a high specific gravity), and relatively low urine output. Diabetes insipidus typically produces the opposite clinical situation of hypernatremia: hypovolemia, high urine output (>300–500 ml/h), and low urine specific gravity.

Cushing Disease

Cushing disease is caused by a pituitary tumor that causes excessive production of corticotropin from the anterior pituitary (Figure 79.3), leading to excessive cortisol, hyperpigmentation, abdominal striae, dorsal cervical adipose deposition (buffalo hump), and thinning of the skin. Diagnosis is typically confirmed with serum cortisol and corticotropin blood sampling; treatment consists of transsphenoidal surgery and replacement of pituitary hormones as needed. Box 79.1 shows the processes that can affect the hypothalamic-pituitary axis, which can be remembered with the mnemonic SATCHMO.

Figure 79.3 Cushing Disease.
A corticotropin-secreting adenoma results in excess production of endogenous glucocorticoids and feedback inhibition of corticotropin-releasing factor (CRF).

Figure 79.3 Cushing Disease.

A corticotropin-secreting adenoma results in excess production of endogenous glucocorticoids and feedback inhibition of corticotropin-releasing factor (CRF).

(Used with permission of Mayo Foundation for Medical Education and Research.)

a Mnemonic: SATCHMO.

  • Pituitary apoplexy is a medical emergency that can result in a neuroendocrine crisis from a lack of pituitary hormone production, profound vasopressor-refractory hypotension due to the lack of stress hormones, blindness from optic nerve or chiasm compression, coma, and death.

Thyroid and Parathyroid Disorders

Pathophysiology

The thyroid gland responds to thyrotropin and produces triiodothyronine (T3) and tetraiodothyronine (T4), collectively known as thyroxine. Thyroid hormones modulate the rate of cellular metabolism, and parathyroid glands are important in calcium homeostasis. Deficiencies in T3 and T4 lead to hypothyroidism, and excessive amounts of T3 and T4 lead to hyperthyroidism.

Causes and General Manifestations of Thyroid Disease

Hypothyroidism may be due to multiple causes (Box 79.2). Neurologic and psychiatric symptoms of patients with hypothyroidism regardless of the cause include depression, anxiety, reduced reflexes (Woltman sign), slowed psychomotor ability, cognitive decline, myopathy, and neuropathy (peripheral painful neuropathy or carpal tunnel syndrome [or both]). Other systemic symptoms include fatigue, weight gain, dry skin, cold intolerance, constipation, hair thinning, oligomenorrhea, and myxedema when severe.

Hyperthyroidism may also be due to several causes (Box 79.2). Neuropsychiatric manifestations of hyperthyroidism may include anxiety, tremor, psychomotor hyperactivity, myopathy, and brisk reflexes. Systemic symptoms include palpitations (atrial fibrillation and malignant arrhythmias can develop in severe cases), exophthalmos (in 25%-50% of patients) (Figure 79.4), onycholysis, and diarrhea.

Figure 79.4 Exophthalmos in Hyperthyroidism.

Figure 79.4 Exophthalmos in Hyperthyroidism.

(Used with permission of Mayo Foundation for Medical Education and Research.)

Determination of the thyrotropin concentration is typically a good screening test for thyroid disorders. If the thyrotropin level is abnormal, determination of free T3 or free T4 can be considered along with thyroid antibodies (anti–thyroid peroxidase and anti-thyrotropin receptor) in selected cases (Table 79.1) in addition to seeking an endocrinology consultation.

Table 79.1 Diagnosis of Thyroid Diseases

Disease

Thyrotropin

T3

T4

Comment

Primary hypothyroidism

Primary thyroid disease

Secondary hypothyroidism

Pituitary dysfunction

Tertiary hypothyroidism

  • Hypothalamic dysfunction

  • Cannot be distinguished from secondary hypothyroidism biochemically; requires MRI of the brain

Primary hyperthyroidism

Primary thyroid disease or excess intake of thyroid replacement

Abbreviations and symbols: MRI, magnetic resonance imaging; T3, triiodothyronine; T4, tetraiodothyronine; ↓, decreased; ↑, increased.

Selected Disorders

Cretinism

Cretinism results from congenital pituitary failure. Infants have impaired growth and development. Thyrotropin, T3, and T4 levels are low.

Myxedema Coma

Severe primary hypothyroidism can result in coma, hypothermia, hyponatremia, and hemodynamic instability. Typically, myxedema coma is precipitated by an event in a patient with preexisting hypothyroidism (eg, stroke, cold, burns, sepsis, or medications). These patients require neurologic intensive care evaluation and thyroid hormone replacement with T4 intravenously or shorter-acting T3 (5 mcg intravenously every 8 hours) if they are comatose; when the patient is awake, the medication is gradually converted to an oral form. Vitamin B12 levels should be checked to exclude concomitant autoimmune thyroiditis with pernicious anemia.

Thyrotoxicosis

Patients with thyrotoxicosis may present with tachycardia (atrial fibrillation), tremors, seizures, and hyperthyroid myopathy. Cardiac arrest may occur. The condition is diagnosed by measuring thyrotropin, T3, and T4 levels; testing for thyrotropin receptor antibodies for possible Graves disease; and evaluating the thyroid with ultrasonography (for toxic thyroid adenoma). In an intensive care unit, β‎-blockers, methimazole, or propylthiouracil (thionamides) may be used to block thyroid hormone synthesis. In these patients, it is important to avoid the use of an iodinated contrast agent. Glucocorticoids also decrease the conversion of T4 to T3 and suppress autoimmune cases of thyroid disease (Graves).

Thyrotoxic Periodic Paralysis

In patients with hypothyrodism, periodic paralysis (typically, a few hours of motor weakness ranging from mild proximal weakness to complete flaccid paralysis) may be precipitated by large carbohydrate meals or with rest after exercise (or by use of acetazolamide). Laboratory findings include suppressed thyrotropin and increased T3 and T4 levels.

During attacks, laboratory tests may show an increased creatine kinase level, hypokalemia, hypocalcemia, and hypophosphatemia. An electrocardiogram may show transient large QRS complexes during attacks, and an electromyogram may show reduced compound muscle action potential amplitudes during attacks.

Medication Adverse Effects

Drugs used to treat hyperthyroidism can have adverse effects. For example, carbimazole can cause headache and myopathy, and propylthiouracil can cause encephalopathy.

Parathyroid Disorders

Table 79.2 reviews clinical manifestations and recommendations for evaluation in disorders of the parathyroid.

Table 79.2 Symptoms, Evaluation, and Management of Parathyroid Disease

Disease State

Symptoms

Evaluation and Management

Hyperparathyroidism

  • Neurologic

    • Encephalopathy (moderate to severe), headache

    • Proximal myopathy or myalgia

  • Systemic

    • “Stones, bones, abdominal groans, and psychiatric overtones” refers to hypercalciuric kidney stones, osteopenic changes on plain radiographs (changes in the hand or bones), and vague abdominal pain

  • Parathyroid hormone levels, serum calcium with albumin or ionized calcium

  • Endocrinology consultation

Hypoparathyroidism

  • Central nervous system

    • Oral, tongue, and acral paresthesia

    • Encephalopathy

    • Hypokinesia

    • Seizures

  • Peripheral nervous system

    • Cramps, fasciculations

    • Carpopedal spasm

    • Chvostek and Trousseau signs (if hypocalcemic)

    • Opisthotonus or tetany (if severe hypocalcemia)

  • Parathyroid hormone levels, serum calcium with albumin or ionized calcium, and vitamin D levels

  • May see basal ganglia calcification

  • Replace calcium (intravenously if severely low) and vitamin D levels

  • Endocrinology consultation

  • Typically, myxedema coma is precipitated by an event in a patient with preexisting hypothyroidism (eg, stroke, cold, burns, sepsis, or medications).

Adrenal Disorders

Pathophysiology

The adrenal glands are involved with the synthesis of stress hormones, corticosteroids, and mineralocorticoids. The term Cushing syndrome refers to a condition resulting from long-term exposure to excessive glucocorticoids. The syndrome is most commonly caused by the administration of exogenous glucocorticoids. Cushing disease refers to a condition with clinical manifestations resulting from excessive corticotropin secretion by the pituitary.

Causes and General Manifestations of Adrenal Disease

Clinical manifestations of both Cushing syndrome and Cushing disease include abdominal obesity, thinning of skin, high blood pressure, and hair thinning. Exogenous corticosteroids can lead to atrophy of the adrenal glands, which then do not respond to produce endogenous corticosteroids in response to stress.

Adrenal insufficiency most commonly results from withdrawal of exogenous corticosteroids used to suppress the immune system. Patients with hypoadrenalism or Addison disease can present with encephalopathy, seizure from hypoglycemia, hypokalemia, stupor or coma, and refractory hypotension. Adrenal insufficiency rarely occurs as a result of pituitary failure (eg, pituitary apoplexy).

  • Patients with hypoadrenalism or Addison disease can present with encephalopathy, seizure from hypoglycemia, hypokalemia, stupor or coma, and refractory hypotension.

Diabetes Mellitus and Glucose Dysregulation

Overview

Type 1 diabetes mellitus is typically an autoimmune disease that occurs within the first 2 decades of life. The endogenous insulin deficiency can result in severe hyperglycemia and diabetic ketoacidosis (DKA). Type 2 diabetes mellitus is often an adult-onset disorder (beyond the second decade of life) and is typically associated with impaired end-organ insulin sensitivity and obesity. Type 2 diabetes mellitus, when uncontrolled, can lead to hyperosmolar nonketotic state (HONK), which can also produce acidosis and be life-threatening but is typically devoid of ketone production (ketosis). Diabetes mellitus can lead to several neurologic complications (Box 79.3).

Abbreviations: CPM, central pontine myelinolysis; DKA, diabetic ketoacidosis; HONK, hyperosmolar nonketotic state.

Selected Disorders

DKA and HONK

Both DKA and HONK are associated with volume depletion due to the osmotic diuretic effect of glucosuria on the kidney. Severe dehydration and electrolyte depletion can result. Neurologic manifestations include mental status changes with deterioration to coma, rarely focal neurologic signs (hemiparesis and hemianopsia), and seizures.

Management of DKA and HONK involves replacement with physiologic saline and cautious insulin administration with frequent serum glucose monitoring. The goal is to decrease the serum glucose level from more than 300 mg/dL to approximately 200 mg/dL. This is followed by further slow, steady correction over 24 to 48 hours to minimize the risk of cerebral edema caused by osmolar tonicity shifts in brain parenchyma. Patients with both DKA and HONK require frequent electrolyte monitoring and replacement since acidosis causes intracellular potassium to leach into interstitial and intravascular spaces. Therefore, while acidosis is being corrected, potassium gradually shifts back into cells, and profound hypokalemia may result. Similar depletion of phosphate or severe hypophosphatemia may occur during correction of DKA or HONK and can cause rhabdomyolysis. Coma or seizures (or both) may occur in DKA or HONK.

Hypoglycemia

Hypoglycemia is injurious to brain tissue because its metabolism is based on glucose. Mild hypoglycemia can cause encephalopathy; moderate to severe hypoglycemia (<40 mg/dL), especially when prolonged, can cause seizures and coma. Prodromal somatic symptoms, which occur as serum glucose levels decrease, result from underlying neurohormonal activation of the sympathetic nervous system and stress hormone release of cortisol and adrenaline. The symptoms include diaphoresis, pallor, light-headedness, dizziness, visual disturbance, and tremulousness. They can be blocked partially in patients taking β‎-blockers. Hypoglycemia can cause focal deficits and, if prolonged and severe, can result in a diffuse hypoxic-ischemic brain injury type of pattern on magnetic resonance imaging and computed tomography, coma, and death. Hypoglycemia should be corrected rapidly with sublingual dextrose or intravenous 50% dextrose to prevent prolonged hypoglycemia. To prevent Wernicke-Korsakoff syndrome, thiamine deficiency should be considered in nutritionally deficient patients before dextrose administration.

  • Volume depletion due to the osmotic diuretic effect of glucosuria on the kidney can result in severe dehydration and electrolyte depletion with neurologic manifestations that include mental status changes with deterioration to coma, rarely focal neurologic signs (hemiparesis and hemianopsia), and seizures.

Congenital Endocrine Disorders and Tumors of the Endocrine System

Multiple Endocrine Neoplasia

Multiple endocrine neoplasia disorders are associated with particular types of endocrine tumors (Box 79.4). Patients with pheochromocytoma may present with episodic headache, hypertension, and hemorrhagic stroke. Diagnosis of pheochromocytoma is typically investigated with measurement of 24-hour fractionated urinary catecholamines and metanephrines.

Abbreviations: CRH, corticotropin-releasing hormone; GH, growth hormone.

Tumors of the thyroid may cause dysphonia from structural compression on the trachea or glottic region, recurrent laryngeal nerve paralysis, and diaphragm weakness.

  • Patients with pheochromocytoma may present with episodic headache, hypertension, and hemorrhagic stroke.

Notes:

Abbreviations: ADH, antidiuretic hormone; DKA, diabetic ketoacidosis; HONK, hyperosmolar nonketotic state; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; T3, triiodothyronine; T4, tetraiodothyronine