Endocrine Disorders
ADRENAL HYPOFUNCTION
Adrenal hypofunction is classified as primary or secondary.
Primary adrenal hypofunction or insufficiency (Addison’s disease) originates within the adrenal gland and is characterized by the decreased secretion of mineralocorticoids, glucocorticoids, and androgens. It’s defined as destruction of more than 90% of both adrenal glands and is usually caused by an autoimmune process. Addison’s disease is relatively uncommon and can occur at any age and in both sexes. Secondary adrenal hypofunction is due to impaired pituitary secretion of adrenocorticotropin (ACTH) and is characterized by decreased glucocorticoid secretion.
With early diagnosis and adequate replacement therapy, the prognosis for adrenal hypofunction is good.
CLINICAL TIP
Adrenal crisis (addisonian crisis) is a critical deficiency of mineralocorticoids and glucocorticoids that generally follows sepsis, trauma, surgery, omission of steroid therapy, or other acute physiologic stress. This medical emergency mandates immediate, vigorous treatment.Causes
Primary Hypofunction (Addison’s Disease)
Bilateral adrenalectomy
Hemorrhage into adrenal gland
Neoplasms
Tuberculosis, histoplasmosis, and cytomegalovirus
Family history of autoimmune disease
Secondary Hypofunction (Glucocorticoid Deficiency)
Hypopituitarism (causing decreased ACTH secretion)
Abrupt withdrawal of long-term corticosteroid therapy
Removal of an ACTH-secreting tumor
Pituitary injury by tumor or infiltrative or autoimmune process
Pathophysiology
Addison’s disease is a chronic condition that results from partial or complete adrenal destruction. In most cases, cellular atrophy is limited to the cortex, although medullary involvement may occur, resulting in catecholamine deficiency.
ACTH acts primarily to regulate the adrenal release of glucocorticoids (primarily cortisol); mineralocorticoids, including aldosterone; and sex steroids that supplement those produced by the gonads. ACTH secretion is controlled by corticotrophinreleasing hormone from the hypothalamus and by negative feedback control by the glucocorticoids.
Cortisol deficiency causes decreased liver gluconeogenesis. Glucose levels of patients on insulin may be dangerously low.
Aldosterone deficiency causes increased renal sodium loss and enhances potassium reabsorption. Sodium excretion causes a reduction in water volume that leads to hypotension.
Androgen deficiency may result in decreased hair growth in axillary and pubic areas, loss of erectile function, or decreased libido.
Signs and Symptoms
Primary Hypofunction
Weakness, fatigue
Nausea, vomiting, anorexia, weight loss
Conspicuous bronze color of the skin, especially on hands, elbows, and knees; darkening of scars
Cardiovascular abnormalities, including orthostatic hypotension, decreased cardiac size and output, and weak, irregular pulse
Decreased tolerance for even minor stress
Fasting hypoglycemia
Craving for salty food
Secondary Hypofunction
Similar to primary hypofunction; differences include:
hyperpigmentation absent because ACTH and melanocyte-stimulating hormone levels are low
possibly normal blood pressure and electrolyte balance because aldosterone secretion is near normal
usually normal androgen secretion.
COMPLICATIONS
Adrenal crisis (profound weakness and fatigue, nausea, vomiting, dehydration, hypotension, confusion)
Diagnostic Test Results
Blood test for plasma cortisol levels confirms adrenal insufficiency.
Metyrapone test is used to detect secondary adrenal hypofunction.
Rapid corticotropin stimulation test by I.V. or I.M. administration of cosyntropin, a synthetic form of corticotropin, after baseline sampling for cortisol and corticotropin (samples drawn for cortisol 30 and 60 minutes after injection), differentiates between primary and secondary adrenal hypofunction. A low corticotropin level indicates a secondary disorder. An elevated level is indicative of a primary disorder.
Laboratory studies reveal decreased plasma cortisol level (less than 10 µg/dL in the morning; less in the evening) and decreased serum sodium and fasting blood glucose levels.
Serum chemistry reveals increased serum potassium, calcium, and blood urea nitrogen levels.
Complete blood count shows elevated hematocrit and increased lymphocyte and eosinophil counts.
X-rays show adrenal calcification if the cause is infectious.
Treatment
Primary or Secondary Adrenal Hypofunction
Lifelong corticosteroid replacement, usually with cortisone or hydrocortisone, which have a mineralocorticoid effect
I.V. hydrocortisone
Primary Adrenal Hypofunction
Oral fludrocortisone, a synthetic mineralocorticoid, to prevent dangerous dehydration, hypotension, hyponatremia, and hyperkalemia
 ADRENAL HORMONE SECRETION |
CUSHING’S SYNDROME
Cushing’s syndrome is a cluster of clinical abnormalities caused by excessive adrenocortical hormones (particularly cortisol) or related corticosteroids and, to a lesser extent, androgens and aldosterone. Cushing’s disease (ACTH excess) accounts for about 70% of the cases of Cushing’s syndrome.
AGE ALERT
Cushing’s syndrome caused by ectopic corticotropin secretion is most common in adult men, with the peak incidence between ages 40 and 60. In 30% of patients, Cushing’s syndrome results from a cortisol-secreting tumor. Adrenal tumors, rather than pituitary tumors, are more common in children, especially girls.Causes
Pituitary hypersecretion of ACTH
Autonomous, ectopic ACTH secretion by a tumor outside the pituitary (usually malignant, frequently a pancreatic tumor or oat cell carcinoma of the lung)
Administration of synthetic glucocorticoids or steroids
Adrenal adenoma or a cancerous adrenal tumor
Pathophysiology
Cortisol excess results in anti-inflammatory effects and excessive catabolism of protein and peripheral fat to support hepatic glucose production. The mechanism may be ACTH-dependent, in which elevated plasma ACTH levels stimulate the adrenal cortex to produce excess cortisol, or ACTH-independent, in which excess cortisol is produced by the adrenal cortex or exogenously administered. This suppresses the hypothalamic-pituitary-adrenal axis, also present in ectopic ACTH-secreting tumors.
COMPLICATIONS
Osteoporosis
Peptic ulcer
Diabetes mellitus or impaired glucose tolerance
Ischemic heart disease and heart failure
Signs and Symptoms
Fat pads above the clavicles, over the upper back (buffalo hump), on the face (moon face), and throughout the trunk (truncal obesity); slender arms and legs
Increased susceptibility to infection; decreased resistance to stress
Hypertension, left ventricular hypertrophy, bleeding and ecchymosis, and dyslipidemia
Increased androgen production — clitoral hypertrophy, mild virilism, hirsutism, and amenorrhea or oligomenorrhea in women; sexual dysfunction
Sodium and secondary fluid retention, increased potassium excretion, and ureteral calculi
Irritability and emotional lability
Little or no scar formation; poor wound healing
Purple striae, facial plethora, and acne
Muscle weakness
Pathologic fractures; skeletal growth retardation in children
Diagnostic Test Results
Laboratory studies reveal hyperglycemia, hypernatremia, glucosuria, hypokalemia, and metabolic acidosis; elevated urinary free cortisol levels; elevated salivary free cortisol; and elevated serum cortisol.
Dexamethasone suppression test confirms the diagnosis and determines the cause, possibly an adrenal tumor or a nonendocrine, corticotropin-releasing tumor.
Ultrasound, computed tomography scan, and magnetic resonance imaging detect the presence of a pituitary or adrenal tumor.
Treatment
Specific for cause of hypercortisolism — pituitary, adrenal, and ectopic
Surgery for tumors of adrenal or pituitary glands or other tissue, such as lung
Radiation therapy for tumor
Cortisol replacement therapy after surgery
Antihypertensives
Potassium supplements
Diuretics
Antineoplastic and antihormone agents
For inoperable tumor, drugs such as mitotane or aminoglutethimide to block steroid synthesis
CLINICAL TIP
Most patients with Cushing’s syndrome are treated with transsphenoidal surgery, which has a high cure rate (80%). Pharmacotherapy is usually used as adjunctive rather than primary therapy. MANIFESTATIONS OF CUSHING’S SYNDROME |
DIABETES INSIPIDUS
Adisorder of water metabolism, diabetes insipidus results from a deficiency of circulating vasopressin (also called antidiuretic hormone, or ADH) or from renal resistance to this hormone. The three forms of diabetes insipidus are neurogenic, nephrogenic, and psychogenic. Neurogenic diabetes insipidus is caused by a deficiency of ADH; nephrogenic diabetes insipidus, by the resistance of renal tubules to ADH. Diabetes insipidus is characterized by excessive fluid intake and hypotonic polyuria. A decrease in ADH levels leads to altered intracellular and extracellular fluid control, causing renal excretion of a large amount of urine.
AGE ALERT
Diabetes insipidus may begin at any age and is slightly more common in men than in women.In uncomplicated diabetes insipidus, the prognosis is good with adequate water replacement, and patients usually lead normal lives.
Causes
Neurogenic: stroke, hypothalamic or pituitary tumor, cranial trauma, or surgery
Nephrogenic: X-linked recessive trait, end-stage renal failure
Psychogenic: primary polydipsia or sarcoidosis
Transient diabetes insipidus: certain drugs, such as lithium, phenytoin, or alcohol
Pathophysiology
Diabetes insipidus is related to an insufficiency of ADH, leading to polydipsia and polyuria.
Neurogenic or central, diabetes insipidus is an inadequate ADH response to changes in plasma osmolarity. A lesion of the hypothalamus, infundibular stem, or posterior pituitary partially or completely blocks ADH synthesis, transport, or release.
Neurogenic diabetes insipidus has an acute onset. A threephase syndrome can occur, which involves:
progressive loss of nerve tissue and increased diuresis
normal diuresis
polyuria and polydipsia, reflecting permanent loss of the ability to secrete adequate ADH.
Nephrogenic diabetes insipidus is caused by an inadequate renal response to ADH. The collecting duct’s permeability to water doesn’t increase in response to ADH. Nephrogenic diabetes insipidus is generally related to disorders and drugs that damage the renal tubules or inhibit the generation of cyclic adenosine monophosphate in the tubules. In addition, hypokalemia or hypercalcemia impairs the renal response to ADH. A rare genetic form of nephrogenic diabetes insipidus is an X-linked recessive trait.
Psychogenic diabetes insipidus is caused by an extremely large fluid intake. This primary polydipsia may be idiopathic or reflect psychosis or sarcoidosis. The polydipsia and resultant polyuria wash out ADH more quickly than it can be replaced. Chronic polyuria may overwhelm the renal medullary concentration gradient, rendering the kidneys partially or totally unable to concentrate urine.
Regardless of the cause, insufficient ADH causes the immediate excretion of large volumes of dilute urine and consequent plasma hyperosmolality. In conscious individuals, the thirst mechanism is stimulated, usually for cold liquids.
COMPLICATIONS
Severe dehydration
Shock
Renal failure
Central nervous system damage
Bladder distention
Hydronephrosis
Signs and Symptoms
Polydipsia and polyuria up to 20 L/d (cardinal symptoms)
Nocturia
Sleep disturbance and fatigue
Headache and visual disturbance
Abdominal fullness, anorexia, and weight loss
Fever
Changes in level of consciousness
Hypotension
Tachycardia
Diagnostic Test Results
Urinalysis shows almost colorless urine of low osmolality and low specific gravity.
Water deprivation test identifies vasopressin deficiency, resulting in renal inability to concentrate urine.
Treatment
Vasopressin to control fluid balance and prevent dehydration until the cause of diabetes insipidus can be identified and eliminated
Hydrochlorothiazide with potassium supplement
Desmopressin acetate
Chlorpropamide
Fluid intake to match output
 MECHANISM OF ADH DEFICIENCY |
CLINICAL TIP
LABORATORY VALUES FOR PATIENTS WITH DIABETES INSIPIDUS
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DIABETES MELLITUS
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting from lack of insulin, lack of insulin effect, or both. Three general classifications are recognized:
type 1 — absolute insulin insufficiency
type 2 — insulin resistance with varying degrees of insulin secretory defects
gestational diabetes — manifested during pregnancy.
AGE ALERT
Although possible at any age, type 1 usually manifests before age 30. Type 2 usually occurs in obese adults after age 40.Causes
Heredity
Environment (infection, toxins)
Stress, diet, and lack of exercise in genetically susceptible persons
Pregnancy
Pathophysiology
Type 1 and type 2 diabetes mellitus are two separate and distinct pathophysiological entities. In persons genetically susceptible to type 1 diabetes, a triggering event, possibly a viral infection, causes production of autoantibodies, which kill the beta cells of the pancreas. This leads to a decline in and an ultimate lack of insulin secretion. Insulin deficiency, when more than 90% of the beta cells have been destroyed, leads to hyperglycemia, enhanced lipolysis, and protein catabolism.
Type 2 diabetes mellitus is a chronic disease caused by one or more of the following factors: impaired insulin production, inappropriate hepatic glucose production, or peripheral insulin receptor insensitivity.
Gestational diabetes mellitus is glucose intolerance during pregnancy in a woman not previously diagnosed with diabetes. This may occur if placental hormones counteract insulin, causing insulin resistance.
COMPLICATIONS
Cardiovascular disease
Nephropathy
Retinopathy
Neuropathy
Ketoacidosis and hyperosmolar coma
Infections
Signs and Symptoms
Polyuria and polydipsia
Nausea; anorexia (common) or polyphagia (occasional)
Weight loss (usually 10% to 30%; persons with type 1 diabetes often have almost no body fat at diagnosis)
Headaches, fatigue, lethargy, reduced energy levels, and impaired school or work performance
Muscle cramps, irritability, and emotional lability
Vision changes such as blurring
Numbness and tingling
Abdominal discomfort and pain; diarrhea or constipation
Recurrent vaginal candidiasis
Diagnostic Test Results
In Men and Nonpregnant Women
Two of the following criteria obtained more than 24 hours apart, using the same test twice or any combination, are indicators of the disease:
fasting plasma glucose level of 126 mg/dL or more
typical symptoms of uncontrolled diabetes and random blood glucose level of 200 mg/dL or more
blood glucose level of 200 mg/dL or more 2 hours after ingesting 75 g of oral dextrose.
Other criteria include:
diabetic retinopathy on ophthalmologic examination
other diagnostic and monitoring tests, including urinalysis for acetone and glycosylated hemoglobin (reflects glycemic control over the past 2 to 3 months).
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