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yperadrenalism (Cushing Syndrome) Overview: Cushing syndrome is due to a hyperfunctioning adrenal gland, which is producing an excess amount of cortisol

. Cushing syndrome produces characteristic signs and symptoms and resultant body habitus. Symptoms and signs Hypertension, weight gain, fatigability, weakness. Truncal obesity, with wasting of arms and legs; moon facies and accumulation of fat in the posterior neck; cutaneous striae, hirsutism, and acne. Proximal muscle weakness with atrophy of type 2 fast-twitch myofibers. Inhibition of uptake of glucose by cells leads to hyperglycemia, glucosuria, and polydipsia. Resorption of bone, causing osteoporosis. Thinning of skin on the top of hands (very characteristic sign of Cushing syndrome in young adults). Causes of Cushing syndrome: Cushing syndrome can result from both exogenous and endogenous causes. Administration of exogenous corticosteroids is the most common overall cause of this syndrome. Endogenous causes of Cushing syndrome can be ACTH-dependent or ACTH-independent. ACTH-dependent causes of Cushing syndrome ACTH-secreting pituitary adenoma (also called Cushing disease) is responsible for 70–80% of cases of endogenous Cushing syndrome. Ectopic ACTH secretion by small cell lung carcinoma. These patients usually present with symptoms related to lung disease rather than adrenal disease. Ectopic secretion by carcinoid tumor. These patients usually present with symptoms of adrenal disease. Other tumors producing ACTH include pancreatic, thyroid, and adrenal tumors. ACTH-independent causes of Cushing syndrome Adrenal gland adenoma or hyperplasia (Figures 18-12 and 18-13). Adenomas are more common than hyperplasia as an ACTH-independent cause of Cushing syndrome. Hyperplasia of the adrenal glands in patients with Cushing syndrome is usually secondary due to the stimulus provided by increased ACTH production, and is not the primary cause of the increased cortisol. orphology of Cushing syndrome Gross and microscopic: Depends upon the source of ACTH or cortisol. With increased cortisol levels, Crooke hyalinechange occurs in the anterior pituitary gland. Crooke hyaline change is eosinophilic condensation within cytoplasm of ACTH-secreting pituitary basophils. Diagnosis of Cushing syndrome (Table 18-4) Increased 24-hour urine free cortisol level, which is almost 100% sensitive and specific. Patients also have loss of diurnal pattern of cortisol secretion. The normal diurnal pattern is cortisol levels, which are highest in the morning and lowest at midnight. If the patient has elevated cortisol and is given low-dose dexamethasone, and if the cause of elevated cortisol is not Cushing syndrome, the dexamethasone will inhibit ACTH and produce a lower level of cortisol. If dexamethasone does not lower the ACTH level, the patient should be given high-dose dexamethasone. High-dose dexamethasone will inhibit an ACTH-secreting pituitary adenoma, but will not

affect adrenal gland hyperplasia or an adenoma-secreting cortisol (since adrenal gland hyperplasia or an adenoma do not require the input of ACTH). High-dose dexamethasone will not inhibit ectopic production of ACTH (e.g., by small cell carcinoma of the lung).
Table 18-4. Cortisol Level Suppression by Dexamethasone Testing

Condition Causing Hyperadrenalism ACTH-secreting pituitary adenoma Adrenal gland hyperplasia Functional adrenal adenoma Ectopic ACTH-production

Suppression with Low-dose Dexamethasone No No No No

Suppression with High-dose Dexamethasone Yes No No No

Target System Intermediary metabolism

Specific Target Liver

Physiologic Function Increased expression of gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, glucose-6phosphatase, and fructose2,6-bisphosphatase Permissive for lipolytic signals (catecholamines, GH) leading to elevated plasma FFA to fuel gluconeogenesis Degradation of fibrillar muscle proteins by activating the ubiquitin pathway, thereby providing amino acid substrates for gluconeogenesis Maintains plasma glucose during fasting (antihypoglycemic action); increases plasma glucose during stress (hyperglycemic action) Decreased reabsorption of calcium

Cushing Disease Increased hepatic glucose output; together with insulin, increased hepatic glycogen stores

Addison Disease Diminished hepatic glucose output and glycogen stores

Adipose tissue

Overall effect (together with insulin): central obesity (truncal obesity, moon facies, and buffalo hump) Muscle weakness and wasting mainly in proximal muscles; increased urinary nitrogen excretion (urea from amino acids)

Decreased adiposity and decreased lipolysis

Skeletal muscle

Muscle weakness, decreased muscle glycogen stores; decreased urinary nitrogen excretion

Plasma glucose

Impaired glucose tolerance, insulin- Hypoglycemia, increased resistant diabetes mellitus; increased insulin sensitivity plasma glucose is due to decreased peripheral glucose utilization and increased hepatic glucose output Hypercalciuria without hypercalcemia leading to secondary hyperparathyroidism Retardation of bone growth mainly through decreased GH; hypercalcemia possible

Calcium homeostasis

Kidney

Bone, cartilage

Inhibition of collagen Retardation of bone growth and synthesis and bone deposition bone age by direct action and by decreasing GH; osteoporosis in adults Inhibition of calcium, magnesium, and phosphate absorption by antagonizing calcitriol actions Decreases endogenous opioid Scanty menses due to suppressed Scanty menses by

Gastrointestinal tract

Other endocrine Hypothalamus,

Target System systems

Specific Target pituitary

Physiologic Function production; depresses gonadotroph responsiveness to GnRH; stimulates GH gene expression by the pituitary; inhibits GH secretion via the hypothalamus

Cushing Disease gonadotroph sensitivity to GnRH; suppressed GH secretion by hypothalamic action; minimal suppression of the TRH-TSH axis

Addison Disease upregulated CRHendogenous opioid pathway-mediated suppression of GnRH; suppressed GH secretion; hypothyroidism (if present) is due to autoimmune mechanism

Pancreas

Inhibits insulin secretion by decreasing the efficacy of cytoplasmic Ca2+ on the exocytotic process

Absolute hyperinsulinemia with Absolute hypoinsulinemia relative hypoinsulinemia (lower with relative plasma insulin than expected for the hyperinsulinemia degree of hyperglycemia) Increased responses to sympathoadrenal activation Decreased responses to sympathoadrenal activation

Adrenal medulla Increases PNMT expression and activity (epinephrine synthesis) Carrier proteins (CBG, SHBG, TBG) Immune system Thymus, lymphocytes Monocytes

Decreases all major hormone- Decrease in total T4, free T4 binding proteins remains normal Causes age-related involution Immunocompromised state; of the thymus; induces lymphocytopenia thymic atrophy Inhibits monocyte proliferation and antigen presentation; decreased production of IL-1, IL-6, and TNF Monocytopenia in peripheral blood Relative lymphocytosis in peripheral blood Monocytosis in peripheral blood

Granulocytes

Demargination of neutrophils Peripheral blood: granulocytosis, by suppressing the expression eosinopenia of adhesion molecules Inhibition of inflammation by inhibiting PLA2, thereby inhibiting production of leukotrienes and prostaglandins; suppresses COX-2 expression No significant effect Increased hemoglobin and hematocrit are due to ACTHmediated overproduction of androgens

Peripheral blood: granulocytopenia, eosinophilia

Inflammatory response

Erythrocytes

Anemia is more pronounced in women and is due to loss of adrenal androgens; anemia may be related to direct autoimmune targeting of gastric parietal cells Darkening of the skin is due to ACTH-mediated stimulation of epidermal melanocortin 1 receptors; vitiligo may occur due to direct autoimmune destruction of melanocytes in circumscribed areas

Skin and connective tissue

Antiproliferative for fibroblasts and keratinocytes

Easy bruisability due to dermal atrophy; striae or sites of increased tension, especially sites of adipose tissue accumulation; poor wound healing; hirsutism and acne are due to ACTH-mediated increase of adrenal androgens; hyperpigmentation is a direct effect of ACTH on melanocortin 1 receptors

Target System Breast

Specific Target Mammary epithelium Type II alveolar cell Heart

Physiologic Function Mandatory requirement for lactation Stimulation of surfactant production Increased contractility

Cushing Disease Cushing disease may be associated with galactorrhea

Addison Disease Addison disease is not associated with galactorrhea

Lung Cardiovascular system

Hypertension

Lower peripheral resistance; hypertension with further postural decrease in blood pressure (orthostatic hypotension); low-voltage ECG

Vasculature

Increased vascular reactivity to vasoconstrictors (catecholamines, angiotensin II) Increased GFR and nonphysiologic actions on mineralocorticoid receptors Hypokalemic alkalosis, increased Hyponatremia, ECF volume due to hyperkalemic acidosis, and mineralocorticoid activity (increased decreased ECF volume are mainly due to loss of DOC, saturation of type 2 11 - mineralocorticoid activity hydroxysteroid dehydrogenase by high levels of cortisol) Hyponatremia due to SIADH Increased ADH mainly via hypovolemia-related baroreceptor mechanism Depression

Na+, K+, and ECF volume

Kidney

Posterior pituitary Psychiatric parameters of CNS function Mood Eucortisolemia maintains emotional balance Increases appetite

Initially, euphoria; long-term, depression, psychosis Hyperphagia

Appetite

Decreased appetite in spite of improved taste and smell

Sleep Memory

Suppression of REM sleep Sensitizes hippocampal glutamate receptors, induces atrophy of dendrites Increasing intraocular pressure

Sleep disturbances Impaired memory, bilateral hippocampal atrophy Cataract formation; increased intraocular pressure Decreased intraocular pressure

Eye