clinical chem spring chapter 21
Diagnosis: Cushing's Syndrome Steps in Diagnosis
Document cortisol excess by: Urine free cortisol (and/or metabolites) Random plasma cortisol levels Baseline a.m. cortisol concentrations (Cortisol highest 6-8am) Determine if diurnal rhythm is lost: late-night values remain high. Determine loss of normal cortisol suppression by dexamethasone (glucocorticoid steroid medication - suppresses ACTH production).
Adrenal etiology (cause) should be considered in any patient with high blood pressure (BP) accompanied by:
Electrolyte abnormality Unexplained change in weight Inappropriate virilization (female develops male sex characteristics, or a newborn boy has increased male characteristics at birth) Anxiety Weakness Orthostasis (Orthostatic hypotension: fall in blood pressure between supine and upright reading: systolic >20 mmHg and/or diastolic >10 mmHg) Palpitations; Headache; Chest pain; or Abdominal pain
Adrenal Cortex Disorders: Hyperfunction Hyperaldosteronism (↑ Aldosterone) Can lead to metabolic alkalosis, hypertension, & hypokalemia Primary hyperaldosteronism CONN'S DISEASE
Excess ↑ Aldosterone by the adrenal glands (Adrenal Tumor) Low Renin High Na+ and H2O retention (hypernatremia) and low plasma K+(hypokalemia) which leads to ↑↑ BP
Diagnosis: Cushing's Syndrome ACTH Source in Dexamethasone Non-Suppression
60-70% of patients with non-suppressible ACTH secretion to high-dose dexamethasone will have Cushing's disease. Cushing's disease is the most common form of endogenous Cushing's syndrome. It is caused by a tumor in the pituitary gland that secretes excessive amounts of ACTH. Scintigraphy may be used to localize neuroendocrine tumors.
Diagnosis: Cushing's Syndrome Determinations Necessary for Diagnosis
ACTH-dependent vs. ACTH-independent Hypercortisolism Pituitary vs. Ectopic (nonpituitary) ACTH secretion
urine and plasma catecholamine measurements ( in adrenal medulla)
Accurate measurement/ interpretation of catecholamines in plasma is challenging because catecholamines: are hydrophilic circulate in plasma in low levels (50% bound to albumin) have short half-lives (seconds to 2 min.) produce wide, rapidly fluctuating plasma levels.
The Adrenal Cortex: Steroid Hormones Cortex Steroidogenesis
Adrenal Cortex Steroids: Aldosterone (mineralocorticoid) - Zone G Cortisol (glucocorticoid) - Zone F DHEAS (Androgen/Estrogen Precursor) - Zone R All adrenal cortex steroids are derived by enzymatic conversion of a common precursor, Cholesterol.
Adrenal gland
Adrenal Gland (ad—near or at; renes—kidneys; sometimes called "suprarenal" glands) 2 endocrine glands that sit on top of the kidneys
two parts of adrenal gland
Adrenal Gland: 2 distinct parts Adrenal cortex (outer part of the gland) Adrenal medulla (inner part of the gland
Diagnosis of Pheochromocytoma Greek phaios "dark", chroma "color", kytos "cell", -oma "tumor") (from adrenal medulla)
Fractionated metanephrines & catecholamines (in a 24-hour urine collection): best test for diagnosis Total plasma catecholamines & urine metanephrines: most sensitive screening profile Plasma metanephrines (measured by HPLC or RIA): touted as most specific & sensitive diagnostic test Urine metanephrines: possibly most sensitive urine test Serum chromogranin A & plasma catecholamines (Chromogranin A costored and secreted in quantum with catecholamines) Clonidine suppression test (Clonidine- med used to treat high blood pressure) - patients without pheochromocytoma will have a fall in total catacholamines after clonidine treatment by >500pg/mL Radiologic localization: CT, MRI, PET scanning
Causes of Sympathetic Hyperactivity (from adrenal medulla)
Autonomic (nervous system) dysfunction Panic attack (emotions) Stress responses: hypoglycemia, injury, infection, psychosis, seizures Drugs: decongestants, appetite suppressors, stimulants, bronchodilators, MAO inhibitors, thyroid hormone, cortisol, etc. Foods containing tyramine (naturally occurring monoamine - causes catecholamine release): imported beer, red wine, soy sauce, overripe/fermented foods, smoked or aged meats Pheochromocytoma (catecholamine-producing tumor of the adrenal medulla). Symptoms: HTN (hypertension), palpitations, diaphoresis (sweating). HTN may be refractory to treatment.
Adrenal cortex disorder- hypofunction Adrenal Insufficiency (↓ Cortisol, other adrenal hormones Tertiary Adrenal Insufficiency
Cause: Destruction/dysfunction of hypothalamus ( decr. CRH secretion) resulting in inadequate ACTH/ Cortisol Exogenous Glucocorticoid administration (Suppresses CRH, decreases ACTH and Cortisol secretion)
Adrenal cortex disorder- hypofunction Adrenal Insufficiency (↓ Cortisol, other adrenal hormones Secondary Adrenal Insufficiency
Cause: Destruction/dysfunction of pituitary ( decr. ACTH secretion) resulting in inadequate cortisol production Tumors/ Hemorrhage/ Infiltrative processes of Pituitary Glucocorticoid therapy
Adrenal Cortex Disorders: Hypofunction Adrenal Insufficiency (↓ Cortisol, other adrenal hormones Primary Adrenal Insufficiency (Addison's Disease)
Causes: Destruction/dysfunction of adrenal glands Autoimmune adrenalitis (70%) Other causes of adrenal destruction: Infectious disease (fungal, HIV, TB), Metastasis
Cushing's Syndrome (↑Cortisol) Characteristics Adrenal Cortex Disorders: Hyperfunction
Characteristics: "Moonface" "Buffalo hump" (fat above the shoulder blades) Spindly legs Fat in facial area or strange redistribution of fat.
Regulation of Cortex Steroids (from adrenal cortex)
Hypothalamic (CRH) - Pituitary (ACTH) - Adrenal Axis: (HPA) Renin - Angiotensin - Aldosterone System
Functions of cortisol
Increase blood sugar through gluconeogenesis Aid in the metabolism of fat, protein, and carbohydrates Suppress the immune system
Fight or flight causes
Increase in cardiac output Increased blood pressure Diversion of blood to muscle/ brain Mobilization of "fuel" from storage
Adrenal Androgens
DHEA/ DHEA-S (Androgen precursors) - R Zone DHEA and DHEA-S are precursors to: Androgens (androstenedione, testosterone, 5-dihydrotestosterone) - adrenal Estrogens (estradiol, estrone) - peripheral tissues Men: < 5% of testosterone from adrenal/ peripheral tissues Women: 40 - 65% of testosterone from adrenals
Diagnosis: Cushing's Syndrome Algorithm for Cushing's Workup
Day 1 8:00 a.m.: Empty bladder & start baseline urine collection. 11:00 p.m.: Collect saliva sample for cortisol level; ingest dexamethasone (1 mg); empty bladder; end baseline urine collection. Optional extended workups: Begin overnight dexamethasone-suppressed urine collection. Day 2 8:00 a.m.: Empty bladder; venous blood or saliva for cortisol; ACTH; dexamethasone; hold samples until needed.
Diagnosis: Cushing's Syndrome Inferior Petrosal Sinus Sampling
Inferior Petrosal Sinus: where pituitary drains Source of ACTH hypersecretion can be investigated by simultaneous sampling of blood from inferior petrosal sinus & a peripheral vein. Petrosal sinus to peripheral blood ACTH ratio of >2-3 is 97% sensitive & 100% specific for ACTH hypersecretion from pituitary gland, or Cushing's disease. Imaging with CT or MRI is used to localize pituitary or ectopic ACTH-secreting tumors. Outcome for patients with Cushing's syndrome similar to that for patients with type 1 diabetes
Adrenal cortex disorders- hypofunction Isolated hypoaldosteronism
Insufficient aldosterone secretion Causes: adrenal gland destruction chronic heparin therapy unilateral adrenalectomy G-layer enzyme deficiencies
Adrenal medulla functions
Medulla responds to sympathetic (excitation) nervous system stimulation to secrete catecholamines Secretes catecholamines: Epinephrine (EPI- adrenaline) & Norepinephrine (NE - noradrenaline) directly into circulation (not via efferent axons) Acts as first responder to stress (within seconds - cortisol takes 20 min.) to promote fight-or-flight response
Adrenal Androgen Hypersecretion diagnosis and treatment
Diagnosis: high levels of DHEA-S, DHEA, testosterone Treatment: surgical removal of tumors; exogenous DHEA
Adrenal Gland: Pathology
Most pathologic conditions affect blood pressure & electrolyte balance.
Biosynthesis of Catecholamines (in adrenal medulla)
Norepinephrine & epinephrine synthesized by conversion of phenylalanine substrates in tightly regulated manner (Phenylalanine > Tyrosine > DOPA > dopamine > NE > EPI)
Diagnosis of Primary Aldosteronism Three criteria
PA/PRA Ratio > 25 (Plasma Aldo/ plasma renin activity) Low plasma renin that fails to increase w/ volume depletion (hypovolemia) High Aldo that fails to decrease w/ saline/angiotensin inhibition
aldosterone
Part of the Renin - Angiotensin - Aldosterone System: Responds to low blood pressure and results in increased blood volume and pressure. Drugs that interfere with the secretion or action of aldosterone (e.g. Lisinopril - ACE inhibitor) are antihypertensives - will lower blood pressure: reduce sodium and water retention but increase retention of potassium. Aldosterone has opposite function of ANH (atrial natriuretic hormone - secreted by heart).
Outcome and Prognosis of Treatment for Pheochromocytoma
Patients with familial pheochromocytomas are more likely to have recurrence. Long-term monitoring is indicated in all patients
Diagnosis: Cushing's Syndrome CRH Stimulation Test to Determine ACTH Dependency
Distinguishes types of disease (central vs. primary adrenal) CRH is injected, then cortisol & ACTH levels are measured. Localization Procedures Adrenal Cushing's: adrenal CT (tumor vs. hyperplasia) & adrenal MRI T2-weighted image to discern carcinoma Pituitary Cushing's: pituitary MRI Ectopic Cushing's: chest CT Treatment (all types): Surgery, radiation, and/or medications to suppress adrenal cortisol production
Adrenal Androgen Hypersecretion Excess adrenal androgen due to
"Virilizing" adenoma with too much testosterone produced. Virilization: the development of male physical characteristics (such as muscle bulk, body hair, and deep voice) in a female or precociously in a boy, typically as a result of excess androgen production. ↑Androgens in female results in overdeveloped male characteristics: hirsutism, deepening voice, more muscular arms and legs. ↑Androgens in prepubescent boys, may cause premature secondary sex characteristics such as deep voice, beard, enlarged penis and a sex drive. Not a true puberty.
Aldosterone mineralocorticoid) - G Zone
Role in Regulation of Blood Pressure Increases reabsorption of sodium and water in kidney Retains sodium (Na+) Secrets potassium (K+) Increases water retention Results in increase in blood volume and blood pressure
Treatment of Pheochromocytoma
Surgery, following appropriate medical preparation Removal is a high-risk procedure. Catecholamines fall to normal within 1 week of resection.
Adrenal Insufficiency (↓ Cortisol, other adrenal hormones) Adrenal Cortex Disorders: Hypofunction
Symptoms: weakness, fatigue, anorexia, nausea, diarrhea, abdominal pain, weight loss Diagnosis: Low baseline cortisol levels (8am) & ACTH > 200 pg/mL Treatment: Synthetic steroids from G & R zones are replaced.
Catecholamine Degradation (in adrenal medulla)
Three methods of catecholamine elimination: 1) Reuptake into secretory vesicles 2) Uptake in non-neuronal cells (mostly liver) 3) Degradation: Two enzymes (COMT - catechol methyltransferase & MAO - monoamine oxidase) produce metabolites (metanephrines and vanillylmandelic acid - VMA) from free catecholamines. Metabolites & free catecholamines are filtered into urine & excreted
Diagnosis Algorithm Tests: Diagnosis of Primary Aldosteronism
Urinary potassium excretion (>30mmol/d) Upright PA/PRA ratio (in overnight dehydration - incr. PRA) > 25 Captopril (ACE inhibitor) suppression - PA remains high in 1o aldosteronism 8-hydroxycorticosterone levels - > 100ng/dL suggest Aldosterone-Producing Adenoma (APA) Adrenal imaging - Visualize adrenal abnormality
Adrenal "Incidentaloma"
adrenal mass, typically >1 cm in diameter, found incidentally in CT, MRI, & ultrasound imaging of abdomen Autopsy studies report frequency of adrenal adenomas at about 6%, & prevalence increases with age. All lesions should be assessed for malignancy or hypersecretion. Surgery should be considered if adrenal mass is cancerous; autonomously secreting cortisol, Aldo, or catecholamines; ≥4 cm in diameter; or growing.
ACTH-dependent vs. ACTH-independent Hypercortisolism:
determined via 2-site IRMA assay for ACTH Immunoradiometric assay (IRMA) and 2-site IRMA techniques employ purified radioactive antibodies to convert soluble antigens
Pituitary vs. Ectopic (nonpituitary) ACTH secretion
determined via high-dose Dexamethasone Suppression Test - Dexamethasone = glucocorticoid steroid medication - suppresses ACTH production. ACTH-secreting pituitary adenoma "relatively" resistant to negative feedback regulation by glucocorticoids (dexamethasone), ectopic are "completely" resistant.
Adrenal Hypofunction is treated with
exogenous hormone replacement
Three layers of adrenal gland
inner- sex -15% middle-sugar- 75% outer-salt-10% the cortex is 90% of this area and the medulla is only 10%
Urine catecholamines/ metabolites are assayed using:
liquid chromatography fluorometry LC/MS/MS 24-hour urine levels are more accurate.
Adrenal Hyperfunction is treated with
pharmacologic suppression or surgery.
Cushing's Syndrome (↑Cortisol) Adrenal Cortex Disorders: Hyperfunction
↑Cortisol results in glucose excess (hyperglycemia) and protein shortage. Causes: Overproduction of CRH or ACTH causing ↑Cortisol Adrenal tumors that secrete cortisol independent of ACTH Ectopic ACTH-secreting tumors located in places other than the pituitary, most commonly the lung Prolonged exogenous steroid use
Adrenal cortex disorders Congenital Adrenal Hyperplasia (Adrenogenital Syndrome)
An inherited family of enzyme disorders affecting cortisol, aldosterone (Aldo), and sex steroid production. Clinical presentation depends on affected enzyme: Most common form of Congenital Adrenal Hyperplasia (95%) is 21-hydroxylase deficiency, and is detected by elevated 17-OH-progesterone and androgen excess. Treatment: Oral glucocorticoids to replace deficient cortisol and suppress ACTH-stimulated androgen excess.
Cortisol glucocorticoid) - F Zone
Cortisol synthesis is critical to glucose homeostatis and hemodynamics (fluid dynamics of blood flow) Released in response to stress and low blood-glucose concentration. Cortisol disorders result in glucose and blood pressure abnormalities. Cortisol levels fluctuate day and night in a circadian rhythm: Peaks ~8 AM ; Lowest ~4 AM
Adrenal cortex- outer part of the gland
Produces essential hormones (vital to life): Aldosterone - Controls blood pressure & electrolyte balance Cortisol- Regulates metabolism (blood glucose homeostasis) and suppresses immune system (anti-inflammatory). Released in response to stress and low blood glucose. Also produces: Androgens: (sulfated DHEA (dehydropiandrosterone) to DHEAS = androgen precursors) - to produce sex hormones (testosterone/ estradiol)
Adrenal medulla (inner part of the gland
Produces nonessential hormones (don't need them to live) : Adrenaline (epinephrine) and Noradrenaline (norepinephrine) - reaction to stress (fight or flight)
what does the adrenal gland produce
Production of steroid hormones (cortex) and catecholamines (medulla
Adrenal Cortex Disorders: Hyperfunction Hyperaldosteronism (↑ Aldosterone) Can lead to metabolic alkalosis, hypertension, & hypokalemia Secondary Hyperaldosteronism:
RAS (Renin-Angiotensin System) activated aldosterone secretion Elevated Renin