Flashcards in Adrenal Disorders Deck (98):
Adrenal Anatomy and Physiology
a. Each adrenal gland is actually two functionally distinct glands: the outer adrenal cortex which synthesizes and secretes steroid hormones (cortisol, aldosterone, and sex steroids) and the central adrenal medulla, which secretes catecholamines.
b. The adrenal cortex consists of three separate layers, or zones; each zone produces a specific hormone determined by the presence and/or absence of key enzymes in the same cholesterol metabolic pathway.
1. The main product of the outermost zona glomerulosa is the mineralocorticoid aldosterone.
2. The middle layer, zona fasciculata, is responsible for cortisol production.
3. The innermost zona reticularis produces androgens.
An overproduction or underproduction of any of these hormones, along with the hormones of the adrenal medulla, can create significant disorders:
a. Cortex Hormones
i. Excess-->Cushing’s syndrome
ii. Deficiency--> Addison’s disease & Secondary hypocortisolism
i. Excess-->Primary aldosteronism
ii. Deficiency-->Addison’s disease
i. Excess-->Hirsutism, virilization
a. Cortisol, the major hormone product of the fasiculata layer of the adrenal gland, is necessary for maintenance of cardiovascular balance.
b. Cortisol production and release is controlled by the Hypothalamic-Pituitary-Adrenal axis.
i. A disruption of this axis at any point can cause adrenal insufficiency.
c. A deficiency of cortisol (hypocortisolism) results in decreased cardiac output and decreased vascular tone.
d. It is a well-known observation that patients who lack cortisol have low blood pressure that is poorly responsive to pressors (norepinephrine, epinephrine, dopamine).
i. These patients have a relative hypovolemia (blood flow seen by tissues), which causes stimulation of ADH, increased free water reabsorption by the collecting tubule in the kidney, and therefore, hyponatremia.
e. If primary adrenal cortex destruction is the cause of hypocortisolism, these patients also lack aldosterone and adrenal androgens.
Patients with Low Cortisol
a. It is a well-known observation that patients who lack cortisol have low blood pressure that is poorly responsive to pressors (norepinephrine, epinephrine, dopamine).
b. These patients have a relative hypovolemia (blood flow seen by tissues), which causes stimulation of ADH, increased free water reabsorption by the collecting tubule in the kidney, and therefore, hyponatremia.
What causes adrenal insufficiency?
Adrenal insufficiency can be divided into two categories: primary (adrenal gland) and secondary (pituitary, hypothalamus).
a. Primary Adrenal Insufficiency
Autoimmune: Addison’s Disease
Infectious: TB, Fungi, HIV
Metabolic: Adrenoleukodystropy, Adrenomyeloneuropathy
b. Secondary Adrenal Insufficiency
i. Following supraphysiological exogenous glucocorticoids for more than 3 weeks
iii. Following cure of Cushing’s syndrome
iv. Hypothalamic/pituitary lesions (tumor, surgery, radiation, infectious,
hemorrhagic, infiltrative, metastatic)
Distinguish primary from secondary adrenal insufficiency.
a. Clinically, patients with primary adrenal disease can have hyperpigmentation due to increased production of POMC (ACTH precursor in the pituitary) with release of the by-product melanocyte stimulating hormone (MSH), which causes the hyperpigmentation.
b. Patients with hypothalamic or pituitary disease have low ACTH and MSH levels and, therefore, no hyperpigmentation.
i. This lack of hyperpigmentation--> secondary adrenal insufficiency
c. ACTH is a good laboratory test to separate primary from secondary disease.
i. Also, patients with primary gland failure lack cortisol and aldosterone resulting in not only hyponatremia, but hyperkalemia, while patients with secondary disease have preserved aldosterone synthesis and are normokalemic.
Causes of Primary Adrenal Deficiency
a. Autoimmune destruction of the adrenal gland (Addison’s disease) is by far the most common cause of primary adrenal insufficiency in developed countries, whereas tuberculosis remains the most common cause in developing countries.
b. In autoimmune adrenal insufficiency, the adrenal cortex shows lymphocytic infiltration, cell destruction, and fibrosis, but there is an intact adrenal medulla. Interestingly, this form of adrenal insufficiency is associated with other autoimmune disorders, such as:
i. Hypothyroidism (25%)
ii. Graves’ disease (11%)
iii. Premature ovarian (13%) or testicular (2%) failure
iv. Type I DM (10%)
v. Autoimmune hypoparathyroidism (4%)
c. Addison’s disease can also be associated with other nonendocrine autoimmune disorders, such as pernicious anemia (B12 deficiency), vitiligo (focal skin depigmentation), alopecia, myasthenia gravis, Sjogren’s syndrome, rheumatoid arthritis, or thrombocytopenic purpura.
Clinical Manifestation of adrenal insufficiency
a. The signs and symptoms of adrenal insufficiency include fatigue, weakness, postural dizziness, anorexia, nausea, vomiting, diarrhea, abdominal pain, weight loss, myalgias, arthralgias, headaches, salt craving and, in primary adrenal insufficiency, hyperpigmentation.
b. Acute symptoms and signs include fever, hypotension and confusion.
c. Laboratory abnormalities include hyponatremia and, in primary adrenal insufficiency, hyperkalemia.
d. One can also see hypoglycemia (cortisol is a counter-regulatory hormone to insulin action), azotemia and rarely hypercalcemia.
e. A complete blood count (CBC) can show anemia (hemodilution) and increased eosinophil count (cortisol lowers eosinophil levels).
f. Suspicion should be heightened particularly when there are other identifiable risk factors for adrenal insufficiency such as: other autoimmune diseases, coagulopathy/sepsis/trauma (adrenal hemorrhage), HIV/AIDS, known malignancy, recent glucocorticoid treatment/withdrawal, recent complicated delivery (pituitary infarct), or head trauma (pituitary infarct).
Diagnosis of Adrenal Insufficiency
a. The best way to confirm the diagnosis of adrenal insufficiency is a Cortrosyn (synthetic ACTH) stimulation test of adrenal reserve.
b. A baseline serum cortisol is measured followed by an intravenous injection of 250 ug of synthetic ACTH (Cortrosyn).
i. Blood is drawn at 30 and/or 60 minutes for serum cortisol.
c. A stimulated level greater than 20 ug/dl indicates adequate adrenal reserves.
i. A caveat to this diagnosis is recent (less than 6 months and as little as 2 weeks) pituitary or hypothalamic injury: in this situation, the adrenal gland can still respond to Cortrosyn stimulation.
ii. Chronic secondary insufficiency results in an atrophied adrenal glands that can’t respond to Cortrosyn.
d. An abdominal X-ray that shows calcification of the adrenals is suggestive for tuberculosis.
e. Most otherwise healthy individuals (no HIV, disseminated TB or fungal infection) can be assumed to have autoimmune destruction as the cause of their disease and serum antibody testing is not performed.
i. A serum ACTH level prior to Cortrosyn stimulation can help separate primary from secondary disease if there is a question.
Adrenal Insufficiency Treatment
a. Adrenal insufficiency is treated with glucocorticoids.
b. In life-threatening disease, saline infusion and ‘stress-dose’ steroids (hydrocortisone 100 mg i.v. every six hours) are given until the patient is stabilized.
c. Oral glucocorticoids (hydrocortisone 15-25 mg a day in 2 doses, about 2/3 of the dose in AM) or prednisone 4-5 mg per day, in AM) are given as replacement therapy on a chronic basis.
d. Fludrocortisone (Florinef) is given at 0.05-0.1 mg per day to replace aldosterone deficiency in primary adrenal gland failure.
a. Aldosterone is a steroid hormone that is produced in the glomerulosa zone of the adrenal cortex and is critical in maintenance of sodium balance, intravascular volume and blood pressure.
b. Aldosterone functions through a nuclear receptor in the distal collecting tubule cells of the kidney to reabsorb sodium in exchange for potassium.
c. Primary hyperaldosteronism was previously considered an infrequent cause of hypertension.
i. However, with increased availability of screening it is now thought to be the most common cause of secondary hypertension (~10% of cases of hypertension overall).
Aldosterone and the RAAS System
a. The regulation of aldosterone production is part of the feedback loop called the renin-angiotensin-aldosterone pathway
b. The juxtaglomerular cells in the kidney sense renal perfusion pressure (this generally reflects blood pressure) and release renin if the pressure is low.
c. Renin stimulates conversion of angiotensinogen from the liver to angiotensin I, which is then converted to angiotensin II in the lung by angiotensin converting enzyme (ACE).
d. Angiotensin II is a potent vasoconstrictor, but also stimulates production and release of aldosterone from the adrenal gland. ACE inhibitors block the conversion of AI to AII and are therefore potent antihypertensive medications.
e. Aldosterone increases sodium reabsorption, which enhances water reabsorption, increasing intravascular volume and blood pressure.
f. The resulting increased blood pressure is sensed by the juxtaglomerular cells, and renin production is accordingly decreased.
Primary Hyperaldosteronism and how it affects RAAS
a. In patients with primary aldosteronism, the RAAS feedback loop is perturbed.
b. Rather than intravascular volume and blood pressure as the driving force, the adrenal cortex primarily secretes too much aldosterone, which leads ultimately to hypertension.
c. Levels of renin and angiotensin II, which are under normal feedback mechanisms, are expectedly low and therefore measurement of plasma renin activity (PRA) is useful in the diagnosis of aldosteronism.
There are four basic types of primary aldosteronism:
1. Aldosterone-producing adenoma (APA) (34%)
2. Idiopathic hyperaldosteronism (IHA); a.k.a. Bilateral Adrenal Hyperplasia (66%)
3. Glucocorticoid-remediable hyperaldosteronism (GRA) (rare)
4. Aldosterone-producing carcinoma (rare)
It was once thought that most cases of primary aldosteronism were due to an APA. However, with increasing recognition of this disorder, a lower percentage of cases are associated with a functioning adrenal adenoma. Instead, bilateral adrenal hyperplasia is apparent in many of these cases, and IHA is much more common than previously thought.
The pathophysiologic mechanisms causing the more common APA and IHA are unknown, but the mechanism causing GRA has been uncovered and is quite interesting.
Aldosterone-producing adenoma (APA)
Idiopathic hyperaldosteronism (IHA); a.k.a.
Bilateral Adrenal Hyperplasia (66%)
Glucocorticoid-remediable hyperaldosteronism (GRA) (rare)
a. The aldosterone-producing glomerulosa layer of the adrenal cortex expresses the enzyme aldosterone synthase, which is the final step in the production of aldosterone from 18-hydroxycorticosterone.
b. The adjoining fasiculata layer of the adrenal cortex, which produces cortisol, expresses the 11Beta-hydroxylase enzyme which is under normal stimulatory control by the pituitary hormone ACTH.
c. Basically, in patients with GRA, there is a genetic rearrangement fusing the regulatory promoter of 11-Beta hydroxylase with the structural component of aldosterone synthase in a hybrid glomerulosa/fasiculata layer producing aldosterone synthase under the positive control of ACTH
d. This GRA is an autosomal dominant disorder, requiring the rearrangement in only one allele, and the diagnosis should be suspected in people with a family history of hypertension that presents at an early age.
The pathophysiology of this disease to diagnose primary aldosteronism
a, Since the normal feedback loop is disrupted, we would expect the plasma aldosterone (PA) level to be high and the plasma renin activity (PRA) to be suppressed, so the basic screening testing includes a baseline PA and PRA levels.
i. If the PA/PRA ratio is > 20 with a PA > 15 ng/dL, this is highly suggestive of primary aldosteronism.
b. Spironolactone interferes with the measurements and should be avoided or discontinued before the testing.
i. Also, the patient should be euvolemic and the potassium level normal (by replacement) at the time the test is performed to avoid confounding physiologic stimuli to renin and aldosterone.
c. The biochemical diagnosis of primary aldosteronism is usually confirmed with a suppression test prior to anatomic localization. Again, spironolactone should be avoided.
d. Patients with suspected aldosteronism by screening are challenged with an intravenous saline load which should suppress aldosterone levels in a patient with essential hypertension, but has little effect on a patient with primary aldosteronism.
i Two liters of saline are infused over four hours and serum aldosterone is measured.
ii. A level less than 5 ng/dl rules out primary aldosteronism, while a level greater than 10 ng/dl confirms the diagnosis.
e. An oral salt suppression test with a high salt diet for 3 days may also be used to confirm the diagnosis. A 24 hour urine aldosterone on the 3rd day > 12 mcg confirms the diagnosis.
a, Cells of the adrenal medulla are known as chromaffin cells due to the dark appearance of oxidized catecholamines upon tissue fixation.
b. Chromaffin cell tumors which produce excess norepinephrine and epinephrine are pheochromocytomas.
c. Most pheochromocytomas arise from adrenal medullary chromaffin cells, but they can also occur in extra-adrenal chromaffin tissue anywhere along the sympathetic chain, in which case they are often referred to as paragangliomas.
d. Pheochromocytomas are rare, with an annual incidence of 2-8 new cases/million people
a. The pathophysiologic cause of many cases of pheochromocytoma has recently been uncovered.
i. Neuroendocrine cells contain a cell-surface receptor called ret which binds to a factor called glial-derived neurotrophic growth factor (GDNF), causing intracellular signaling to stimulate cell synthesis of norepinephrine and epinephrine.
b. A somatic mutation in the ret receptor causing constitutive activation and hormone production is believed to be the cause of many cases of pheochromocytoma.
i. Interestingly, germline mutations of this gene cause multiple endocrine neoplasia (MEN) syndromes affecting many neuroendocrine systems.
-Pheochromocytoma (adrenal medulla)
-Medullary thyroid carcinoma (calcitonin-secreting C cells)
-Medullary thyroid carcinoma
c. Germline mutations in at least five other genes responsible for heritable pheochromocytomas have been identified: the VHL gene (von-Hippel-Lindau syndrome; pheochromocytoma, renal cell carcinoma, renal/pancreatic cysts, CNS hemangioblastomas, retinal angiomas, and islet cell tumors); the NF-1 gene (Neurofibromatosis type 1, or von Recklinghausen’s disease; pheochromocytoma, hyperparathyroidism, duodenal carcinoids, medullary thyroid carcinoma, and/or optic nerve tumors); and genes for the B, C, and D subunits of mitochondrial succinate dehydrogenase are involved in familial paraganglioma.
a. Pheochromocytoma is a rare cause of hypertension, with an incidence of 1 per 1,000-10,000 hypertensive patients.
i. It is frequently sought, but rarely present in 1 out of 200 of those investigated.
ii. However, it has devastating consequences (hypertensive crisis, myocardial infarction) if not appropriately diagnosed and treated.
b. The basic triad of symptoms for pheochromocytoma are headache, diaphoresis and palpitations.
i. If none of those symptoms are present, the likelihood of pheochromocytoma is low.
c. Conversely, the presence of all three symptoms, associated with severe resistant hypertension (> 160/100, on multiple antihypertensive medications), has been reported to have a specificity of > 90% for pheochromocytoma and should greatly raise suspicion of this diagnosis.
i. Hypertension may be episodic paralleling tumor activity.
d. Other signs and symptoms include anxiety, epigastric pain, orthostatic hypotension (due to volume depletion) and chest pain.
The signs and symptoms of pheochromocytoma are related to the pathophysiology of excess catecholamine secretion.
Catecholamines act through adrenergic receptors throughout the body.
a. Binding to alpha-1 receptors primarily mediates vasoconstriction and causes hypertension.
b. Binding to Beta-1 receptors mediate positive inotropic (contraction) and chronotropic (heart rate) effects in the heart and increased sweating and tremulousness through other systems, while binding to Beta-2 receptors primarily mediates vasodilation in muscle beds.
c. Epinephrine, which acts mainly through the Beta-receptors, causes tachycardia, sweating and tremulousness, but not significant hypertension (due to the Beta2-mediated vasodilation causing a widened pulse pressure.
d. Norepinephrine, which acts through both alpha- and beta-receptors, causes a similar set of signs and symptoms with the exception of significant hypertension due to the alpha-receptor stimulation.
a. In patients with a suspected pheochromocytoma, it is important establish a biochemical diagnosis prior to the anatomic localization, since 5-10% of people will have an adrenal mass on CT scan, and a majority of these masses are non-functioning.
b. On the other hand, an imaging study may discover an adrenal incidentaloma, and biochemical testing is also indicated in this situation to rule out a pheochromocytoma.
c. This complicated pathway explains why we measure certain products to make the biochemical diagnosis of pheochromocytoma: a 24-hour urinary collection for catecholamines (epinephrine, norepinephrine) as well as the metabolites (metanephrines, normetanephrines, and VMA).
d. Urine catecholamine and metanephrine levels above 2-fold the upper limit of normal have a high specificity of 98%, and are the preferred screening test, although they have a lower sensitivity of 90%.
e. Plasma metanephrine levels have a high sensitivity of 97%, meaning that a negative result is more likely to exclude the diagnosis, but the specificity is only 85%, so this test results in more false positives.
f. Malignant tumors tend to express a less differentiated phenotype, and dopamine, a precursor to norepinephrine and epinephrine, is likely to be produced at higher levels.
There is a 10% rule that applies to pheochromocytomas:
10% malignant (dopamine secretion)
10% recur after surgical removal
Localization of the tumor is usually much easier once the diagnosis is made.
a. 90% of tumors are in the adrenal gland and are not hard to find, usually being greater than 4 cm.
b. 10% of tumors arise outside the adrenals within the midline sympathetic chain (remember the adrenal medulla arises as part of the sympathetic chain).
c. 98% of all tumors will arise in the abdomen, so a CT or MRI scan of the abdomen is the best place to start.
Treatment of pheochromocytomas
a. Treatment of pheochromocytomas is achieved by surgical removal after appropriate medical treatment to avoid a hypertensive crisis during surgery.
b. Treatment is started with an alpha-adrenergic receptor blocker (phenoxybenzamine, prazosin, terazosin or doxazosin) followed by a beta blocker (such as labetalol), or a calcium channel blocker alone.
c, A beta blocker should never be started before an alpha-blocker, because the unopposed alpha-adrenergic effect will result in worsened hypertension.
d. Volume expansion with intravenous fluids is necessary as the treatment results in vasodilation.
The physiological regulation of cortisol
a. The physiological regulation of cortisol secretion is mediated by hypothalamic CRH and pituitary-derived ACTH.
b. The activity of this anatomic circuit produces a pulsatile and circadian rhythm of cortisol secretion such that peak cortisol levels occur shortly after awakening (at about 7-8 AM), and the nadir occurs in the late evening.
c. CRH is secreted into the portal hypophyseal system and is the main regulator of pituitary ACTH secretion.
d. Many types of stresses, including physical, emotional, and chemical, such as pain, trauma, hypoglycemia, cold exposure, surgery, and pyrogens can stimulate CRH, and subsequent ACTH and cortisol secretion.
e. Excess endogenous or exogenous glucocorticoids exert a negative feedback at both the level of the hypothalamus and the pituitary, and excess ACTH exerts a "short feedback" loop on its own secretion.
Clinical Features of Cushing’s Syndrome
1. Obesity: This is the most common manifestation and weight gain is usually the earliest symptom of Cushing's syndrome. The obesity tends to be central, but fat is also redistributed to the face (moon facies), supraclavicular, and dorsocervical areas ("buffalo hump"). The latter two, particularly the supraclavicular fat pads, are more specific findings for the clinical diagnosis of Cushing's syndrome.
2. Skin changes: Cortisol-induced atrophy of the epidermis leads to thinning and transparent appearance of the skin, facial plethora, easy bruising, and striae. The latter are purplish-red, depressed below the skin surface, and wider than the pinkish-white striae that occur after pregnancy or weight loss. Acne is also found due to androgen excess.
3. Insulin resistance and hyperglycemia: As described above, glucocorticoids have multiple metabolic effects that lead to insulin resistance.
4. Hirsutism: As production of cortisol is stimulated within the adrenal glands, concentrations of cortisol precursor molecules begin to accumulate and spill over into other metabolic pathways, such as sex steroid synthesis pathways. The resulting increase of adrenal androgens can cause a darkening and coarsening of the hair, and females complain of increased hair over the face, upper thighs, abdomen, and breasts. More overt virilization can occur in women with adrenal carcinoma.
5. Hypertension: Elevated diastolic BP is a classic feature, and it contributes greatly to the morbidity and mortality of Cushing's. The increased sodium retention also leads to edema. Congestive heart failure (22%) can be aggravated due to the increased BP and the increased fluid load.
6. Gonadal Dysfunction: Elevated adrenal androgens can result in amenorrhea and infertility in 75% of premenopausal women. In males, adrenal androgens suppress gonadotropins and decrease testosterone, and this may cause a decreased libido.
7. Muscle Weakness: Proximal muscle weakness most often occurring in the lower extremities is a fairly frequent complaint. This is due to the catabolic effects of glucocorticoids on muscle tissues, to the steroid-induced myopathy, and possibly due to electrolyte imbalances.
8. Osteoporosis: Glucocorticoids inhibit osteoblast activity, and this inhibition of bone formation results in net excess bone resorption in Cushing’s syndrome, resulting in osteoporosis. Pathological fractures can be found in the ribs and vertebral bodies in severe cases
Diagnosing of Cushing's Syndrome
a. The objectives of the diagnostic evaluation of patients suspected of having Cushing's syndrome are:
(1) to establish that the patient actually has Cushing's syndrome; and
(2) to determine the precise etiology of the hypercortisolism.
*A key aid in establishing the clinical diagnosis of hypercortisolism is to examine sequential photographs of the patient, which span several years.
b. Once Cushing's is suspected on clinical grounds, the 24 hr urinary free cortisol (UFC) determination and the overnight 1 mg dexamethasone suppression test (DST) are used as screening tests.
c. If the overnight 1 mg DST is normal (8 AM plasma cortisol is < 1.8 ug/dL after administration of 1 mg dexamethasone at 11 PM the night before), the diagnosis is very unlikely; if the UFC is also normal, Cushing's syndrome is excluded.
d. Elevated midnight salivary cortisol levels can also help diagnose Cushing’s syndrome.
e. Such measurements identify the disruption of the normal circadian rhythm of cortisol secretion in Cushing’s syndrome, which normally nadirs during the night.
Distinguish ACTH-dependent and ACTH-independent causes of Cushing's
a. Once the diagnosis of hypercortisolism (Cushing's syndrome) has been confirmed by clinical evaluation and screening laboratory tests, a plasma ACTH level can distinguish ACTH-dependent and ACTH-independent causes.
b. ACTH-dependent causes include Cushing’s disease and ectopic ACTH syndrome.
c. If plasma ACTH is low in a patient with Cushing’s syndrome, the adrenal glands are the likely source (exogenous glucocorticoids should also be considered).
d. The causes of adrenal Cushing’s syndrome include cortisol-producing adrenal adenomas or carcinomas, and nodular adrenal hyperplasia, including Primary Pigmented Nodular Adrenal Disease (PPNAD) and Massive Macronodular Adrenal Disease (MMAD).
Adrenal Imaging Techniques
a. CT, MRI, ultrasonography, and isotope scanning with iodocholesterol can be used to define adrenal lesions. In patients with ACTH hyposecretion, these procedures exclude the presence of a solitary adrenal adenoma/carcinoma and thus confirm bilateral adrenal hyperplasia or nodular adrenal hyperplasia.
b. These procedures also effectively localize adrenal tumors, since these tumors are usually >1.5 cm in order to cause significant cortisol production and result in Cushing's syndrome.
c. However, due to the up to 10% incidence of silent adrenal nodules, biochemical testing must be performed in conjunction with the localization studies to insure that the identified lesion is biologically significant.
a. In primary adrenal disease, surgical removal of the isolated adenoma, of the adrenal affected with macronodular hyperplasia, or of the adrenal gland containing the carcinoma, is the treatment of choice.
b. Bilateral adrenalectomy may be required to adequately treat macronodular hyperplasia with bilateral involvement.
c. Medical therapy is also usually adjunctive or temporizing and not curative, and involves the use of drugs that inhibit adrenal cortisol production.
i. These drugs include ketoconazole, metyrapone, etomidate and mitotane; however, mitotane is the only adrenolytic agent and is used palliatively in patients with adrenal carcinoma.
ii. Mifepristone is a cortisol receptor blocker and is also useful.
b. Three layers of the cortex
i. zona glomerulosa---> mineral corticoid (aldosterone)
ii. zona fasciculata---> Glucocorticoid
iii. zona reticularis--> sex hormones
*Salt, Sugar, Sex
c. Adrenal medulla
i. Ne and Epi
Adrenal Functional Histology and Regulation
a. Aldosterone is released in response to:
1. ↑ angiotensin II
2. ↑ serum potassium
3. ↑ ACTH (lesser stimulus)
b. Cortisol is released in response to:
↑ Arginine vasopressin (lesser stimulus)
c. Androgens are released in response to
1. ↑ ACTH
d. Norepinephrine and epinephrine are released in response to sympathetic nervous system activation and its synthesis is dependent on high local concentrations of cortisol
Adrenal Hormone Function
a. Aldosterone binds mineralocorticoid receptor to regulate:
i. Blood volume
ii. Salt/water homeostasis
b. Cortisol binds glucocorticoid receptor to regulate:
i. Energy balance
ii. Cardiovascular, metabolic and immune homeostasis
c. Androgens bind androgen receptor to regulate pubarche
d. Norepinephrine and epinephrine bind adrenergic receptors to regulate cardiovascular effects and bronchial dilatation
The Hypothalamic-Pituitary-Adrenal Axis
a. Stimulants of CRH:
i. Circadian rhythm
ii. Physical stressors
b. Stimulants of ACTH:
ii. Arginine vasopressin
c. Cortisol has negative feedback on ACTH and CRH
Primary and Secondary Adrenal Insufficiency
a. Primary Adrenal Insufficiency
i. Adrenal Gland cannot make cortiosl, aldosterone, or sex hormones
ii. lose both cortisol and aldosterone
b. Secondary Adrenal Insufficiency---> defect at the pituitary or hypothalamus
i. can still make Aldosterone! The main stimuli for aldosterone is K+ and angiotensin II
ii. Will lose cortisol though
Primary adrenal insufficiency
Deficiency of both glucocorticoids and mineralocorticoids
Secondary adrenal insufficiency
Deficiency of glucocorticoids only
Causes of Adrenal Insufficiency
a. Primary (adrenal gland)
i. Autoimmune: Addison’s Disease (~70%)
-autoimmune is the greatest cause
ii. Infectious: TB (10-20%), Fungi, HIV
iii. Infiltrative: Amyloid
iv. Hemorrhage: trauma, anticoagulants
v. Metastatic cancer
vi. Metabolic: Adrenoleukodystropy, Adrenomyeloneuropathy
vii. Drugs: aminoglutethimide, ketoconazole, etomidate (block cortisol production in the adrenal gland; rifampin and phenytoin (increase cortisol metabolism)
i. Drugs:(most common cause) Withdraw of chronic glucocorticoids, High dose opioids
ii. Tumor: Pituitary adenoma, meningioma, others
v. Infectious: TB, Fungi, HIV
vi. Hemorrhage: apoplexy, trauma, anticoagulants
vii. Infiltrative: Amyloid
viii. Metastatic cancers
Fatigue Anorexia Abdominal Pain
Weakness Nausea Weight Loss
Myalgias Vomiting Postural Dizziness
-Salt Craving (1o Only)
b. Signs All:
c. First degree signs only (defect at adrenal gland itself)
1. Vitiligo--> loss of skin color in blotches
Hyperkalemia (1st degree Only)
Adrenal Crisis - Emergency
b. Give stress dose steroids
i. Hydrocortisone 100mg IV every 8 hours
ii. or they will die
Why do these signs and symptoms occur in Primary Adrenal Insufficiency?
Primary Adrenal Insufficiency:
1. Hyponatremia (low Na)
2. Hyperkalemia (high K)
3. Hypotension (low BP)
b. Because both glucocorticoid deficiency and mineralocorticoid deficiency
i. hold onto potassium without aldosterone
ii. also lose tremendous amounts of salt when missing aldosterone
iii. High BP with a cortisol and aldosterone loss
c. With secondary adrenal insufficiency, will still have aldosterone to keep a water-salt balance
i. will be missing cortisol
Hyperpigmentation in Primary Adrenal Insufficiency
a. Hyperpigmentation due to increased POMC processing
i. will have extremely high ACTH with primary adrenal insuffciency
ii. the high ACTH will become POMC
b. ACTH and MSH (Melanocyte stimulating hormone) are both breakdown products of POMC (Pro-opiomelanocortin)
c. Not seen in Secondary Adrenal Insufficiency? WHY?
i. will have aldosterone functioning, will not have high ACTH
a. Half of persons with autoimmune adrenalitis have at least one other autoimmune disorder
b. Polyglandular autoimmune syndromes (APS): often associated with Addison disease
Type 1: adrenal insufficiency, hypoparathyroidism, mucocutaneous candidiasis, and risk of primary hypogonadism, celiac sprue, vitiligo, hypophysitis, pernicious anemia
Type 2: adrenal insufficiency, autoimmune thyroiditis, and risk of type 1 diabetes, vitiligo, primary hypogonadism, pernicious anemia, celiac sprue
Diurnal Rhythm of Cortisol
a. Normal: 7-8 AM cortisol above 18 mg/dL (or above 16 at least).
b. Adrenal insufficiency: 7-8 AM cortisol below 5 mg/dL.
c. When less than 16-18 mg/dL, may represent normal function or partial or complete adrenal insufficiency.
Testing for Primary Adrenal Insufficiency (AI)
1. Look at the 7-8 AM serum cortisol
i. if greater than 16-18 mg/dl, than no Adrenal Insufficiency
ii. If below 16 mg/dl--> need to test
2. If below 16 mg/dl; than get a Cosyntropin stimulation test (synthetic ACTH test)
i. give them 250 mg IV of this synthetic ACTH
ii. check to see if adrenal gland made any cortisol
3. If the adrenal gland made cortisol, than no adrenal insufficency
4. If no cortisol made---> THERE IS ADRENAL INSUFICIENCY
If baseline cortisol is low, perform an ACTH stimulation test
Cosyntropin is synthetic ACTH
Primary Adrenal Insufficiency
ACTH (Cosyntropin) Stimulation Test
Serum Cortisol ug/dl
1. See if patient is full insufficiency or partial adrenal insufficiency
2. Partial insufficiency will need cortisol during times of stress (disease, surgery, ect)
3. Full adrenal insufficiency need cortisol treatment all the time
Primary Adrenal Insufficiency and Secondary Adrenal Insufficiency
1. Serum Cortisol
< 5 ug/dl Baseline
< 20 ug/dl after Cosyntropin (250 ug)
2. Plasma ACTH
> 100 pg/ml
3. Adrenal CT Scan
Small glands: Autoimmune, Metabolic
Large gland: All Other Causes
1. Serum Cortisol
< 5 ug/dl Baseline
< 20 ug/dl after Cosyntropin (250 ug) (if chronic)
2. Plasma ACTH
Inappropriately low or normal
3. MRI pituitary
May show pathology
Treatment of Adrenal Insufficiency
i. Replace both glucocorticoids and mineralocorticoids
ii. Hydrocortisone 15-30 mg/day or prednisone 5-6 mg/day
iii. Fludrocortisone 0.05-0.1 mg/day
i. Replace glucocorticoids as above
ii. No mineralocorticoid replacement
iii. Fix underlying cause if possible
Juxtaglomerular Apparatus and Renin Regulation
a. Renin is released in response to:
↓ afferent arteriole volume (low renal perfusion)
↓ distal tubule sodium conc. (tubuloglomerular feedback)
b. Renin is decreased in response to:
↑afferent arteriole volume
(high renal perfusion pressure)
↑ distal tubule sodium conc. (tubuloglomerular feedback)
Renin Angiotensin Aldosterone System (RAAS)
a. Potassium and angiotensin II stimulate aldosterone synthetase in the zone glomerulosa
b. ACTH can also stimulate aldosterone synthetase (to a lesser extent)
c. Aldosterone regulates extracellular volume and potassium balance
i. Aldosterone binds mineralocorticoid receptor in the distal cortical collecting duct principal cells
ii. Moves to nucleus to stimulate transcription of genes to increase number of Na and K channels
iii. Results in increased Na reabsorption and promotes K and proton secretion
Factors that affect amount of Aldosterone
a. Increased circulating potassium levels induce production of aldosterone which promotes sodium ion reabsorption in exchange for potassium ions in the distal tubule and collecting duct of the nephron.
b. Increases sodium reabsorption leads to an increase in plasma volume and an increase in BP which in turn switches off renin production in the kidney and reduces the production of the vasoconstrictor angiotensin II.
c. Angiotensin II also induces the production of aldosterone via a direct effect on the adrenal glands.
Causes of Hyperaldosteronism
a. Primary aldosteronism (Conn’s)
b. Secondary aldosteronism
Cirrhosis, heart failure
c. Liddle’s Syndrome
i. mutation in epithelial sodium channel
d. Deoxycorticosterone mediated
i. Genetic recombination of genes
e. Licorice ingestion
Symptoms and Signs of Primary Aldosteronism
a. Clinical Signs:
1. Resistant hypertension
3. Mild hypernatremia
4. Metabolic alkalosis
5. Muscle weakness can occur
*b. Potassium may fall to severely low levels.
i. Potassium wasting is common in mineralocorticoid excess syndromes but is not absolute
ii. Patients may have hyperaldosteronism and normal serum potassium
Who should be screened for primary hyperaldosteronism?
a. Age under 30 with hypertension
i. Especially if no obesity or family history
b. Unexplained hypokalemia and hypertension
c. Resistant hypertension
i. more than 2 medications
d. Adrenal incidentaloma and hypertension
Testing for Hyperaldosteronism
a. Early morning aldosterone : renin ratio
i. Check aldosterone and plasma renin activity
ii. Ratio >20
-With aldo >15 ng/dL and normal potassium at time of testing
b. Stop interfering medications before testing
i. Especially mineralocorticoid receptor antagonists
c. If ratio elevated, further testing required
i. Need to demonstrate inappropriate aldosterone secretion after salt loading
-Given 2L normal saline over 4 hours and measure aldosterone
ii. Normal: aldosterone suppresses below 5 ng/dL
iii. Hyperaldo: aldosterone above 10 ng/dL
d. Once biochemical diagnosis certain, CT or MRI should be performed to look for adenoma or hyperplasia
e. Then adrenal vein sampling (AVS) should be done for lateralization
Adrenal Vein Sampling (AVS) for Lateralization
a. Even if adrenal adenoma
i. 10% of population has adrenal incidentalomas
b. Need experienced Interventional Radiologist
c. Catheters into right and left adrenal veins
d. Relies on finding a several fold difference in aldosterone secretion between two sides
e. If not different, could be idiopathic hyperaldosteronism (or bilateral adrenal hyperplasia)
f. If there is an adenoma on one side and patient is less than 35 years old, can consider skipping AVS
a. If unilateral aldosterone secreting adenoma, surgical resection often leads to cure
b. If bilateral adrenal hyperplasia is the cause, treat with a mineralocorticoid antagonist (spironolactone 25-100 mg daily or eplerenone)
c. If not a surgical candidate despite unilateral aldosterone secreting adenoma, can use medical therapy.
Cortisol Cortisone Shunt
a. Mineralocorticoid receptor has higher affinity for cortisol than aldosterone
b. Aldosterone sensitive tissues (like kidney) have 11-beta HSD2 to shunt cortisol to cortisone
a. Prevents inactivation of cortisol in kidney
b. MCR activated by cortisol
c. Leads to hypertension and hypokalemia (type of pseudohyperaldosteronism)
Glucocorticoid excess (Cushing’s syndrome)
a. ACTH dependent
i. Pituitary adenoma
ii. Ectopic ACTH production
b. ACTH independent
i. Adrenocortical adenoma
ii. Adrenocortical carcinoma
iii. Nodular adrenal hyperplasia
c. Iatrogenic or surreptitious
i. Exogenous glucocorticoid use (oral, nasal, inhalers, injections, creams)
d. Endogenous Cushing's syndrome is rare
e. Pharmacologic use of corticosteroids is common
-10 million Americans take steroids (glucocorticoids) every year
Signs/Symptoms of Cushing’s (hypercortisolism)
1. Hirsutism (abnormal hair growth)
2. Red and round face
4. Easy bruising
5. Weight gain
6. Central obesity; thin extremities
7. Purple, thick striae
8. Proximal muscle weakness – especially lower extremities
9. HTN, Hyperglymcemia from the high cortisol
Supraclavicular fat pads
Dorsocervical fat pad
Diabetes mellitus type 2
ACTH dependent hypercortisolemia
1. ACTH dependent hypercortisolemia
i. Diseases: Cushing’s Disease
Pituitary mediated hypercortisolemia
Tumor in the anterior pituitary
ii. Clinical findings:
1) High ACTH
2) High cortisol
3) Feedback mechanism does not work to turn off ACTH
2. ACTH independent hypercortisolemia
Adrenal mediated hypercortisolemia
Tumor adrenal cortex
Adrenal cortical adenoma
Adrenal cortical carcinoma
Bilateral adrenal hyperplasia
Both adrenal glands are over producing
ii. Clinical Findings:
1) High cortisol production
2) Low ACTH
3) Feedback mechanism still works
Diagnosis of Hypercortisolism
1) 24 hr urinary free cortisol
2) Midnight salivary cortisol
i. Diurnal rhythm: normally cortisol should be low at midnight
3. 1 mg dexamethasone suppression test
i. Patient takes 1mg of dex at 11pm-12am the night before a 7-8am blood draw for cortisol
i. Normal: cortisol suppresses to <1.8 ng/dL
d. Laboratory test for cortisol does not cross react with dexamethasone
Diagnosing Source of Hypercortisolism
a. Distinguish ACTH dependent from ACTH independent hypercortisolism
i. Baseline 7-8 AM cortisol and ACTH
ii. If ACTH low (independent), implies an adrenal source – do adrenal imaging
iii. If ACTH high (dependent), implies pituitary or ectopic source
b. Distinguish pituitary from ectopic source of ACTH
i. MRI pituitary
-About 55% of corticotroph adenomas are seen on MRI
-10% of population has pituitary incidentalomas
ii. 8 mg dex suppression test
-Pituitary source: cortisol suppresses to <5 ng/dL or more than 50% of baseline
*Still some sensitivity of pituitary corticotroph cells
-Not always reliable
iii. Inferior Petrosal Sinus Sampling (IPSS)
-new and great test
Inferior Petrosal Sinus Sampling (IPSS)
a. Must be done by experienced Interventional Radiologist
i. Used for diagnosing Cushing Disease (high cortisol)
b. Catheters from groin to pituitary region (petrosal sinuses)
c. Draw baseline ACTH and at intervals after stimulation with CRH (or desmopressin)
i. If pituitary source, ACTH should be higher in petrosal sinus than central IVC
ii. If ectopic source, ACTH will be similar in the sinus as the central IVC
a. Correct the underlying cause
b. Surgical adrenalectomy or transsphenoidal pituitary surgery or removal of ectopic source is first line
c. Medical treatment is second line
i. ACTH secretion inhibitors
ii. Cortisol synthesis inhibitors
Adrenolytic agents (mitotane)
iii. Cortisol receptor blocker
Synthetic Glucocorticoids – most common cause of hypercortisolism
a. Developed to exploit the anti-inflammatory and immunosuppressant effects of glucocorticoids
vasculitis (giant cell arteritis)
allergy (dermatologic, asthma)
inflammatory bowel disease
lymphoma (lympholytic effect)
cerebral edema and spinal cord injury
Side effects of chronic glucocorticoids
a. Iatrogenic Cushing’s Syndrome
b. Associated with use of any supraphysiologic dose, i.e. > 5 mg prednisone or equivalent
c. Remember to ask patients about any medications taken orally, injected, inhaled, nasally, topically in creams for asthma, arthritis, COPD, rash, inflammation, rheumatologic disorders, etc.
Adrenal Medulla Physiology
a. Medulla receives input from sympathetic nervous system through preganglionic fibers from thoracic spinal cord
b. Medulla is like a nerve ganglion but lacks synapses from postganglionic fibers and releases secretions directly into blood
Adrenal Medullary Catecholamines
a. Tyrosine enters chromaffin cells and is converted by tyrosine hydroxylase to dopa, which is the rate limited step in catecholamine synthesis
b. Cortisol also promotes epinephrine synthesis in medulla by upregulating PNMT enzyme which converts norepinephrine to epinephrine
c. Medulla secretes 20% norepinephrine and 80% epinephrine
Fight or Flight Response of Catecholamines
Mobilize‘fuels’ (high energy demand)
Redistribution of blood flow
Decreased urinary output and digestive functions
Increased heart rate and blood pressure
Increased activity of sweat glands (ACh mediated)
Dilation of pupils
Pheochromocytomas and Paragangliomas
a. Derived from chromaffin cells of embryonic neural crest origin
b. Tumors are often benign but cause problems for two reasons
i. Mass effect
ii. Over-secretion of catecholamines/metanephrines
iii. Leads to hypertension, heart disease, stroke and death
Pheochromocytomas and Paragangliomas
a. Head and neck paragangliomas (HNPGL)
b. Adrenal medulla tumors = pheochromocytomas (PCC)
c. Tumors at other sites = paragangliomas (PGL)
Clinical Presentation of Pheochromocytomas and Paragangliomas
a. Classic Triad
Pheo/Para Screening Tests
The two best tests for screening:
1. Plasma Met
2. Urine Met
(Pheochromocytomas and Paragangliomas dx)
a. Ideally drawn after 20 minute rest* and in fasting state
b. No acetaminophen for 5 days
c. Different normal ranges for hypertensive patients
d. Different ranges for sitting and standing
e. If borderline values can repeat supine after rest and/or order 24 hour urine metanephrines and catecholamines
Other Screening Tests for Pheochromocytomas and Paragangliomas
a. Plasma Catecholamines
i. less reliable
ii. often abnormal
iii. often only useful in established pheochromocytoma or known mutation carriers
b. Clonidine suppression test
i. Normally plasma met decrease more than 40% 3hrs after 0.3mg clonidine given
ii. Rarely done
Interfering medications for testing Pheochromocytomas and Paragangliomas
b. Selective serotonin reuptake inhibitors
c. Serotonin norepinephrine reuptake inhibitors
d. Marijuana and other illicit drugs
Next Step after Positive Screening for Pheochromocytomas and Paragangliomas
a. If biochemical tests are positive, patient need radiographic imaging to localize the tumor
b. Start with CT/MRI abdomen/pelvis (adrenal protocol)
i. The majority of tumors will be intra-adrenal or extra-adrenal in abdomen/pelvis
c. I-123 Metaiodobenzylguanidine (MIBG): localization for extra-adrenal, recurrent, and metastatic tumors
7.1 cm Right Adrenal Mass of Pheochromocytomas
a. CT Scan
Imaging characteristics of pheochromocytoma:
b. HU >10
Less than 50% washout on delayed contrast imaging
Treatment for Pheochromocytoma/Paraganglioma
b. Must do peri-operative blockade prior to surgery
c. α-blocker as 1st line therapy
Calcium channel blocker as 2nd line
Add β-blocker to control expected reflex tachycardia from α-blockade
Peri-operative Blockade Regimen
a. No major RCTs
i. No one accepted protocol
b. Endocrine Society guidelines recommend:
1) α-blocker as 1st line therapy
2) Calcium channel blocker as 2nd line
3) Add β-blocker to control expected reflex tachycardia from α-blockade
Alpha blockade for Pheochromocytoma/Paraganglioma
b. Non-selective and non-competitive antagonist
i. 10-20mg every 12-8 hours
c. Doxazosin; Prazosin; Terazosin
Selective α1 and competitive antagonist
a. Laparoscopic adrenalectomy
b. Adrenocortical sparing surgery
-For bilateral adrenal tumors
-For patients with genetic syndromes at risk for future contralateral adrenal tumor
-Risk of recurrence
During Surgery for Pheochromocytoma/Paraganglioma
Typical response is to see BP surges when tumor is manipulated and severe hypotension once tumor is removed
Intra-op may need IV phentolamine (alpha antagonist) to prevent BP surges
Post-op can require alpha agonist to support BP (phenylephrine/norepi) for first 48 hours
*Not a rule of 10 anymore
Multiple Endocrine Neoplasia Type 2 (MEN2)
Activating RET mutations on chromosome 10q11.2
1 in 40,000 individuals
Medullary thyroid carcinoma (MTC)
Pheochromocytomas (50% of patients)
Can be bilateral
Cutaneous lichen amyloidosis
MTC, pheo, multiple neuromas,
Clinical Genetic Testing
a. 30-40% of patients with Pheo/Para have a susceptibility gene mutation
b. All patients with Pheo/Para need referral for consideration of clinical genetic testing
c. Helps to guide screening and surveillance in patients and their family members
i. For additional primary Pheo/Para
ii. For recurrences
iii. For metastatic disease
iv. Other associated tumors
Follow up for Pheochromocytoma/Paraganglioma
a. Life-long follow up
b. For recurrence, metastatic disease and additional primary tumors
c. If genetic mutation, screen for other associated tumor types
a. Defined by the presence of distant metastases
i. WHO definition
b. Can have a long latency period - even up to 20 years
c. Occur more often from extra-adrenal PGL and tumors over 4-5cm
d. 5 year survival is ~50%
i. 2-5 years vs indolent course up to 20 years
a. Ranges 2-10% depending on the study
b. Increases with age
i. Closer to 10% in elderly
ii. Closer to 1% in those under 30 years old
Evaluation of Adrenal Incidentalomas
a. Two questions for every incidental nodule
b. Secreting or non-secreting?
c. Benign or malignant?
i. If malignant, is it a primary or metastasis?
ii. Does patient have a prior history of malignancy?
Hormonal evaluation for Adrenal Incidentalomas
a. All adrenal nodules should be ruled out for hormonal hypersecretion
b. Plasma metanephrines or 24hr urine mets/cats
i. Screen for pheochromocytoma
c. 1 mg overnight dex suppression test
i. Screen for hypercortisolism
d. If patient is hypertensive, screen for primary aldosteronism
i. ±aldosterone/plasma renin activity
Imaging – CT scan
a. Hounsfield scale (HU)
i. Semi-quantitative method of measuring x-ray attenuation
ii. Based on water = 0 HU
iii. Adipose tissue non-contrast = -20 to -150 HU
b. So, if an adrenal mass has HU < 10 on non-contrast CT
(ie, has density close to water and fat) ---> likely is a benign adrenal nodule with high intracellular lipid
Imaging – MRI Scan
a. MRI is as effective as CT scanning for distinguishing benign from malignant lesions
b. Benign lipid rich nodules have signal drop out on out of phase imaging
Imaging Characteristics of Benign Adrenal Masses
1. Less than 4cm
2. Homogeneous with smooth or regular borders
3. HU <10 on non-contrast CT scan
4. Rapid enhancement of contrast; rapid loss of contrast
a. Surgical removal
i. Size >4 cm
ii. Progressive growth especially if HU > 20
iii. Hormone hypersecretion
i. HU <10
ii. Size <4 cm
iv. Imaging every 6, 12 and 24 months
v. Hormone profile annually for 4 years
Diagnose Primary Adrenal Insufficiency
1. Serum Cortisol
< 5 ug/dl Baseline
< 20 ug/dl after Cosyntropin (250 ug)
2. Plasma ACTH
> 100 pg/ml
3. Adrenal CT Scan
Small glands: Autoimmune, Metabolic
Large gland: All Other Causes
Diagnose Secondary Adrenal Insufficiency
1. Serum Cortisol
< 5 ug/dl Baseline
< 20 ug/dl after Cosyntropin (250 ug) (if chronic)
2. Plasma ACTH
Inappropriately low or normal
3. MRI pituitary
May show pathology