Adrenal Disorders Flashcards
(98 cards)
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.
- The middle layer, zona fasciculata, is responsible for cortisol production.
- 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
1. Cortisol
i. Excess–>Cushing’s syndrome
ii. Deficiency–> Addison’s disease & Secondary hypocortisolism
- Aldosterone
i. Excess–>Primary aldosteronism
ii. Deficiency–>Addison’s disease - Androgens
i. Excess–>Hirsutism, virilization
ii. Deficiency–>????
b. Medulla
1. Epinephrine
i. Excess—>Pheochromocytoma
2. Norepinephrine
Cortisol/Adrenal Insufficiency
Summary Intro
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 Infiltrative: Amyloid Hemorrhage Metastatic Metabolic: Adrenoleukodystropy, Adrenomyeloneuropathy Surgery
b. Secondary Adrenal Insufficiency
i. Following supraphysiological exogenous glucocorticoids for more than 3 weeks
ii. Opioids
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.
Aldosterone Physiology
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:
- Aldosterone-producing adenoma (APA) (34%)
- Idiopathic hyperaldosteronism (IHA); a.k.a. Bilateral Adrenal Hyperplasia (66%)
- Glucocorticoid-remediable hyperaldosteronism (GRA) (rare)
- 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.
Pheochromocytomas
Summary Introductions
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
Pheochromocytomas
Pathophysiology summary
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.
MEN 2A:
-Pheochromocytoma (adrenal medulla)
-Medullary thyroid carcinoma (calcitonin-secreting C cells)
-Hyperparathyroidism (parathyroid)
MEN 2B
-Pheochromocytoma
-Medullary thyroid carcinoma
-Mucosal neuromas
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.
Pheochromocytoma
Clinical Manifestations
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.
Pheochromocytoma Diagnosis
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% extra-adrenal
10% bilateral
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.
