• Primary (adrenal disorders, f aldosterone is renin independent)

adrenal hyperplasia (70%). adenoma (Conn's syndrome, 25%). carcinoma (5%) glucocorticoid-remediable aldosteronism (GRA; ACTH-dep. promoter rearrangement)

• Secondary (extra-adrenal disorders. T aldosterone is renin dependent)

Primary reninism: renin-secreting tumor Secondary reninism renovascular disease: RAS. malignant hypertension edematous states w 1 effective arterial volume: CHF. cirrhosis, nephrotic syndrome hypovolemia, diuretics. Bartter's (defective Na K 2CI transporter receiving loop diuretic). Gitelman's (defective renal Na CI transporter - receiving thiazide diuretic)

• Nonaldosterone mineralocorticoid excess mimics hyperaldosteronism

Cushing's syndrome. CAH (some enzyme defects -• shunting to mineralocorticoids) 11 fi-OHSD deficiency (buildup of Cortisol, which binds to mineralocorticoid receptor) Licorice (glycyrrhizinic acid inhibits 11(5-OHSD). exogenous mineralocorticoids Liddle's syndrome (constitutively activated overexpressed distal tubular renal Na channel) Clinical manifestations

• Mild to moderate diastolic HTN. headache, muscle weakness, polyuria, polydipsia; I no peripheral edema because of "escape" from Na retention; malignant HTN is rare

• Classically hypokalemia (but often normal), metabolic alkalosis, mild hypernatremia

Diagnostic studies

• 5-10% of Pts w HTN; . screen if HTN • hypokalemia, adrenal mass, or refractory HTN

• Aldosterone (>15-20 ng dl) and plasma aldosterone:renin ratio (>20 if 1°)

obtain 8 a.m. paired values (off spironolactone & eplerenone for 6 wks); Se & Sp >85%

• ACEI ARB. diuretics. CCB can T renin activity •; PAC PRA ratio and (i-blockers may T

PAC PRA ratio; . avoid, «-blockers generally best to control HTN during dx testing. I • Confirm with sodium suppression test (fail to suppress aldo after sodium load) oral salt load (• KCI) * 3 d./ 24-h urine (- if aldo >12 p.g d while Na -200 mEq d) or 2L NS over A h. measure aldo at end of infusion (> if aldo -5 ng dl)

Figure 7-4 Approach to tinpcctcd hjrperaWo«eron«im

Suspect Hyperaldosteronism 1

Plasma renin & aldosterone a.m. collection

Non-aldosterone mineralocorticoid excess

Cushing's syndrome CAH (some torms) 11P-OHSD deliciency Licorice (chronic ingestion) Liddle's syndrome Exogenous mineratocorticoids salt suppression test

If Hyperaldosteronism

* aldosterone aldo:renin -J 10


Renovascular disease CHF. cirrhosis, nephrotic -i Hypovolemia & diuretic use

Bartter's syndrome Gitelman's syndrome Renin-secreting tumor

Adrenal CT or MRI / \ lesion no lesion

* * no Adenoma localize adrenal vein localization Hyperplasia Carcinoma - sampling -► or GRA

(Adapted Trendi in Endocrine Mftobofevn 1999:5:97)


• Hyperplasia — spironolactone or eplerenone; GRA - glucocorticoids - spironolactone

Adrenal Insufficiency


• Primary adrenocortical disease Addison's disease autoimmune: isolated or in assoc w PGA syndromes (see table on page 7-2) infection: tuberculosis. CMV. histoplasmosis vascular hemorrhage (usually in setting of sepsis), thrombosis, and trauma metastatic disease: (90% of adrenals must be destroyed to cause insufficiency) deposition diseases: hemochromatosis, amyloidosis, sarcoidosis drugs: ketoconazole. etomidate («iven after single dose), rifampin, anticonvulsants

• Secondary pituitary failure of ACTH secretion (but aldosterone intact b c RAA axis)

any cause of primary or secondary hypopituitarism (see "Pituitary Disorders") glucocorticoid therapy (occurs after ^2 wks of "suppressive doses." which are extremely variable: even 7.5 mg d of prednisone can be suppressive) megestrol (a progestin with some glucocorticoid activity)

Clinical manifestations (N£/m 1996:335:1206)

• Primary or secondary: weakness and fatigability (99%). anorexia (99%).

orthostatic hypotension (90%). nausea (86%). vomiting (75%). hyponatremia (88%)

• Primary only (extra s s due to lack of aldosterone and T ACTH): marked orthostatic hypotension (because volume-depleted), hyperpigmentation (seen in creases, mucous membranes, pressure areas, nipples), hyperkalemia

• Secondary only: other manifestations of hypopituitarism (see "Pituitary Disorders") Diagnostic studies

• Early a.m. serum Cortisol: <3 p.g dl virtually diagnostic. >18 pig dl rules it out (except in I

critical illness—see below)

• T dose (250 pg) cosyntropin stimulation test (testing ability of ACTH T Cortisol)

normal 60-min post-ACTH Cortisol ^18 pg dl abnormal in primary b c adrenal gland diseased and unable to give adequate output abnormal in chronic secondary b c adrenals atrophied and unable to respond may be normal in acute secondary b c adrenals still able to respond

• I dose (1 pg) cort stim: ? more sensitive than high-dose test (controversial)

• Other tests to evaluate HPA axis (w guidance by endocrinologist): insulin-induced hypoglycemia (measure serum Cortisol response): metyrapone (blocks Cortisol synthesis and therefore stimulates ACTH. measure plasma 11 -deoxycortisol and urinary 17-hydroxycorticosteroid levels)

• Other lab abnormalities: hypoglycemia, eosinophilia. lymphocytosis. * neutropenia

• Imaging studies to consider pituitary MRI to detect pituitary abnormalities adrenal CT: small, noncalcified adrenals in autoimmune, enlarged in metastatic disease, hemorrhage, infection, or deposition (although they may be normal-appearing)

Adrenal insufficiency and critical illness (nejm 2003:348 727)

• Controversial: no consensus exists on diagnosing relative adrenal insufficiency

• Serum free Cortisol may be more useful in critically ill Pt (ne;m 2004:350:1629)

• Perform ACTH stim as soon as possible in critically ill Pt suspected to have adrenal insuffic.

-» insufficiency if baseline Cortisol < 15 pg dl or if A ^9 pg dl poor prognosis also associated with elevated baseline Cortisol -34 p.g dl

• Initiate corticosteroids early if adrenal insufficiency suspected:

hydrocortisone 50-100 mg IV q6-8h use dexamethasone 2-4 mg IV q6h ♦• fludrocortisone 50 jig daily prior to ACTH stim. but change to hydrocortisone once test performed Treatment

• Acute adrenal insufficiency

Hydrocortisone IV as above + volume resuscitation with normal saline

• Chronic adrenal insufficiency

Hydrocortisone: 20-30 mg PO qd (2 3 in am. 1 3 in pm) or prednisone 5 mg PO qd Fludrocortisone (not needed in 2° adrenal insufficiency): 0.05-0.1 mg PO qam back-up dexamethasone 4 mg IM prefilled syringe given to Pt for emergency situations


Clinical manifestations (five Ps)

• Pressure (hypertension, paroxysmal in 50%. severe and resistant to therapy)

• Palpitations (tachycardia, tremor, wt loss, fever)

• Perspiration (profuse)

• Pallor (vasoconstrictive spell)

• "Rule of 10": 10% extra-adrenal (known as paraganglioma). 10% in children,

10% multiple or bilateral. 10% recur (t in paraganglioma). 10% malignant (T in paraganglioma). 10% familial. 10% incidentaloma

• Emotional stress does not trigger paroxysms, but abdominal manipulation can trigger catecholamine release: some reports of IV contrast causing paroxysms

• Associated with MEN 2A 2B.Von Hippel Lindau. neurofibromatosis type 1. familial paraganglioma (mutations in succinate dehydrogenase gene B and D)

Diagnostic studies

• 24° urinary fractionated metanephrines and catecholamines: 90% Se. 98% Sp screening test of choice if low-risk (as false © with severe illness, renal failure. OSA. labetalol due to assay interference.TCAs. medications containing sympathomimetics)

• Plasma free metanephrines: 99% Se. 89% Sp u*ma 2002J87 1427)

screening test of choice if high-risk, but f rate of false © in low-preval. population

• Adrenal CT or MRI; consider MIBG scintigraphy if CT MRI 0. PET can be used to localize nonadrenal mass, but usually easy to find


• «-blockade first (usually phenoxybenzamine) • (i-blockade (often propranolol) -»surgery

Adrenal Incidentalomas


• 4% of Pts undergoing abdominal CT scan have incidentally discovered adrenal mass; 1 prevalence T with age

Differential diagnosis

• Nonfunctioning mass: adenoma, cysts, abscesses, granuloma, hemorrhage, lipoma. | myelolipoma, primary or metastatic malignancy

I • Functioning mass: pheochromocytoma.adenoma (Cortisol.aldosterone, sex hormones), nondassical CAH. other endocrine tumor, carcinoma

• Nonadrenal mass: renal, pancreatic, gastric, artifact

Workup (NEJM 2007;356:601)

• Rule out subclinical Cushing's syndrome in all Pts using 1 mg overnight DST (Sp

91%). Abnormal results require confirmatory testing.

• Rule out hyperaldosteronism if hypertensive w plasma aldo & renin (see above).

• Rule out pheochromocytoma in oil Pts (b c of morbidity un Rx'd pheo) using 24-h urine fractionated metanephrines and catecholamines or plasma free metanephrines.

• Rule out metastatic cancer and infection by history or CT-guided biopsy if suspicious

• CT and MRI characteristics may suggest adenoma vs. carcinoma

Benign features: size • 4 cm; smooth margins, homogenous and hypodense appearance; unenhanced CT <10 Hounsfield units or CT contrast-medium washout >50% at 10 min. Can follow such incidentalomas w periodic scans. Suspicious features: size -4 cm or t size on repeat scan; irregular margins, heterogeneous, dense, or vascular appearance: unenhanced CT 10 Hounsfield units or CT contrast-medium washout < 50% at 10 min; h o malignancy or young age (incidentaloma less common). Such incidentalomas warrant FNA biopsy, repeat scan in 3 mos, or resection.

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