This document discusses adrenal insufficiency and its causes, signs and symptoms, diagnostic evaluation, and treatment. It covers primary, secondary, and tertiary adrenal insufficiency. Diagnostic tests include morning cortisol levels and cosyntropin stimulation testing. Treatment involves glucocorticoid and mineralocorticoid replacement. Complications like adrenal crisis are also addressed.

2. ADRENAL INSUFFICIENCY
• Picha ya HPA na Reserve ya drenal gland

3. ADRENAL INSUFFICIENCY..
Etiology:
Primary = adrenocortical disease = Addison’s disease
1.Autoimmune: isolated or in assoc w/ APS
2.Infection: TB, CMV, histoplasmosis, paracoccidioidomycosis,syphillis
3.Vascular: hemorrhage (usually in setting of sepsis Eg:Warerhouse-
Friderichson), adrenal vein thrombosis, HIT, trauma
4.Metastatic disease: (90% of adrenals must be destroyed to cause
insufficiency)
5.Deposition diseases: hemochromatosis, amyloidosis, sarcoidosis
6.Drugs: azole antifungals, etomidate (even after single dose),
rifampin, anticonvulsants
Nelson syndrome

4. ADRENAL INSUFFICIENCY..
Secondary = pituitary failure of ACTH secretion
• But aldosterone intact b/c RAA axis
• Any cause of primary or secondary hypopituitarism
-Hypophysitis
• Glucocorticoid therapy (can occur after ≤2 wk of
“suppressive doses”; dose effect variable; even <10 mg of
prednisone daily chronically can be suppressive
• Megestrol (a progestin with some glucocorticoid activity)

5. ADRENAL INSUFFICIENCY
Tertiary causes:
• Refers to causes that relate to hypothalamic
abnormalities that reduce corticotropin-releasing
hormone (CRH) secretion.
– Abrupt cessation of high-dose glucocorticoid
therapy
– Correction (cure) of hypercortisolism (Cushing's
syndrome)

6. ADRENAL INSUFFICIENCY-Symptoms
• 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
↑ ACTH): marked orthostatic hypotension (because
volume depleted), salt craving, hyperpigmentation
(seen in creases, mucous membranes, pressure areas,
nipples), hyperkalemia
• Secondary only: ± other manifestations of
hypopituitarism

7. ADRENAL INSUFFICIENCY-Diagnostic studies
• Early a.m. serum cortisol: <3 µg/dL virtually diagnostic; ≥18 µg/dL generally
consistent with intact adrenal function
• Standard (250 µg) cosyntropin stimulation test (testing ability of ACTH → ↑
cortisol)
• Normal = 60-min (or 30-min) post-ACTH cortisol ≥18 µg/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
(very rarely, may be normal in acute pituitary injury b/c adrenals still able to
respond→ use early a.m. cortisol instead)
• All glucocorticoids (incl creams, inh. & drops) affect test. Must know exposure to
interpret.

9. ADRENAL INSUFFICIENCY-Diagnostic studies
cont..
• Other tests : renin, aldosterone, insulin-induced hypoglycemia
(measure serum cortisol response)
• Metyrapone (blocks cortisol synthesis and therefore stimulates
ACTH, measure plasma 11-deoxycortisol and urinary 17-
hydroxycorticosteroid levels)
• ACTH: ↑ in 1°, ↓ or low-normal in 2°
• Imaging studies to consider pituitary MRI to detect anatomical
abnormalities
• Adrenal CT: small, noncalcified adrenals in autoimmune, enlarged in
metastatic disease, hemorrhage, infection or deposition (although
they may be normal-appearing)

10. ADRENAL INSUFFICIENCY-Treatment
• Acute insufficiency: volume resusc. w/ normal saline +
hydrocortisone IV
• Chronic insufficiency:
(1) prednisone ~4–5 mg PO qam or hydrocortisone
15–25 mg PO qd (⅔ a.m., ⅓ early p.m.)
(2) fludrocortisone (not needed in 2° adrenal
insufficiency) 0.05–0.2 mg PO qam
(3) backup dexamethasone 4-mg IM prefilled
syringe given to Pt for emergency situations

11. ADRENAL CRISIS IN ADRENAL
INSUFFICIENCY
• Precipitants: bilateral adrenal hemorrhage or
infarction, pituitary infarction, pre-existing
adrenal insufficiency + serious infection or GI
illness
• Presentation: shock + anorexia, N/V, abd pain,
weakness, fatigue, confusion, coma, fever Lab
findings: hyponatremia, hyperkalemia (1°)
• Rx: hydrocortisone 50–100 mg IV q8 + IVF; do not
delay for dx tests

12. HYPERCORTISOLISM
• Cushing’s syndrome = cortisol excess.
• Cushing’s disease = Cushing’s syndrome 2° to
pituitary ACTH hypersecretion.

13. Etiologies
• Most commonly iatrogenic caused by exogenous glucocorticoids
• Cushing’s disease (60–70%): ACTH-secreting pituitary adenoma (usually microadenoma) or
hyperplasia
• Adrenal tumor (15–25%): adenoma or (rarely) carcinoma
• Ectopic ACTH (5–10%): SCLC, carcinoid, islet cell tumors, medullary thyroid cancer,pheo
Clinical manifestations
 Nonspecific: glucose intolerance or DM, HTN, obesity, oligo- or amenorrhea, osteoporosis
 More specific: central obesity w/ extremity wasting, dorsocervical fat pads, spont. Bruising
 Most specific: proximal myopathy, rounded facies, facial plethora, wide purple striae
– Other: depression, insomnia, psychosis, impaired cognition, hypokalemia, acne, hirsutism,
 hyperpigmentation (if ↑ ACTH), fungal skin infxns, nephrolithiasis, polyuria

15. Treatment
• Surgical: resection of pituitary adenoma, adrenal
tumor or ectopic ACTH-secreting tumor,
-Or bilat surgical adrenalectomy if unable to
control source of ACTH
• Medical: cabergoline, pasireotide, mitotane,
ketoconazole, or metyrapone to ↓ cortisol,
and/or mifepristone to block cortisol action at
glucocorticoid receptor; frequently used
as bridge to surgery or when surgery
contraindicated

16. Treatment-Cont…
• Radiation: can do pituitary XRT, but not
effective immediately (takes 6 mo to 2 y)
• Glucocorticoid replacement therapy × 6–36
mo after TSS (lifelong glucocorticoid +
Mineralocorticoid replacement if medical
or surgical adrenalectomy)

17. HYPERALDOSTERENOSIMS
• Primary (adrenal disorders, renin-independent increase in aldosterone; JCEM 2015;100:1)
• adrenal hyperplasia (60–70%), adenoma (Conn’s syndrome, 30–40%), carcinoma
• glucocorticoid-remediable aldosteronism (GRA; ACTH-dep. rearranged promoter)
• Secondary (extra-adrenal disorders, ↑ aldosterone is renin-dependent)
• Primary reninism: renin-secreting tumor (rare)
• Secondary reninism: renovascular disease: RAS, malignant hypertension; edematous
• states w/ ↓ effective arterial volume: CHF, cirrhosis, nephrotic syndrome;
• hypovolemia, diuretics, T2D, Bartter’s (defective Na/K/2Cl transporter ≈ receiving
• loop diuretic), Gitelman’s (defective renal Na/Cl transporter ≈ receiving thiazide
• diuretic)
• Nonaldosterone mineralocorticoid excess mimics hyperaldosteronism
• 11β-HSD defic. (→ lack of inactivation of cortisol, which binds to mineralocorticoid
• recept.)
• Black licorice (glycyrrhizic acid inhibits 11β-HSD), extreme hypercortisolism
• (overwhelming 11β-HSD), exogenous mineralocorticoids
• Liddle’s syndrome (constitutively activated/overexpressed distal tubular renal Na
• channel)

18. Clinical Manifestations
• Mild-to-moderate HTN (11% of Pts w/ HTN
refractory to 3 drugs; Lancet
• 2008;371:1921) headache, muscle weakness,
polyuria, polydipsia; no peripheral edema
• because of “escape” from Na retention;
malignant HTN is rare
• Classically hypokalemia (but often normal),
metabolic alkalosis, mild hypernatremia

19. HYPERALDOSTERENISM-Diagnosis
• 5–10% of Pts w/ HTN; ∴ screen if HTN + hypoK, adrenal mass, refractory/early
onset
• HTN
• Screening: aldo (>15–20 ng/dL) and plasma aldo:renin ratio (>20 if 1°) obtain 8
a.m.
• paired values (off spironolactone & eplerenone for 6 wk); Se & Sp >85%
• ACEI/ARB, diuretics, CCB can ↑ renin activity → ↓ PAC/PRA ratio and βBs may ↑
• PAC/PRA ratio;∴ avoid. α-blockers generally best to control HTN during dx testing.
• Confirm with sodium suppression test (fail to suppress aldo after sodium load) oral
salt
• load (+ KCl) × 3 d, ✔ 24-h urine (⊕ if urinary aldo >12 μg/d while urinary Na >200
• mEq/d) or 2L NS over 4 h, measure plasma aldo at end of infusion (⊕ if aldo >5
ng/dL)

21. HYPERALDOSTERONISM-Treatment
• Adenoma → adrenalectomy vs. medical Rx w/
spironolactone or eplerenone
• Hyperplasia → spironolactone or eplerenone;
GRA → glucocorticoids ± spironolactone
• Carcinoma → adrenalectomy

22. PHAEOCHROMOCYTOMA
• Neuroendocrine neoplasm leads to inappropriate and paroxysmal release of
adrenergic
• agents including epinephrine, norephinephrine, and rarely dopamine
• Pressure (hypertension, paroxysmal in 50%, severe & resistant to Rx, occ
orthostatic)
• Pain (headache, chest pain)
• Palpitations (tachycardia, tremor, wt loss, fever)
• Perspiration (profuse)
• Pallor (vasoconstrictive spell)
• Paroxysms can be triggered by meds (eg, β-blockers) abdominal manipulation
• Associated with MEN2A/2B, von Hippel Lindau, NF1, familial paraganglioma
(mutations
• in succinate dehydrogenase gene B, C and D) or TMEM127 mutations
• Up to 40% of pheos/paragangliomas thought to have underlying genetic etiology;
genetic
• testing frequently recommended

23. Phaeochromocytoma-Dx Studies
• 24° urinary fractionated metanephrines: 85–97% Se, 69–95% Sp. Screening test of
choice
• if low-risk (b/c false ⊕ with severe illness, renal failure, OSA, labetalol due to assay
• interference, acetaminophen, TCAs, medications containing sympathomimetics).
• Plasma-free metanephrines: 89–100% Se, 79–97% Sp (JAMA 2002;287:1427).
Screening test of
• choice if high risk, but ↑ rate of false ⊕ in low-prevalence population. False ⊕
rate lower
• if patient supine for 30 min (estimated 2.8× ↑ false ⊕ if seated).
• Adrenal CT generally better than MRI; PET for known metastatic disease or to
localize
• nonadrenal mass but usually easy to find; consider MIBG scintigraphy if CT/MRI ⊖
• Consider genetic testing if bilateral disease, young Pt, ⊕ FHx, extra-adrenal

24. Phaeochromocytoma-Treatment
• α-blockade first (usually phenoxybenzamine) ±
β-blockade (often propranolol) → surgery
• Preoperative volume expansion is critical due
to possible hypotension after tumor excision

25. ADRENAL INCIDENTALOMAS
• 4% of Pts undergoing abdominal CT scan have
incidentally discovered adrenal mass;
• prevalence ↑ with age
Differential diagnosis
• Nonfunctioning mass: adenoma, cysts, abscesses,
granuloma, hemorrhage, lipoma,
• myelolipoma, primary or metastatic malignancy
• Functioning mass: pheochromocytoma, adenoma
(cortisol, aldosterone, sex hormones),
• nonclassical CAH, other endocrine tumor, carcinoma

26. Hormonal Work Up
• 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 ALL Pts (b/c of
morbidity unRx’d pheo) using 24-h urine
• fractionated metanephrines or plasma-free
metanephrines

27. Malignancy Work Up
• CT and MRI characteristics may suggest adenoma vs. carcinoma
• Benign features: unenhanced CT <10 Hounsfield units or CT contrast-
medium washout
• >50% at 10 min; size <4 cm; smooth margins, homogenous and hypodense
• appearance; can follow such incidentalomas w/ periodic scans
• Suspicious features: size >6 cm or ↑ size on repeat scan; irregular margins,
• heterogeneous, dense or vascular appearance; h/o malignancy or young
age. Such
• incidentalomas warrant resection or repeat scan at short interval.
• Rule out metastatic cancer (and infection) in Pts w/ h/o cancer; ~50% of
adrenal
• incidentalomas are malignant

28. Follow-up
• If hormonal workup ⊖ and appearance
benign, yearly fxnal testing for 4 y w/ follow-
up
• imaging at 6, 12, & 24 mo reasonable
approach, but controversial

29. “In learning you will teach and in teaching
you will learn”-Phill Collins