#Cushing syndrome #Addison Disease #Adrenal Insufficiency #Adrenal Excess #Hyperaldosteronism #Nelson Syndrome #Dr.Hamisi Mkindi #Samuel Kalluvya Adrenal insufficiency can be caused by diseases of the adrenal gland (primary), Interference with corticotropin (ACTH) secretion by the pituitary gland (secondary) Interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus (tertiary) 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 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) 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. 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) Cushing's syndrome may be either corticotropin (ACTH) dependent or independent. 80 percent of endogenous Cushing's syndrome cases are ACTH dependent, and approximately 20 percent are ACTH independent Primary (adrenal disorders, renin-independent increase in aldosterone) Adrenal hyperplasia (60–70%), adenoma (Conn’s syndrome, 30–40%), glucocorticoid-remediable aldosteronism (GRA; ACTH-dep. rearranged promoter) Secondary (extra-adrenal disorders, ↑ aldosterone is renin-dependent) -Primary reninism:

1. THE ADRENAL GLAND
Topic Review December 14th, 2022
Presenter: Hamisi Mkindi, M.D,Resident,Internal Medicine
Supervisor:Prof.Samuel E. Kalluvya: Head of
Endocrinology,Diabetes and Infectious
diseases,Bugando Medical Center

2. THE ADRENAL GLAND
 Under and Over production of hormones
 Clinical Conditions and presentations
 Diagnostic criteria and managementt

4. AT THE ADRENAL
CORTEX…

9. ADRENAL
INSUFFICIENCY
 Adrenal insufficiency can be caused
by diseases of the adrenal gland
(primary),
 Interference with corticotropin (ACTH)
secretion by the pituitary gland
(secondary)
 Interference with
corticotropin-releasing hormone (CRH)
secretion by the hypothalamus (tertiary)

10. 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

11. 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)

12. 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)

13. 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

14. 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.

16. 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)

17. 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

18. 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

19. CUSHING SYNDROME

20. CUSHING SYNDROME
 Exogenous
 Endogenous
-ACTC dependent/ACTH
independent

21. HYPERCORTISOLISM-CUSHING
SYNDROME
 Cushing's syndrome may be either
corticotropin (ACTH) dependent or
independent.
 80 percent of endogenous Cushing's
syndrome cases are ACTH dependent,
and approximately 20 percent are
ACTH independent

22. CUSHING SYNDROME
CONT…
 Cushing’s syndrome = cortisol excess.
 Cushing’s disease = Cushing’s
syndrome 2° to pituitary ACTH
hypersecretion.

23. 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

24.  Routine Labs:
-Elevated WBC>11,000/mm3
-Hypokalemia/Metabolic alkalosis due
to increased K excretion/Na
retention/Water flux

25. 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

27. 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

29. 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)

30. HYPERALDOSTERONISM
 Characterized by excessive secretion of
aldosterone which causes increases in
sodium reabsorption and loss of K ion
and hydrogen ions.
 Primary
 Secondary

31. HYPERALDOSTERENOSI
MS
 Primary (adrenal disorders, renin-independent increase in aldosterone)
Adrenal hyperplasia (60–70%), adenoma (Conn’s syndrome, 30–40%),
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), Gitelman’s (defective renal Na/Cl transporter)
 Nonaldosterone mineralocorticoid excess mimics hyperaldosteronism
11β-HSD defic. (→ lack of inactivation of cortisol, which binds to
mineralocorticoid recept.)
Exogenous mineralocorticoids
Liddle’s syndrome (constitutively activated/overexpressed distal
tubular renal Na channel)

32. Clinical Manifestations
 Mild-to-moderate HTN (11% of Pts w/ HTN
refractory to 3 drugs.
 Headache, muscle weakness, polyuria,
polydipsia; no peripheral edema
 Classically hypokalemia (but often normal),
metabolic alkalosis, mild hypernatremia

33. 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°) (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)

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

36. PHAEOCHROMOCYTOMA

37. 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
 Up to 40% of pheos/paragangliomas thought to have underlying genetic
etiology; genetic testing frequently recommended

38. 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
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

39. TREATMENT
 Surgical Resection
 Pre operative alpha adrenergic blockade,then beta
adrenergic block.
 Alpha adrenergic blockade
10-14 days before surery
Phenoxybenzamine
Daily BP monitoring
High Na diet(>5g/day)-2nd/3rd day ofalpha blockade
Long term alpha adrenerg block.Eg…Zosin
IV Phentolamne-Perioperative
Beta Blockade
Propanolol(1st day),switch to long acting
Catecholamine synsthesis inhibitors ex.Metyrosine

41. THE END
“In learning you will teach and in
teaching you will learn”-Phill Collins