1. Adrenal gland hyperfunction

2. Objectives Define Cushing’s syndrome.
At the end of this lecture, the student should be able to:
Define Cushing’s syndrome.
Recognize the etiology of Cushing’s syndrome.
Describe the clinical features and complication of Cushing’s disease
Outline the diagnosis and treatment options.
Classify hyperaldosteronism.
Describe clinical features of Conn’s syndrome
State diagnosis and treatment

3. CASE SCENARIO
A 28 y old unmarried female presented with weight gain, bruising easily, menstrual irregularity and striae. On examination she is hypertensive. Her blood tests reveal hypokalemia. What is the most likely diagnosis?

5. Cushing’s Syndrome
A multisystem disorder resulting from chronic exposure to inappropriately elevated concentrations of free circulating glucocorticoids.
Incidence of 1–2 per 100,000 population per year.

6. Causes of Cushing's Syndrome
ACTH- Dependent Cushing‘s
1- Cushing's disease
2- Ectopic ACTH syndrome (by bronchial or pancreatic carcinoid tumors, small cell lung cancer, medullary thyroid carcinoma, pheochromocytoma ) F/M(1:1)
ACTH- Independent Cushing‘s F/M (4:1)
Adrenocortical adenoma, Adrenocortical CA
Rare: primary pigmented nodular adrenal disease; ACTH-independent massive adrenal hyperplasia.  

7. Exogenous
ACTH treatment
Glucocorticoid treatment
Pseudo-Cushing's syndrome
chronic activation of (HPA), usually mild and
temporary.
Major depressive disorder
Alcoholism
Obesity, PCOS
Obstructive sleep apnea

9. Cushing’s Disease (ACTH- producing pituitary adenoma)
Most common cause of Cushing’s syndrome (in 90%)
F/M (4:1), more in male in prepuberty cases
3rd or 4th decade of life

10. Clinical features Truncal obesity Moon face
Fat deposits (supraclavicular fossa and buffalo hump)
HTN
Hirsutism
Amenorrhea and impotence
Depression
Thin skin
Easy bruising
Hypercoagulation
Purplish wide abdominal striae
Proximal muscle weakness
Osteoporosis
Diabetes Mellitus
Avascular necrosis
Wound healing impaired
Pysch symptoms
Hyperpigmentation
Hypokalemic alkalosis

13. Ectopic ACTH All the previous symptoms but….. Ectopic dominated by :
Hypokalemic alkalosis (dominant feature)
Fluid retention
HTN
Glucose intolerance
Steroid psychosis
Absence of other features may be explained by more sudden onset by acquired ACTH from tumor.

14. Complications of Cushing's if Untreated
Diabetes
HTN
Osteoporotic fractures and avascular necrosis
Infections
Psychosis

15. Screening Test
Overnight dexamethasone suppression test (1 mg at 11 pm, cortisol measured at 8-9 am) plasma cortisol> 50 nmol/L Or
24 hour urine free cortisol
increased > 50 microgram/ day
Midnight plasma or salivary cortisol
> 130 nmol/L

16. False Positives False negatives Severe depression Severe stress
Estrogen (pregnancy or oral CP)
Morbid obesity
False negatives
Phenytoin/phenobarbital/rifampin (accelerated metabolism of dexamethasone)

17. Confirmatory Test Low dose dexamethasone suppression test
Dexamethasone 0.5 mg q 6 x 48 hours
plasma cortisol > 50 nmol/L Or
Measure urine cortisol during the last 24 hours (urine free cortisol >40 micrograms/d)

18. Differential diagnosis 1
ACTH levels may distinguish:
ACTH independent (adrenal or exogenous glucocorticoids)
from
ACTH dependent (pituitary, ectopic ACTH)
ACTH independent- low ACTH to<5 pg/ml
ACTH dependent-ACTH normal or high>15pg/ml
In addition ectopic ACTH levels are usually 8x higher than pituitary caused ACTH secreting adenomas

19. ACTH independent
CT adrenals:
Bilateral micronodular or macronodular hyperplasia or unilateral adrenal mass
( adrenal tumor workup)

21. ACTH- dependent Differential diagnosis 2
MRI pituitary
CRH test (ACTH increase>40% at min & cortisol > 20% at min after CRH 100 µg IV)
High dose DEX test (cortisol suppression > 50 % after q6h 2 mg DEX for 2 days)

22. Positive (Cushing’s disease)
Negative test (Ectopic ACTH)
Equivocal
(Inferior petrosal sinus sampling)
petrosal/ peripheral ACTH ratio > 2 at baseline, > 3 at 2-5 min after CRH 100 µg i.v

23. Inferior petrosal sinus sampling Positive (Cushing’s disease) Negative ( locate and remove ectopic ACTH source)

25. Treatment Transsphenoidal surgery Pituitary radio-therapy
Bilateral or unilateral adrenalectomy
Medical therapy

26. Treatment
Cushing’s Disease: Transphenoidal resection of pituitary adenoma
Adrenal neoplasms: resection
Ectopic ACTH: resection if possible
Bilateral adrenal hyperplasia: may need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement)

27. ‘Medical’ Adrenalectomy
Medications that inhibit steroidogenesis
Ketoconazole (600 to 1200 mg/day) inhibits cortisol synthesis by a direct action on the P450 cytochrome enzyme
Metyrapone, blocks the 11-ß hydroxylase enzyme (exacerbates female virilization)
(2-3 g/day)
Mitotane(2-3 g/day)- has a cytotoxic effect on both normal and malignant tissue.
Aminoglutethinide (1g/day)
Ocreotide, major side effect is adrenal insufficiency, therefore start at lowest dose and titrate

28. Mineralocorticoid Excess

31. Primary Hyperaldosteronism
(high aldosterone and low renin)
Adrenal (Conn's) adenoma
Bilateral (micronodular) adrenal hyperplasia

32. Secondary hyperaldosteronism (high aldosterone and renin)
Diuretics, HF, liver F, NS, RAS
Renin secreting renal tumor
Low aldosterone and renin
Congenital adrenal hyperplasia (high DOC)
Liquorice misuse
Liddle's syndrome

33. Conn's syndrome An aldosterone-producing adrenal adenoma
Represents 5- 12% of hypertension causes
Peak age years
Most patients are women

34. Clinical features Often asymptomatic
Proximal muscle weakness to flaccid paralysis (because of low potassium level)
Hypokalemic Hypertension
Leg edema due to sodium retention

35. Investigations Low K and high bicarbonate Upper normal Na
Screening test: Aldosterone renin ratio > 750pmol/L:ng/ml/h and aldosterone > 450 pmol/L
Confirmation of diagnosis: saline infusion( 2Lsaline over 4h IV), oral Na test, fludrocortisone suppression test

36. If still negative: Abdominal CT (unilateral adrenal mass, bilateral hyperplasia or normal adrenal morphology)
Adrenal vein catheterization to measure aldosterone
Iodo- noncholesterol scanning

37. Management A. Unilateral Adrenal Adenoma and age<40 y
Unilateral adrenalectomy preceded by medical treatment for few weeks
If >40y and still surgery is indicated we depend on result of vein sampling(if positive then surgery but if negative treat by drugs).
B. Bilateral Adrenal Hyperplasia
Spironolactone (Aldactone) up to 400mg/d and Amiloride (10- 40mg/d)

38. References Davidson’s Principles of Internal Medicine 20th Edition.
Harrison’s Principles of Internal Medicine 18th Edition.

39. 1- A cushinoid appearance would be an expected finding in all of the following conditions EXCEPT:
a- Chronic alcohol abuse.
b- Pituitary microadenoma.
c- ACTH- secreting bronchial carcinoma.
d- Adrenocortical adenoma.
2- The typical clinical features of Conn's syndrome include all of the following EXCEPT:
a- Hypertension
b- Muscle weakness
c- Hypokalemic alkalosis
d- High aldosterone and high renin