ADRENAL DISORDERS

Umar Zein

FK UNPRISU
Medan
Cross section through the adrenal
gland– cortex and medulla

salt

sugar

sex
 Hypothalamus-Pituitary-Adrenal axis
Circadian regulation
Stress:
Physical stress
+ Emotional stress
Hypoglycemia
- Cold exposure
- Pain
CRH Cortisol
Adrenal cortex
+ -

ACTH +
Anterior lobe
of pituitary gland

CRH=corticothropin releasing hormone; ACTH=adrenocorticothropin hormone. Kirk LF. Am Fam Physician 2000
Regulation of aldosterone secretion
Components
of renin-
angiotensin-
aldosterone
system
Action of aldosterone on the renal tubule.
Production of
catecholamines

COMT = Catecholamine Ortho Methyl Transferase)

Adrenocortical disorders
 Cushing’s Syndrome
• Supraphysiologic glucocoticoid exposure
(excess cortisol)
– Protein catabolic state
– Liberation of amino acids by muscle
– AA are transformed into glucose and glycogen and
then transformed into fat
• The source of excess glucocorticoids may be
exogenous or endogenous
 Cushing’s Syndrome
Symptoms and Sign Percent of Patients
• Weight gain, round facies and 97
truncal obesity
• Weakness 87
• Hypertension 82
• Hirsutism (in women) 80
• Amenorrhea 77
• Cutaneous striae 67
• Ecchymoses 65
• Osteoporosis Common
• Hyperglycemia Common
 Causes of Cushing’s Syndrome
• ACTH Dependent (80%)
– Cushing’s Disease (85%)
• Primary excretion of ACTH from pituitary
– 95% have identifiable pituitary adenoma
– Basophilic or chromophobe
• Bilateral adrenocortical hyperplasia
• 70% of endogenous cases
• F>M (3:1)
– Ectopic source (15%)
• Produce ACTH or CRH
• Small cell lung CA (most common), carcinoid tumors,
medullary thyroid, pancreas, ovarian,
pheochromocytoma, small-cell CA of prostate
 Causes of Cushing’s Syndrome
• ACTH Independent
– Exogenous steroid use (common)
• PO or topical
• Most common cause (overall)

– Adrenal adenomas (10%)

– Adrenal carcinoma (5%)
• Most common cause in children
 Cause of Cushing’s Syndrome
• Pseudo-Cushing’s disease
– Mimic clinical signs and symptoms
– Non-endocrine causes
• Alcoholism
• Major depression
• Morbid obesity
• Acute illness
 Diagnosis of Cushing’s Syndrome
• Clinical assessment
• Screening tests :
– Baseline glucocorticoids (a.m. and p.m. serum cortisol
levels, 24-hr urinary free cortisol excretion; 11 p.m.
Salivary cortisol)
– Low dose dexamethasone suppression test or combined
low-dose dexamethasone-oCRH
• Subtype diagnosis
– Plasma ACTH concentration
– Dynamic testing (oCRH stimulation test, metyrapon
stimulation test, high dose dexamethasone supression test)
– all with limited utility or prescision
– Directed computerized imaging (pituitary, adrenals, lungs,
etc)
– Pituitary venous sampling for ACTH with CRH stimualtion
 Diagnosis of Cushing’s Syndrome
• Screening tests
– 24 hour urinary cortisol (UFC)
• RIA : 80-108µg (221-298nmol)
• Baseline 24-hour UFC measurements may be high : Carbamazepin,
high urine volume, severe illness, CS, alcoholism, depression, sleep
apnea.
– Overnight 1-mg dexamethasone supression test (DST)
• A failure to supress serum cortisol with 1-mg DST is positive
screen and should lead to confirmatory evaluations.
• Causes for cortisol non-supression with the overnight 1-mg DST
incl : CS, patient error in taking, estrogen therapy, pregnancy, renal
failure, stress, drugs (anticonvulsants, rifampisin), obesity,
psychiatric disorder (depression, panic attacks)
 Diagnosis of Cushing’s Syndrome
• Confirmatory tests for CS
– When baseline 24-hour UFC is >300µg (828 nmol) and the clinical
and the clinical picture is consisten with CS : no additional
confirmatory studies are needed.
– 2-day low dose DST
• 24-hour UFC < 300µg : should confirmed with the low dose DST
(dexamethasone 0.5 mg, orally every 6 hours for 48 hours); 24-hour
urinary cortisol excretion > 20 µg (55nmol) confirm diagnosis.
• The low dose DST works best for those patients that carry of low index of
suspicion for CS.
– Dexamethasone –oCRH test
• To correct false negative supression with DST (pituitary dependent CS)
– Late night plasma or salivary cortisol
• A midnight sleeping serum cortisol concentration > 1.8µg/dl (>50nmol/L)
is 100% sensitive in patients with Cushing’s syndrome.
 Clinical Suspicion of
Cushing’s Syndrome

24 hour UFC 1 mg DST

No supression
Confirm with 24 hr UFC
Normal
supression
Elevated Intermediate
(>300µg/d) (90-300µg/d) Normal
(<90µg/d) Cushing’s Syndrome
Repeat, if normal
unlikely

Diurnal variation
And/or Dex-CRH test

Cushing’ Syndrome Cushing’ syndrome doubful

PsudoCushing’s
Treat underlying illness
Follow clinical examination
Repeat evaluation
Continue Evaluation
 Differential Subtype Evaluation Tests
• Plasma ACTH concentration
– ACTH dependent (‘normal’ to high levels of ACTH or ACTH independent
(low/undetectable ACTH)
– IRMA assay : normal 10-60 pg/ml, plasma ACTH values are <5 pg/ml in
adrenal dependent disease, 10 to 200 pg/ml in pituitary-dependent disease, and
50 to >200 pg/ml in ectopic ACTH syndrome
• ACTH Dependent Disease
– Pituitary MRI
– Inferior petrosal venous sampling (IPSS) with CRH stimulation
• Measure petrosal venous sinus ACTH level and correlate to plasma levels
• The most important advanced in the past 2 decades for subtype evaluation of CS
• IPSS does not diagnose Cushing’s syndrome
– CRH stimulation test
– High dose DST
– Positron emission scanning: occult neuroendocrine and ather ACTH-secreting
tumors
No test is perfect for subtype evaluation of Cushing’s syndrome!
 Confirm CS

ACTH

Undetectable Normal to increased

Adrenal Pituitary MRI

Unilateral Bilateral Pituitary Tumor Normal-

mass masses Cushing’s Ds equivocal

IPSS with

Search ectopic
 Cushing’s Syndrome
• Treatment program :
– The resolution of hypercorticolism
– The parellel treatmet of the complications of CS (e.g. hypertension,
osteoporosis, diabetes mellitus, mucle rehabilitation)
– Management of glucocorticoid withdrawal and hypothalamic
pituitary-adrenal (HPA) axis recovery
• Treatment: Surgical
– Cushing’s disease
• Transphenoidal surgery (TSS)
– The treatment choice
– The longterm surgical cure rate for ACTH secreting microadenomas is
80-90%.
– Transient post-op diabetes insipidus, adrenal insufficiency, CSF
rhinorrhea, meningitis
• Tansphenoidal irradiation
– If TSS is not curative.
– High success rate in kids (80%)
– Low success in adults (20%)
 Cushing’s Syndrome
• Treatment: Surgical
– Cushing’s disease
• Bilateral adrenalectomy
– If failed pituitary surgery
– Life-long steroid replacement
– Adrenal lesions/carcinoma
• Removal of primary lesion
• Survival based on underlying disease
– Ectopic ACTH lesions
• Remove lesion
• Survival based on primary disease
• May need bilateral adrenalectomy to control symptoms if primary
tumor unresectable
 Cushing’s Syndrome
• Treatment: Medical
– Used as prep for surgery or poor operative candidate
• Metyrapone- inhibits conversion of deoxycortisol to cortisol
• Aminoglutethimide-inhibits desmolase
– Cholesterol to pregnenolone
– Blocks synthesis of all 3 corticosteroids
– Side effects: N/V, anorexia, lethargy
• Ketoconazole- an imidazole that blocks cholesterol synthesis
• Mitotane (O-P-DDD)-inhibits conversion to pregnenolone
– Inhibits final step in cortisol synthesis
– Destroys adrenocortical cells (spares glomerulosa cells)
 Addison Disease
• Background: Thomas Addison first described the
clinical presentation of primary adrenocortical
insufficiency (Addison disease) in 1855 in his classic
paper, On the Constitutional and Local Effects of
Disease of the Supra-Renal Capsules.
• Pathophysiology:
– Addison disease is adrenocortical insufficiency due to the
destruction or dysfunction of the entire adrenal cortex.
– It affects both glucocorticoid and mineralocorticoid
function.
– The onset of disease usually occurs when 90% or more of
both adrenal cortices are dysfunctional or destroyed.
 Cortisol 

• Abdominal pain Gluconeogenesis  Renal K Secretion  ACTH 

• Anorexia Glucose uptake  Renal Na secretion 
• Vomiting
• Diarhea Hyperpigmentation

Fluid intake  Hypoglycemia Hyperkalemia

Hyponatremia
dehydration

Hypotension
Hypovolemia

Renal perfusion  Decreased Body Weight

BUN  General Weakness
 Addison Disease
• Primary adrenal insufficiency
– Causes
• Infectious
– TB – most common cause in 3rd world countries
– HIV, histoplasmosis, blastomycosis, coccidiomycosis
• Autoimmune disorders – anti-adrenal antibodies (most
cause common)
• Medications – ketoconazole, aminoglutethamide,
etomidate
• Adrenal hemorrhage
• Lymphoma, bilateral adrenal metastasis, Kaposi’s sarcoma
• Infiltrative – amylodosis, sarcoidosis,
adrenoleukodystrophy
 Addison Disease
• Secondary adrenal insufficiency
– Pituitary failure – panhypopitutarism,
Sheehan’s syndrome (post-partum pituitary
injury)
• Tertiary adrenal insufficiency
– Adrenal suppression due to glucocorticoid use
• Chronic suppression
• Sudden cessation of replacement glucocorticoids
• Inadequate increase during stress, trauma, surgery
 Primary Adrenal Insufficiency
Symptoms and sign Percent of
Patients
Weakness and fatigue 99
Hyperpigmentation 98
Unexplained weight loss 97
Anorexia, nausea, and vomiting 90
Hypotension (BP < 110/70 mmHg) 88
Hyponatremia 88
Hyperkalemia 64
 Primary versus secondary adrenal
insufficiency
Manifestations Primary Secondary
Hyperpigmentation Yes No
Pallor No Yes
Low Na Yes No
High K Yes No
Hypotension Yes No
Cortisol level Low Low
ACTH level High Low
 Addison Disease
Response to cosyntropin test or rapid ACTH stimulation test

Cortisol Aldosteron Diagnosis Comments

Increased Increased Normal

Decreased Decreased Primary adrenal End organ failure (Addison’s
insufficiency disesase)
Decreased Increased Secondary adrenal Pituitary diseases, hypothalamic
insufficiency disease
Increased Decreased Isolated aldosterone Very rare
deficiency
 Addison Crisis
• Acute adrenal insufficiency
– Similar causes
• Adrenal hemorrhage
• Chronic steroid use and trauma/stress/surgery
– Hypotension, volume depletion, fever, nausea
and vomiting, tachycardia, weakness,
hypoglycemia
– Premed prior to interventions
 Addison Crisis
Treatment acut of adrenal crisis
• The five S’s management are salt, sugar, steroid, support,
and search for presipitating illness.
• General and supportive measure
– Correct volume depletion, dehydration, and hypoglycemia with IV
0.9% saline with 5% dextrose
– Evaluate and correct infection and other precipitating factors
• Glucocorticoid replacement
– Administer hydrocortisone 100 mg every 6 hours for 24 hours
– When the patient is stable, reduce the dosage to 50 mg every 6
hours
– Taper to maintenance theraphy by day 4 or 5 and add
mineralocorticoid theraphy as required
– Maintain or increase the dose to 200-400 mg/d if complications
persist or occur
 Addison Crisis
Maintenance therapy
• Glucocorticoid and mineralocorticoid
– Oral dose hydrocortisone : 10-20 mg in the morning
and 5-10 mg later in day.
– Fludrocortisone : 0,05-0,2 mg/d orally in the morning.
• Response to theraphy
– General clinical sign, good appetite and sense of well
being.
– Signs of Cushing’s syndrome indicate overtreatment
Disorders of adrenal medullary
function
 Pheochromocytoma
• Pheochromocytoma is a rare catecholamine-secreting
tumor derived from chromaffin cells.
• Tumors that arise outside the adrenal gland are termed
extra-adrenal pheochromocytomas or paragangliomas.
• Because of excessive catecholamine secretion,
pheochromocytomas may precipitate life-threatening
hypertension or cardiac arrhythmias
• It is associated with spectacular cardivascular disturbances
and, when corectly diagnosed and treated  curable.
When undiagnosed  fatal
• Prevalence estimates – 0.01% to 0.1% of the hypertensive
population
 Pathophysiology
• The clinical manifestations of a pheochromocytoma result
from excessive catecholamine secretion by the tumor.
• Catecholamines typically secreted, either intermittently or
continuously, include norepinephrine and epinephrine and
rarely dopamine.
• The biological effects of catecholamines are well known.
• Most pheochromocytomas contain norepinephrine
predominantly, in comparison with the normal adrenal
medulla, which is composed of roughly 85% epinephrine.
• Familial pheochromocytomas are an exception because
they secrete large amounts of epinephrine. Thus, the
clinical manifestations of a familial pheochromocytoma
differ from those of a sporadic pheochromocytoma.
Receptor catecholamine :
• Receptor  (NE)
• Receptor  (EPI)
 Pheochromocytoma
• Symptoms :
– Due to the pharmacologic effects excess circulating
catecholamines
– A typical paroxysm (the 5 P’s)
• Pressure – sudden major increase in blood pressure
• Pain – abrupt onset of throbbing headache ; chest and
abdominal pain
• Perspiration – profuse generalized diaphoresis
• Palpitation
• Pallor
• Clinical sign :
• Hypertension,orthostatic hypotension, grade II to III
retinopathy, tremor, weight loss, fever, painless hematuria,
hyperglycemia, erythrocytosis
 Pheochromocytoma
• Diagnosis :
– Demonstration of excessive amounts catecholamines in
plasma or urine or degradation product in urine
• Urinary metanephrine, normetanephrine, vanilmandelic acid (VMA),
and free catecholamine in 24-hour periode
• Direct measurement plasma NE and EPI. Levels > 2000 pg/ml are
abnormal and suggestive Pheochromocytoma
– Clonidine suppression test
• Clonidine orally 0,3 mg; plasma catecholamine : before oral
clonidine and again at 1,2 and 3 hr after oral clonidine
• Plasma catecholamine >500pg/ml
– Glucagon stimulation test
 Pheochromocytoma
• Treatment :
– Surgical resection is only definitive therapy
– Preoperative preparation with alpha blockade
reduce the incidence intraoperative hypertensive
crisis and postoperative hypotension
– The most commonly used agents are
phenoxybenzamine (10-20 mg 2-3 times/d, or
prazosin 1mg 3 times/day, advanced to 5 mg 3
times/day (7-28 days before surgery)
– Other agents labetalol or Ca channel blocker
Glucocorticoid therapy for non
endocrine disorders
 Principles
• Antiinflamatory and immunosuppressive
therapy; rheumatoid arthritis, SLE, asthma,
glomerulonephritis
• Because of their side effect : minimum
effective dose and shortest possible duration
of therapy
• Modes of administration : orally,
parenterally, topically or inhalation
 Synthetic glucocorticoid
Relative Potencies of Steroid Hormones

Compound Glucocorticoid Mineralocorticoid Duration

activity activity
Hydrocortisone 1 1 Short
Cortisone 0,7 0,7 Short
Prednisone 4 0,7 Short
Methylprednisone 5 0,5 Short
Dexamethasone 30 0 Long
Fludrocortisone 10 400 Long
 Side effects
1. HPA axis suppression
– Suppress CRH and ACTH secretion (negative feedback)
– Doses of prednisone >5mg/d
– It is difficult to predict the development or degree of supression :
• Clinical feature Cushing’s syndrome
• Glucocorticoid equivalen to 10-20mg of prednisone/day for 3 weeks
or more
2. Cushing’s syndrome
– Steroid induced osteoporosis
– Inhaled glucocorticoid : local effect (dysphonia and oral
candiasis) and systemic effect, glaucoma, cataracts, osteoporosis,
and growth retardation
3. Steroid withdrawal
– Glucocorticoids must be tapered downward
– Patients may develop fatigue, arthralgia, and desquamation of the
skin
– Even after the dose  to physiologic levels, HPA axis suppression
persists for 9-10 months or more
Terima kasih