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Mardianto Divisi Endokrin dan Metabolik Bagian Penyakit Dalam FK USU RSUP H. Adam Malik Medan

Cross section through the adrenal gland cortex and medulla

salt sugar


Hypothalamus-Pituitary-Adrenal axis
Circadian regulation Stress: Physical stress + Emotional stress Hypoglycemia Cold exposure Pain CR H

Cortis Cortis ol ol

+ ACT ACT H Anterior lobe H of pituitary gland

Adrenal cortex

ticothropin releasing hormone; ACTH=adrenocorticothropin hormone. Kirk LF. Am Fam Physician 2000

Regulation of aldosterone secretion

Components of reninangiotensinaldosterone system

Action of aldosterone on the renal tubule.

Production of catecholamines

COMT = Catechol amine Ortho Methyl Transferase)

Adrenocortical disorders

Cushings 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

Causes of Cushings Syndrome

ACTH Dependent (80%)
Cushings Disease (85%)
Primary excretion of ACTH from pituitary
Microadenoma, macroadenoma or corticotrophic hyperplasia Basophilic or chromophobe

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 Cushings 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 Cushings Syndrome

Pseudo-Cushings disease
Mimic clinical signs and symptoms Non-endocrine causes
Alcoholism Major depression Morbid obesity Acute illness

Cushings Syndrome
Symptoms and Sign
Weight gain, round facies and truncal obesity Weakness Hypertension Hirsutism (in women) Amenorrhea Cutaneous striae Ecchymoses Osteoporosis Hyperglycemia

Percent of Patients
97 87 82 80 77 67 65 Common Common

Diagnosis of Cushings 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 lowdose 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 Cushings Syndrome

Screening tests
24 hour urinary cortisol (UFC)
RIA : 80-108g (221-298nmol) Baseline 24-hour UFC measurements may be high : Carbamazepin, high urine volume, severe illness, CS, alcoholism, depression, sleep apnea.

Late night plasma or salivary cortisol

A midnight sleeping serum cortisol concentration > 1.8g/dl (>50nmol/L) is 100% sensitive in patients with Cushings syndrome.

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 Cushings Syndrome

Confirmatory tests for CS
When baseline 24-hour UFC is >300g (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 < 300g : should confirmed with the low dose DST (dexamethasone 0.5 mg, orally every 6 hours for 48 hours); 24hour urinary cortisol excretion > 20 g (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)

Clinical Suspicion of Cushings Syndrome 24 hour UFC 1 mg DST

No supression Confirm with 24 hr UFC Normal supression Elevated (>300g/d) Intermediate (90-300g/d) Normal (<90g/d) Repeat, if normal

Cushings Syndrome unlikely

Diurnal variation And/or Dex-CRH test

Cushing Syndrome

Continue Evaluation

Cushing syndrome doubful PsudoCushings Treat underlying illness Follow clinical examination Repeat 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 Cushings 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 Cushings syndrome!

Cushings 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
Cushings disease
Transphenoidal surgery (TSS)
The treatment choice The longterm surgical cure rate for ACTH secreting microadenomas is 8090%. 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%)

Cushings Syndrome
Treatment: Surgical
Cushings 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

Cushings 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)

Addisons 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.

Abdominal pain Anorexia Vomiting Diarhea
Fluid intake dehydration Hypotension Hypovolemia Renal perfusion BUN Decreased Body Weight General Weakness

Gluconeogenesis Glucose uptake

Renal K Secretion Renal Na secretion


Hyperpigmentation Hypoglycemia Hyperkalemia Hyponatremia

Addisons 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, Kaposis sarcoma Infiltrative amylodosis, sarcoidosis, adrenoleukodystrophy

Addisons Disease
Secondary adrenal insufficiency
Pituitary failure panhypopitutarism, Sheehans 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
Weakness and fatigue Hyperpigmentation Unexplained weight loss Anorexia, nausea, and vomiting Hypotension (BP < 110/70 mmHg) Hyponatremia Hyperkalemia

Percent of Patients
99 98 97 90 88 88 64

Primary Adrenal Insufficiency

A triphasic pattern : Phase 1 : few/no symptoms, non spesific malaise, pigmentation Phase 2 : gradually worsening simptoms ; lethargy, weight loss, increased pigmentation over exposed areas, hypotension, anorexia, nausea, diarhoea, loss axillary, pubic and body hair Phase 3 : decompentation ; adrenal crisis,

Primary versus secondary adrenal insufficiency

Manifestations Hyperpigmentation Pallor Low Na High K Hypotension Cortisol level ACTH level Primary Yes No Yes Yes Yes Low High Secondary No Yes No No No Low Low

Addisons 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

Addisons Crisis
Treatment acut of adrenal crisis
The five Ss 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

Addisons 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 Cushings syndrome indicate overtreatment

Disorders of adrenal medullary function

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

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)

Symptoms :
Due to the pharmacologic effects excess circulating catecholamines A typical paroxysm (the 5 Ps)
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

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

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