ADRENAL DISORDERS

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

sex

CRHCRH CortisolCortisolCortisolCortisol

Circadian regulationCircadian regulationStress:Physical stressEmotional stressHypoglycemiaCold exposurePain

Stress:Physical stressEmotional stressHypoglycemiaCold exposurePain

+

--

Hypothalamus-Pituitary-Adrenal axis

Anterior lobeof pituitary glandAnterior lobeof pituitary gland

ACTHACTHACTHACTH

CortisolCortisolCortisolCortisol

Adrenal cortexAdrenal cortex+

+

-

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

Regulation of aldosterone secretion

Components of renin-angiotensin-aldosterone 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– 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 Cushing’s Syndrome

• ACTH Dependent (80%)– Cushing’s Disease (85%)

• Primary excretion of ACTH from pituitary– Microadenoma, macroadenoma or corticotrophic hyperplasia

– Basophilic or chromophobe

• F>M (3:1)• 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)• 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– Non-endocrine causes

• Alcoholism

• Major depression

• Morbid obesity

• Acute illness

Cushing’s Syndrome

Symptoms and Sign Percent of Patients

• Weight gain, round facies and

truncal obesity

• Weakness

• Hypertension

97

87

82• Hypertension

• Hirsutism (in women)

• Amenorrhea

• Cutaneous striae

• Ecchymoses

• Osteoporosis

• Hyperglycemia

82

80

77

67

65

Common

Common

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 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.

– Late night plasma or salivary cortisol – 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.

– 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 • 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)

Clinical Suspicion of Cushing’s Syndrome

1 mg DST

Normalsupression

24 hour UFC

Elevated(>300µg/d)

Intermediate(90-300µg/d) Normal

(<90µg/d)Repeat, if normal

Cushing’s Syndrome

No supressionConfirm with 24 hr UFC

Cushing’ Syndrome

Diurnal variationAnd/or Dex-CRH test

Repeat, if normalCushing’s Syndrome

unlikely

Continue Evaluation

Cushing’ syndrome doubful

PsudoCushing’s

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– 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!

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– 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– 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– 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’s 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: • 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

• Anorexia

• Vomiting

• Diarhea

Gluconeogenesis ↓Glucose uptake ↓

Renal K Secretion ↓Renal Na secretion ↑

ACTH ↑

Fluid intake ↓ Hypoglycemia Hyperkalemia

Hyperpigmentation

dehydration

Hypotension

Hypovolemia

Renal perfusion ↓BUN ↑

Hyperkalemia

Hyponatremia

Decreased Body Weight

General Weakness

Addison’s Disease

• Primary adrenal insufficiency– Causes

• Infectious

– TB – most common cause in 3rd world countries

– HIV, histoplasmosis, blastomycosis, coccidiomycosis

• Autoimmune disorders – anti-adrenal antibodies (most • 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’s 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 99Weakness and fatigue

Hyperpigmentation

Unexplained weight loss

Anorexia, nausea, and vomiting

Hypotension (BP < 110/70 mmHg)

Hyponatremia

Hyperkalemia

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 Primary Secondary

Hyperpigmentation

Pallor

Yes

No

No

YesPallor

Low Na

High K

Hypotension

Cortisol level

ACTH level

No

Yes

Yes

Yes

Low

High

Yes

No

No

No

Low

Low

Addison’s Crisis

• Acute adrenal insufficiency

– Similar causes

• Adrenal hemorrhage

• Chronic steroid use and trauma/stress/surgery• Chronic steroid use and trauma/stress/surgery

– Hypotension, volume depletion, fever, nausea and vomiting, tachycardia, weakness, hypoglycemia

– Premed prior to interventions

Addison’s 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– 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’s Crisis

Maintenance therapy

• Glucocorticoid and mineralocorticoid

– Oral dose hydrocortisone : 10-20 mg in the morning

and 5-10 mg later in day. 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

functionfunction

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, • 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. • 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 α (NE)

• Receptor β (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 painabdominal 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 periodeand 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 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