IPD 2.

1 Penyakit Kelenjar Adrenal

Hipotalamus-pituitari-sumbu adrenal (axis); regulasi sirkadian; korteks adrenal; CRH; ACTH

Potongan cross sectional kelenjar adrenal-korteks dan medula; zona kapsul; glomerulosa
Regulasi sekresi aldosteron

Aksi/kerja aldosteron pada tubulus ginjal

Produksi katekolamin

COMT = Catecholamine Ortho Methyl Transferase)

Kelainan / gangguan adrenokortikal

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

Penyebab cushing’ 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)
– 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

• ACTH Independent
– Exogenous steroid use (common)
• PO or topical
• Most common cause (overall)
– Adrenal adenomas (10%)
– Adrenal carcinoma (5%)
• Most common cause in children

• Pseudo-Cushing’s disease
– Mimic clinical signs and symptoms
– Non-endocrine causes
• Alcoholism
• Major depression
• Morbid obesity
• Acute illness

Tanda dan gejala; persentase pasien; lemah; hipertensi; 97%; ekimosis; osteoporosis

Hiperkortikol – cushing’s syndrome

• Moon face (round, red, and full)
• Buffalo hump (a collection of fat between the shoulders)
• Central obesity with protruding abdomen and thin extremities
• Weight gain
• Weakness
• Backache
• Headache
• Acne or superficial skin infections
• Thin skin with easy bruising
• Thirst
• Increased urination
 • Purple striations on the skin of the abdomen, thighs, and breasts
• Mental changes
• Impotence or cessation of menses
• Facial hair growth

Diagnosis 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 stimulation

• 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
• 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)

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)

Tes evaluasi subtipe diferensial

• 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!

Cushing’s syndrome
• Treatment program :
– The resolution of hypercorticolism
– The parellel treatmet of the complications of CS (e.g. hypertension, osteoporosis,
diabetes mellitus, muscle 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%)

• 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

• 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)

Cushing’s disease: peningkatan glukokortikoid

• Etiology: Functional Cortical Adenoma or ACTH secreting Pituitary Adenoma
• Usually Young Adult Females
• Clinical: Weight gain with fatty accumulation in upper back (“Buffalo Hump”) and face
(“Moon Facies”); Delayed wound healing; Depression
• Laboratory: Hypertension and High Blood Sugar
• Dental: Poor Wound Healing; Risk of Adrenal (STRESS) Crisis

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:
– 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.

Kortisol menurun; nyeri abdomen; gluconeogenesis; sekresi K ginjal; ACTH; anoreksia; Na

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
Hiperpigmentasi kuku; lemah; lelah; kehilangan berat badan; anoreksia; muntah; mual; hipotensi

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

Secondary adrenal insufficiency

Pituitary failure – panhypopitutarism, Sheehan’s syndrome (post-partum pituitary injury)

Perbedaan manifestasi primer dan sekunder; hiperpigmentasi; muka pucat; Na rendah; K tinggi

Tertiary adrenal insufficiency

– Adrenal suppression due to glucocorticoid use
• Chronic suppression
• Sudden cessation of replacement glucocorticoids
• Inadequate increase during stress, trauma, surgery