PENYAKIT PADA KELENJAR ADRENAL

Calvin Damanik Bagian Penyakit Dalam FK UMI Medan

Histology
Cortex
90% of adult gland Derived from mesoderm
Begins during 5th week of development Mesothelial cell migration

Glomerulosa, fasciculata, reticularis Zonation occurs until about 18 months of age

Histology
Medulla
Derived from neuroectoderm
Neural crest cell migration Begins during 7th week of development Primitive medulla by 20th week

Continues growth until cortex atrophy (18 months)

Cross section through the adrenal gland cortex and medulla

salt sugar

sex

Cortisol and Glucocorticoid Receptors

The vast majority of glucocorticoid activity in most mammals is from cortisol, also known as hydrocortisone. Cortisol binds to the glucocorticoid receptor in the cytoplasm and the hormone-receptor complex is then translocated into the nucleus Only about 10% of circulating cortisol is free. The remaining majority circulates bound to plasma proteins, particularly corticosteroidbinding globulin (transcortin).

Hypothalamus-Pituitary-Adrenal axis
Circadian regulation

+ CRH

Stress: Physical stress Emotional stress Hypoglycemia Cold exposure Pain Cortisol

+ ACTH

Adrenal cortex

Anterior lobe of pituitary gland

CRH=corticothropin releasing hormone; ACTH=adrenocorticothropin hormone.

Kirk LF. Am Fam Physician 2000

Aldosterone synthesis
ACTH also stimulates aldosterone synthesis. However the ACTH stimulation is more transient than the other stimuli and is diminished within several days. ACTH provides a tonic control of aldosterone synthesis. In the absence of ACTH, sodium depletion still activates renin-angiotensin system to stimulate aldosterone synthesis. Aldosterone levels fluctuate diurnallyhighest concentration being at 8 AM, lowest at 11 PM, in parallel to cortisol rhythms.

Regulation of aldosterone secretion: Activation of renin-angiotensin system in response to hypovolemia is predominant stimulus for aldosterone synthesis.

Components of reninangiotensinaldosterone system

Action of aldosterone on the renal tubule. Sodium reabsorption from tubular urine into the tubular cells is stimulated. At the same time, potassium secretion from the tubular cell into urine is increased. Na+/K+ATPase, and Na+ channels work together to increase volume and pressure, and decrease K +.

Adrenocortical disorders

Cushings Syndrome
Excess Cortisol
Protein catabolic state Liberation of amino acids by muscle AA are transformed into glucose and glycogen and then transformed into fat Loss of calcium in urine Weakened muscles and elastic tissues

Causes of Cushings Syndrome

ACTH Dependent (80%)
Cushings Disease (85%)
Primary excretion of ACTH from pituitary
95% have identifiable pituitary adenoma Basophilic or chromophobe

Ectopic source (15%)

Bilateral adrenocortical hyperplasia 70% of endogenous cases F>M (3:1)

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
Diagnosis of Cushings syndrome
History / Physical Examination ------> CLINICAL DIAGNOSIS (Symptoms and signs) Laboratory Examination (Screening Test & Defenitive Test) THE PRINCIPLE OF LABORATORY INTERPRETATION

Cushings Syndrome
Diagnosis of Cushings syndrome
Labs
24 hour urinary cortisol
2-3 consecutive days Verify with creatinine values

Spot AM/PM serum cortisol

Circadian variation AM ACTH surge causes increased cortisol PM should see at least 50% drop in cortisol level

Low-dose dexamethasone suppression test

Cushings Syndrome
Dexmethasone suppression test
Synthetic glucocorticoid (30x more potent as inhibitor) Low dose
0.5mg po q6 hours x48 hours Measure cortisol, 17-hydroxycorticosteroid Fall in all steroid levels in pseudo-Cushing and normals Differentiates presence/absence of Cushings syndrome

Alternative dosing
1mg po at midnight and measure 8am cortisol Much less sensitive

Cushings Syndrome
Diagnose cause of Cushings syndrome
History (steroid use?) Serum ACTH
Elevated : Cushings disease, ectopic ACTH Suppressed: primary adrenal source Correlate with cortisol levels

High-dose dexamethasone suppression test Metyrapone test

Cushings Syndrome
Dexmethasone suppression test
High Dose
2mg po q6 hours x48 hours Measure cortisol and urinary free cortisol Ectopic ACTH and adrenal tumors- no suppression Cushings disease- suppress to <50% of baseline Usually only used if ACTH/Cortisol assays unavailable or equivocal

Cushings Syndrome
Metyrapone test
Inhibits 11-B-hydroxylase Blocks conversion of 11-deoxycortisol to cortisol Plasma cortisol levels fall and ACTH increases Marked increase in 17-hydroxycorticosteroid levels and 11-deoxycortisol levels
Cushings Disease- normal or supernormal increase in levels Ectopic ACTH or adrenal sources- no response

Risks adrenal insufficiency

Cushings Syndrome
Petrosal vein sampling
Measure petrosal venous sinus ACTH level and correlate to plasma levels Invasive with morbidity Usually not used

Adrenal venous sampling

Measure cortisol and aldosterone Not used anymore

Cushings Syndrome
Radiographic Localization
CT of sella turcica
Unenhanced and gadolinium enhanced MRI Radionuclide imaging for somatostatin receptors >60% sensitive 1st study if diagnosed with Cushings syndrome

CT of chest/abdomen with 3mm cuts through adrenal

Adrenal hyperplasia
Thickening and elongation of adrenal rami bilaterally Multinodularity of cortex bilaterally

Cushings Syndrome
Radiographic Localization
CT of adrenal glands
Adenomas- usually >2cm but <5cm
Low attenuation (lipid content) Atrophy of opposite gland

Carcinoma- indistinguishable from adenomas

>5cm Necrosis, calcifications, irregularity, invasion

MRI of adrenal- usually not needed

Signal intensity much higher than in spleen = carcinoma Adjacent organ and/or vascular involvement

Cushings syndrome suspect

11 pm salivary cortisol Disrupted circadian rhythm 24-hour UFC Filtered load of cortisol Low dose dexamethasone Supression test Attenuated negative feedback

Normal

Equivocal

Abnormal

Cushings syndrome excluded Repeat if high index of suspicious

Dexamethasone test

Cushings syndrome established

Confirm CS ACTH

Undetectable
Adrenal

Normal to increased
Pituitary MRI Bilateral masses Pituitary tumor

Unilateral mass

Normalequivocal
IPSS with Search ectopic

Cushings Syndrome
Treatment: Surgical
Cushings disease
Transphenoidal hypophysectomy
>90% cure rate 1st time, 50% salvage cure 2nd attempt Exploration even if no obvious adenoma Transient post-op diabetes insipidus, adrenal insufficiency, CSF rhinorrhea, meningitis

Tansphenoidal irradiation
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
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

Addisons Disease
Response to cosyntropin test or rapid ACTH stimulation test
Cortisol Increased Decreased Decreased Increased Aldosteron Increased Decreased Increased Decreased Diagnosis Normal Primary adrenal insufficiency Secondary adrenal insufficiency Isolated aldosterone deficiency Comments

End organ failure (Addisons disesase) Pituitary diseases, hypothalamic disease Very rare

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
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

General and supportive measure

Correct volume depletion, dehydration, and hypoglycemia with IV saline and glucose Evaluate and correct infection and other precipitating factors

PATOFISIOLOGI PENYAKIT ADDISON

Cortisol ACTH Skin Hyperpigmentation Glukoneogenesis

Abd.Pain Anorexia Vomiting Diarrhea

Glucose Uptake Renal K Secretion

Renal Na secretion

HYPOGLYCEMIA

HIPERKALEMIA

HIPONATREMIA
HYPOTENSION HYPOVOLEMIA

+
Fluid Intake

DEHIDRASI

RENAL PERFUSION

General Weakness Decreased Body Weight

B.U.N

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
Adrenal medullary tumor composed of chromaffin cells and capable of secreting biogenic amine and peptides, including epinephrine, norepinephrine, and dopamine. Such tumor arise from neural crest-derived cells Because of this common origin, neoplasma of the sympathetic ganglia , such as neuroblastoma, paragangliomas, and ganggliomneuromas, may produce similar amines and peptides.

COMT = Catecholamine Ortho Methyl Transferase)

Receptor catecholamine : Receptor (NE) Receptor (EPI)

Pheochromocytoma
Signs and symptoms :
The classic triad of sudden severe headaches, diaphoresis, and palpitations
Hipertensive in 95-95% of cases and is paroxismal in 25-50% of these. Orthostatic hypotension, tremor, pallor, flushing, anxiety and constipation

Nonclassic manifestations :
Hyperglycemia, severe diarrhea, hypercalcemia Arrhytmia, congestive cardiomyopathy, seizure, altered mental status, cerebral infarction/hemorrhage

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 : prazosin 1mg 3 times/day, advanced to 5 mg3 times/day (7-28 days before surgery) Other agents labetalol or Ca channel blocker Goals of theraphy : BP <160/90 mmHg.

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 Hydrocortisone Cortisone Prednisone Methylprednisone Dexamethasone Fludrocortisone Glucocorticoid Mineralocorticoid activity activity 1 0,7 4 5 30 10 1 0,7 0,7 0,5 0 400 Duration Short Short Short Short Long 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 :

2. Cushings syndrome

Clinical feature Cushings syndrome Glucocorticoid equivalen to 10-20mg of prednisone/day for 3 weeks or more

3. Steroid withdrawal

Steroid induced osteoporosis Inhaled glucocorticoid : local effect (dysphonia and oral candiasis) and systemic effect, glaucoma, cataracts, osteoporosis, and growth retardation

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

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