penyakit kel adrenal.ppt

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    PENYAKIT PADA

    KELENJAR ADRENALCalvin Damanik

    Bagian Penyakit Dalam FK UMIMedan

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    Histology

    Cortex

    90% of adult gland

    Derived from mesoderm Begins during 5th week of development

    Mesothelial cell migration

    Glomerulosa, fasciculata, reticularisZonation occurs until about 18

    months of age

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    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)

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    Cross section through the adrenalgland cortex and medulla

    salt

    sugar

    sex

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    Cortisol and GlucocorticoidReceptors

    The vast majority of glucocorticoid activity inmost mammals is from cortisol, also known as

    hydrocortisone. Cortisol binds to the glucocorticoid receptor in

    the cytoplasm and the hormone-receptorcomplex is then translocated into the nucleus

    Only about 10% of circulating cortisol is free.The remaining majority circulates bound toplasma proteins, particularly corticosteroid-binding globulin (transcortin).

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    CRH

    Anterior lobeof pituitary gland

    ACTH

    Cortisol

    Circadian regulation

    Stress:Physical stressEmotional stressHypoglycemiaCold exposurePain

    Adrenal cortex+

    +

    +

    --

    -

    Hypothalamus-Pituitary-Adrenal axis

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

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    Aldosterone synthesis

    ACTH also stimulates aldosterone synthesis. However the ACTH stimulation is more

    transient than the other stimuli and isdiminished within several days.

    ACTH provides a tonic control of aldosteronesynthesis.

    In the absence of ACTH, sodium depletion stillactivates renin-angiotensin system tostimulate aldosterone synthesis.

    Aldosterone levels fluctuate diurnallyhighestconcentration being at 8 AM, lowest at 11 PM,in parallel to cortisol rhythms.

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    Regulation of

    aldosteronesecretion:Activation ofrenin-angiotensin

    system inresponse tohypovolemia ispredominant

    stimulus foraldosteronesynthesis.

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    Componentsof renin-angiotensin-aldosteronesystem

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    Action of aldosterone onthe renal tubule.

    Sodium reabsorptionfrom tubular urine intothe tubular cells isstimulated. At the same

    time, potassiumsecretion from thetubular cell into urine isincreased. Na+/K+-ATPase, and Na+channels work togetherto increase volume andpressure, and decreaseK+.

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    Adrenocortical disorders

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    Cushings Syndrome

    Excess Cortisol

    Protein catabolic state

    Liberation of amino acids by muscle

    AA are transformed into glucose andglycogen and then transformed into fat

    Loss of calcium in urine

    Weakened muscles and elastic tissues

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    Causes of Cushings Syndrome

    ACTH Dependent (80%) Cushings 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

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    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

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    Cause of Cushings Syndrome

    Pseudo-Cushings disease

    Mimic clinical signs and symptoms

    Non-endocrine causes Alcoholism

    Major depression

    Morbid obesity

    Acute illness

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    Cushings Syndrome

    Diagnosis of Cushings syndrome

    History / Physical Examination ------>CLINICAL DIAGNOSIS (Symptoms andsigns)

    Laboratory Examination (ScreeningTest & Defenitive Test) THE PRINCIPLEOF LABORATORY INTERPRETATION

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    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

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    Cushings Syndrome Dexmethasone suppression test

    Synthetic glucocorticoid (30x more potent asinhibitor)

    Low dose 0.5mg po q6 hours x48 hours Measure cortisol, 17-hydroxycorticosteroid

    Fall in all steroid levels in pseudo-Cushing andnormals

    Differentiates presence/absence of Cushings

    syndrome

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

    Much less sensitive

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    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

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    Cushings Syndrome

    Metyrapone test Inhibits 11-B-hydroxylase

    Blocks conversion of 11-deoxycortisol tocortisol

    Plasma cortisol levels fall and ACTHincreases

    Marked increase in 17-hydroxycorticosteroidlevels and 11-deoxycortisol levels

    Cushings Disease- normal or supernormalincrease in levels

    Ectopic ACTH or adrenal sources- no response

    Risks adrenal insufficiency

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    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

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    Cushings Syndrome

    Radiographic Localization

    CT of sella turcica

    Unenhanced and gadolinium enhanced MRI

    Radionuclide imaging for somatostatin receptors

    >60% sensitive

    1ststudy 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

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    Cushings Syndrome

    Radiographic Localization

    CT of adrenal glands

    Adenomas- usually >2cm but 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

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    Cushings syndromesuspect

    11 pm salivary cortisolDisrupted circadian

    rhythm

    24-hour UFC Filtered load of cortisol

    Low dose dexamethasoneSupression test

    Attenuated negative feedback

    Normal Equivocal Abnormal

    Cushings syndromeexcluded

    Repeat if high indexof suspicious

    Dexamethasone test Cushings syndromeestablished

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    Confirm CS

    ACTH

    Undetectable Normal to increased

    Adrenal Pituitary MRI

    Unilateralmass

    Bilateralmasses

    Pituitarytumor

    Normal-equivocal

    IPSS with

    Search ectopic

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    Cushings Syndrome

    Treatment: Surgical

    Cushings disease

    Transphenoidal hypophysectomy

    >90% cure rate 1st time, 50% salvage cure 2ndattempt

    Exploration even if no obvious adenoma

    Transient post-op diabetes insipidus, adrenalinsufficiency, CSF rhinorrhea, meningitis

    Tansphenoidal irradiation

    High success rate in kids (80%)

    Low success in adults (20%)

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    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 ifprimary tumor unresectable

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    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 cholesterolsynthesis

    Mitotane (O-P-DDD)-inhibits conversion to pregnenolone

    Inhibits final step in cortisol synthesis

    Destroys adrenocortical cells (spares glomerulosa cells)

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    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

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    Addisons Disease

    Secondary adrenal insufficiency Pituitary failure panhypopitutarism,

    Sheehans syndrome (post-partum pituitary

    injury) Tertiary adrenal insufficiency

    Adrenal suppression due to glucocorticoiduse

    Chronic suppression Sudden cessation of replacement glucocorticoids

    Inadequate increase during stress, trauma,surgery

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    Addisons Disease

    Response to cosyntropin test or rapid ACTH stimulation test

    Cortisol Aldosteron Diagnosis Comments

    Increased

    Decreased

    Decreased

    Increased

    Increased

    Decreased

    Increased

    Decreased

    Normal

    Primary adrenalinsufficiency

    Secondary adrenal

    insufficiencyIsolated aldosteronedeficiency

    End organ failure (Addisonsdisesase)

    Pituitary diseases, hypothalamic

    diseaseVery rare

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    Addisons Crisis

    Acute adrenal insufficiencySimilar causes

    Adrenal hemorrhage

    Chronic steroid use andtrauma/stress/surgery

    Hypotension, volume depletion, fever,nausea and vomiting, tachycardia,

    weakness, hypoglycemiaPremed prior to interventions

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    Addisons Crisis

    Treatment acut of adrenal crisis Glucocorticoid replacement

    Administer hydrocortisone 100 mg every 6 hours for 24hours

    When the patient is stable, reduce the dosage to 50 mgevery 6 hours

    Taper to maintenance theraphy by day 4 or 5 and addmineralocorticoid theraphy as required

    Maintain or increase the dose to 200-400 mg/d ifcomplications persist or occur

    General and supportive measure Correct volume depletion, dehydration, and hypoglycemia

    with IV saline and glucose

    Evaluate and correct infection and other precipitatingfactors

    PATOFISIOLOGI PENYAKIT ADDISON

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    PATOFISIOLOGI PENYAKIT ADDISON

    Cortisol ACTH

    Abd.Pain

    Anorexia

    Vomiting

    Skin Hyperpigmentation

    Glukoneogenesis

    Glucose UptakeHYPOGLYCEMIA

    Renal K Secretion

    Renal Na secretion

    HIPERKALEMIA

    HIPONATREMIA

    HYPOTENSION

    HYPOVOLEMIA

    Diarrhea

    Fluid Intake

    +

    DEHIDRASI

    RENAL PERFUSION

    B.U.N

    General Weakness

    Decreased Body

    Weight

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    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 inthe morning.

    Response to theraphy

    General clinical sign, good appetite andsense of well being.

    Signs of Cushings syndrome indicateovertreatment

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    Disorders of adrenal

    medullary function

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    Pheochromocytoma

    Adrenal medullary tumor composed ofchromaffin cells and capable of secretingbiogenic 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 asneuroblastoma, paragangliomas, andganggliomneuromas, may produce similaramines and peptides.

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    COMT = Catecholamine Ortho Methyl Transferase)

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    Receptor catecholamine :

    Receptor (NE) Receptor (EPI)

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    Pheochromocytoma

    Signs and symptoms : The classic triad of sudden severe

    headaches, diaphoresis, and palpitations

    Hipertensive in 95-95% of cases and isparoxismal 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, cerebralinfarction/hemorrhage

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    Pheochromocytoma

    Diagnosis :

    Demonstration of excessive amounts catecholamines inplasma 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 areabnormal and suggestive Pheochromocytoma

    Clonidine suppression test

    Clonidine orally 0,3 mg; plasma catecholamine : before oralclonidine and again at 1,2 and 3 hr after oral clonidine

    Plasma catecholamine >500pg/ml

    Glucagon stimulation test

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    Pheochromocytoma

    Treatment :

    Surgical resection is only definitive therapy

    Preoperative preparation : prazosin 1mg 3times/day, advanced to 5 mg3 times/day (7-28days before surgery)

    Other agents labetalol or Ca channel blocker

    Goals of theraphy : BP

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    Glucocorticoid therapy for non

    endocrine disorders

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    Principles

    Antiinflamatory and immunosuppressivetherapy; rheumatoid arthritis, SLE, asthma,

    glomerulonephritis Because of their side effect : minimum

    effective dose and shortest possible durationof therapy

    Modes of administration : orally,parenterally, topically or inhalation

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    Synthetic glucocorticoid

    Relative Potencies of Steroid Hormones

    Compound Glucocorticoid

    activity

    Mineralocorticoid

    activity

    Duration

    Hydrocortisone

    Cortisone

    Prednisone

    Methylprednisone

    Dexamethasone

    Fludrocortisone

    1

    0,7

    4

    5

    30

    10

    1

    0,7

    0,7

    0,5

    0

    400

    Short

    Short

    Short

    Short

    Long

    Long

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    Side effects1. 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 Cushings syndrome Glucocorticoid equivalen to 10-20mg of prednisone/day for 3

    weeks or more

    2. Cushings 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

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