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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