Adrenal Disorders Kuliah

7/30/2019 Adrenal Disorders Kuliah

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ADRENAL DISORDERS

Divisi Endokrin dan Metabolik

Bagian Penyakit Dalam FK USURSUP H. Adam Malik

Medan


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Cross section through the adrenalgland cortex and medulla

salt

sugar

sex


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CRH

Anterior lobeof pituitary gland

ACTH

Cortisol

Circadian regulationStress: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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Regulation of aldosterone secretion


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Componentsof renin-angiotensin-aldosteronesystem


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Action of aldosterone on the renal tubule.


10/48COMT = Catecholamine Ortho Methyl Transferase)

Production of

catecholamines


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Adrenocortical disorders


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Cushings 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 beexogenous or endogenous


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Cushings Syndrome

Symptoms and Sign Percent of Patients

Weight gain, round facies and

truncal obesity

Weakness Hypertension

Hirsutism (in women)

Amenorrhea

Cutaneous striae

Ecchymoses

Osteoporosis

Hyperglycemia

97

8782

80

77

67

65

Common

Common


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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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Diagnosis of Cushings Syndrome

Clinical assessment Screening tests :

Baseline glucocorticoids (a.m. and p.m. serum cortisollevels, 24-hr urinary free cortisol excretion; 11 p.m.Salivary cortisol)

Low dose dexamethasone suppression test or combinedlow-dose dexamethasone-oCRH

Subtype diagnosis

Plasma ACTH concentration

Dynamic testing (oCRH stimulation test, metyraponstimulation 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


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Screening tests

24 hour urinary cortisol (UFC) RIA : 80-108g (221-298nmol)

Baseline 24-hour UFC measurements may be high : Carbamazepin,

high urine volume, severe illness, CS, alcoholism, depression, sleepapnea.

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 DSTincl : CS, patient error in taking, estrogen therapy, pregnancy, renalfailure, stress, drugs (anticonvulsants, rifampisin), obesity,psychiatric disorder (depression, panic attacks)


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Confirmatory tests for CS

When baseline 24-hour UFC is >300g (828 nmol) and the clinicaland the clinical picture is consisten with CS : no additionalconfirmatory studies are needed.

2-day low dose DST

24-hour UFC < 300g : should confirmed with the low dose DST

(dexamethasone 0.5 mg, orally every 6 hours for 48 hours); 24-hoururinary cortisol excretion > 20 g (55nmol) confirm diagnosis.

The low dose DST works best for those patients that carry of low index ofsuspicion for CS.

DexamethasoneoCRH test

To correct false negative supression with DST (pituitary dependent CS)

Late night plasma or salivary cortisol

A midnight sleeping serum cortisol concentration > 1.8g/dl (>50nmol/L)is 100% sensitive in patients with Cushings syndrome.


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Clinical Suspicion of

Cushings Syndrome

1 mg DST

Normal

supression

24 hour UFC

Elevated

(>300g/d)

Cushing Syndrome

Intermediate

(90-300g/d)

Diurnal variation

And/or Dex-CRH test

Normal

(


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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 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 Cushings 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 Cushings syndrome!


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Confirm CS

ACTH

Undetectable Normal to increased

Adrenal Pituitary MRI

Unilateralmass

Bilateralmasses

Pituitary TumorCushings Ds

Normal-equivocal

IPSS with

Search ectopic


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Cushings 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 hypothalamicpituitary-adrenal (HPA) axis recovery

Treatment: Surgical Cushings disease

Transphenoidal surgery (TSS) The treatment choice

The longterm surgical cure rate for ACTH secreting microadenomas is80-90%.

Transient post-op diabetes insipidus, adrenal insufficiency, CSFrhinorrhea, meningitis

Tansphenoidal irradiation If TSS is not curative.

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 if primary

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 cholesterol synthesis

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

Inhibits final step in cortisol synthesis

Destroys adrenocortical cells (spares glomerulosa cells)


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Addison Disease

Background: Thomas Addison first described theclinical presentation of primary adrenocorticalinsufficiency (Addison disease) in 1855 in his classicpaper, On the Constitutional and Local Effects of

Disease of the Supra-Renal Capsules. Pathophysiology:

Addison disease is adrenocortical insufficiency due to thedestruction or dysfunction of the entire adrenal cortex.

It affects both glucocorticoid and mineralocorticoidfunction.

The onset of disease usually occurs when 90% or more ofboth adrenal cortices are dysfunctional or destroyed.


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Cortisol

Abdominal pain Anorexia

Vomiting

Diarhea

Gluconeogenesis Glucose uptake

Renal K Secretion Renal Na secretion ACTH

Fluid intake

dehydration

HypotensionHypovolemia

Renal perfusion BUN

Hypoglycemia HyperkalemiaHyponatremia

Hyperpigmentation

Decreased Body Weight

General Weakness


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Addison Disease

Primary adrenal insufficiency Causes Infectious

TBmost common cause in 3rd world countries

HIV, histoplasmosis, blastomycosis, coccidiomycosis Autoimmune disordersanti-adrenal antibodies (most

cause common)

Medicationsketoconazole, aminoglutethamide,etomidate

Adrenal hemorrhage

Lymphoma, bilateral adrenal metastasis, Kaposis sarcoma

Infiltrativeamylodosis, sarcoidosis,adrenoleukodystrophy


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Addison Disease

Secondary adrenal insufficiency

Pituitary failurepanhypopitutarism,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


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Primary Adrenal Insufficiency

Symptoms and sign Percent of

Patients

Weakness and fatigue

Hyperpigmentation

Unexplained weight loss

Anorexia, nausea, and vomiting

Hypotension (BP < 110/70 mmHg)

Hyponatremia

Hyperkalemia

99

98

97

90

88

88

64


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Primary versus secondary adrenal

insufficiencyManifestations Primary Secondary

Hyperpigmentation

Pallor

Low Na

High K

HypotensionCortisol level

ACTH level

Yes

No

Yes

Yes

YesLow

High

No

Yes

No

No

NoLow

Low


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Addison 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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Addison Crisis

Acute adrenal insufficiency

Similar causes

Adrenal hemorrhage

Chronic steroid use and trauma/stress/surgeryHypotension, volume depletion, fever, nausea

and vomiting, tachycardia, weakness,hypoglycemia

Premed prior to interventions


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Addison Crisis

Treatment acut of adrenal crisis The five Ss management are salt, sugar, steroid, support,

and search for presipitating illness.

General and supportive measure

Correct volume depletion, dehydration, and hypoglycemia with IV0.9% 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 6hours

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

Maintain or increase the dose to 200-400 mg/d if complicationspersist or occur


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Addison 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 wellbeing.

Signs of Cushings syndrome indicate overtreatment


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Disorders of adrenal medullary

function


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Pheochromocytoma

Pheochromocytoma is a rare catecholamine-secretingtumor derived from chromaffin cells.

Tumors that arise outside the adrenal gland are termedextra-adrenal pheochromocytomas or paragangliomas.

Because of excessive catecholamine secretion,pheochromocytomas may precipitate life-threateninghypertension or cardiac arrhythmias

It is associated with spectacular cardivascular disturbancesand, when corectly diagnosed and treated curable.When undiagnosed fatal

Prevalence estimates0.01% to 0.1% of the hypertensivepopulation


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Pathophysiology

The clinical manifestations of a pheochromocytoma resultfrom excessive catecholamine secretion by the tumor.

Catecholamines typically secreted, either intermittently orcontinuously, include norepinephrine and epinephrine andrarely dopamine.

The biological effects of catecholamines are well known.

Most pheochromocytomas contain norepinephrinepredominantly, in comparison with the normal adrenalmedulla, which is composed of roughly 85% epinephrine.

Familial pheochromocytomas are an exception becausethey secrete large amounts of epinephrine. Thus, theclinical manifestations of a familial pheochromocytomadiffer from those of a sporadic pheochromocytoma.


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Receptor catecholamine :

Receptor (NE)

Receptor (EPI)


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Pheochromocytoma Symptoms :

Due to the pharmacologic effects excess circulatingcatecholamines

A typical paroxysm (the 5 Ps) Pressuresudden major increase in blood pressure

Painabrupt onset of throbbing headache ; chest andabdominal pain

Perspirationprofuse generalized diaphoresis

Palpitation

Pallor

Clinical sign : Hypertension,orthostatic hypotension, grade II to III

retinopathy, tremor, weight loss, fever, painless hematuria,hyperglycemia, erythrocytosis


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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 with alpha blockade

reduce the incidence intraoperative hypertensivecrisis and postoperative hypotension

The most commonly used agents arephenoxybenzamine (10-20 mg 2-3 times/d, or

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

Other agents labetalol or Ca channel blocker


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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 more2. Cushings syndrome

Steroid induced osteoporosis

Inhaled glucocorticoid : local effect (dysphonia and oralcandiasis) 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 theskin

Even after the dose to physiologic levels, HPA axis suppression

persists for 9-10 months or more


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Adrenal Disorders Kuliah