adrenal disorders-kuliah update

7/31/2019 Adrenal Disorders-kuliah Update

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ADRENAL DISORDERS

Mardianto

Divisi Endokrin dan MetabolikBagian Penyakit Dalam FK USU

RSUP H. Adam Malik

Medan


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Cross section through the adrenalgland cortex and medulla

salt

sugar

sex


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CRCRHH

Anterior lobeof pituitary gland

Anterior lobeof pituitary gland

ACTACTHH

ACTACTHH

CortisCortisolol

CortisCortisolol

Circadian regulation

Circadian regulationStress:Physical stressEmotional stressHypoglycemiaCold exposurePain

Stress:Physical stressEmotional stressHypoglycemiaCold exposurePain

Adrenal cortex

Adrenal cortex+

+

+

--

-

Hypothalamus-Pituitary-Adrenal axis

Kirk LF. Am Fam Physician 200icothropin 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.


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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 be

exogenous or endogenous


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Causes of Cushings Syndrome

ACTH Dependent (80%)Cushings 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


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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

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

87

82

80

77

67

65

Common

Common


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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 combined low-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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Diagnosis of Cushings Syndrome Screening tests

24 hour urinary cortisol (UFC)

RIA : 80-108g (221-298nmol)

Baseline 24-hour UFC measurements may be high : Carbamazepin, highurine volume, severe illness, CS, alcoholism, depression, sleep apnea.

Late night plasma or salivary cortisol

A midnight sleeping serum cortisol concentration > 1.8g/dl (>50nmol/L) is100% sensitive in patients with Cushings 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)


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Diagnosis of Cushings Syndrome

Confirmatory tests for CS When baseline 24-hour UFC is >300g (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 < 300g : should confirmed with the low dose DST

(dexamethasone 0.5 mg, orally every 6 hours for 48 hours); 24-

hour urinary cortisol excretion > 20 g (55nmol) confirm

diagnosis.

The low dose DST works best for those patients that carry of lowindex of suspicion for CS.

Dexamethasone oCRH test

To correct false negative supression with DST (pituitary dependent

CS)


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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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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 is 80-

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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Addisons Disease

Background: Thomas Addison first described theclinical presentation of primary adrenocorticalinsufficiency (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 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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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 insufficiencyPituitary failure panhypopitutarism, Sheehans

syndrome (post-partum pituitary injury)

Tertiary adrenal insufficiencyAdrenal 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 fatigueHyperpigmentation

Unexplained weight loss

Anorexia, nausea, and vomiting

Hypotension (BP < 110/70 mmHg)Hyponatremia

Hyperkalemia

9998

97

90

8888

64


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Primary Adrenal Insufficiency

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,


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Primary versus secondary adrenal

insufficiencyManifestations Primary Secondary

Hyperpigmentation

PallorLow Na

High K

Hypotension

Cortisol level

ACTH level

Yes

NoYes

Yes

Yes

Low

High

No

YesNo

No

No

Low

Low


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Addisons Crisis

Acute adrenal insufficiencySimilar 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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Addisons 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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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 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-secreting tumorderived 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. Whenundiagnosed fatal

Prevalence estimates 0.01% 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 because theysecrete large amounts of epinephrine. Thus, the clinicalmanifestations of a familial pheochromocytoma differ fromthose 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) Pressure sudden major increase in blood pressure

Pain abrupt onset of throbbing headache ; chest andabdominal pain

Perspiration profuse generalized diaphoresis Palpitation Pallor

Clinical sign : Hypertension,orthostatic hypotension, grade II to IIIretinopathy, tremor, weight loss, fever, painless hematuria,hyperglycemia, erythrocytosis


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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 areabnormal 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


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Pheochromocytoma

Treatment :Surgical resection is only definitive therapy

Preoperative preparation with alpha blockade reduce

the incidence intraoperative hypertensive crisis andpostoperative 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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