pathophysiology of adrenalmed.mui.ac.ir/sites/default/files/users/dakheli/adrenal...

Pathophysiology Of AdrenalPathophysiology Of AdrenalPathophysiology Of Adrenal Pathophysiology Of Adrenal DisorderDisorder

Dr.RezvanDr.Rezvan SalehidoostSalehidoostAssistant Professor of Endocrinology

Pathophysiology Of Adrenal DisorderPathophysiology Of Adrenal Disorder

Th d l l d li t th i lThe adrenal glands lie at the superior pole of each kidney and are composed of two distinct regions: the cortex and the medulladistinct regions: the cortex and the medulla.


Th d l i h iThe adrenal cortex comprises three anatomic zones: Outer zona glomerulosa, which secretes the aldosteroneI t di t f i l t hi h t ti l Intermediate zona fasciculata, which secretes cortisol

Inner zona reticularis, which secretes adrenal androgens


Th d l d ll iThe adrenal medulla is functionally related to the sympathetic nervous system y p yand secretes the catecholamines(epinephrine and norepinephrine) in response tonorepinephrine) in response to stress.


The synthesis of all steroid hormonesThe synthesis of all steroid hormones begins with cholesterol and is catalyzed by a series of regulated enzyme‐mediateda series of regulated, enzyme‐mediated reactions.


The e i a iote iThe renin‐angiotensin‐aldosterone system is the major regulator of aldosterone secretion.

Renal juxtaglomerular cells t i i tsecrete renin in response to a

decrease in circulating volume or a reduction in renal perfusion pressure.


Renin is the rate‐limiting enzyme that cleaves the angiotensinogen molecule synthesized by the livermolecule, synthesized by the liver, to produce the bioinactivedecapeptide angiotensin I.

Angiotensin I is rapidly converted to the octapeptide angiotensin II byto the octapeptide angiotensin II by angiotensin‐converting enzymein the lungs and other tissues.


Angiotensin II is a potent vasopressor; it stimulates aldosterone production but does not stimulate cortisol production.

1. Angiotensin II2. plasma potassium level3. plasma volume4. ACTH level i fl ld t tiinfluence aldosterone secretion.


Cortisol is secreted by the adrenal glands in response to adrenocorticotropic hormoneadrenocorticotropic hormone (ACTH).

(ACTH) is a 39‐amino‐acid neuropeptide that is regulated by

ti t i l i hcorticotropin‐releasing hormone (CRH) and vasopressin (AVP) produced in the hypothalamus .

Glucocorticoids exert ti f db k CRHnegative feedback on CRH

and ACTH secretion.


Aldosterone binds to the mineralocorticoid receptor.

In contrast cortisol binds to both the mineralocorticoid receptor andIn contrast, cortisol binds to both the mineralocorticoid receptor and glucocorticoid receptors.

β h d idThe intracellular enzyme 11β‐hydroxysteroiddehydrogenase (11β‐HSD) type II, which catabolizes cortisol to inactive cortisone limits the functional binding tocortisol to inactive cortisone, limits the functional binding to the former receptor.


Binding of aldosterone to the cytosol mineralocorticoidreceptor leads to sodium (Na+) absorption and potassiump ( ) p p(K+) and hydrogen (H+) secretion by the renal tubules.

Th lt t i i l N + d d i l K+The resultant increase in plasma Na+ and decrease in plasma K+provide a feedback mechanism for suppressing renin and,subsequently, aldosterone secretion.


Adrenal androgen precursors include dehydroepiandrosterone(DHEA) d it lf t d(DHEA) and its sulfate and androstenedione.

These are synthesized in the zonareticularis under the influence of ACTH.


Adrenal androgen have minimal intrinsic androgenic activity, they contribute to androgenicity by their peripheral conversion to testosterone g y y p pand dihydrotestosterone.

In men excessive levels of adrenal androgens have no clinicalIn men, excessive levels of adrenal androgens have no clinical consequences.

I th lt i hi ti d i ili tiIn women they result in acne, hirsutism, and virilization.


Because of gonadal production of androgens and the secretion of norepinephrine by sympathetic ganglia, deficiencies of adrenal androgens and catecholamines are not clinically recognized.

SYNDROMES OF SYNDROMES OF DRENOCORTICAL DRENOCORTICAL HYPOFUNCTIONHYPOFUNCTIONHYPOFUNCTIONHYPOFUNCTION

Adrenal insufficiencyAdrenal insufficiencyAdrenal insufficiencyAdrenal insufficiency

Laboratory abnormalities may include: hyponatremia hyperkalemia

ild t b li id i mild metabolic acidosis Azotemia anemia anemia lymphocytosis, and eosinophilia hypoglycemiayp g y

Adrenal insufficiencyAdrenal insufficiency

C if i f d l


Common manifestations of adrenal insufficiency:

anorexia weight loss increasing fatigue increasing fatigue vomiting, diarrhea salt craving muscle and joint pain abdominal pain postural dizziness p increased pigmentation

Adrenal Insufficiency

Adrenal insufficiency, Adrenal insufficiency, DiagnosisDiagnosisDiagnosisDiagnosis

In a patient with chronic symptoms suggestive of adrenalinsufficiency, a basal morning plasma cortisol measurement and 1‐hour cosyntropin test should be performed. y p p

In the cosyntropin test, 0.25 mg of cosyntropin is given intravenously or intramuscularly, and plasma cortisol is y y pmeasured after 0, 30, and 60 minutes.

A normal response is a plasma cortisol concentrationp phigher than 20 μg/dL at any time during the test.


Once the diagnosis of adrenal insufficiency is made, the distinction between primary and secondary d l i ffi i d b bl h dadrenal insufficiency needs to be established.


Secondary adrenal insufficiency results from inadequate stimulation of the adrenal cortex by ACTH.y

To distinguish primary from secondary adrenal insufficiency,b l i l ACTH l h ld b bt i da basal morning plasma ACTH value should be obtained.

Mineralocorticoid levels are normal in secondary adrenalyInsufficiency.

Acute Adrenal insufficiencyAcute Adrenal insufficiencyAcute Adrenal insufficiencyAcute Adrenal insufficiency

Acute adrenal insufficiency is a medical emergency, and treatment should not be delayed pending l b t ltlaboratory results.

In a critically ill patient with hypovolemia, a plasma sample y p yp p pfor cortisol, ACTH, aldosterone, and renin should be obtained, and then treatment with hydrocortisone (100 mg IV bolus) and parenteral saline administration should be initiated.

Adrenal insufficiencyAdrenal insufficiencyTreatmentTreatmentTreatmentTreatment

All patients should wear a medical information bracelet and should be instructed in the use of intramuscular emergency hydrocortisone injections.


Addison’s disease may be part of two distinct autoimmune polyglandular syndromes.

Type I polyglandular autoimmune syndrome characterizes by the triad of hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis which usually manifests in childhood. y

Less common manifestations include:hypothyroidism gonadal failure gastrointestinal malabsorption insulin‐hypothyroidism, gonadal failure, gastrointestinal malabsorption, insulin‐dependent diabetes mellitus, alopecia areata and totalis, pernicious nemia, vitiligo, chronic active hepatitis, keratopathy, hypoplasia of dental enamel and nails, hypophysitis, asplenism, and cholelithiasis.yp p y p


T II l l d l t i d l


Type II polyglandular autoimmune syndrome, also called Schmidt’s syndrome, is characterized by Addison’s disease, autoimmune thyroid disease (Graves’ disease

H hi t ’ th iditi ) d i li d d t di b tor Hashimoto’s thyroiditis), and insulin‐dependent diabetes mellitus.

O h i d di i l dOther associated diseases include:pernicious anemia, vitiligo, gonadal failure, hypophysitis, celiac disease, myasthenia gravis, primary biliary cirrhosis, Sjö ’ d l th t d P ki ’Sjögren’s syndrome, lupus erythematosus, and Parkinson’s disease. This syndrome usually develops in adults.

Congenital AdrenalCongenital Adrenal Hyperplasia(CAH)Hyperplasia(CAH)Congenital Adrenal Congenital Adrenal Hyperplasia(CAH)Hyperplasia(CAH)

Congenital adrenal hyperplasia (CAH) refers toCongenital adrenal hyperplasia (CAH) refers to autosomal recessive disorders of adrenal steroid biosynthesis that result in glucocorticoid and

l d d f dmineralocorticoid deficiencies and compensatory increase in ACTH secretion.

Congenital Adrenal HyperplasiaCongenital Adrenal HyperplasiaCongenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia

Five major types of CAH exist, and the clinical manifestations of each type depend on which steroids are in excess and which are deficient.

21α‐Hydroxylase (CYP21) deficiency is the most common of these disorders and accounts for about 95% of patients with CAHdisorders and accounts for about 95% of patients with CAH.

11β‐Hydroxylase (CYP11B1) deficiency 3β‐HSD type II deficiency 17α‐hydroxylase (CYP17) deficiency steroidogenic acute regulatory protein (StAR) deficiency

MineralocorticoidMineralocorticoid DeficiencyDeficiency

Mineralocorticoid deficiency can result from

Mineralocorticoid Mineralocorticoid Deficiency Deficiency

Mineralocorticoid deficiency can result from decreased renin secretion by the kidneys.

Hypoangiotensinemia leads to hypoaldosteronismwith hyperkalemia and hyperchloremic metabolicwith hyperkalemia and hyperchloremic metabolic acidosis.

SYNDROMES OF ADRENOCORTICAL SYNDROMES OF ADRENOCORTICAL HYPERFUNCTIONHYPERFUNCTIONHYPERFUNCTIONHYPERFUNCTION

SYNDROMES OF ADRENOCORTICAL HYPERFUNCTIONSYNDROMES OF ADRENOCORTICAL HYPERFUNCTION

Hypersecretion of the glucocorticoid hormone cortisol results in Cushing’s syndrome a metabolic disorder that affectsin Cushing s syndrome, a metabolic disorder that affects carbohydrate, protein, and lipid metabolism.

Hypersecretion of mineralocorticoids such as aldosterone results in a syndrome of hypertension and electrolyte disturbances.

DiagnosisDiagnosisDiagnosisDiagnosis

Diagnosis of Cushing’s syndrome can be established by

Collecting urine for 24 hours and measuring the urinary free cortisol (UFC)

The overnight dexamethasone suppression testg ppDexamethasone, 1 mg, is given orally at 11:00 pm or midnight, and plasma cortisol is measured the following morning at 8:00 am. A morning plasma cortisol level greater than 1.8 μg/dL suggests hypercortisolism.


Cortisol is normally secreted in a diurnal manner: The plasmaconcentration is highest in the early morning (between 6:00 and8:00 am) and lowest around midnight.) g

Most patients with Cushing’s syndrome have blunted diurnal variation.variation.

Because of the difficulty of obtaining nighttime plasma cortisol levels measurement of late‐night salivary cortisol has beenlevels, measurement of late‐night salivary cortisol has been developed to assess hypercortisolism.


Once the diagnosis of Cushing’s syndrome is established, the cause of the hypercortisolism needs to be ascertained.

The initial approach is to measure basal ACTH levels, which are normal or elevated in Cushing’s disease and the ectopic ACTH syndromenormal or elevated in Cushing s disease and the ectopic ACTH syndrome but are suppressed in primary adrenal Cushing’s syndrome.

P i i h d ACTH l l d d lPatients with a suppressed ACTH level can proceed to adrenal imaging studies.

TreatmentTreatmentTreatmentTreatment

The preferred treatment for all forms of Cushing’s syndrome is appropriate surgery.pp p g y

A more appealing option for patients with Cushing’s disease who remain hypercortisolemic after pituitary surgery isremain hypercortisolemic after pituitary surgery is radiotherapy and bilateral adrenalectomy followed by lifelong glucocorticoid and mineralocorticoid replacement the a ytherapy.

TreatmentTreatmentTreatmentTreatment

In patients with the ectopic ACTH syndrome, the goal is to localize the tumor by appropriate scans so it can be removed surgicallysurgically..

il t lil t l d l td l tA unilateral unilateral adrenalectomyadrenalectomy is the treatment of choice in patients with a cortisol‐secreting adrenal adenoma.

Primary Mineralocorticoid ExcessPrimary Mineralocorticoid Excess

Primary Mineralocorticoid ExcessPrimary Mineralocorticoid ExcessPrimary Mineralocorticoid ExcessPrimary Mineralocorticoid Excess

Primary aldosteronism is usually recognized during evaluationf h t i h k l iof hypertension or hypokalemia .

Up to 5% of patients with p phypertension have primary aldosteronism.

These patients are usually between the ages of 30 and 50 years, and the female‐to‐male ratio is 2 : 1female to male ratio is 2 : 1.

Primary Mineralocorticoid Primary Mineralocorticoid Excess, Clinical Excess, Clinical PresentationsPresentationsPresentationsPresentations

Hypertension, hypokalemia, and metabolic alkalosis are the main clinical manifestations of hyperaldosteronism.

Most of the presenting symptoms are related to hypokalemia.

Symptoms in patients with hypokalemia are fatigue, muscle weakness, nocturia, lassitude, headaches, paresthesias and intermittent paralysis.

Blood pressure can range from minimally elevated to very high.

pathophysiology of adrenalmed.mui.ac.ir/sites/default/files/users/dakheli/adrenal...

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