Assistant Professor of Endocrinology

Transcription

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2 Pathophysiology Of Adrenal Disorder Dr.Rezvan Salehidoost Assistant Professor of Endocrinology

3 Pathophysiology Of Adrenal Disorder The adrenal glands lie at the superior pole of each kidney and are composed of two distinct regions: the cortex and the medulla.

4 Pathophysiology Of Adrenal Disorder The adrenal cortex comprises three anatomic zones: Outer zona glomerulosa, which secretes the aldosterone Intermediate t zona fasciculata, which h secretes cortisol Inner zona reticularis, which secretes adrenal androgens

5 Pathophysiology Of Adrenal Disorder The adrenal medulla is functionally related to the sympathetic nervous system and secretes the catecholamines (epinephrine and norepinephrine) in response to stress.

6 Pathophysiology Of Adrenal Disorder The synthesis of all steroid hormones begins with cholesterol and is catalyzed by a series of regulated, enzyme mediated reactions.

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8 Pathophysiology Of Adrenal Disorder The renin angiotensin iote i aldosterone system is the major regulator of aldosterone secretion. Renal juxtaglomerular cells secrete renin in response to a decrease in circulating volume or a reduction in renal perfusion pressure.

9 Pathophysiology Of Adrenal Disorder Renin is the rate limiting enzyme that cleaves the angiotensinogen molecule, synthesized by the liver, to produce the bioinactive decapeptide angiotensin I. Angiotensin I is rapidly converted to the octapeptide angiotensin II by angiotensin converting enzyme in the lungs and other tissues.

10 Pathophysiology Of Adrenal Disorder Angiotensin II is a potent vasopressor; it stimulates aldosterone production but does not stimulate cortisol production. 1. Angiotensin II 2. plasma potassium level 3. plasma volume 4. ACTH level influence aldosterone secretion.

11 Pathophysiology Of Adrenal Disorder Cortisol is secreted by the adrenal glands in response to adrenocorticotropic hormone (ACTH). (ACTH) is a 39 amino acid neuropeptide that is regulated by corticotropin releasing t i i hormone (CRH) and vasopressin (AVP) produced in the hypothalamus. Glucocorticoids exert negative feedback on CRH and ACTH secretion.

12 Pathophysiology Of Adrenal Disorder Aldosterone binds to the mineralocorticoid receptor. In contrast, cortisol binds to both the mineralocorticoid receptor and glucocorticoid receptors. The intracellular enzyme 11β hydroxysteroidβ dehydrogenase (11β HSD) type II, which catabolizes cortisol to inactive cortisone, limits the functional binding to the former receptor.

13 Pathophysiology Of Adrenal Disorder Binding of aldosterone to the cytosol mineralocorticoid receptor leads to sodium (Na+) absorption and potassium (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.

14 Pathophysiology Of Adrenal Disorder Adrenal androgen precursors include dehydroepiandrosterone (DHEA) and its sulfate and androstenedione. These are synthesized in the zona reticularis under the influence of ACTH.

15 Pathophysiology Of Adrenal Disorder Adrenal androgen have minimal intrinsic androgenic activity, they contribute to androgenicity by their peripheral p conversion to testosterone and dihydrotestosterone. In men, excessive levels of adrenal androgens have no clinical consequences. In women they result in acne, hirsutism, and virilization. ili

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

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18 SYNDROMES OF DRENOCORTICAL HYPOFUNCTION

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22 Adrenal insufficiency Laboratory abnormalities may include: hyponatremia hyperkalemia mild metabolic tbli acidosis i Azotemia anemia lymphocytosis, and eosinophilia hypoglycemia y

23 Adrenal insufficiency Common manifestations i of adrenal insufficiency: anorexia weight loss increasing fatigue vomiting, diarrhea salt craving muscle and joint pain abdominal pain postural dizziness increased pigmentation

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26 Adrenal Insufficiency

27 Adrenal insufficiency, Diagnosis In a patient with chronic symptoms suggestive of adrenal insufficiency, a basal morning plasma cortisol measurement and 1 hour cosyntropin test should be performed. In the cosyntropin test, 0.25 mg of cosyntropin is given intravenously or intramuscularly, and plasma cortisol is measured after 0, 30, and 60 minutes. A normal response is a plasma cortisol concentration higher than 20 μg/dl at any time during the test.

28 Adrenal insufficiency Once the diagnosis of adrenal insufficiency is made, the distinction between primary and secondary adrenal linsufficiency i needs to be established. h d

29 Adrenal insufficiency Secondary adrenal insufficiency results from inadequate stimulation of the adrenal cortex by ACTH. To distinguish primary from secondary adrenal insufficiency, a basal morning plasma ACTH value should be obtained. Mineralocorticoid levels are normal in secondary adrenal Insufficiency.

30 Acute Adrenal insufficiency Acute adrenal insufficiency is a medical emergency, and treatment should not be delayed pending laboratory results. In a critically ill patient with hypovolemia, a plasma sample y p yp p p for cortisol, ACTH, aldosterone, and renin should be obtained, and then treatment with hydrocortisone (100 mg IV bolus) and parenteral saline administration should be initiated.

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

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

33 Adrenal insufficiency Type II polyglandular l l autoimmune syndrome, d also called Schmidt s syndrome, is characterized by Addison s disease, autoimmune thyroid disease (Graves disease or Hashimoto s thyroiditis), and insulin dependent d tdiabetes mellitus. Oh Other associated ddiseases include: pernicious anemia, vitiligo, gonadal failure, hypophysitis, celiac disease, myasthenia gravis, primary biliary cirrhosis, Sjögren ssyndrome, lupus erythematosus, t and Parkinson s disease. This syndrome usually develops in adults.

34 Congenital Adrenal Hyperplasia(CAH) Congenital adrenal hyperplasia (CAH) refers to autosomal recessive disorders of adrenal steroid biosynthesis that result in glucocorticoid and mineralocorticoid df deficiencies and compensatory increase in ACTH secretion.

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

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37 Mineralocorticoid Deficiency Mineralocorticoid deficiency can result from decreased renin secretion by the kidneys. Hypoangiotensinemia leads to hypoaldosteronism with hyperkalemia and hyperchloremic metabolic acidosis.

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39 SYNDROMES OF ADRENOCORTICAL HYPERFUNCTION

40 SYNDROMES OF ADRENOCORTICAL HYPERFUNCTION Hypersecretion of the glucocorticoid hormone cortisol results in Cushing ss 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.

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44 Diagnosis 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 test Dexamethasone, 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.

45 Diagnosis Cortisol is normally secreted in a diurnal manner: The plasma concentration is highest in the early morning (between 6:00 and 8:00 am) and lowest around midnight. Most patients with Cushing s syndrome have blunted diurnal variation. Because of the difficulty of obtaining nighttime plasma cortisol levels, measurement of late night salivary cortisol has been developed to assess hypercortisolism.

46 Diagnosis 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 ss disease and the ectopic ACTH syndrome but are suppressed in primary adrenal Cushing s syndrome. P i ih d ACTH l l d d l Patients with a suppressed ACTH level can proceed to adrenal imaging studies.

47 Treatment The preferred treatment for all forms of Cushing s syndrome is appropriate p surgery. A more appealing option for patients with Cushing s disease who remain hypercortisolemic after pituitary surgery is radiotherapy and bilateral adrenalectomy followed by lifelong glucocorticoid and mineralocorticoid replacement therapy.

48 Treatment In patients with the ectopic ACTH syndrome, the goal is to localize the tumor by appropriate scans so it can be removed surgically. A unilateral l adrenalectomy is the treatment of choice in patients with a cortisol secreting adrenal adenoma.

49 Primary Mineralocorticoid Excess

50 Primary Mineralocorticoid Excess Primary aldosteronism is usually recognized during evaluation of hypertension or hypokalemia. Up to 5% of patients with hypertension have primary aldosteronism. These patients are usually between the ages of 30 and 50 years, and the female to male ratio is 2 : 1.

51 Primary Mineralocorticoid Excess, Clinical Presentations 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.

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