PHYSIOLOGY

The adrenal glands are located on the upper pole of each kidney and consist of two distinct regions:

The cortical-

-The bone marrow.

The adrenal cortex is, in turn, three anatomical areas:

the glomerular zone, the outermost, which secretes aldosterone, mineralocorticoid hormone;

collated the area, mid-term, which secretes cortisol;

the zona reticularis, the innermost, which secretes adrenal androgens.

particular we have that:

Glomerular area, consists of parenchymal cells that synthesize and secrete mineralocorticoid hormones to maintain water balance

The glomerular area owes its name to the particular organization of the glandular tissue in cell cords wrapped around itself to form rounded structures ("clusters"). It produces mineralocorticoids, especially aldosterone, which increases sodium reabsorption in the distal tubule and collecting duct, also increases the elimination of potassium and hydrogen ions. A result of the reabsorption of sodium is an increase of circulating blood volume with elevated blood pressure.

. Fasciculata zone, however, synthesizes and secretes glucocorticoids and controls the metabolism of carbohydrates, fats and proteins)

The zona fasciculata is the middle layer between the layers of the adrenal cortex, located between the zona glomerulosa and zona reticularis. He works to synthesize and secrete glucocorticoids and a small amount of androgens (DHEAS, or dehydroepiandrosterone). Cancer of the collated area can lead to primary hypersecretion of the adrenal cortex.

Reticulated area (producing sex hormones like androgen, estrogen and progesterone).

The adrenal medulla, which is at the center of the gland, is, from the functional point of view, connected to the sympathetic nervous system and secrete catecholamines, epinephrine and norepinephrine in response to stress. The synthesis of all steroid hormones originating from cholesterol and is catalyzed by a series of enzymatic reactions regulated. Glucocorticoids affect metabolism, cardiovascular function, behavior and inflammation / immunity. Cortisol, the natural human glucocorticoid, is secreted by the adrenal glands in response to hormonal stimulation ultradian, circadian and stress-induced, mediated adrenocorticotropic hormone (adrenocorticotropic hormone, ACTH). The plasma cortisol circadian rhythm has a well defined, with concentrations highest in the morning. ACTH, a neuropeptide of 39 amino acids, is part of a molecular precursor, the pro-opio-melanocortin (POMC), which also contains the (beta-endorphin, beta-lipotropin, the peptide corticotropin-like intermediate lobe ( corticotropin-like intermediate-lobe peptide, CLIP) and various melanocyte-stimulating hormone (melanocyte-stimulating hormones, MSH). The secretion of ACTH by the pituitary is regulated primarily by two hypothalamic polypeptides: the corticotropin-releasing hormone ( short-cotropin-releasing hormone, CRH), a peptide of 41 amino acids, and vasopressin, a decapeptide. Glucocorticoids exert negative feedback on the secretion of CRH and ACTH. The hypothalamic-pituitary-adrenal axis (hypothalamic-pituitary-adrenal , HPA) interacts and affects the reproductive function, growth and thyroid function at various levels, with greater participation at all levels of glucocorticoids.



Actions of glucocorticoids
Maintain metabolic homeostasis

Regulate blood sugar, have permissive effects on gluconeogenesis (see carbohydrate), increase glycogen synthesis, lead to increased levels of insulin, lipolytic hormones have permissive effects, increased catabolism, reduce anabolism (except fat), inhibit the growth hormone axis, inhibit the reproductive axis and also have mineralocorticoid activity of cortisol.

Affect connective tissues

Cause the loss of collagen and connective tissue

Influencing the calcium homeostasis

Stimulate osteoclasts, inhibit osteoblasts, reduces the intestinal absorption of calcium, stimulate the release of parathyroid hormone, increases the urinary excretion of calcium, reduces the reabsorption of phosphate

Maintain cardiovascular function

Increase cardiac output, increased vascular tone, have permissive effects on hormones pressure, increase sodium retention

Influence the behavior and cognitive function

Affect the immune system

Increase the concentration of intravascular leukocytes, reduce the migration of inflammatory cells to sites of damage, suppress the immune system (timolisi, suppression of cytokines, prostanoid, kinin, serotonin, histamine, and the activity of the collagenase plasminaogeno).



The renin-angiotensin-aldosterone system is the most important factor controlling the secretion of aldosterone. The juxtaglomerular cells secrete renin in the kidney in response to the decrease in blood volume and / or reduction of renal perfusion pressure. Renin is the rate-limiting enzyme that cleaves angiotensinogen to 60 kDa, synthesized in the liver, bioinattivo decapeptide angiotensin I. This is rapidly converted nell'octapeptide angiotensin II by angiotensin converting enzyme (angiotensin-converting enzyme, ACE) in the lungs and other tissues. Angiotensin II is a potent vasoconstrictor and also stimulates the production of aldosterone, but not that of cortisol. It is the predominant regulator of aldosterone secretion, but this is also affected by serum potassium, sodium balance and ACTH. The average ACTH probably the circadian rhythm of aldosterone, by determining the concentration peaks during the morning. Aldosterone binds to mineralocorticoid receptors type I and cortisol binds to glucocorticoid receptors of type II. The binding of aldosterone to mineralocorticoid receptors in the renal cytosol induces the efflux of Na + in the extracellular fluid and the secretion of K + and H + through the sodium-potassium pump. The resulting increase in sodium and decrease in serum potassium induce a feedback mechanism to suppress the secretion of renin and, consequently, that of aldosterone. About 5% of cortisol and aldosterone were 40% unbound form. The rest is bound to corticosteroid binding globulin and albumin.

The adrenal androgens include dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) and androstenedione. These are summarized in the lattice under the influence of ACTH and other adrenal androgen stimulating factors. Although the adrenal androgens possess a minimal intrinsic androgenic activity, contribute all'androgenicità by its peripheral conversion to testosterone and dihydrotestosterone. In adult males, excess adrenal androgens has no clinical consequences, and females, however, the peripheral conversion of excessive amounts of adrenal androgens causes acne, hirsutism and virilization. Because of the gonadal production of androgens and estrogens and secretion of norepinephrine by sympathetic ganglia, the lack of adrenal androgens and catecholamines is not clinically evident.

. Adrenocortical hypofunction syndromes

Primary adrenal disorders

Combined deficiency of glucocorticoid and mineralocorticoid



Autoimmune
Isolated autoimmune disease (Addison's disease)

Poliendocrina syndrome type I

Poliendocrina syndrome type II

Infections
Tuberculosis

Mycosis

Cytomegalovirus

HIV
.

Vascular

Bilateral adrenal hemorrhage

Sepsis

Coagulopathy

Thrombosis / embolism

Myocardial adrenal

Infiltration
Carcinoma / lymphoma, metastatic

Sarcoidosis

Amyloidosis

Hemochromatosis

Congenital
Congenital adrenal hyperplasia

21-hydroxylase deficiency in

Deficiency of 3beta-ol-dehydrogenase

Deficit-desmolasi 20.22

Adrenal insensitivity to ACTH

Congenital adrenal hypoplasia

Adrenoleukodystrophy

Adrenomyeloneuropathy
.

Iatrogenic
Bilateral adrenalectomy

Drugs: metyrapone, aminoglutethimide, trilostano, ketoconazole, o, p '-DDD, RU 486

Isolated mineralocorticoid deficiency

Deficit of corticosterone-metilossidasi

Isolated defect of the zona glomerulosa

Heparin therapy

Critical illness

Angiotensin converting enzyme inhibitors

Secondary adrenal disorders

Secondary adrenal insufficiency

Hypothalamic-pituitary dysfunction

Exogenous glucocorticoids

By removing an ACTH-secreting tumor

Hypoaldosteronism iporeninemico
Diabetic Nephropathy

Tubulointerstitial disease

Obstructive uropathy

Autonomic neuropathy

Nonsteroidal anti-inflammatory drugs

Beta-adrenergic
.



Glucocorticoid insufficiency can be primary, consequently the destruction or dysfunction of the adrenal cortex, or secondary, caused dall'iposecrezione of ACTH. The autoimmune destruction of the adrenal glands (Addison's disease) is the most common cause of primary adrenal insufficiency in the industrialized world, accounting for about 65% of cases. In this condition are deficient both the secretion of glucocorticoids that the secretion of mineralocorticoids, if untreated, is usually fatal. The function of the adrenal medulla is usually spared. About 10% of patients with Addison's disease have antibodies anti-adrenal axis. In the past, tuberculosis was the most common cause of adrenal insufficiency, but in the developed world its incidence has been decreasing since the 60s and is currently responsible for about 15-20% of cases. Calcified adrenal glands can be observed in 50% of cases of tuberculous adrenal insufficiency. Fungal infections and cytomegalovirus, metastatic infiltration of adrenal glands, sarcoidosis, amyloidosis, hemochromatosis, traumatic damage at the expense of both adrenal glands, bilateral adrenal hemorrhage and sepsis (meningococcemia usually) are not causes frequent adrenal insufficiency. Patients infected with HIV often have low adrenal reserve in the absence of adrenal insufficiency occurs. The causes of congenital adrenal dysfunction include congenital adrenal hyperplasia, adrenal insensitivity to ACTH, adrenal hypoplasia congenita and two demyelinating disorder of lipid metabolism: the adrenoleukodystrophy and adrenomyeloneuropathy. The causes of iatrogenic adrenal insufficiency include bilateral adrenalectomy, agents that inhibit the biosynthesis of cortisol (metyrapone, aminoglutethimide, trilostano, ketoconazole), drugs adrenolytic (o, p'-DDD) and the glucocorticoid antagonist RU 486.



Addison's disease may belong to two different autoimmune syndromes polighiandolari. Poliendocrina syndrome type I, also called ectodermal dystrophy poliendocrina-candidiasis-autoimmune (autoimmune polyendocrine-candidiasis-ectodermal dystrophy, APECED) or autoimmune polyglandular failure syndrome, is characterized by the triad hypoparathyroidism, adrenal insufficiency and mucocutaneous candidiasis. Other less common manifestations include hypothyroidism, gonadal failure, gastrointestinal malabsorption, diabetes mellitus, insulin-dependent, the arch and total alopecia, pernicious anemia, vitiligo, chronic active hepatitis, keratopathy, the 'dental enamel hypoplasia and nail, the pituitary gland, the splenic and hepatic cholelithiasis. This syndrome occurs in children. Poliendocrina autoimmune syndrome type II, also known as Schmidt syndrome, is characterized by Addison's disease, the autoimmune thyroid disease (Graves' disease or Hashimoto's thyroiditis) and insulin-dependent diabetes mellitus. Other diseases associated with less frequent include pernicious anemia, vitiligo, gonadal failure, hypophysitis, celiac disease, myasthenia gravis, primary biliary cirrhosis, Sjogren's syndrome, lupus and Alzheimer's disease. This syndrome usually occurs in adults.



Symptoms.

Adrenal insufficiency typically begins with weight loss, worsening weakness, vomiting, diarrhea, or anorexia and desire for salt. They can also be muscle pain, joint and abdominal and postural dizziness. Often signs of hyperpigmentation (extensor surfaces, creases on palms and on the oral mucosa) as a result of the increased production of pituitary ACTH and other POMC-related peptides. Laboratory abnormalities may include hyponatremia and hyperkalemia, mild metabolic acidosis, the azotemia, hypercalcemia, anemia, lymphocytosis and eosinophilia. There may be too low blood sugar, especially in children.

Acute adrenal insufficiency is a medical emergency and you should not delay treatment while awaiting the laboratory results. In a seriously ill patient with postural hypotension and hypovolaemia should perform a blood test for the evaluation of cortisol, ACTH and plasma renin activity, then, should immediately establish treatment with an intravenous bolus of 100 mg of hydrocortisone and administration injecting saline solution. A plasma cortisol level greater than 18 mg / dl to exclude the diagnosis of adrenal crisis, whereas a value below 18 mg / dl associated with shock may be indicative of adrenal insufficiency. In the case of a patient with chronic symptoms should perform a test to one hour with the cosintropina. In this test dose of 0.25 mg of ACTH [1 -24] (cosintropina) intravenously, and then assessing the plasma cortisol in O, 30 and 60 minutes. A normal response consists of a plasma cortisol level greater than 18 mg / dl at any time of the test. A patient with a basal morning plasma cortisol less than 12 mg / dl and a concentration of cortisol after stimulation of less than 18 mg / dl probably presents a frank adrenal insufficiency and should be treated appropriately. Basal plasma cortisol levels between 10 and 18 mg / dl are probably indicative of a reduced adrenal reserve and the need for cortisol replacement therapy in conditions of stress.



Once the diagnosis of adrenal insufficiency, it is necessary to distinguish between primary and secondary form shape. This follows an inadequate stimulation of the adrenal cortex by ACTH. This may be related to lesions located anywhere along the hypothalamic-pituitary axis, or as a sequela of prolonged HPA axis suppression by exogenous glucocorticoids. Secondary adrenal insufficiency presents with manifestations similar to those of primary adrenal insufficiency with some important differences, since the ACTH and other POMC-related peptides are reduced-indicated in secondary adrenal insufficiency, hyperpigmentation is not present. Furthermore, since normal levels of mineralocorticoids, the symptoms related to the desire for salt, as well as the anus

Laboratory abnormalities represented by un'iperkaliemia by acidosis and metabolic, are not present. However, hyponatremia is often found in connection all'inappropriata ADH secretion that accompanies the lack of glucocorticoids, resulting in altered excretion of fluids. Since the secretion of corticotropin is the most preserved among all pituitary hormones, a patient with secondary adrenal insufficiency due to a pituitary lesion usually presents the accompanying symptoms and / or laboratory abnormalities indicative of hypothyroidism, hypogonadism, or growth hormone deficiency . To distinguish primary from secondary adrenal insufficiency should be evaluated-smatico basal plasma ACTH and plasma renin in the morning after standing (2 hours). Plasma ACTH concentrations greater than 20 pg / ml (normal values are between 5 and 30 pg / ml) are indicative of primary adrenal insufficiency, whereas a value of less than 20 pg / ml is probably secondary adrenal insufficiency. A plasma level of renin assessed in an upright position than 3/ng/ml/h is indicative of primary adrenal insufficiency, whereas a value of less than 3 ng / ml / h is probably secondary adrenal insufficiency. The test to be deleted is cosintropina an hour-indicated in secondary adrenal in primary schools. Secondary adrenal insufficiency commonly occurs after discontinuation of long-term glucocorticoid therapy. When you need a prolonged treatment with glucocorticoids, administered every other day lead to less suppression of HPA compared to daily dosing. The natural history of recovery from iatrogenic adrenal suppression include, sequentially, a gradual increase in the levels of ACTH, followed by normalization of plasma cortisol levels and, therefore, the normalization of the cortisol response to ACTH. The complete recovery of HPA axis function can take a year, the rate-limiting step appears to be the recovery of CRH-secreting neurons.



Treatment

Acute adrenal insufficiency after stabilization, patients with Addison's disease require glucocorticoid replacement therapy is that mineralocorticoid for life. Unfortunately, many doctors tend to treat their patients with an excess of glucocorticoids and to underestimate the mineralocorticoid therapy. Since the excessive administration of glucocorticoids results in an insidious weight gain and osteoporosis, it is recommended to administer the minimum dose tolerated without incurring the symptoms of cortisol deficiency of glucocorticoids (usually pain). It is recommended that a treatment regimen of 15-20 mg of hydrocortisone in the morning and 5 mg at 4 pm, which mimics the physiological dose. While the glucocorticoid replacement therapy is quite uniform in most patients, replacement therapy with mineralocorticoids varies enormously. The initial dose of fludrocortisone, a mineralocorticoid synthesis, should be 100 (microg / day and should be adjusted to maintain plasma renin in the upright position between 1 and 3 ng / ml / h. Patients undergoing stress (eg interventions) should receive a dose of 150-300 mg of hydrocortisone daily.



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