Mineralocorticoid disorder

Mineralocorticoid disorders can have high or low aldosterone production. Even in hyperaldosteronism disorders, circulating aldosterone and aldosterone metabolite excretion can be in the upper normal range. For this reason it is important to determine the aldosteroneirenin ratio. 

An endocrine disorder first described by the British Physician Thomas Addison in the mid 1800 s. The adrenal glands fail to produce sufficient amounts of glucocorticoid hormones (cortisol) and sometime mineralocorticoid (aldosterone). If left untreated it is life-threatening, the patient will show muscle weakness, hyperpigmentation and even depression. Typical treatment is hydrocortisone replacement therapy. 

The major mineralocorticoid, aldosterone, is secreted by cells of the zona glomerulosa. Primary hyperaldosteronism (Conn s syndrome) is associated with potassium depletion which is, in mm, responsible for the observed neuromuscular abnormalities seen in the disorder. These are similar to those seen in hypokalemic periodic paralysis (PP), with episodic and severe exacerbations of fixed muscle weakness. Muscle biopsy shows occasional muscle necrosis and vacuoles often these feamres are accompanied by mbular aggregates as in hypokalemic PP. All these changes can be attributed to the hypokalemia and not to excess aldosterone production per se. 

In depressed patients, cortical-hypothalamic-pituitary-adrenal axis hyperactivity can be explained by the hypersecretion of CRF, and secondary pituitary and adrenal gland hypertrophy. Impaired negative feedback at various CNS sites, including the hippocampus and pituitary are also likely to contribute. Downregulation of hippocampal mineralocorticoid receptors and expression is reported in depressed suicides [50]. In bipolar disorder, hyperactivity of the cortical-hypothalamic-pituitary-adrenal axis has been observed [51]. This increase in cortical-hypothalamic-pituitary-adrenal axis activity has also been observed in mixed mood states, mania and in depression in rapidcycling patients. Partial reversal of HPA overactivity is associated with treatment and recovery from depression. 

Steroids have mineralocorticoid and glucocorticoid effects. Betamethasone has little, if any, mineralocorticoid effect. However, it should be used with caution in patients predisposed to hypertension since mineralocorticoid effects may lead to sodium and water retention and an increase in blood pressure. When used systemically, especially at high doses, steroid therapy is associated with a risk of psychiatric reactions such as euphoria, irritability, mood lability and sleep disorders. Glucocorticoid side-effects include diabetes and osteoporosis. 

Endocrine disorders Primary or secondary adrenal cortical insufficiency (hydrocortisone or cortisone is the drug of choice synthetic analogs may be used in conjunction with mineralocorticoids in infancy, mineralocorticoid supplementation is important) congenital adrenal hyperplasia nonsuppurative thyroiditis hypercalcemia associated with cancer. 

Kellner M, Wiedemann K, Yassouridis A, Levengood R, Guo LS, Holsboer F, Yehuda R (2000) Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder. Biol Psychiatry 47 107-111 Kellner M, Baker DG, Yassomidis A, Bettinger S, Otte C, Naber D, Wiedemann K (2002a) Mineralocorticoid receptor fimction in patients with posttramnatic stress disorder. Am J Psychiatry 159 1938-1940... 

Fluorination of corticosteroids at C-9 or/and C-6 increases glucocorticoid activity, while mineralocorticoid activity, responsible for sodium retention (the main adverse effect of corticoids), is decreased (cf. Chapter 4). Fluorocorticoster-oids were the first fluorinated compounds to be used clinically. They are still major drugs against many inflammatory disorders rheumatoid polyarthritis, ORL (asthma, rhinitis), brain edema, dermatological, allergies, anaphylactic shock, Quincke s edema). 

Primary aldosteronism usually results from the excessive production of aldosterone by an adrenal adenoma. However, it may also result from abnormal secretion by hyperplastic glands or from a malignant tumor. The clinical findings of hypertension, weakness, and tetany are related to the continued renal loss of potassium, which leads to hypokalemia, alkalosis, and elevation of serum sodium concentrations. This syndrome can also be produced in disorders of adrenal steroid biosynthesis by excessive secretion of deoxycorticosterone, corticosterone, or 18-hydroxycorticosterone—all compounds with inherent mineralocorticoid activity. 

Mutations in each of the three domains mentioned above can potentially disrupt gene transcription and lead to hormone resistance or other hormonally related disorders (Table 4). Information about glucocorticoid, mineralocorticoids, androgens, estrogens, retinoic acid, vitamin D, and the AH receptor is summarized in Table 4. Mineralocorticoid, estrogen, and AH receptors are discussed in greater detail below. 

The adrenal cortex synthesizes corticosteroids (glucocorticoids and mineralocor-ticoids), which differ in activities. In humans, cortisol is the main glucocorticoid, and aldosterone is a main mineralocorticoid. Steroid therapy causes severe potential side effects, hence a careful consideration is always exercised before starting therapy. These are used in variety of disorders such as rheumatic disorder, renal disease, allergic manifestation, bronchial asthma, skin diseases, infectious diseases, malignancy, and hepatic diseases. 

Several relatively common disorders result in aldosterone secretion abnormalities and aberrations of electrolyte status. In Addison s disease, the adrenal cortex is often destroyed through autoimmune processes. One of the effects is a lack of aldosterone secretion and decreased Na+ retention by the patient. In a typical Addison s disease patient, serum [Na+] and [CL] are 128 and 96 meq/L, respectively (see Table 16.2 for normal values). Potassium levels are elevated, 6 meq/L or higher, because the Na+ reabsorption system of the kidney, which is under aldosterone control, moves K+ into the urine just as it moves Na+ back into plasma. Thus, if more Na+ is excreted, more K+ is reabsorbed. Bicarbonate remains relatively normal. The opposite situation prevails in Cushing s disease, however, in which an overproduction of adrenocorticosteroids, especially cortisol, is present. Glucocorticoids have mild mineralocorticoid activities, but ACTH also increases aldosterone secretion. This may be caused by an oversecretion of ACTH by a tumor or by adrenal hyperplasia or tumors. Serum sodium in Cushing s disease is slightly elevated, [K+] is below normal (hypokalemia), and metabolic alkalosis is present. The patient is usually hypertensive. A more severe electrolyte abnormality is seen in Conn s syndrome or primary aldosteronism, usually caused by an adrenal tumor. Increased blood aldosterone levels result in the urinary loss of K+ and H+, retention of Na+ (hypernatremia), alkalosis, and profound hypertension. 

New MI, Wilson RC Steroid disorders in children congenital adrenal hyperplasia and apparent mineralocorticoid excess. Proc Natl Acad Sci USA 96 12790-12797,1999. 

The most common cause of hyponatremia in hospital patients is SIADH. However, other disorders can cause dilutional hyponatremia and must be differentiated from SIADH. These conditions include (1) congestive heart failure, (2) renal insufficiency, (3) nephrotic syndrome, (4) liver cirrhosis, and (5) hypothyroidism. Excessive administration of hypotonic fluids and treatment with drugs that stimulate AVP (e.g., chlorpropamide, vincristine, clofibrate, carbamazepine, nicotine, phenothiazines, and cyclophosphamide) can cause dilutional hyponatremia as well. Hyponatremia may also occur from renal or extrarenal sodium losses (depietional hyponatremia) as a result of vomiting, diarrhea, excessive sweating, diuretic abuse, saltlosing nephropathy, or mineralocorticoid deficiency. 

Even when time of sampling, posture, drug intake, and diet are controlled, it is often difficult to identify disorders of mineralocorticoid secretion on the basis of basal hormone concenti ations alone. A variety of dynamic tests have therefore been developed to help document hypersecretion or hyposecretion of aldosterone and renin. 

A deficiency of ll -hydroxylase is the second most common form of CAH, with an incidence of 1 per 100,000 births, and is associated with manifestations of virilization, elevated concentrations of plasma androstenedione and DHEA-S, and hypertension. The mineralocorticoid-induced hypertension is caused by an elevation of DOC 11-deoxycortisol concentrations are markedly raised in subjects with this enzyme defect,The major distinguishing characteristic of this disorder from 21-hydroxylase deficiency, besides the elevated plasma concentrations of 11-deoxycortisol, is hypertension elicited by the salt retention caused by increased concentrations of DOC, A deficiency of 3 -hydroxysteroid dehydrogenase-isomerase has been reported and leads to an elevation in the ratio of 17a-hydroxypregnenolone to that of 17a-hydroxyprogesterone and to an increased ratio of DHEA to androstenedione. In severe forms of this rare disorder, female infants have pseudohermaphroditism, and male infants present with incomplete masculinization. Patients with this disorder usually present in early infancy with complete adrenal insufficiency including salt wasting. A late-onset form has also been reported in patients with premature pubarche with hirsutism, acne, and menstrual irregularities. The... 

Management of these disorders usually consists of treatment of the underlying cause of mineralocorticoid excess. In patients in whom the mineralocorticoid excess cannot be corrected, chronic pharmacologic therapy may be required. 

Management of these disorders usually consists of treatment of the underlying cause of the mineralocorticoid excess. Patients who are taking corticosteroids may require a dosage reduction or may need to be switched to a corticosteroid with less mineralocorticoid activity. Patients with an endogenous source of excess mineralocorticoid activity may require surgery or the administration of spironolactone, amiloride, or triamterene. " " ... 

The major disease clearly linked with disordered sodium homeostasis, among other diseases, is hypertension, and this is observed in very small populations with genetic defects including glucocorticoid-responsive aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess (AME) (Anke 2002). Cystic fibrosis is another genetically determined defect in the chloride channels. This leads to the secretion of sweat with high NaCl concen-... 

REPLACEMENT THERAPY Adrenal insufficiency can result from structural or functional lesions of the adrenal cortex (primary adrenal insufficiency or Addison s disease) or from structural or functional lesions of the anterior pituitary or hypothalamus (secondary adrenal insufficiency). In developed countries, primary adrenal insufficiency most frequently is secondary to autoimmune adrenal disease, whereas tuberculous adrenalitis is the most frequent etiology in underdeveloped countries. Other causes include adrenalectomy, bilateral adrenal hemorrhage, neoplastic infiltration of the adrenal glands, acquired immunodeficiency syndrome, inherited disorders of the steroidogenic enzymes, and X-Unked adrenoleukodystrophy. Secondary adrenal insufficiency resulting from pituitary or hypothalamic dysfunction generally presents in a more insidious manner than does the primary disorder, probably because mineralocorticoid biosynthesis is preserved. 

Semisynthetic analogues exhibiting high mineralocorticoid activity are not employed in the treatment of rheumatic disorders because of toxic side effects resulting from a disturbance of electrolyte and water balance. Some newer synthetic steroids (Table 33.2) are relatively free of sodium-retaining activity. They may show other toxic manifestations, however, and eventually need to be withdrawn. 

The adrenal cortex produces glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Corticosteroids promote sodium retention and potassium excretion. Corticotropin (Acthar) is an ACTH dmg that is used to diagnosis adrenal gland disorders. 

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