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Primary adrenal insufficiency: Endocrine Society practice guidelines

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Primary adrenal insufficiency: Endocrine Society practice guidelines

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones, primarily cortisol; but may also include impaired production of aldosterone (a mineralocorticoid), which regulates sodium conservation, potassium secretion, and water retention. Craving for salt or salty foods due to the urinary losses of sodium is common.

Addison’s disease and congenital adrenal hyperplasia can manifest as adrenal insufficiency. If not treated, adrenal insufficiency may result in severe abdominal pains, vomiting, profound muscle weakness and fatigue, depression, extremely low blood pressure (hypotension), weight loss, kidney failure, changes in mood and personality, and shock (adrenal crisis). An adrenal crisis often occurs if the body is subjected to stress, such as an accident, injury, surgery, or severe infection; death may quickly follow.

Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland does not make adequate amounts of the hormones that assist in regulating adrenal function. This is called secondary or tertiary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus, respectively.

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In 2016 Feb, Endocrine Society came out with guidelines on diagnosis and treatment of primary adrenal insufficiency. Following are its major recommendations:-

Who Should Be Tested and How?

The Task Force recommends diagnostic testing to exclude primary adrenal insufficiency (PAI) in acutely ill patients with otherwise unexplained symptoms or signs suggestive of PAI (volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation or, especially in children, hypoglycemia).

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The Task Force recommends confirmatory testing with the corticotropin stimulation test in patients with clinical symptoms or signs suggesting PAI when the patient’s condition and circumstance allow.

In patients with severe adrenal insufficiency symptoms or adrenal crisis, the Task Force recommends immediate therapy with intravenous (iv) hydrocortisone at an appropriate stress dose prior to the availability of the results of diagnostic tests.

Optimal Diagnostic Tests

The Task Force suggests the standard dose (250 μg for adults and children ≥2 y of age, 15 μg/kg for infants, and 125 μg for children <2 y of age) iv corticotropin stimulation (30 or 60 min) test over other existing diagnostics tests to establish the diagnosis of adrenal insufficiency. Peak cortisol levels below 500 nmol/L (18 μg/dL) (assay dependent) at 30 or 60 minutes indicate adrenal insufficiency.

The Task Force suggests the low-dose (1 μg) corticotropin test for diagnosis of PAI only when the substance itself is in short supply.

If a corticotropin stimulation test is not feasible, the Task Force suggests using a morning cortisol <140 nmol/L (5 μg/dL) in combination with adrenocorticotropic hormone (ACTH) as a preliminary test suggestive of adrenal insufficiency (until confirmatory testing with corticotropin stimulation is available).

The Task Force recommends measurement of plasma ACTH to establish PAI. The sample can be obtained at the same time as the baseline sample in the corticotropin test or paired with the morning cortisol sample. In patients with confirmed cortisol deficiency, a plasma ACTH >2-fold the upper limit of the reference range is consistent with PAI.

The Task Force recommends the simultaneous measurement of plasma renin and aldosterone in PAI to determine the presence of mineralocorticoid deficiency.

The Task Force suggests that the etiology of PAI should be determined in all patients with confirmed disease.

Treatment of Primary Adrenal Insufficiency in Adults

Glucocorticoid Replacement Regimen

The Task Force recommends glucocorticoid therapy in all patients with confirmed PAI.

The Task Force suggests using hydrocortisone (15–25 mg) or cortisone acetate (20–35 mg) in two or three divided oral doses per day; the highest dose should be given in the morning at awakening, the next either in the early afternoon (2 h after lunch; two-dose regimen) or at lunch and afternoon (three-dose regimen). Higher frequency regimens and size-based dosing may be beneficial in individual cases.

As an alternative to hydrocortisone, the Task Force suggests using prednisolone (3–5 mg/d), administered orally once or twice daily, especially in patients with reduced compliance.

The Task Force suggests against using dexamethasone for the treatment of PAI because of risk of Cushingoid side effects due to difficulties in dose titration.

The Task Force suggests monitoring glucocorticoid replacement using clinical assessment including body weight, postural blood pressure, energy levels, signs of frank glucocorticoid excess.

The Task Force suggests against hormonal monitoring of glucocorticoid replacement and to adjust treatment only based on clinical response.

Mineralocorticoid Replacement in PAI

The Task Force recommends that all patients with confirmed aldosterone deficiency receive mineralocorticoid replacement with fludrocortisone (starting dose, 50–100 μg in adults) and not restrict their salt intake.

The Task Force recommends monitoring mineralocorticoid replacement primarily based on clinical assessment (salt craving, postural hypotension, or edema), and blood electrolyte measurements.

In patients who develop hypertension while receiving fludrocortisone, the Task Force suggests reducing the dose of fludrocortisone.

If blood pressure remains uncontrolled, the Task Force suggests initiating antihypertensive treatment and continuing fludrocortisone.

Dehydroepiandrosterone Replacement

The Task Force suggests a trial of dehydroepiandrosterone (DHEA) replacement in women with PAI and low libido, depressive symptoms, and/or low energy levels despite otherwise optimized glucocorticoid and mineralocorticoid replacement.

The Task Force suggests an initial period of 6 months of DHEA replacement. If the patient does not report a sustained, beneficial effect of replacement after 6 months, the DHEA should be discontinued.

The Task Force suggests monitoring DHEA replacement by measuring morning serum DHEA sulfate (DHEAS) levels (aiming at the midnormal range) before the intake of the daily DHEA replacement dose.

Treatment during Pregnancy

The Task Force suggests that pregnant patients with PAI be monitored for clinical symptoms and signs of glucocorticoid over- and under-replacement (e.g., normal weight gain, fatigue, postural hypotension or hypertension, hyperglycemia), with at least one review per trimester.

The Task Force suggests that, based on the individual clinical course, an increase in hydrocortisone dose should be implemented, in particular during the third trimester.

In pregnant women with PAI, The Task Force suggests using hydrocortisone over cortisone acetate, prednisolone, or prednisone and recommend against using dexamethasone because it is not inactivated in the placenta.

The Task Force recommends hydrocortisone stress dosing during the active phase of labor, similar to that used in major surgical stress.

Treatment and Monitoring during Childhood

In children with PAI, the Task Force suggests treatment with hydrocortisone in three or four divided doses (total starting daily dose of 8 mg/m2 body surface area) over other types of glucocorticoid replacement therapies, with doses adjusted according to individual need.

In children with PAI, the Task Force suggests avoiding synthetic, long-acting glucocorticoids (e.g., prednisolone, dexamethasone).

The Task Force suggests monitoring glucocorticoid replacement by clinical assessment, including growth velocity, body weight, blood pressure, and energy levels.

In children with PAI and confirmed aldosterone deficiency, the Task Force recommends treatment with fludrocortisone (starting dosage, 100 μg/d). For infants, the Task Force recommends sodium chloride supplements in the newborn period and up to the age of 12 months.

Management and Prevention of Adrenal Crisis in Patients with PAI

The Task Force recommends that patients with suspected adrenal crisis should be treated with an immediate parenteral injection of 100 mg (50 mg/m2 for children) hydrocortisone, followed by appropriate fluid resuscitation and 200 mg (50–100 mg/m2 for children) of hydrocortisone/24 hours (via continuous iv therapy or 6 hourly injection); age- and body surface-appropriate dosing is required in children.

If hydrocortisone is unavailable, the Task Force suggests prednisolone as an alternative. Dexamethasone is the least-preferred alternative and should only be given if no other glucocorticoid is available.

For the prevention of adrenal crisis, the Task Force suggests adjusting glucocorticoid dose according to severity of illness or magnitude of the stressor.

The Task Force suggests patient education concerning glucocorticoid adjustments in stressful events and adrenal crisis-prevention strategies including parenteral self- or lay-administration of emergency glucocorticoids.

The Task Force recommends that all patients should be equipped with a steroid emergency card and medical alert identification to inform health personnel of the need for increased glucocorticoid doses to avert or treat adrenal crisis and the need of immediate parenteral steroid treatment in the event of an emergency.

The Task Force recommends that every patient should be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.

Additional Monitoring Requirement

The Task Force suggests that adults and children with PAI be seen by an endocrinologist or a healthcare provider with endocrine expertise at least annually. Infants should be seen at least every 3 to 4 months.

The Task Force suggests that PAI patients be evaluated annually for symptoms and signs of over- and under-replacement.

The Task Force suggests periodic screening for autoimmune diseases known to be more prevalent in PAI patients in whom autoimmune origin of PAI has not been excluded. The optimal frequency of screening is unknown but can be done annually. These conditions include thyroid disease, diabetes mellitus, premature ovarian failure, celiac disease, and autoimmune gastritis with vitamin B12 deficiency.

The Task Force suggests patient education about increasing the dosage of glucocorticoids during intercurrent illness, fever, and stress. This education includes identification of precipitating symptoms and signs and how to act in impending adrenal crisis.

The Task Force suggests genetic counseling for patients with PAI due to monogenic disorders.

You can read the full Guideline by clicking on the link :

Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. [181 references] PubMed

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