Endocrinology

Adrenal Insufficiency in Adrenoleukodystrophy

Males with adrenoleukodystrophy (ALD) are at high risk for primary adrenal insufficiency.  The largest studies suggest roughly 80 to 86% of males with ALD will develop adrenal insufficiency in their lifetime, with the majority developing adrenal insufficiency during childhood.  Because of newborn screening, adrenal insufficiency can be detected before a child has significant symptoms and treated with standard therapies.

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What do the adrenal glands usually do and how does ALD affect the adrenal glands?

The adrenal glands sit on top of the kidneys and are under the control of the pituitary gland, which makes ACTH.  The adrenal cortex is responsible for making several classes of hormones, including mineralocorticoids (which regulate salt balance in the body), glucocorticoids (which help maintain blood pressure and blood sugar levels during stress) and androgens (which promote the development of secondary sexual characteristics, including pubic hair).  In ALD, the elevated very long-chain fatty acids preferentially accumulate in the adrenal cortex and disrupt the production of glucocorticoids (usually measured as cortisol), androgens and less frequently mineralocorticoids.

What are the signs and symptoms of adrenal insufficiency?

The signs and symptoms of adrenal insufficiency tend to be subtle and challenging to identify. The goal is to detect the adrenal insufficiency before the patient develops symptoms (see screening recommendations below), but caregivers should be aware of common signs and symptoms and alert the child’s medical provider if signs or symptoms develop.  The table below lists common signs and symptoms of primary adrenal insufficiency. Acute symptoms of adrenal insufficiency crisis frequently occur at times of significant stress, including infection or trauma.

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How should males with ALD be monitored for development of adrenal insufficiency?

The Pediatric Endocrine Society helped establish guidance for screening in order to detect adrenal insufficiency early in males with ALD [Regelmann MO, et al. Adrenoleukodystrophy: Guidance for Adrenal Surveillance in Males Identified by Newborn Screen. J Clin Endocrinol Metab. 2018:103(11):4324-4331].  Because ALD has only recently been added to newborn screening, and there is no known way to predict exactly when adrenal insufficiency will develop in boys with ALD, the recommendations are to start screening shortly after diagnosis is confirmed and to monitor every 3-4 months for the first two years of life and then every 4-6 months thereafter.  Screening typically involves measuring cortisol (the glucocorticoid made by the adrenal gland) and ACTH (the hormone that stimulates the production of cortisol). Sometimes the endocrinologist will also recommend a cosyntropin (synthetic ACTH) stimulation test to help better understand the adrenal glands’ ability to respond to stress. Plasma renin activity and electrolytes are the screening tests for mineralocorticoid deficiency.  Because this less frequently occurs in ALD, screening is typically recommended every 6 months during infancy and every 6-12 months or sooner if symptoms of salt-craving are noted in older children.

The reported incidence of adrenal insufficiency in females with ALD is less than 1% and routine monitoring for adrenal dysfunction is not recommended (but if a female has signs or symptoms of adrenal insufficiency, she should be checked).

How is adrenal insufficiency diagnosed?

Adrenal insufficiency is typically diagnosed when the cortisol is low and the ACTH is elevated.  There is significant debate in the pediatric endocrine community regarding the exact cutoff values for cortisol and ACTH to define adrenal insufficiency.  The reason for debate is there are poor normal reference range data in young children and during the first two years of life, the normal secretion of ACTH and cortisol is still developing, so relatively low cortisol levels or ACTH values just slightly above the established adult reference ranges may be normal for a child.  An expert in pediatric endocrinology should be consulted to help interpret test results and confirm the diagnosis. The diagnosis of adrenal insufficiency is made based on a combination of the laboratory tests, as well as an assessment for signs and symptoms of adrenal insufficiency. In cases of borderline test results, it may be reasonable to consider treating with hydrocortisone during times of stress but to hold off on starting daily treatment (see discussion of treatment below).

Once adrenal insufficiency is diagnosed, what should be expected?

The standard treatment for adrenal insufficiency is steroid replacement.  In most growing children, hydrocortisone is the preferred medication to replace cortisol.  Hydrocortisone is usually taken by mouth three times per day. During times of stress (fever, illness, trauma, anesthesia), the dose of hydrocortisone needs to be increased to mimic the normal rise in cortisol during stress in order to maintain normal blood pressure and blood sugar.  If a child is experiencing severe stress and is unable to take hydrocortisone by mouth, the hydrocortisone is administered as an injection, either into the muscle or through an IV. Caregivers are trained to give the intramuscular hydrocortisone once a child has been diagnosed with adrenal insufficiency.  The pediatric endocrinologist will also provide you with emergency care instructions for home and school/daycare.

Hydrocortisone is generally a safe medication when prescribed to replace the cortisol the adrenal glands should be making.  Hydrocortisone is initially dosed based on the child’s weight and height and then adjustments to the dose are made based on follow up assessments of growth, symptoms and additional laboratory tests.  Once on replacement hydrocortisone therapy, your child should have routine follow up with a pediatric endocrinologist, typically every 3-6 months.

If mineralocorticoid deficiency develops, the treatment is fludrocortisone (a mineralocorticoid), typically once daily, as well as salt replacement, as necessary.