Adrenal insufficiency

April 8th, 2016 |

Johanna Assies, M.D., Ph.D. and Stephan Kemp, Ph.D.

Men

The endocrine systemAt least 80% of patients with childhood cerebral ALD and adrenomyeloneuropathy (AMN) have clinical and biochemical evidence of adrenal insufficiency. Adrenal insufficiency may also be the only clinical manifestation of ALD, the “Addison-only phenotype”.

Addisonian crisis is a common cause of acute presentation of ALD.

Adrenal insufficiency often precedes the onset of the neurological symptoms. Thus far there are no correlations between the ALD genotype and the endocrinological phenotype.
There are no correlations between VLCFA concentrations and ACTH or between VLCFA levels and clinical endocrinological symptoms.

Screening of at-risk family members showed there was a high prevalence of unrecognized adrenal insufficiency in pre-symptomatic boys with ALD (age: 4.5 ± 3,5 years). At baseline, 81% had impaired adrenal function. Serum ACTH was elevated in 69% patients and the ACTH stimulation test was abnormal in 43% of patients. By the end of the follow-up (2 ± 1.7 years), 86% patients had borderline or clear adrenal insufficiency (age of onset: 4.8 ± 3.7 years).
A key finding was that 70% of the patients studied by 2 years of age already showed increased serum ACTH levels.

This is a very important finding, as unrecognized adrenal insufficiency frequently can result in morbidity and even mortality. Careful monitoring, early identification of impaired adrenal reserve, and timely initiation of therapy can prevent this.

Plasma ACTH is the most sensitive laboratory marker for adrenal dysfunction in children, adolescents and adults and serial measurement i.e.. every 6 months is recommended to identify the patients with (sub clinical) adrenal involvement.

Adrenal hormone therapy is mandatory to all ALD patients who have adrenal insufficiency, and it may be lifesaving.

There is no evidence that adrenal hormone therapy alters neurological progression.

Women

Unlike the affected men clinical overt adrenal insufficiency is exceptionally rare in women with ALD. Studies in a large group of women with ALD demonstrated that adrenal insufficiency is present in about 1% of females with ALD.

Moreover, a sub clinical decrease in the glucocorticoid reserve as measured by corticotropin-releasing hormone (CRH) testing is present in 63% of women with ALD. Thus far none of the Dutch women with ALD studied has signs of adrenal dysfunction.

VLCFA and adrenocortical cells

EM picture of an adrenal with lipid inclusionsThere are several reasons for the impaired steroid synthesis in patients with ALD. Very long-chain fatty acids (VLCFA) accumulate in the adrenocortical cells and have a direct toxic effect on intracellular membranes and enzymes. Characteristic lamellar lipid inclusions ultimately leading to cell death can be seen (see picture).
VLCFA-esters are also poor substrates for hydrolases, leading to shortage of intracellular cholesterol for steroid synthesis. Moreover, accumulation of VLCFAs in the outer cell membranes of the adrenocortical cells hinder the capacity of the adrenocortical cells to respond to ACTH.

Because 80% of ALD patients develop adrenal insufficiency before the onset of neurological symptoms, a young man or boy with primary adrenal insufficiency should always be tested for ALD.

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