Adrenocortical insufficiency
August 24th, 2010 |Men
At least 70% of patients with childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN) have clinical and biochemical evidence of primary adrenocortical insufficiency. Primary adrenocortical insufficiency may also be the only clinical manifestation of X-ALD, the “Addison-only phenotype”.
Addisonian crisis is a common cause of acute presentation of X-ALD.
Adrenocortical insufficiency often precedes, but may co-exist or develop after the onset of the neurological symptoms. Thus far there are no correlations between the X-ALD genotype and the endocrinological phenotype.
There are no correlations between VLCFA concentrations and ACTH or between VLCFA levels and clinical endocrinological symptoms.
Recently, screening of at-risk family members showed there was a high prevalence of unrecognized adrenocortical insufficiency in asymptomatic boys with X-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 adrenocortical 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 adrenocortical dysfunction in children, adolescents and adults and serial measurement ie. every 6 months is recommended to identify the patients with (sub clinical) adrenal involvement.
Adrenal hormone therapy is mandatory to all X-ALD patients who have adrenal insufficiency, and it may be lifesaving.
Although it is generally thought not to alter neurological progression two recent reports documented moderate improvement in evoked responses and motor function in patients with adrenomyeloneuropathy.
Women
Unlike the affected men clinical overt adrenocortical insufficiency is exceptionally rare in female carriers. Studies in a large group of carriers demonstrated that adrenocortical insufficiency is present in about 1% of females with X-ALD.
Moreover, a sub clinical decrease in the glucocorticoid reserve as measured by corticotropin-releasing hormone (CRH) testing is present in 63% of X-ALD heterozygous women. Thus far none of the Dutch carriers studied has signs of adrenocortical dysfunction.
VLCFA and adrenocortical cells
There are several reasons for the impaired steroid synthesis in patients with X-ALD. Very long chain fatty acids (VLCFAs) 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.
Primary adrenocortical insufficiency (Addison’s disease)
Prior to 1920, tuberculosis was the major cause of primary adrenocortical insufficiency. The etiology of primary adrenocortical insufficiency has changed over time. X-linked adrenoleukodystrophy has now been shown to be one of the most frequent causes of Addison’s disease in men, with frequencies between 13-62% in countries without widespread tuberculosis.
Because 30-60% of X-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 adrenoleukodystrophy.
