Around 80% of males diagnosed with X-linked adrenoleukodystrophy (ALD) will develop adrenal insufficiency, a retrospective study suggests. The risk, although variable with age, is higher during the first 10 years of life.
Based on these findings, researchers advise routine testing of the adrenal glands every 4 to 6 months until age 10.
Primary adrenal insufficiency occurs when the adrenal glands, located above the kidneys, fail to produce enough vital hormones, such as sex hormones and cortisol. It is one of the major symptoms in boys and men with X-linked ALD. However, the natural history of adrenal insufficiency among male patients with ALD remains poorly studied.
With newborn screening being adopted in the Netherlands and some areas of the United States as the method of choice for ALD diagnosis (before patients develop any symptoms), it is important to understand the natural history of adrenal insufficiency so that clinicians know when to initiate adrenal function assessments, how often, and until what age.
Now, a group of researchers conducted a retrospective review of medical records of male patients with ALD followed at the Massachusetts General Hospital (MGH), Boston, and at the Academic Medical Center (AMC), in the Netherlands, between 2002 and 2016.
Researchers focused specifically on signs of adrenal insufficiency, defined as low levels of cortisol after stimulation with cosyntropin, a synthetic form of the adrenocorticotropic hormone (ACTH). ACTH is normally produced in the adrenal glands and regulates the levels of cortisol.
The team also analyzed the time at which patients developed spinal cord and/or cerebral disease, two other main manifestations of ALD.
In all, they reviewed the records of 159 male patients with ALD (86 from MGH and 73 from AMC), with a median age of 24 years.
Results showed that adrenal insufficiency affected 71.1% of the ALD patients analyzed (113 of 159). The youngest patient with adrenal insufficiency was 7 months old.
Adrenal insufficiency was the first manifestation of ALD in 60 of 159 (37.7%) patients. Spinal cord disease and cerebral disease were the first symptoms in 25.2% and 14.5% of the patients, respectively.
Researchers found that 14 years was the median time it took for 50% of the patients to develop adrenal insufficiency; by age 56, 80% of them had it.
The risk of developing adrenal insufficiency was dependent on age, being highest in early childhood up to 10 years — from zero to 10 years old, 46.8% of the patients had adrenal insufficiency, dropping to 28.6% in patients ages 11-40. In the group of patients older than 40, 5.6% had adrenal insufficiency.
According to these results, researchers suggested that routine testing of the adrenal glands should be performed “every 4 to 6 months until 10 years of age, annual testing thereafter until 40 years of age, and solely on-demand testing in case endocrine symptoms manifest from age 41 years onward.”
Blood tests to measure the ratio between different very long-chain fatty acids (VLCFA) — those accumulating in blood and body tissues, especially in the brain and spinal cord, and the cause of ALD — were also performed.
Researchers hypothesized that the ratio of VLCFA might be linked with the risk of developing adrenal insufficiency, spinal cord disease, or cerebral disease. However, although useful for the diagnosis of ALD, no link was found between the VLCFA ratios and the risk for any of the three conditions.
Overall, the results suggest that “the risk for adrenal insufficiency varies over time, warranting an age-dependent follow-up frequency of adrenal function. Over time, long-term prospective follow-up of babies diagnosed through newborn screening will elucidate the true natural history of adrenal insufficiency in ALD,” the researchers said.