Adrenal insufficiency and the use of mineralocorticoid treatment in male patients with adrenoleukodystrophy; a retrospective analysis of an institutional database

Abstract

Introduction

Adrenoleukodystrophy (ALD) patients exhibit three primary clinical phenotypes: primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral demyelination due to the accumulation of saturated very long-chain fatty acids in the adrenal cortex and central nervous system white matter and axons. We investigated the diagnosis of adrenal insufficiency (AI) and the use of mineralocorticoid treatment in male ALD patients.

Methods

A retrospective chart review of electronic medical records was conducted for all ALD patients at a single institution between January 1, 2011, and December 6, 2021.

Results

Among the 437 ALD patients, 82% were male and 18% were female. Of the male ALD patients, 60% (213 out of 358) had a diagnosis of AI, and 39% (84 out of 213) of those with AI were prescribed mineralocorticoid replacement therapy.

Conclusion

AI is highly prevalent among ALD patients, with approximately 40% of those with a diagnosis of AI undergoing mineralocorticoid replacement therapy. Further research is warranted to delineate the characteristics of patients predisposed to developing mineralocorticoid deficiency within the context of ALD and AI.

Introduction

Adrenoleukodystrophy (ALD) is a neurodegenerative disorder that affects both the white matter and axons of the central nervous system, as well as the adrenal cortex, due to the accumulation of saturated very long-chain fatty acids (VLCFA)( [1,2,3]. It is an X-linked inherited disorder caused by a defective gene, ABCD1, located on Xq28 [2]. The defective gene causes the accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues, including the white matter of the brain, spinal cord, and adrenal cortex. This buildup of VLCFA in the zona fasciculata and reticularis of the adrenal cortex, while relatively sparing the zona glomerulosa, is thought to contribute to the development of primary adrenal insufficiency [4,5,6,7].

Male patients with ALD typically manifest three primary clinical phenotypes: adrenal insufficiency (AI), adrenomyeloneuropathy (AMN), and cerebral demyelination (cerebral ALD) [2, 8]. While progressive spinal cord disease can develop in women with ALD, AI and cerebral ALD are rare in this population, occurring in less than 1% of cases [4,5,6]. This X-linked inherited disorder primarily affects men, while women are mostly carriers and tend to develop mild clinical manifestations after the age of 60 [6, 7].

A study reported a lifetime prevalence of adrenal insufficiency in male ALD patients of approximately 80% [7]. In this study, the median time to the onset of adrenal insufficiency was 14 years (95% CI, 9.70 to 18.30 years) and the cumulative proportion of patients developing adrenal insufficiency varied by age group, being highest in early childhood: 46.8% (SEM 0.041%) for ages 0 to 10 years, 28.6% (SEM 0.037%) for ages 11 to 40 years, and 5.6% (SEM 0.038%) for those over 40 years [7]. This underscores the importance of age-based regular screening for AI in this demographic.

Elevated adrenocorticotropic hormone (ACTH) and impaired cortisol response to ACTH administration are the primary biochemical indicators of primary AI, often preceding clinical symptoms by two years [9, 10]. As VLCFAs primarily accumulate in the zona fasciculata and reticularis, the relative preservation of the zona glomerulosa explains why most patients with adrenal insufficiency do not develop mineralocorticoid deficiency [6, 7]. Mineralocorticoid deficiency is reported in 40% of patients with ALD [6].

Methods

The University of Minnesota’s Adrenoleukodystrophy Comprehensive Clinic is one of the leading centers worldwide for the assessment and treatment of ALD patients. Among the 152 transplant centers for ALD, the University of Minnesota accounts for 38% of the contributions, while the remaining 151 centers collectively contribute 62%. Most patients undergoing their initial evaluation and diagnosis at their respective institutions.

We conducted a retrospective analysis of electronic medical records (EMR) at the University of Minnesota spanning from January 1, 2011, to December 6, 2021, encompassing all patients diagnosed with ALD. Approval for the study protocol (Study00014492) was obtained from the Institutional Review Board. Data extraction was facilitated by the informatics consulting services of the Clinical and Translational Science Institute and securely maintained within the Academic Health Center Secure Data Environment. The study included only individuals who had given their consent to use their data for research purposes.

All patients who provided consent for EMR research were included. Age and self-report race and ethnicity data were obtained from patients’ EMR. Individual chart reviews were performed to confirm ALD diagnoses utilizing VLCFA results, genetic assessments, or documented diagnoses in medical history or visit notes. Diagnosis of AI was ascertained through thorough chart reviews, confirming documented diagnoses in medical history or progress notes. We reviewed glucocorticoid medications, including both oral and injectable forms. The use of mineralocorticoids was determined by whether fludrocortisone was prescribed. Although cortisol, ACTH, aldosterone, and renin levels were assessed, most patients did not have these lab results recorded in their EMR. These labs might have been completed at their initial evaluation and diagnosis at their respective institutions prior to referral to the University of Minnesota. The authors didn’t have access to laboratory and other assessment completed outside of University of Minnesota.

Statistical method

Demographic data for all ALD patients and those with AI were summarized using descriptive statistics. To investigate the association between demographics and AI, Wilcoxon rank-sum tests for continuous variables and Chi-square or Fisher’s exact tests for categorical variables. Glucocorticoid use was also summarized. Data analysis was conducted using R (version 4.1.2, R Core Team) [11].

Results

Out of 437 patients with ALD, 82% (358/437) were males and 18% (79/437) were females. Table 1 provides demographic details of male patients with ALD and by diagnosis of AI. The median age among male patients with ALD was 14, ranging from 0 to 92 years. There was a significant difference in median age for those with and without diagnosis of AI on their medical chart (16 vs. 11 p < 0.001). No differences were seen for self-reported race and ethnicity.

Table 1 Male patients with adrenoleukodystrophy: comparison of demographics by adrenal insufficiency (AI)

60% (213/358) of male patients with ALD had a diagnosis of AI mentioned on their chart. 39% (84/213) of patients with AI and ALD were on mineralocorticoid replacement therapy, fludrocortisone at the dose of 0.05-01 mg per day.

Table 2 provides details on adrenal insufficiency diagnosis and fludrocortisone use. Cortisol and renin labs were available for 62% (220/358) and 50% (179/358) of patients with ALD, respectively. Glucocorticoid medications prescribed for patients with AI and ALD included hydrocortisone (190/213), prednisone (38/213), dexamethasone (66/213), and other (33/213). 7% (15/213) patients did have the diagnosis of AI but didn’t have glucocorticoid medications prescribed. 39% of (56/145) those without a diagnosis of AI on their chart were prescribed glucocorticoid medication. Table 3 describes glucocorticoid use by adrenal insufficiency diagnosis for all male ALD patients.

Table 2 Summary of diagnosis of adrenal insufficiency and fludrocortisone use for male ALD¹ patients

Table 3 Glucocorticoid use by adrenal insufficiency diagnosis for all male ALD patients

Discussion

This chart review study, utilizing EMR data, provides a descriptive analysis of AI prevalence among ALD patients and the utilization of mineralocorticoid therapy in this group. Our findings suggest a lower AI prevalence compared to studies relying on biochemical evidence, potentially because biochemical abnormalities precede clinical symptoms by two years [7, 9, 10]. Furthermore, the introduction of newborn screening programs for ALD, recommended by the US Department of Health and Human Services, has been underway in recent years [12]. This might have led to a larger population of young ALD patients who have not yet developed AI.

Approximately 40% of AI and ALD patients received mineralocorticoid replacement therapy, which could be due to the preferential VLCFA accumulation in the zona reticularis and zona fasciculata of the adrenal cortex, while sparing the zona glomerulosa [13]. The treatment of adrenal insufficiency in patients with adrenoleukodystrophy (ALD) is similar to other patients with primary adrenal insufficiency, involving the replacement of glucocorticoids. However, unlike other patients with primary adrenal insufficiency, those with ALD may not always require mineralocorticoid replacement, as the loss of mineralocorticoid function is not universal in these patients.

While our study benefits from a large patient database, AI diagnosis based on medical chart documentation rather than biochemical evidence may underestimate prevalence. We were unable to assess and include ACTH, cortisol, aldosterone, renin, sodium, potassium, and ACTH stimulation tests in this study, as suggested by the reviewers, because these lab results were not available for the majority of patients in our EMR system.

In conclusion, AI prevalence remains high among male ALD patients, with approximately 40% of those with both conditions receiving mineralocorticoid replacement therapy. Our study represents the second attempt to quantify mineralocorticoid treatment prevalence in males diagnosed with both ALD and AI. Further research is necessary to identify individuals at risk of developing mineralocorticoid deficiency in the context of ALD and AI.