Are Patients with Adrenal Insufficiency and X-linked Adrenoleukodystrophy Substrate-Limited?

Abstract

BACKGROUND X-linked adrenoleukodystrophy (X-ALD) results from inherited defects in the ATP-Binding Cassette Subfamily D Member 1 gene (ABCD1), which encodes adrenoleukodystrophy protein (ALDP), a peroxisomal protein involved in intracellular lipid transport. X-ALD phenotypes include various combinations of cerebral, neurological, and adrenal abnormalities, with up to 70% of affected males demonstrating primary adrenocortical insufficiency (AI). The pathogenesis of X-ALD is largely attributed to the accumulation of very long chain fatty acids (VLCFAs). It has been suggested that impaired intracellular transport of cholesterol may also play a role in the pathogenesis of AI in X-ALD. The objective of this case study is to review the mechanisms of cholesterol transport and availability in steroidogenic cells in patients with X-ALD who develop AI. CASE INFORMATION A 27-month-old male was referred for evaluation of adrenal function following a diagnosis of X-ALD. Serial laboratory results revealed progressive decline of both baseline and stimulated adrenal function. DISCUSSION In steroidogenic cells, cytosolic free cholesterol is incorporated into the outer mitochondrial membrane (OMM) by a complex of proteins, including mitochondrial transport protein TSPO. Steroidogenic acute regulatory protein transports cholesterol from the OMM to the inner mitochondrial membrane (IMM) where the initial steps of steroidogenesis occur. If cholesterol isn’t available at the IMM, no steroid hormones are produced. Because cholesterol is critical for steroid hormone synthesis, adrenal cortical cells have redundant mechanisms of cholesterol acquisition to ensure an adequate supply, including from circulating lipoproteins, intracellular stores, and de novo synthesis. Disorders affecting lipid and lipoprotein metabolism—as well as lipid lowering treatments, such as use of statins—could potentially alter adrenocortical function. However, there are few reports of AI in these disorders. CONCLUSION Because cortisol is essential for health and the body’s response to stress, redundant mechanisms of acquiring cholesterol allow steroidogenic cells to acquire cholesterol in spite of ALDP deficiency. The inability to process VLCFAs and accumulation of lipids in X-ALD, however, appears to overwhelm the adrenal cortical cells, resulting in cell death and primary AI.