Autoimmune Primary Adrenal Insufficiency: Understanding the Past, Present, and Future

Abstract

Introduction: Primary adrenal insufficiency (PAI), or Addison's disease, results from adrenal gland dysgenesis or destruction, leading to impaired production of glucocorticoids, mineralocorticoids, and adrenal androgens. Our understanding of the etiology, pathophysiology, and clinical manifestations of PAI has significantly evolved since this condition was originally described.

Results: Over the past 3 decades, the epidemiology and demographics of PAI has shifted, with autoimmune PAI now recognized as the most common cause. This shift has been influenced by increasing awareness of autoimmunity and the widespread use of immune modulating medications, such as immune checkpoint inhibitors. The diagnosis of PAI is often delayed, likely due to its nonspecific clinical presentation. This delay may result in increased morbidity and mortality from adrenal crisis. While treatment involves lifelong hormone replacement therapy, optimizing glucocorticoid dosing remains a challenge. Emerging therapeutic approaches focus on preserving residual adrenal function and preventing disease progression, offering hope for improved long-term outcomes.

Conclusion: This review provides an updated overview of the epidemiology, pathophysiology, and future directions in the care of autoimmune PAI. It examines key pathophysiologic and autoimmune features of PAI and explores future directions aimed at identifying genetic and molecular markers that may change the diagnosis, treatment, and outcome of this important endocrinopathy.

Keywords: 21-hydroxylase antibodies; autoimmunity; primary adrenal insufficiency.