Purpose: Deficiency of the adrenocortical axis is, except for glucocorticoid-induced adrenal deficiency, most commonly associated with failure of multiple pituitary axes and is less common isolated. Isolated adrenocorticotropic hormone deficiency (IAD) has been first described by Steinberg et al. in 1954. Acquired idiopathic IAD is defined by a secondary adrenal insufficiency with otherwise normal pituitary function, absence of structural pituitary defects, no history of prolonged glucocorticoid therapy and exclusion of other causes of failure of the HPA axis. Due to the nonspecific clinical presentation and consequently underreporting of IAD, precise data on the prevalence and incidence are lacking. Nevertheless, idiopathic acquired IAD is considered to be a rare disease. In this descriptive systematic review we aimed to analyse the clinical characteristics, association with auto-immune diseases and follow-up of previously published cases.
Methods: A structured search was conducted after developing a search strategy combining terms for acquired (idiopathic) IAD. Articles describing an adult patient presentation with diagnosis of ACTH deficiency using dynamic testing, no deficiency of other pituitary axes and MRI of the brain/pituitary protocolled as normal, were included. Exclusion criteria were cases describing congenital IAD, cases with another etiology for IAD and articles were full text was not available.
Results: In total 41 articles were included consisting of 84 cases of acquired idiopathic IAD. Cases were mostly female (55%) with mean age of diagnosis 53.5 ± 18 years. Lethargy was the most common presenting symptom (35%), followed by weight loss (25%), anorexia (23%) and myalgia/arthralgia (11%). 30% of cases had an autoimmune disease at diagnosis. The most frequent auto-immune disease was Hashimoto hypothyroidism (17%). Pituitary antibodies were positive in 27% of cases where measured. Most cases of IAD associated with malignancy could be attributed to glucocorticoid use.
Conclusion: Main findings of this descriptive systematic review, including the largest case series of acquired idiopathic IAD to date, suggest an association between acquired idiopathic IAD and underlying auto-immune etiology due to the high prevalence of auto-immune diseases in this population. The value of the presence of anti-pituitary antibodies has yet to be investigated. In this review we could not withhold acquired idiopathic IAD as a form of paraneoplastic syndrome as authors have recently suggested. Our systematic review also highlights the lack of a clear definition and diagnostic work-up. Based on the findings in this review a proposition is made for a flow chart to diagnose acquired idiopathic IAD.