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Idiopathic Isolated ACTH deficiency - How much do we know?

 

Y Chok, M Martineau, West Middlesex University Hospital.

 

Introduction: Idiopathic isolated ACTH deficiency (IIAD) is a rare cause of adrenal insufficiency, which was first described by Steinberg in 1954. 300 cases has been described in the literature, however due to the lack of uniformity in the diagnostic criteria, the prevalence of IIAD is difficult to be established. Here we describe a patient with IIAD after an acute illness. He has been followed up for 4 years.

 

Case presentation: A 42 years old flight attendant who had no known medical illness was first hospitalised in Kuala Lumpur for gastroenteritis with pre-renal impairment and hyponatremia. He presented with headache, nausea, vomiting, abdominal pain and diarrhoea. In Singapore, a diagnosis of Legionella pneumonia was made. A short synacthen test performed for investigation of hyponatremia (Na 123 mmol/L) showed inadequate response (0 min: 11nmol/L, 30 mins: 56nmol/L and 60 mins: 71nmol/L) and patient was commenced on prednisolone. Thyroid function test was normal, HIV antigen and antibody test were negative. Tests for serum ACTH, FSH, LH, testosterone, IGF-1, and prolactin were not performed during the acute event.

 

We first met him 2 months after his acute illness. Prior to this incident he had been fit and well with stable weight, absence of excessive lethargy or increased skin pigmentation. A repeated Short Synacthen test 6 months after acute illness showed ACTH 5.6ng/L, baseline cortisol at 0 min is 10 mmol/L, cortisol at 30 mins is 27 mmol/L and cortisol at 60 mins is 28 mmol/L. The rest of the pituitary hormones was normal at 6 months post-acute illness. MRI of the pituitary 7 months post-acute event was normal. Aldosterone and plasma renin aldosterone ratio are normal. These results were consistent with the diagnosis of isolated ACTH deficiency.

 

We followed the patient up with 6 monthly clinic appointments, regular biochemistry tests and thyroid function tests. He remained fit and well on Prednisolone 3mg once a day. During a recent clinic visit, 4 years after patientís acute illness, pituitary hormone function tests and short synacthen test were repeated. Apart from ACTH, pituitary hormone function tests were normal. SST revealed inadequate response at both 30 and 60 minutes, further confirming the diagnosis of Isolated ACTH deficiency.

 

Discussion: In adults, isolated ACTH deficiency (IAD) has been described after discontinuation of glucocorticoid therapy, lymphocytic hypophysitis, traumatic brain injury, hypothyroidism, and post radiotherapy. Cases of Nivolumab induced IAD has been increasingly reported with the increase usage of checkpoint inhibitors over the last few years. IIAD is a diagnosis of exclusion.

 

The diagnosis of IIAD can be easily missed as it often presents insidiously. Hyponatremia can frequently be the only abnormality on biochemistry testing, and they are usually euvolemic. Case series have revealed a close association of IIAD and autoimmune diseases, in particular with autoimmune hypothyroidism. Other autoimmune diseases associated with IIAD have also been reported, e.g. Graves disease, Crohnís disease and Type 1 Diabetes. The high prevalence of autoimmune diseases in IIAD would suggest that at least some of the IIAD cases might be autoimmune in origin.

 

The natural history of IIAD is not well elucidated. 2 cases of complete recovery of hypothalamic pituitary adrenal axis in IIAD has been described in the literature. Initial IIAD can also progress to more extensive hypopituitarism. Consequently, it is advisable to retest pituitary hormones to ensure the integrity of all pituitary axes and also to reassess the need to continue glucocorticoid.

 

With regards to corticotrophin stimulation test, conflicting reports regarding its response has been described in the medical literature. This might suggest that IIAD is a heterogenous disorder which can be caused by either pituitary ACTH deficiency or a hypothalamic Corticotrophin-releasing hormone deficiency.