Endogenous hyperinsulinaemic hypoglycaemia (EHH) is a clinical condition caused by excess insulin secretion. Insulinoma is the most common cause of EHH, with an incidence of 1–4 persons per million in the general population.1 Other causes of EHH include pancreatic islet cell hyperplasia, nesidioblastosis2 and the presence of anti-insulin or anti-insulin receptor antibodies.

The manifestation of symptoms, signs or both, associated with blood glucose values below 55 mg/dl, insulin greater than or equal to 3 μU/mL, C-peptide greater than or equal to 0.6 ng/mL, proinsulin of at least 5.0 pmol/l and beta hydroxybutyrate less than or equal to 2.7 mmol/l, makes it possible to document EHH and subsequently perform localisation diagnostic studies and finally confirm the aetiology.3

In hypoglycaemia episodes, counterregulatory hormones such as cortisol, growth hormone (GH), glucagon, adrenaline and noradrenaline play an essential role in elevating blood glucose to the normal range. However, the physiological response of these hormones to acute and chronic hypoglycaemia is not the same. In experimental models in which intravenous insulin is administered to induce acute hypoglycaemia, recovery from hypoglycaemia coincides with the counterregulatory hormones' response and increased endogenous glucose production. Reduced glucose utilisation does not seem to play an essential role. The main hormone involved in this case is glucagon, and catecholamines do not appear to be initially important, although they take on a critical role when the glucagon response is deficient.4 Erturk et al. assessed the response of ACTH and cortisol in an insulin hypoglycaemia test in 193 patients and observed that cortisol values above 18 μg/dl was indicative of an adequate response of the hypothalamic-pituitary-adrenal axis.5

In contrast, a decrease in the response of the counterregulatory hormones is observed in recurrent hypoglycaemia episodes. As published by Davis et al.,6 Widam7 and Moheet,8 by provoking two or more episodes of hypoglycaemia on different days in healthy patients, they observed a reduction in the blood glucose threshold value required to trigger a counterregulatory hormone response. This phenomenon has also been observed in clinical studies in patients with hypoglycaemia in other contexts.9 In a study involving 112 patients with type 2 diabetes with hypoglycaemia, 23 of them (20.5%) had an inadequate cortisol response (<18 μg/dl).10 Another experimental study in patients with type 1 diabetes, in which the hypoglycaemic clamp procedure was performed, found a similar defective response of cortisol concentration with a decrease in the latter (20 ± 3 μg/dl in euglycaemia and 10 ± 2 μg/dl in hypoglycaemia; P < .01).11 In neonates with hyperinsulinaemic hypoglycaemia in whom cortisol values were tested against hypoglycaemia, there was also an inadequate cortisol response to hypoglycaemia.12 For adult patients with EHH (insulinoma, nesidioblastosis), studies are limited and the results are mixed. Some publications have compared pre- and post-surgery counterregulatory hormone values in patients with insulinoma by performing a hypoglycaemic clamp procedure, finding that there is an inadequate initial response that normalises after surgical treatment.13, 14

When the hypoglycaemic episode does not occur spontaneously, the fasting test can be used to recreate the circumstances in which symptomatic hypoglycaemia is likely to occur. At the Hospital Italiano de Buenos Aires, a national reference centre for the study and treatment of hypoglycaemic syndromes for 30 years, an average of 5 fasting tests a year are performed. In these years of experience, variability in cortisol response in hypoglycaemic seizure during the fasting test has been observed in EHH patients. Considering that there are no data related to this observation available in Latin America, the primary objective of this study is to evaluate the behaviour of baseline plasma cortisol values and in hypoglycaemic seizures during the fasting tests performed at our centre over the last 15 years, whereas the secondary objective is to establish the relationship between the baseline cortisol value and duration of EHH.