Original article
Evaluation of plasma cortisol during fasting test in patients with endogenous hyperinsulinemic hypoglycemia. Fifteen years experience
Evaluación del cortisol plasmático durante el test de ayuno en pacientes con síndrome hipoglucémico por hiperinsulinismo endógeno. Experiencia de 15 años
María Eugenia Gullacea,
, María Victoria Ortuñob, Teresa Mabel Canterosc, Belén Boscoc, Cintia Rodriguezc, Javier Giuntac, Lucas Costad, Andrea Kozakc, Valeria de Miguelc, Luis Grosembacherc
Corresponding author
a Unidad de Endocrinología, Hospital Municipal de Agudos «Dr. Leónidas Lucero», Bahía Blanca, Argentina
b Servicio de Endocrinología, Hospital Alemán, Ciudad de Buenos Aires, Argentina
c Servicio de Endocrinología, Hospital Italiano de Buenos Aires, Ciudad de Buenos Aires, Argentina
d Unidad de Bioestadística, Facultad de Ciencias Médicas, Universidad Nacional del Litoral, Santa Fe, Argentina
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Experiencia de 15 años" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Other causes of EHH include pancreatic islet cell hyperplasia, nesidioblastosis<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and the presence of anti-insulin or anti-insulin receptor antibodies.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The manifestation of symptoms, signs or both, associated with blood glucose values below 55<span class="elsevierStyleHsp" style=""></span>mg/dl, insulin greater than or equal to 3<span class="elsevierStyleHsp" style=""></span>μU/mL, C-peptide greater than or equal to 0.6<span class="elsevierStyleHsp" style=""></span>ng/mL, proinsulin of at least 5.0<span class="elsevierStyleHsp" style=""></span>pmol/l and beta hydroxybutyrate less than or equal to 2.7<span class="elsevierStyleHsp" style=""></span>mmol/l, makes it possible to document EHH and subsequently perform localisation diagnostic studies and finally confirm the aetiology.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> 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<span class="elsevierStyleHsp" style=""></span>μg/dl was indicative of an adequate response of the hypothalamic-pituitary-adrenal axis.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In contrast, a decrease in the response of the counterregulatory hormones is observed in recurrent hypoglycaemia episodes. As published by Davis et al.,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Widam<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and Moheet,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In a study involving 112 patients with type 2 diabetes with hypoglycaemia, 23 of them (20.5%) had an inadequate cortisol response (<18<span class="elsevierStyleHsp" style=""></span>μg/dl).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> 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<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>μg/dl in euglycaemia and 10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>μg/dl in hypoglycaemia; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.01).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In neonates with hyperinsulinaemic hypoglycaemia in whom cortisol values were tested against hypoglycaemia, there was also an inadequate cortisol response to hypoglycaemia.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> 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.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">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.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Material and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">This was an observational, descriptive, retrospective and cross-sectional study. All patients over 15 years of age referred for EHH who presented a positive fasting test (see <a class="elsevierStyleCrossRef" href="#sec0045">Appendix B</a> Annex 2: Fasting test protocol) between January 2007 and December 2021 were included. Patients with a positive fasting test in whom baseline cortisol and/or cortisol during hypoglycaemic seizure was not measured were excluded, as were those with a diagnosis of adrenal insufficiency previously treated with glucocorticoids, subjects who used corticosteroids during the fasting test and those who did not meet the inclusion criteria. All the data evaluated came from secondary databases of the electronic medical record data repository, which contains all the medical information of each patient in the Hospital Italiano de Buenos Aires health system.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The following variables were considered for analysis: serum cortisol, measured by chemiluminescence (reference range: 5−25<span class="elsevierStyleHsp" style=""></span>μg/dl), at the beginning of the fasting test and during hypoglycaemic seizure, and EHH duration in years.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The statistical analysis was carried out with the software SPSS v.19.0. The quantitative variables are described with medians with their respective interquartile ranges. The qualitative variables are described with their absolute frequencies. Median comparison tests and linear correlation tests were performed. <span class="elsevierStyleItalic">P</span>-values <.05 were considered to be statistically significant.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Ethical considerations</span><p id="par0045" class="elsevierStylePara elsevierViewall">This study was conducted in accordance with ethical principles in line with national and international human health research standards. The protocol was approved by the institutional Research Protocols Ethics Committee.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">Of a total of 27 patients, six were excluded for the use of corticosteroids during the fasting test, leaving a final sample of 21 patients. Fourteen were female, median age was 39 years (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>32–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>50), 16 had a confirmed diagnosis of insulinoma, one nesidioblastosis, two malignant insulinoma and two with positive fasting test without an aetiological diagnosis. Since neither our centre nor Argentina has the capability to measure sulphonylureas in blood or urine, these data could not be collected.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The median body mass index (BMI) was 27<span class="elsevierStyleHsp" style=""></span>kg/m<span class="elsevierStyleSup">2</span> (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>23.5–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>30.7). The median duration of the fasting test was seven hours (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3.5–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>28) and the time from symptom onset to diagnosis was two years (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.2–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5.5). Baseline cortisol was 11.8<span class="elsevierStyleHsp" style=""></span>μg/dl (340.68<span class="elsevierStyleHsp" style=""></span>nmol/l) and cortisol during hypoglycaemic seizure was 11.6<span class="elsevierStyleHsp" style=""></span>μg/dl (303.44<span class="elsevierStyleHsp" style=""></span>nmol/l); the comparison between the two dependent samples showed no differences (Z<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.08; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05). No significant correlation was observed between baseline cortisol and cortisol during hypoglycaemic seizure (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.16; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05) (<a class="elsevierStyleCrossRef" href="#sec0045">Appendix B</a>, see Annex 1: Fig. 1). A negative correlation was found between the blood glucose value during seizure (median 39<span class="elsevierStyleHsp" style=""></span>mg/dl; Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>34–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>42.5) and cortisol during hypoglycaemic seizure (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.53; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.01) (see <a class="elsevierStyleCrossRef" href="#sec0045">Appendix B</a>, Annex 1: Fig. 2 and Table 1).</p><p id="par0060" class="elsevierStylePara elsevierViewall">A negative correlation was observed between the time since diagnosis and baseline cortisol (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>17; r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.54; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.025) (see <a class="elsevierStyleCrossRef" href="#sec0045">Appendix B</a>, Annex 1: Fig. 3). This correlation was not found with cortisol (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.19; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05) nor with blood glucose during hypoglycaemic seizure (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.21; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05). No relationship was found between patient age and baseline cortisol and cortisol during hypoglycaemic seizure (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.07; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05 and r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.03; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05). No correlation was found between baseline cortisol and BMI or between the time since diagnosis and BMI.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">Defects have been observed in the response threshold of counterregulatory hormones in patients with EHH, although to date it has proved impossible to determine the causal mechanism. Studies evaluating the effect of repeat episodes of hypoglycaemia in healthy individuals have suggested a defect in cortisol secretion, as published by Davis et al.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and Widom and Simonson.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The latter also ascertained that the blood glucose values required to stimulate the secretion of counterregulatory hormones were increasingly lower following repeated stimuli.</p><p id="par0070" class="elsevierStylePara elsevierViewall">This study assessed cortisol levels during a fasting test in people with EHH, finding that cortisol values were not elevated as would be expected in response to a hypoglycaemic seizure. In line with our findings, other reports of cases with insulinomas mention that they might present hypoglycaemia unawareness and a reduction in counterregulatory hormone response, similar to what has been observed in hypoglycaemia in patients with diabetes mellitus on insulin therapy.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,16,17</span></a> Mitrakou et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> also observed that spontaneous and repeat episodes of hypoglycaemia in six patients with insulinoma reduced the counterregulatory hormone response as previously reported, although neurogenic and neuroglycopenic symptoms also diminished.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In contrast, Vella et al.,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> in a study including 65 patients with insulinoma, eight with NIPHS (<span class="elsevierStyleItalic">noninsulinoma pancreatogenous hypoglycaemia syndrome</span>) vs 23 controls during a 72-h fasting test, concluded that patients with insulinoma had significantly higher cortisol values than controls in hypoglycaemia (contrary to our finding). However, the controls never reached hypoglycaemic values that would render it possible to draw an adequate comparison (the lowest blood glucose value was 63<span class="elsevierStyleHsp" style=""></span>mg/dl).</p><p id="par0080" class="elsevierStylePara elsevierViewall">In this study, no significant differences were found when dependent samples were compared between baseline cortisol and cortisol during hypoglycaemic seizure (see <a class="elsevierStyleCrossRef" href="#sec0045">Appendix B</a>, Annex 1: Fig. 1), i.e. no increase in cortisol was observed during the hypoglycaemic event. No significant relationship was found when the correlation was performed. This would reinforce the idea of a lack of a counterregulatory cortisol response to low blood glucose levels in people with recurrent hyperinsulinaemic hypoglycaemia. Similar results may be inferred in patients with insulinoma in previous studies, although the statistical analysis of these results was not reported in all of them,<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,18</span></a> except for Simonson et al., who described it in patients with type 1 diabetes mellitus.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">When blood glucose values during hypoglycaemic seizure and cortisol values during hypoglycaemia were correlated, a negative trend emerged: the lower the blood glucose values, the higher the cortisol values, which is what would be expected in a normal physiological response (see <a class="elsevierStyleCrossRef" href="#sec0045">Appendix B</a>, Annex 1: Fig. 2). Our study found no relationship between patient age and baseline cortisol and cortisol values during hypoglycaemic seizure. This was not reported in previous studies.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Furthermore, a negative correlation was found between symptom progression time and the diagnosis of insulinoma, and baseline cortisol (see <a class="elsevierStyleCrossRef" href="#sec0045">Appendix B</a>, Annex 1: Fig. 3), which could translate into a chronic adaptation to a reduced response of the counterregulatory system to recurrent hypoglycaemia. Other studies published to date have not described the correlation between symptom onset and the diagnosis of insulinoma,<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,18</span></a> meaning that our study is the first to consider the correlation between these two variables.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Both Vea et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and Maran et al.,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Davis and Shamoon<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and Mitrakou et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> studied patients before and after insulinoma resection surgery: nine weeks, three, five and six months, respectively, showing an improvement in post-surgical counterregulatory hormone values, achieving values similar to those of healthy subjects. Since this is a retrospective study and we do not have such data, it would be interesting to be able to analyse our post-surgical results for the future. However, it should be borne in mind that to assess the recovery of cortisol response in these cases, it would not be feasible to repeat a fasting test as at diagnosis, but rather this should be studied using a hypoglycaemic clamp, as was reported in the studies mentioned above.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,18,21,22</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">It is hypothesised that the diminished response of counterregulatory hormones to recurrent hypoglycaemia may be due to several reasons. One paper posits that the central nervous system may adapt to recurrent hypoglycaemia, as evaluated <span class="elsevierStyleItalic">in vivo</span> in rats with insulinoma implants before and after their excision.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In patients with diabetes, it has been proposed that this may be due to paracrine effects at the pancreatic islet level in the case of glucagon,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> or to subclinical autonomic neuropathy in the case of epinephrine.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Rizza et al.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> published that patients with insulinoma have hyperinsulinaemia associated with diminished glucose production and utilisation, with a predominance of decreased hepatic gluconeogenesis compared to healthy individuals, possibly due to a direct hepatic effect of insulin. What is not clear is whether these effects are due to hyperinsulinaemia per se, as suggested by Rizza et al.,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> as well as by Davis and Shamoon,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> or whether they are also secondary to defects in the release of other counterregulatory hormones (e.g. cortisol).</p><p id="par0110" class="elsevierStylePara elsevierViewall">On the other hand, the decreased counterregulatory response is attributed to a possible adrenal insufficiency (AI). In their case report, Kaffel et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> posit that one patient with insulinoma presented reversible hypopituitarism secondary to insulinoma. Some studies hypothesise that repeat exposure to hyperinsulinaemic hypoglycaemia episodes may lead to secondary AI through the attenuation of the hypothalamic-pituitary-adrenal axis.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,27</span></a> Only one patient in our study underwent a synthetic tetracosactide (Synacthen<span class="elsevierStyleSup">Ⓡ</span>) stimulation test prior to surgery, which resulted in cortisol within normal pre- and post-stimulus values. Although the stimulation test is not part of the pre-insulinoma work-up if AI is not suspected, it would be interesting to consider it for future studies evaluating the cortisol response in these cases.</p><p id="par0115" class="elsevierStylePara elsevierViewall">In conclusion, this paper confirms that cortisol values remain inappropriately low during a hypoglycaemic seizure, reinforcing the hypothesis of the lack of response of this counterregulatory hormone in cases of recurrent hypoglycaemia. Furthermore, this same state of recurrent hypoglycaemia was found to have a prolonged association with lower baseline cortisol values the longer the duration of EHH. We believe that given the low prevalence of this condition, having these results in Latin America is extremely valuable.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Main findings</span><p id="par0165" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0120" class="elsevierStylePara elsevierViewall">The time between symptom onset and diagnosis was 2 years.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0125" class="elsevierStylePara elsevierViewall">No differences were found between baseline cortisol and cortisol during the seizure.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0130" class="elsevierStylePara elsevierViewall">No significant relationship was observed between baseline cortisol and cortisol during hypoglycaemic seizure.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">•</span><p id="par0135" class="elsevierStylePara elsevierViewall">A negatively-trending correlation between blood glucose during the seizure and baseline cortisol was found.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">•</span><p id="par0140" class="elsevierStylePara elsevierViewall">The longer the duration of EHH, the lower the baseline cortisol values.</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">This study received no specific funding from public, private or non-profit organisations.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres2042996" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1746803" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2042997" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0045" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1746804" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Ethical considerations" ] ] ] 6 => array:2 [ "identificador" => "sec0020" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0030" "titulo" => "Main findings" ] 9 => array:2 [ "identificador" => "sec0035" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-06-25" "fechaAceptado" => "2023-09-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1746803" "palabras" => array:4 [ 0 => "Cortisol in hypoglycemia" 1 => "Fasting test" 2 => "Insulinoma" 3 => "Recurrent hypoglycemia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1746804" "palabras" => array:4 [ 0 => "Cortisol en hipoglucemia" 1 => "Test de ayuno" 2 => "Insulinoma" 3 => "Hipoglucemia recurrente" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Endogenous hyperinsulinemic hypoglycemia (EHH) is a rare clinical condition. The aim of this study was to evaluate baseline plasma cortisol concentration and its concentration during hypoglycemic crisis in fasting tests (FT) performed in our center. Secondarily, the aim was to establish the relationship between baseline cortisol and the time of evolution of EHH.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A retrospective, observational, descriptive study was carried out which included patients with hypoglycemic disorder with positive FT.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of a total of 21 patients, 16 presented insulinoma, 1 nesidioblastosis, 2 malignant insulinoma and 2 EHH without pathological diagnosis. The time from the onset of symptoms to diagnosis was 2 years (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.5–Q2<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5.5). The comparison between median baseline cortisol (BC)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11.8 mcg/dl (nmol/L 340.68) (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>14.1) and median cortisol during hypoglycemic episode (HC)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11.6 mcg/dl (nmol/L: 303.44) (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7.8–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16.1) showed no differences (Z<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.08; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05). When correlating BC with HC, no significant relationship was observed (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.16; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05). When correlating the glycemic value in the crisis and the HC, a slight negative trend was found (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.53; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.01). In addition, we found that recurrent hypoglycemic disorder is associated with lower baseline cortisol values ​​the longer the time of its evolution.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We confirmed that cortisol values ​​remain low during hypoglycemic episodes, reinforcing the hypothesis of lack of response of this counterregulatory hormone in cases of recurrent hypoglycemia.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El síndrome hipoglucémico por hiperinsulinismo endógeno (SHHE) es una condición clínica poco frecuente.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Objetivos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El objetivo primario fue evaluar el cortisol plasmático basal y en la crisis hipoglucémica durante los tests de ayuno y el objetivo secundario, establecer la relación entre cortisol basal y el tiempo de evolución del SHHE.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Materiales y métodos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Estudio retrospectivo, observacional y descriptivo que incluyó pacientes adultos con síndrome hipoglucémico con test de ayuno positivo.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">De un total de 21 pacientes, 16 presentaron insulinoma, 1 nesidioblastosis, 2 insulinoma maligno y 2 SHHE sin diagnóstico anatomopatológico. El tiempo de síntomas del inicio del cuadro hasta el diagnóstico fue 2 años (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.5–Q2<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5.5). La comparación entre la mediana de cortisol basal<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11.8 mcg/dl (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>14.1) y la mediana de cortisol durante la crisis hipoglucémica<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11.6<span class="elsevierStyleHsp" style=""></span>mcg/dl (Q1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7.8–Q3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16.1) no mostró diferencias (Z<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.08; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05). No se observó relación significativa entre cortisol basal y cortisol en la crisis hipoglucémica (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.16; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05). Se halló correlación con tendencia negativa entre la glucemia de la crisis y el cortisol basal (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.53; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>,01). Ademsás, cuanto mayor fue el tiempo de evolución del síndrome hipoglucémico, menores fueron los valores de cortisol basal.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusiones</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Los valores de cortisol se mantienen bajos durante la crisis hipoglucémica reforzando la hipótesis de la falta de respuesta de esta hormona contrarreguladora en casos de hipoglucemia recurrente.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0045" "titulo" => "Conclusiones" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0160" class="elsevierStylePara elsevierViewall">The following are Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0050" ] ] ] ] "multimedia" => array:2 [ 0 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.doc" "ficheroTamanyo" => 57049 ] ] 1 => array:5 [ "identificador" => "upi0010" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc2.doc" "ficheroTamanyo" => 16794 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:27 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and management of insulinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. 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