Letter to the Editor
Cushing's syndrome in a patient with macronodular adrenal hyperplasia secondary to aberrant hormone receptors
Síndrome de Cushing por hiperplasia suprarrenal macronodular bilateral con receptores aberrantes
María Molina Vega
, Araceli Muñoz Garach, José Antonio López Medina, Francisco Tinahones Madueño
Corresponding author
Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain
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They are often of exogenous origin and, less frequently, come from the adrenal cortex (endogenous CS). Endogenous CS is classified as ACTH-dependent or ACTH-independent, the latter assuming 15–20% of cases; most of them due to unilateral adenomas or carcinomas. Less than 2% result from primary bilateral nodular hyperplasia (macro or micronodular). Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of CS, and is identified, in many cases, with the expression of aberrant G-protein coupled receptors.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1–3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 61-year-old patient with a history of diabetes mellitus type 2 (DM2), high blood pressure (HBP) and obesity. In the initial examination he presented axillary acanthosis nigricans, predominantly truncal obesity (BMI 45<span class="elsevierStyleHsp" style=""></span>kg/m<span class="elsevierStyleSup">2</span>) and red-wine coloured striae on his abdomen. The initial analytical study showed a normal blood count and basic biochemistry, except fasting glycaemia 258<span class="elsevierStyleHsp" style=""></span>mg/dl and HbA<span class="elsevierStyleInf">1c</span> 8.8%. In the hormonal study a basal plasma cortisol of 17.5<span class="elsevierStyleHsp" style=""></span>μg/dl stood out (normal range 5–25<span class="elsevierStyleHsp" style=""></span>μg/dl), as well as the ACTH of 2.83<span class="elsevierStyleHsp" style=""></span>pg/dl (normal value 5–50<span class="elsevierStyleHsp" style=""></span>pg/dl) and urinary free cortisol (UFC) of 49.4<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h (normal range 20–100<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h). The study was extended with a dexamethasone suppression test of 1<span class="elsevierStyleHsp" style=""></span>mg, with no response: plasma cortisol 12<span class="elsevierStyleHsp" style=""></span>μg/dl. Subsequently, two Liddle tests were performed with plasma cortisol values of 5.3 and 5.03<span class="elsevierStyleHsp" style=""></span>μg/dl (correct inhibition<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1.8<span class="elsevierStyleHsp" style=""></span>μg/dl). Two determinations of night salivary cortisol were also altered (0.382 and 0.292<span class="elsevierStyleHsp" style=""></span>μg/dl–normal<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>0.27<span class="elsevierStyleHsp" style=""></span>μg/dl). After these results an adrenal CT scan was performed, showing the presence of homogeneous hypodense nodules of 3.3<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2.6<span class="elsevierStyleHsp" style=""></span>cm on the right adrenal and 3.2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1.9<span class="elsevierStyleHsp" style=""></span>cm on the left. Given the clinical presentation and the frequent association of BMAH with the existence of aberrant receptors, a study of these receptors was carried out using a modified protocol of the original described by Lacroix et al.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> These protocols are based on the determination of the plasma cortisol levels in circumstances that transiently modify the concentration of the various known stimuli. Both ectopic (receptors for <span class="elsevierStyleItalic">gastric</span> inhibitory polypeptide [GIP], beta-adrenergic receptors, vasopressin–V2 and V3–angiotensin <span class="elsevierStyleSmallCaps">II</span>–AT-II–, glucagon and serotonin 5-HT7) and eutopic (receptors for vasopressin–V1–, luteinising hormone [LH] and human chorionic gonadotropin [hCG] receptors, for serotonin 5-HT4 and leptin) aberrant receptors can be identified.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">5,6</span></a> The test was performed over three days. The first was the postural test (beta-adrenergic receptors, V2 and V3 and AT-II) and the mixed food test (GIP or glucagon like peptide 1 receptors). On the second day stimuli with gonadotropin releasing hormone (LH and hCG receptors) and metoclopramide (5-HT4 receptor) were performed. Stimuli with glucagon and vasopressin (V1 receptors) were carried out on the third day. Modification of the cortisolemia of >50% and negative <25% is considered a positive response. Between 25 and 50% is considered partial.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a> In our case, the response was positive to metoclopramide, with cortisol rising from 10.72<span class="elsevierStyleHsp" style=""></span>μg/dl at baseline to 22.59<span class="elsevierStyleHsp" style=""></span>μg/dl at 90<span class="elsevierStyleHsp" style=""></span>min of stimulus, indicating the presence of 5-HT4 aberrant receptors. Currently, the most common clinical presentation of CS associated with BMAH is as an incidental finding. Endocrinological evaluation usually shows slight alterations in the secretion of cortisol, with abnormal response to suppression tests, although the UFC is usually normal and presents as a subclinical CS, with non-specific findings such as obesity, HBP or DM2. However, it can also be found in the study of a manifest CS. It is usually detected in the fifth or sixth decade of life.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> Studies in patients with BMAH and CS have shown that 77–87% had aberrant cortisol response to at least one of the stimuli, most were to vasopressin and serotonin.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> The presence of aberrant receptors may facilitate medical treatment. Medications such as octreotide have been used in the case of GIP-dependent CS, the OPC-21268 V1 receptor antagonist for vasopressor dependent, propranolol in catecholamines dependent or leuprolide for LH dependent.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> However, there is no clinical experience with antagonists of 5-HT 4 or V1 receptors. Usually, bilateral laparoscopic adrenalectomy is the treatment of choice. Given that this operation requires supplementation with corticosteroids for life, unilateral adrenalectomy has been suggested in selected cases, removing the larger one.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a> Following this recommendation, the patient underwent laparoscopic right adrenalectomy with adrenocortical adenoma pathology. In the analytical test after surgery the patient presented basal plasma cortisol of 10.86<span class="elsevierStyleHsp" style=""></span>μg/dl, ACTH of 7.69<span class="elsevierStyleHsp" style=""></span>pg/dl and UFC of 37.7<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h.</p><p id="par0015" class="elsevierStylePara elsevierViewall">This case demonstrates the importance of being highly suspicious when diagnosing less common forms of CS that may blend in with other conditions such as DM2, obesity and HBP. The classic treatment of CS can be modified in the future by furthering study into these entities.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Molina Vega M, Muñoz Garach A, López Medina JA, Tinahones Madueño F. Síndrome de Cushing por hiperplasia suprarrenal macronodular bilateral con receptores aberrantes. Med Clin (Barc). 2016;147:226–227.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cushing's syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Lacroix" 1 => "R.A. Feelders" 2 => "C.A. Stratakis" 3 => "L.K. 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