Letter to the Editor
Non-Islet Cell Tumour Hypoglycemia
Hipoglucemia tumoral no relacionada con células de islotes
Gema López-Gallardo
, Bothayna Oulad Ahmed, Alfonso Soto Moreno
Corresponding author
Unidad de Gestión de Endocrinología y Nutrición, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
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We describe a patient with NICTH caused by RCC and we conducted a literature search in PUBMED from 2018 to 2023 including the following terms (non-islet cell tumour induced hypoglycaemia) AND (IGF2 induced hypoglycaemia). A 56-year-old male with history of locally advanced RCC and under treatment with pembrolizumab and axitinib was admitted to the emergency department for a low level of consciousness and a blood sugar level of 24<span class="elsevierStyleHsp" style=""></span>mg/dl (1.33<span class="elsevierStyleHsp" style=""></span>mmol/L). Routine clinical laboratories were all within normal limits. The serum level of growth hormone (GH) was normal. Serum cortisol secretion and adrenocorticotropic hormone were normal. Despite marked hypoglycemia (30<span class="elsevierStyleHsp" style=""></span>mg/dl), the serum insulin level was less than 0.2<span class="elsevierStyleHsp" style=""></span>μIU/mL (normal range: 2.6–24.9) and the C-peptide level was 0.33<span class="elsevierStyleHsp" style=""></span>ng/mL (normal range: 1.1–4.0<span class="elsevierStyleHsp" style=""></span>nmol/L) and beta-hydroxybutyrate 51<span class="elsevierStyleHsp" style=""></span>μmol/L (20.00–270.00). Antibodies against insulin and against insulin receptor were negative. The serum IGF-II level was 668<span class="elsevierStyleHsp" style=""></span>ng/mL (normal range: 350–1000<span class="elsevierStyleHsp" style=""></span>ng/mL), and the IGF-I level was less than 31<span class="elsevierStyleHsp" style=""></span>ng/ml (15–225), IGF-II: IGF-I ratio was 21 (reference range<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10), confirming a diagnosis of non-islet cell hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> Computed tomographic (CT) scan revealed progression in the volume of the right renal-hepatic mass, liver metastasis, pulmonary and right bronchopulmonary adenopathies and progression of bone metastasis and peritoneal implants. It was initiated an intravenous destroxe infusion and 30<span class="elsevierStyleHsp" style=""></span>mg of prednisone per day. Despite these measures, the nocturnal hypoglycemia persisted and was recommended 30<span class="elsevierStyleHsp" style=""></span>g of cornstarch at night. A flash glucose monitor was implanted to set alarms and prevent hypoglycemia. Since the patient was receiving immunotherapy as treatment, a differential diagnosis between insulin autoimmune and IGF II-mediated hypoglycemia was necessary.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In IGF II-mediated hypoglycaemia, the diagnosis is supported by the detection of low serum concentrations of insulin, proinsulin and C-peptide with normal or elevated serum IGFII and negative anti-insulin antibodies. In contrast, the insulin, proinsulin, C-peptide and anti-insulin antibodies will be high in autoimmune insulin-mediated hypoglycaemia.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Tumours producing hypoglycemia are classified into insulin-producing tumours and the much less-common non-islet cell tumours. NICTH is a rare syndrome with nearly 290 cases reported in the English language medical literature in the past quarter century. Hypoglycemia can be the initial symptom, in other cases, it might develop when distance metastasis has occurred, as in our case. Pro-IGF-II precursors (known as big IFG-II) are associated with NICTH and formed due to abnormal processing of the precursor in tumours with aberrant IGF-II gene transcription and gene expression.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Although many reported cases of NICTH detail high IGF-II levels, low and normal IGF-II levels are also reported. In our case, despite the patient had IGF II levels within normal limits, a suppressed IGF-I levels and a IGF-II/IGFI ratio<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>10 suggested NICTH.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Tumours of mesenchymal or hepatic origin are most commonly described with NICTH, although it is now recognized that a wide variety of tumour types can result in production of big IGF-II. To our knowledge, RCCs causing NICTH have only been reported in few cases.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">3–5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In patients in whom surgery is possible, removal of the tumour can cure hypoglycemia. However, surgery was not possible in this patient due to advanced metastatic disease. In this case, in addition to prednisone and dextrose perfusion, glucose sensor implantation was a useful tool to prevent severe hypoglycemia.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical considerations</span><p id="par0035" class="elsevierStylePara elsevierViewall">Verbal informed consent.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0040" class="elsevierStylePara elsevierViewall">No.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">No.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.W. de Groot" 1 => "B. 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