Clinical Overview > Condition/ Syndrome > Hypoglycaemia

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Nishant Raizada Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

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S H Rahaman Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

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D Kandasamy Department of Radiology, All India Institute of Medical Sciences, New Delhi, India

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V P Jyotsna Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

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Summary

Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycaemia, which is known to occur in association with the use of sulfhydryl-containing drugs and autoimmune disorders. We describe a patient with hitherto an unreported association of IAS with ankylosing spondylitis. We have also performed and described a simplified method of polyethylene glycol (PEG) precipitation of an insulin bound antibody in the serum.

Learning points

  • IAS should be considered in differential diagnosis of endogenous hyperinsulinemic hypoglycaemia.

  • Ankylosing spondylitis can be associated with IAS apart from several other autoimmune diseases.

  • Very high serum insulin levels (100–10 000 μU/ml) are frequently seen in IAS.

  • When faced with very high serum insulin before suspecting insulinoma, it is advisable that PEG precipitation of serum be done to identify antibody bound insulin.

  • A clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.

Open access
G K Dimitriadis Warwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK
Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, UK
Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK

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K Gopalakrishnan Department of Histopathology, Coventry and Warwickshire, Pathology Service, UHCW NHS Trust, Coventry, UK

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R Rao Warwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK

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D K Grammatopoulos Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK
Department of Clinical Biochemistry and Histopathology, Coventry and Warwickshire, Pathology Service, UHCW NHS Trust, Coventry, UK

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H S Randeva Warwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK
Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK

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M O Weickert Warwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK

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N Murthy Warwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK

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Summary

We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0′) 390 nmol/l, Cort (30′) 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period.

Learning points

  • NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms.

  • NICTH can masquerade as other pathologies thus causing diagnostic confusion.

  • Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential.

  • Mutational analysis of GISTs should be carried out in all cases as it guides treatment decision.

  • Tailored management of hypoglycaemia, in this case using growth hormone and targeted cyto-reductive therapy, minimizes the risk of possible life-threatening complications.

Open access
Sally K Abell Department of Endocrinology and Diabetes, St Vincent's Hospital, PO Box 2900, Fitzroy, Melbourne, 3065 Victoria, Australia

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Jessie Teng Department of Endocrinology and Diabetes, St Vincent's Hospital, PO Box 2900, Fitzroy, Melbourne, 3065 Victoria, Australia

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Anthony Dowling Department of Oncology, St Vincent's Hospital, PO Box 2900, Fitzroy, Melbourne, 3065 Victoria, Australia

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Michael S Hofman Department of Medicine, University of Melbourne, Parkville, Melbourne, Victoria, Australia
Molecular Imaging, Centre for Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Victoria, Australia

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Richard J MacIsaac Department of Endocrinology and Diabetes, St Vincent's Hospital, PO Box 2900, Fitzroy, Melbourne, 3065 Victoria, Australia
Department of Medicine, University of Melbourne, Parkville, Melbourne, Victoria, Australia

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Nirupa Sachithanandan Department of Endocrinology and Diabetes, St Vincent's Hospital, PO Box 2900, Fitzroy, Melbourne, 3065 Victoria, Australia

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Summary

This paper details the case of a 77-year-old male with refractory hypoglycaemia due to inoperable metastatic pancreatic neuroendocrine tumour (pNET) co-secreting insulin and gastrin. Multiple medical therapies were trialled with limited success, and we describe the complications experienced by our patient. Somatostatin analogues can ameliorate hypoglycaemia and may have tumour-stabilising effects; however, in our case resulted in paradoxical worsening of hypoglycaemia. This rendered our patient hospital dependent for glycaemic support including continuous dextrose infusion. Although this is a reported adverse effect with initiation of therapy, we describe successful initiation of short-acting octreotide as an inpatient followed by commencement of long-acting octreotide. Hypoglycaemic collapse occurred only after dose titration of long-acting octreotide. We outline the pitfalls of somatostatin analogue therapy and the mechanisms that may contribute to worsening hypoglycaemia. This rare side effect cannot be reliably predicted, necessitating close supervision and glucose monitoring during therapy. Our patient achieved disease stabilisation and gradual resolution of hypoglycaemia with peptide receptor radionuclide therapy (PRRT), an emerging therapeutic option for metastatic neuroendocrine tumours with high efficacy and low toxicity. We present a brief but comprehensive discussion of currently available and novel therapies for insulin secreting pNETs.

Learning points

  • Hypoglycaemia due to malignant insulin secreting pNET is frequently severe and may be life-threatening despite supportive therapies.

  • Octreotide can ameliorate hypoglycaemia, and may have anti-proliferative and tumour-stabilising effects in malignant pNETs that are surgically unresectable.

  • Paradoxical worsening of hypoglycaemia may occur with octreotide initiation and dose titration, necessitating close supervision and glucose monitoring.

  • PRRT is emerging as a therapeutic option with high efficacy and low toxicity.

Open access
Mauro Boronat Section of Endocrinology and Nutrition, Hospital Universitario Insular, 35016 Las Palmas de Gran Canaria, Spain
Department of Medical and Surgical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

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Rosa M Sánchez-Hernández Section of Endocrinology and Nutrition, Hospital Universitario Insular, 35016 Las Palmas de Gran Canaria, Spain

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Julia Rodríguez-Cordero Section of Endocrinology and Nutrition, Hospital Universitario Insular, 35016 Las Palmas de Gran Canaria, Spain

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Angelines Jiménez-Ortega Section of Endocrinology and Nutrition, Hospital Universitario Insular, 35016 Las Palmas de Gran Canaria, Spain

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Francisco J Nóvoa Section of Endocrinology and Nutrition, Hospital Universitario Insular, 35016 Las Palmas de Gran Canaria, Spain
Department of Medical and Surgical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

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Summary

Treatment with continuous s.c. insulin infusion (CSII) provides better glycemic control and lower risk of hypoglycemia than conventional therapy with multiple daily insulin injections. These benefits have been related to a more reliable absorption and an improved pharmacokinetic profile of insulin delivered through CSII therapy. However, even for patients treated with CSII, exaggerated postmeal hyperglycemic excursions and late postabsorptive hypoglycemia can still constitute a therapeutic challenge. Two female patients with type 1 diabetes who began treatment with CSII required to increase their previous breakfast insulin-to-carbohydrate ratio in order to achieve postprandial glycemic goals. However, they simultaneously presented recurrent episodes of late hypoglycemia several hours after breakfast bolus. Advancing the timing of the bolus was ineffective and bothersome for patients. In both cases, the best therapeutic option was to set a basal insulin rate of zero units per hour during 6 h after breakfast. Even so, they need to routinely take a midmorning snack with 10–20 g of carbohydrates to avoid late postabsorptive hypoglycemia. They have been using this insulin schedule for about 3 years without complications. The action of prandial insulin delivered through insulin pumps can be inappropriately delayed for the requirements of some patients. Although suspension of basal rate can be an acceptable therapeutic alternative for them, these cases demonstrate that new strategies to improve the bioavailability of prandial insulin infused through CSII are still needed.

Learning points

  • CSII remains the most physiologically suitable system of insulin delivery available today.

  • Additionally, the duration of action of prandial insulin delivered through insulin pumps can be excessively prolonged in some patients with type 1 diabetes.

  • These patients can present recurrent late episodes of hypoglycemia several hours after the administration of insulin boluses.

  • The routine suspension of basal insulin for several hours, leaving meal bolus to cover both prandial and basal insulin requirements, can be a therapeutic option for these subjects.

Open access
Chiara Baratelli Dipartimento di Oncologia, Oncologia Medica

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Maria Pia Brizzi Dipartimento di Oncologia, Oncologia Medica

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Marco Tampellini Dipartimento di Oncologia, Oncologia Medica

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Giorgio Vittorio Scagliotti Dipartimento di Oncologia, Oncologia Medica

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Adriano Priola SCDU Radiologia

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Massimo Terzolo Dipartimento di Scienze Cliniche e Biologiche, Medicina Interna, Università di Torino, Azienda Ospedaliero Universitaria San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano, Italy

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Anna Pia Dipartimento di Scienze Cliniche e Biologiche, Medicina Interna, Università di Torino, Azienda Ospedaliero Universitaria San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano, Italy

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Alfredo Berruti Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica Università di Brescia, Oncologia Medica, Azienda Ospedaliera Spedali Civili, Brescia, Italy

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Summary

Insulinoma is a rare form of insulin-secreting pancreatic islet cell neuroendocrine (NE) tumor. The medical treatment of the malignant NE disease of the pancreas deeply changed in the last years, thanks to the introduction of new target molecules, as everolimus. Even if the exact mechanism is not actually known, one of the side effects of everolimus, hyperglycemia, has been demonstrated to be useful to contrast the typical hypoglycemia of the insulinoma. We report the case of a patient with a metastatic malignant insulinoma treated with intermittent everolimus, obtaining an important improvement in the quality of life; this suggests the necessity of preclinical studies to analyze the cellular pathways involved in insulin-independent gluconeogenesis.

Learning points

  • Effect of somatostatin analogs is long-lasting in the control of functioning NE tumors.

  • Persistent everolimus control of hypoglycemia despite serum insulin levels and disease progression.

  • Open issue: are disease progression and the increase in serum markers the only valid criteria to reject a treatment?

Open access
Kamel Mohammedi Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Charbel Abi Khalil Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Sophie Olivier Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Imane Benabad Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Ronan Roussel Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Michel Marre Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

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Summary

Hypoglycemia is a common medical emergency. It is the most frequent complication induced by anti-diabetic treatment. However, it can be observed in other conditions unrelated to diabetes such as insulinoma, autoimmune disorders, and neoplasia. Herein, we report the case of a rare cause of severe and recurrent hypoglycemia in a 77-year-old woman with a malignant solitary fibrous tumor (MSFT). A 77-year-old woman was admitted to the emergency department for loss of consciousness induced by severe hypoglycemia. Her standard laboratory findings were unremarkable. HbA1c, albumin, renal, liver, thyroid, and adrenal function tests were normal. Cerebral CT scan was also normal. At the time of confirmed hypoglycemia, the serum level of insulin and C-peptide was low. On the basis of the past medical history and the absence of other comment etiologies, a paraneoplastic cause was suspected. Thus, the diagnosis of a non-islet cell tumor-induced hypoglycemia (NICTH) was established by the presence of incompletely processed precursors of IGF2 (big IGF2) in plasma electrophoresis. However, the IGF1 level was low. Therapy with corticosteroids improved hypoglycemia and clinical symptoms. NICTH is a rare cause of hypoglycemia. It should be considered in patients with mesenchymal or malignant epithelial tumors suffering from recurrent episodes of hypoglycemia. The diagnosis will be established in the case of low serum insulin concentrations and elevated levels of big IGF2. Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels.

Learning points

  • NICTH is a very rare condition that should be considered in patients known to have mesenchymal or malignant epithelial tumors and suffering from recurrent episodes of hypoglycemia.

  • The diagnosis of an NICTH is established on the basis of the hypoinsulinemic hypoglycemia, the MSFT history, and the presence of paraneoplastic secretion of IGF1 or an immature form of IGF2.

  • Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels in NICTH.

Open access
N Jassam Harrogate District Hospital, Harrogate HG2 7SX, UK

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N Amin Leeds Children's Hospital NHS Trust, Leeds, UK

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P Holland Leeds Children's Hospital NHS Trust, Leeds, UK

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R K Semple Wellcome Trust, Cambridge University Hospital, Cambridge, UK

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D J Halsall Clinical Biochemistry Department, Addenbrooke's Hospital, Cambridge, UK

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G Wark SAS Peptides Hormone Section, Royal Surrey County Hospital, Surrey, UK

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J H Barth Blood Sciences Department, Leeds Teaching Hospitals NHS Trust, Leeds, UK

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Summary

A lean 15-year-old girl was diagnosed with type 1 diabetes based on symptomatic hyperglycaemia and positive anti-islet cell antibodies. Glycaemia was initially stabilised on twice-daily mixed insulin. After 11 months from the time of diagnosis, she complained of hyperglycaemia and ketosis alternating with hypoglycaemia. This progressively worsened until prolonged hospital admission was required for treatment of refractory hypoglycaemia. A high titre of anti-insulin antibodies was detected associated with a very low recovery of immunoreactive (free) insulin from plasma after precipitation with polyethylene glycol, suggesting the presence of insulin in bound complexes. Insulin autoimmune syndrome was diagnosed and metabolic fluctuations were initially managed supportively. However, due to poor glucose control, immunosuppressive therapy was initiated first with steroids and plasmapheresis and later with anti-CD20 antibody therapy (Rituximab). This treatment was associated with a gradual disappearance of anti-insulin antibodies and her underlying type 1 diabetes has subsequently been successfully managed with an insulin pump.

Learning points

  • Anti-insulin antibodies may result in low levels of free insulin.

  • Polyclonal anti-insulin antibodies can interfere with the pharmacological action of administered insulin, resulting in hypoglycaemia and insulin resistance, due to varying affinities and capacities.

  • In this patient, rituximab administration was associated with a gradual disappearance of anti-insulin antibodies.

  • It is hypothesised that this patient had subcutaneous insulin resistance (SIR) caused by insulin capture at the tissue level, either by antibodies or by sequestration.

  • A prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR syndrome.

Open access
S Solomou Department of Endocrinology, Barts and the London School of Medicine, QMUL, W SmithfieldEC1A 7BE, London, UK

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R Khan Department of Endocrinology, Barts and the London School of Medicine, QMUL, W SmithfieldEC1A 7BE, London, UK

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D Propper Department of Oncology, Barts and the London School of Medicine, QMUL, W SmithfieldEC1A 7BE, London, UK

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D Berney Department of Histopathology, Barts and the London School of Medicine, QMUL, W SmithfieldEC1A 7BE, London, UK

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M Druce Department of Endocrinology, Barts and the London School of Medicine, QMUL, W SmithfieldEC1A 7BE, London, UK

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Summary

A 33-year-old male was diagnosed with a metastatic neuroendocrine carcinoma of uncertain primary. He defaulted from follow-up without therapy and some months later developed episodic severe hypoglycaemia, which was found to be associated with inappropriately elevated insulin and C-peptide levels. It was considered likely that the neuroendocrine tumour was the source of the insulin secretion. Diazoxide and somatostatin analogue were used to control hypoglycaemia. Much later in the course of the disease, he developed metabolic derangement, increased skin pigmentation and psychological disturbance, without frankly Cushingoid physical findings. Investigations revealed highly elevated cortisol levels (the levels having previously been normal) with markedly raised ACTH levels, consistent with the co-secretion of ACTH and insulin by the tumour. Treatment with metyrapone improved his psychological state and electrolyte imbalance. Unfortunately, despite several cycles of first-, second- and third-line chemotherapy from the start of the first hormonal presentation onwards, imaging revealed widespread progressive metastatic disease and the patient eventually passed away. This case highlights the importance of keeping in mind the biochemical heterogeneity of endocrine tumours during their treatment.

Learning points

  • The clinical presentation of insulin-secreting tumours includes symptoms of neuroglycopaenia and sympathetic overstimulation.

  • Tumour-associated hypoglycaemia can be due to pancreatic insulinomas, and although ectopic hormone production occurs in a number of tumours, ectopic secretion of insulin is rare.

  • A possible switch in the type of hormone produced can occur during the growth and progression of neuroendocrine tumours and, when treating neuroendocrine tumours, it is important to keep in mind their biochemical heterogeneity.

Open access
Pinaki Dutta Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Anuradha Aggarwal Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Yashpal Gogate Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Uma Nahar Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Viral N Shah Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Mandeep Singla Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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N Khandelwal Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Anil Bhansali Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Summary

We describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity.

Learning points

  • NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia.

  • Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH.

  • IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.

Open access