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Adrian Po Zhu Li Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Sheela Sathyanarayan Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Salvador Diaz-Cano Departments of Cellular Pathology and Molecular Pathology, Queen Elizabeth Hospital, Birmingham, UK
Division of Cancer Studies, King’s College London, London, UK

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Sobia Arshad Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Eftychia E Drakou Department of Clinical Oncology, Guy’s Cancer Centre – Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, UK

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Royce P Vincent Department of Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
Faculty of Life Sciences and Medicine, School of Life Course Sciences, King’s College London, London, UK

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Ashley B Grossman Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
Barts and the London School of Medicine, Centre for Endocrinology, William Harvey Institute, London, UK
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK

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Simon J B Aylwin Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Georgios K Dimitriadis Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
Obesity, Type 2 Diabetes and Immunometabolism Research Group, Department of Diabetes, Faculty of Life Sciences, School of Life Course Sciences, King’s College London, London, UK
Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK

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Summary

A 49-year-old teacher presented to his general physician with lethargy and lower limb weakness. He had noticed polydipsia, polyuria, and had experienced weight loss, albeit with an increase in central adiposity. He had no concomitant illnesses and took no regular medications. He had hypercalcaemia (adjusted calcium: 3.34 mmol/L) with hyperparathyroidism (parathyroid hormone: 356 ng/L) and hypokalaemia (K: 2.7 mmol/L) and was admitted for i.v. potassium replacement. A contrast-enhanced CT chest/abdomen/pelvis scan revealed a well-encapsulated anterior mediastinal mass measuring 17 × 11 cm with central necrosis, compressing rather than invading adjacent structures. A neck ultrasound revealed a 2 cm right inferior parathyroid lesion. On review of CT imaging, the adrenals appeared normal, but a pancreatic lesion was noted adjacent to the uncinate process. His serum cortisol was 2612 nmol/L, and adrenocorticotrophic hormone was elevated at 67 ng/L, followed by inadequate cortisol suppression to 575 nmol/L from an overnight dexamethasone suppression test. His pituitary MRI was normal, with unremarkable remaining anterior pituitary biochemistry. His admission was further complicated by increased urine output to 10 L/24 h and despite three precipitating factors for the development of diabetes insipidus including hypercalcaemia, hypokalaemia, and hypercortisolaemia, due to academic interest, a water deprivation test was conducted. An 18flurodeoxyglucose-PET (FDG-PET) scan demonstrated high avidity of the mediastinal mass with additionally active bilateral superior mediastinal nodes. The pancreatic lesion was not FDG avid. On 68Ga DOTATE-PET scan, the mediastinal mass was moderately avid, and the 32 mm pancreatic uncinate process mass showed significant uptake. Genetic testing confirmed multiple endocrine neoplasia type 1.

Learning points

  • In young patients presenting with primary hyperparathyroidism, clinicians should be alerted to the possibility of other underlying endocrinopathies.

    In patients with multiple endocrine neoplasia type 1 (MEN-1) and ectopic adrenocorticotrophic hormone syndrome (EAS), clinicians should be alerted to the possibility of this originating from a neoplasm above or below the diaphragm.

  • Although relatively rare compared with sporadic cases, thymic carcinoids secondary to MEN-1 may also be associated with EAS.

  • Electrolyte derangement, in particular hypokalaemia and hypercalcaemia, can precipitate mild nephrogenic diabetes insipidus.

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Minna Koivikko Department of Internal Medicine, University of Oulu and Oulu University Hospital, Oulu, Finland

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Tapani Ebeling Department of Internal Medicine, University of Oulu and Oulu University Hospital, Oulu, Finland

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Markus Mäkinen Department of Pathology, University of Oulu, Oulu, Finland

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Juhani Leppäluoto Institute of Biomedicine, University of Oulu, Oulu, Finland

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Antti Raappana Department of Otorhinolaryngology, University of Oulu and Oulu University Hospital, Oulu, Finland

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Petteri Ahtiainen Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä, Finland

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Pasi Salmela Department of Internal Medicine, University of Oulu and Oulu University Hospital, Oulu, Finland

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Summary

Multiple endocrine neoplasia type 1 NM_001370259.2(MEN1):c.466G>C(p.Gly156Arg) is characterized by tumors of various endocrine organs. We report on a rare, growth hormone-releasing hormone (GHRH)-releasing pancreatic tumor in a MEN1 patient with a long-term follow-up after surgery. A 22-year-old male with MEN1 syndrome, primary hyperparathyroidism and an acromegalic habitus was observed to have a pancreatic tumor on abdominal CT scanning, growth hormone (GH) and insulin-like growth factor 1 (IGF1) were elevated and plasma GHRH was exceptionally high. GHRH and GH were measured before the treatment and were followed during the study. During octreotide treatment, IGF1 normalized and the GH curve was near normal. After surgical treatment of primary hyperparathyroidism, a pancreatic tail tumor was enucleated. The tumor cells were positive for GHRH antibody staining. After the operation, acromegaly was cured as judged by laboratory tests. No reactivation of acromegaly has been seen during a 20-year follow-up. In conclusion, an ectopic GHRH-producing, pancreatic endocrine neoplasia may represent a rare manifestation of MEN1 syndrome.

Learning points

  • Clinical suspicion is in a key position in detecting acromegaly.

  • Remember genetic disorders with young individuals having primary hyperparathyroidism.

  • Consider multiple endocrine neoplasia type 1 syndrome when a person has several endocrine neoplasia.

  • Acromegaly may be of ectopic origin with patients showing no abnormalities in radiological imaging of the pituitary gland.

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Ana Dugic Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Michael Kryk Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Claudia Mellenthin Department of Surgery, HFR Fribourg, Fribourg, Switzerland

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Christoph Braig Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Lorenzo Catanese Department for Nephrology, Angiology and Rheumatology, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Sandy Petermann Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Jürgen Kothmann Department for Nephrology, Angiology and Rheumatology, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Steffen Mühldorfer Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Summary

Drinking fruit juice is an increasingly popular health trend, as it is widely perceived as a source of vitamins and nutrients. However, high fructose load in fruit beverages can have harmful metabolic effects. When consumed in high amounts, fructose is linked with hypertriglyceridemia, fatty liver and insulin resistance. We present an unusual case of a patient with severe asymptomatic hypertriglyceridemia (triglycerides of 9182 mg/dL) and newly diagnosed type 2 diabetes mellitus, who reported a daily intake of 15 L of fruit juice over several weeks before presentation. The patient was referred to our emergency department with blood glucose of 527 mg/dL and glycated hemoglobin (HbA1c) of 17.3%. Interestingly, features of diabetic ketoacidosis or hyperosmolar hyperglycemic state were absent. The patient was overweight with an otherwise unremarkable physical exam. Lipase levels, liver function tests and inflammatory markers were closely monitored and remained unremarkable. The initial therapeutic approach included i.v. volume resuscitation, insulin and heparin. Additionally, plasmapheresis was performed to prevent potentially fatal complications of hypertriglyceridemia. The patient was counseled on balanced nutrition and detrimental effects of fruit beverages. He was discharged home 6 days after admission. At a 2-week follow-up visit, his triglyceride level was 419 mg/dL, total cholesterol was 221 mg/dL and HbA1c was 12.7%. The present case highlights the role of fructose overconsumption as a contributory factor for severe hypertriglyceridemia in a patient with newly diagnosed diabetes. We discuss metabolic effects of uncontrolled fructose ingestion, as well as the interplay of primary and secondary factors, in the pathogenesis of hypertriglyceridemia accompanied by diabetes.

Learning points

  • Excessive dietary fructose intake can exacerbate hypertriglyceridemia in patients with underlying type 2 diabetes mellitus (T2DM) and absence of diabetic ketoacidosis or hyperosmolar hyperglycemic state.

  • When consumed in large amounts, fructose is considered a highly lipogenic nutrient linked with postprandial hypertriglyceridemia and de novo hepatic lipogenesis (DNL).

  • Severe lipemia (triglyceride plasma level > 9000 mg/dL) could be asymptomatic and not necessarily complicated by acute pancreatitis, although lipase levels should be closely monitored.

  • Plasmapheresis is an effective adjunct treatment option for rapid lowering of high serum lipids, which is paramount to prevent acute complications of severe hypertriglyceridemia.

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Pooja Sahni Division on Endocrinology and Metabolic Medicine and Department of Internal Medicine, St Vincent Hospital, Worcester, Massachusetts, USA

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Nitin Trivedi Division on Endocrinology and Metabolic Medicine and Department of Internal Medicine, St Vincent Hospital, Worcester, Massachusetts, USA

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Abdulkadir Omer Division on Endocrinology and Metabolic Medicine and Department of Internal Medicine, St Vincent Hospital, Worcester, Massachusetts, USA

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Summary

A 65-year-old obese Caucasian woman presented with symptomatic postprandial hypoglycemic episodes, resolution of symptoms with carbohydrate intake and significantly elevated anti-insulin antibody levels. She did not have any evidence for the use of oral antidiabetic medications, insulin, herbal substances, performing strenuous exercise or history of bariatric surgery. Fingerstick blood glucose readings revealed blood sugar of 35 mg/dL and 48 mg/dL, when she had these symptoms. Her medical history was significant for morbid obesity, hypothyroidism and gastro esophageal reflux disease. Her home medications included levothyroxine, propranolol and omeprazole. A blood sample obtained during the symptoms revealed the following: fingerstick blood sugar 38 mg/dL, venous blood glucose 60 mg/dL (normal (n): 70–99 mg/dL), serum insulin 202 IU/mL (n: <21), proinsulin 31.3 pmol/L (n: <28.9), C-peptide 8 ng/mL (n: 0.9–7), beta-hydroxybutyrate 0.12 mmol/L (n: 0.02–0.27) anti-insulin antibody >45.4 U/mL (n: <0.4). The result obtained while screening for serum sulfonylurea and meglitinides was negative. The repeated episodes of postprandial hypoglycemia associated with significantly elevated anti-insulin antibodies led to a diagnosis of insulin antibody syndrome (IAS). Significant improvement of hypoglycemic symptoms and lower anti-insulin antibody levels (33 U/mL) was noted on nutritional management during the following 6 months. Based on a report of pantoprazole-related IAS cases, her omeprazole was switched to a H2 receptor blocker. She reported only two episodes of hypoglycemia, and anti-insulin antibody levels were significantly lower at 10 U/mL after the following 12-month follow-up.

Learning points:

  • Initial assessment of the Whipple criteria is critical to establish the clinical diagnosis of hypoglycemia accurately.

  • Blood sugar monitoring with fingerstick blood glucose method can provide important information during hypoglycemia workup.

  • Autoimmune hypoglycemia is a rare cause of hypoglycemia, which can be diagnosed on high index of clinical suspicion and systematic evaluation.

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Benjamin G Challis Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Chung Thong Lim Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Alison Cluroe Department of Histopathology, Cambridge University Hospitals Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK

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Ewen Cameron Department of Gastroenterology, Cambridge University Hospitals Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK

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Stephen O’Rahilly Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Summary

McKittrick–Wheelock syndrome (MWS) is a rare consequence of severe dehydration and electrolyte depletion due to mucinous diarrhoea secondary to a rectosigmoid villous adenoma. Reported cases of MWS commonly describe hypersecretion of mucinous diarrhoea in association with dehydration, hypokalaemia, hyponatraemia, hypochloraemia and pre-renal azotemia. Hyperglycaemia and diabetes are rarely reported manifestations of MWS. Herein we describe the case of a 59-year-old woman who presented with new-onset diabetes and severe electrolyte derangement due to a giant rectal villous adenoma. Subsequent endoscopic resection of the tumour cured her diabetes and normalised electrolytes. This case describes a rare cause of ‘curable diabetes’ and indicates hyperaldosteronism and/or whole-body potassium stores as important regulators of insulin secretion and glucose homeostasis.

Learning points

  • McKittrick–Wheelock syndrome (MWS) is typically characterised by the triad of pre-renal failure, electrolyte derangement and chronic diarrhoea resulting from a secretory colonic neoplasm.

  • Hyperglycaemia and new-onset diabetes are rare clinical manifestations of MWS.

  • Hyperaldosteronism and/or hypokalaemia may worsen glucose tolerance in MWS.

  • Aggressive replacement of fluid and electrolytes is the mainstay of acute management, with definitive treatment and complete reversal of the metabolic abnormalities being achieved by endoscopic or surgical resection of the neoplasm.

Open access
Taiba Zornitzki Endocrinology, Diabetes and Metabolic Unit, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Bilu 176100, Rehovot, Israel

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Hadara Rubinfeld Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, 49100, Israel
Sackler School of Medicine, Tel-Aviv University, Tel Aviv, 69978, Israel

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Lyudmila Lysyy Endocrinology, Diabetes and Metabolic Unit, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Bilu 176100, Rehovot, Israel

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Tal Schiller Endocrinology, Diabetes and Metabolic Unit, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Bilu 176100, Rehovot, Israel

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Véronique Raverot Laboratoire d'Hormonologie – CBPE, Hospices Civils de Lyon, 59 bd Pinel69677, Bron Cedex, France

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Ilan Shimon Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, 49100, Israel
Sackler School of Medicine, Tel-Aviv University, Tel Aviv, 69978, Israel

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Hilla Knobler Endocrinology, Diabetes and Metabolic Unit, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Bilu 176100, Rehovot, Israel

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Summary

Acromegaly due to ectopic GHRH secretion from a neuroendocrine tumor (NET) is rare and comprises <1% of all acromegaly cases. Herein we present a 57-year-old woman with clinical and biochemical features of acromegaly and a 6 cm pancreatic NET (pNET), secreting GHRH and calcitonin. Following surgical resection of the pancreatic tumor, IGF1, GH and calcitonin normalized, and the clinical features of acromegaly improved. In vitro studies confirmed that the tumor secreted large amounts of both GHRH and calcitonin, and incubation of pNET culture-derived conditioned media stimulated GH release from a cultured human pituitary adenoma. This is a unique case of pNET secreting both GHRH and calcitonin. The ability of the pNET-derived medium to stimulate in vitro GH release from a human pituitary-cell culture, combined with the clinical and hormonal remission following tumor resection, confirmed the ectopic source of acromegaly in this patient.

Learning points

  • Signs, symptoms and initial work-up of acromegaly due to ectopic GHRH secretion are similar to pituitary-dependent acromegaly. However, if no identifiable pituitary lesion is found, somatostatin receptor scan and further imaging (CT, MRI) should be performed.

  • Detection of GHRH in the blood and in the tumor-derived medium supports the diagnosis of ectopic GHRH secretion.

  • Functional bioactivity of pNET-secreted GHRH can be proved in vitro by releasing GH from human pituitary cells.

Open access
Benjamin G Challis Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Nicolai J Wewer Albrechtsen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark

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Vishakha Bansiya Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Keith Burling Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Peter Barker Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Bolette Hartmann Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark

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Fiona Gribble Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Stephen O'Rahilly Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Jens J Holst Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark

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Helen L Simpson Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Summary

Pancreatic neuroendocrine tumours (pNETs) secreting proglucagon are associated with phenotypic heterogeneity. Here, we describe two patients with pNETs and varied clinical phenotypes due to differential processing and secretion of proglucagon-derived peptides (PGDPs). Case 1, a 57-year-old woman presented with necrolytic migratory erythema, anorexia, constipation and hyperinsulinaemic hypoglycaemia. She was found to have a grade 1 pNET, small bowel mucosal thickening and hyperglucagonaemia. Somatostatin analogue (SSA) therapy improved appetite, abolished hypoglycaemia and improved the rash. Case 2, a 48-year-old male presented with diabetes mellitus, diarrhoea, weight loss, nausea, vomiting and perineal rash due to a grade 1 metastatic pNET and hyperglucagonaemia. In both cases, plasma levels of all measured PGDPs were elevated and attenuated following SSA therapy. In case 1, there was increased production of intact glucagon-like peptide 1 (GLP-1) and GLP-2, similar to that of the enteroendocrine L cell. In case 2, pancreatic glucagon was elevated due to a pancreatic α-cell-like proglucagon processing profile. In summary, we describe two patients with pNETs and heterogeneous clinical phenotypes due to differential processing and secretion of PGDPs. This is the first description of a patient with symptomatic hyperinsulinaemic hypoglycaemia and marked gastrointestinal dysfunction due to, in part, a proglucagon-expressing pNET.

Learning points

  • PGDPs exhibit a diverse range of biological activities including critical roles in glucose and amino acid metabolism, energy homeostasis and gastrointestinal physiology.

  • The clinical manifestations of proglucagon-expressing tumours may exhibit marked phenotypic variation due to the biochemical heterogeneity of their secreted peptide repertoire.

  • Specific and precise biochemical assessment of individuals with proglucagon-expressing tumours may provide opportunities for improved diagnosis and clinical management.

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