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Michal Barabas Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust

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Isabel Huang-Doran Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Debbie Pitfield Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust

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Hazel Philips Department of Cardiology, Bedford Hospital NHS Trust, Bedford, UK

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Manoj Goonewardene Department of Cardiology, Bedford Hospital NHS Trust, Bedford, UK

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Ruth T Casey Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust

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Benjamin G Challis Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust
IMED Biotech Unit, Clinical Discovery Unit, AstraZeneca, Cambridge, UK

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Summary

A 67-year-old woman presented with a generalised rash associated with weight loss and resting tachycardia. She had a recent diagnosis of diabetes mellitus. Biochemical evaluation revealed elevated levels of circulating glucagon and chromogranin B. Cross-sectional imaging demonstrated a pancreatic lesion and liver metastases, which were octreotide-avid. Biopsy of the liver lesion confirmed a diagnosis of well-differentiated grade 2 pancreatic neuroendocrine tumour, consistent with metastatic glucagonoma. Serial echocardiography commenced 4 years before this diagnosis demonstrated a progressive left ventricular dilatation and dysfunction in the absence of ischaemia, suggestive of glucagonoma-associated dilated cardiomyopathy. Given the severity of the cardiac impairment, surgical management was considered inappropriate and somatostatin analogue therapy was initiated, affecting clinical and biochemical improvement. Serial cross-sectional imaging demonstrated stable disease 2 years after diagnosis. Left ventricular dysfunction persisted, however, despite somatostatin analogue therapy and optimal medical management of cardiac failure. In contrast to previous reports, the case we describe demonstrates that chronic hyperglucagonaemia may lead to irreversible left ventricular compromise. Management of glucagonoma therefore requires careful and serial evaluation of cardiac status.

Learning points:

  • In rare cases, glucagonoma may present with cardiac failure as the dominant feature. Significant cardiac impairment may occur in the absence of other features of glucagonoma syndrome due to subclinical chronic hyperglucagonaemia.

  • A diagnosis of glucagonoma should be considered in patients with non-ischaemic cardiomyopathy, particularly those with other features of glucagonoma syndrome.

  • Cardiac impairment due to glucagonoma may not respond to somatostatin analogue therapy, even in the context of biochemical improvement.

  • All patients with a new diagnosis of glucagonoma should be assessed clinically for evidence of cardiac failure and, if present, a baseline transthoracic echocardiogram should be performed. In the presence of cardiac impairment these patients should be managed by an experienced cardiologist.

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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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Kun Zhang Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Lukas J Lehner Department of Nephrology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Damaris Praeger Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Gert Baumann Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Fabian Knebel Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Marcus Quinkler Department of Endocrinology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Torsten K Roepke Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Summary

Neuroendocrine tumours (NETs) represent a broad spectrum of tumours, of which the serotonin-producing carcinoid is the most common and has been shown to cause right ventricular heart failure. However, an association between heart failure and NETs other than carcinoid has not been established so far. In this case report, we describe a 51-year-old patient with a glucagon-producing NET of the pancreas who developed acute heart failure and even cardiogenic shock despite therapy. Heart failure eventually regressed after initialising i.v. treatment with the somatostatin analogue octreotide. Chromogranin A as a tumour marker was shown to be significantly elevated, and it decreased with clinical improvement of the patient. The effects of long-time stimulation of glucagon on the myocardium have not been studied yet; however, sarcoplasmic reticulum calcium leak can be discussed as a possible mechanism for glucagon-induced heart failure.

Learning points

  • Glucagonoma can be a cause for heart failure.

  • i.v. infusion of octreotide can be successfully used to treat glucagonoma-induced acute heart failure.

  • We suggest that cardiac function should be monitored in all NET patients.

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