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Jenny S W Yun Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Chris McCormack Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Michelle Goh Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Cherie Chiang Department of Internal Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
University of Melbourne, Parkville, Victoria, Australia

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Summary

Acanthosis nigricans (AN) is a common dermatosis associated with hyperinsulinemia and insulin resistance. However, AN has been rarely reported in patients with insulinoma, a state of persistent hyperinsulinemia. We present a case of metastatic insulinoma, in whom AN manifested after the first cycle of peptide receptor radionuclide therapy (PRRT). A 40-year-old man was diagnosed with metastatic insulinoma after 5 months of symptomatic hypoglycemia. Within 1 month post PRRT, the patient became euglycemic but developed a pigmented, pruritic rash which was confirmed on biopsy as AN. We discuss the rare manifestation of AN in subjects with insulinoma, the role of insulin in the pathogenesis of AN, malignant AN in non-insulin-secreting malignancies and association with other insulin-resistant endocrinopathies such as acromegaly.

Learning points

  • Acanthosis nigricans (AN) is a common dermatosis which is typically asymptomatic and associated with the hyperinsulinemic state.

  • Malignant AN can rapidly spread, cause pruritus and affect mucosa and the oral cavity.

  • AN is extremely rare in patients with insulinoma despite marked hyperinsulinemia.

  • Peptide receptor radionuclide therapy might have triggered TGF-α secretion in this subject which led to malignant AN.

  • Rapid spread or unusual distribution of pruritic AN warrants further investigation to exclude underlying malignancy.

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R K Dharmaputra Diabetes and Vascular Medicine Department, Monash Health, Victoria, Australia

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K L Wan Monash Health Pathology, Monash Health, Victoria, Australia

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N Samad Diabetes and Vascular Medicine Department, Monash Health, Victoria, Australia

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M Herath Diabetes and Vascular Medicine Department, Monash Health, Victoria, Australia
Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia

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J Wong Diabetes and Vascular Medicine Department, Monash Health, Victoria, Australia
Department of Endocrinology, Monash Health, Victoria, Australia

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S Sarlos Diabetes and Vascular Medicine Department, Monash Health, Victoria, Australia
Department of Endocrinology, Monash Health, Victoria, Australia
Department of Medicine, School of Clinical Sciences, Monash University, Victoria, Australia

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S R Holdsworth Department of Immunology, Monash Health, Victoria, Australia

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N Naderpoor Diabetes and Vascular Medicine Department, Monash Health, Victoria, Australia
Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia

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Summary

Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab.

Learning points

  • Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded.

  • Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia.

  • Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS).

  • Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

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Shivani Patel Department of Diabetes and Endocrinology, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

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Venessa Chin The Kinghorn Cancer Centre, Sydney, New South Wales, Australia
St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia

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Jerry R Greenfield Department of Diabetes and Endocrinology, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia

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Summary

Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200–1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40–4.80) and low free T4: 5.9 pmol/L (reference range: 8.0–16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI).

Learning points:

  • Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.

  • Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.

  • Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.

  • Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.

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Senhong Lee of Endocrinology, Monash Health, Clayton, Victoria, Australia

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Aparna Morgan of Endocrinology, Monash Health, Clayton, Victoria, Australia

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Sonali Shah of Endocrinology, Monash Health, Clayton, Victoria, Australia

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Peter R Ebeling of Endocrinology, Monash Health, Clayton, Victoria, Australia
Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia

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Summary

We report a case of a 67-year-old man with type 2 diabetes presented with diabetic ketoacidosis, two weeks after his first dose of nivolumab therapy for non–small-cell lung carcinoma. He was started on empagliflozin two days prior in the setting of hyperglycaemia after the initiation of nivolumab therapy. Laboratory evaluation revealed an undetectable C-peptide and a positive anti-glutamic acid decarboxylase (GAD) antibody. He was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. He subsequently has developed likely autoimmune thyroiditis and autoimmune encephalitis.

Learning points:

  • Glycemic surveillance in patients receiving immune checkpoint inhibitors is recommended.

  • Early glycemic surveillance after commencement of anti-programmed cell death-1 (PD-1) inhibitors may be indicated in selected populations, including patients with underlying type 2 diabetes mellitus and positive anti-glutamic acid decarboxylase (GAD) antibody.

  • Sodium-glucose co transporter-2 (SGLT2) inhibitors should be used with caution in patients on immunotherapy.

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Florence Gunawan Geelong University Hospital, Barwon Health, Geelong, Victoria, Australia

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Elizabeth George
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Adam Roberts
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Summary

Immune checkpoint inhibitors are the mainstay of treatment for advanced melanoma, and their use is being increasingly implicated in the development of autoimmune endocrinopathies. We present a case of a 52-year-old man with metastatic melanoma on combination nivolumab and ipilumimab therapy who developed concurrent hypophysitis, type 1 diabetes mellitus (T1DM) and diabetes insipidus. He presented prior to third cycle of combination treatment with a headache, myalgias and fatigue. Biochemistry and MRI pituitary confirmed anterior pituitary dysfunction with a TSH: 0.02 mU/L (0.5–5.5 mU/L), fT4: 5.2 pmol/L (11–22 pmol/L), fT3: 4.0 pmol/L (3.2–6.4 pmol/L), cortisol (12:00 h): <9 nmol/L (74–286 nmol/L), FSH: 0.7 IU/L (1.5–9.7 IU/L), LH: <0.1 IU/L (1.8–9.2 IU/L), PRL: 1 mIU/L (90–400 mIU/L), SHBG: 34 nmol/L (19–764 nmol/L) and total testosterone: <0.4 nmol/L (9.9–27.8 nmol/L). High-dose dexamethasone (8 mg) was administered followed by hydrocortisone, thyroxine and topical testosterone replacement. Two weeks post administration of the third cycle, he became unwell with lethargy, weight loss and nocturia. Central diabetes insipidus was diagnosed on the basis of symptoms and sodium of 149 mmol/L (135–145 mmol/L). Desmopressin nasal spray was instituted with symptom resolution and normalization of serum sodium. Three weeks later, he presented again polyuric and polydipsic. His capillary glucose was 20.8 mmol/L (ketones of 2.4 mmol), low C-peptide 0.05 nmol/L (0.4–1.5 nmol/L) and HbA1c of 7.7%. T1DM was suspected, and he was commenced on an insulin infusion with rapid symptom resolution. Insulin antibodies glutamic acid decarboxylase (GAD), insulin antibody-2 (IA-2) and zinc transporter-8 (ZnT8) were negative. A follow-up MRI pituitary revealed findings consistent with recovering autoimmune hypophysitis. Immunotherapy was discontinued based on the extent of these autoimmune endocrinopathies.

Learning points:

  • The most effective regime for treatment of metastatic melanoma is combination immunotherapy with nivolumab and ipilumimab, and this therapy is associated with a high incidence of autoimmune endocrinopathies.

  • Given the high prevalence of immune-related adverse events, the threshold for functional testing should be low.

  • Traditional antibody testing may not be reliable to identify early-onset endocrinopathy.

  • Routine screening pathways have yet to be adequately validated through clinical trials.

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Sarah Y Qian Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Australia

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Matthew J L Hare Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Australia

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Alan Pham Department of Anatomical Pathology, The Alfred Hospital, Melbourne, Australia

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Duncan J Topliss Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Australia
Department of Medicine, Monash University, Melbourne, Australia

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Summary

Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an uncommon and challenging case of insulinoma soon after upper gastrointestinal surgery. A 63-year-old man presented with 6 months of post-prandial hypoglycaemia beginning after a laparoscopic revision of Toupet fundoplication. Hyperinsulinaemic hypoglycaemia was confirmed during a spontaneous episode and in a mixed-meal test. Localisation studies including magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) and gallium dotatate positron emission tomography (68Ga Dotatate PET) were consistent with a small insulinoma in the mid-body of the pancreas. The lesion was excised and histopathology was confirmed a localised well-differentiated neuroendocrine pancreatic neoplasm. There have been no significant episodes of hypoglycaemia since. This case highlights several key points. Insulinoma should be sought in proven post-prandial hyperinsulinaemic hypoglycaemia – even in the absence of fasting hypoglycaemia. The use of nuclear imaging targeting somatostatin and GLP1 receptors has improved accuracy of localisation. Despite these advances, accurate surgical resection can remain challenging.

Learning points:

  • Hypoglycaemia is defined by Whipple’s triad and can be provoked by fasting or mixed-meal tests.

  • Although uncommon, insulinomas can present with post-prandial hypoglycaemia.

  • In hypoglycaemia following gastrointestinal surgery (i.e. bariatric surgery or less commonly Nissen fundoplication) dumping syndrome or non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) should be considered.

  • Improved imaging techniques including MRI, endoscopic ultrasound and functional nuclear medicine scans aid localisation of insulinomas.

  • Despite advances in imaging and surgical techniques, accurate resection of insulinomas remains challenging.

Open access
E S Scott Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia

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G R Fulcher Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
University of Sydney, Sydney, Australia

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R J Clifton-Bligh Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
University of Sydney, Sydney, Australia
Cancer Genetics Laboratory, Hormones & Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia

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Pancreatogenic diabetes is characterised by recurrent severe hypoglycaemia due to changes in both endocrine and exocrine functions. There are no guidelines to manage these individuals. Herein, we describe the post-operative management of two people who developed pancreatogenic diabetes following total pancreatectomy for neuroendocrine malignancy. In both individuals, diabetes was managed using sensor-augmented predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII). We demonstrate the benefit of sensor-augmented CSII in averting hypoglycaemia whilst optimising glycaemic control. Expected rates of severe hypoglycaemia in individuals with pancreatogenic diabetes can be averted with the use of continuous glucose monitoring (CGM) technology, optimising quality of life and reducing the risk of diabetes-related complications.

Learning points:

  • There are no clear guidelines to manage people with pancreatogenic diabetes.

  • We describe the use of CGM with predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII) in the management of two individuals post-pancreatectomy.

  • Predictive low-glucose suspend technology can achieve excellent glycaemic control whilst avoiding recurrent and severe hypoglycaemia in people with pancreatogenic diabetes.

  • Predictive low-glucose suspend CGM should be considered as an effective therapeutic option for the management of pancreatogenic diabetes.

Open access