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Open access

Acute presentation of immunotherapy-related diabetes mellitus without ketoacidosis, low C-peptide or elevated HbA1c

Cun An Phang, Shejil Kumar, and Peter Rohl

Summary

The rapid rise in the use of immune checkpoint inhibitors as systemic cancer therapy has seen the emergence of immunotherapy-induced diabetes, a severe irreversible immunotherapy-related adverse event. Affected patients typically present with diabetic ketoacidosis (DKA) and low C-peptide consistent with insulin deficiency secondary to autoimmune β-cell destruction. We present the unusual case of a 61-year-old female with metastatic ampullary duodenal adenocarcinoma with primary tumour adjacent to the pancreatic head. She was commenced on immunotherapy after conventional systemic chemotherapy. Acute-onset hyperglycaemia was detected after 7 weeks on weekly blood glucose monitoring, with no glucocorticoid use or prior history of diabetes. On presentation, there was no evidence of DKA, and her glycated haemoglobin level was within the normal non-diabetic range at 5.3%, reflecting the acuity of her presentation. Initial serum C-peptide was preserved; however, it became undetectable a few weeks later, confirming insulin deficiency. We describe a case of atypical presentation of immunotherapy-induced diabetes, review the existing literature on this emerging clinical entity and discuss the differential diagnosis for new-onset diabetes mellitus in patients with metastatic cancer.

Learning points

  • Regular proactive glycaemic monitoring in patients receiving immunotherapy, particularly antibodies against programmed death ligand 1 and PD1, can facilitate very early detection of immunotherapy-induced diabetes, prompting insulin commencement and avoiding life-threatening presentations of diabetic ketoacidosis.

  • Glycated haemoglobin can be within the normal range in patients diagnosed acutely with immunotherapy-induced diabetes.

  • Serum C-peptide can be preserved initially in patients diagnosed with immunotherapy-induced diabetes but is likely to become undetectable during their illness.

  • New-onset diabetes in patients with metastatic cancer carries a broad differential diagnosis.

DOI:
https://doi.org/10.1530/EDM-22-0291
Volume 2022: Issue 1
Open access

A case series and literature review of necrobiosis lipoidica

Matthew J Verheyden, Natassia Rodrigo, Anthony J Gill, and Sarah J Glastras

Summary

Necrobiosis lipoidica (NL) is a rare and chronic disease characterised by yellow-brown, atrophic, telangiectatic plaques usually located on the lower extremities, with pathological features of collagen necrobiosis and dermal inflammation. Most cases are seen in those with diabetes mellitus, particularly type 1 diabetes (T1DM), and many without diabetes have evidence of abnormal glucose tolerance or family history of autoimmune disease. In this study, we describe four patients with NL and T1DM. A common theme is late identification and delay in diagnosis. Hence, we discuss the clinical features, need for clinicopathological correlation, and the management and prognostic implications for this distinctive entity. While most remain relatively asymptomatic, others progress to debilitating disease with pruritus, dysesthesia, and pain. Pain is often intense in the presence of ulcerated plaques, a morbid complication of NL. Diagnosis requires the integration of both clinical and histopathological findings. NL has proven a challenging condition to treat, and despite the numerous therapeutic modalities available, there is no standard of care. Hence, in this study, we provide an overview of current management strategies available for NL.

Learning points

  • Necrobiosis lipoidica (NL) is classically seen in patients with type 1 diabetes.

  • Koebner phenomenon, defined as the appearance of new skin lesions on previously unaffected skin secondary to trauma, is a well-recognised feature in NL.

  • Background skin phototype contributes to variable yellow appearance of lesions in NL.

  • Diagnosis of NL requires careful clinicopathological correlation.

  • NL is a chronic disease often refractory to treatment leading to significant morbidity for the patient and a management conundrum for the multidisciplinary healthcare team.

  • No standard therapeutic regimen has been established for the management of NL.

DOI:
https://doi.org/10.1530/EDM-21-0185
Volume 2022: Issue 1
Open access

Acanthosis nigricans in a patient with metastatic insulinoma post peptide receptor radionuclide therapy

Jenny S W Yun, Chris McCormack, Michelle Goh, and Cherie Chiang

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.

DOI:
https://doi.org/10.1530/EDM-21-0150
Volume 2022: Issue 1
Open access

Accidental exposure to glimepiride from adulterated medication resulting in severe hypoglycaemia

Annabelle G Hayes, Mahesh M Umapathysivam, and David J Torpy

Summary

Sulphonylureas are insulinotropic and are not only useful in patients with diabetes but also act in non-diabetic individuals where hypoglycaemia and hyperinsulinism mimic insulinoma. We present a 63-year-old man who presented with inadvertent sulphonylurea-induced life-threatening hypoglycaemia on two occasions, resulting in hazardous and invasive investigation. Biochemistry revealed endogenous hyperinsulinaemia, with elevated serum c-peptide and insulin concentrations during symptomatic hypoglycaemia, and plasma glucose of 1.7 mmol/L. There was no history of sulphonylurea use prompting anatomical insulinoma studies to locate an insulinoma. However, a routine plasma insulinoma screen-detected glimepiride. Directed history implicated a medication taken for erectile dysfunction prior to disturbed consciousness, with alcohol. The tablets, obtained online, were analysed by mass spectrometry and contained tadalafil and dapoxetine as advertised but also contained glimepiride.

Learning points

  • Symptomatic unexplained hypoglycaemia requires investigation with plasma glucose level, c-peptide, insulin level, pro-insulin, beta-hydroxybutyrate, and a sulphonylurea screen regardless of known exposure to sulphonylureas.

  • Consider contamination of alternative or undisclosed medication, including PDE-5 inhibitor erectile dysfunction drugs.

  • Concomitant alcohol may impair glycogenolysis and gluconeogenesis, exacerbating hypoglycaemia.

DOI:
https://doi.org/10.1530/EDM-21-0129
Volume 2022: Issue 1
Open access

The use of SGLT2 inhibitors in achieving glycaemic control in maturity-onset diabetes of the young type 3

Arunan Sriravindrarajah, Amelia Fernandes, Ted Wu, and Samantha Hocking

Summary

Maturity-onset diabetes of the young type 3 (MODY3) accounts for approximately 50% of cases of MODY. First-line treatment with sulfonylureas has been well established for individuals with MODY3. In contrast, the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors in the treatment of individuals with MODY3 remains unclear. This case illustrates the in vivo effect of an SGLT2 inhibitor in a 30-year-old woman with MODY3 with poor glycaemic control despite the treatment with supramaximal doses of sulfonylurea and metformin. The addition of a SGLT2 inhibitor resulted in a rapid improvement in glycaemic control without any hypoglycaemic episodes. This case suggests that SGLT2 inhibitors may be an effective and potent treatment option in addition to sulfonylureas for individuals with MODY3.

Learning points

  • Maturity-onset diabetes of the young type 3 (MODY3) arises from mutations in the hepatocyte nuclear factor-1alpha gene, which controls the expression of sodium-glucose co-transporter 2 (SGLT2) in the kidneys.

  • Paradoxically, despite individuals with MODY3 having reduced expression of SGLT2, SGLT2 inhibitors induce higher glycosuria in individuals with MODY3 compared to individuals with type 2 diabetes mellitus.

  • SGLT2 inhibitors may be an effective treatment for achieving glycaemic control in individuals with MODY3.

DOI:
https://doi.org/10.1530/EDM-21-0102
Volume 2021: Issue 1
Open access

A novel approach to a rare case of non-islet cell hypoglycaemia

R K Dharmaputra, K L Wan, N Samad, M Herath, J Wong, S Sarlos, S R Holdsworth, and N Naderpoor

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.

DOI:
https://doi.org/10.1530/EDM-21-0040
Volume 2021: Issue 1
Open access

Multifocal insulinoma secondary to insulinomatosis: persistent hypoglycaemia despite total pancreatectomy

Jennifer R Snaith, Duncan McLeod, Arthur Richardson, and David Chipps

Summary

Insulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure.

Learning points:

  • Insulinomas are usually benign and managed surgically.

  • Insulinomatosis is characterised by multifocal benign insulinomas with a tendency to recur early. It is rare.

  • Multifocal or recurrent insulinomas should raise suspicion of MEN-1 syndrome, or insulinomatosis.

  • Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumour staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones.

  • The ideal treatment strategy is unknown. Total pancreatectomy may not offer cure.

DOI:
https://doi.org/10.1530/EDM-20-0091
Volume 2020: Issue 1
Open access

Successful medical management of insulinoma with diazoxide for 27 years

Annabelle M Warren, Duncan J Topliss, and Peter Shane Hamblin

Summary

Despite improvements in localisation techniques and surgical advances, some patients with insulinoma will not be cured by surgery or may not be suitable for surgery. Medical management with diazoxide is an option for such cases. This case report details 27 years of successful management of insulinoma using diazoxide. It has been effective and safe, with only minor adverse effects.

Learning points:

  • Long term diazoxide use can be a safe, effective option for insulinoma when it cannot be localised or removed surgically.

  • Common adverse effects include peripheral oedema, hyperuricaemia, and hirsutism.

  • 68Ga-NOTA-exendin-4 PET/CT scan should be considered for insulinoma localisation when other modalities have been unhelpful.

DOI:
https://doi.org/10.1530/EDM-20-0132
Volume 2020: Issue 1
Open access

Myopathy secondary to empagliflozin therapy in type 2 diabetes

Frank Gao, Stephen Hall, and Leon A Bach

Summary

Sodium/glucose co-transporter 2 (SGLT2) inhibitors are novel oral hypoglycaemic agents that are increasingly used in the management of type 2 diabetes mellitus (T2DM). They are now recommended as second-line pharmacotherapy (in conjunction with metformin) in patients with type 2 diabetes and established atherosclerotic heart disease, heart failure or chronic kidney disease due to their favourable effects on cardiovascular and renal outcomes. We report a case of a 69-year-old man who developed muscle pain, weakness and wasting after commencing the SGLT2 inhibitor empagliflozin. This persisted for 1 year before he underwent resistance testing, which confirmed muscle weakness. His symptoms resolved within weeks of ceasing empagliflozin, with improvement in muscle strength on clinical assessment and resistance testing and reversal of MRI changes. No other cause of myopathy was identified clinically, on biochemical assessment or imaging, suggesting that empagliflozin was the cause of his myopathy.

Learning points:

  • Empagliflozin, a commonly used SGLT2 inhibitor, was associated with myopathy.

  • A high degree of suspicion is required to diagnose drug-induced myopathy, with a temporal relationship between starting the medication and symptom onset being the main indicator.

  • Recognition of drug-induced myopathy is essential, as discontinuation of the offending drug typically improves symptoms.

DOI:
https://doi.org/10.1530/EDM-20-0017
Volume 2020: Issue 1
Open access

Durvalumab-induced diabetic ketoacidosis followed by hypothyroidism

Shivani Patel, Venessa Chin, and Jerry R Greenfield

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.

DOI:
https://doi.org/10.1530/EDM-19-0098
Volume 2019: Issue 1