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Open access

Jose León Mengíbar, Ismael Capel, Teresa Bonfill, Isabel Mazarico, Laia Casamitjana Espuña, Assumpta Caixàs and Mercedes Rigla

Summary

Durvalumab, a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules, is increasingly used in advanced neoplasias. Durvalumab use is associated with increased immune-related adverse events. We report a case of a 55-year-old man who presented to our emergency room with hyperglycaemia after receiving durvalumab for urothelial high-grade non-muscle-invasive bladder cancer. On presentation, he had polyuria, polyphagia, nausea and vomiting, and laboratory test revealed diabetic ketoacidosis (DKA). Other than durvalumab, no precipitating factors were identified. Pre-durvalumab blood glucose was normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. Simultaneously, he presented a thyroid hormone pattern that evolved in 10 weeks from subclinical hyperthyroidism (initially attributed to iodinated contrast used in a previous computerised tomography) to overt hyperthyroidism and then to severe primary hypothyroidism (TSH: 34.40 µU/mL, free thyroxine (FT4): <0.23 ng/dL and free tri-iodothyronine (FT3): 0.57 pg/mL). Replacement therapy with levothyroxine was initiated. Finally, he was tested positive for anti-glutamic acid decarboxylase (GAD65), anti-thyroglobulin (Tg) and antithyroid peroxidase (TPO) antibodies (Abs) and diagnosed with type 1 diabetes mellitus (DM) and silent thyroiditis caused by durvalumab. When durvalumab was stopped, he maintained the treatment of multiple daily insulin doses and levothyroxine. Clinicians need to be alerted about the development of endocrinopathies, such as DM, DKA and primary hypothyroidism in the patients receiving durvalumab.

Learning points:

  • Patients treated with anti-PD-L1 should be screened for the most common immune-related adverse events (irAEs).

  • Glucose levels and thyroid function should be monitored before and during the treatment.

  • Durvalumab is mainly associated with thyroid and endocrine pancreas dysfunction.

  • In the patients with significant autoimmune background, risk–benefit balance of antineoplastic immunotherapy should be accurately assessed.

Open access

A Chinoy, N B Wright, M Bone and R Padidela

Summary

Hypokalaemia at presentation of diabetic ketoacidosis is uncommon as insulin deficiency and metabolic acidosis shifts potassium extracellularly. However, hypokalaemia is a recognised complication of the management of diabetic ketoacidosis as insulin administration and correction of metabolic acidosis shifts potassium intracellularly. We describe the case of a 9-year-old girl with newly diagnosed type 1 diabetes mellitus presenting in diabetic ketoacidosis, with severe hypokalaemia at presentation due to severe and prolonged emesis. After commencing management for her diabetic ketoacidosis, her serum sodium and osmolality increased rapidly. However, despite maximal potassium concentrations running through peripheral access, and multiple intravenous potassium ‘corrections’, her hypokalaemia persisted. Seventy two hours after presentation, she became drowsy and confused, with imaging demonstrating central pontine myelinolysis – a rare entity seldom seen in diabetic ketoacidosis management in children despite rapid shifts in serum sodium and osmolality. We review the literature associating central pontine myelinolysis with hypokalaemia and hypothesise as to how the hypokalaemia may have contributed to the development of central pontine myelinolysis. We also recommend an approach to the management of a child in diabetic ketoacidosis with hypokalaemia at presentation.

Learning points:

  • Hypokalaemia is a recognised complication of treatment of paediatric diabetic ketoacidosis that should be aggressively managed to prevent acute complications.

  • Central pontine myelinolysis is rare in children, and usually observed in the presence of rapid correction of hyponatraemia. However, there is observational evidence of an association between hypokalaemia and central pontine myelinolysis, potentially by priming the endothelial cell membrane to injury by lesser fluctuations in osmotic pressure.

  • Consider central pontine myelinolysis as a complication of the management of paediatric diabetic ketoacidosis in the presence of relevant symptoms with profound hypokalaemia and/or fluctuations in serum sodium levels.

  • We have suggested an approach to the management strategies of hypokalaemia in paediatric diabetic ketoacidosis which includes oral potassium supplements if tolerated, minimising the duration and the rate of insulin infusion and increasing the concentration of potassium intravenously (via central line if necessary).

Open access

Osamah A Hakami, Julia Ioana, Shahzad Ahmad, Tommy Kyaw Tun, Seamus Sreenan and John H McDermott

Summary

Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy and improved outcomes for patients with advanced disease. Pembrolizumab, a monoclonal antibody that acts as a programmed cell death 1 (PD-1(PDCD1)) inhibitor, has been approved for the treatment of advanced melanoma and other solid tumours. Immune-related adverse events (irAEs) including endocrinopathies have been well described with this and other PD-1 inhibitors. While hypothyroidism and hyperthyroidism, and less commonly hypophysitis, are the most common endocrinopathies occurring in patients treated with pembrolizumab, the incidence of type 1 diabetes mellitus (T1DM) was low in clinical trials. We report a case of pembrolizumab-induced primary hypothyroidism and T1DM presenting with severe diabetic ketoacidosis (DKA). A 52-year-old male patient was treated with pembrolizumab for metastatic melanoma. He presented to the emergency department with a 1-day history of nausea and vomiting 2 weeks after his seventh dose of pembrolizumab, having complained of polyuria and polydipsia for 2 months before presentation. He had been diagnosed with thyroid peroxidase (TPO) antibody-negative hypothyroidism, requiring thyroxine replacement, shortly after his fifth dose. Testing revealed a severe DKA (pH: 6.99, glucose: 38.6 mmol/L, capillary ketones: 4.9 and anion gap: 34.7). He was treated in the intensive care unit as per the institutional protocol, and subsequently transitioned to subcutaneous basal-bolus insulin. After his diabetes and thyroid stabilised, pembrolizumab was recommenced to treat his advanced melanoma given his excellent response. This case highlights the importance of blood glucose monitoring as an integral part of cancer treatment protocols composed of pembrolizumab and other ICIs.

Learning points:

  • The incidence of T1DM with pembrolizumab treatment is being increasingly recognised and reported, and DKA is a common initial presentation.

  • Physicians should counsel patients about this potential irAE and educate them about the symptoms of hyperglycaemia and DKA.

  • The ESMO guidelines recommend regular monitoring of blood glucose in patients treated with ICIs, a recommendation needs to be incorporated into cancer treatment protocols for pembrolizumab and other ICIs in order to detect hyperglycaemia early and prevent DKA.

Open access

Miriam Hinaa Ahmad and Ismat Shafiq

Summary

We report a case of a 21-year-old African American female with history of pre-diabetes, and a diagnosis of a rare leukemia, blastic-plasmacytoid dendritic neoplasm (BPDCN), who developed diabetic ketoacidosis (DKA) after the third dose of PEG-asparaginase infusion. She was successfully treated with insulin. Asparaginase is a vital part of treatment protocols for acute lymphoblastic leukemia (ALL) in combination with other chemotherapeutic drugs. Asparaginase therapy has been reported to cause hyperglycemia especially when used in conjunction with glucocorticoids for the treatment of ALL in the pediatric population. Multiple mechanisms for hyperglycemia have been hypothesized which include decreased insulin secretion, impaired insulin receptor function and excess glucagon formation. Hyperglycemia is usually self-limiting but can deteriorate to diabetic ketoacidosis. DKA is a rare adverse effect with asparaginase therapy with an incidence rate of about 0.8%.

Learning points:

  • DKA is a rare finding following asparaginase therapy.

  • Hyperglycemia is most commonly seen with asparaginase treatment when used along with glucocorticoid.

  • Frequent blood glucose monitoring and prompt initiation of insulin treatment with hyperglycemia can prevent severe complications.

  • Patients and physician education on this complication can reduce morbidity due to DKA.

Open access

Sebastian Hörber, Sarah Hudak, Martin Kächele, Dietrich Overkamp, Andreas Fritsche, Hans-Ulrich Häring, Andreas Peter and Martin Heni

Summary

Diabetic ketoacidosis is a life-threatening complication of diabetes mellitus. It usually occurs in patients with type 1 diabetes where it is typically associated with only moderately increased blood glucose. Here, we report the case of a 52-year-old female patient who was admitted to the emergency unit with severely altered mental status but stable vital signs. Laboratory results on admission revealed very high blood glucose (1687 mg/dL/93.6 mmol/L) and severe acidosis (pH <7) with proof of ketone bodies in serum and urine. Past history revealed a paranoid schizophrenia diagnosed 10 years ago and for which the patient was treated with risperidone for many years. Acute treatment with intravenous fluids, intravenous insulin infusion and sodium bicarbonate improved the symptoms. Further laboratory investigations confirmed diagnosis of autoimmune type 1 diabetes. After normalization of blood glucose levels, the patient could soon be discharged with a subcutaneous insulin therapy.

Learning points:

  • Diabetic ketoacidosis as first manifestation of type 1 diabetes can occur with markedly elevated blood glucose concentrations in elder patients.

  • Atypical antipsychotics are associated with hyperglycemia and an increased risk of new-onset diabetes.

  • First report of risperidone-associated diabetic ketoacidosis in new-onset type 1 diabetes.

  • Patients treated with atypical antipsychotics require special care and regular laboratory examinations to detect hyperglycemia and diabetic ketoacidosis.

  • In cases when the diagnosis is in doubt, blood gas analysis as well as determination of C-peptide and islet autoantibodies can help to establish the definite diabetes type.

Open access

Gordon Sloan, Tania Kakoudaki and Nishant Ranjan

Summary

We report a case of a 63-year-old man who developed diabetic ketoacidosis (DKA) associated with canagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor. He presented acutely unwell with a silent myocardial infarction, diverticulitis and DKA with a minimally raised blood glucose level. Standard therapy for DKA was initiated. Despite this, ketonaemia persisted for a total of 12 days after discontinuation of canagliflozin. Glucosuria lasting for several days despite discontinuation of the medications is a recognised phenomenon. However, this is the longest duration of ketonaemia to be reported. The cause of prolonged SGLT-2 inhibition remains uncertain. Deviation from the normal DKA treatment protocol and use of personalised regimens may be required in order to prevent relapse into ketoacidosis while avoiding hypoglycaemia in those that develop this condition.

Learning points:

  • Diabetic ketoacidosis (DKA) may develop in the presence of lower-than-expected blood glucose levels in patients treated with a sodium glucose co-transporter 2 (SGLT-2) inhibitor.

  • Certain individuals prescribed with SGLT-2 inhibitors may be more at risk of DKA, for example, those with a low beta cell function reserve, excessive alcohol consumption and a low carbohydrate diet.

  • In order to reduce the risk of SGLT-2 inhibitor-associated DKA, all patients must be carefully selected before prescription of the medication and appropriately educated.

  • Increased serum ketone levels and glucosuria have been reported to persist for several days despite discontinuation of their SGLT-2 inhibitor.

  • Physicians should consider individualised treatment regimens for subjects with prolonged DKA in the presence of SGLT-2 inhibition.

Open access

Clarissa Ern Hui Fang, Mohammed Faraz Rafey, Aine Cunningham, Sean F Dinneen and Francis M Finucane

Summary

A 28-year-old male presented with 2 days of vomiting and abdominal pain, preceded by 2 weeks of thirst, polyuria and polydipsia. He had recently started risperidone for obsessive-compulsive disorder. He reported a high dietary sugar intake and had a strong family history of type 2 diabetes mellitus (T2DM). On admission, he was tachycardic, tachypnoeic and drowsy with a Glasgow Coma Scale (GCS) of 10/15. We noted axillary acanthosis nigricans and obesity (BMI 33.2 kg/m2). Dipstick urinalysis showed ketonuria and glycosuria. Blood results were consistent with diabetic ketoacidosis (DKA), with hyperosmolar state. We initiated our DKA protocol, with intravenous insulin, fluids and potassium, and we discontinued risperidone. His obesity, family history of T2DM, acanthosis nigricans and hyperosmolar state prompted consideration of T2DM presenting with ‘ketosis-prone diabetes’ (KPD) rather than T1DM. Antibody markers of beta-cell autoimmunity were subsequently negative. Four weeks later, he had modified his diet and lost weight, and his metabolic parameters had normalised. We reduced his total daily insulin dose from 35 to 18 units and introduced metformin. We stopped insulin completely by week 7. At 6 months, his glucometer readings and glycated haemoglobin (HbA1c) level had normalised.

Learning points:

  • Risperidone-induced diabetic ketoacidosis (DKA) is not synonymous with type 1 diabetes, even in young white patients and may be a manifestation of ‘ketosis-prone’ type 2 diabetes (KPD).

  • KPD is often only confirmed after the initial presentation, when islet autoimmunity and cautious phasing out of insulin therapy have been assessed, and emergency DKA management remains the same.

  • As in other cases of KPD, a family history of T2DM and presence of cutaneous markers of insulin resistance were important clinical features suggestive of an alternative aetiology for DKA.

Open access

Alexandra Rose Pain, Josh Pomroy and Andrea Benjamin

Summary

Hamman’s syndrome (spontaneous subcutaneous emphysema and pneumomediastinum) is a rare complication of diabetic ketoacidosis (DKA), with a multifactorial etiology. Awareness of this syndrome is important: it is likely underdiagnosed as the main symptom of shortness of breath is often attributed to Kussmaul’s breathing and the findings on chest radiograph can be subtle and easily missed. It is also important to be aware of and consider Boerhaave’s syndrome as a differential diagnosis, a more serious condition with a 40% mortality rate when diagnosis is delayed. We present a case of pneumomediastinum, pneumopericardium, epidural emphysema and subcutaneous emphysema complicating DKA in an eighteen-year-old patient. We hope that increasing awareness of Hamman’s syndrome, and how to distinguish it from Boerhaave’s syndrome, will lead to better recognition and management of these syndromes in patients with diabetic ketoacidosis.

Learning points:

  • Hamman’s syndrome (spontaneous subcutaneous emphysema and pneumomediastinum) is a rare complication of DKA.

  • Presentation may be with chest or neck pain and shortness of breath, and signs are subcutaneous emphysema and Hamman’s sign – a precordial crunching or popping sound during systole.

  • Boerhaave’s syndrome should be considered as a differential diagnosis, especially in cases with severe vomiting.

  • The diagnosis of pneumomediastinum is made on chest radiograph, but a CT thorax with water-soluble oral contrast looking for contrast leak may be required if there is high clinical suspicion of Boerrhave’s syndrome.

  • Hamman’s syndrome has an excellent prognosis, self-resolving with the correction of the ketoacidosis in all published cases in the literature.

Open access

A Majid and B J Wheeler

Summary

In clinical practice, seizures independent of hypoglycemia are observed in patients with type 1 diabetes mellitus (T1DM) more frequently than expected by chance, suggesting a link. However, seizures during management of diabetic ketoacidosis (DKA) have generally been considered a bad prognostic factor, and usually associated with well-known biochemical or neurological complications. We present the case of a 17-year-old girl with known T1DM managed for severe DKA complicated by hypocapnic seizure. We review the literature on this rare occurrence as well as outline other possible differentials to consider when faced with the alarming combination of DKA and seizure.

Learning points:

  • Seizures during DKA treatment require immediate management as well as evaluation to determine their underlying cause.

  • Their etiology is varied, but a lowered seizure threshold, electrolyte disturbances and serious neurological complications of DKA such as cerebral edema must all be considered.

  • Sudden severe hypocapnia may represent a rare contributor to seizure during the treatment of DKA.

Open access

Cliona Small, Aoife M Egan, El Muntasir Elhadi, Michael W O’Reilly, Aine Cunningham and Francis M Finucane

Summary

We describe three patients presenting with diabetic ketoacidosis secondary to ketosis prone type 2, rather than type 1 diabetes. All patients were treated according to a standard DKA protocol, but were subsequently able to come off insulin therapy while maintaining good glycaemic control. Ketosis-prone type 2 diabetes (KPD) presenting with DKA has not been described previously in Irish patients. The absence of islet autoimmunity and evidence of endogenous beta cell function after resolution of DKA are well-established markers of KPD, but are not readily available in the acute setting. Although not emphasised in any current guidelines, we have found that a strong family history of type 2 diabetes and the presence of cutaneous markers of insulin resistance are strongly suggestive of KPD. These could be emphasised in future clinical practice guidelines.

Learning points:

  • Even in white patients, DKA is not synonymous with type 1 diabetes and autoimmune beta cell failure. KPD needs to be considered in all patients presenting with DKA, even though it will not influence their initial treatment.

  • Aside from markers of endogenous beta cell function and islet autoimmunity, which in any case are unlikely to be immediately available to clinicians, consideration of family history of type 2 diabetes and cutaneous markers of insulin resistance might help to identify those with KPD and are more readily apparent in the acute setting, though not emphasised in guidelines.

  • Consideration of KPD should never alter the management of the acute severe metabolic derangement of DKA, and phasing out of insulin therapy requires frequent attendance and meticulous and cautious surveillance by a team of experienced diabetes care providers.