Diagnosis and Treatment > Investigation > Haemoglobin A1c
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Summary
This case report describes a family pedigree of a mother and her children with an E227K mutation in the KCNJ11 gene. People with this particular gene mutation typically present with transient neonatal diabetes; with more than half the cohort relapsing into permanent diabetes in adolescence or early adulthood. However, the mother developed diabetes as an adolescent and thus was initially diagnosed as having Type 1 Diabetes. All her children have inherited the same genetic mutation but with differing presentations. Her second, third and fourth child presented with transient neonatal diabetes which remitted at varying times. Her first child is 16 years old but had not developed diabetes at the time of writing. The KCNJ11 gene codes for the KIR6.2 subunit of the KATP channels of the pancreatic beta cells. Mutations in this gene limit insulin release from beta cells despite high blood glucose concentrations. Most people with diabetes caused by this genetic mutation can be successfully managed with glibenclamide. Learning of the genetic mutation changed the therapeutic approach to the mother’s diabetes and enabled rapid diagnosis for her children. Through this family, we identified that an identical genetic mutation does not necessarily lead to the same diabetic phenotype. We recommend clinicians to consider screening for this gene in their patients whom MODY is suspected; especially in those presenting before the age of 25 who remain C-peptide positive.
Learning points:
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KATP channel closure in pancreatic beta cells is a critical step in stimulating insulin release. Mutations in the KIR6.2 subunit can result in the KATP channels remaining open, limiting insulin release.
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People with KCNJ11 mutations may not present with neonatal diabetes as the age of presentation of diabetes can be highly variable.
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Most affected individuals can be treated successfully with glibenclamide, which closes the KATP channels via an independent mechanism.
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All first degree relatives of the index case should be offered genetic testing, including asymptomatic individuals. Offspring of affected individuals should be monitored for neonatal diabetes from birth.
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Affected individuals will require long-term follow-up as there is a high risk of recurrence in later life.
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia
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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:
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Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.
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Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.
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Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.
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Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.
Research Support Center, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan
Asahina Shinryoujo, Fujieda, Shizuoka, Japan
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Research Support Center, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan
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Summary
Type B insulin resistance syndrome is characterized by the presence of autoantibodies to the insulin receptor. We present a 57-year-old male admitted to a hospital due to body weight loss of 16 kg and hyperglycemia of 13.6 mmol/L. He was diagnosed with type B insulin resistance syndrome because the anti-insulin receptor antibodies were positive. We informed him that some hyperglycemic cases of this syndrome had been reported to be spontaneously remitted in 5 years, and he did not agree to be treated with high-dose glucocorticoids and/or immunosuppressive agents due to his concern for their adverse effects such as hyperglycemia and immunosuppression. He chose to be treated with insulin and voglibose, but fair glucose control could not be obtained. Six years later, he agreed to be treated with low-dose glucocorticoids practicable in outpatient settings. One milligram per day of betamethasone was tried orally and reduced gradually according to the values of glycated hemoglobin. After 30 months of glucocorticoid treatment, the anti-insulin receptor antibodies became undetectable and his fasting plasma glucose and glycated hemoglobin were normalized. This case suggests that low-dose glucocorticoids could be a choice to treat type B insulin resistance syndrome in outpatient settings.
Learning points:
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Type B insulin resistance syndrome is an acquired autoimmune disease for insulin receptors.
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This case suggested the possibility of long-lasting, low-dose glucocorticoid therapy for the syndrome as an alternative for high-dose glucocorticoids or immunosuppressive agents.
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Since the prevalence of autoimmune nephritis is high in the syndrome, a delay of immunosuppressive therapy initiation might result in an exacerbation of nephropathy.
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Summary
Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia.
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Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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Department of Pathology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
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Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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Summary
We report the renal histology of a 66-year-old man with hypertension, cardiovascular disease, and a 30-year history of type 2 diabetes mellitus with proliferative diabetic retinopathy, diabetic neuropathy, and diabetic foot status post toe amputation. Urinary protein excretion was 1.4 g/gCr, serum creatinine level 0.86 mg/dL, estimated glomerular filtration rate 69 mL/min/1.73 m2, and HbA1c 13–15%, despite using insulin. Light microscopy showed global glomerulosclerosis in 37% of the glomeruli, but the remaining glomeruli were intact. Significant polar vasculosis was present, while arteriolar sclerosis was mild. Electron microscopy revealed a thickened glomerular basement membrane, which is compatible with the early stage of diabetic glomerulopathy. The presented case was unique because glomerular changes seen typically in diabetes were not seen in the patient, despite the long-standing history of diabetes and diabetic comorbidities, while prominent polar vasculosis was found. Polar vascular formation helps preserve the glomeruli by allowing hyperosmotic blood bypass the glomeruli; this decreases intraglomerular pressure and minimizes glomerular endothelial damage.
Learning points:
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A 66-year-old man with a 30-year history of type 2 diabetes mellitus with poor glycemic control underwent renal biopsy, which showed scarce glomerular changes typically seen in diabetic kidney disease and instead revealed significant polar vasculosis.
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Past studies demonstrated that the increased small vessels around the vascular hilus in diabetic patients originated from the afferent arterioles and drained into the peritubular capillaries.
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Polar vascular formation may preserve glomerular function by allowing the blood flow to bypass the glomeruli and decreasing the intraglomerular pressure, which minimizes endothelial damage of the glomerular tufts.
HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland
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HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland
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Summary
We describe two cases of SGLT2i-induced euglycaemic diabetic ketoacidosis, which took longer than we anticipated to treat despite initiation of our DKA protocol. Both patients had an unequivocal diagnosis of type 2 diabetes, had poor glycaemic control with a history of metformin intolerance and presented with relatively vague symptoms post-operatively. Neither patient had stopped their SGLT2i pre-operatively, but ought to have by current treatment guidelines.
Learning points:
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SGLT2i-induced EDKA is a more protracted and prolonged metabolic derangement and takes approximately twice as long to treat as hyperglycaemic ketoacidosis.
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Surgical patients ought to stop SGLT2i medications routinely pre-operatively and only resume them after they have made a full recovery from the operation.
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While the mechanistic basis for EDKA remains unclear, our observation of marked ketonuria in both patients suggests that impaired ketone excretion may not be the predominant metabolic lesion in every case.
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Measurement of insulin, C-Peptide, blood and urine ketones as well as glucagon and renal function at the time of initial presentation with EDKA may help to establish why this problem occurs in specific patients.
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Summary
Measurement of glycated haemoglobin (HbA1c) has been utilised in assessing long-term control of blood glucose in patients with diabetes, as well as diagnosing diabetes and identifying patients at increased risk of developing diabetes in the future. HbA1c reflects the level of blood glucose to which the erythrocyte has been exposed during its lifespan, and there are a number of clinical situations affecting the erythrocyte life span in which HbA1c values may be spuriously high or low and therefore not reflective of the true level of glucose control. In the present case series, we describe the particulars of three patients with diabetes who had spuriously low HbA1c levels as a result of dapsone usage. Furthermore, we discuss the limitations of HbA1c testing and the mechanisms by which it may be affected by dapsone in particular.
Learning points:
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Various conditions and medications can result in falsely low HbA1c.
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Dapsone can lead to falsely low HbA1c by inducing haemolysis and by forming methaemoglobin.
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Capillary glucose measurement, urine glucose measurements and fructosamine levels should be used as alternatives to HbA1c for monitoring glycaemic control if it was falsely low or high.
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Summary
We report our experience on managing a case of florid Cushing’s disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital.
Learning points:
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Severe Cushing’s syndrome is associated with high morbidity and mortality.
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Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression.
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Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital.
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During treatment with etomidate, accumulation of serum 11β-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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Summary
A 62-year-old Asian British female presented with increasing tiredness. She had multiple co-morbidities and was prescribed steroid inhalers for asthma. She had also received short courses of oral prednisolone for acute asthma exacerbations in the last 2 years. Unfortunately, the frequency and dose of steroids for asthma was unclear from history. Her type 2 diabetes mellitus (DM) control had deteriorated over a short period of time (HbA1c: 48–85 mmol/mol). Blood tests revealed undetectable cortisol and ACTH (<28 mmol/L, <5.0 ng/L). Renin, electrolytes and thyroid function were within normal limits. A diagnosis of secondary adrenal insufficiency, likely due to long-term steroid inhaler and recurrent short courses of oral steroids for asthma exacerbations was made. Patient was commenced on hydrocortisone 10 mg, 5 mg and 5 mg regimen. Steroid inhaler was discontinued following consultation with respiratory physicians. Despite discontinuation of inhaled steroids, patient continued not to mount a response to Synacthen®. Upon further detailed history, patient admitted taking a ‘herbal’ preparation for chronic osteoarthritic knee pain. Toxicology analysis showed presence of dexamethasone, ciprofloxacin, paracetamol, diclofenac, ibuprofen and cimetidine in the herbal medication. Patient was advised to discontinue her herbal preparation. We believe the cause of secondary adrenal insufficiency in our patient was the herbal remedy containing dexamethasone, explaining persistent adrenal suppression despite discontinuation of all prescribed steroids, further possibly contributing to obesity, hypertension and suboptimal control of DM. In conclusion, a comprehensive drug history including herbal and over-the-counter preparations should be elucidated. Investigation for the presence of steroids in these preparations should be considered when patients persist to have secondary adrenal insufficiency despite discontinuation of prescribed steroid medications.
Learning points:
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The likelihood of complementary and alternative medicines (CAMs) in medication-induced secondary adrenal insufficiency should be considered in any patient presenting with potential symptoms of adrenal insufficiency.
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If the contents of CAM preparation cannot be ascertained, toxicology screening should be considered.
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Patients should be advised to stop taking CAM preparation when it contains steroids and hydrocortisone replacement therapy commenced, with periodic reassessment of adrenal function, and then if indicated weaned accordingly.
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Patients should be informed about the contents of CAM therapies, so they can make a truly informed choice regarding the risks and benefits.
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This case also highlights a need to increase regulatory processes over CAM therapies, given their propensity to contain a number of undisclosed medications and potent steroids.
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Endocrinology and Metabolism Department, Instituto Tecnológico de Estudios Superiores de Monterrey Tec Salud, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Summary
In patients with gastric bypass (GB), high glucose variability (GV) and hypoglycemia have been demonstrated, which could impact the metabolic status and eating behavior. We describe the glucose patterns determined through continuous glucose monitoring (CGM) in two patients with >5 years follow-up after GB and significant weight recovery, who reported hypoglycemic symptoms that interfered with daily activities, and their response to a nutritional and psycho-educative prescription. Case 1: A 40-year-old woman without pre-surgical type 2 diabetes (T2DM) and normal HbA1c, in whom CGM showed high GV and hypoglycemic episodes that did not correlate with the time of hypoglycemic symptoms. Her GV reduced after prescription of a diet with low glycemic index and modification of meal patterns. Case 2: A 48-year-old male with pre-surgical diagnosis of T2DM and current normal HbA1c, reported skipping meals. The CGM showed high GV, 15% of time in hypoglycemia and hyperglycemic spikes. After prescription of a low glycemic index diet, his GV increased and time in hypoglycemia decreased. Through the detailed self-monitoring needed for CGM, we discovered severe anxiety symptoms, consumption of simple carbohydrates and lack of meal structure. He was referred for more intensive psychological counseling. In conclusion, CGM can detect disorders in glucose homeostasis derived both from the mechanisms of bariatric surgery, as well as the patient’s behaviors and mental health, improving decision-making during follow-up.
Learning points:
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High glycemic variability is frequent in patients operated with gastric bypass.
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Diverse eating patterns, such as prolonged fasting and simple carbohydrate ingestion, and mental health disorders, including anxiety, can promote and be confused with worsened hypoglycemia.
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CGM requires a detailed record of food ingested that can be accompanied by associated factors (circumstances, eating patterns, emotional symptoms). This allows the detection of particular behaviors and amount of dietary simple carbohydrates to guide recommendations provided within clinical care of these patients.