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A Case of Unexpected Hyperglycemia

A Case of Unexpected Hyperglycemia Case Description A 43-year-old male with a history of metastatic undifferentiated pleomorphic sarcoma (UPS), hypertension, hypothyroidism, and depression presented to the outpatient clinic for a regularly scheduled blood draw. The patient reported new-onset symptoms of decreased appetite over the preceding 3 weeks, accompanied by weight loss, frequent urination, dry mouth, and insatiable thirst over the previous 4 days. To evaluate these symptoms, the patient’s provider requested that a serum glucose measurement be performed. The patient had no previous history of hyperglycemia or diabetes and his last glucose measurement 1 year prior was 114 mg/dL. Leading up to this encounter, the patient had been receiving intravenous infusions of pembrolizumab every 3 weeks for 2 years to treat his UPS. His outpatient medications included levothyroxine, sertraline, hydrochlorothiazide, and amlodipine. Initial laboratory results (Table 1) revealed a serum glucose concentration of 947 mg/dL with increased serum beta-hydroxybutyrate (BHB). Besides low serum chloride, the rest of his results, including potassium and total CO2, were unremarkable. He did not appear to be lethargic or confused and there were no signs of respiratory distress or fever. He had a regular cardiovascular rhythm and blood pressure. He denied dizziness, headaches, light-headedness, or visual disturbances. He also denied chest tightness, shortness of breath, vomiting, fever, or diarrhea. The clinician called the laboratory to confirm the accuracy of the serum glucose result and the patient was subsequently referred to the emergency department (ED) for further evaluation of hyperglycemia. Table 1. Laboratory results. Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L s = serum; ED = Emergency Department; POCT = point-of-care testing. Open in new tab Table 1. Laboratory results. Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L s = serum; ED = Emergency Department; POCT = point-of-care testing. Open in new tab In the ED, additional testing was performed 8 h after the initial blood draw. Since sodium was not ordered in his original blood draw, a point-of-care (POC) sodium was obtained which revealed hyponatremia. Initial POC blood gas results showed a slightly acidic pH and a very low pO2, while pCO2 and a calculated bicarbonate measurement were within the reference interval. Case Discussion The differential diagnosis of hyperglycemia includes type 1 (T1DM) and type 2 diabetes mellitus (T2DM), stress-induced hyperglycemia, hyperglycemia induced by certain medications or chemicals, Cushing’s disease, and iatrogenic hyperglycemia. This patient had characteristic symptoms of diabetes mellitus, including polyuria, polydipsia, and weight-loss which prompted his caregiver to order a serum glucose measurement. High glucose concentrations can be life threatening, therefore it is critical to properly identify and treat the underlying cause of hyperglycemia. In T1DM, insulin deficiency arises due to destruction of the beta cells of the pancreas, a process that is often autoimmune-mediated. Untreated T1DM can escalate to diabetic ketoacidosis (DKA), a serious condition that can result in coma or death. T2DM arises from insulin resistance or insufficiency and typically develops as a result of obesity. In T2DM, uncontrolled glucose can lead to hyperglycemic hyperosmotic state (HHS), which also may result in coma, seizures, and death. Patients in DKA or HHS may present with blurred vision, mental confusion, nausea, and vomiting in addition to excessive thirst, frequent urination, and dry mouth. The laboratory criteria for DKA include a random serum glucose ≥ 250 mg/dL, bicarbonate ≤ 18 mEq/L, anion gap > 12 mmol/L, arterial pH < 7.3, and presence of ketoacids (1). Anion gap (Na—[Cl+ HCO3]) is a useful parameter for identifying the underlying cause of metabolic acidosis. In DKA, the anion gap is increased due to the presence of ketoacids BHB and acetoacetate. HHS is characterized by glucose ≥ 600 mg/dL and serum osmolality > 350 mOsm/kg. Typically, there is mild or no ketosis in HHS and therefore metabolic acidosis is not usually present (1). In this case, the anion gap was not able to be reliably calculated as sodium was measured several hours after the chloride and total CO2. Although mild acidemia was observed, the patient was not considered to be in DKA or HHS, based on his clinical presentation and laboratory values, including normal pCO2 and calculated bicarbonate. Strangely, the POC pO2 was measured as 28 mmHg, which was not consistent with the patient’s condition. An explanation for this low result is not immediately clear. The laboratory plays an important role in the diagnosis and management of DM, as well as the differentiation between T1DM and T2DM. Tests for the evaluation of DM include random or fasting glucose, HbA1c, ketoacids (BHB, acetoacetate), C-peptide, and islet autoantibodies. Although a random serum glucose ≥ 200 mg/dL in conjunction with the classic symptoms of DM are considered diagnostic (2), the provider in this case wanted to ensure that the glucose result was accurate as it was inconsistent with the patient’s historical results. As part of the laboratory investigation into the high glucose, the laboratory performed an HbA1c measurement. An HbA1c ≥6.5% is also diagnostic for DM (2). The high HbA1c of 10.5% demonstrated that this patient’s glucose had been increased for several months at least and gave evidence that the serum glucose measurement of 947 mg/dL was reliable (Table 2). Table 2. Additional laboratory tests utilized in the investigation of T1DM. Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Open in new tab Table 2. Additional laboratory tests utilized in the investigation of T1DM. Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Open in new tab Further workup for this patient included testing for C-peptide and glutamic acid decarboxylase 65-kilodalton isoform (GAD65) autoantibodies (Table 2). C-peptide is released from pancreatic beta cells upon cleavage of proinsulin. C-peptide is not included as part of the diagnostic criteria for DM but may be useful in the differentiation of T1DM from T2DM (in nonacute settings) (3). In this case, the patient had a low C-peptide value (Table 2). This is consistent with T1DM, in which insulin production is deficient. In contrast, in T2DM the pancreatic beta cells typically produce enough insulin, but insulin action may be impaired. Consequently, C-peptide concentrations may be normal to increase in T2DM. GAD65 is an enzyme that is produced by pancreatic islet cells, and autoantibodies for this enzyme are detectable in approximately 80% of patients with T1DM (2) which can also be used to differentiate between T1DM and T2DM. GAD65-positive autoantibodies > 0.03 nmol/L are consistent with T1DM in the setting of a polyendocrine syndrome, helping to confirm the diagnosis of T1DM for this patient. It should be noted that up to 5% of patients with T2DM may also have GAD65 autoantibodies. Drug-induced DM occurs most notably with corticosteroid use. Pentamidine, diazoxide, and thiazides have also been implicated in the progression to hyperglycemia (4). More recently, the use of immune checkpoint inhibitors, primarily those that target programmed cell death protein 1 (PD-1) such as pembrolizumab, have been linked to the development of new-onset autoimmune polyendocrine disorders, including diabetes and thyroid disease (5, 6). This is consistent with the patient’s presentation of autoimmune hypothyroidism and now the new-onset T1DM. PD-1, also known as CD279, is a type I transmembrane protein receptor that is found on the surface of T-cells. Interaction between PD-1 and its ligands, programmed death ligand 1 or 2 (PD-L1 or PD-L2), inhibits adaptive immune response. Tumor cells that exhibit the PD-L1 ligand on their surface will interact with the PD-1 on the surface of T-cells and evade immune response. Therapeutics that inhibit this immune-response evasion by tumor cells are commonly known as checkpoint inhibitors and have been shown to be effective anticancer therapies (7). Three PD-1 inhibitors have been approved by the FDA since 2014: nivolumab, pembrolizumab, and cemiplimab. Two and a half years prior to this presentation, the patient was prescribed olaratumab/doxorubicin for his metastatic UPS. One year later, cancer progression led the physicians to consider a change in treatment, right before results of the ANNOUNCE trial led to the market withdrawal of olaratumab (8). Due to the activity that pembrolizumab showed against UPS during the SARC028 trial (9), it was prescribed for this patient’s sarcoma. One year into receiving pembrolizumab, the patient was diagnosed with autoimmune hypothyroidism, and 1 year following that he presented with the signs and symptoms above. It has been demonstrated that the decrease of the regulation of immune response can lead to development of autoimmunity. As such, immune-related adverse events (irAEs) have been reported in patients prescribed checkpoint inhibitors for their cancers (10), and this information is now included in the prescribing information document for pembrolizumab. It is still unknown why some patients are more susceptible to irAEs upon taking checkpoint inhibitors, but they have severe side effects that need to be considered before a patient is treated. Case Resolution To manage his hyperglycemia, the patient was administered 1 L of saline (0.9% NaCl) and two16 unit doses of insulin aspart. Five hours after the initiation of insulin, his repeat serum glucose measurement was 231 mg/dL. The patient was diagnosed with T1DM and began an at-home insulin regimen. At his 1-month follow-up after regular insulin administration, his fasting glucose was 96 mg/dL. Conclusion Pembrolizumab is an anticancer therapeutic that is being used more frequently in clinical practice. Although uncommon, T1DM can develop in response to pembrolizumab administration. Untreated DM can lead to potentially life-threatening complications; therefore, it is important that clinicians and laboratorians are aware of this adverse effect to prevent delays in care. Points to Remember Polyuria, polydipsia, and unexplained weight loss are classic signs of diabetes mellitus; Untreated hyperglycemia associated with diabetic ketoacidosis or hyperglycemic hyperosmolar state can be life-threatening; Several laboratory tests can be utilized in the diagnosis and management of diabetes, including random or fasting glucose, HbA1c, ketones, and GAD antibodies; Immune-related adverse events (irAEs), including new-onset endocrine disorders such as diabetes, have been associated with the use of checkpoint inhibitors. Author Contributions All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. C.A. Gleue, statistical analysis. Authors' Disclosures or Potential Conflicts of Interest No authors declared any potential conflicts of interest. Acknowledgments The authors acknowledge Dr. Nikola A. Baumann for encouraging this manuscript and Dr. Brad Karon for his expert guidance. References 1 Evan Dingle H , Slovis C. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome management . Emerg Med 2018 ; 50 : 161 – 71 . Google Scholar Crossref Search ADS WorldCat 2 Sacks DB , Arnold M, Bakris GL, Bruns DE, Horvath AR, Kirkman MS, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus . Clin Chem 2011 ; 57 : e1 – e47 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Walikonis JE , Lennon VA. Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus . Mayo Clin Proc 1998 ; 73 : 1161 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 4 McPherson RA , Pincus MR, editors. Henry’s clinical diagnosis and management by laboratory methods . 23rd Ed. St. Louis : Elsevier Inc .; 2017 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 5 Delivanis DA , Gustafson MP, Bornschlegl S, Merten MM, Kottschade L, Withers S, et al. Pembrolizumab-induced thyroiditis: comprehensive clinical review and insights into underlying involved mechanisms . J Clin Endocrinol Metab 2017 ; 102 : 2770 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Bluestone JA , Anderson M, Herold KC, Stamatouli AM, Quandt Z, Perdigoto AL, et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors . Diabetes 2018 ; 67 : 1471 – 80 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 7 Barrios DM , Do MH, Phillips GS, Postow MA, Akaike T, Nghiem P, et al. Immune checkpoint inhibitors to treat cutaneous malignancies . J Am Acad Dermatol 2020 ; 83 : 1239 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Tap WD , Wagner AJ, Papai Z, Ganjoo KN, Yen C-C, Schoffski P, et al. ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS) . J Clin Oncol 2019 ; 37 : LBA3 . Google Scholar Crossref Search ADS WorldCat 9 Tawbi HA , Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial . Lancet Oncol 2017 ; 18 : 1493 – 501 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Husebye ES , Anderson MS, Kämpe O. Autoimmune polyendocrine syndromes. Ingelfinger JR, editor . N Engl J Med 2018 ; 378 : 1132 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Nonstandard Abbreviations: UPS undifferentiated pleomorphic sarcoma BHB beta-hydroxybutyrate ED emergency department POC point-of-care T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus DKA diabetic ketoacidosis HHS hyperglycemic hyperosmotic state GAD25 glutamic acid decarboxylase 65-kilodalton isoform PD-1 programmed cell death protein 1 PD-L1 programmed death ligand 1 irAE immune-related adverse events © American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Chemistry Oxford University Press

A Case of Unexpected Hyperglycemia

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Oxford University Press
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© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: [email protected].
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0009-9147
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1530-8561
DOI
10.1093/clinchem/hvab089
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Abstract

Case Description A 43-year-old male with a history of metastatic undifferentiated pleomorphic sarcoma (UPS), hypertension, hypothyroidism, and depression presented to the outpatient clinic for a regularly scheduled blood draw. The patient reported new-onset symptoms of decreased appetite over the preceding 3 weeks, accompanied by weight loss, frequent urination, dry mouth, and insatiable thirst over the previous 4 days. To evaluate these symptoms, the patient’s provider requested that a serum glucose measurement be performed. The patient had no previous history of hyperglycemia or diabetes and his last glucose measurement 1 year prior was 114 mg/dL. Leading up to this encounter, the patient had been receiving intravenous infusions of pembrolizumab every 3 weeks for 2 years to treat his UPS. His outpatient medications included levothyroxine, sertraline, hydrochlorothiazide, and amlodipine. Initial laboratory results (Table 1) revealed a serum glucose concentration of 947 mg/dL with increased serum beta-hydroxybutyrate (BHB). Besides low serum chloride, the rest of his results, including potassium and total CO2, were unremarkable. He did not appear to be lethargic or confused and there were no signs of respiratory distress or fever. He had a regular cardiovascular rhythm and blood pressure. He denied dizziness, headaches, light-headedness, or visual disturbances. He also denied chest tightness, shortness of breath, vomiting, fever, or diarrhea. The clinician called the laboratory to confirm the accuracy of the serum glucose result and the patient was subsequently referred to the emergency department (ED) for further evaluation of hyperglycemia. Table 1. Laboratory results. Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L s = serum; ED = Emergency Department; POCT = point-of-care testing. Open in new tab Table 1. Laboratory results. Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L Analyte . Patient result . Reference interval . Outpatient Laboratory Results collected at 2:35pm  Glucose, random (s) 947 mg/dL (52.5 mmol/L) 70 - 140 mg/dL (3.9–7.8 mmol/L)  Beta-hydroxybutyrate (s) 3.3 mmol/L <0.4 mmol/L  Total CO2 (s) 24 mmol/L 22–29 mmol/L  Potassium (s) 4.4 mmol/L 3.6–5.2 mmol/L  Chloride (s) 84 mmol/L 98–107 mmol/L  Creatinine, enzymatic (s) 1.11 mg/dL (98 µmol/L) 0.74–1.35 mg/dL (65–119 µmol/L)  ALT (s) 33 U/L 7– 55 U/L  AST (s) 19 U/L 8–48 U/L  Bilirubin, total (s) 0.5 mg/dL (8.6 µmol/L) < 1.2 mg/dL (< 20.5 µmol/L)  Cortisol (s) 16 µg/dL 7–25 µg/dL  TSH (s) 2.8 mIU/L 0.3– 4.2 mIU/L ED Results collected at 10:56pm  pH (POCT) 7.34 7.35–7.45  pCO2 (POCT) 48 mmHg 35–48 mmHg  pO2 (POCT) 28 mmHg 83–108 mmHg  Base excess (POCT) 0 mmol/L −2–3 mmol/L  Calculated bicarbonate (POCT) 25 mmol/L 22–29 mmol/L  Sodium (POCT) 129 mmol/L 135–145 mmol/L s = serum; ED = Emergency Department; POCT = point-of-care testing. Open in new tab In the ED, additional testing was performed 8 h after the initial blood draw. Since sodium was not ordered in his original blood draw, a point-of-care (POC) sodium was obtained which revealed hyponatremia. Initial POC blood gas results showed a slightly acidic pH and a very low pO2, while pCO2 and a calculated bicarbonate measurement were within the reference interval. Case Discussion The differential diagnosis of hyperglycemia includes type 1 (T1DM) and type 2 diabetes mellitus (T2DM), stress-induced hyperglycemia, hyperglycemia induced by certain medications or chemicals, Cushing’s disease, and iatrogenic hyperglycemia. This patient had characteristic symptoms of diabetes mellitus, including polyuria, polydipsia, and weight-loss which prompted his caregiver to order a serum glucose measurement. High glucose concentrations can be life threatening, therefore it is critical to properly identify and treat the underlying cause of hyperglycemia. In T1DM, insulin deficiency arises due to destruction of the beta cells of the pancreas, a process that is often autoimmune-mediated. Untreated T1DM can escalate to diabetic ketoacidosis (DKA), a serious condition that can result in coma or death. T2DM arises from insulin resistance or insufficiency and typically develops as a result of obesity. In T2DM, uncontrolled glucose can lead to hyperglycemic hyperosmotic state (HHS), which also may result in coma, seizures, and death. Patients in DKA or HHS may present with blurred vision, mental confusion, nausea, and vomiting in addition to excessive thirst, frequent urination, and dry mouth. The laboratory criteria for DKA include a random serum glucose ≥ 250 mg/dL, bicarbonate ≤ 18 mEq/L, anion gap > 12 mmol/L, arterial pH < 7.3, and presence of ketoacids (1). Anion gap (Na—[Cl+ HCO3]) is a useful parameter for identifying the underlying cause of metabolic acidosis. In DKA, the anion gap is increased due to the presence of ketoacids BHB and acetoacetate. HHS is characterized by glucose ≥ 600 mg/dL and serum osmolality > 350 mOsm/kg. Typically, there is mild or no ketosis in HHS and therefore metabolic acidosis is not usually present (1). In this case, the anion gap was not able to be reliably calculated as sodium was measured several hours after the chloride and total CO2. Although mild acidemia was observed, the patient was not considered to be in DKA or HHS, based on his clinical presentation and laboratory values, including normal pCO2 and calculated bicarbonate. Strangely, the POC pO2 was measured as 28 mmHg, which was not consistent with the patient’s condition. An explanation for this low result is not immediately clear. The laboratory plays an important role in the diagnosis and management of DM, as well as the differentiation between T1DM and T2DM. Tests for the evaluation of DM include random or fasting glucose, HbA1c, ketoacids (BHB, acetoacetate), C-peptide, and islet autoantibodies. Although a random serum glucose ≥ 200 mg/dL in conjunction with the classic symptoms of DM are considered diagnostic (2), the provider in this case wanted to ensure that the glucose result was accurate as it was inconsistent with the patient’s historical results. As part of the laboratory investigation into the high glucose, the laboratory performed an HbA1c measurement. An HbA1c ≥6.5% is also diagnostic for DM (2). The high HbA1c of 10.5% demonstrated that this patient’s glucose had been increased for several months at least and gave evidence that the serum glucose measurement of 947 mg/dL was reliable (Table 2). Table 2. Additional laboratory tests utilized in the investigation of T1DM. Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Open in new tab Table 2. Additional laboratory tests utilized in the investigation of T1DM. Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Analyte . Result . Reference Interval . Hemoglobin A1c 10.5% 4.0–5.6% C-peptide 0.8 ng/mL 1.1–4.4 ng/mL GAD65, Antibody 0.05 nmol/L < 0.02 nmol/L Open in new tab Further workup for this patient included testing for C-peptide and glutamic acid decarboxylase 65-kilodalton isoform (GAD65) autoantibodies (Table 2). C-peptide is released from pancreatic beta cells upon cleavage of proinsulin. C-peptide is not included as part of the diagnostic criteria for DM but may be useful in the differentiation of T1DM from T2DM (in nonacute settings) (3). In this case, the patient had a low C-peptide value (Table 2). This is consistent with T1DM, in which insulin production is deficient. In contrast, in T2DM the pancreatic beta cells typically produce enough insulin, but insulin action may be impaired. Consequently, C-peptide concentrations may be normal to increase in T2DM. GAD65 is an enzyme that is produced by pancreatic islet cells, and autoantibodies for this enzyme are detectable in approximately 80% of patients with T1DM (2) which can also be used to differentiate between T1DM and T2DM. GAD65-positive autoantibodies > 0.03 nmol/L are consistent with T1DM in the setting of a polyendocrine syndrome, helping to confirm the diagnosis of T1DM for this patient. It should be noted that up to 5% of patients with T2DM may also have GAD65 autoantibodies. Drug-induced DM occurs most notably with corticosteroid use. Pentamidine, diazoxide, and thiazides have also been implicated in the progression to hyperglycemia (4). More recently, the use of immune checkpoint inhibitors, primarily those that target programmed cell death protein 1 (PD-1) such as pembrolizumab, have been linked to the development of new-onset autoimmune polyendocrine disorders, including diabetes and thyroid disease (5, 6). This is consistent with the patient’s presentation of autoimmune hypothyroidism and now the new-onset T1DM. PD-1, also known as CD279, is a type I transmembrane protein receptor that is found on the surface of T-cells. Interaction between PD-1 and its ligands, programmed death ligand 1 or 2 (PD-L1 or PD-L2), inhibits adaptive immune response. Tumor cells that exhibit the PD-L1 ligand on their surface will interact with the PD-1 on the surface of T-cells and evade immune response. Therapeutics that inhibit this immune-response evasion by tumor cells are commonly known as checkpoint inhibitors and have been shown to be effective anticancer therapies (7). Three PD-1 inhibitors have been approved by the FDA since 2014: nivolumab, pembrolizumab, and cemiplimab. Two and a half years prior to this presentation, the patient was prescribed olaratumab/doxorubicin for his metastatic UPS. One year later, cancer progression led the physicians to consider a change in treatment, right before results of the ANNOUNCE trial led to the market withdrawal of olaratumab (8). Due to the activity that pembrolizumab showed against UPS during the SARC028 trial (9), it was prescribed for this patient’s sarcoma. One year into receiving pembrolizumab, the patient was diagnosed with autoimmune hypothyroidism, and 1 year following that he presented with the signs and symptoms above. It has been demonstrated that the decrease of the regulation of immune response can lead to development of autoimmunity. As such, immune-related adverse events (irAEs) have been reported in patients prescribed checkpoint inhibitors for their cancers (10), and this information is now included in the prescribing information document for pembrolizumab. It is still unknown why some patients are more susceptible to irAEs upon taking checkpoint inhibitors, but they have severe side effects that need to be considered before a patient is treated. Case Resolution To manage his hyperglycemia, the patient was administered 1 L of saline (0.9% NaCl) and two16 unit doses of insulin aspart. Five hours after the initiation of insulin, his repeat serum glucose measurement was 231 mg/dL. The patient was diagnosed with T1DM and began an at-home insulin regimen. At his 1-month follow-up after regular insulin administration, his fasting glucose was 96 mg/dL. Conclusion Pembrolizumab is an anticancer therapeutic that is being used more frequently in clinical practice. Although uncommon, T1DM can develop in response to pembrolizumab administration. Untreated DM can lead to potentially life-threatening complications; therefore, it is important that clinicians and laboratorians are aware of this adverse effect to prevent delays in care. Points to Remember Polyuria, polydipsia, and unexplained weight loss are classic signs of diabetes mellitus; Untreated hyperglycemia associated with diabetic ketoacidosis or hyperglycemic hyperosmolar state can be life-threatening; Several laboratory tests can be utilized in the diagnosis and management of diabetes, including random or fasting glucose, HbA1c, ketones, and GAD antibodies; Immune-related adverse events (irAEs), including new-onset endocrine disorders such as diabetes, have been associated with the use of checkpoint inhibitors. Author Contributions All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. C.A. Gleue, statistical analysis. Authors' Disclosures or Potential Conflicts of Interest No authors declared any potential conflicts of interest. Acknowledgments The authors acknowledge Dr. Nikola A. Baumann for encouraging this manuscript and Dr. Brad Karon for his expert guidance. References 1 Evan Dingle H , Slovis C. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome management . Emerg Med 2018 ; 50 : 161 – 71 . Google Scholar Crossref Search ADS WorldCat 2 Sacks DB , Arnold M, Bakris GL, Bruns DE, Horvath AR, Kirkman MS, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus . Clin Chem 2011 ; 57 : e1 – e47 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Walikonis JE , Lennon VA. Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus . Mayo Clin Proc 1998 ; 73 : 1161 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 4 McPherson RA , Pincus MR, editors. Henry’s clinical diagnosis and management by laboratory methods . 23rd Ed. St. Louis : Elsevier Inc .; 2017 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 5 Delivanis DA , Gustafson MP, Bornschlegl S, Merten MM, Kottschade L, Withers S, et al. Pembrolizumab-induced thyroiditis: comprehensive clinical review and insights into underlying involved mechanisms . J Clin Endocrinol Metab 2017 ; 102 : 2770 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Bluestone JA , Anderson M, Herold KC, Stamatouli AM, Quandt Z, Perdigoto AL, et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors . Diabetes 2018 ; 67 : 1471 – 80 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 7 Barrios DM , Do MH, Phillips GS, Postow MA, Akaike T, Nghiem P, et al. Immune checkpoint inhibitors to treat cutaneous malignancies . J Am Acad Dermatol 2020 ; 83 : 1239 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Tap WD , Wagner AJ, Papai Z, Ganjoo KN, Yen C-C, Schoffski P, et al. ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS) . J Clin Oncol 2019 ; 37 : LBA3 . Google Scholar Crossref Search ADS WorldCat 9 Tawbi HA , Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial . Lancet Oncol 2017 ; 18 : 1493 – 501 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Husebye ES , Anderson MS, Kämpe O. Autoimmune polyendocrine syndromes. Ingelfinger JR, editor . N Engl J Med 2018 ; 378 : 1132 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Nonstandard Abbreviations: UPS undifferentiated pleomorphic sarcoma BHB beta-hydroxybutyrate ED emergency department POC point-of-care T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus DKA diabetic ketoacidosis HHS hyperglycemic hyperosmotic state GAD25 glutamic acid decarboxylase 65-kilodalton isoform PD-1 programmed cell death protein 1 PD-L1 programmed death ligand 1 irAE immune-related adverse events © American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Clinical Chemistry – Oxford University Press

Published: Aug 3, 2021

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