HBA1C AN INACCURATE MEASURE OF GLYCEMIC CONTROL IN A FEMALE WITH HEREDITARY SPHEROCYTOSIS DESPITE NORMAL HEMOGLOBIN LEVELS

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1 Case Report HBA1C AN INACCURATE MEASURE OF GLYCEMIC CONTROL IN A FEMALE WITH HEREDITARY SPHEROCYTOSIS DESPITE NORMAL HEMOGLOBIN LEVELS Nora Alghothani, MD, MPH; Kathleen M. Dungan, MD, MPH ABSTRACT Objective: Earlier cases have documented a discrepancy between glycated hemoglobin A1c (HbA1C) levels and glycemic control in patients with diabetes and previously diagnosed hereditary spherocytosis (HS). However, this has not been reported in patients with normal hemoglobin (Hb) and red blood cell (RBC) indices. Methods: A 22-year-old Caucasian woman with type 1 diabetes since age 11 was referred to Endocrinology for persistent hyperglycemia. Results: The initial HbA1C was 5.1% with normal Hb, hematocrit, mean cell volume, mean corpuscular Hb concentration, and RBC distribution. Given self-reported hyperglycemia, fructosamine was checked and was elevated (358 mmol/l, normal [nl] mmol/l). Peripheral smear was normal. Professional retrospective continuous glucose monitoring (CGM) demonstrated marked hyperglycemic excursions, particularly in the evenings, with mean sensor glucose of 195 mg/dl ± 48, corresponding HbA1C of 5.5%, and fructosamine of 370 mmol/l. She later reported new diagnosis of HS in her mother, prompting workup for HS. A reticulocyte count was elevated at 5.4% (nl %), and an osmotic fragility test was supportive of HS with increased erythrocyte osmotic fragility. Conclusion: This case demonstrates a marked distortion of HbA1C in a patient with previously undiagnosed HS with normal Hb and other RBC indices. Given the relatively high frequency of mild HS, early testing should be considered in patients with an apparent discrepancy in HbA1C and meter readings, even in the absence of anemia. Alternate glycemic markers are necessary to monitor glucose control in affected patients. (AACE Clinical Case Rep. 2015;1:e194-e198) Abbreviations: CBC = complete blood count; CGM = continuous glucose monitoring; CSII = continuous subcutaneous insulin infusion; Hb = hemoglobin; HbA1C = glycated hemoglobin A1c; HS = hereditary spherocytosis; MDI = multiple dose injection; nl = normal; RBC = red blood cell INTRODUCTION Submitted for publication August 21, 2014 Accepted for publication September 29, 2014 From the Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Columbus, Ohio. Address correspondence to Dr. Kathleen M. Dungan; The Ohio State University Division of Endocrinology, Diabetes & Metabolism; 5th Floor McCampbell Hall; 1581 Dodd Drive; Columbus, OH Kathleen.dungan@osumc.edu DOI: /EP14394.CR To purchase reprints of this article, please visit: Copyright 2015 AACE. See accompanying article, p Diabetes is a costly illness affecting at least 8% of the United States population and is a leading cause of renal failure, limb amputations, and cardiovascular disease (1). The American Diabetes Association (ADA) recommends the use of hemoglobin A1c (HbA1c) testing to manage diabetes (2). However, the HbA1c has its limitations and may be misleading in patients with hemoglobinopathies or disturbances in erythropoiesis. HbA1c is reported to be falsely low in clinically relevant cases of hereditary spherocytosis (HS) given the shortened erythrocyte lifespan and reduced overall glucose uptake (3). However, mild HS with normal hemoglobin (Hb) levels accounts for 20 to 30% of cases (4) and is associated with a higher incidence of diabetes (5). We present here the first known case of a patient with This material is protected by US copyright law. To purchase commercial reprints of this article, visit For permission to reuse material, please visit e194 AACE CLINICAL CASE REPORTS Vol 1 No. 3 Summer 2015

2 HbA1c, Glycemic Control Discrepancy, AACE Clinical Case Rep. 2015;1(No. 3) e195 marked distortion of HbA1c and asymptomatic HS with normal Hb levels. CASE REPORT The patient was a 22-year-old Caucasian woman with type 1 diabetes diagnosed at age 11 who was referred to Endocrinology for persistent hyperglycemia. Her regimen consisted of insulin glargine 16 units twice daily and insulin lispro 8 units with meals. Her exam was normal without evidence for jaundice or hepatosplenomegaly. Her initial HbA1c was 5.1% (normal [nl] %) using the cation-exchange high performance liquid chromatography method, and routine chemistry and complete blood count (CBC) revealed normal creatinine (0.67 mg/dl, nl mg/dl), Hb (12.7 g/dl, nl g/dl), hematocrit (35.7%, nl 35-45%), mean cell volume (85.5 fl, nl fl), mean corpuscular Hb concentration (35.5 g/dl, nl g/dl), and red blood cell (RBC) distribution (14.7, nl ). Given self-reported hyperglycemia, fructosamine, which measures the glycosylation of serum proteins rather than Hb, was checked and found to be elevated (358 mmol/l, nl mmol/l). A peripheral smear was then obtained to assess for the presence of schistocytes or other RBC abnormalities that may falsely lower HbA1c, and found to be normal. One year after presentation, total bilirubin was slightly elevated at 1.7 mg/ dl (normal <1.5 mg/dl) with a normal direct bilirubin (0.1 mg/dl). A summary of serial laboratory values and concomitant treatment is shown in Table 1. The patient started subcutaneous continuous insulin infusion 2 years after presentation. At years 3 and 4 after presentation, professional retrospective continuous glucose monitoring (CGM) demonstrated marked hyperglycemic excursions, particularly in the evenings, with elevated mean sensor glucose and discordant HbA1c (Fig. 1 A-B). Four years after her initial presentation, she reported a new diagnosis of spherocytosis in her mother, which prompted a work-up for HS. A reticulocyte count was elevated at 5.4% (nl %) and an osmotic fragility test, which compares resistance of normal and pathologic red cells to various osmotic pressures, was supportive of HS with increased erythrocyte osmotic fragility due to spherocytosis (initial hemolysis began at 0.75% NaCl and completed at 0.50%, nl 0.45 and 0.30%). In year 5, she started realtime CGM in preparation for pregnancy, and glucose values dropped significantly (Table 1 and Fig. 1 C). DISCUSSION HS is a mostly autosomal dominant hemolytic anemia that is characterized by a RBC membrane defect that results in loss of membrane surface area and leads to abnormal osmotic fragility, increased destruction, and shortened lifespan of RBCs (6). The transformation of RBCs to a spherical shape is not always apparent on peripheral blood smear as was the case in our patient. The severity of HS may range from mild to life threatening. Although some patients may present with significant anemia, jaundice, and splenomegaly, others including our patient with mild HS, have no apparent anemia and are entirely asymptomatic. These patients are able to maintain normal Hb levels despite accelerated erythrocyte destruction due to a compensatory increase in erythropoietin-driven erythropoiesis (4) as reflected by higher reticulocyte counts and possibly elevated bilirubin. Date (Year after initial visit) 3/2007 (Baseline) 12/2008 (Year 1) 8/2009 (Year 2) 8/2010 (Year 3) 12/2011 (Year 4) 8/2012 (Year 5) Therapy Random Glucose (mg/dl) Fructosamine (mmol/l) Table 1 Patient Labs A1c ( %) H/H ( g/dl/35-45%) Total BR/Direct BR (<1.5 mg/dl/<0.3 mg/dl) MDI /35.7 NA MDI / /0.1 CSII / /0.2 CSII / /0.2 CSII /35.6 NA CSII + RTCGM /34.0 NA Abbreviations: BR = bilirubin; CSII = continuous subcutaneous insulin infusion; H/H = hemoglobin/hematocrit; MDI = multidose injection; RT-CGM = real-time continuous glucose monitoring.

3 e196 HbA1c, Glycemic Control Discrepancy, AACE Clinical Case Rep. 2015;1(No. 3) A B C Hour Glucose Sensor Overlay - Readings & Averages (mg/dl) Breakfast Lunch Dinner Glucose (mg/dl) AM 2 AM 4 AM 6 AM 8 AM 10 AM 12 PM 2 PM 4 PM 6 PM 8 PM 10 PM 12 AM Fig. 1. Continuous Glucose Monitoring Data. A, Retrospective CGM obtained during year 3 of follow-up on continuous subcutaneous insulin infusion with HbA1c 5.5% & Fructosamine 370 mmol/l, 195 ± 48 mg/dl. B, Retrospective CGM during year 4 of follow-up with concomitant HbA1c 5.2% and fructosamine 365 mmol/l (mean sensor glucose 228 ± 102 mg/dl. C, Real-time CGM during year 5 of follow-up with concomitant HbA1c of 4.0% and fructosamine of 289 mmol/l (mean sensor glucose 131 ± 60 mg/dl).

4 HbA1c, Glycemic Control Discrepancy, AACE Clinical Case Rep. 2015;1(No. 3) e197 The incidence of HS is thought to be much higher than previously reported, as mild cases are often not diagnosed. Kutter et al conclude an incidence of HS as high as 1 in 250 in a general European population (3), as well as a higher incidence of diabetes among patients with HS (5) when detected by baseline hematologic data rather than overt clinical symptoms, as hemolysis is often well compensated and tolerated. This conclusion impacts the use of HbA1c to diagnose and monitor diabetes as it may seriously underestimate the glucose load. The shortened RBC lifespan reduces exposure of Hb protein to circulating glucose and in turn leads to a falsely low level that underestimates glucose load (7). There have been previous case reports documenting inaccurate use of HbA1c in patients with HS leading to delayed diagnosis of diabetes (8) and failure to recognize severity of hyperglycemia in a patient with type 1 diabetes (9) as well as in a woman with type 2 diabetes whose poor glycemic control became apparent only after splenectomy (10). As all 3 patients reported had anemia, our case is the first to document such discrepancy between HbA1c and glycemic control in the absence of a low Hb level and abnormalities in other routine RBC indices. In 1 case, the Hb was transiently normal several years after diagnosis of HS, but other RBC indices were not reported (8). This case highlights the importance of additional testing, including an assessment of reticulocyte counts and bilirubin in patients with an apparent discrepancy in HbA1c and meter readings, even in the setting of normal CBC and peripheral blood smear. Additional evaluation for a clinically relevant discrepancy between HbA1c and glucose control should include a careful evaluation for Hb variants and disorders known to affect erythropoiesis. In many cases such as thyroid, renal, or liver disease, multiple factors may affect erythropoiesis in either direction, particularly during treatment. Therefore, the net discrepancy between HbA1c and glucose control may be small or difficult to predict. History should focus on personal or family history of disorders such as RBC disorders or recent transfusion, as well as medications that affect erythropoiesis. Exam should focus on assessment of physical features of associated diseases, such as hepatosplenomegaly. Laboratory evaluation should include a CBC, peripheral smear, Hb electrophoresis, reticulocyte count, TSH, and liver and renal function tests. Unfortunately, Hb variants may be clinically silent and may not be detected on routine laboratory testing (11). The American Association for Clinical Chemistry and ADA recommend reviewing manufacturer product instructions to determine specific interference factors and to guide selection in patients with a suspected discrepancy in HbA1c and glucose levels. The Boronate affinity chromotography assay methods are usually less affected by Hb variants. If HbA1c values remain inconsistent with the clinical presentation despite appropriate selection of an assay method, repeat testing using a method that is based on an analytical principle that is different from the initial measure is recommended. However, all methods are affected by abnormal erythropoiesis. A statement from the American Association of Clinical Endocrinologists/ American College of Endocrinology also cautions on the potential for spherocytosis to cause misleading HbA1c results in the diagnosis of diabetes (13). Furthermore, alternate glycemic markers may be necessary to monitor glycemic control in patients with HS or discrepant HbA1c and glucose. Fructosamine, which measures glycosylation of serum proteins (primarily albumin), and reflects mean glucose over about a 2-week duration given the shorter lifespan of albumin (14), was used in the case of our patient to more accurately reflect her diabetic control. However, there are limitations for its use, including falsely low readings in cases of hypoalbuminemia and interference by marked hyperbilirubinemia (>29 mg/dl) (15). The latter, however would only be clinically relevant in cases of marked hemolysis, and the patient would be expected to have other signs or symptoms. Other more recently developed markers may also be considered when available to monitor glycemic control in patients with medical conditions that distort HbA1c. Glycoalbumin was developed to counter the problems associated with fructosamine, as it is not affected by low-molecular weight substances such as bilirubin and may better indicate glycemic control in patients with advanced renal or liver failure (16,17). 1,5-Anhydroglucitol is an inverse marker of glycemic control that appears most useful to establish changes over very short intervals or to reflect postprandial glucose (17,18). Prospective studies with diverse populations and longer-term follow-up however are needed to better establish the utility of each of these markers in guiding therapy and preventing complications. CONCLUSION In conclusion, although often a harmless anomaly, clinically silent HS may be may delay the diagnosis and appropriate management of diabetes. A reticulocyte count should be included in the evaluation of patients with discordant HbA1c, even in the absence of anemia, and self-monitored blood glucose readings, alternative markers of glucose control, and use of CGM should be considered. Ultimately, only large-scale studies of patients with mild HS will allow us to understand its true impact on the diagnosis of diabetes and the role of alternate forms of glucose monitoring, particularly among patients with normal RBC indices. DISCLOSURE K.M.D. reports consulting activities with Eli Lilly and research support from Novo Nordisk and Merck. Dr. Alghothani has no multiplicity of interest to disclose.

5 e198 HbA1c, Glycemic Control Discrepancy, AACE Clinical Case Rep. 2015;1(No. 3) REFERENCES 1. Centers for Disease Control and Prevention National Diabetes Fact Sheet. Available at: gov/diabetes/pubs/factsheet11.htm. 2. American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2012;35:S11-S Kutter D, Thoma J. Hereditary spherocytosis and other hemolytic anomalies distort diabetic control by glycated hemoglobin. Clin Lab. 2006;52: Rocha S, Costa E, Catarino C, et al. Erythropoietin levels in the different clinical forms of hereditary spherocytosis. Br J Haematol. 2005;131: Kutter D. Hereditary spherocytosis is more frequent than expected: What to tell the patient? Bull Soc Sci Med Grand Duche Luxembg 2005: Bolton-Maggs PH, Langer JC, Iolascon A, et al. Guidelines for the diagnosis and management of hereditary spherocytosis-2011 update. Br J Haematol. 2012;156: Sacks DB. A1c vs. glucose testing: a comparison. Diabetes Care. 2011;34: Arnold JG, McGowan HJ. Delay in diagnosis of diabetes mellitus due to inaccurate use of hemoglobin A1C levels. J Am Board Fam Med. 2007;20: Liew CF, Cheah JS. Hereditary spherocytosis, a pitfall in the assessment of glycaemic control. Singapore Med J. 2003;44: McCready F, Cundy T. Effects of splenectomy for hereditary spherocytosis on glycated haemoglobin in a woman with Type 2 diabetes. Diabet Med. 2009;26: Little RR, Roberts WL. A review of variant hemoglobins interfering with hemoglobin A1c measurement. J Diabetes Sci Technol. 2009;3: Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2011;57:e1-e Lin MJ, Hoke C, Ettinger B, Coyne RV. Technical performance evaluation of BM/Hitachi serum fructosamine assay. Clin Chem. 1996;42: Ambruster DA. Fructosamine: structure, analysis, and clinical usefulness. Clin Chem 1987;33: American Association of Clinical Endocrinologists Board of Directors; American College of Endocrinologists Board of Trustees. American Association of Clinical Endocrinologists/American College of Endocrinology statement on the use of hemoglobin A1c for the diagnosis of diabetes. Endocr Pract. 2010;16: Vos FE, Schollum JB, Coulter CV, Manning PJ, Duffull SB, Walker RJ. Assessment of markers of glycaemic control in diabetic patients with chronic kidney disease using continuous glucose monitoring. Nephrology (Carlton) 2012;17: Dungan KM. Predicting outcomes and assessing control with alternate glycemic markers. Diabetes Technol Ther. 2012;14: Kim WJ, Park CY, Lee KB, et al. Serum 1,5-anhydroglucitol concentrations are a reliable index of glycemic control in type 2 diabetes with mild or moderate renal dysfunction. Diabetes Care. 2012;35: