Impact of Mean Cell Hemoglobin on Hb A 1c –Defined Glycemia Status Santiago Rodriguez-Segade, 1,2* Javier Rodriguez Garcia, 2 Jose ´ M. Garcı ´a-Lo ´ pez, 3 Francisco Gude, 4 Felipe F. Casanueva, 3,5 Santiago RS-Alonso, 6 and Fe ´ lix Camin ˜a 1 BACKGROUND: Several hematological alterations are asso- ciated with altered hemoglobin A 1c (Hb A 1c ). However, there have been no reports of their influence on the rates of exceeding standard Hb A 1c thresholds by patients for whom Hb A 1c determination is requested in clinical practice. METHODS: The initial data set included the first profiles (complete blood counts, Hb A 1c , fasting glucose, and renal and hepatic parameters) of all adult patients for whom such a profile was requested between 2008 and 2013 inclusive. After appropriate exclusions, 21 844 pa- tients remained in the study. Linear and logistic regres- sion models were adjusted for demographic, hematolog- ical, and biochemical variables excluded from the predictors. RESULTS: Mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) correlated negatively with Hb A 1c . Fasting glucose, MCH, and age emerged as predictors of Hb A 1c in a stepwise regression that dis- carded sex, hemoglobin, MCV, mean corpuscular hemo- globin concentration (MCHC), serum creatinine, and liver disease. Mean Hb A 1c in MCH interdecile intervals fell from 6.8% (51 mmol/mol) in the lowest (27.5 pg) to 6.0% (43 mmol/mol) in the highest (32.5 pg), with similar results for MCV. After adjustment for fasting glu- cose and other correlates of Hb A 1c , a 1 pg increase in MCH reduced the odds of Hb A 1c – defined dysglycemia, diabetes and poor glycemia control by 10%–14%. CONCLUSIONS: For at least 25% of patients, low or high MCH or MCV levels are associated with increased risk of an erroneous Hb A 1c – based identification of glycemia status. Although causality has not been demonstrated, these parameters should be taken into account in inter- preting Hb A 1c levels in clinical practice. © 2016 American Association for Clinical Chemistry Hemoglobin (Hb) 7 A 1c is a measure of time-averaged glycemia. High Hb A 1c levels are strongly predictive of diabetic complications (1, 2 ), and possibly also predic- tive of cardiovascular morbidity among both diabetic and nondiabetic patients (3, 4 ). The American Diabetes As- sociation (ADA) regards Hb A 1c as a parameter that in the absence of abnormal red cell turnover allows diagno- sis of diabetes and the screening of persons at high risk of diabetes (2). Conditions or events in which the mean age of red blood cells is altered include blood loss, blood transfusions, anemia, chronic kidney or liver disease, in- gestion of high doses of vitamin C, erythropoietin treat- ment, and hematological conditions such as sickle-cell disease (5–7 ). Unusually low Hb A 1c levels are found when mean erythrocyte life span is shortened, as by glucose-6-phosphate dehydrogenase deficiency; unusu- ally high levels when erythrocyte life span is lengthened, as by deficiency of vitamin B 12 , folate, or iron; and both high and low levels may be found among patients with end-stage kidney disease (8). However, even among he- matologically normal people, erythrocyte life span varies sufficiently to cause clinically relevant differences in Hb A 1c (9). Most studies of the impact of such effects have in- vestigated the influence of iron deficiency on the Hb A 1c - based diagnosis of diabetes and prediabetes in commu- nity samples, finding that iron deficiency raises Hb A 1c levels, without any concomitant rise in glucose indices, even in the absence of anemia (10 –15 ). A few studies have also reported negative correlation between Hb A 1c on the one hand and, on the other, hemoglobin, mean 1 Department of Biochemistry and Molecular Biology, 2 University Hospital Clinical Bio- chemistry Laboratory, 3 Division of Endocrinology, 4 Clinical Epidemiology Unit, Univer- sidade de Santiago de Compostela, 15782-Santiago de Compostela, A Corun ˜ a, Spain; 5 Physiopathology of Obesity and Nutrition Biomedical Research Network Consortium; and 6 the Division of Pneumology, University Hospital Clinical Complex (CHUAC), A Corun ˜ a, Spain. * Address correspondence to this author at: Clinical Biochemistry Laboratory, Complejo Hospitalario Universitario de Santiago, Travesı ´a de la Choupana s/n, 15706 Santiago de Compostela, Spain. Fax +34-881814934 E-mail ssegade@telefonica.net. Received March 18, 2016; accepted July 27, 2016. Previously published online at DOI: 10.1373/clinchem.2016.257659 © 2016 American Association for Clinical Chemistry 7 Nonstandard abbreviations: Hb A 1c , hemoglobin A 1c ; MCH, mean corpuscular hemoglo- bin; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentra- tion; JDS, Japan Diabetes Society; NGSP, National Glycohemoglobin Standardization Program; eGFR, estimated glomerular filtration rate; eAG, estimated average glucose; JDS/JSCC, Japanese Diabetes Society and Japanese Society for Clinical Chemistry; NGSP, US National Glycohemoglobin Standardization Program. Clinical Chemistry 62:12 1570–1578 (2016) Endocrinology and Metabolism 1570 Downloaded from https://academic.oup.com/clinchem/article/62/12/1570/5612041 by guest on 22 October 2022