A Case of Inappropriately High Glycated Hemoglobin

Abstract

Hemoglobin is a tetramer formed of two alpha and two beta globin chains. On exposure to high levels of blood glucose, hemoglobin gets non-enzymatically glycated at different sites in the molecule. HbA1c is formed when glucose gets added on to the N-terminal valine residue of the beta chain of hemoglobin. The development of chronic vascular complications of diabetes such as retinopathy, nephropathy and cardiovascular disease is intimately linked to the level of glycemic control attained by the individual with diabetes. We report a case of convulsions and monoplegia admitted to emergency department, showing unusually high glycated hemoglobin but plasma glucose not as high. The patient was not a known diabetic and we could not find any of the other documented conditions that are known to elevate glycated hemoglobin to such disproportionately high levels. Screening for abnormal hemoglobins was negative in the patient. Oral hypoglycemic drug treatment over 3 months and withdrawal of other medications only marginally lowered glycated hemoglobin.

Introduction

Glycated hemoglobin (HbA1c) alone, at a level of ≥6.5 % (≥48 mmol/mol) is a cut-off for diagnosing diabetes, when the test has been performed in a laboratory using a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay [1]. Measurement of glycated hemoglobin is recommended for checking blood sugar control in people who might be pre-diabetic and monitoring blood sugar control in patients with more elevated levels, termed diabetes mellitus [2]. The levels of HbA1c in the blood reflect the glucose levels to which the erythrocyte has been exposed during its lifespan (approximately 117 days in men and 106 days in women). Therefore, the HbA1c is an index of the level of glycemic control over the preceding 2–3 months, the immediately preceding 30 days contributing 50 % to HbA1c [3].

Case Report

A 62 year old male was admitted through emergency with complaint of convulsion over left side of the body for last 2 days prior to admission. There was no history of fever, vomiting, headache, loss of consciousness, respiratory distress. On examination, his blood pressure was 110/70 mmHg, pulse 145/min, respiratory rate 20/min, body temperature 98 °F. Chest and cardiovascular system examination did not reveal any abnormal finding. However he had right lower limb monoplegia. His laboratory tests were as follows [reference ranges in parentheses]: urea-32 mg % [15–40], creatinine 0.5 mg % [0–1.3], fasting plasma glucose 208 mg/dl [70–110], cholesterol 101 mg/dl [<200], triglyceride 99 mg/dl [<150], HDL 36 mg/dl [>40], LDL 45 mg/dl [<100], albumin 2.2 g/dl [3.5–5], alanine transferase 15 U/L [0–41], sodium 139 mmol/l [136–145], potassium 3.8 mmol/l [3.5–5.2], chloride 96 mmol/l [96–106], bicarbonate 20 mmol/l [22–28], thyroid stimulating hormone 1.59 µIU/ml [0.25–5], free T4 11.64 pmol/l [9–20], C reactive protein 89.41 mg/l [up to 6], iron 84 µg/dl [45–182], total iron binding capacity 137.1 µg/dl [250–450], transferring saturation 38.7 %, ferritin-545.7 ng/ml [30–300], procalcitonin 0.35 ng/ml [<2], viral serology negative, microalbumin creatinine ratio-77.9 mcg/mg [<30]. HbA1c was 21.2 % [4–6] in HbA1c mode and 20.7 % on repeating with same sample in HbA2 mode (Fig. 1). On repeat testing next day, random plasma glucose was 141 mg% [60–140], and HbA1C 20.2 % by another instrument. The estimated glucose levels [4] did not correlate with the actual plasma glucose of the patient. Due to discrepancy between glucose levels and HbA1c, serum fructosamine assay by spectrophotometry was carried out to reveal poor glycemic control 461 µmol/l [good control 202–282].

Fig. 1.

Elevated HbA1c in short (Hb A1c) programme and extended (HbA₂) programme

Hematological investigations were as follows: total leukocyte count 10,500 cells/cumm [4,000–10,000], erythrocyte count 4.77 million/cumm [4.5–5.5], platelet 1.52 lakhs/cumm [1.5–4], INR 1.18, erythrocyte sedimentation rate 100 mm 1st hour [5–15], packed cell volume 34.4 % [33–43], MCV 88.8 f l [76–90], MCH 28.2 p [25–31], MCHC 32 % [31–36], neutrophils were 73 % [40–80], lymphocyte 22 % [20–40], monocytes 4 % [2–10] and eosinophil 1 % [1–6].

Screening for abnormal hemoglobins by high performance liquid chromatography (HPLC), by Biorad D-10, (Biorad, California, USA), revealed hemoglobin A1a 1.8 %, unknown peak 1.8 %, A1b 2.7 %, labile A1C 1.8 %, A1C 20.7 %, P3 7.3 %, A0 64.6 %, hemoglobin A2 1.8 % [2.4–3.6] hemoglobin F not recognized [0–0.8 %]. The patient’s sample tested negative for abnormal hemoglobins by HPLC. CT scan of brain showed age related cerebral atrophy. MRI brain showed generalized brain atrophy with periventricular deep white matter ischemia. There was no acute infarct or bleed.

The patient had never taken any medicines for diabetes mellitus. He was a known hypertensive and hypothyroid, under medication. There was no history of hematological disease in the family.

The patient was diagnosed as type 2 diabetes mellitus, essential hypertension, partial seizure and right lower limb monoplegia. The low albumin and microalbuminuria may indicate an early nephropathy, while CRP, ESR and ferritin were raised as a result of an exacerbation of chronic obstructive pulmonary disease. He was treated conservatively with multispeciality approach with PPI, antibiotic, anticonvulsants, antiemetic, 20 % human albumin, oral hypoglycemic agents, neurotropics, electrolyte management, proper fluid and other supportive care. Continuous monitoring of capillary blood glucose during the hospital stay ranged from 170 to 205 mg/dl. He responded well to the treatment and was discharged after 7 days in hemodynamically stable condition.

At 3 months follow up, his glycated hemoglobin had reduced marginally He did not complain of seizures and mentioned regaining some strength in the limb over the last 3 months.

Discussion

It is well known that HbA1c captures chronic hyperglycemia in the prior 2–3 months, is well correlated to chronic diabetes complications, and has less preanalytical problems and biological variability than plasma glucose, with a noninferior standardization, thus HbA1c was recommended for diabetes diagnosis and risk stratification [5].

There are several situations in which the level of HbA1c may not faithfully reflect the glycemic control in a given patient. Higher A1C levels associated with increasing age in individuals with normal glucose tolerance may be due to changes in the rate of glycation associated with aging and less likely factors such as worsening kidney function with aging or anemia [6]. A1C levels are significantly higher in patients with overt hypothyroidism [7]. Inappropriately high HbA1c are seen in iron deficiency, vitamin B12 deficiency, alcoholism, uremia, hyperbilirubinemia, chronic use of large dose aspirin or opiates [3]. Corticosteroids like prednisone, anti seizure medications like phenytoin, antiviral medication used to treat human immunodeficiency virus, including fosamprenavir and saquinavir can elevate HbA1c in absence of diabetes mellitus. Malondialdehyde, which is increased in patients with iron deficiency anemia, enhances the glycation of hemoglobin [8]. Conditions that affect erythrocyte turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly when the A1c result does not correlate with the patients clinical situation [9]. Post splenectomy, alcoholism, opiate addiction, lead poisoning, hyperbilirubinemia, chronic aspirin therapy increase lifespan of red blood cells and slow production of new red blood cells, thus increasing HbA1c.

In our case however, we could not find any of the above mentioned conditions that could elevate glycated hemoglobin to such disproportionately high levels. Research into other interfering factors in blood may be required to throw light in such cases. In this patient, though suffering from Type 2 diabetes mellitus as per fasting plasma glucose and HbA1c (supported by fructosamine), HbA1c was disproportionately elevated compared to fasting plasma glucose and serial capillary blood glucose measurements while in the hospital.

Therefore, at least in this patient, efforts to optimize the plasma glucose based on HbA1c levels only, could lead to hypoglycemia. In India, where plasma glucose testing is not expensive, the authors recommend fasting plasma glucose, a post 75 g plasma glucose along with HbA1c testing for confirmatory diagnosis and correct treatment of diabetes mellitus.