Continuing Education Activity

The Hexokinase method is one of the diagnostic methods to quantify glucose concentration in different biological fluids. The robustness and accuracy of this method make it one of the most used methods for plasma glucose estimation. Quantifying plasma glucose concentration helps the clinician evaluate the patient’s glycemic state. This activity reviews the principle, method, and safety of the hexokinase method. It shows the clinical utility of this method in the diagnosis or monitoring of different clinical conditions affecting plasma glucose concentration. This activity also shows the role of the interprofessional team in the quantification, quality control, and interpretation of results in different clinical scenarios.

Objectives:

• Describe the principle and method of plasma glucose estimation by the hexokinase method.
• Outline pre-analytical, analytical, and post-analytical variables affecting plasma glucose estimation results.
• Identify interfering factors and biological variations affecting plasma glucose levels.
• Review the interpretation of results considering variables affecting the plasma glucose estimation.

Introduction

Glucose is an aldose-monosaccharide having the chemical formula of CHO. Humans derive glucose by consuming food of plant or animal origin. Complex carbohydrates present in these foods are digested in the gastrointestinal tract, converted to simple monosaccharides, and absorbed.[1][2][1] 

Digestion of disaccharides of milk (lactose) and table sugar (sucrose) gives galactose and fructose, respectively. These monosaccharides can also be converted to glucose during body metabolism. Apart from diet, glucose can be generated from breaking down liver glycogen (glycogenolysis) and non-carbohydrate sources via gluconeogenesis.[3][4][5]

Plasma glucose level is very meticulously regulated within a defined range. This is done with the help of highly regulated control exerted by insulin and glucagon hormones. Insulin hormone is secreted in response to high plasma glucose levels, which are encountered after a meal. Insulin increases glycolysis, glycogenesis, lipogenesis, and protein anabolism, while it decreases glycogenolysis, gluconeogenesis, lipolysis, and protein catabolism.[6] 

On the other hand, glucagon is secreted in response to low plasma glucose levels, which are generally encountered during fasting. It increases plasma glucose levels by increasing glycogenolysis and gluconeogenesis. It decreases glycogenesis and glycolysis. Catecholamines, glucocorticoids, thyroid hormones, etc., also increase plasma glucose levels.[7][8]

Any pathology that disturbs the balance of these regulatory mechanisms can alter the plasma glucose level. Plasma glucose is the commonly ordered investigation to evaluate the fluctuation in these mechanisms.[9] Plasma glucose levels measured in different physiological scenarios, such as fasting, 2-hour post-prandial, etc., are utilized to screen, diagnose, and monitor ongoing pathological conditions.

Many point-of-care testing devices are utilized in emergency and home care settings which use capillary blood to estimate the plasma glucose via a biosensor-based chip. The major drawbacks of such devices are imperfection in dispensing the blood sample to the biosensor chip, interference by tissue interstitial fluid, lack of timely calibration and quality control, etc.[10]

Various chemical and enzymatic methods are available for plasma glucose estimation. Due to higher time requirements and relatively less accuracy and precision than the enzymatic methods, chemical methods such as Folin Wu and O-Toluidine methods are less utilized in clinical laboratory setups. In the hospital’s clinical laboratory, enzymatic methods based on Glucose Oxidase-Peroxidase (GOD-POD) method, glucose dehydrogenase (GDH) method, hexokinase (HK) method, etc., are utilized commonly.[11] 

In the GOD-POD method, beta-D-glucose is first oxidized by the GOD enzyme, leading to hydrogen peroxide (H2O2) formation. This H2O2 reacts with a colorless chromogen substrate in the presence of peroxidase (POD) to produce a colored product. The intensity of color produced is proportional to the glucose concentration in the sample. The GOD enzyme can act on beta-D-glucose only. At equilibrium, alpha and beta isomers of D-glucose are at 36% and 64%, respectively. To optimize the results, a mutarotase enzyme should be added, or an extended incubation time is needed to complete the reaction.[12] 

In the GDH method, the GDH enzyme acts on beta-D-glucose and NAD+ (nicotinamide adenine dinucleotide) to form gluconolactone and NADH (Dihydronicotinamide adenine dinucleotide). The amount of NADH generated is proportional to the glucose concentration in the sample. This method also requires mutarotase or extended incubation time to complete the reaction.[13]

Hexokinase (HK) method is an exact and accurate method for plasma glucose estimation. Serum or plasma is first deproteinized by barium hydroxide, and zinc sulfate and clear supernatant are used for the reaction.[11] Glucose in the sample first reacts with adenosine triphosphate (ATP) with the help of the HK enzyme to form glucose-6-phosphate. Glucose-6-phosphate is then acted upon by glucose-6-phosphate dehydrogenase (G6PD) in the presence of NADP+ (nicotinamide adenine dinucleotide phosphate) or NAD+ to form NADPH (Dihydronicotinamide-adenine dinucleotide phosphate) or NADH and 6-phosphogluconate. The amount of NADPH or NADH generated is measured by recording absorbance at 340 nm, which is proportional to the glucose concentration in the sample.[14] 

The cofactor utilized in the G6PD reaction depends upon the origin of the enzyme used in the reaction. If G6PD of leuconostoc mesenteroides bacteria is used, NAD+ is used as a cofactor. While G6PD from yeast or higher plant requires NADP+ as a cofactor.[15] 

Due to its high accuracy and precision, this method is the reference method for plasma glucose estimation. The need for deproteinization increases the turnaround time for glucose estimation. To minimize the turnaround time in the hospital clinical laboratory, the deproteinization step is not performed, and plasma or serum is directly added to the reagents as per assay protocol. The effect of interfering substances in plasma or serum can be nullified by sample blanking. It will eliminate the error occurring due to the presence of any interfering substance in plasma or serum, which can absorb 340 nm radiation and affect the final result.[1]

Specimen Requirements and Procedure

Plasma or serum are commonly used specimens for plasma glucose estimation. Two to three ml of venous blood is collected in a vacutainer containing potassium salt of oxalate or ethylenediaminetetraacetic acid (EDTA) as an anticoagulant and sodium fluoride (NaF) as an inhibitor of glycolysis. Sodium fluoride reduces the availability of magnesium (Mg++) ions which are essential for the enolase enzyme activity of the red blood cells. Inhibition of the enolase enzyme leads to inhibition of glucose utilization by red blood cells via glycolysis.[16] 

Glycolysis reduces plasma glucose levels by 5 to 7 percent in coagulated-uncentrifuged blood in one hour at room temperature. Thus, adding NaF will reduce the variation in plasma glucose level due to sample storage or delayed estimation. Plasma should be separated by centrifugation and used to estimate plasma glucose as per assay protocol.[17]

Blood can be collected in a plain or vacutainer containing a clot activator for serum samples. Alternatively, a vacutainer with other anticoagulants such as potassium oxalate, potassium EDTA, sodium citrate, or heparin without the addition of sodium fluoride can also be used for the plasma sample. In such cases, plasma or serum should be separated as early as possible and transferred to another sample tube to minimize the effect of glucose utilization by red blood cells.[18]

Analysis of glucose levels in cerebrospinal fluid (CSF) should be done as early as possible because bacteria and/or pus cells and/or other types of cells may alter the glucose concentration. CSF can be utilized directly as a sample, the same as plasma or serum, for assay without any pre-treatment.[19]

Glucose concentration in 24 hours urine specimen is scarcely prescribed. Variation in glucose concentration is very high in such urine specimens due to bacterial activity, temperature, and pH-related effects. Commercially available diagnostic kits are designed to estimate glucose levels in plasma or serum specimens. Urine glucose levels in a person with uncontrolled diabetes mellitus are too high for these kits’ linearity. If needed to be processed, urine samples should be adjusted for pH, linearity range, and other interfering substances utilizing NAD+/NADP+ or having absorbance at 340 nm.[20]

Diagnostic Tests

Plasma glucose estimation is prescribed in different clinical and physiological scenarios. Screening and diagnosis of diabetes mellitus, impaired glucose tolerance, fasting hyperglycemia, etc., are based on the plasma glucose level of random, fasting, or 2 hours post-prandial blood specimen. A glucose tolerance test is also done to diagnose and confirm the diagnosis of diabetes mellitus (DM). Diagnosis of gestational diabetes mellitus (GDM) can be made based on plasma glucose levels at different specific time intervals after the glucose load. Random plasma glucose (RBG) is frequently prescribed in the emergency department and intensive care units while handling critically ill patients.[21][22]

Testing Procedures

The required quantity of specimen is added to the reagents per the assay protocol provided by the diagnostic kit manufacturer. After the prescribed incubation period, the absorbance at 340 nm is taken, and concentration is calculated using sample blank, reagent blank, and calibration data.

Interfering Factors

Hemolysed specimen contains many substances with absorbance at 340 nm, which interfere with the plasma glucose results. Enzymes released from hemolysis red blood cells also alter enzymatic reactions during the assay. The hemolyzed specimen having more than 0.5 g of hemoglobin is unsuitable for analysis by the hexokinase method. Hypertriglyceridemia and hyperbilirubinemia also create interference and provides falsely elevated value of plasma glucose. Sample blanking should be done to nullify the effect of triglyceride and bilirubin in the plasma glucose result.[23][24]

Results, Reporting, and Critical Findings

Criteria for diagnosis of DM have been defined and updated from time to time by American Diabetes Association (ADA). Diagnosis of DM is based on the cut-off values for plasma glucose levels in fasting, 2 hours post 75g glucose load (oral glucose tolerance test - OGTT), and values of HbA1c fraction of glycated hemoglobin. The below-mentioned table shows the cut-off values prescribed by ADA for the diagnosis of DM.[21][22]

Table

less than 100 mg/dl (<5.6 mmol/L)

An FPG value between 100 to 125 mg/dl (5.6 to 6.9 mmol/L) is impaired fasting glucose. While OGTT value between 140 to 199 mg/dl (7.8 to 11.0 mmol/L) is known as impaired glucose tolerance. The presence of any of these conditions classifies the patient under a pre-diabetic state. Such patients should be advised to adopt a healthy balanced diet and active lifestyle. These patients should be regularly monitored for their disease progress and the effect of dietary and lifestyle modifications.[21][22]

The Clinical & Laboratory Standards Institute (CLSI) has advised reporting the critical values of different laboratory parameters. The plasma glucose level of less than 40 mg/dL or more than 399 mg/dL is defined as a critical value according to CLSI guidelines. The laboratory and the hospital must have a robust communication system for notifying these critical values to the treating clinician or the ward’s nursing station so that life-saving measures can commence as early as possible for the patient’s well-being. It is also advised that the critical values should be read back by the notification-receiving individual to ensure accuracy.

Documentation of the communication also needs to be maintained with regards to the date and time of call attempts, names and designation of the person making and receiving calls, details communicated, the hospital’s superior officer notified in case of failed communication attempt, etc.[25]

Clinical Significance

Plasma glucose level is under effective hormonal and metabolic control in a healthy person. Any disturbance in this balance can alter plasma glucose levels in the form of hypoglycemia or hyperglycemia.

A plasma glucose level of less than 70 mg/dL is considered hypoglycemia. However, signs and symptoms of hypoglycemia may not be visible until the plasma glucose levels drop to 55 mg/dL or lower. Signs and symptoms of hypoglycemia are mainly due to a reduced supply of glucose to the central nervous system (CNS) and activation of the sympathetic nervous system. Hypoglycemia can initially cause tremors, sweating, lightheadedness, tachycardia, etc., due to the activation of the sympathetic nervous system. CNS dysfunction due to hypoglycemia can lead to headaches, confusion, blurred vision, dizziness, seizures, loss of consciousness, etc. If timely measures are not taken to restore the glucose level, it can lead to serious and permanent damage to the brain, causing coma and death.[26][27]

The causes of hypoglycemia are different in different age groups. Small for gestational age or prematurity is one of the common causes of hypoglycemia in neonates. Respiratory distress syndrome, infections, maternal gestational diabetes mellitus, etc., can also lead to hypoglycemia in neonates. Inborn errors of carbohydrate metabolisms, such as glycogen storage diseases, galactosemia, hereditary fructose intolerance, malnourished or neglected child, etc., are causes of hypoglycemia in infants. Alcohol, liver diseases, insulinoma, skipped meals after insulin or oral hypoglycaemic agent, Addison disease (glucocorticoid deficiency), etc., are common causes of hypoglycemia in adults.[28][29]

Plasma glucose levels more than the reference range for the physiological state are known as hyperglycemia. DM is the most common cause of hyperglycemia. Immunological damage to the beta cells of the pancreas leads to the destruction of these cells leading to a deficiency of insulin in patients with type 1 DM. The gradual development of insulin resistance can initially be compensated by the hypersecretion of insulin from beta cells of pancreatic islets. As the capacity of these cells becomes exhausted, hyperglycemia leads to the development of type 2 DM.[30] 

Other causes of hyperglycemia include endocrine disorders such as Cushing syndrome, pheochromocytoma, acromegaly, etc. medications such as glucocorticoids, parenteral nutrition, intravenous dextrose infusion, etc., pancreatic disorders which reduce the functionality of the endocrine pancreas such as pancreatitis, pancreatic malignancy, hemochromatosis, etc. Gestational diabetes mellitus is when a woman without a history of DM develops hyperglycemia during her pregnancy. It occurs due to the development of insulin resistance due to an altered hormonal state during pregnancy.[28][31]

Quality Control and Lab Safety

For optimum accuracy and precision of the test results, timely calibration as per the laboratory’s quality policy should be done. Calibration is routinely done while introducing the parameter for the first time in the instrument, change of the reagent lot after major maintenance of the instrument, replacing the light source, replacing the wavelength filter, violating quality control rules, etc.[32] 

After installation and calibration of the parameter, a quality check is done using commercially available internal quality control materials of different levels. Results of this quality control material are inserted in Levey-Jennings Charts, and these charts are observed for compliance with Westgard rules. Prompt suitable action should be taken upon violating any of the Westgard rules. Participation in External Quality Assurance Scheme (EQAS) should be encouraged as it helps laboratory physicians to evaluate the accuracy and bias of the results and provide confidence regarding the stability of the laboratory testing method.[33][34]

Caution must be taken while handling the reagents. Protective gear, such as hand gloves, an apron, eyeglasses, etc., should be used while handling the patient’s samples and reagents. None of the reagents or samples should be mouth pipetted. In case of exposure of the patient’s sample or reagents to the eye, skin, or mucosa, the contacted part should be thoroughly rinsed with water. Medical consultation of the exposed person should rule out the effects of infectious agents present in the patient’s sample or toxic/irritant chemicals in the reagents.[35]

Enhancing Healthcare Team Outcomes

Identifying abnormalities related to plasma glucose levels is best done with an interprofessional team that includes experts in the field of internal medicine, emergency medicine, intensivists, medical biochemistry, and laboratory medicine, along with nurses and laboratory technicians.

Clinical correlation of a patient’s plasma glucose levels with his history and other investigations can help the clinician to understand and diagnose the underlying pathology. Precise plasma glucose levels, along with HbA1c values, help the clinician plan and monitor the treatment regimen for the patients individually.

Review Questions

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Disclosure: Amit Sonagra declares no relevant financial relationships with ineligible companies.

Disclosure: Anita Motiani declares no relevant financial relationships with ineligible companies.