The Use of Clinical Biochemistry in the Management of Diabetes Mellitus

Su-Mei Tham

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Introduction

Clinical biochemistry is the branch of laboratory medicine in which chemical and biochemical methods are applied to the study of disease. Biochemical investigations are involved, to some extent, in every branch of clinical medicine. The results of biochemical tests may be used for diagnosis and monitoring of diseases, to help decide treatment plans, as well as assessing prognosis. They are also of some value in screening for diseases. However, clinical biochemistry plays only a part in the overall assessment and management of the patient. For some patients, biochemical analyses play a very small role in the diagnosis or management of their condition, whereas for others, a diagnosis is made from the results of certain biochemical tests only. Diabetes Mellitus is one such condition1. The aim of this essay is to analyse the importance of biochemical testing in the management of diabetes mellitus and its complications, including diabetic ketoacidosis (DKA) and hyperosmolar non-ketotic (HONK) coma. It is important to understand how biochemical testing is used in the management of diabetes, as the current cost of diabetes in the UK is 7% of the total National Health Service budget. Patients with diabetes have a 10-30% reduction in life expectancy and current poor glycaemic control in individuals has increased the use of hospital beds six fold2. It is, therefore, very important to gain good glycaemic control, with the use of biochemical tests, in order to reduce complications and their costs to the NHS. I will also discuss the limitations of biochemical testing, including the areas where errors are likely to occur and the future of point of care testing in the management of patients with diabetes.

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Metabolic Disturbances in Type 1 and Type 2 Diabetes Mellitus

Metabolic disturbance Hyperglycaemia (resulting in glycosuria) Dehydration Polyuria Polydipsia Lipolysis and proteolysis

Type 1 Present

Type 2 Present

Present Present Present Present (resulting in weight loss)

Present Present Present Not present

Ketogenesis

Present (resulting in ketoacidosis)

Not present

Method

The best way to show the use of clinical biochemistry in the management of patients with diabetes mellitus is to show it in clinical practice. I attended a diabetes clinic on two occasions and saw, firsthand, how the results of biochemistry tests affected the management of the patient. I have selected a patient from those that attended the clinic as an example of a patient with well controlled diabetes. My essay also hopes to show how biochemical tests are used in the management of DKA and HONK patients. Whilst acting as the On-Duty Biochemist, my convenor came across both a HONK and DKA patient, and I have included these patients in my clinical cases.

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Clinical Case 1

A patient with well controlled diabetes mellitus

A 75 year old female with type 2 diabetes (diagnosed 2001) attended the diabetes clinic for her 6 month review. Complications of her diabetes include morbid obesity, hypertension, hyperlipidaemia, ischaemic heart disease and cataracts. She is currently on metformin and sitagliptin for her diabetes and simvastatin for her high cholesterol. Blood tests were done on the day she attended for the clinic and the following biochemical test results were obtained:

In the long-term management of diabetic patients, good glycaemic control is usually observed by monitoring their HbA1c. A target HbA1c of less than 7% is recommended to reduce the risk of vascular complications. Many patients require adjustment of their current therapy in order to achieve this. Usually, if the patient is on insulin, their dose will be increased slowly over a period of time in order to bring their HbA1c value down to below 7%. This patient is currently taking metformin and sitagliptin for her diabetes, so in this instance, the patients dose of metformin could be increased. However, because her HbA1c is close to 7%, it is unlikely her medication dose will be increased, as this could be brought down through exercise and education on good diet alone.
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In type 2 diabetics, it is also important to monitor their weight, cholesterol and triglyceride levels. This is because obesity is associated with increased risk of complications in type 2 diabetics. This is monitored by measuring the patients HDL and LDL levels. HDL is known as protective cholesterol and LDL is harmful cholesterol, especially if deposited in coronary arteries2. This is particularly important in this patients case, as she is already known to have ischaemic heart disease which could be exacerbated by poor diabetic control. It is common for diabetic patients to also have thyroid function tests when performing their usual blood tests. This is because diabetes (type 1 or type 2) both have a degree of autoimmunity involved in the pathogenesis of the disease. This may, therefore, increase the patients likelihood of developing other autoimmune diseases, in particular thyroid diseases. Hence, it is common practice to also order thyroid function tests along with the other blood tests to aid early detection of such conditions3. In this patient, her results show raised TSH levels, which will be monitored every time she attends the clinic, for further development.

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Complications of Diabetes Mellitus

In some patients with poor glycaemic control, complications may occur. There are both acute and long-term complications associated with sustained periods of hyperglycaemia. The acute complications, DKA and HONK are caused by sudden changes in the patients metabolic state due to the lack of insulin. These changes are observable in the results of the patients biochemical tests. These tests are, therefore, essential in the management of diabetic patients presenting with acute complications.

Diabetic Ketoacidosis (DKA) DKA is a medical emergency and the metabolic disturbances caused are the consequences of lack of insulin: The Pathophysiology of Diabetic Ketoacidosis4

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Lack of insulin also affects the bodys potassium balance. Insulin increases potassium uptake by cells, so lack of insulin means potassium cannot be taken up, making the patient appear to have normal or raised potassium levels in biochemical test results. The patient is in fact hypokalaemic, as the potassium is excreted by the kidneys due to the osmotic diuresis. Insulin, administered as part of their treatment (see below), stimulates potassium to be taken up by the cells and the patient becomes hypokalaemic. This has dangerous consequences owing to the effects of potassium on the heart and is considered in the treatment of DKA patients with the intravenous infusion of potassium (see below)4.

Treatment The treatment of DKA involves the administration of three agents1: 1. Fluids 2. Insulin 3. Potassium It is very important to gain good venous access and document all fluids given, as the patients saline is cut back as the patients fluid and electrolyte deficit improves. The detailed management of a patient with DKA is shown below: A Treatment Regime for Diabetic Ketoacidosis1

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Insulin is administered intravenously by an infusion pump, commencing initially at 6 units/hour. This dose is adjusted according to the patients blood glucose levels, monitored hourly at the bedside until it falls below 15 mmol/L. It is then monitored at 2-hourly intervals. It is also recommended that the plasma glucose be confirmed by the lab every 2-4 hours.

Clinical Case 2

Diabetic Ketoacidosis

A 16 year old male, with an 8 year history of type 1 diabetes, was admitted to hospital with persistent vomiting. He said he felt hot and sweaty, but denied any abdominal pain or diarrhoea. He is currently on an insulin regime (Novomix 30) for his diabetes (62 units mane, 45 units nocte). On admission, his stats were as follows: 35.9oC 124/min 119/62 22/min 100%

Temperature Pulse B/P Respiratory rate O2 SATs

His biochemical test results on admission are shown below:

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Urinalysis Results BLD PRO NIT KET GLU pH SG LEU NEG NEG NEG + +++ 5 1.015 NEG

The diagnosis of DKA was made using the results of biochemical tests shown above. Typical biochemical features of a DKA are shown in the table below5: Biochemical Feature Hyperglycaemia Notes This is shown by a markedly raised blood glucose level, almost 4 times that of the upper limit in this patients case. Metabolic Acidosis This can be seen in the low bicarbonate levels. The breakdown of ketone bodies releases hydrogen ions, causing the patient to become acidotic. The body attempts to correct this shift in pH with its natural buffering system, bicarbonate ions, which combine with H+ ions to form carbonic acid. The carbonic acid can then dissociate to water and carbon dioxide. Because of the high H+ ion concentration, the patients bicarbonate levels are low. Raised plasma and urine ketones These levels are raised due to the -oxidation of fatty acids. Although both plasma and urine ketone levels should be raised, this is not the case in this patient, who only has one + for ketones in urine. This could be because the urine dipstick test used to detect the ketones may give false negatives, due to the fact that the test detects acetoacetate, but not -hydroxybutyrate. In the early stages of DKA, more -hydroxybutyrate is produced than acetoacetate (8:1 ratio), so urine ketone levels appear low. As the

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DKA is treated, -hydroxybutyrate is converted to acetoacetate and the test becomes more positive. Hyperkalaemia As mentioned earlier, lack of insulin causes potassium to be released from cells, so the patient may appear hyperkalaemic or normal. However, as insulin therapy is administered, the patient can become quickly hypokalaemic, so potassium levels must be monitored very closely and potassium replacement is often required. Raised plasma creatinine and urea This is due to dehydration, as osmotic diuresis occurs because an increased blood glucose level exceeds that of the renal threshold.

Once DKA was diagnosed in this patient, the DKA pathway was commenced. Treatment of this patient included intravenous access, administration of normal saline (0.9% solution) and insulin infusion. Insulin was administered at an initial dose of 6 units per hour. Finger prick glucose tests were carried out every hour and the dose adjusted accordingly:

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Venous blood samples were also sent to the laboratory for testing at intervals. The results are shown below: Time (hours) Normal range Sodium (mmol/L) Potassium (mmol/L) Bicarbonate (mmol/L) Urea (mmol/L) Creatinine (mmol/L) Plasma glucose (mmol/L) 136 144 3.5 5.0 20 30 2.3 7.5 <135 3.6 8.0 1 136 4.9 17 8.2 101 23.7 6.7 79 2.9 72 6 136 4.3 134 3.7 21

The principal aim of treatment of DKA patients is to correct the acidosis. This is more important in terms of morbidity and mortality than correcting the hyperglycaemia5. The patient made a full recovery.

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Hyperosmolar Non-Ketotic Coma (HONK) HONK is defined as the presence of hyperglycaemia without the marked hyperketonaemia and acidosis seen in DKA5. It usually occurs in older patients, possibly because type 2 diabetes is associated with late onset. Patients are often dehydrated, as osmotic diuresis occurs, resulting in reduced levels of consciousness. The pathophysiology of HONK has many similarities to that of DKA there is relative insulin deficiency in the presence of excess catabolic hormone concentration. However, in HONK, lipolysis and ketogenesis do not occur. The reason for this is unclear. It has been suggested that the low circulating levels of insulin is just sufficient to prevent lipolysis, or that the hyperosmolality found in HONK may have an inhibitory effect on lipolysis and ketogenesis13. Biochemistry test results, therefore, show some differences to that of a DKA patients, as acidosis does not occur, (unless lactic acidosis develops). Precipitating factors of a HONK include severe illness, dehydraton, certain drugs, e.g. glucocorticoids and thiazide diuretics, myocardial infarction, stroke and infections5.

Treatment Treatment of HONK patient is similar to that of DKA patients. The following agents must be administered and the precipitating factor treated: Agent Fluids Notes (comparison to DKA) 0.45% saline (half-normal saline) is usually administered. Rehydration should be slower in HONK patients than in DKA patients to avoid neurological damage as a result of a rapid fall in plasma osmolality. Insulin This is the same as in DKA patients. 6 units per hour is initially administered and this dose is adjusted according to bedside monitoring of blood glucose levels. Potassium Potassium requirements in HONK patients is usually less than that of a DKA patients as acidosis has not occurred. Heparin HONK patients appear to have an increased risk of thromoboembolism, so prophylactic heparin is also usually administered.

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Clinical Case 3

Hyperosmolar Non-Ketotic Coma

A 79 year old female was admitted to hospital with slurred speech and increasing confusion. She has a history of anxiety, depression, chronic kidney disease, chronic confusion and recurrent urinary tract infections, for which she has just finished a course of oral antibiotics. She is currently taking metformin and gliclazide for her diabetes. Her stats on admission were as follows: Temperature Pulse B/P Respiratory rate 36.4oC 101/min 148/80 26/min

Her biochemical test results on admission are shown below:

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Urinalysis results BLD PRO NIT KET GLU pH SG LEU + + NEG + +++ 5 1.010 NEG

The following biochemical features are typical of a HONK5: Biochemical Feature Notes

Raised plasma creatinine This occurs as a result of dehydration due to osmotic dieresis. and urea Hyperglycaemia Hyperosmolar plasma Blood glucose levels rise as a direct result of lack of insulin. The plasma becomes hyperosmolar as water is lost due to dieresis. Absence of ketones or metabolic acidosis Hypernatraemia (only initially) Lipolysis does not occur so ketones are not produced and the patient does not become acidotic. This is because there is increased cellular uptake of glucose and water from the extra-cellular fluid, resulting in hypernatraemia. This is usually corrected with treatment, but it may be necessary to switch from an isotonic solution (i.e. normal saline) to a hypotonic solution for rehydration. The sodium concentration must, therefore, be monitored very carefully to decide which treatment is necessary.

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Treatment of this patient was with a similar treatment to the DKA patients. She was started on a GKI regime Glucose, Potassium and Insulin. The glucose is given in the form of 10% dextrose solution with 2.0mmol of potassium chloride added to the solution and 10 units of Actrapid insulin. This is an alternative management pathway. There is no evidence that suggests the GKI regime has any benefit over the use of standard 0.45% saline solution6. Bedside glucose testing allowed the patients blood glucose levels to be monitored and the insulin dose altered accordingly:

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Venous blood samples were also sent to the laboratory at intervals and the results were as follows: Time (hours) Normal range Sodium (mmol/L) Potassium (mmol/L) 136 144 3.5 5.0 2.3 7.5 <135 12 128 Unsuitable for analysis Urea (mmol/L) Creatinine (mmol/L) 9.6 89 3.5 60 36 143 3.9

It is worth noting that in this instance, glucose levels were not measured in the laboratory. It is recommended that blood glucose levels be measured in the laboratory as errors are more likely to occur in bedside monitoring (see Discussion). Bicarbonate levels are also not monitored in this patient. This is because acidosis is not likely to occur in HONK. It is more important for bicarbonate levels to be monitored in DKA patients. The patient recovered from the HONK, but unfortunately, due to other medical conditions, the patient was later discharged for palliative care. It is worth noting that there is a higher mortality rate associated with HONKs than with DKAs5. This is most likely because HONK patients are usually older at presentation than DKA patients and so are more likely to have other underlying disorders and complications.

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Discussion

The use of biochemical tests in the diagnosis and monitoring of diabetes is both far and wide. It is vital for the diagnosis of diabetes, but the diagnosis can only be made if the patients present with the symptoms. There are still many cases of undetected, and untreated, diabetes (approximately 850 000 in the UK7). It is not uncommon for a diagnosis of diabetes to be made when the patient presents with a complication. As mentioned earlier, HbA1c is also being studied as a potential diagnostic tool for diabetes. HbA1c is currently being used only if other diagnostic tests are also carried out but maybe, when more data and evidence is available, HbA1c could be used as a diagnostic tool in its own right. This would be beneficial to the patient, as it means a period of fasting is not required. It would also save time, as a blood sample can be taken as soon as a patient presents with the symptoms of diabetes and a diagnosis could be made potentially within 24 hours.

Point-of-Care Testing Point-of-care testing has been defined as any investigation carried out in a clinical setting or the patients home for which the result is available without reference to a laboratory and perhaps rapidly enough to affect patient management8. In diabetes, this could refer to the use of glucose monitors in the long-term management of patients, or the use of machines, e.g. ABG measurements, on the wards in acute complications. The use of finger prick testing to monitor blood glucose levels is well established in diabetics. Monitors, such as Accu-chek, were originally designed and marketed to be used by patients in their homes so they can monitor their blood glucose levels before meals. This provides them with an idea of when their blood glucose levels may be too high or low, e.g. before meals or following exercise, so their insulin dose may be adjusted as their physician sees necessary. However, recently, such monitors have been found being used in the clinical setting without additional regulatory framework and limited training of their proper use from staff. Some monitors account for possible errors from the user, e.g. some monitors warn when a blood sample is inadequate, but there is still limited understanding among healthcare

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workers of their inaccuracy9. For this reason, it has been suggested that blood glucose levels also be confirmed by the laboratories every 2-4 hours during treatment1. Errors that are likely to occur on the wards can be classified as either human errors, or errors of judgment. Human errors, such as poor specimen collection or an incompetent user, are likely to produce inaccurate results. Errors of judgment include carrying out the wrong test, or too many irrelevant tests. Regardless of the accuracy of the results produced, results are irrelevant and hence, incur unnecessary costs. Both human error and errors of judgment can be improved by training staff in the correct use of the equipment. This, however, is likely to be costly and may still result in errors, leading to a quality issue. Point-of-care testing was introduced to be both immediate and convenient, but it is important for healthcare professionals to understand their limitations. Point-of-care testing on wards is also likely to be costly when you consider the cost of the equipment and the cost of training staff in their correct use. For these reasons, it is unlikely that the role of the biochemical laboratory in the diagnosis and monitoring of diabetes mellitus will ever be diminished.

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References 1. Gaw A, Murphy MJ, Cowan RA, O'Reilly D St. J, Stewart MJ, Shepherd J. Clinical Biochemistry: Churchill Livingstone, 2004. (Illustrated Colour Text). 2. British Heart Foundation. High Cholesterol http://www.bhf.org.uk/hearthealth/conditions/high-cholesterol.aspx (accessed 19th April 2011. 3. 4. Patricia W. Thyroid Disease and Diabetes. Clinical Diabetes 2000;18(1):38 - 40. Baynes JW, Dominiczak MH. Glucose Homeostasis, Fuel Metabolism, and Insulin. In: Medical Biochemistry, 2nd ed.: Elsevier Mosby, 2005:273 - 97. 5. Smith J, Nattrass M. Hyperglycaemic Comas. In: Diabetes and Laboratory Medicine. ACB Venture Publications, 2004:71 - 93. 6. Savage MW, Kilvert A. ABCD guidelines for the management of hyperglycaemic emergencies in adults. Pract Diab Int 2006;23(5):227-31. 7. Diabetes UK. What is diabetes? 2009. http://www.diabetes.org.uk/Guide-todiabetes/Introduction-to-diabetes/What_is_diabetes/ (accessed 17th April 2011. 8. 9. Hobbs R. Near patient testing in primary care. BMJ 1996;312:263-4. Pitkin AD, Coursin D, Rice MJ. Point of Care Devices Should Not Be Relied Upon for Perioperative Glucose Measurement. Anesthesia & Analgesia 2011;112(1):247-8.

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