Diabetes mellitus - making the diagnosis

Professor Mark Strachan highlights some pitfalls for the unwary diagnostician

MAKING a diagnosis of diabetes is, on the face of it, easy. One needs simply to demonstrate that an individual has an elevated blood glucose concentration. However, there are potential pitfalls for the unwary and I shall consider several of these in this article.

Using HbA1c as a diagnostic test

The traditional diagnostic criteria for diabetes (a fasting plasma glucose ≥ 7.0 mmol/l and/or a random or two hour post glucose-challenge plasma glucose ≥ 11.1 mmol/l) are based around epidemiological data that essentially identify individuals at a higher risk of diabetic retinopathy. The World Health Organisation has also approved glycated haemoglobin (HbA1c) as a diagnostic test for diabetes, with the diagnosis confirmed if HbA1c is ≥ 48 mmol/mol (6.5 per cent).

HbA1c is more familiarly used as a tool to monitor the degree of glycaemic control in individuals with confirmed diabetes. Glucose binds irreversibly to haemoglobin in red blood cells in direct proportion to the prevailing plasma glucose concentration. Red blood cells have an average lifespan of 120 days and so HbA1c broadly gives a measure of average glycaemic control over that period.

There are very strong epidemiological data linking HbA1c to risk of diabetes complications and the HbA1c level is a powerful driver in making alterations to antidiabetic treatment. Therefore, it makes logical sense that HbA1c should also be used as a diagnostic test for diabetes. HbA1c has the additional advantages that it can be measured without the need for fasting and obviates the need for a glucose tolerance test. Many areas of the country are already using HbA1c as a diagnostic test for diabetes, despite its increased cost in relation to plasma glucose, and it is likely that its use will become more common.

The implications of making a diagnosis of diabetes for an individual can be profound – the individual is turned into a “patient”. Getting travel insurance, life assurance and critical illness cover may be more difficult and more expensive and there may be an impact on employment. It is important to get the diagnosis right and it must be remembered that HbA1c is not a perfect diagnostic test.

Anything that alters haemoglobin or the lifespan of a red blood cell will alter the relationship between HbA1c and average glycaemia. Thus, haemolytic anaemia, haemoglobinopathies, acute blood loss, splenomegaly and some antiretroviral drugs can result in an artificially low HbA1c. The result may also be lower in renal dialysis patients and be altered by iron and vitamin B12 deficiency. HbA1c will also give a falsely reassuring result if there has been a recent rapid rise in blood glucose; therefore it cannot be used as a diagnostic test for gestational diabetes, steroid-induced diabetes and type 1 diabetes.

Whatever diagnostic test for diabetes is used, it is important to send a second confirmatory test in asymptomatic individuals. Samples can be mislabelled and laboratory errors can occur. To avoid confusion in interpretation, the second confirmatory test should be the same as the first, i.e. if HbA1c has been used on the first occasion it should also be tested on the second. Do not delay seeking an urgent opinion though (waiting on a second confirmatory test result) if the individual is ill, has significant symptoms or is a child.

What type of diabetes?

Confirming that an individual has diabetes is only part of the job. The key question to answer next is: “what type of diabetes does this person have?” At its extremes, diabetes is a consequence either of insulin deficiency or insulin resistance, though many individuals with diabetes probably have a bit of both.

Insulin deficiency is the hallmark of type 1 diabetes, where there is autoimmune destruction of the insulin-producing cells of the pancreas. Type 1 diabetes classically presents in children and young adults and there is often a short history of increasing osmotic symptoms and weight loss. Central obesity is the commonest substrate of insulin resistance and predisposes to type 2 diabetes, with its trusty lieutenants of hypertension and dyslipidaemia.

It is important to be alert to other potential causes of diabetes: pancreatic pathology (most commonly chronic pancreatitis or post-pancreatic surgery, but more rarely tumours), drugs (including steroid therapy and some antipsychotic medications), endocrine disorders (classically Cushing’s syndrome, acromegaly and phaeochromocytoma) and the reasonably common monogenic forms of diabetes. Monogenic diabetes, often referred to as maturity onset diabetes of the young (MODY), is inherited in an autosomal dominant fashion and classically presents in young adults, with hyperglycaemia that can be managed with dietary modification or oral antidiabetic therapy.

I always say to my registrars in diabetes and endocrinology that, when seeing an individual with newly diagnosed diabetes, they should ask themselves: “Why has this person developed diabetes?” Type 1 diabetes can occur in overweight individuals as well as slim people and can present at any age. The consequences of missing a diagnosis of type 1 diabetes can be extremely serious because insulin deficiency can lead to diabetic ketoacidosis. Therefore, testing for elevated urine or blood ketone concentrations is essential in all people with newly diagnosed diabetes.

Making the referral

The finding of ketonuria or ketonaemia, in conjunction with an elevated blood glucose, is highly suspicious for type 1 diabetes and mandates an urgent referral to a diabetes centre. The timing with which the individual actually needs to be seen in the diabetes centre will depend on the age and clinical state of the individual, but I would always recommend that this initial referral happens by telephone rather than by mail. I appreciate that making telephone contact with specialists can be time consuming and frustrating for colleagues in primary care, but letters and emails can go astray or lie unread for several days and a delay of even one or two days can mean the difference between a patient who can be managed exclusively on an out-patient basis and one who is admitted to hospital with severe metabolic decompensation.

If the patient does not have elevated blood or urine ketones, then there is usually less urgency about initiation of treatment. If the individual has central obesity and evidence of hypertension and dyslipidaemia, a diagnosis of type 2 diabetes can be made but remember the rare possibilities of Cushing’s syndrome and acromegaly. If an individual is slim (body mass index <25 kg/ m2), then type 2 diabetes is a less plausible diagnosis and that is when real consideration needs to be given to some of the other potential causes listed above. By definition, if the individual is slim, then there must be a degree of insulin deficiency rather than insulin resistance. One caveat to that is ethnicity. Individuals of South Asian origin have more central obesity (and thus more insulin resistance) for a given body mass index (BMI) than individuals of Caucasian origin. Thus, in insulin resistance terms, a BMI of 23 kg/m2 in a South Asian man is roughly equivalent to a BMI of about 25 kg/m2 in a Caucasian man.

Do not presume that because an individual is young that they must have type 1 diabetes. Type 2 diabetes used to occur exclusively in middle-aged and older adults, but in our increasingly obese societies we are now seeing young adults and even teenagers presenting with typical type 2 diabetes.

Key points

• HbA1c or glucose can be used to diagnose diabetes, but there are certain situations where HbA1c may be unreliable.

• Obtain a second, confirmatory test in asymptomatic patients but never delay therapy in symptomatic patients, children and individuals who are ill.

• Type 1 diabetes can occur at any age and in individuals who are overweight.

• Check urine or blood ketone levels in all people with a new presentation of diabetes. Phone your local diabetes centre for advice if you suspect someone has type 1 diabetes.

• Always think to yourself: “Why has this person developed diabetes?” Make the correct diagnosis of the type of diabetes and do not presume that an older individual has type 2 diabetes and that a younger individual has type 1 diabetes.

Professor Mark WJ Strachan is Associate Medical Director at the Western General Hospital, Edinburgh, and an Honorary Professor at the University of Edinburgh