Diabetes Diagnosis and Monitoring, April 2002 Author Peter Colman

7/27/2019 Diabetes Diagnosis and Monitoring, April 2002 Author Peter Colman

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UNIT 1, APRIL 2002

DiabetesDiagnosisand Monitoring

COMMONSENSE

PATHOLOGY

C o n t e n t sC o n t e n t s Who to screen Who to screen Unusual cases Unusual cases Monitoring for complications Monitoring for complications

Common Sense Pathology is a joint initiative of

The Royal College of Pathologists of Australasia The Royal College of Pathologists of Australasia


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Topics that will be covered include:

ALLERGY

CARDIAC MARKERS

FATIGUE

THROMBOPHILIA

METABOLIC SYNDROME

Look out for future issues of

COMMON SENSE

PATHOLOGY


3/13

Dear Reader

It is with great pleasure that the Royal College of Pathologists of Australasia and Australian Doctor

present a new series of Common Sense Pathology.

The first series was very well received and lauded as providing clear concise information that is useful

and necessary for general practitioners, indeed back copies are still eagerly sought. Common Sense

Pathology has been sorely missed since its demise in 1999 due to the cessation of a Federal Government

funding initiative.

The College and Australian Doctor are delighted to have reached an agreement to produce a new series.

Suitable topics to present on the appropriate use of pathology in the clinical setting abound, and we lookforward to a productive association. We thank Dr Peter Clyne for reviewing each article.

The 2002 series will consist of six articles, each of which will be published as a separate booklet and

delivered with your Australian Doctor. In addition the articles will be posted on the College website at

www.rcpa.edu.au. It is hoped you will find this first article on diagnosis and monitoring of diabetes to be

a valuable education and reference tool.

Both the College and Australian Doctor are pleased to be able to provide this resource to the medical

fraternity.

Yours sincerely

Dr Matthew Meerkin Dr Kerri Parnell

Editor Medical Editor

Common Sense Pathology Australian Doctor

Commonsense Pathology is a joint initiative ofAustralian Doctor and The Royal College ofPathologists of Australasia.

It is published by Reed Business InformationTower 2, 475 Victoria Ave, Locked Bag 2999Chatswood DC NCW 2067.

Ph: (02) 94222999 Fax: (02) 94222800E-mail: [email protected] site www.australiandoctor.com.au(Inc in NSW) ACN 000 146 921

ABN 47 000 146 921ISSN 1039-7116

2002 by The Royal College of Pathologists ofAustralasia website www.rcpa.edu.au

CEO Dr Debra GravesE-mail: [email protected] Pathology EditorDr Matthew MeerkinE-mail: [email protected]

Australian DoctorMedical Editor Dr Kerri ParnellE-mail: [email protected]

Managing Editor, Healthcare Kellie BissetE-mail: [email protected]

Sales Director, Healthcare Neil CoveyE-mail: [email protected]

Production Manager Kirsty MilenkovicE-mail: [email protected]


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Associate Professor Peter ColmanDirector, Department of Diabetes and EndocrinologyRoyal Melbourne Hospital

Diabetes diagnostic criteria and determining the cause

The Australian Diabetes, Obesity and Lifestyle Study (AusDiab), the first accurate national diabetes

prevalence study in this country, has recently reported its frightening findings (1). The prevalence of

diabetes in the Australian population aged 25 years and older is 7.5% (8% for males and 7% for females).

The prevalence rises from 2.5% in people 35 to 44 years to 23.6% in those 75 years and over. For eachknown case there is one undiagnosed case. Furthermore, the prevalence of impaired glucose metabolism

(either impaired glucose tolerance or impaired fasting glycemia) in the population is 16.3% (17.3% for

males and 15.3% for females). In the light of these dramatic figures this issue of Commonsense Pathology

will address the diagnostic criteria for diabetes and impaired glucose metabolism, the current approaches

taken to case finding for diabetes and extra diagnostic tests that might be indicated to determine the cause

of diabetes in unusual cases. It will also look at investigations used routinely in managing patients with

diabetes.

CASE 1

A 56-year-old woman presents to her GP with a three-month history of thirst, polyuria and nocturia up to

four times. Recently she has also noticed blurring of vision. Her weight is 94kg and height 1.71m with a

body mass index (BMI) of 32. She has had hypertension for several years. Her mother had diabetes later in

life and ultimately needed treatment with insulin. Her capillary glucose on the surgery glucometer is

15mmol/L.

Question 1.

What further tests are needed to confirm the diagnosis of diabetes?

She should have blood taken for a laboratory plasma glucose, either fasting or random. Use of office

glucometers is not recommended for diagnosis on the basis of several studies which examined the

sensitivity and specificity compared to an oral glucose tolerance test (oGTT). In one study using a cutoff of

5.8mmol/L the glucometer achieved a sensitivity of 79% in men but only 40% in women, while specificity

was 86% and 84% respectively for men and women (2).

The criteria for diagnosis of diabetes in the setting of classical symptoms would be a fasting plasmaglucose of above 7mmol/L or random plasma glucose of over 11.1mmol/L (3). In this situation an oGTT is

unnecessary.

In contrast, the diagnosis of diabetes in an asymptomatic individual should never be made on the basis of a

single abnormal plasma glucose value. For the asymptomatic person, at least one additional plasma

glucose test result with a value in the diabetic range (either fasting or random) is essential. It is also

important to remember that severe hyperglycemia detected under conditions of acute infective, traumatic,

circulatory or other stress may be transitory and should not be regarded as diagnostic for diabetes. The

situation should be reviewed when the acute stress has passed.

Question 2.

Why cant the HbA1c be used for diagnosis?

HbA1c has been suggested and evaluated as a potential test for screening and diagnosing type 2 diabetes inkeeping with a desire to have a simple and single test which could replace the oGTT. However the WHO

recommends that HbA1c should not be used for diagnosis of diabetes due to low sensitivity and lack of

standardisation. One study examined HbA1c measurement in cohorts from the NHANES III study (4).

Using the current WHO criteria for diagnosis 60% of people with diabetes diagnosed on the basis of a

fasting plasma glucose of 7.0 to 7.7mmol/L had normal HbA1c. Measurement of HbA1c is not yet

Diabetes

Diagnosis

and Monitoring

The criteria for diagnosis of diabetes in the setting of classical symptoms would be a fasting plasmaglucose of greater or equal to 7mmol/L or random plasma glucose greater or equal to 11.1mmol/L(3).

In this situation an oGTT is unnecessary.


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standardised around the world and therefore it is not currently possible to produce diagnostic thresholds that

would be valid in all laboratories. Current regulations in Australia on the clinical use of HbA1c measurement

which attract a Medicare benefit preclude its use for this purpose.

Question 3.

What other investigations should be performed at the time of diagnosis of diabetes?

As type 2 diabetes can be undiagnosed for many years it is important to look for evidence of retinopathy andnephropathy at diagnosis. She should have a retinal examination through dilated pupils and once her diabetes

is controlled, her urine should be checked for a subclinical increase in albumin excretion (microalbuminuria).

There are several methods of testing for microalbuminuria, which differ in the type of urine collection and

the method of measurement. Initial screening can be performed on early morning urine samples using either

an albumin:creatinine ratio or a semi-quantitative dipstick technique such as Micral-II. Subsequent testing is

best performed on a timed overnight or a 24-hour urine specimen. She should also have a fasting lipid profile

(cholesterol, triglyceride, HDL-cholesterol and LDL cholesterol) and treatment according to guidelines as

diabetes is associated with a higher absolute risk of coronary heart disease (5).

CASE 2

A 58-year-old woman, whose mother had type 2 diabetes, presents asking whether she should be tested fordiabetes. She has a BMI of 29 and is on enalapril for hypertension. Her fasting cholesterol is 5.8mmol/l,

triglyceride 2.6mmol/L and HDL cholesterol 0.9mmol/L. She has no symptoms of diabetes. A fasting glucose

is 6.5mmol/L.

Question 1.

Should she be tested for diabetes?

Yes. The draft Australian National Evidence Based Guidelines (6) suggest tests for undiagnosed diabetes in

the following:

People with previous history of impaired glucose tolerance or impaired fasting glycemia

Women with previous gestational diabetes

People aged 55 or over

Aboriginal and Torres Strait Islanders aged 35 and over

High risk non-English-speaking background groups (Indian subcontinent, Pacific Islands, Chinese origin)

aged 35 and over

All people with a clinical history of a cardiovascular event (myocardial infarction, angina or stroke)

Women with polycystic ovary syndrome who are obese

People aged 45 or over who have one or more of the following risk factors:

Obesity (BMI > 30)

First degree relative with type 2 diabetes

Hypertension

Question 2.

With a fasting glucose of 6.5mmol/L, how would you proceed to diagnose this patients carbohydrate

status?

For patients with a fasting glucose between 5.5 and 7.0mmol/L or a random glucose between 7.8 and11.0mmol/L an oGTT should be performed. The diagnostic results for the oGTT are interpreted as follows:

Fasting glucose (mmol/L) 2 hour post glucose load (mmol/L) Diagnosis


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Question 4.

How often should people, identified as being at risk through risk factor assessment, be retested?

The draft Australian Evidence Based Guidelines suggest periodic testing for undiagnosed diabetes by

measuring fasting plasma glucose according to the following schedule:

Each year for people with impaired glucose tolerance or impaired fasting glucose

Every three years for at-risk people with a plasma glucose within the normal range

Each year for people with an initial plasma glucose consistent with a diagnosis of diabetes or IGT/IFGwhich is not confirmed on subsequent testing

CASE 3

A 65-year-old woman with a past history of Menieres disease, reflux oesophagitis and osteoarthritis

presents to her GP with mild fatigue and slight weight loss. Her body weight is 57kg and height 1.62m

(BMI 21.7). She is normotensive and has no evidence of vascular disease. There is a history of diabetes in

her mother and brother both developed diabetes in middle age and were treated with oral hypoglycemic

agents. Fasting glucose is 6.5mmol/L and an oGTT test iss performed. Diabetes is diagnosed with fasting

glucose 8.2mmol/L and two-hour 19.3mmol/L. Her HbA1c at diagnosis is 10.1%. With diet, the HbA1c

falls to 7.5% but after six months again rises to 8.7% so a sulphonylurea is instituted. HbA1c fallspromptly to 6.1%. Two years later, her HbA1c rises to 10% despite increase in the sulphonylurea and the

addition of metformin.

Question 1.

What further testing might assist her management?

The clinical scenario of rapid failure of control of diabetes with oral hypoglycemic agents and the low BMI

in this patient suggests she may have slowly progressive type 1 diabetes. An assay for glutamic acid

decarboxylase antibodies (GADAb) or a measurement of insulin production (fasting insulin or C-peptide

with a simultaneous plasma glucose measurement) will assist in making this diagnosis. GADAb are

elevated at 56 U (normal


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CASE 4

A 19-year-old female student with a three-month history of skin infections and a recent Bartholins

abscess feels generally unwell for several weeks with cramps, nausea and dizziness, but no polyuria or

thirst. She has lost approximately 3 kg in weight. There is a family history of diabetes. Urinalysis shows +

ketones and +++ glucose. Arandom blood glucose is 18.7mmol/L. Her BMI is 23 (height 170cm, weight

66.8kg). Ablood sample is sent for GADAb and insulin. Due to her low BMI, weight loss, rapid onset of

symptoms and ketonuria, a presumptive diagnosis of type 1 diabetes is made and she is commenced on

short acting insulin before meals and intermediate acting insulin before bed.

Her antibody result is negative. Re-evaluation of the family history reveals that diabetes has been

inherited in an autosomal dominant fashion through several generations. Her insulin is stopped and she

has perfect glycemic control on a low dose of a sulphonylurea.

Question 1.

Does she have type 1 diabetes?

No, it is more likely that she has maturity onset diabetes of the young (MODY). The clinical syndrome of

MODY has been recognised for some years, but over the past 10 years a number of single gene defects in

beta cell dysfunction have been described. These patients are frequently characterised by onset of mildhyperglycemia at an early age (generally before age 25). These gene defects are generally inherited in an

autosomal dominant pattern. Patients with these forms of diabetes, formerly all referred to as MODY,

have impaired insulin secretion with minimal or no defect in insulin action. Abnormalities at a number of

different genetic loci on different chromosomes have been described. The most common form is

associated with mutations on chromosome 12. At least three different forms of MODY have been

described involving three different chromosomal abnormalities. Point mutations in mitochondrial DNA

have also been found to be associated with diabetes mellitus and deafness. Sensorineural deafness starts

rather early in life and often precedes diabetes mellitus, which emerges at 20-40 years. This form of

diabetes has strict maternal inheritance but male and female children are affected at the same rate. Only a

daughter can transfer the disease to her progeny.

Question 2.Why is it important to recognise these genetically determined forms of diabetes?

These are the first of the genetically characterised forms of diabetes. With time it is likely that many more

genetic types will be determined. Within the different types there are quite marked differences in the

diabetic syndrome. While currently these forms can only be diagnosed in very specialised centres, it is

likely that the technology to assist diagnosis will be increasingly available in the relatively near future and

it is possible that more targeted therapies will become available for these monogenic types of diabetes.

CASE 5

A 66-year-old man presents for his annual review for diabetes complications screening. He has had type 2

diabetes for 17 years and was initially controlled on diet and oral hypoglycemic agents but three years

ago was converted to insulin. Currently he is on Biphasic 30/70 insulin mix 50 units before breakfast and

30 units before his evening meal. His HbA1c is 7.3%. His blood pressure is 130/75. He had a dilated

fundus examination six months ago, which revealed stable background diabetic retinopathy. Examination

of the feet reveals strong pedal pulses; he has reduced sensation to 10 gram monofilament consistent with

a peripheral neuropathy. A urine dipstick examination reveals + glucose, negative urinary protein and

negative ketones.

Question 1.

Should he have any further testing for nephropathy?

Yes, he should have a test for microalbuminuria, despite the negative test for protein. This should be

performed annually with a measurement of albumin excretion rate (AER). This can be done either in a

24 hour urine sample, timed overnight urine collections or by measuring albumin:creatinine ratio (ACR)

in an early morning urine sample. Results are interpreted as below:

Albuminuria AER (ug/min) ACRM F

Normal 35


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Correcti on t o tabl eon previous pageAn error appeared i n t he tabl e on test i ng f o r nephr opat hy The t abl e bel ow i s t he cor r ect ed ver s i on .

Testi ngfor nephropathy

I t shoul d al s o be noted that i n Case 1, Quest i on 1, a f a s t i nggl ucose of greater than or equal t o 7mmol / L or a t wo- hourpost - gl ucose l e ve l of 11 . 1 mmol /L or greater i s di agnost i c ofdi abetes

Al bum nur i a AER( pg/m n) ACRM FNormal 35


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Because of the marked biological variation of the albumin excretion rate, the diagnosis of persistent

microalbuminuria requires serial measurements with at least two out three samples abnormal, as well as

the exclusion of non-specific factors that elevate the rate, such as exercise, poorly controlled hyper-

glycemia, urinary tract infection and cardiac failure.

Question 2.

Why is it important to identify patients with microalbuminuria and how should these patients bemanaged?

Microalbuminuria is an independent risk factor in patients with type 2 diabetes, increasing the risk of

cardiovascular death 3-4 times. Microalbuminuria has an 80% positive predictive value for development

of overt nephropathy in patients with type 1 diabetes. Patients with microalbuminuria are much more

likely to be hypertensive, have hyperlipidemia and an increased risk of ischemic heart disease. These

patients should be specifically targeted for intensive blood glucose, hypertension and lipid control. There

are a number of studies in patients with type 1 diabetes and microalbuminuria demonstrating that ACE

inhibitors reduce the rate of decline in GFR and reduce the albumin excretion rate. The outcomes in type

2 diabetes have been more varied. A recent study, in which 590 hypertensive patients with type 2 diabetes

and microalbuminuria were treated with the angiotensin receptor blocker, irbesartan 150mg, 300mg daily

or placebo, demonstrated reductions of level of urinary albumin by 24%, 38% with 150mg or 300mg

irbesartan compared to 2% with placebo(15)

.The choice between an ACE inhibitor or an angiotensin receptor blocker in patients with

microalbuminuria is uncertain. Both appear to be renoprotective with the largest study being done with

irbesartan. However, it is uncertain if the survival benefit seen with ramipril in the HOPE study also

occurs with angiotensin receptor blockers (16).

References:(1) Dunstan D, Zimmet P, Welborn T, et al on behalf of the AusDiab Steering Committee. Diabesity and associated disorders inAustralia 2000. The accelerating epidemic. Australian diabetes, obesity and lifestyle report, Melbourne: International Diabetes

Institute, 2000

(2) Aiao Q, Keinanen-Kiukaanniemi S, Rajala U, Uusimaki A, Kivela SL. Random capillary whole blood glucose test as a screeningtest for diabetes mellitus in a middle-aged population. Scan J Clin Lab Invest 1995;55:3-8.

(3) Colman PG, Thomas DW, Zimmet PZ, Welbourn TA, Garcia-Webb P, Moore PM. New classification and criteria for diagnosis

of diabetes mellitus. Med J Aust 1999; 170: 375-378.

(4) Davidson MB, Schriger DL, Peters AL, Lorber B. Relationship between fasting plasma glucose and glycosylated hemoglobin.Potential for false-positive diagnoses of type 2 diabetes using new diagnostic criteria. JAMA 1999; 281:1203-11.

(5) Lipid Management Guidelines 2001. Med J Aust 2001; 175 (supplement):S57-S88

(6) Australian Centre for Diabetes Strategies. National evidence based guidelines for the management of type 2 diabetes. Part 3.Evidence based guideline for case detection and diagnosis of type 2 diabetes. Available at www.diabetesaustralia.com.au/docs/Part3-Detection-and-Diagnosis.PDF Last sighted Dec 18,2001

(7) Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or

metformin. New Engl J Med 2002;346:393-403.

(8) Pan Xiao-Ren, Li GW, Hu YH et al. Effects of diet and exercise in preventing diabetes in people with impaired glucose

tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20:537-44.

(9) Tuomilehto J, Lindstrom J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with

impaired glucose tolerance. N Engl J Med 2001; 344:1343-1350.

(10) Turner R et al. (1997). UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction ofinsulin requirement in type 2 diabetes. Lancet 350: 1288-1293.

(11) Humphrey ARG, McCarty DJ, MacKay IR, Rowley MJ, Dwyer T, Zimmet P (1998). Autoantibodies to glutamic aciddecarboxylase and phenotypic features associated with early insulin treatment in individuals with adult onset diabetes mellitus. Diab.Medicine 15:112-119.

(12) Littorin B et. al (1999) Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need forinsulin treatment. Diabetes Care 22:409-412.

(13) The Diabetes Control and Complications Research Group. Effect of intensive insulin therapy on residual cell function inpatients with type 1 diabetes in the diabetes control and complications trial. Ann Intern Med 1998; 113:49-51.

(14) Kobayashi T, Nakanishi K, Murase T, Kosaka K (1996). Small doses of subcutaneous insulin as a strategy for preventingslowly progressive b-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 45:622-626.

(15) Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of

diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870-878.

(16) Heart Outcomes Prevention Evaluation Study Investigators. The Effects of ramipril on cardiovascular and microvascular

outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355:253-259.


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Diabetes Diagnosis and Monitoring, April 2002 Author Peter Colman

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