Criterios Diagnosticos de DM


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Criterios Diagnosticos de DM

  1. 1. P O S I T I O N S T A T E M E N TDiagnosis and Classification of DiabetesMellitus AMERICAN DIABETES ASSOCIATION therefore do not require insulin. Other individuals who have some residual insu- lin secretion but require exogenous insu- lin for adequate glycemic control canDEFINITION AND cardiovascular symptoms and sexual dys- survive without it. Individuals with ex-DESCRIPTION OF DIABETES function. Patients with diabetes have an tensive b-cell destruction and thereforeMELLITUSdDiabetes is a group of increased incidence of atherosclerotic car- no residual insulin secretion require in-metabolic diseases characterized by hy- diovascular, peripheral arterial, and cere- sulin for survival. The severity of the met-perglycemia resulting from defects in in- brovascular disease. Hypertension and abolic abnormality can progress, regress,sulin secretion, insulin action, or both. abnormalities of lipoprotein metabolism or stay the same. Thus, the degree of hy-The chronic hyperglycemia of diabetes is are often found in people with diabetes. perglycemia reflects the severity of theassociated with long-term damage, dys- The vast majority of cases of diabetes underlying metabolic process and itsfunction, and failure of different organs, fall into two broad etiopathogenetic cate- treatment more than the nature of theespecially the eyes, kidneys, nerves, heart, gories (discussed in greater detail below). process itself.and blood vessels. In one category, type 1 diabetes, the cause Several pathogenic processes are in- is an absolute deficiency of insulin secre- CLASSIFICATION OFvolved in the development of diabetes. tion. Individuals at increased risk of de- DIABETES MELLITUS ANDThese range from autoimmune destruc- veloping this type of diabetes can often be OTHER CATEGORIEStion of the b-cells of the pancreas with identified by serological evidence of an OF GLUCOSEconsequent insulin deficiency to abnor- autoimmune pathologic process occurring REGULATIONdAssigning a type ofmalities that result in resistance to insulin in the pancreatic islets and by genetic diabetes to an individual often dependsaction. The basis of the abnormalities in markers. In the other, much more preva- on the circumstances present at the timecarbohydrate, fat, and protein metabo- lent category, type 2 diabetes, the cause is a of diagnosis, and many diabetic individ-lism in diabetes is deficient action of in- combination of resistance to insulin action uals do not easily fit into a single class. Forsulin on target tissues. Deficient insulin and an inadequate compensatory insulin example, a person with gestational di-action results from inadequate insulin se- secretory response. In the latter category, a abetes mellitus (GDM) may continue tocretion and/or diminished tissue respon- degree of hyperglycemia sufficient to cause be hyperglycemic after delivery and mayses to insulin at one or more points in the pathologic and functional changes in var- be determined to have, in fact, type 2complex pathways of hormone action. ious target tissues, but without clinical diabetes. Alternatively, a person whoImpairment of insulin secretion and de- symptoms, may be present for a long acquires diabetes because of large dosesfects in insulin action frequently coexist in period of time before diabetes is detected. of exogenous steroids may become nor-the same patient, and it is often unclear During this asymptomatic period, it is moglycemic once the glucocorticoids arewhich abnormality, if either alone, is the possible to demonstrate an abnormality in discontinued, but then may develop di-primary cause of the hyperglycemia. carbohydrate metabolism by measurement abetes many years later after recurrent Symptoms of marked hyperglycemia in- of plasma glucose in the fasting state or episodes of pancreatitis. Another exampleclude polyuria, polydipsia,weight loss,some- after a challenge with an oral glucose load. would be a person treated with thiazidestimes with polyphagia, and blurred vision. The degree of hyperglycemia (if any) who develops diabetes years later. BecauseImpairment of growth and susceptibility to may change over time, depending on the thiazides in themselves seldom cause severecertain infections may also accompany extent of the underlying disease process hyperglycemia, such individuals probablychronic hyperglycemia. Acute, life-threaten- (Fig. 1). A disease process may be present have type 2 diabetes that is exacerbated bying consequences of uncontrolled diabetes but may not have progressed far enough the drug. Thus, for the clinician and patient,are hyperglycemia with ketoacidosis or the to cause hyperglycemia. The same disease it is less important to label the particularnonketotic hyperosmolar syndrome. process can cause impaired fasting glu- type of diabetes than it is to understand the Long-term complications of diabetes cose (IFG) and/or impaired glucose toler- pathogenesis of the hyperglycemia and toinclude retinopathy with potential loss ance (IGT) without fulfilling the criteria treat it effectively.of vision; nephropathy leading to renal for the diagnosis of diabetes. In some in-failure; peripheral neuropathy with risk dividuals with diabetes, adequate glyce- Type 1 diabetes (b-cell destruction,of foot ulcers, amputations, and Charcot mic control can be achieved with weight usually leading to absolute insulinjoints; and autonomic neuropathy caus- reduction, exercise, and/or oral glucose- deficiency)ing gastrointestinal, genitourinary, and lowering agents. These individuals Immune-mediated diabetes. This form of diabetes, which accounts for onlyc c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c 5–10% of those with diabetes, previouslySection on gestational diabetes diagnosis revised Fall 2010. encompassed by the terms insulin-DOI: 10.2337/dc12-s064© 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly dependent diabetes, type 1 diabetes, or cited, the use is educational and not for profit, and the work is not altered. See juvenile-onset diabetes, results from a cel- licenses/by-nc-nd/3.0/ for details. lular-mediated autoimmune destructionS64 DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012
  2. 2. Position StatementFigure 1dDisorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normo-glycemia without requiring continuous therapy (i.e., “honeymoon” remission); **in rare instances, patients in these categories (e.g., Vacor toxicity,type 1 diabetes presenting in pregnancy) may require insulin for survival.of the b-cells of the pancreas. Markers of C-peptide. Immune-mediated diabetes Type 2 diabetes (ranging fromthe immune destruction of the b-cell in- commonly occurs in childhood and ado- predominantly insulin resistanceclude islet cell autoantibodies, autoanti- lescence, but it can occur at any age, even with relative insulin deficiency tobodies to insulin, autoantibodies to GAD in the 8th and 9th decades of life. predominantly an insulin secretory(GAD65), and autoantibodies to the ty- Autoimmune destruction of b-cells defect with insulin resistance)rosine phosphatases IA-2 and IA-2b. has multiple genetic predispositions and This form of diabetes, which accounts forOne and usually more of these autoanti- is also related to environmental factors ;90–95% of those with diabetes, previ-bodies are present in 85–90% of individ- that are still poorly defined. Although pa- ously referred to as non–insulin-depen-uals when fasting hyperglycemia is tients are rarely obese when they present dent diabetes, type 2 diabetes, or adult-initially detected. Also, the disease has with this type of diabetes, the presence of onset diabetes, encompasses individualsstrong HLA associations, with linkage to obesity is not incompatible with the diag- who have insulin resistance and usuallythe DQA and DQB genes, and it is influ- nosis. These patients are also prone to have relative (rather than absolute) insu-enced by the DRB genes. These HLA-DR/ other autoimmune disorders such as lin deficiency At least initially, and oftenDQ alleles can be either predisposing or Graves’ disease, Hashimoto’s thyroiditis, throughout their lifetime, these individu-protective. Addison’s disease, vitiligo, celiac sprue, als do not need insulin treatment to sur- In this form of diabetes, the rate of autoimmune hepatitis, myasthenia gravis, vive. There are probably many differentb-cell destruction is quite variable, being and pernicious anemia. causes of this form of diabetes. Althoughrapid in some individuals (mainly infants Idiopathic diabetes. Some forms of type the specific etiologies are not known, au-and children) and slow in others (mainly 1 diabetes have no known etiologies. toimmune destruction of b-cells does notadults). Some patients, particularly chil- Some of these patients have permanent occur, and patients do not have any of thedren and adolescents, may present with insulinopenia and are prone to ketoaci- other causes of diabetes listed above orketoacidosis as the first manifestation of dosis, but have no evidence of autoim- below.the disease. Others have modest fasting munity. Although only a minority of Most patients with this form of di-hyperglycemia that can rapidly change patients with type 1 diabetes fall into abetes are obese, and obesity itself causesto severe hyperglycemia and/or ketoaci- this category, of those who do, most are of some degree of insulin resistance. Patientsdosis in the presence of infection or other African or Asian ancestry. Individuals who are not obese by traditional weightstress. Still others, particularly adults, with this form of diabetes suffer from criteria may have an increased percentagemay retain residual b-cell function suffi- episodic ketoacidosis and exhibit varying of body fat distributed predominantly incient to prevent ketoacidosis for many degrees of insulin deficiency between the abdominal region. Ketoacidosis sel-years; such individuals eventually be- episodes. This form of diabetes is strongly dom occurs spontaneously in this type ofcome dependent on insulin for survival inherited, lacks immunological evidence diabetes; when seen, it usually arises inand are at risk for ketoacidosis. At this for b-cell autoimmunity, and is not HLA association with the stress of anotherlatter stage of the disease, there is little associated. An absolute requirement for illness such as infection. This form ofor no insulin secretion, as manifested by insulin replacement therapy in affected diabetes frequently goes undiagnosed forlow or undetectable levels of plasma patients may come and go. many years because the DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012 S65
  3. 3. Diagnosis and Classificationdevelops gradually and at earlier stages is forms result from mutations in other tran- With the exception of that caused byoften not severe enough for the patient to scription factors, including HNF-4a, cancer, damage to the pancreas must benotice any of the classic symptoms of HNF-1b, insulin promoter factor (IPF)- extensive for diabetes to occur; adreno-diabetes. Nevertheless, such patients are 1, and NeuroD1. carcinomas that involve only a smallat increased risk of developing macro- Point mutations in mitochondrial portion of the pancreas have been associ-vascular and microvascular complica- DNA have been found to be associated ated with diabetes. This implies a mech-tions. Whereas patients with this form of with diabetes and deafness The most anism other than simple reduction indiabetes may have insulin levels that common mutation occurs at position b-cell mass. If extensive enough, cystic fi-appear normal or elevated, the higher 3,243 in the tRNA leucine gene, leading brosis and hemochromatosis will alsoblood glucose levels in these diabetic to an A-to-G transition. An identical damage b-cells and impair insulin secre-patients would be expected to result in lesion occurs in the MELAS syndrome tion. Fibrocalculous pancreatopathy mayeven higher insulin values had their b-cell (mitochondrial myopathy, encephalopa- be accompanied by abdominal pain radi-function been normal. Thus, insulin se- thy, lactic acidosis, and stroke-like syn- ating to the back and pancreatic calcifica-cretion is defective in these patients and drome); however, diabetes is not part of tions identified on X-ray examination.insufficient to compensate for insulin re- this syndrome, suggesting different phe- Pancreatic fibrosis and calcium stonessistance. Insulin resistance may improve notypic expressions of this genetic lesion. in the exocrine ducts have been found atwith weight reduction and/or pharmaco- Genetic abnormalities that result in autopsy.logical treatment of hyperglycemia but is the inability to convert proinsulin to in- Endocrinopathies. Several hormonesseldom restored to normal. The risk of sulin have been identified in a few fami- (e.g., growth hormone, cortisol, gluca-developing this form of diabetes increases lies, and such traits are inherited in an gon, epinephrine) antagonize insulin ac-with age, obesity, and lack of physical ac- autosomal dominant pattern. The resul- tion. Excess amounts of these hormonestivity. It occurs more frequently in women tant glucose intolerance is mild. Similarly, (e.g., acromegaly, Cushing’s syndrome,with prior GDM and in individuals with the production of mutant insulin mole- glucagonoma, pheochromocytoma, re-hypertension or dyslipidemia, and its fre- cules with resultant impaired receptor spectively) can cause diabetes. This gen-quency varies in different racial/ethnic sub- binding has also been identified in a few erally occurs in individuals withgroups. It is often associated with a strong families and is associated with an autoso- preexisting defects in insulin secretion,genetic predisposition, more so than is the mal inheritance and only mildly impaired and hyperglycemia typically resolvesautoimmune form of type 1 diabetes. How- or even normal glucose metabolism. when the hormone excess is resolved.ever, the genetics of this form of diabetes Genetic defects in insulin action. There Somatostatinoma- and aldostero-are complex and not clearly defined. are unusual causes of diabetes that result noma-induced hypokalemia can cause from genetically determined abnormali- diabetes, at least in part, by inhibitingOther specific types of diabetes ties of insulin action. The metabolic ab- insulin secretion. Hyperglycemia gener-Genetic defects of the b-cell. Several normalities associated with mutations of ally resolves after successful removal offorms of diabetes are associated with the insulin receptor may range from the tumor.monogenetic defects in b-cell function. hyperinsulinemia and modest hyperglyce- Drug- or chemical-induced diabetes.These forms of diabetes are frequently mia to severe diabetes. Some individuals Many drugs can impair insulin secretion.characterized by onset of hyperglycemia with these mutations may have acanthosis These drugs may not cause diabetes byat an early age (generally before age 25 nigricans. Women may be virilized and themselves, but they may precipitate di-years). They are referred to as maturity- have enlarged, cystic ovaries. In the past, abetes in individuals with insulin resis-onset diabetes of the young (MODY) and this syndrome was termed type A insulin tance. In such cases, the classification isare characterized by impaired insulin se- resistance. Leprechaunism and the Rabson- unclear because the sequence or relativecretion with minimal or no defects in in- Mendenhall syndrome are two pediatric importance of b-cell dysfunction and in-sulin action. They are inherited in an syndromes that have mutations in the sulin resistance is unknown. Certain tox-autosomal dominant pattern. Abnormali- insulin receptor gene with subsequent ins such as Vacor (a rat poison) andties at six genetic loci on different chro- alterations in insulin receptor function intravenous pentamidine can perma-mosomes have been identified to date. and extreme insulin resistance. The former nently destroy pancreatic b-cells. SuchThe most common form is associated has characteristic facial features and is drug reactions fortunately are rare. Therewith mutations on chromosome 12 in a usually fatal in infancy, while the latter is are also many drugs and hormones thathepatic transcription factor referred to as associated with abnormalities of teeth and can impair insulin action. Examples in-hepatocyte nuclear factor (HNF)-1a. A nails and pineal gland hyperplasia. clude nicotinic acid and glucocorticoids.second form is associated with mutations Alterations in the structure and func- Patients receiving a-interferon have beenin the glucokinase gene on chromosome tion of the insulin receptor cannot be reported to develop diabetes associated7p and results in a defective glucokinase demonstrated in patients with insulin- with islet cell antibodies and, in certainmolecule. Glucokinase converts glucose resistant lipoatrophic diabetes. Therefore, instances, severe insulin deficiency. Theto glucose-6-phosphate, the metabolism it is assumed that the lesion(s) must reside list shown in Table 1 is not all-inclusive,of which, in turn, stimulates insulin secre- in the postreceptor signal transduction but reflects the more commonly recog-tion by the b-cell. Thus, glucokinase pathways. nized drug-, hormone-, or toxin-inducedserves as the “glucose sensor” for the Diseases of the exocrine pancreas. Any forms of diabetes.b-cell. Because of defects in the glucoki- process that diffusely injures the pancreas Infections. Certain viruses have beennase gene, increased plasma levels of glu- can cause diabetes. Acquired processes associated with b-cell destruction. Diabe-cose are necessary to elicit normal levels include pancreatitis, trauma, infection, pan- tes occurs in patients with congenital ru-of insulin secretion. The less common createctomy, and pancreatic carcinoma. bella, although most of these patientsS66 DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012
  4. 4. Position StatementTable 1dEtiologic classification of diabetes mellitus have HLA and immune markers charac- teristic of type 1 diabetes. In addition,I. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deficiency) A. Immune mediated coxsackievirus B, cytomegalovirus, ade- B. Idiopathic novirus, and mumps have been impli-II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency cated in inducing certain cases of the to a predominantly secretory defect with insulin resistance) disease.III. Other specific types A. Genetic defects of b-cell function Uncommon forms of immune-mediated 1. Chromosome 12, HNF-1a (MODY3) diabetes. In this category, there are two 2. Chromosome 7, glucokinase (MODY2) known conditions, and others are likely 3. Chromosome 20, HNF-4a (MODY1) to occur. The stiff-man syndrome is an 4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) autoimmune disorder of the central ner- 5. Chromosome 17, HNF-1b (MODY5) 6. Chromosome 2, NeuroD1 (MODY6) vous system characterized by stiffness of 7. Mitochondrial DNA the axial muscles with painful spasms. 8. Others Patients usually have high titers of the B. Genetic defects in insulin action GAD autoantibodies, and approximately 1. Type A insulin resistance 2. Leprechaunism one-third will develop diabetes. 3. Rabson-Mendenhall syndrome Anti-insulin receptor antibodies can 4. Lipoatrophic diabetes cause diabetes by binding to the insulin 5. Others receptor, thereby blocking the binding of C. Diseases of the exocrine pancreas insulin to its receptor in target tissues. 1. Pancreatitis 2. Trauma/pancreatectomy However, in some cases, these antibodies 3. Neoplasia can act as an insulin agonist after binding 4. Cystic fibrosis to the receptor and can thereby cause 5. Hemochromatosis hypoglycemia. Anti-insulin receptor anti- 6. Fibrocalculous pancreatopathy 7. Others bodies are occasionally found in patients D. Endocrinopathies with systemic lupus erythematosus and 1. Acromegaly other autoimmune diseases. As in other 2. Cushing’s syndrome states of extreme insulin resistance, pa- 3. Glucagonoma tients with anti-insulin receptor antibod- 4. Pheochromocytoma 5. Hyperthyroidism ies often have acanthosis nigricans. In the 6. Somatostatinoma past, this syndrome was termed type B 7. Aldosteronoma insulin resistance. 8. Others Other genetic syndromes sometimes E. Drug or chemical induced 1. Vacor associated with diabetes. Many genetic 2. Pentamidine syndromes are accompanied by an in- 3. Nicotinic acid creased incidence of diabetes. These in- 4. Glucocorticoids clude the chromosomal abnormalities of 5. Thyroid hormone Down syndrome, Klinefelter syndrome, 6. Diazoxide 7. b-adrenergic agonists and Turner syndrome. Wolfram’s syn- 8. Thiazides drome is an autosomal recessive disorder 9. Dilantin characterized by insulin-deficient diabe- 10. g-Interferon tes and the absence of b-cells at autopsy. 11. Others F. Infections Additional manifestations include diabetes 1. Congenital rubella insipidus, hypogonadism, optic atrophy, 2. Cytomegalovirus and neural deafness. Other syndromes are 3. Others listed in Table 1. G. Uncommon forms of immune-mediated diabetes 1. “Stiff-man” syndrome 2. Anti-insulin receptor antibodies Gestational diabetes mellitus 3. Others For many years, GDM has been defined as H. Other genetic syndromes sometimes associated with diabetes any degree of glucose intolerance with 1. Down syndrome onset or first recognition during preg- 2. Klinefelter syndrome 3. Turner syndrome nancy. Although most cases resolve with 4. Wolfram syndrome delivery, the definition applied whether 5. Friedreich ataxia or not the condition persisted after preg- 6. Huntington chorea nancy and did not exclude the possibility 7. Laurence-Moon-Biedl syndrome that unrecognized glucose intolerance 8. Myotonic dystrophy 9. Porphyria may have antedated or begun concomi- 10. Prader-Willi syndrome tantly with the pregnancy. This definition 11. Others facilitated a uniform strategy for detectionIV. Gestational diabetes mellitus and classification of GDM, but its limi-Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of tations were recognized for many years.insulin does not, of itself, classify the patient. As the ongoing epidemic of obesity DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012 S67
  5. 5. Diagnosis and ClassificationTable 2dCategories of increased risk for abdominal or visceral obesity), dyslipide- communication). Finally, evidence fromdiabetes* mia with high triglycerides and/or low the Diabetes Prevention Program (DPP),FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 HDL cholesterol, and hypertension. wherein the mean A1C was 5.9% (SD mmol/l) [IFG] Structured lifestyle intervention, aimed 0.5%), indicates that preventive interven-2-h PG in the 75-g OGTT 140 mg/dl (7.8 at increasing physical activity and pro- tions are effective in groups of people with mmol/l) to 199 mg/dl (11.0 mmol/l) [IGT] ducing 5–10% loss of body weight, and A1C levels both below and above 5.9%A1C 5.7–6.4% certain pharmacological agents have been (9). For these reasons, the most appropri- demonstrated to prevent or delay the de- ate A1C level above which to initiate pre-*For all three tests, risk is continuous, extendingbelow the lower limit of the range and becoming velopment of diabetes in people with IGT; ventive interventions is likely to bedisproportionately greater at higher ends of the the potential impact of such interventions somewhere in the range of 5.5–6%.range. to reduce mortality or the incidence of As was the case with FPG and 2-h PG, cardiovascular disease has not been dem- defining a lower limit of an intermediate onstrated to date. It should be noted that category of A1C is somewhat arbitrary,diabetes has led to more type 2 diabetes in the 2003 ADA Expert Committee report as the risk of diabetes with any measurewomen of childbearing age, the number of reduced the lower FPG cut point to define or surrogate of glycemia is a continuum,pregnant women with undiagnosed type 2 IFG from 110 mg/dl (6.1 mmol/l) to 100 extending well into the normal ranges. Todiabetes has increased. mg/dl (5.6 mmol/l), in part to ensure that maximize equity and efficiency of pre- After deliberations in 2008–2009, the prevalence of IFG was similar to that of ventive interventions, such an A1C cutInternational Association of Diabetes and IGT. However, the World Health Organi- point should balance the costs of “falsePregnancy Study Groups (IADPSG), an zation (WHO) and many other diabetes negatives” (failing to identify those whointernational consensus group with rep- organizations did not adopt this change in are going to develop diabetes) againstresentatives from multiple obstetrical and the definition of IFG. the costs of “false positives” (falsely iden-diabetes organizations, including the As A1C is used more commonly to tifying and then spending intervention re-American Diabetes Association (ADA), diagnose diabetes in individuals with risk sources on those who were not going torecommended that high-risk women factors, it will also identify those at higher develop diabetes anyway).found to have diabetes at their initial pre- risk for developing diabetes in the future. Compared to the fasting glucose cut-natal visit, using standard criteria (Table When recommending the use of the A1C point of 100 mg/dl (5.6 mmol/l), an A1C3), receive a diagnosis of overt, not gesta- to diagnose diabetes in its 2009 report, cutpoint of 5.7% is less sensitive but moretional, diabetes. Approximately 7% of all the International Expert Committee (3) specific and has a higher positive predic-pregnancies (ranging from 1 to 14%, de- stressed the continuum of risk for diabe- tive value to identify people at risk forpending on the population studied and tes with all glycemic measures and did not later development of diabetes. A largethe diagnostic tests employed) are com- formally identify an equivalent intermedi- prospective study found that a 5.7% cut-plicated by GDM, resulting in more than ate category for A1C. The group did note point has a sensitivity of 66% and speci-200,000 cases annually. that those with A1C levels above the lab- ficity of 88% for the identification of oratory “normal” range but below the di- subsequent 6-year diabetes incidenceCATEGORIES OF INCREASED agnostic cut point for diabetes (6.0 to (10). Receiver operating curve analysesRISK FOR DIABETESdIn 1997 and ,6.5%) are at very high risk of develop- of nationally representative U.S. data2003, The Expert Committee on Diagno- ing diabetes. Indeed, incidence of diabe- (NHANES 1999-2006) indicate that ansis and Classification of Diabetes Mellitus tes in people with A1C levels in this range A1C value of 5.7% has modest sensitivity(1,2) recognized an intermediate group of is more than 10 times that of people with (39-45%) but high specificity (81-91%)individuals whose glucose levels do not lower levels (4–7). However, the 6.0 to to identify cases of IFP (FPG .100 mg/meet criteria for diabetes, yet are higher ,6.5% range fails to identify a substantial dl) (5.6 mmol/l) or IGT (2-h glucose .than those considered normal. These peo- number of patients who have IFG and/or 140 mg/dl) (R.T. Ackerman, personalple were defined as having impaired fast- IGT. Prospective studies indicate that communication). Other analyses suggesting glucose (IFG) [fasting plasma glucose people within the A1C range of 5.5– that an A1C of 5.7% is associated with(FPG) levels 100 mg/dl (5.6 mmol/l) to 6.0% have a 5-year cumulative incidence diabetes risk similar to the high-risk par-125 mg/dl (6.9 mmol/l)], or impaired glu- of diabetes that ranges from 12 to 25% ticipants in the DPP (R.T. Ackerman, per-cose tolerance (IGT) [2-h values in the (4–7), which is appreciably (three- to sonal communication). Hence, it isoral glucose tolerance test (OGTT) of eightfold) higher than incidence in the reasonable to consider an A1C range of140 mg/dl (7.8 mmol/l) to 199 mg/dl U.S. population as a whole (8). Analyses 5.7 to 6.4% as identifying individuals(11.0 mmol/l)]. of nationally representative data from the with high risk for future diabetes and to Individuals with IFG and/or IGT have National Health and Nutrition Examina- whom the term pre-diabetes may be ap-been referred to as having pre-diabetes, tion Survey (NHANES) indicate that the plied if desired.indicating the relatively high risk for the A1C value that most accurately identifies Individuals with an A1C of 5.7–6.4%future development of diabetes. IFG and people with IFG or IGT falls between 5.5 should be informed of their increased riskIGT should not be viewed as clinical and 6.0%. In addition, linear regression for diabetes as well as cardiovascular dis-entities in their own right but rather risk analyses of these data indicate that among ease and counseled about effective strate-factors for diabetes as well as cardiovas- the nondiabetic adult population, an FPG gies, such as weight loss and physicalcular disease. They can be observed as of 110 mg/dl (6.1 mmol/l) corresponds activity, to lower their risks. As with glu-intermediate stages in any of the disease to an A1C of 5.6%, while an FPG of 100 cose measurements, the continuum of riskprocesses listed in Table 1. IFG and IGT mg/dl (5.6 mmol/l) corresponds to an is curvilinear, so that as A1C rises, the riskare associated with obesity (especially A1C of 5.4% (R.T. Ackerman, personal of diabetes rises disproportionately.S68 DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012
  6. 6. Position StatementAccordingly, interventions should be Table 3dCriteria for the diagnosis of diabetesmost intensive and follow-up should be A1C $6.5%. The test should be performed in a laboratory using a method that is NGSP certifiedparticularly vigilant for those with A1C and standardized to the DCCT assay.*levels above 6.0%, who should be consid- ORered to be at very high risk. However, just FPG $126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*as an individual with a fasting glucose of OR98 mg/dl (5.4 mmol/l) may not be at neg- 2-h plasma glucose $200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed asligible risk for diabetes, individuals with described by the World Health Organization, using a glucose load containing the equivalent ofA1C levels below 5.7% may still be at 75 g anhydrous glucose dissolved in water.*risk, depending on level of A1C and pres- ORence of other risk factors, such as obesity In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasmaand family history. glucose $200 mg/dl (11.1 mmol/l). Table 2 summarizes the categories of *In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.increased risk for diabetes. Evaluation ofpatients at risk should incorporate aglobal risk factor assessment for both di- microvascular and, to a lesser extent, glucose in certain individuals. In addi-abetes and cardiovascular disease. Screen- macrovascular complications and is tion, the A1C can be misleading in pa-ing for and counseling about risk of widely used as the standard biomarker tients with certain forms of anemia anddiabetes should always be in the prag- for the adequacy of glycemic manage- hemoglobinopathies, which may alsomatic context of the patient’s comorbidi- ment. Prior Expert Committees have not have unique ethnic or geographic distri-ties, life expectancy, personal capacity to recommended use of the A1C for diag- butions. For patients with a hemoglobin-engage in lifestyle change, and overall nosis of diabetes, in part due to lack of opathy but normal red cell turnover, suchhealth goals. standardization of the assay. However, as sickle cell trait, an A1C assay without A1C assays are now highly standardized interference from abnormal hemoglobinsDIAGNOSTIC CRITERIA FOR so that their results can be uniformly should be used (an updated list is avail-DIABETES MELLITUSdFor deca- applied both temporally and across pop- able at, the diagnosis of diabetes has been ulations. In their recent report (3), an In- html). For conditions with abnormal redbased on glucose criteria, either the FPG ternational Expert Committee, after an cell turnover, such as anemias from he-or the 75-g OGTT. In 1997, the first extensive review of both established and molysis and iron deficiency, the diagnosisExpert Committee on the Diagnosis and emerging epidemiological evidence, rec- of diabetes must employ glucose criteriaClassification of Diabetes Mellitus revised ommended the use of the A1C test to di- exclusively.the diagnostic criteria, using the observed agnose diabetes, with a threshold of The established glucose criteria forassociation between FPG levels and pres- $6.5%, and ADA affirms this decision. the diagnosis of diabetes remain valid.ence of retinopathy as the key factor with The diagnostic A1C cut point of 6.5% is These include the FPG and 2-h PG.which to identify threshold glucose level. associated with an inflection point for ret- Additionally, patients with severe hyper-The Committee examined data from three inopathy prevalence, as are the diagnostic glycemia such as those who present withcross-sectional epidemiologic studies that thresholds for FPG and 2-h PG (3). The severe classic hyperglycemic symptomsassessed retinopathy with fundus pho- diagnostic test should be performed or hyperglycemic crisis can continue to betography or direct ophthalmoscopy and using a method that is certified by the Na- diagnosed when a random (or casual)measured glycemia as FPG, 2-h PG, and tional Glycohemoglobin Standardization plasma glucose of $200 mg/dl (11.1A1C. These studies demonstrated glyce- Program (NGSP) and standardized or mmol/l) is found. It is likely that in suchmic levels below which there was little traceable to the Diabetes Control and cases the health care professional wouldprevalent retinopathy and above which Complications Trial reference assay. also measure an A1C test as part of thethe prevalence of retinopathy increased in Point-of-care A1C assays are not suffi- initial assessment of the severity of the di-an apparently linear fashion. The deciles ciently accurate at this time to use for di- abetes and that it would (in most cases) beof the three measures at which retinopa- agnostic purposes. above the diagnostic cut point for diabe-thy began to increase were the same for There is an inherent logic to using a tes. However, in rapidly evolving diabe-each measure within each population. more chronic versus an acute marker of tes, such as the development of type 1Moreover, the glycemic values above dysglycemia, particularly since the A1C is diabetes in some children, A1C may notwhich retinopathy increased were similar already widely familiar to clinicians as a be significantly elevated despite frankamong the populations. These analyses marker of glycemic control. Moreover, diabetes.helped to inform a new diagnostic cut the A1C has several advantages to the Just as there is less than 100% con-point of $126 mg/dl (7.0 mmol/l) for FPG, including greater convenience, cordance between the FPG and 2-h PGFPG and confirmed the long-standing di- since fasting is not required, evidence to tests, there is not full concordance be-agnostic 2-h PG value of $200 mg/dl suggest greater preanalytical stability, and tween A1C and either glucose-based(11.1 mmol/l). less day-to-day perturbations during pe- test. Analyses of NHANES data indicate A1C is a widely used marker of riods of stress and illness. These advan- that, assuming universal screening of thechronic glycemia, reflecting average tages, however, must be balanced by undiagnosed, the A1C cut point ofblood glucose levels over a 2- to 3-month greater cost, the limited availability of $6.5% identifies one-third fewer casesperiod of time. The test plays a critical role A1C testing in certain regions of the of undiagnosed diabetes than a fastingin the management of the patient with developing world, and the incomplete glucose cut point of $126 mg/dl (7.0diabetes, since it correlates well with both correlation between A1C and average mmol/l) (cdc website tbd). However, DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012 S69
  7. 7. Diagnosis and Classificationpractice, a large portion of the population that when a test whose result was above Table 4dScreening for and diagnosis ofwith type 2 diabetes remains unaware of the diagnostic threshold is repeated, the GDMtheir condition. Thus, it is conceivable second value will be below the diagnostic Perform a 75-g OGTT, with plasma glucosethat the lower sensitivity of A1C at the cut point. This is least likely for A1C, measurement fasting and at 1 and 2 h, atdesignated cut point will be offset by the somewhat more likely for FPG, and most 24-28 of weeks gestation in women nottest’s greater practicality, and that wider likely for the 2-h PG. Barring a laboratory previously diagnosed with overt diabetes.application of a more convenient test error, such patients are likely to have test The OGTT should be performed in the(A1C) may actually increase the number results near the margins of the threshold morning after an overnight fast of at leastof diagnoses made. for a diagnosis. The healthcare profes- 8 h. Further research is needed to better sional might opt to follow the patient The diagnosis of GDM is made when any of thecharacterize those patients whose glyce- closely and repeat the testing in 3–6 following plasma glucose values aremic status might be categorized differ- months. exceededently by two different tests (e.g., FPG and The decision about which test to use c Fasting: $92 mg/dl (5.1 mmol/l)A1C), obtained in close temporal approx- to assess a specific patient for diabetes c 1 h: $180 mg/dl (10.0 mmol/l)imation. Such discordance may arise from should be at the discretion of the health c 2 h: $153 mg/dl (8.5 mmol/l)measurement variability, change over care professional, taking into account thetime, or because A1C, FPG, and post- availability and practicality of testing anchallenge glucose each measure different individual patient or groups of patients.physiological processes. In the setting of Perhaps more important than which di- These new criteria will significantlyan elevated A1C but “nondiabetic” FPG, agnostic test is used, is that the testing for increase the prevalence of GDM, primar-the likelihood of greater postprandial glu- diabetes be performed when indicated. ily because only one abnormal value, notcose levels or increased glycation rates There is discouraging evidence indicating two, is sufficient to make the diagnosis.for a given degree of hyperglycemia may that many at-risk patients still do not re- The ADA recognizes the anticipated sig-be present. In the opposite scenario (high ceive adequate testing and counseling for nificant increase in the incidence of GDMFPG yet A1C below the diabetes cut this increasingly common disease, or for its to be diagnosed by these criteria and ispoint), augmented hepatic glucose pro- frequently accompanying cardiovascular sensitive to concerns about the “medical-duction or reduced glycation rates may risk factors. The current diagnostic criteria ization” of pregnancies previously catego-be present. for diabetes are summarized in Table 3. rized as normal. These diagnostic criteria As with most diagnostic tests, a test changes are being made in the context ofresult diagnostic of diabetes should be Diagnosis of gestational diabetes worrisome worldwide increases in obe-repeated to rule out laboratory error, GDM carries risks for the mother and sity and diabetes rates, with the intent ofunless the diagnosis is clear on clinical neonate. The Hyperglycemia and Adverse optimizing gestational outcomes forgrounds, such as a patient with classic Pregnancy Outcomes (HAPO) study women and their babies.symptoms of hyperglycemia or hypergly- (11), a large-scale (;25,000 pregnant Admittedly, there are few data fromcemic crisis. It is preferable that the same women) multinational epidemiologic randomized clinical trials regarding ther-test be repeated for confirmation, since study, demonstrated that risk of adverse apeutic interventions in women who willthere will be a greater likelihood of con- maternal, fetal, and neonatal outcomes now be diagnosed with GDM based oncurrence in this case. For example, if the continuously increased as a function of only one blood glucose value above theA1C is 7.0% and a repeat result is 6.8%, maternal glycemia at 24-28 weeks, even specified cutpoints (in contrast to thethe diagnosis of diabetes is confirmed. within ranges previously considered nor- older criteria that stipulated at least twoHowever, there are scenarios in which re- mal for pregnancy. For most complica- abnormal values). Expected benefits tosults of two different tests (e.g., FPG and tions, there was no threshold for risk. their pregnancies and offspring is inferredA1C) are available for the same patient. In These results have led to careful reconsid- from intervention trials that focused onthis situation, if the two different tests are eration of the diagnostic criteria for GDM. women with more mild hyperglycemiaboth above the diagnostic thresholds, the After deliberations in 2008-2009, the than identified using older GDM diag-diagnosis of diabetes is confirmed. IADPSG, an international consensus nostic criteria and that found modest On the other hand, when two differ- group with representatives from multiple benefits (13,14). The frequency of theirent tests are available in an individual and obstetrical and diabetes organizations, in- follow-up and blood glucose monitoringthe results are discordant, the test whose cluding ADA, developed revised recom- is not yet clear but likely to be less inten-result is above the diagnostic cut point mendations for diagnosing GDM. The sive than women diagnosed by the oldershould be repeated, and the diagnosis is group recommended that all women not criteria. Additional well-designed clinicalmade on the basis of the confirmed test. known to have diabetes undergo a 75-g studies are needed to determine the op-That is, if a patient meets the diabetes OGTT at 24-28 weeks of gestation. Addi- timal intensity of monitoring and treat-criterion of the A1C (two results $6.5%) tionally, the group developed diagnostic ment of women with GDM diagnosedbut not the FPG (,126 mg/dl or 7.0 cutpoints for the fasting, 1-h, and 2-h by the new criteria (that would notmmol/l), or vice versa, that person should plasma glucose measurements that con- have met the prior definition of GDM).be considered to have diabetes. Admit- veyed an odds ratio for adverse outcomes It is important to note that 80-90% oftedly, in most circumstance the “nondia- of at least 1.75 compared with women women in both of the mild GDM studiesbetic” test is likely to be in a range very with mean glucose levels in the HAPO (whose glucose values overlapped withclose to the threshold that defines diabetes. study. Current screening and diagnostic the thresholds recommended herein) Since there is preanalytic and analytic strategies, based on the IADPSG state- could be managed with lifestyle therapyvariability of all the tests, it is also possible ment (12), are outlined in Table 4. alone.S70 DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012
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