低血糖诊断与治疗：内分泌学会临床指南 JCEM

Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline Philip E. Cryer, Lloyd Axelrod, Ashley B. Grossman, Simon R. Heller, Victor M. Montori, Elizabeth R. Seaquist, and F. John Service Washington University School of Medicine (P.E.C.), St. Louis, Missouri 63110; Massachusetts General Hospital and Harvard Medical School (L.A.), Boston, Massachusetts 02114; Barts and the London School of Medicine, Queen Mary University of London (A.B.G.), London E1 2AD, United Kingdom; University of Sheffield (S.R.H.), Sheffield S10 2TN, United Kingdom; University of Minnesota (E.R.S.), Minneapolis, Minnesota 55455; and Mayo Clinic (V.M.M., F.J.S.), Rochester, Minnesota 55905 Objective: The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus. Evidence: Using the recommendations of the Grading of Recommendations, Assessment, Devel- opment and Evaluation (GRADE) system, the quality of evidence is graded very low (QEEE), low (QQEE), moderate (QQQE), or high (QQQQ). Conclusions:We recommend evaluation and management of hypoglycemia only in patients in whomWhipple’s triad—symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented. In patients with hypoglycemia without diabetes mel- litus, we recommend the following strategy. First, pursue clinical clues to potential hypogly- cemic etiologies—drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having en- dogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, �-hydroxy- butyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction—addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations—in persons with diabetes. (J Clin Endocrinol Metab 94: 709–728, 2009) Summary of Recommendations 1.0 Workup for a hypoglycemic disorder 1.1We recommend evaluation andmanagement of hypoglyce- miaonly inpatients inwhomWhipple’s triad—symptoms, signs,or both consistent with hypoglycemia, a low plasma glucose concen- tration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented (1QQQQ). 2.0 Evaluation and management of hypoglycemia in persons without diabetes mellitus 2.1 Compared with a much less thorough workup, we rec- ommend the following strategy in patients with hypoglycemia without diabetes mellitus (1QQQE): • Review the history, physical findings, and all available laboratory data seeking clues to specific disorders—drugs, ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/jc.2008-1410 Received July 2, 2008. Accepted December 8, 2008. First Published Online December 16, 2008 Abbreviations: CSII, Continuous sc insulin infusion; HAAF, hypoglycemia-associated au- tonomic failure; HbA1C, hemoglobin A1C; MDI, multiple daily insulin injection; MEN-1, multiple endocrine neoplasia, type 1; MRI, magnetic resonance imaging; NIPHS, nonin- sulinoma pancreatogenous hypoglycemia syndrome; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. S P E C I A L F E A T U R E C l i n i c a l P r a c t i c e G u i d e l i n e J Clin Endocrinol Metab, March 2009, 94(3):709–728 jcem.endojournals.org 709 by Xiaohui Yu on March 30, 2009 jcem.endojournals.orgDownloaded from critical illnesses, hormone deficiencies, nonislet cell tumors. • When the cause of the hypoglycemic disorder is not evident, i.e. in a seemingly well individual, measure plasma glucose, insulin, C-peptide, proinsulin, and �-hydroxybutyrate con- centrations and screen for oral hypoglycemic agents, during an episode of spontaneous hypoglycemia, and observe the plasma glucose response to iv injection of 1.0 mg glucagon. These steps will distinguish hypoglycemia caused by endog- enous (or exogenous) insulin from that caused by othermech- anisms. Also, measure insulin antibodies. • When a spontaneous hypoglycemic episode cannot be ob- served, formally recreate the circumstances in which symp- tomatic hypoglycemia is likely to occur, i.e. during a fast of up to72hor after amixedmeal.The findings of symptoms, signs, or both with plasma concentrations of glucose less than 55 mg/dl (3.0mmol/liter), insulin of at least 3.0�U/ml (18 pmol/ liter), C-peptide of at least 0.6 ng/ml (0.2 nmol/liter), and proinsulin of at least 5.0 pmol/liter document endogenous hyperinsulinism; �-hydroxybutyrate levels of 2.7 mmol/liter or less and an increase in plasma glucose of at least 25 mg/dl (1.4 mmol/liter) after iv glucagon indicate mediation of the hypoglycemia by insulin (or by an IGF). • In a patient with documented fasting or postprandial endog- enous hyperinsulinemic hypoglycemia, negative screening for oral hypoglycemic agents, and no circulating insulin antibod- ies, conduct procedures for localizing an insulinoma. These may include computed tomography or magnetic resonance imaging (MRI), transabdominal and endoscopic ultrasonog- raphy, and, if necessary, selective pancreatic arterial calcium injectionswithmeasurements of hepatic venous insulin levels. • Tailor treatment to the specific hypoglycemic disorder, taking into account the burden of hypoglycemia on patient well- being and patient preferences. 3.0 Evaluation and management of hypoglycemia in persons with diabetes mellitus 3.1We suggest that persons with diabetes become concerned about the possibility of developing hypoglycemia when the self- monitored blood glucose concentration is falling rapidly or is no greater than 70 mg/dl (3.9 mmol/liter) (2QEEE). 3.2Given the established long-termmicrovascular benefits of glycemic control, we recommend that the therapeutic gly- cemic goal be the lowest mean glycemia [e.g. hemoglobin A1c (HbA1C)] that can be accomplished safely in a given patient at a given point in the progression of that individual patient’s diabetes (1QQQQ). 3.3 We recommend that the prevention of hypoglycemia in diabetes involve addressing the issue in each patient contact and, if hypoglycemia is a problem,making adjustments in the regimen based on review and application of the principles of intensive glycemic therapy—diabetes self-management (supported by ed- ucation and empowerment), frequent self-monitoring of blood glucose, flexible and appropriate insulin or insulin secretagogue regimens, individualized glycemic goals, and ongoing profes- sional guidance and support—and consideration of each of the known risk factors for hypoglycemia (1QQQE). 3.4 We recommend that both the conventional risk factors and those indicative of compromised defenses against hypogly- cemia be considered in a patient with recurrent treatment-in- duced hypoglycemia (1QQQQ). The conventional risk factors are excessive or ill-timed dosing of, or wrong type of, insulin or insulin secretagogue and conditions underwhich exogenous glu- cose delivery or endogenous glucose production is decreased, glucose utilization is increased, sensitivity to insulin is increased, or insulin clearance is decreased. Compromised defenses against hypoglycemia are indicated by the degree of endogenous insulin deficiency, a history of severe hypoglycemia, hypoglycemia un- awareness, or both as well as recent antecedent hypoglycemia, prior exercise or sleep, and lower glycemic goals per se. 3.5 With a history of hypoglycemia unawareness (i.e. recur- rent hypoglycemia without symptoms), we recommend a 2- to 3-wk period of scrupulous avoidance of hypoglycemia, with the anticipation that awareness of hypoglycemiawill return inmany patients (1QQEE). 3.6Unless the cause is easily remediable,we recommend that an episode of severe hypoglycemia should lead to a fundamental re- view of the treatment regimen and the glycemic goals (1QQQQ). 3.7 We recommend that urgent treatment of hypoglycemia should be accomplished by ingestion of carbohydrates if that is feasible, or by parenteral glucagon or glucose if it is not feasible (1QQQQ). Method of Development of Evidence-Based Recommendations The Task Force followed the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation system (1) with guidance from the methodologist (V.M.M.).Adetaileddescriptionof this grading schemehasbeen published (2). In brief, strong recommendations use the phrase “we recommend” and the number 1, and weak recommenda- tions use the phrase “we suggest” and the number 2. The Task Force has confidence that patients who receive care according to the recommendations will derive, on average, more good than harm. Suggestions require more careful consideration of the pa- tient’s circumstances, values, andpreferences.Cross-filled circles (Q) indicate the quality of the evidence:QEEE denotes very low quality evidence;QQEE, low quality;QQQE, moderate quality; and QQQQ, high quality. The quality of the evidence indicates the panel’s confidence that the estimates of risks and benefits associated with the recommended course of action compared with an alternative course of action are correct and unlikely to change importantly with new research. Linked to each recommendation is a description of the Evi- dence, the Values that panelists considered in making the rec- ommendation (when making these explicit was necessary), and Remarks, a section inwhich panelists offer technical suggestions for testing conditions. The latter come from the unsystematic observations of the panelists and should, therefore, be consid- ered suggestions. 710 Cryer et al. Evaluation and Management of Adult Hypoglycemia J Clin Endocrinol Metab, March 2009, 94(3):709–728 by Xiaohui Yu on March 30, 2009 jcem.endojournals.orgDownloaded from 1.0 Workup for a Hypoglycemic Disorder Recommendation 1.1We recommend evaluation and management of hypogly- cemia only in patients in whom Whipple’s triad—symptoms, signs, or both consistent with hypoglycemia, a low plasma glu- cose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented (1QQQQ). 1.1 Evidence Clinical hypoglycemia is a plasma (or serum) glucose con- centration low enough to cause symptoms and/or signs, includ- ing impairment of brain function. The clinical manifestations of hypoglycemia are nonspecific, it is not possible to state a single plasma glucose concentration that categorically defines hypo- glycemia, and a lowmeasured plasma glucose concentration can be artifactual. Therefore, hypoglycemia is confirmed by docu- mentation of Whipple’s triad (3): symptoms, signs, or both con- sistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentrationisraised. IntheabsenceofWhipple’s triad, thepatient may be exposed to unnecessary evaluation, costs, and potential harms, without expectation of benefit. This very large potentially beneficial effect of documenting Whipple’s triad upgrades the evi- dence (based on consistent clinical observations), thus supporting a rating of high quality. (A rare exception would be a patient who is physically unable to communicate symptoms.) Symptoms of hypoglycemia are categorized as neuroglyco- penic (the result of brain glucose deprivation per se) and neuro- genic or autonomic (largely the result of the perception of phys- iological changes caused by the sympathoadrenal discharge triggered by hypoglycemia) (4). Awareness of hypoglycemia is mainly the result of the perception of neurogenic symptoms (4), which are largely sympathetic neural, rather than adrenomed- ullary, in origin (5). Some neurogenic symptoms, such as palpi- tations, tremor, and arousal/anxiety, are adrenergic whereas others, such as sweating, hunger, and paresthesias, are cholin- ergic (4). Neuroglycopenic symptoms (4) range from behavioral changes, fatigue, and confusion to seizure and loss of conscious- ness, i.e. functional brain failure (6). Seemingly complete recov- ery after the glucose level is raised is the rule, although on rare occasions neurological recovery is delayed. Profound, prolonged hypoglycemia can cause brain death (6). Signs of hypoglycemia, such as diaphoresis and pallor, are often subtle, although neu- roglycopenic manifestations are often observable. In healthy individuals, symptoms of hypoglycemia develop at ameanplasma glucose concentration of approximately 55mg/dl (3.0 mmol/liter) (7). However, the glycemic thresholds for this and other responses to hypoglycemia shift to lower plasma glu- cose concentrations in patients with recurrent hypoglycemia (7– 10). Furthermore, whereas arteriovenous plasma glucose con- centration differences are clinically negligible in the postabsorptive state, antecubital venous plasma glucose concen- trations are as much as one third lower than arterial glucose concentrations (which are relevant to maintaining brain glucose metabolism) when insulin secretion is increased substantially, e.g. after a glucose load, causing glucose extraction across the forearm (11). Finally, because of the provision of alternative circulating fuels to the brain (specifically ketones), lower plasma glucose concentrations occur in healthy individuals, particularly in women and children, without symptoms or signs during ex- tended fasting (7). For all of these reasons, it is not possible to state a single plasma glucose concentration that categorically defines hypoglycemia. Plasma glucose concentrations used to document Whipple’s triad, in the absence of insulin or insulin secretagogue treatment of diabetes,must bemeasuredwith a reliable laboratorymethod, not with self-monitoring of blood glucose. Although a distinctly low, reliablymeasuredplasmaglucose concentrationobtained in theabsenceof recognized symptomsor signs shouldnotbe ignored, that finding raises the possibility of “pseudohypoglycemia”—an artifact of continued glucosemetabolismby the formed elements of thebloodafter thesample isdrawn.Thatmayoccurwhentheblood sample is collected in a tube that does not contain an inhibitor of glycolysis and separation of the plasma (or serum) from the formed elements is delayed, particularly in the setting of erythrocytosis, leukocytosis, or thrombocytosis (12). Documentation of Whipple’s triad establishes that a hypo- glycemic disorder exists. Its etiology may be apparent (e.g. in a patient with insulin-treated diabetes) or a diagnostic challenge (e.g. in a seemingly well individual with an insulinoma). On the other hand, in a person who does not have diabetes mel- litus an unequivocally normal plasma glucose concentration [e.g. �70 mg/dl (3.9 mmol/liter) (7)] during a symptomatic episode indicates that those symptoms are not the result of hypoglycemia. 1.1 Values Hypoglycemia is rare in persons who do not have drug- treated diabetes mellitus (12–15). Furthermore, not requiring Whipple’s triad to initiate a workup will very likely expose pa- tients who do not have a specific pathology causing hypoglyce- mia to unnecessary evaluations, costs, and potential harmswith- out expectation of benefit. Therefore, we believe it is important to document Whipple’s triad before concluding that a hypogly- cemic disorder exists. On the other hand, hypoglycemia is com- mon in persons with insulin- or insulin secretagogue-treated di- abetes mellitus (12, 16). Confirmation of Whipple’s triad, e.g. with self-monitoring of blood glucose, during an episode of sus- pected hypoglycemia is advisable in such a patient. However, if that is not practical, it is reasonable to assume the episode is caused by hypoglycemia for therapeutic purposes because the probability of that assumption is high and the potential negative impact of an untreated episode is considerable. 2.0 Evaluation and Management of Hypoglycemia in Persons without Diabetes Mellitus Background Because of the effectiveness of the normal defenses against falling plasma glucose concentrations (7), hypoglycemia is an J Clin Endocrinol Metab, March 2009, 94(3):709–728 jcem.endojournals.org 711 by Xiaohui Yu on March 30, 2009 jcem.endojournals.orgDownloaded from uncommon clinical event (12–15) except in persons who use drugs that lower plasma glucose levels, particularly insulin or an insulin secretagogue, to treat diabetes mellitus (12, 16). Hypo- glycemia is a fact of life formost personswith type 1 diabetes and many with type 2 diabetes. Although persons with diabetes are not spared the risk for the same hypoglycemic disorders as those without diabetes, the vast majority of their hypoglycemic epi- sodes are the result of treatment of their diabetes. Furthermore, the pathophysiology of hypoglycemia in diabetes is distinct, and the diagnostic and management approaches are different from those in individuals without diabetes (12, 16). Therefore, we address hypoglycemia in persons without diabetes and in those with diabetes separately. Physiology and pathophysiology Glucose is anobligatemetabolic fuel for thebrainunder phys- iological conditions (6, 7). Because the brain cannot synthesize glucose, use physiological circulating concentrations of alterna- tive fuels effectively, or store more than a fewminutes’ supply as glycogen, maintenance of brain function, and ultimately sur- vival, requires a virtually continuous supply of glucose from the circulation. That, in turn, requires maintenance of the plasma glucose level within the physiological range because blood-to- brain glucose transport is a direct function of the arterial plasma glucose concentration. Redundant glucose counterregulatory mechanisms normally effectively prevent or rapidly correct hy- poglycemia (7). The critical physiological defenses include: 1) a decrease in insulin secretion as glucose levels decline within the physiological range; 2) an increase in glucagon secretion; or, in its absence, 3) an increase in epinephrine secretion, both occur- ring as glucose levels decline just below the physiological range. Increased cortisol and GH secretion are involved in defense against prolonged hypoglycemia. If these defenses fail to abort the episode, plasma glucose levels will continue to fall. Symp- toms, which prompt the behavioral defense of food ingestion, normally develop at a mean plasma glucose concentration of approximately 55 mg/dl (3.0 mmol/liter). At that and lower glu- cose levels, insulin secretion is suppressed virtually completely (7, 17); plasma insulin levels are below 3 �U/ml (18 pmol/liter), C-peptide levels are below 0.6 ng/ml (0.2 nmol/liter), and pro- insulin levels are below 5.0 pmol/liter (14). Because external losses are normally negligible, hypoglyce- mia develops when the sum of glucose utilization from the cir- culation (largely by the brain but also by obligatory glycolytic tissues, such as the renal medullae and erythrocytes, and insulin- sensitive tissues, such as muscle) exceeds the sum of glucose de- livery into the circulation (from ingested carbohydrates and he- patic and renal glucose production) (12–15). Because of the capacity to increase endogenous glucose production substan- tially, hypoglycemia is typically the result of absolutely low rates of glucose production or rates of glucose production that are low relative to high rates of glucose utilization. Recom