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低血糖

著者: 大杉満 国立国際医療研究センター病院 糖尿病内分泌代謝科

監修: 野田光彦 国際医療福祉大学市川病院 糖尿病・代謝・内分泌内科

著者校正/監修レビュー済:2019/05/09
参考ガイドライン:
Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline.
患者向け説明資料

概要・推奨   

  1. 一般的には糖尿病治療に伴う低血糖が大多数を占めるため、糖尿病治療の調整や低血糖の予防を講ずることに十分な時間を割くべきである。インスリノーマなどの疾患を想定して検査に進むには、低血糖の3徴が揃った時に行うべきである(推奨度1)。
  1. 絶食試験を適切に行うには、絶食時間を十分とること、十分な監視下で安全性を担保しながら適切な検体を用いれば、十分な感度・特異度が得られる。また日本ではまだ実施数が少ないものの肥満外科手術(胃バイパス術)後の低血糖症例が増えてきている。
  1. 糖尿病の治療により低血糖を頻回に引き起こすと、低血糖の症状が出現しなくなる「無自覚性低血糖」が知られるが、一時期的に血糖コントロールをゆるめ、低血糖を回避することでこの現象に対処することができる。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
大杉満 : 未申告[2021年]
監修:野田光彦 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、推奨文のエビデンスとなる文献を追加した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 低血糖症状があること、低血糖が検査などで証明され、かつ血糖が上昇すると症状が改善する場合に低血糖の原因検索を行う。
  1. 問診、身体所見などから、薬剤、重篤な基礎疾患、内分泌不全、(膵島腫瘍以外の)腫瘍性疾患が存在しないかまずは疑う。
  1. やみくもに採血を行うのではなく、十分な低血糖で採血された検体を用いると、正確な原因診断が可能になる。
  1. 絶食試験や、画像診断も内分泌専門医の監督のもと行われるべきである。
病歴・診察のポイント  
  1. 病歴・診察により、患者の全身状態が良好なのか、他の疾患(心疾患、肝疾患、腎疾患)があり全身状態が不良なのか、また入院中の患者かがどうかを確認する。

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文献 

著者: Philip E Cryer, Lloyd Axelrod, Ashley B Grossman, Simon R Heller, Victor M Montori, Elizabeth R Seaquist, F John Service, Endocrine Society
雑誌名: J Clin Endocrinol Metab. 2009 Mar;94(3):709-28. doi: 10.1210/jc.2008-1410. Epub 2008 Dec 16.
Abstract/Text 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, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (plus sign in circle ooo), low (plus sign in circle plus sign in circle oo), moderate (plus sign in circle plus sign in circle plus sign in circle o), or high (plus sign in circle plus sign in circle plus sign in circle plus sign in circle).
CONCLUSIONS: We recommend evaluation and management of hypoglycemia only in patients in whom Whipple'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 mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic 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 endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, 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.

PMID 19088155  J Clin Endocrinol Metab. 2009 Mar;94(3):709-28. doi: 10・・・
著者: B Hirshberg, A Livi, D L Bartlett, S K Libutti, H R Alexander, J L Doppman, M C Skarulis, P Gorden
雑誌名: J Clin Endocrinol Metab. 2000 Sep;85(9):3222-6. doi: 10.1210/jcem.85.9.6807.
Abstract/Text Insulinoma causes fasting hypoglycemia due to inappropriate insulin secretion. Its diagnosis is based on demonstrating Whipple's triad during a supervised 72-h fast. For 75 yr, the 72-h fast has been the cornerstone for the diagnosis; however, it has never been critically assessed using newer assays for insulin, C peptide, and proinsulin. Thus, the aim of the current study is to assess the need for a full 72-h fast for the diagnosis of insulinoma. Patients with suspected hypoglycemia with documented glucose concentrations below 45 mg/dL were admitted to the NIH. Data obtained during the supervised fast of patients with pathologically proven insulinoma over a 30-yr period (1970-2000) were reviewed. We identified 127 patients with insulinoma. The average age of patients was 42.7 +/- 15.9 yr, with a predominance of females (62%). 107 patients had a benign tumor, 20 had malignant insulinoma, and 15 patients had multiple endocrine neoplasia type 1. The fast was terminated due to hypoglycemia in 44 patients (42.5%) by 12 h, 85 patients (66.9%) by 24 h, and 120 (94.5%) by 48 h. Seven patients fasted beyond 48 h despite subtle neuroglycopenic symptoms and glucose and insulin concentrations diagnostic of insulinoma. Immunoreactive proinsulin was elevated at the beginning of the fast in 90% of 42 patients. Proinsulin in noninsulinoma, in contrast to insulinoma, patients is usually suppressible; therefore, samples taken in the suppressed state have the greatest diagnostic value. We conclude that with the current available insulin and proinsulin assays, the diagnosis of insulinoma can be made within 48 h. Thus, the 48-h fast should replace the 72-h fast in textbooks and hospital protocols as the new diagnostic standard.

PMID 10999812  J Clin Endocrinol Metab. 2000 Sep;85(9):3222-6. doi: 10・・・
著者: F J Service, N Natt
雑誌名: J Clin Endocrinol Metab. 2000 Nov;85(11):3973-4. doi: 10.1210/jcem.85.11.6934.
Abstract/Text
PMID 11095416  J Clin Endocrinol Metab. 2000 Nov;85(11):3973-4. doi: 1・・・
著者: Kimberly A Placzkowski, Adrian Vella, Geoffrey B Thompson, Clive S Grant, Carl C Reading, J William Charboneau, James C Andrews, Ricardo V Lloyd, F John Service
雑誌名: J Clin Endocrinol Metab. 2009 Apr;94(4):1069-73. doi: 10.1210/jc.2008-2031. Epub 2009 Jan 13.
Abstract/Text OBJECTIVE: The objective of the study was to assess changes in the presentation and diagnostic and radiological evaluation of patients with surgically confirmed insulinoma at the Mayo Clinic 1987-2007.
METHODS: A retrospective analysis of patients with insulinoma was conducted. Patients with prior gastric bypass were excluded.
RESULTS: A total of 237 patients [135 women (57%)] were identified. Hypoglycemia was reported solely in the fasting state in 73%, the fasting and postprandial state in 21%, and exclusively postprandially in 6%. There was a predominance of men in the postprandial symptom group. Considering the period of study by quartile, outpatient evaluation increased from 35 to 83% and successful preoperative localization improved from 74 to 100% comparing the first to the fourth quartiles. Although the rates of localization by noninvasive techniques remained static at approximately 75%, the addition of invasive modalities has resulted in successful preoperative localization in all patients in the past 10 yr. The sensitivity and specificity of the established diagnostic criteria using insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose response to iv glucagon were greater than 90% and greater than 70%, respectively.
CONCLUSIONS: Although fasting hypoglycemia is characteristic of patients with insulinoma, postprandial symptoms have been reported with increasing, albeit low, frequency. Trends in the evaluation and preoperative management include a shift to outpatient diagnostic testing, an emphasis on successful preoperative localization to avoid blind pancreatic exploration, and a validation of the diagnostic criteria for hyperinsulinemic hypoglycemia.

PMID 19141587  J Clin Endocrinol Metab. 2009 Apr;94(4):1069-73. doi: 1・・・
著者: C G Fanelli, L Epifano, A M Rambotti, S Pampanelli, A Di Vincenzo, F Modarelli, M Lepore, B Annibale, M Ciofetta, P Bottini
雑誌名: Diabetes. 1993 Nov;42(11):1683-9. doi: 10.2337/diab.42.11.1683.
Abstract/Text To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 +/- 0.05 to 0.045 +/- 0.03 episodes/patient-day) and an increase in HbA1c (5.8 +/- 0.3 to 6.9 +/- 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.

PMID 8405713  Diabetes. 1993 Nov;42(11):1683-9. doi: 10.2337/diab.42.・・・
著者: C Fanelli, S Pampanelli, L Epifano, A M Rambotti, A Di Vincenzo, F Modarelli, M Ciofetta, M Lepore, B Annibale, E Torlone
雑誌名: Diabetologia. 1994 Dec;37(12):1265-76. doi: 10.1007/BF00399801.
Abstract/Text Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on "conventional" insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n = 16), or maintenance of the original "conventional" therapy (control group, CON, n = 5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5 +/- 0.05 to 0.045 +/- 0.02 episodes/patient-day; HbA1c increased from 5.83 +/- 0.18 to 6.94 +/- 0.13% (range in non-diabetic subjects 3.8-5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p < 0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.

PMID 7895957  Diabetologia. 1994 Dec;37(12):1265-76. doi: 10.1007/BF0・・・
著者: I Cranston, J Lomas, A Maran, I Macdonald, S A Amiel
雑誌名: Lancet. 1994 Jul 30;344(8918):283-7. doi: 10.1016/s0140-6736(94)91336-6.
Abstract/Text Hypoglycaemia without warning is a dangerous complication of insulin-dependent diabetes mellitus and it limits the use of intensified insulin therapy to reduce chronic diabetic complications. To investigate the possibility of restoring awareness; symptomatic, cognitive, and hormonal responses to controlled hypoglycaemia were studied in insulin-dependent diabetic patients with long disease duration (6 with good glycaemic control and 6 with poor control) before and after hypoglycaemia avoidance. At the start of the study, all had loss of hypoglycaemia awareness. Responses to the initial challenge were small (pooled area under curve [AUC] adrenaline 5.75 [SE 0.07] nmol/L per 260 min, pooled AUC symptom score 80 [1.3]) and only started when plasma glucose was significantly lower than the 2.8 (0.1) mmol/L at which cognitive function deteriorated. After 4.1 (1.1) months' scrupulous hypoglycaemia avoidance, hormone and symptom responses to the challenge were increased (AUC adrenaline 15.9 [0.1] nmol/L per 260 min, p = 0.01; AUC symptom score 275 [7], p < 0.001), starting at plasma glucose concentrations significantly higher than that causing cognitive dysfunction. Glycosylated haemoglobin did not deteriorate significantly. We conclude that the normal hierarchy of subjective awareness before cognitive dysfunction during hypoglycaemia can be restored by avoiding hypoglycaemia. This is independent of disease duration or initial metabolic control.

PMID 7914259  Lancet. 1994 Jul 30;344(8918):283-7. doi: 10.1016/s0140・・・
著者: S Dagogo-Jack, C Rattarasarn, P E Cryer
雑誌名: Diabetes. 1994 Dec;43(12):1426-34. doi: 10.2337/diab.43.12.1426.
Abstract/Text To test the hypothesis that the neuroendocrine (including autonomic) responses to hypoglycemia are dissociated from the symptomatic responses to hypoglycemia in insulin-dependent diabetes mellitus (IDDM) patients with hypoglycemia awareness and during reversal of hypoglycemia unawareness in IDDM, we used the hyperinsulinemic stepped hypoglycemic (5.0, 4.4, 3.9, 3.3, 2.8, and 2.2 mmol/l) clamp technique to quantitate these responses in nondiabetic control subjects and IDDM patients with hypoglycemia awareness and with hypoglycemia unawareness. The latter were restudied after 3 days, 3-4 weeks, and 3 months of scrupulous avoidance of iatrogenic hypoglycemia. At baseline, symptom responses were virtually nil in unaware patients (P = 0.0001 vs. nondiabetic); these were increased in aware patients (P = 0.0183 vs. nondiabetic). In contrast, several neuroendocrine responses were comparably reduced in both unaware and aware patients: epinephrine (P = 0.0222 and 0.0156), pancreatic polypeptide (P = 0.0004 and 0.0003), glucagon (P = 0.0112 and 0.0109), and cortisol (P = 0.0214 and 0.0450). In initially unaware patients, symptom responses increased (P = 0.0001) during avoidance of hypoglycemia. Demonstrable after 3 days, these were entirely normal after 3-4 weeks and 3 months. In contrast, none of the neuroendocrine responses increased. Thus, we conclude that several neuroendocrine responses to hypoglycemia (including the adrenomedullary and parasympathetic components of the autonomic response) can be dissociated from symptomatic responses in IDDM patients with hypoglycemia awareness and during reversal of hypoglycemia unawareness in IDDM. Avoidance of iatrogenic hypoglycemia sufficient to reverse the clinical syndrome of hypoglycemia unawareness did not reverse the key elements (deficient glucagon and epinephrine responses) of the clinical syndrome of defective glucose counterregulation. This implies that the mechanisms of hypoglycemia unawareness and of defective glucose counterregulation are, at least in part, different in IDDM.

PMID 7958494  Diabetes. 1994 Dec;43(12):1426-34. doi: 10.2337/diab.43・・・
著者: Pratik Choudhary, Michael R Rickels, Peter A Senior, Marie-Christine Vantyghem, Paola Maffi, Thomas W Kay, Bart Keymeulen, Nobuya Inagaki, Frantisek Saudek, Roger Lehmann, Bernhard J Hering
雑誌名: Diabetes Care. 2015 Jun;38(6):1016-29. doi: 10.2337/dc15-0090.
Abstract/Text Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Individualized therapy for such patients should include a composite target: optimal glucose control without problematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithm based on evidence of efficacy given the limitations of educational, technological, and transplant interventions. All patients with problematic hypoglycemia should undergo structured or hypoglycemia-specific education programs (stage 1). Glycemic and hypoglycemia treatment targets should be individualized and reassessed every 3-6 months. If targets are not met, one diabetes technology-continuous subcutaneous insulin infusion or continuous glucose monitoring-should be added (stage 2). For patients with continued problematic hypoglycemia despite education (stage 1) and one diabetes technology (stage 2), sensor-augmented insulin pumps preferably with an automated low-glucose suspend feature and/or very frequent contact with a specialized hypoglycemia service can reduce hypoglycemia (stage 3). For patients whose problematic hypoglycemia persists, islet or pancreas transplant should be considered (stage 4). This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia; it should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources. Standardized reporting of hypoglycemia outcomes and inclusion of patients with problematic hypoglycemia in studies of new interventions may help to guide future therapeutic strategies.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
PMID 25998294  Diabetes Care. 2015 Jun;38(6):1016-29. doi: 10.2337/dc1・・・

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