今日の臨床サポート

低カルシウム血症

著者: 小泉賢洋 東海大学 腎内分泌代謝内科

著者: 深川雅史 東海大学 腎内分泌代謝内科

監修: 花房規男 東京女子医科大学 血液浄化療法科

著者校正済:2021/06/23
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 低Ca血症を来す可能性がある薬剤の種類は多岐にわたる
  1. 低Ca血症を補正する際には、高Ca尿症を回避するために定期的に尿検査を行うべきである(推奨度2)
  1. 低Mg血症を伴う低Ca血症では、まず積極的にMgの補正を行う(推奨度2)
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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:
小泉賢洋 : 特に申告事項無し[2021年]
深川雅史 : 講演料(協和キリン,アストラゼネカ),奨学(奨励)寄付など(中外製薬,小野薬品,鳥居薬品,協和キリン)[2021年]
監修:花房規男 : 講演料(協和キリン,ノーベルファーマ,キッセイ薬品,バイエル薬品株式会社)[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 低カルシウム(Ca)血症とは、副甲状腺ホルモン(PTH)と活性型ビタミンDのいずれか、あるいは両方の作用が不十分で、尿中にCaが出てしまう病態である。
  1. 実臨床において遭遇する低Ca血症の多くは、慢性腎臓病に起因している。糸球体濾過量(GFR)が約60mL/分未満になると、腎での活性型ビタミンDの産生が低下する。また、ほぼ同時に細胞内外でのP蓄積(必ずしも血清P濃度は上昇しない)が起こり、二次性副甲状腺機能亢進症を伴った低Ca血症とP過剰状態を来す(慢性腎臓病を原因とする低Ca血症[CKD-MBD]の詳細は、“ 慢性腎臓病に伴う骨ミネラル代謝異常 ”の項を参照)[1][2]
  1. その他、留意すべき低Ca血症の原因として、薬剤性と低Ma血症が挙げられる。多くの薬剤により低Ca血症を来すことが知られている。低Ma血症については、PTH分泌抑制やPTH抵抗性の誘発が関与しているとされている[3][4][5]
問診・診察のポイント  
問診:
  1. 薬剤歴:ループ利尿薬、Caキレート(クエン酸、ホスカルネット)、ビタミンD欠乏あるいは抵抗性を惹起する薬剤(フェニトイン、フェノバルビタールなど)、骨吸収阻害薬(ビスホスホネート製剤、デノスマブ、エストロゲンなど)、胃酸分泌抑制に起因する腸管Ca吸収減少を惹起する薬剤(プロトンポンプ阻害薬、H2受容体拮抗薬)、Mg異常に起因するPTH低下(Mg含有制酸薬および緩下剤、シスプラチンなど)[6]
  1. 透析患者におけるCa受容体作動薬(シナカルセト,エボカルセト,エテルカルセチド)

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文献 

著者: J A Delmez, E Slatopolsky
雑誌名: Am J Kidney Dis. 1992 Apr;19(4):303-17.
Abstract/Text Control of phosphorus accumulation in chronic renal insufficiency is crucial to the prevention of secondary hyperparathyroidism and metastatic calcification. In early renal failure, calcitriol levels are normal and parathyroid hormone levels are elevated. The phosphorus levels are maintained in the normal range by the phosphaturia induced by hyperparathyroidism. In this situation, dietary phosphorus restriction increases calcitriol levels and suppresses parathyroid hormone secretion. As renal failure progresses into late stages, hyperphosphatemia is evident along with low levels of calcitriol and worsening hyperparathyroidism. Phosphorus restriction will not affect calcitriol concentrations, yet parathyroid levels may decline. During long-term dialysis, urinary excretion of phosphorus is usually minimal. Therefore, phosphorus balance is determined primarily by the net amount absorbed by the bowel and the quantity removed during dialytic therapy. Given an adequate diet, no form of conventional dialysis is able to fully compensate for the gastrointestinal absorption of phosphorus. Hence, compounds that bind phosphorus in the bowel are often necessary. With the realization that the use of phosphorus binders containing aluminum leads to aluminum accumulation and its sequelae: osteomalacia, dementia, myopathy, and anemia, other phosphorus binders have been evaluated. Calcium carbonate has been investigated the most thoroughly and is in wide use. It is inexpensive and contains a high percent of elemental calcium. However, it is only modestly potent in the binding of phosphorus, and large doses are often necessary to attain satisfactory control of phosphorus. This may lead to hypercalcemia. One approach to this problem is to decrease the concentration of calcium in the dialysate. Alternatively, a more effective phosphorus binder may be used. Calcium acetate has been shown in acute studies to have twice the binding capacity of phosphorus per calcium absorbed than calcium carbonate. Whether use of this compound decreases the incidence of hypercalcemia is unproven. Calcium citrate increases the gastrointestinal absorption of aluminum and offers no advantage over calcium carbonate. Other compounds, such as calcium ketoacids and calcium alginate, have not been extensively studied and are not generally available. The use of phosphorus binders containing magnesium in conjunction with a dialysate low in magnesium may be efficacious. Large doses of magnesium will cause diarrhea and thus limit its use as a single agent. Reasons for failure to control hyperphosphatemia include poor compliance, improper prescription of binders, poor dissolution rates seen with some generic brands of calcium carbonate, and the presence of severe hyperparathyroidism. Optimal control of serum phosphorus in dialysis patients should always be viewed in the context of adequate nutrition and protein intake.

PMID 1562018  Am J Kidney Dis. 1992 Apr;19(4):303-17.
著者: A Levin, G L Bakris, M Molitch, M Smulders, J Tian, L A Williams, D L Andress
雑誌名: Kidney Int. 2007 Jan;71(1):31-8. doi: 10.1038/sj.ki.5002009. Epub 2006 Nov 8.
Abstract/Text Abnormalities of mineral metabolism occur early in chronic kidney disease. Quantification of the prevalence of these abnormalities has not been described using current assays nor in large unselected populations. This outpatient cohort cross-sectional study was conducted in 153 centers, (71% primary care practices). Blood for parathyroid hormone (PTH), vitamin D metabolites, creatinine, calcium (Ca), and phosphorus (P) were drawn between June and October 2004. Low 1,25-dihydroxyvitamin D (1,25 OH2 D3) was defined as <22 pg/ml. The 1814 patients had a mean age of 71.1 years old; 48% had diabetes mellitus (DM). Low 1,25 OH2 D3 was evident at all estimated glomerular filtration rate (eGFR) levels: 13% in those with eGFR >80 ml/min, >60% in those with eGFR <30 ml/min. High PTH (>65pm/dl) occurred in 12% with eGFR >80 ml/min. Serum Ca and P were normal until eGFR was <40 ml/min. Significant differences in the mean and median values of 1,25 OH2 D3, PTH, but not 25(OH)D3 levels, were seen across deciles of eGFR (P<0.001). Multivariate analysis revealed that DM, increased urinary albumin/creatinine ratio and lower eGFR predicted lower values of 1,25 OH2 D3. A high prevalence of mineral metabolite abnormalities occurs in a large unreferred US cohort. Low 1,25 OH2 D3 and elevated PTH are common at higher eGFR than previously described. As bone, cardiovascular disease, and mineral metabolite are correlated; further studies are necessary to determine the importance of these findings relative to outcomes.

PMID 17091124  Kidney Int. 2007 Jan;71(1):31-8. doi: 10.1038/sj.ki.500・・・
著者: L R Chase, E Slatopolsky
雑誌名: J Clin Endocrinol Metab. 1974 Mar;38(3):363-71. doi: 10.1210/jcem-38-3-363.
Abstract/Text
PMID 4360918  J Clin Endocrinol Metab. 1974 Mar;38(3):363-71. doi: 10・・・
著者: R K Rude, S B Oldham, F R Singer
雑誌名: Clin Endocrinol (Oxf). 1976 May;5(3):209-24.
Abstract/Text Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We have studied seventeen patients with this syndrome in an attempt to determine the pathogenesis of the hypocalcaemia. Mean initial serum calcium concentration was 5-6 mg/dl and mean initial serum magnesium concentration was 0-75 mg/dl. Serum immunoreactive parathyroid hormone (IPTH) was measured in sixteen patients in the untreated state. Despite severe hypocalcaemia, serum IPTH was either undetectable (less than 150 pg/ml) or normal (less than 550 pg/ml) in all but two patients. Serial measurements made during the initial 4 days of magnesium therapy in four patients showed an increase in serum IPTH within 24h, but a delayed increase in serum calcium, which required approximately 4 days to reach normal values. The effect of the rapid normalization of serum magnesium on serum IPTH and serum calcium concentration was studied in three patients. Within 1 min after 144-300 mg of elemental magnesium was administered i.v., serum IPTH had risen from undetectable to 3600 pg/ml and 1725 pg/ml in two patients and from 425 pg/ml to 937 pg/ml in the third. Serum calcium concentrations were unchanged after 30-60 min. These data provide evidence for impaired parathyroid gland function in most of the magnesium deficient patients. The rapidity with which serum IPTH rose in response to magnesium therapy indicates that this may reflect a defect in parathyroid hormone (PTH) secretion rather than its biosynthesis. The failure of serum calcium concentration to increase during the initial days of magnesium repletion, at a time when serum IPTH concentrations were normal or elevated, suggests end-organ resistance to PTH in these patients. The renal response to PTH was examined in two magnesium deficient patients by measurement of urinary cyclic AMP excretion following administration of parathyroid extract. In both patients there was a minimal increase in urinary cyclic AMP concentrations. In contrast, when the hepatic response to glucagon was tested on the same patients by measurement of plasma cyclic AMP concentrations following administration of glucagon, normal increases were observed. These results suggest that adenylate cyclase systems of various organs may be affected differentially by a state of magnesium deficiency. It is suggested that magnesium deficiency may result in defective cyclic AMP generation in the parathyroid glands and in the PTH target organs. This could be the principal mechanism operative in both impaired PTH secretion and end-organ resistance to PTH which together contribute to the development of hypocalcaemia.

PMID 182417  Clin Endocrinol (Oxf). 1976 May;5(3):209-24.
著者: J J Freitag, K J Martin, M B Conrades, E Bellorin-Font, S Teitelbaum, S Klahr, E Slatopolsky
雑誌名: J Clin Invest. 1979 Nov;64(5):1238-44. doi: 10.1172/JCI109578.
Abstract/Text Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83+/-0.1 mg/100 ml) and experimental dogs (serum Mg 1.34+/-0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5+/-3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1+/-1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8+/-0.2 to 17.5+/-0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5+/-0.1 pmol/min, and increased to only 7.1+/-0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency.

PMID 227929  J Clin Invest. 1979 Nov;64(5):1238-44. doi: 10.1172/JCI・・・
著者: George Liamis, Haralampos J Milionis, Moses Elisaf
雑誌名: J Bone Miner Metab. 2009;27(6):635-42. doi: 10.1007/s00774-009-0119-x.
Abstract/Text Hypocalcemia (defined as total serum calcium lower than 8.5 mg/dl or as ionized serum calcium lower than 4.7 mg/dl) is a relatively common metabolic abnormality observed in hospitalized patients. Although it is associated with certain pharmacological agents such as bisphosphonates and cisplatin, hypocalcemia may occasionally develop in the course of treatment with drugs used in everyday clinical practice, including antiepileptics, aminoglycosides, and proton pump inhibitors. Hypocalcemia associated with drug treatment can be easily missed as a consequence of coexistence of multiple factors contributing to low serum calcium levels. Drug-related hypocalcemia is usually mild and asymptomatic but may be severe as well. Effective clinical management can be handled through awareness of this adverse effect induced by certain pharmaceutical compounds on serum calcium concentrations. Herein, we review pertinent clinical information on the incidence of hypocalcemia associated with specific drug treatment and discuss the underlying pathophysiological mechanisms.

PMID 19730969  J Bone Miner Metab. 2009;27(6):635-42. doi: 10.1007/s00・・・
著者: Patrick B Mark, Emmanouil Mazonakis, David Shapiro, Richard J Spooner, R Stuart C Rodger
雑誌名: Nephrol Dial Transplant. 2005 Jul;20(7):1499-500. doi: 10.1093/ndt/gfh836. Epub 2005 Apr 19.
Abstract/Text
PMID 15840670  Nephrol Dial Transplant. 2005 Jul;20(7):1499-500. doi: ・・・
著者: N H Bell, P H Stern
雑誌名: N Engl J Med. 1978 Jun 1;298(22):1241-3. doi: 10.1056/NEJM197806012982206.
Abstract/Text
PMID 651964  N Engl J Med. 1978 Jun 1;298(22):1241-3. doi: 10.1056/N・・・
著者: K K Winer, J A Yanovski, G B Cutler
雑誌名: JAMA. 1996 Aug 28;276(8):631-6.
Abstract/Text OBJECTIVE: To test the hypothesis that treatment with human parathyroid hormone 1-34 (PTH 1-34) can maintain normal serum calcium without hypercalciuria in patients with hypoparathyroidism.
DESIGN: Randomized crossover trial lasting 20 weeks. Each 10-week arm consisted of a 2-week inpatient dose-adjustment phase followed by an 8-week outpatient phase.
SETTING: Tertiary care center.
PATIENTS: A total of 10 patients with hypoparathyroidism were enrolled consecutively over a 15-month period. Half of the patients were prior National Institutes of Health patients, and the other 5 patients were referred from outside physicians.
INTERVENTIONS: A dose of PTH 1-34 was administered each morning by subcutaneous injection. Calcitriol was given orally twice daily with supplemental calcium carbonate.
MAIN OUTCOME MEASURES: Serum and urine calcium and phosphorus levels.
RESULTS: Once-daily treatment with PTH 1-34 maintained serum calcium in the normal range with decreased urine calcium excretion (P<.05 at 2 weeks and P<.Ol at 10 weeks) compared with calcitriol treatment. Biochemical markers of bone turnover increased significantly (P<.Ol at 10 weeks) during PTH 1-34 treatment.
CONCLUSIONS: Treatment of hypoparathyroidism with PTH 1-34 reduces urine calcium excretion compared with treatment with calcitriol and calcium.

PMID 8773636  JAMA. 1996 Aug 28;276(8):631-6.
著者: R H Porter, B G Cox, D Heaney, T H Hostetter, B J Stinebaugh, W N Suki
雑誌名: N Engl J Med. 1978 Mar 16;298(11):577-81. doi: 10.1056/NEJM197803162981101.
Abstract/Text In an effort to maintain normal serum calcium levels without inducing hypercalciuria, we treated seven hypoparathyroid patients for up to 25 months with chlorthalidone, a thiazide-like sulfonamide diuretic, plus a salt-restricted diet, without added vitamin D. Mean 24-hour calcium excretion decreased from 179 to 88 mg (P less than 0.001), and mean serum calcium increased from 8.2 to 9.3 mg per deciliter (P less than 0.05). Diuretic therapy or moderate salt restriction alone was not as effective as combined therapy. Beneficial effects were sustained for as long as therapy was maintained. The rise in serum calcium, which involves the filterable and ionized fractions, cannot be due entirely to reduced excretion and may in part be explained by increased intestinal absorption. Oral chlorthalidone plus a low salt diet appears to be an effective alternative to vitamin D in the maintenance therapy of at least some patients with hypoparathyroidism.

PMID 628374  N Engl J Med. 1978 Mar 16;298(11):577-81. doi: 10.1056/・・・
著者: F Santos, M J Smith, J C Chan
雑誌名: Am J Dis Child. 1986 Feb;140(2):139-42.
Abstract/Text Urine calcium excretion was evaluated in 19 patients before and after calcitriol (1,25-dihydroxyvitamin D3) treatment that was followed up for a five- to seven-year period. The effects of increases of calcitriol dosage and modifications of calciuria with hydrochlorothiazide were systematically examined. The urine calcium excretion before calcitriol therapy was 2.3 +/- 0.8 mg/kg/day (mean- +/- SEM) and the urine calcium-creatinine concentration ratio was 0.12 +/- 0.04. With the dose of calcitriol at 23 ng/kg/day, these values increased to 3.2 +/- 0.8 mg/kg/day and 0.19 +/- 0.04, respectively. Following double dose of calcitriol (44 ng/kg/day), increments in calciuria and urinary calcium/creatinine concentration of 1.4 +/- 0.6 mg/kg/day and 0.10 +/- 0.03, respectively, were observed. With concomitant administration of hydrochlorothiazide (1 to 2 mg/kg/day) therapy at maintenance dose and calcitriol (31 ng/kg/day), the urine calcium excretion effectively decreased by 1.3 +/- 0.6 mg/kg/day and the urine calcium-creatinine concentration ratio by 0.05 +/- 0.02. The results suggest that children with calcium-phosphate disorders who require long-term treatment with calcitriol must be carefully monitored in terms of urine calcium excretion, especially when the dosages are increased to achieve maximal therapeutic efficacy. Calciuria induced by calcitriol administration is effectively reversed by addition of hydrochlorothiazide to the treatment regimen.

PMID 3753816  Am J Dis Child. 1986 Feb;140(2):139-42.
著者: T B Connor, P Toskes, J Mahaffey, L G Martin, J B Williams, M Walser
雑誌名: Johns Hopkins Med J. 1972 Aug;131(2):100-17.
Abstract/Text
PMID 5050732  Johns Hopkins Med J. 1972 Aug;131(2):100-17.
著者: I N Cholst, S F Steinberg, P J Tropper, H E Fox, G V Segre, J P Bilezikian
雑誌名: N Engl J Med. 1984 May 10;310(19):1221-5. doi: 10.1056/NEJM198405103101904.
Abstract/Text We measured serum concentrations of calcium and parathyroid hormone in seven pregnant women who were receiving intravenous magnesium sulfate for the suppression of premature labor. After administration of magnesium sulfate, the mean (+/- S.E.M.) serum magnesium level rose rapidly from the normal base-line level of 2.0 +/- 0.2 mg per deciliter to 6.1 +/- 0.4 mg per deciliter (0.8 +/- 0.1 to 2.5 +/- 0.2 mmol per liter) (P less than 0.001) at 30 minutes and remained markedly elevated. Concentrations of total and ionized calcium fell gradually in all subjects from normal base-line concentrations, 8.6 +/- 0.2 and 4.4 +/- 0.1 mg per deciliter (2.2 +/- 0.1 and 1.1 +/- 0.03 mmol per liter), respectively, into the hypocalcemic range, reaching a nadir of 7.6 +/- 0.2 and 3.9 +/- 0.1 mg per deciliter (1.9 +/- 0.1 and 0.98 +/- 0.03 mmol per liter), respectively, at three hours (P less than 0.001). Parathyroid hormone levels fell rapidly in response to magnesium infusion, from 13.1 +/- 2.5 to 7.8 +/- 0.7 pg per milliliter at 30 minutes, and were significantly below base-line levels for two hours despite frank hypocalcemia. These results suggest that hypermagnesemia rapidly decreases the secretion of parathyroid hormone in vivo in human subjects and that parathyroid hormone levels remain depressed despite concomitant hypocalcemia. The results also suggest that the hypocalcemia associated with hypermagnesemia may be due in part to the suppressive effects of hypermagnesemia on parathyroid hormone secretion.

PMID 6709029  N Engl J Med. 1984 May 10;310(19):1221-5. doi: 10.1056/・・・
著者: Mark S Cooper, Neil J L Gittoes
雑誌名: BMJ. 2008 Jun 7;336(7656):1298-302. doi: 10.1136/bmj.39582.589433.BE.
Abstract/Text
PMID 18535072  BMJ. 2008 Jun 7;336(7656):1298-302. doi: 10.1136/bmj.39・・・

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