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副甲状腺機能低下症

著者: 井上大輔 帝京大学 ちば総合医療センター

監修: 平田結喜緒 公益財団法人 兵庫県予防医学協会 健康ライフプラザ

著者校正/監修レビュー済:2022/01/19
参考ガイドライン:
 
  1. 難病情報センター(副甲状腺機能低下症 指定難病235).https://www.nanbyou.or.jp/entry/4427.(2021年12月閲覧)
  1. 難病情報センター(偽性副甲状腺機能低下症 指定難病237).https://www.nanbyou.or.jp/entry/233.(2021年12月閲覧)
患者向け説明資料

概要・推奨   

  1. 副甲状腺機能低下症でintact PTH が30pg/ml以上あれば偽性と考え、確定診断および病型分類のためにEllsworth-Howard試験を行うことが勧められる(推奨度2)。
  1. 骨粗鬆症治療薬として用いられているヒトPTH皮下注射製剤は、分泌低下型の副甲状腺機能低下症の治療薬として推奨されない(推奨度4)。
  1. 尿中Ca排泄量が多く血清Ca濃度の維持が困難な副甲状腺機能低下症に対しては、活性型ビタミンDに加えてサイアザイド系利尿薬の併用が勧められる(推奨度2)。
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  1. 閲覧にはご契約が必要となります。閲 覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
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:
井上大輔 : 講演料(中外製薬,アムジェン,アステラス,第一三共),奨学(奨励)寄付など(中外製薬,第一三共, ロシュ・ダイアグノスティックス)[2021年]
監修:平田結喜緒 : 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、マイナーな改訂を加えた。概要欄では重要度の低い推奨を除いた。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 副甲状腺機能低下症は副甲状腺ホルモン(PTH)分泌低下によるものとPTH作用不全に基づくものの2つに大別される。
  1. 低アルブミン(Alb)血症がある場合、血清カルシウム(Ca)濃度は補正式:補正Ca=実測Ca(mg/dl)+(4-Alb(g/dl))で評価する。
  1. 低Ca血症および正~高リン(P)血症の存在と腎不全の除外(Cr<2.0mg/dl)が診断の基本である。
  1. intact PTH<30pg/mlであればPTH分泌低下によるもので、特発性、続発性、種々の先天性疾患が含まれる。
  1. intact PTH>30pg/mlであればPTH作用不全による偽性副甲状腺機能低下症と診断できるが、診断の確定および病型分類のためにPTH試験(Ellsworth-Howard試験)の施行が望ましい。
  1. 偽性では低身長、丸顔、肥満、短頚、短指などの特徴的身体所見(Albright遺伝性骨異栄養症:AHO)や他の内分泌異常の合併がみられる(Ia、 Ic型)。
  1. 低マグネシウム(Mg)血症は、主にPTH分泌不全により副甲状腺機能低下症をもたらすが、作用不全も混在した複雑な病態を示すことがある。
  1. 副甲状腺機能低下症は、指定難病であり、中等症以上の場合などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。([ https://www.nanbyou.or.jp/wp-content/uploads/upload_files/File/235-201704-kijyun.pdf 平成27年7月施行])
  1. 難病法に基づく医療費助成制度
 
  1. 副甲状腺機能低下症でintact PTH が30pg/ml以上あれば偽性と考え、確定診断および病型分類のためにEllsworth-Howard試験を行うことが勧められる(推奨度2o)。(参考文献:[1][2]
  1. 研究背景:
    厚生労働省難治性疾患克服研究事業ホルモン受容機構異常調査研究班による診断基準ではintact PTHが30以上であれば偽性、30未満であればPTH分泌低下による副甲状腺機能低下症と診断する、と記載されている。
  1. 研究事例の説明:
    少数例の検討ではあるが、班研究による全国調査で主治医よりPTH値が報告された例では、この基準の正診率はほぼ100%であった。したがってEllsworth-Howard(E-H)試験が偽性の診断に必須とはいえないが、病型診断のためには必要である。
  1. 結論:
    副甲状腺機能低下症でintact PTH が30pg/mlであれば偽性と診断される。診断の確定もしくは確認、および病型分類のためにE-H試験を行うことが望ましい。
  1. 追記:
    厚生労働省難治性疾患克服研究事業ホルモン受容機構異常調査研究班より、低Ca血症の診断フローチャートが発表されており、副甲状腺機能低下症のうちintact PTHが30pg/ml以上の例にはE-H試験の施行が望ましい、との記載がある。
  1. コメント:
    偽性副甲状腺機能低下症では、PTH負荷後の尿中P排泄反応がみられない。さらに尿中cAMP反応もみられないものをI型、cAMP反応はみられるものをII型と呼ぶ。II型は、その存在自体にいまだ疑問の余地が残されており、今後も解析症例の蓄積が求められる。
病歴・診察のポイント  
  1. テタニーに特有なChvostek徴候、Trousseau徴候やAHO特有の身体徴候(低身長、丸顔、肥満、短頚、短指など)の有無を確認する。軽度のテタニー症状として筋肉のつっぱり感やこむら返りなどを訴えることがある。

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文献 

著者: Seiji Fukumoto, Noriyuki Namba, Keiichi Ozono, Mika Yamauchi, Toshitsugu Sugimoto, Toshimi Michigami, Hiroyuki Tanaka, Daisuke Inoue, Masanori Minagawa, Itsuro Endo, Toshio Matsumoto
雑誌名: Endocr J. 2008 Oct;55(5):787-94. Epub 2008 May 19.
Abstract/Text Serum calcium (Ca) level is maintained within a narrow range mainly by actions of parathyroid hormone (PTH) and 1,25-dihydroxyvitmain D [1,25(OH)(2)D]. While it is not rare to encounter hypocalcemia in clinical practice, there is currently no practical guideline for the differential diagnosis of hypocalcemia. We therefore propose flowcharts for the differential diagnosis of hypocalcemia and hypoparathyroidism, especially PTH-deficient hypoparathyroidism in which many genetic or other causes have been identified recently. Hypocalcemia can be divided into two categories, hypocalcemia with low serum phosphate level, and one with normal to elevated serum phosphate level. Deficient actions of 1,25(OH)(2)D, loss of Ca into urine, and deposition of Ca in bone or soft tissues are main causes of hypocalcemia with low to low normal serum phosphate level. Hypocalcemia with high normal to high serum phosphate level includes chronic renal failure and hypoparathyroidism. Hypoparathyroidism is subdivided into PTH-deficient hypoparathyroidism and pseudohypoparathyroidism. Recent investigations identified several causes of PTH-deficient hypoparathyroidism, including genetic abnormalities and parathyroid autoantibodies, which should be differentiated from idiopathic hypoparathyroidism. Physical and laboratory findings, the time of the onset of diseases and accompanying illness can be clues for identifying causes of PTH-deficient hypoparathyroidism.

PMID 18490837  Endocr J. 2008 Oct;55(5):787-94. Epub 2008 May 19.
著者: S Abe, K Tojo, K Ichida, T Shigematsu, T Hasegawa, M Morita, O Sakai
雑誌名: Intern Med. 1996 Feb;35(2):129-34.
Abstract/Text A 47-year-old man was admitted for evaluation of unsteady gait, postural instability, and dysarthria. On admission, neurological examinations revealed cerebellar ataxia, extrapyramidal signs including parkinsonism and positive Trousseau's sign. Laboratory findings revealed severe hypocalcemia and hyperphosphatemia, and serum intact parathyroid hormone was not detectable. Brain computed tomography revealed severe calcification of basal ganglia and dentate nuclei. He was diagnosed as idiopathic hypoparathyroidism; treatment with 1 alpha (OH) vitamin D3 brought marked improvement of neurological manifestations. We report a rare case of idiopathic hypoparathyroidism presenting with extrapyramidal and cerebellar dysfunction with a review of literature.

PMID 8680101  Intern Med. 1996 Feb;35(2):129-34.
著者: Giovanna Mantovani
雑誌名: J Clin Endocrinol Metab. 2011 Oct;96(10):3020-30. doi: 10.1210/jc.2011-1048. Epub 2011 Aug 3.
Abstract/Text CONTEXT: The term pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of various hormones (primarily PTH) that activate cAMP-dependent pathways via Gsα protein. The two main subtypes of PHP, PHP type Ia, and Ib (PHP-Ia, PHP-Ib) are caused by molecular alterations within or upstream of the imprinted GNAS gene, which encodes Gsα and other translated and untranslated products.
EVIDENCE ACQUISITION: A PubMed search was used to identify the available studies (main query terms: pseudohypoparathyroidism; Albright hereditary osteodystrophy; GNAS; GNAS1; progressive osseous heteroplasia). The most relevant studies until February 2011 have been included in the review.
EVIDENCE SYNTHESIS AND CONCLUSIONS: Despite the first description of this disorder dates back to 1942, recent findings indicating complex epigenetic alterations beside classical mutations at the GNAS complex gene, pointed out the limitation of the actual classification of the disease, resulting in incorrect genetic counselling and diagnostic procedures, as well as the gap in our actual knowledge of the pathogenesis of these disorders. This review will focus on PHP type I, in particular its diagnosis, classification, treatment, and underlying molecular alterations.

PMID 21816789  J Clin Endocrinol Metab. 2011 Oct;96(10):3020-30. doi: ・・・
著者: Y Li, Y H Song, N Rais, E Connor, D Schatz, A Muir, N Maclaren
雑誌名: J Clin Invest. 1996 Feb 15;97(4):910-4. doi: 10.1172/JCI118513.
Abstract/Text Acquired hypoparathyroidism (AH) has been considered to result from an autoimmune process but the self-antigens have not been identified. We studied 25 patients with AH, of which 17 had type I autoimmune polyglandular syndrome and 8 had AH associated with autoimmune hypothyroidism. Five of 25 (20%) AH sera reacted to a membrane-associated antigen of 120-140 kD in human parathyroid gland extracts using immunoblot analysis. This is the exact size of the calcium sensing receptor (Ca-SR). The AH sera were then tested by immunoblot using a membrane fraction of HEK-293 cells transfected with Ca-SR cDNA. Eight of 25 (32%) AH sera reacted to a 120-140-kD protein, which closely matched that recognized by the anti-Ca-SR IgG raised in rabbits. The Ca-SR cDNA was translated in vitro into two parts in order to identify the antigenic epitopes. By using this technique, 14 of 25 (56%) AH sera were positive to the extracellular domain of the Ca-SR, whereas none of the AH patients sera reacted to the intracellular domain. The reactivity of the positive sera was completely removed after pre-absorption with the Ca-SR containing membranes. Sera from 50 patients with various other autoimmune diseases as well as 22 normal controls were also tested, and none of them was positive. In conclusion, the Ca-SR has been identified as an autoantigen in AH.

PMID 8613543  J Clin Invest. 1996 Feb 15;97(4):910-4. doi: 10.1172/JC・・・
著者: Annika Söderbergh, Anne Grethe Myhre, Olov Ekwall, Gennet Gebre-Medhin, Håkan Hedstrand, Eva Landgren, Aaro Miettinen, Petra Eskelin, Maria Halonen, Tiinamaija Tuomi, Jan Gustafsson, Eystein S Husebye, Jaakko Perheentupa, Mikhail Gylling, Michael P Manns, Fredrik Rorsman, Olle Kämpe, Thomas Nilsson
雑誌名: J Clin Endocrinol Metab. 2004 Feb;89(2):557-62. doi: 10.1210/jc.2003-030279.
Abstract/Text The prevalence of autoantibodies against nine intracellular enzyme autoantigens, namely 21-hydroxylase, side-chain cleavage enzyme (SCC), 17 alpha-hydroxylase, glutamic acid decarboxylase 65, aromatic L-amino acid decarboxylase, tyrosine phosphatase-like protein IA-2, tryptophan hydroxylase (TPH), tyrosine hydroxylase, cytochrome P450 1A2, and against the extracellular calcium-sensing receptor, was assessed in 90 patients with autoimmune polyendocrine syndrome type I. A multivariate logistic regression analysis was performed for the presence of autoantibodies as independent predictors for different disease manifestations. Reactivities against 21-hydroxylase and SCC were associated with Addison's disease with odds ratios (ORs) of 7.8 and 6.8, respectively. Hypogonadism was exclusively associated with autoantibodies against SCC with an OR of 12.5. Autoantibodies against tyrosine phosphatase-like protein IA-2 were associated with insulin-dependent diabetes mellitus with an OR of 14.9, but with low sensitivity. Reactivities against TPH and, surprisingly, glutamic acid decarboxylase 65, were associated with intestinal dysfunction, with ORs of 3.9 and 6.7, respectively. TPH reactivity was the best predictor for autoimmune hepatitis, with an OR of 27.0. Hypoparathyroidism was not associated with reactivity against any of the autoantigens tested. No reactivity against the calcium-sensing receptor was found. Analysis of autoantibodies in autoimmune polyendocrine syndrome type I patients is a useful tool for establishing autoimmune manifestations of the disease as well as providing diagnosis in patients with suspected disease.

PMID 14764761  J Clin Endocrinol Metab. 2004 Feb;89(2):557-62. doi: 10・・・
著者: Dominique N Long, Sarah McGuire, Michael A Levine, Lee S Weinstein, Emily L Germain-Lee
雑誌名: J Clin Endocrinol Metab. 2007 Mar;92(3):1073-9. doi: 10.1210/jc.2006-1497. Epub 2006 Dec 12.
Abstract/Text CONTEXT: Obesity is a prominent feature of Albright hereditary osteodystrophy (AHO), a disorder caused by heterozygous GNAS mutations that disrupt the stimulatory G protein alpha-subunit Galpha(s). Because Galpha(s) is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [pseudohypoparathyroidism type 1a (PHP1a)], whereas paternal inheritance leads to AHO alone [pseudopseudohypoparathyroidism (pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions.
SETTING: This observational study was conducted at the General Clinical Research Center, Johns Hopkins University School of Medicine; National Institutes of Health.
PATIENTS: Fifty-three patients with AHO (40 with PHP1a and 13 with pseudoPHP) and two with progressive osseous heteroplasia were studied.
MAIN OUTCOME MEASURES: Main outcome measures were weight and height sd score (SDS), body mass index (BMI) percentiles, and BMI z-scores.
RESULTS: Patients with PHP1a had significantly greater mean weight SDS, BMI percentages, and BMI z-scores compared with patients with pseudoPHP. These differences in BMI were secondary to adipose content based on dual energy x-ray absorptiometry analysis. The mean BMI z-score +/- sem for PHP1a was 2.31 +/- 0.18 compared with 0.65 +/- 0.31 in pseudoPHP (P = 0.000032). Twenty-five of 40 (62.5%) patients with PHP1a had mean BMI z-scores greater than two SDS above the mean, whereas no patients with pseudoPHP had BMI z-scores in this range.
CONCLUSIONS: Although the AHO phenotype for PHP1a and pseudoPHP has been thought to be similar, we have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings may implicate paternal imprinting of Galpha(s) in the development of human obesity.

PMID 17164301  J Clin Endocrinol Metab. 2007 Mar;92(3):1073-9. doi: 10・・・
著者: Karen K Winer, Chia Wen Ko, James C Reynolds, Karen Dowdy, Meg Keil, Donna Peterson, Lynn H Gerber, Charles McGarvey, Gordon B Cutler
雑誌名: J Clin Endocrinol Metab. 2003 Sep;88(9):4214-20. doi: 10.1210/jc.2002-021736.
Abstract/Text Hypoparathyroidism is one of the few remaining hormonal insufficiency states for which replacement therapy is unavailable. Previous short-term controlled trials have shown PTH to be a safe and effective treatment of hypoparathyroidism. In this randomized, parallel group, open-label trial, we compared synthetic human PTH-(1-34) (PTH) with conventional therapy, calcitriol and calcium, over a 3-yr period. Twenty-seven patients with confirmed hypoparathyroidism, aged 18-70 yr, were randomized to either twice daily sc PTH or oral calcitriol and calcium. The primary end points were calcium levels in serum and urine. Secondary end points were creatinine clearance, markers of bone turnover, and bone mineral density. Throughout the 3-yr study period, serum calcium levels were similar in both treatment groups within or just below the normal range. Mean urinary calcium excretion was within the normal range from 1-3 yr in PTH-treated patients, but remained above normal in the calcitriol group. Bone mineral content and bone mineral density showed no significant between-group differences over the 3-yr study period. We conclude that treatment with twice daily sc PTH provides a safe and effective alternative to calcitriol therapy and is able to maintain normal serum calcium levels without hypercalciuria for at least 3 yr in patients with hypoparathyroidism.

PMID 12970289  J Clin Endocrinol Metab. 2003 Sep;88(9):4214-20. doi: 1・・・
著者: M R Rubin, J Sliney, D J McMahon, S J Silverberg, J P Bilezikian
雑誌名: Osteoporos Int. 2010 Nov;21(11):1927-34. doi: 10.1007/s00198-009-1149-x. Epub 2010 Jan 22.
Abstract/Text UNLABELLED: Hypoparathyroidism, a disorder characterized by low parathyroid hormone (PTH), is generally treated with oral calcium and vitamin D supplementation. We investigated the effects of PTH(1-84) treatment in 30 hypoparathyroid subjects for 24 months. PTH(1-84) treatment in hypoparathyroidism significantly reduced supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels.
INTRODUCTION: Hypoparathyroidism, a disorder characterized by low PTH, is associated with hypocalcemia, hypercalciuria, and increased bone mineral density (BMD). Conventional therapy with calcium and 1,25-dihydroxyvitamin D can maintain the serum calcium concentration, but doses are high, and control is variable. We investigated the effects of human PTH(1-84) treatment in hypoparathyroidism.
METHODS: Thirty subjects with hypoparathyroidism were treated in an open-label study of PTH(1-84) 100 µg every other day by subcutaneous injection for 24 months, with monitoring of calcium and vitamin D supplementation requirements, serum and 24 h urinary calcium excretion, and BMD by dual energy X-ray absorptiometry.
RESULTS: Requirements for supplemental calcium decreased significantly (3,030±2,325 to 1,661±1,267 mg/day (mean±SD); p<0.05), as did requirements for supplemental 1,25-dihydroxyvitamin D (0.68±0.5 to 0.40±0.5 µg/day; p<0.05). Serum calcium levels and 24 h urinary calcium excretion were mostly unchanged at 24 months. BMD increased at the lumbar spine by 2.9±4% from baseline (p<0.05), while femoral neck BMD remained unchanged and distal one third radial BMD decreased by 2.4±4% (p<0.05).
CONCLUSION: PTH(1-84) treatment in hypoparathyroidism significantly reduces supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels.

PMID 20094706  Osteoporos Int. 2010 Nov;21(11):1927-34. doi: 10.1007/s・・・
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: U Alon, M D Wellons, J C Chan
雑誌名: Pediatr Res. 1983 Feb;17(2):117-9. doi: 10.1203/00006450-198302000-00007.
Abstract/Text To test the effects of chlorothiazide on vitamin-D2-induced hypercalciuria, we carried out 17 metabolic studies lasting 12 days each in adult Sprague-Dawley male rats. Three groups were studied: (A) control rats receiving only the vitamin-D2 vehicle; (B) vitamin-D2-treated rats receiving 50 IU/day; and (C) rats treated in the same manner as group B with the addition of chlorothiazide 20 mg/day for the last 6 days of the study. Urine was collected during the last 3 days, and a blood sample was obtained at the end of each study period. Analysis of the data showed that there were no significant differences between the groups in changes of serum calcium concentration (A, 6.1 +/- 0.1 mg/dl; B, 6.1 +/- 0.2 mg/dl; C, 6.0 +/- 0.2 mg/dl), serum creatinine concentration (A, 0.5 +/- 0.07 mg/dl; B, 0.52 +/- 0.08 mg/dl; C, 0.48 +/- 0.04 mg/dl), and creatinine clearance (A, 4.8 +/- 0.7 ml/min/kg; B, 5.2 +/- 1.2 ml/min/kg; C, 4.9 +/- 0.5 ml/min/kg). The administration of vitamin-D2 significantly increased the urinary calcium excretion from 6.7 +/- 1.0 mg/kg/day to 19.5 +/- 9.7 mg/kg/day (p less than 0.02), but the calciuria was inhibited in group C rats by the addition of chlorothiazide, which restored urinary calcium excretion to 6.8 +/- 2.5 mg/kg/day (p less than 0.02). Evaluation of the ratio of calcium/creatinine excretion (A, 0.19 +/- 0.03; B, 0.53 +/- 0.25; C, 0.20 +/- 0.07) and calcium/sodium excretion (A, 0.22 +/- 0.05; B, 0.48 +/- 0.25; C, 0.19 +/- 0.04) further confirmed these effects of vitamin-D2 and chlorothiazide on urine calcium excretion. We conclude that in rats conventional doses of vitamin-D2 consistently induce marked hypercalciuria, even without hypercalcemia, and that this hypercalciuria can be effectively prevented by chlorothiazide.

PMID 6600835  Pediatr Res. 1983 Feb;17(2):117-9. doi: 10.1203/0000645・・・
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: R B Kurzel, G A Hagen
雑誌名: Am J Perinatol. 1990 Oct;7(4):333-6. doi: 10.1055/s-2007-999516.
Abstract/Text A pregnant patient with idiopathic hypoparathyroidism is presented. Her hypomagnesemic hypocalcemia was unresponsive to conventional therapy, or magnesium supplementation. Sodium restriction with thiazide therapy successfully reduced her renal calcium wastage to control her symptoms and raise her serum calcium levels.

PMID 2222622  Am J Perinatol. 1990 Oct;7(4):333-6. doi: 10.1055/s-200・・・
著者: Kohei Sato, Yukihiro Hasegawa, Jun Nakae, Kenji Nanao, Ikuko Takahashi, Toshihiro Tajima, Nozomi Shinohara, Kenji Fujieda
雑誌名: J Clin Endocrinol Metab. 2002 Jul;87(7):3068-73. doi: 10.1210/jcem.87.7.8639.
Abstract/Text Gain-of-function mutations of the calcium-sensing receptor (CaR) gene cause autosomal dominant and/or sporadic hypocalcemia with hypercalciuria. Because treatment of the hypocalcemia with vitamin D and/or calcium in patients with such mutations results in increased hypercalciuria, nephrocalcinosis, and renal impairment, its use should be limited to alleviating the symptoms of symptomatic patients. Because thiazide diuretics have been successfully used to treat patients with hypercalciuria and hypoparathyroidism, they are theoretically useful in reducing urine calcium excretion and maintaining serum calcium levels in patients with gain-of-function mutations of the CaR gene. In this study, we report on the clinical course, molecular analysis, and effects of hydrochlorothiazide therapy in two Japanese patients with gain-of-function mutations of the CaR gene. Within a few weeks after birth, they developed generalized tonic seizures due to hypocalcemia (serum calcium values: 1.1 mmol/liter and 1.3 mmol/liter, respectively). Despite treatment with the standard dose of 1,25-dihydroxyvitamin D(3) in one patient and 1alpha-hydroxyvitamin D(3) in the other, acceptable serum calcium levels near the lower limit of normal were not established, and their urinary calcium excretion inappropriately increased. Addition of hydrochlorothiazide (1 mg/kg) reduced their urinary calcium excretion and maintained their serum calcium concentrations near the lower limit of normal, allowing the 1,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(3) doses to be reduced, and it alleviated their symptoms. A heterozygous missense mutation was identified in both patients. In one patient, the mutation was A843E in the seventh transmembrane domain of the CaR, and in the other it was L125P in the N-terminal extracellular domain. In vitro transient transfection of their mutant CaR cDNAs into HEK293 cells shifted the concentration-response curve of Ca(2+) to the left. In conclusion, two sporadic cases of hypercalciuric hypocalcemia were due to de novo gain-of-function mutations of the CaR gene. Hydrochlorothiazide with vitamin D(3) successfully reduced the patients' urinary calcium excretion and controlled their serum calcium concentrations and symptoms. Thiazide diuretics are effective in patients with gain-of function mutations of the CaR gene.

PMID 12107202  J Clin Endocrinol Metab. 2002 Jul;87(7):3068-73. doi: 1・・・
著者: S H Pearce, C Williamson, O Kifor, M Bai, M G Coulthard, M Davies, N Lewis-Barned, D McCredie, H Powell, P Kendall-Taylor, E M Brown, R V Thakker
雑誌名: N Engl J Med. 1996 Oct 10;335(15):1115-22. doi: 10.1056/NEJM199610103351505.
Abstract/Text BACKGROUND: The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria.
METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293).
RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor.
CONCLUSIONS: Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

PMID 8813042  N Engl J Med. 1996 Oct 10;335(15):1115-22. doi: 10.1056・・・
著者: M Schroth, J Dötsch, H G Dörr
雑誌名: J Clin Pharm Ther. 2001 Dec;26(6):453-5.
Abstract/Text Idiopathic primary hypoparathyroidism (prHP) is a rare disorder and clinical experience of its management is limited. Prolonged immobilization of such patients can cause hypercalcemia and hypercalciuria. We report on a boy with prHP who developed hypercalcemia and renal failure as a result of calcium and calcitriol substitution not being stopped while he was immobilized for 2 months. Any substitution in patients with prHP must be stopped during prolonged immobilization. Laboratory monitoring is mandatory during this period.

PMID 11722683  J Clin Pharm Ther. 2001 Dec;26(6):453-5.

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