◐General Nephrology

Vitamin D deficiency

Electrolyte約 13 分鐘7 個章節

1.Effect#

  • ↓renin(->↓proteinuria(也因為↑Megalin), ↓CKD progression), increase renal distal tubules Ca(and P(?)(Brenner(p269):↑p.tubules吸收P); 不過也↑FGF23 促進尿磷排泄, 故整體上磷仍維持平衡(活性維生素 D 一方面↑腸道與腎小管吸收鈣磷, 一方面經 FGF23 反向排磷)(記得也有paper寫不會影響renal phosphate resorption)) reabsorption(不過因為骨頭放出Ca,P更多, 所以calcinuria↑ and phosphaturia↑(also due to ↑secreted klotho?(見下圖)), ↓iPTH(因為↑parathyroid gland的CaSR), ↑FGF23, ↑bone formation and ↑bone mineralization and ↑bone resorption(因為會使osteoblast ↑RANKL表現; but long term, frequent exposure to high dose(生理是pg/ml, 我們給ug; 差了100W倍) 1,25 OH vitamin D反而導致Osteoblast RANKL↓(by alteration in the Ca endocrine system? and 因為使immature osteoblasts變成mature osteoblasts(因為immature OB表現較多RANKL))-->osteoclasts↓; 此外藥理濃度的calcitriol也抑制monocytes變成osteoclasts), ↓inflammation(所以vitamin D缺乏可inflammation而↑hepcidin-->iron utilization↓), regulate immune function(innate and adaptive都有; 如:在monocyte可刺激cathelicidin產生), ↓fibrosis
    • Reference:Vitamin D endocrine system and osteoclasts(2014 Bonekey Rep)
  • For BV
    • Lower vascular calcification(生理濃度), 不過要和Ca-P沉積相競爭effect
      • Reference:Vitamin D and secreted Klotho: a long-awaited panacea for vascular calcification?(2012 KI)
      • 所以在Calcitriol在local effect of BV上是抑制鈣化, 但是在systemic因為會造成Ca↑P↑所以會加重鈣化, 若給藥理濃度的calcitriol理論上會加重鈣化, 若給nutritional vitamin D(會有生理濃度的Calcitriol)理論上會抑制鈣化...
      • PRIMO (JAMA 2012; PMID 22337679)：CKD 3-4 期左心室肥厚患者給予 Paricalcitol 48 週未改變左心室質量指數｜左心室質量指數變化 +0.34 vs -0.07 g/m2.7(p=0.96)〔PMID 22337679〕
      • J-DAVID (JAMA 2018; PMID 30535217)：無次發性副甲亢透析患者使用 Alfacalcidol 未降低心血管事件風險｜心血管事件發生率 21.1% vs 17.9%(HR 1.25, 95% CI 0.94-1.67, p=0.13)〔PMID 30535217〕
  • 也有Effect of muscle(補vitamin D老人家似乎跌倒比例↓), pancreas CA(↑?↓?), colon(↓colon CA), breast CA(?), prostate CA(↑?↓?)
    • Reference:The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials.(2014 J Clin Endocrinol Metab)
      • Nonspecific musculoskeletal pain者有vitamin D deficiency者有93%, 所以uptodate建議nonspecific musculoskeletal pain者要check 25-OH vitamin D
      • VITAL (N Engl J Med 2019; PMID 30415629)：25,871 人大型 RCT，每日補充維生素 D3 5.3 年未降低侵襲性癌症或主要心血管事件｜心血管事件 HR 0.97(p=0.69)，侵襲癌 HR 0.96(p=0.47)〔PMID 30415629〕
      • VITAL-Kidney (JAMA 2019; PMID 31703120)：第 2 型糖尿病每日補充維生素 D3 追蹤 5 年未減緩 eGFR 衰退速度｜5 年 eGFR 變化 -12.3 vs -13.1 mL/min/1.73 m2(組間差 0.9, 95% CI -0.7 至 2.5, 無顯著差異)〔PMID 31703120〕

2.名稱#

  • Vit. D2=(ergocalciferol); Vit. D3=(cholecalciferol); 25(OH) D3=(calcifediol)=(calcidiol); synthetic analog of 1 (OH)-D2=(Doxercalciferol); 1(OH)-D3=(Alfacalcidol); 1,25(OH)2 D3=(Calcitriol); 1,25(OH)2 D3 analogue=(Maxacalcitol); 1,25(OH)2 D2 analogue=(Paricalcitol)

3.Origins#

  • Very few foods有vitamin D(除了魚肝油)
      • Wild salmon: 500-1000IU
      • Farmed salmon: 100-250 IU
      • Fortified(強化) milk: 100-200 IU
      • Natural salmon: 600-1000 IU
      • Tuna (canned): 230 IU
      • Cod liver oil: 400-1000 IU (also per 100g per tablespoon)
      • Shiitake mushrooms (fresh): 100 IU
      • Shiitake mushrooms (dried): 1600 IU
      • Egg yolk: 20 IU
      • Beef liver: 70 IU
      • Per 100 grams, unless otherwise specified.
      • Reference:Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).(2013 Curr Med Res Opin.)-table 3.
    • 所以有些國家會在牛奶或穀物添加vitamin D
    • 其實食物能獲得的很少, 約每天100-200 U
  • 有些食物有vitamin D2(t1/2:12hrs(D3的一半), potency也只有vitamin D3的1/2)或Vitamin D3(t1/2:24 hrs)

4.Mechanism#

  • [(7-dehydrocholesterol經UVB變成Vitamin D3) or (from 食物的Vitamin D2)]經liver變成25-OH vitamin D(t1/2:2-3W, bound to Vitamin D binding proteins, 會被GFR過濾出來再被Megalin 再吸收(見下述)), then經許多組織與kidney(proximal tubules)變成1,25 OH2 Vitamin D(t1/2:4-12hrs), kidney合成的calcitriol會放出來到血中但其他組織中合成的calcitriol不會(僅local effect)
    • 1-α hydroxylation會被hypocalcemia, hypophosphatemia, PTH, calcitonin(動物實驗中可微弱刺激近曲小管 1α-hydroxylase, 但人體生理調控仍以 PTH、低血鈣、低血磷為主)促進

5.Deficiency#

  • Vitamin D deficiency
    • Sun exposure↓, 黑人, burns, elderly(皮膚製造and儲存vitamin D↓, intake↓), breast-feeding infants
      • 註:台灣目前因為air pollutions, UVB被擋住, >95% people皆有25-OH vitamin D deficiency/insufficiency, 照陽光只會照到UVA產生skin cancer
      • 註:即使有照射很多陽光,有些人仍缺乏vitamin D(variable responsiveness to UVB)
        • Reference:Low vitamin D status despite abundant sun exposure(2007 J Clin Endocrinol Metab.)
    • Malnutrition, poor GI absorption(including gastric bypass, gastrectomy, pancreatic insufficiency, hepatobiliary tree, proximal small bowel disease or 其他會造成fat吸收不良的疾病)(脂溶性維生素; 看起來是前段腸胃影響大?)
      • 胃酸似乎和vitamin D absorption有關
  • 25 OH Vitamin D deficiency
    • Severe liver disease(liver cirrhosis)(除了↓25 OH hydroxylation外, 若有biliary problems, 也會↓vitamin D GI absorption)
    • Vitamin D-dependent rickets type 1B (VDDR-1B)
      • 25-hydroxylase loss of function mutation(AR)
    • Nephrotic syndrome, CKD
      • 註:CKD者更容易缺25-OH vitamin D and 1,25 OH vitamin D, 因為
        • 1.FGF 23↑-->↓1-α hydroxylase of kidney, ↓25-OH hydroxylase, ↑24-OH hydroxylase(就生理上, 是為了↓GI absorb P)-->(1.↓25-OH vitamin D; 2.↓1,25 OH vitamin D-->↓Megalin(見下述))
        • 2.Megalin↓(Megalin是p. tubules endocytosis 25-OH vitamin D-DBP complex and other proteins(含Alb)的receptor; 會被1,25 OH vitamin D stimulation)
          • Proteinuria者Megalin被其他proteins(including Alb)佔據, 導致25-OH vitamin D吸收↓, 進而導致1,25 OH vitamin D↓, 再惡性循環導致Megalin↓
          • 感覺本來正回饋是為了吸收尿蛋白, 但nephrotic range proteinuria反而因此有反效果(?)
        • 3.若ESRD者補充1,25 OH vitamin D就更抑制liver的25-OH hydroxylase使25-OH vitamin D↓, 也抑制各式組織的1-α hydroxylase並刺激↑24-OH hydroxylase
    • Many drugs(INH, Rifampin, phenytoin, carbamazepine, oxcarbazepine, phenobarbital, theophylline; 因為P450 enzymes↑使25-OH vitamin D代謝成inactive forms)
      • 建議用這些藥物者prophylactically補充vitamin D 400-4000 U/d
  • 1,25 OH2 vitamin D deficiency
    • ESRD
    • Vitamin D-dependent rickets type 1A (VDDR-1A)(=Pseudovitamin D-deficient rickets)
      • 1-α hydroxylase mutation(AR)
    • PTH↓
    • DM
      • 透析班盧教授:DM本身會↑ 24-OH hydroxylase!!!
    • 5-FU + Leucovorin(maybe due to decreased GI vitamin D absorption(mucositis) and decreased 1,25 OH vitamin D production)
  • Vitamin D resistance
    • Hereditary vitamin D-resistant rickets (HVDRR)(AR)
      • Case reports; due to vitamin D receptor mutations(有很多種mutations)
      • Tx:high dose Ca intake

6.Lab#

  • Indications for checking 25-OH vitamin D
    • If risk factors(+)(包含少照陽光, obese, osteoporosis, 黑人...其他見etiologies),...感覺都要測
    • 大多25-OH vitamin D 10-20ng/ml no S/S, but iPTH level 40-50%↑ with accelerated bone loss
      • 多No need of further surveillance, 但level在10-15之間要survey也可
    • 25-OH vitamin D <10ng/ml者會hypocalcemia, secondary hyperparathyroidism-->bone pain/Fx, osteomalacia, muscle weakness, muscle pain
      • Check diet, tissue transglutaminase Ab(celiac disease), LFT, abdominal echo, Cre, BUN, U/A, UPCR, drugs review, one touch, Ca, P, iPTH, X ray for bone pain sites
      • BMD不一定要測, 因為不管有沒有osteoporosis都要補, 可以補完再測BMD
        • 骨質疏鬆合併重度維生素 D 缺乏者(<10-20 ng/mL), 必須先補足維生素 D 再起始 bisphosphonate 或 denosumab, 以免誘發嚴重低血鈣

7.Goal and Tx#

  • Keep 25-OH vitamin D>30ng/ml(其實general population也要>30) 不同guideline有不同的normal range, 取交集是30-40ng/ml（>40-50ng/ml反而有increase Fx, increase some cancers(pancreatic, prostate...), increase mortality的疑慮）
    • 注意實驗室檢驗的25-OH vitamin D是否包含25-OH vitamin D2(因為有些人是補vitamin D2)
      • 由於實驗室量測問題與potency問題, uptodate建議補vitamin D3而非vitamin D2(2C)
    • General: 800-2000 IU(註:40IU=1ug)/d cholecalciferol(Vitamin D3) is likely sufficient and safe(by handbook of dialysis)
      • 補nutritional D身體會自己調控, dosage和上升的25-OH vitamin D不成線性上升, 所以補nutritional D不容易造成vitamin D intoxication, 但目前仍建議每天<4000U/d(不過deficiency者 or CKD-MBD者另當別論)
      • KDIGO 2017 CKD-MBD指引更新(Kidney Int 2017; PMID 28646995)：CKD G3a-G5不建議常規使用calcitriol/維生素D類似物，保留給重度且進行性次發性副甲狀腺亢進；可監測25(OH)D並依一般人群策略矯正缺乏〔PMID 28646995〕
      • Uptodate
        • If 25-OH vitamin D <10(1A)
          • 50000U/w for 6-8w then 800U/d, recheck level 3M later
        • If 25-OH vitamin D 10-20(1A)
          • 800-1000U/d, recheck level 3M later
        • If 25-OH vitamin D 20-30(2B) or normal adults
          • 600-800U/d
        • 若腸胃吸收不好, 有可能會需要很大量的daily dosage(even 50000U/d)

反向連結

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