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首頁 / 電解質與酸鹼 Electrolyte / Hypocalcemia 1.Normal physiology when ↓SCa#
注意sclerostin會↓renal 1α-hydroxylase, 也↓distal tubules吸收Ca
在生理上sclerostin是osteocytes分泌出來的, 會↓bone formation and ↑bone resorption and ↑UCa, 感覺是一種bone覺得自己Ca太多放出來調控的東西
2.Prevalence#
其實不少見
住院病人:10-18%; ICU Pts:60-80%
和hypomagnesium的prevalence類似
Neuro
Spasm(可seizure(大多是simple partial seizure(Jacksonian seizure)), laryngospasm, bronchospasm, respiratory muscle spasm...)->myalgia
可stiffness and clumsiness
Trousseau's sign
好像蠻準的, >90%的sensitivity and specificity
綁血壓帶above SBP 10mmHg > 3mins-->carbopedal spasm(typical:adduction of the thumb, flexion of the MCP, extension of IP joints, and flexion of wrist)
因為 ischemia-->↑↑ excitability of the nerve trunk under the cuff(Maximal at 3mins, 接下來會慢慢回復 )
Chvostek's sign
Tap the facial nerve anterior to the ear-->ipsilateral facial muscles contraction
不過normal people有10%(+), 而mild hypocalcemia Pts有29%(-)
Paresthesias (多start from peri-oral, acrals)
Papilledema (even optic neuritis)/IICP /pseudotumor cerebri !!!!!!!Autonomic
diaphoresis, biliary colic, bronchospasm...
上述都源於神經容易放電?
可Fatigue, anxiety, and depression, memory loss, even confusion, delusion, hallucinations, and frank psychosis
CV
Refractory HF
可能因為Ca和excitation-contraction coupling and epinephrine-induced glycogenolysis in the heart有關
Hypotension
QTc prolongation(可TdP,但是比hypokalemia or hypomagnesemia少見得多)
Arrhythmia(rare)
若是Chronic hypoparathyroidism可以basal ganglia calcifications(up to 20%!!)-->PD, dementia; anterior/posterior subcapsular cataracts/Keratoconjunctivitis, abnormal dentition(dental hypoplasia...)/bone
Dry/coarse/puffy skin/alopecia/brittle nails
Bleeding tendency(?)
4.Etiology#
Spurious hypocalcemia
MRI contrast若使用[(gadodiamide or gadoversetamide) + (blood test of Ca soon after contrast injection) + (colorimetric assays for Ca)]可導致Spurious hypocalcemia
I
Acute pancreatitis(iPTH↑)
Pancreatic enzymes溶解fat而↑free fatty acid-->binds Ca
Sepsis/HIV/sarcoidosis/CaSR activating Ab/APS 等副甲狀腺相關成因 → 見下方 Hypoparathyroidism 段落
M
Osteoblastic metastasis(breast CA, prostate CA(advanced prostate CA 56%↓ionized Ca, 34%↑iPTH)(iPTH↑)
不過breast cancer, prostate CA也可hypercalcemia(兩者都可以HHM and LOH and 分泌cytokines而hypercalcemia)
Tumor lysis syndrome(iPTH↑)
M
Vitamin D deficiency(iPTH↑)
詳見-Vitamin DVitamin D -5.Deficiency
大多要到level<10ng/ml才會hypocalcemia, 不然會藉由iPTH↑而維持血鈣
Hypoparathyroidism
I
HIV(iPTH↓)(原因未知, 會vitamin D deficiency(malabsorption, PI induced decreased hydroxylation),... without compensatory increase of iPTH; 此外也有很多drugs(tenofovir induced Fanconi syndrome...), Abx...影響Ca2+)
Sepsis(upto 80-90% hypocalcemia! )(iPTH↓?)
低鈣原因包含GI吸收↓, iPTH resistance↑, iPTH secretion↓, vitamin D↓
Due to cytokines and hypomagnesium...
註:critical illness者會因為各種原因而hypocalcemia, hypomagnesium, hypophosphatemia
I
Sarcoidosis(parathyroid infiltrations)(iPTH↓)
Sarcoidosis多為hypercalcemia...
Isolated hypoparathyroidism due to activating Ab(non-destructive) to CaSR(iPTH↓)
Autoimmune polyglandular syndrome type 1(APS-1) (又叫Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED); AIRE gene mutation, AR )(APS-2/Schmidt syndrome是Addison+自體免疫甲狀腺/T1DM, 通常不含hypoparathyroidism)
Chronic mucocutaneous candidiasis(先, since childhood), then hypoparathyroid(中), then primary adrenal insufficiency(後, during adolescence))(iPTH↓)
M
Meta to parathyroid(iPTH↓)
Amyloidosis depositions(PTH↓)
M
Hypomagnesium(下述)
Hypermagnesium(下述)(PTH↓)
Iron overload(Infiltration of the parathyroid gland; also↑FGF23 而↓PTH↓vitamin D)(iPTH↓)
Wilson's disease(因為deposition of copper in parathyroid)(PTH↓)
註:Wilson's disease也會造成RTA type I and type II, 因此也會造成medullary nephrocalcinosis
M(the most common)
Post-thyroidectomy/parathyroidectomy, post-neck R/T
Total thyroidectomy: 20% transient, 1-3% permanent hypoparathyroidism
可transient, permanent or intermittent
可因為reserve↓, 導致intermittent hypoparathyroidism
注意hyperthyroidism因為thyroid被切掉也可hungry bone syndrome而hypocalcemia(註:also hypophosphatemia and hypomagnesium)
C
Autosomal dominant hypocalcemia(ADH, 也叫autosomal dominant hypoparathyroidism；ADH1=CASR 活化突變、ADH2=GNA11 活化突變；多為輕中度低血鈣)；其中少數嚴重 CASR 活化突變合併 Bartter 樣失鹽者稱 Bartter syndrome type V(iPTH↓)
=FHH的相反
Activating mutation of CaSR(ADH type 1)
Gain of function mutations of G-α-11(CaSR的下游)(ADH type 2)
所以confirm by genetic tests
S/S
多asymptomatic hypocalcemia(Ca 1.5-2mM), low-normal iPTH level(因為也involve CaSR of parathyroid), high UCa with recurrent nephrocalcinosis/nephrolithiasis(尤其補Ca and vitamin D後會更嚴重), hypomagnesium(50%)
因為有involve parathyroid的CaSR所以才比較會hypocalcemia
Tx
除非有S/S才治療
有S/S者可給Ca and vitamin D with UCa monitoring; 似乎給teriparatide也有幫忙; 也可以用thiazide↓UCa
感覺給thiazide比較好?以免nephrocalcinosis...
DiGeorge syndrome
外觀異常(cleft palate...), TOF, hypoparathyroidism, 胸腺發育異常...
Isolated familial hypoparathyroidism
只影響parathyroid, neonates就會severe hypocalcemia
Hypoparathyroid, deafness, and renal anomalies (HDR)...
Any cause of hyperphosphatemia(iPTH↑), rhabdomyolysis(因為1.hyperphosphatemia, 2.Ca入injuried muscles; 註:所以post AKI of rhabdomyolysis因為Ca2+被放出來有可能hypercalcemia)(iPTH↑)
Hypomagnesium(iPTH↑ or normal or ↓)
常合併Ca↓：
先iPTH resistance↑，後iPTH secretion↓，另1,25 OH vitamin D↓=>可能也和osteoporosis有關
多要Mg<0.5mM才會發生symptomatic hypocalcemia(但heart本身有問題者略低可能就會arrhythmia)
小心甚至有Normomagnesemic magnesium depletion(見hypomagnesiumhypomagnesium )
機制是intracellular Mg depletion-->腺苷酸環化酶活性受損-->cAMP 生成↓-->PTH 分泌↓（標靶器官 PTH 反應亦減弱）
Severe hypermagnesium(>2.5mM)(因為↓PTH secretion)
因為會直接刺激extracellular CaSR(parathyroid+kidney)
所以高低血鎂都會刺激CaSR
Drugs
Bisphosphonate, Denosumab, calcitonin, Cinacalcet(5% Pts hypocalcemia with Ca <1.87, 見CKD-CKD/ESRD-Tx(Anemia/Ca/P/Vitamin D/iPTH/drugs/comorbidities)-cinacalcet)
Foscarnet(Intravascular complexing with calcium (所以total Ca no change but ↓free form Ca) and tubular dysfunction)
Lasix
Phenytoin...
因為P450 enzymes↑使25-OH vitamin D代謝成inactive forms 見Vitamin D deficiency
Cisplatin(by hypomagnesium; also Fanconi syndrome)
5-FU + Leukovorin(maybe due to decreased GI vitamin D absorption(mucositis) and decreased 1,25 OH vitamin D production)
Fluoride poisoning(formation of fluorapatite)
Antacids(因為有胃酸Ca2+才比較會吸收)
所以PPI, H2 blockers...會使Ca2+吸收↓
Acute respiratory alkalosis(iPTH↑)
pH↑0.1, free form Ca↓0.04mM
Lactic acidosis(total Ca no change)
Lactate會和Ca結合, 所以total Ca no change but ↓free form Ca
所以理論上lactic acidosis者要用gas機看free form Ca
註:Lactate, citrate, acetate, phosphate都會和Ca結合
C
Idiopathic hypercalciuria(UCa>4mg/kg/d) renal leak type
註:共有三種type
Absorptive:GI uptake↑-->這個不會hypocalcemia(應該normocalcemia + mildly decreased PTH + UCa↑)
Resorptive:↑bone turnover-->loss of bone Ca to urine(應該normocalcemia + suppressed PTH + UCa↑)
Renal leak(應該hypocalcemia + PTH↑ + UCa↑)
Pseudohypoparathyroidism(renal unresponsiveness to PTH)(iPTH↑)
Type 1(renal resistance to PTH)
Type 1a(renal resistance to PTH)(AD)
會hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism, hyperparathyroid bone disease(osteitis fibrosa)
Bone會Albright hereditary osteodystrophy(AHO)
Round face, short stature, short fourth metacarpal bones, obesity, subcutaneous calcifications, developmental delay, mental retardation
Type 1b(renal resistance to PTH)(AD)
Only renal presentation
沒有AHO
Type 1c
S/S類似type 1a, 但是mutation各式各樣
Pseudo-pseudohypoparathyroidism(PPHP)(vs. Pseudohypoparathyroidism type Ib)
沒有renal presentation==>normal Ca, normal P, normal iPTH level
有Albright hereditary osteodystrophy(AHO)
Type 1a 和PPHP都是loss of functional mutation of GNAS1 gene
和各種receptor接上ligand後G protein刺激cAMP↑有關; mutation會導致GnRH, FSH, LH, TSH, PTH, glucagon, calcitonin resistance
PHP第一屆國際共識指引(Nat Rev Endocrinol 2018; PMID 29959430)：PHP診斷依據PTH抗性、異位骨化、短指(brachydactyly)與早發肥胖等主標準，並須以分子遺傳檢測確認GNAS突變/表觀遺傳異常〔PMID 29959430〕
Maternal transmission of the mutation causes type 1a
Paternal transmission leads to PPHP(父親傳來一個P...)
Type 1b是mutation of proximal tubules(only)中的regulatory elements of GNAS1, 所以只有renal presentation
Type 1c是表現類似type 1a但是mutation各式各樣
Type 2
↓phosphaturic response to PTH but a normal increase in urinary cAMP
沒有AHO
mutation各式各樣
FHHNC
mutation of Claudin-16 or mutation of Claudin-19
H
Massive blood transfusion/TPE(EDTA, Citrate)(iPTH↑), 尤其是liver/renal failure者
total Ca no change but ↓free form Ca
註:不過一般liver failure者是因為一些發炎物質導致bone resorption↑而hypercalcemia
O
CKD(hyperphosphatemia, vitamin D deficiency)(iPTH↑, secondary hyperparathyroidism)
基本上要eGFR<15才會hypocalcemia
5.Lab#
Check (HIV), septic workup, lipase, PSA, CA15-3, VBG, Alb, Ca, iCa, ALP (high in vitamin D deficiency with secondary hyperparathyroidism; osteoblastic meta), Cre, BUN, CK, P, Mg, iPTH , iron profiles(If low iPTH), ceruloplasmin(if low iPTH), vitamin D們, drugs/transfusion review, UCa(low in vitamin D deficiency), UMg(assess for hypomagnesium)
P↑ in tissue breakdown, CKD, iPTH↓, pseudohypoparathyroidism
P↓ in vitamin D deficiency, very poor intake
P normal in mild vitamin D deficiency, hypomagnesium(!!不能因為PTH↓而↑嗎?, 因為PTH level變化沒有很大?)
6.Tx#
大多治療目標是low-normal range SCa level
Tx of underlying, including hypomagnesium
Mg supplement
16mEq IF 10-20mins then 8mEq/100ml/hr until SMg >0.4mM 若找不出原因of hypocalcemia, 仍可能是chronic malabsorption or alcoholism造成的Normomagnesemic magnesium depletion, 仍可考慮補充Mg
Hypoparathyroidism
ESE成人慢性副甲狀腺機能低下指引(Eur J Endocrinol 2015; PMID 26160136)：標準治療為活性維生素D類似物合併口服鈣劑，治療目標維持血鈣於正常偏低值(low-normal)、避免高尿鈣與鈣磷沉積〔PMID 26160136〕
Hypoparathyroidism Tx 用 calcitriol 常規上會↑GI磷吸收而惡化高磷 (需監測P/Ca、配磷結合劑與低磷飲食; 且無PTH時FGF23的phosphaturic效果變差); (原筆記曾寫「calcitriol反而↓高磷」之孤例觀察, 與主流生理矛盾且同庫vitamin D intoxication→磷↑不符, 已標記存疑)
也見CKD/ESRD-Tx(Anemia/Ca/P/Vitamin D/iPTH/drugs/comorbidities)-hungry bone syndrome
也有人用teriparatide 20ug BID來治療hypoparathyroidism, 似乎有效
Palopegteriparatide(Yorvipath) : 長效 PTH 前驅藥，用於傳統治療控制不佳之慢性副甲狀腺機能低下；PaTHway (Adv Ther 2024; PMID 38691316)：長效 PTH 替代療法 52 週顯著改善腎功能並脫離傳統療法｜52W 時 95% 患者完全擺脫口服鈣劑與活性 D 且維持血鈣正常〔PMID 38691316〕
Denosumab注意 : 低eGFR/CKD者用後嚴重低血鈣風險顯著↑，用前矯正Ca/VitD並於每次注射後2-10週密集監測；與bisphosphonate不同, denosumab不需因腎功能調降劑量〔FDA 2024〕
Vitamin D deficiency
50000 IU nutritional D QW for 6-8W, then 800-1000 IU/d
Algorithm
IF Ca 4.5-9mEq/(in 50-100ml N/S or D5W) over 10-20mins(更快可serious cardiac dysfunction including cardiac arrest, 有用digoxin者更要小心digoxin intoxications; 所以除非生命緊急情況, 不然給Ca2+不要IV) (May repeat after 10 to 60 mins if still S/S(+)), followed by cIF 2.5mEq Ca(50ml)/hr(泡成50mEq/L); recheck SCa Q4-6H
註:Ca solution若濃度>0.1mEq/ml(應該是peripheral line?)會vein irritation
=9.3mEq/100ml N/S over 60 mins, recheck SCa 1hr after completion, if still S/S(+) and hypocalcemia, repeat once; followed by Ca 46.5mEq/L, 50ml/hr, recheck SCa Q4-6H with titration(typical adult dosage: 0.025-0.075mEq Ca/kg/hr); if SCa in normal range, change to PO form(Elemental Ca 1.5-2g/d first; 所以約Canat 2# Q6H first ), recheck SCa QD, titrate up elemental Ca 1-2g/d as needed
Q6H 9.3mEq IF Q6H recheck也可
Indication for IF Ca(any)
S/S(+)
Severe neurologic S/S(spasm, tetany, seizure)
Or CV S/S(prolonged QTc, refractory HF, arrhythmia)
No S/S but acutely decrease [cCa to <1.9mM(未<1.9mM但acute ↓仍可考慮) or iCa<0.8mM]
Other mild S/S with cCa > 1.9 mM but no improvement after PO Ca
Poor GI absorption
勿和其他含P or bicarbonate的IVF, or Rocephin一起給
PO AC Elemental Ca 1.5-2g/d(titrate up 1-2g/d or change to IF if no improvement); recheck QD if acute Ca↓, recheck QW if chronic Ca↓, if stable-->Q3-6M
Vitamin D if (hypoparathyroidism or vitamin D deficiency)
