Alkalosis-->Ca and Alb結合↑, 故Ca free form↓(在acute respiratory alkalosis下, pH↑0.1, free form Ca↓0.04mM); acidosis則相反
所以小心有時候pre-ESRD with hypocalcemia and metabolic acidosis, correct metabolic acidosis會使free Ca↓, 會造成hypocalcemia S/S跑出來; 若CKD with metabolic acidosis and low Alb會難以評估free from Ca level, 因為metabolic acidosis ↑free Ca ratio, Alb correction equation會高估Ca(實際free Ca要更低), 一高一低就不知free Ca level, 建議用gas機直接看
EKG:QTc shortens but rare arrhythmia(可AVB, bradycardia)
不過若cCa>4可T wave widening而↑QT interval !!
註:Mg>2.5也會↑QT interval !!
Hypertension
GI:N+V, PUD(less common; 原因為Ca↑刺激gastrin分泌), abdominal pain, pancreatitis(less common; 原因為deposition of Ca in pancreatic ducts and Ca激活trypsinogen within the pancreas), constipation(decreased smooth muscle tone(原因見Resting membrane potentialResting membrane potential) and/or abnormal autonomic function)
Nephro
(1)Impaired generation of interstial osmotic gradients(1.CaSR in the basolateral membrane of TAL被激活, 導致↓ROMK channel, 導致K漏不回tubular lumen, 導致NKCC2無法運作, 導致lumen-positive transepithelial voltage↓, 導致paracellular Na, Ca, Mg無法吸收, 總結果減少loop of henles吸收Na, K, Cl and Ca, Mg-->久了減少osmotic gradient(如下圖) 2.此外CaSR的activation似乎也促進PGE2產生-->↓NKCC2, 也減少osmotic gradient(此作用似乎和angiotensin II有關(?), 因為ARB在老鼠model可reverse此反應)) + (2)刺激CaSR也會↓thin ascending limb吸收NaCl(↓ClC-Ka and ↓paracellular Na+ resorption) + (3)Downregulate of AQP2(Ca被CaSR in the luminal membrane of principal cells sense-->↓AQP2 and ↓ENaC; 為了沖掉Ca的生理保護機制?; 似乎也有其他mechanism↑AQP2 degradation) + (4)Ca deposit in medulla(->cTIN)
Cause NDI(基本上要>2.75mM才明顯), polydipsia, nephrocalcinosis, nephrolithiasis
(rare) type I RTA
但好像也可以metabolic alkalosis(due to hypovolemia, RAAS↑, and 直接刺激分泌H+???(milk-alkali syndrome))
AKI/CKD
Due to renal artery vasoconstriction, dehydration, cTIN/TAIF
Muscle weakness, fatigue, DTR decreased, myalgia, arthralgia/pseudogout, bone pain(may be due to underlying)
Pseudohypercalcemia due to hyperalbuminemia(所以要校正by Alb) or Ca-binding paraproteins in MM(globulins only minimally bind calcium所以除非level很高才會pseudohypercalcemia or 某些特別會binding Ca的paraproteins(似乎多為IgG?, 不過IgG不是帶正電嗎???))
Loss-of-function mutation of CaSR of parathyroid and kidneys(renal機制見hypomagnesiumhypomagnesium-Renal handling of Mg)
Type 1 FHH是CaSR loss of functional mutation; type 2 FHH是GNA11 (guanidine nucleotide-binding protein alpha-11) gene mutation; type 3 FHH是AP2S1 (adaptor-related protein complex 2, sigma 1 subunit) gene mutation
Type 2 and 3的gene一樣是mutation後CaSR對Ca2+不敏感
所以需要higher than normal Ca level(多2.6-3mM) 才能suppress iPTH
iPTH多在high normal range(40-60)
也會mild elevated Mg level, 因為Loops of henle在回收Ca時也會回收Mg
但若在severe S/S者可以考慮subtotal parathyroidectomy or cinacalcet
Neonatal severe hyperparathyroidism(NSHPT)(AR)
=AR form的FHH, 多發生在近親交配的FHH Pts子女
Usually lethal !!
會severe hyperparathyroid hyperplasia, PTH↑↑, severe hypercalcemia(cCa多>3.75), hypocalciuria, severe bone disease...
需要total parathyroidectomy
Primary(single adenoma佔PHPT的80-85%, 剩下的15-20%為hyperplasia, <1%是parathyroid carcinoma(carcinoma多為large(Ex:3 cm), irregular, hard tumor); PHPT各年齡層皆有, 不過老人比較多, peak:60 y/o)/tertiary hyperparathyroidism(小心有時候post-renal transplantation, 因為P↓(40% within the 1st yr, 10% by 4 yrs) +1,25-OH vitamin D↑+原先parathyroid hyperplasia+resorption of tissue calcium phosphate depositions可hypercalcemia(約30% within 1 yr after OP; 多within 3M after OP), 大多parathyroid hyperplasia會慢慢回復(within 1yr but may persist for yrs), 血鈣也跟著下降, 不過有時候hyperplasia不會完全回復)
Avoid sun exposure and vitamin D intake in this situation!
Malignancy(造成hypercalcemia時多clinically apparent)
最容易hypercalcemia的Cancer為breast(但也可以osteoblastic meta而hypocalcemia), lung cancer and MM
A higher incidence of cancer in Pts with primary hyperparathyroidism and a higher incidence of primary hyperparathyroidism in Pts with cancer
所以cancer(+)者的hypercalcemia仍都要測iPTH
註:有PTH是cancer promotor的說法
Metastasis(direct ↑ local osteolysis by the tumor cells(可能仍是藉由local secretion of cytokines(含local secretion of PTHrP, IL-1,6,8...))(也叫local osteolytic hypercalcemia(LOH))(20% of malignancy related hypercalcemia)
iPTH and calcitriol level are low in these Pts(PTHrP不太會刺激1-α hydroxylase, 所以1,25 OH vitamin D level是低的!)
PTHrP可刺激renal and bone的receptors, 其他處不太有反應; 在renal effect上和PTH差不多, 在bone effect上會bone formation↓↓(原因未知, 可能是PTHrP和osteoblast的PTH receptor affinity較差?) and bone resorption↑↑
Uptodate說可以當成tumor markers, 且可預期bisphosphonate的反應, if PTHrP>12 pmol/L, 預期bisphosphonate↓Ca幅度小, 且<14天常需再打且survival較差
Activation of extrarenal 1-α hydroxylase(lymphoma, MM, Ovarian dysgerminomas; by activated macrophages and/or malignant lymphocytes)
Summary
所以breast CA, prostate CA, leukemia, lymphoma皆可因為osteolytic lesions, cytokines, PTHrP而hypercalcemia(breast CA, prostate CA也可因為osteoblastic meta而hypocalcemia); lymphoma更多activation of extrarenal 1-α hydroxylase
Metabolic
Advanced liver disease(acute or chronic)
看cases的lab, 幾乎都是一些T-bil很高 or PT prolongation者
機制未明, 可能是一些發炎物質導致bone resorption↑
Reference
Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!(2016 Clin Cases Miner Bone Metab.)
Hypercalcemia. A complication of advanced chronic liver disease.(1987 Arch Intern Med.)
Acromegaly
大多因為coexisting hyperparathyroidism(MEN I?), 但也可以1, 25 OH vitamin D↑(可能是因為direct action of growth hormone on the renal 1-α hydroxylase activity)
15-20%有hypercalcemia, 不過多mild hypercalcemia而已
Hyperthyroidism
因為thyroid hormone ↑ bone resorption(可能和beta-adrenergic regulation有關)
Estrogen or Tamoxifen in bony metastatic breast CA(因為estrogen刺激ER(+) breast cancer cells ↑bone resorption)-->可以acute hypercalcemia, 多1W左右(4-11 days)after drugs use
其實estrogen也會↑TRPV5
Post-AKI(especially in rhabdomyolysis)
可能是因為mobilization of Ca in injuried muscles(若rhabdomyolysis), improving hyperphosphatemia, mild secondary hyperparathyroidism(delayed resolution of secondary hyperparathyroidism), unknown mechanism of increased calcitriol level
註:所以AKI due to rhabdomyolysis期間會因為hyperphosphatemia and Ca2+跑入injuried muscles而hypocalcemia
另外, If PHPT with 25-OH vitamin D <=20ng/ml則仍建議小心補充25-OH vitamin D(到>20ng/mL)(G2C) with monitoring SCa and UCa
with Ca2+ intake as general population
(Ca intake < 0.4g/d + reducing oxalate intake(以免因為low Ca diet導致oxalate吸收↑導致calcium oxalate stones)) + (avoid sun exposure if Vitamin D related hypercalcemia)
Hydration 200-500ml/hr(似乎太多?可能daily N/S 3000-4000ml/d即可?) adjusted to keep U/O 100-200ml/hr
小心CHF, AKI, elderly易fluid overload
if fluid overload-->stop hydration and use loop diuretics(diuretic並非routine用, 以前routine用是因為very aggressive hydration(10L/d))
Brenner:hydration+loop diuretics約可↓SCa 0.5-1 mM
Calcitonin
Only when Ca > 3.5 and S/S(+)
4 IU/kg Q12H for 2 days, if 2-3 days no effect可double dose (up to 8 IU/kg Q6H)
Onset:4-6 hrs; duration:2 days(tachyphylaxis due to calcitonin receptor downregulation), 效果不強最多↓0.3-0.5mM Ca
↓osteoclast function and ↓kidney再吸收Ca and P
大多沒什麼S/E除mild nausea and rare allergy
抑制Osteoclasts
Endocrine Society 2023 惡性高血鈣指引 (JCEM 2023; PMID 36545746)：
強烈建議使用 Denosumab 或 IV 雙磷酸鹽（Zoledronic acid 或 Pamidronate）作為成人惡性高血鈣（HCM）第一線治療。
條件式建議（Conditional recommendation）：優先選用 Denosumab 勝於 IV 雙磷酸鹽（降鈣療效持久且免除雙磷酸鹽之急性腎毒性風險）。
重度惡性高血鈣（cCa >3.5 mM 或 >14 mg/dL）：起始建議合併 Calcitonin +（Denosumab 或 IV BP），兼顧快速起效（4-6 小時）與持久抗骨吸收。
重度低血鈣最常發生於每次注射後 2 至 10 週（2 to 10 weeks post-dose）。
用藥前必須確認血鈣正常並補足維生素 D 缺乏（25-OH VitD）；用藥期間必須常規合併補充口服鈣劑及活性維生素 D（Calcitriol 或 Alfacalcidol）；每次注射後（特別是第 2-10 週）必須密集監測血鈣。
Bisphosphonate{Aredia(pamidronate) 一般60-90mg(有人說60mg if Ca 3-3.5, 90mg if Ca>3.5) over 2-4hrs[(30-45mg over >4hrs) if [AKI(+) or eGFR<30]] or [Zometa(zoledronate)(better effect, more durable but more S/E(more renal toxicity and more ONJ))一般4mg over 15-30mins (4mg IF over "30-60mins" if AKI(+)(註:eGFR<30不建議使用Zometa)]}
Zometa 4mg(4mg, 8mg效果沒差且8mg more ACM and more renal toxicity) vs. Aredia 90mg
Major pooled analysis(J Clin Oncol 2001; PMID 11208851)：Zometa D10 complete response率較高(88.4% vs 69.7%)，duration亦較長〔PMID 11208851〕
Brenner(p798):Ibandronate(Boniva) seemed minimal to no nephrotoxicity
Brenner(p1799):A newer agent, ibandronate, highly protein-bound, a feature that reduces the risk of rapid influx of the drug into the tubular cells, thereby reducing the risk of renal toxicity
P可高可低(因為↓bone釋出P and ↓Ca->↑iPTH->↑腎臟排除P; but bisphosphate本身促進腎臟再吸收P)
ONJ, atypical femur fractures(多longterm, high dose bisphosphonate才會造成)
