Hypocalcemia may be acquired or hereditary. Etiology is most often autoimmune read more , autoimmune hypoparathyroidism associated with mucocutaneous candidiasis Candidiasis (Mucocutaneous) Candidiasis is skin and mucous membrane infection with Candida species, most commonly Candida albicans. (2012), Surface charge impact in low-magnesium model of seizure in rat hippocampus, Kidwell K. S., Kopp W. E., Albano E. A., Brown A. E. (2013), Ghosts in My Body: Seizure-like presentation of hypocalcemic tetany secondary to hypomagnesemia in a patient receiving cetuximab therapy for metastatic medulloblastoma, Kinoshita H., Kokudo T., Ide T., Kondo Y., Mori T., Homma Y., Yakushiji F. (2010), A patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizure and epilepsy, Persistence of the olfactory receptor current in a wide variety of extracellular environments, Korkmaz H. A., Dizdarer C., Ecevit C. O. Due to its current trace resemble letter A, it is usually referred to as A-type current (IA) (Birnbaum etal., 2004). Diagnose by estimation or measurement of ionized (not total) serum calcium. Accessibility Epub 2022 Jan 26. Because hypocalcemia is the major stimulus for PTH secretion, PTH normally should be elevated in response to hypocalcemia. As a library, NLM provides access to scientific literature. Thus, removing calcium facilitates sodium entry through CNG channels, providing a larger CNG current. Notably, this NALCN is not the voltage-gated sodium channel (NaV) that initiates an action potential. PMC Use for phrases If left untreated, severe hypocalcemia can cause life-threatening complications such as seizures and congestive heart failure. Provocative testing by injection of parathyroid extract or recombinant human PTH fails to raise serum or urinary cAMP. Introduction Symptomatic hypocalcemia in infants and children may manifest as laryngospasm, apnea, seizures, or cardiac arrhythmias and constitutes a medical emergency [ 1, 2 ]. Stiffening and spasms of your muscles (tetany). We did not include it in our analysis if the tested calcium concentration was beyond 5mM due to its irrelevance in the clinical setting. (b) Injected depolarizing current enhances firing frequency. Cleveland Clinic is a non-profit academic medical center. When no etiology (eg, alkalosis, renal failure, drugs, or massive blood transfusion) is obvious, further testing is needed (see table Typical Laboratory Test Results in Some Disorders Causing Hypocalcemia Typical Laboratory Test Results in Some Disorders Causing Hypocalcemia ). Reducing IA will reduce the firing threshold (Han etal., 2007). [19], Because a significant portion of calcium is bound to albumin, any alteration in the level of albumin will affect the measured level of calcium. Note. Second, external calcium can influx into the cells through various calcium-permeable channels such as VGCC, N-methyl-D-aspartate channels, and acetylcholine nicotinic receptors. Oral calcium for postoperative hypoparathyroidism, Oral calcium and vitamin D for chronic hypocalcemia. Therefore, these channels need to overcome a larger hurdle to activate. (https://www.merckmanuals.com/home/hormonal-and-metabolic-disorders/electrolyte-balance/hypocalcemia-low-level-of-calcium-in-the-blood), (https://www.ncbi.nlm.nih.gov/books/NBK344077/), (https://www.ncbi.nlm.nih.gov/books/NBK279022/). After the membrane potential repolarizes back to resting level, a further transient hyperpolarization may be present after the end of the action potential. Would you like email updates of new search results? When will my symptoms go away once I start my medication for hypocalcemia? Please enable it to take advantage of the complete set of features! Risk factors for severe hypocalcemia after subtotal parathyroidectomy include, Evidence of osteitis fibrosa cystica on bone x-rays. Give IV calcium gluconate to patients with tetany; treat others with oral calcium supplements. Transient K+ current is a unique voltage-dependent outward current because it spontaneously inactivates several milliseconds after channel activation. Second, the Mg2+ concentration varies among these studies. The symptoms of hypocalcemia depend on if its mild or severe. The firing frequency increased with the injected DC (Figure 1b). Accordingly, subclinical vitamin D deficiency is fairly common, especially during winter months in temperate climates among the elderly. PTH concentration should be measured as an assay of the intact molecule. The K+ flux across the membrane under resting conditions occurs through the K+ leak channel, a two-pore K+ channel family (K2P channel). Counterintuitively, however, clinical observation has frequently documented hypocalcemia's role in induction of seizures and general excitability processes such as tetany, Chvostek's sign, and bronchospasm. Wise etal. Because the Kir is only weakly inhibited by external calcium (Wegner, 1994), the contribution of Kir modulation in the situation of low external calcium may be small, if any. In the case reported, a combination of dietary and endocrinologic abnormalities resulted in hypocalcemic seizures, which continued despite aggressive correction of serum ionized calcium levels. doi: 10.7759/cureus.32407. Policy. [9] Calcium is tightly regulated by the parathyroid hormone (PTH). It can cause symptoms like tingling, muscle cramps, and heart rhythm problems that can range from mild to life-threatening. The GABA-b receptor is a metabotrophic receptor that enhances G protein-coupled inwardly-rectifying potassium channel (GIRK) channels, which provide a tonic hyperpolarizing current (Mutneja etal., 2005; Hearing etal., 2013). Reference ranges for serum calcium vary by age and sex; see Serum Calcium. These seizures likely occur in patients with predisposing endocrinological abnormalities or renal insufficiency with overall poor calcium homeostasis. (2004), Loss of seizure control due to anticonvulsant-induced hypocalcemia, Calcium indicators and calcium signalling in skeletal muscle fibres during excitation-contraction coupling, Progress in Biophysics & Molecular Biology, Bikson M., Baraban S. C., Durand D. M. (2002), Conditions sufficient for nonsynaptic epileptogenesis in the CA1 region of hippocampal slices, Birnbaum S. G., Varga A. W., Yuan L. L., Anderson A. E., Sweatt J. D., Schrader L. A. Increasing extracellular Ca2+ decreased the total CNG current (Kleene and Pun, 1996). Lu etal. Hypocalcemia (Low Level of Calcium in the Blood). This 20mV difference between K+ reversal potential and resting membrane potential is contributed by a small conducting Na+ leak channel (NALCN), which gives a depolarizing current (DC; Gilon and Rorsman, 2009). A serum ionized calcium concentration < 4.7 mg/dL (< 1.17 mmol/L) is low. 8600 Rockville Pike Unlike in developing countries where hypovitaminosis D and hypocalcemia constitutes a major cause of infantile seizures, the number of neonatal seizures attributed to hypocalcemia in developed countries has decreased dramatically due to the improvement of infant formulas and vitamin D supplementation. . For example, low serum calcium concentrations rarely occur in patients with large amounts of circulating calcitonin due to medullary carcinoma of the thyroid Medullary Thyroid Carcinoma There are 4 general types of thyroid cancer. Y1 - 1997/1/1. Hypocalcemia happens when the level of calcium in your blood (not your bones) is too low. Most of the time, an issue with your parathyroid hormone (PTH) levels and/or vitamin D level(s) is involved with the cause of hypocalcemia. Most thyroid cancers manifest as asymptomatic nodules. However, the same depolarizing pulse inhibits spontaneous inhibitory synaptic current. This is the most simple and straightforward pathway. If you dont consume enough calcium in your diet, your body takes calcium from your bones to use in your blood, which can weaken your bones. For epilepsy specialists or neurophysiologists, we recommend skipping some of the background information. IA provides a resistant force to hinder the start of action potentials (Han and Lucero, 2005). (2014), Hypocalcemic seizure in an adolescent with Down syndrome: A manifestation of unrecognized celiac disease, Cyclic nucleotide-gated channels contribute to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons, Lazarevic V., Pothula S., Andres-Alonso M., Fejtova A. 2022 Apr;38(2):119-126. doi: 10.1177/87551225211070978. Hypocalcemia is a treatable condition. Causes include chronic kidney disease, hypoparathyroidism, and metabolic or respiratory acidosis. 2022 Mar 22;2022:4064588. doi: 10.1155/2022/4064588. Symptoms of mild hypocalcemia can include: If left untreated, over time hypocalcemia can cause neurologic (affecting the nervous system) or psychologic (affecting the mind) symptoms, including: Severe hypocalcemia (very low levels of calcium in your blood) can cause the following symptoms: There are many complex functions and factors involved with maintaining a steady level of calcium in your blood and body. Hille attributed this effect to a simple surface charge. The external calcium represents blood calcium, where the physiological range of total calcium is in the range of 2.2 to 2.6mM. (a) Afterhyperpolarization determines the interspike interval. A basic rule of thumb is that a small AHP translates into a higher firing frequency while a larger AHP will reduce firing frequency. government site. ABSTRACT An eight-year-old boy presented to the emergency department for a first-time seizure. Acidosis increases ionized calcium by decreasing protein binding, whereas alkalosis decreases ionized calcium. (2007), Dopaminergic modulation of spinal neuronal excitability, Hearing M., Kotecki L., Marron Fernandez de Velasco E., Fajardo-Serrano A., Chung H. J., Lujan R., Wickman K. (2013), Repeated cocaine weakens GABA(B)-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex, Charges and potentials at the nerve surface: Divalent ions and pH, Hogan Q., Lirk P., Poroli M., Rigaud M., Fuchs A., Fillip P., Sapunar D. (2008), Restoration of calcium influx corrects membrane hyperexcitability in injured rat dorsal root ganglion neurons, Isaev D., Ivanchick G., Khmyz V., Isaeva E., Savrasova A., Krishtal O., Maximyuk O. Factors that predispose to Vitamin D-deficient Rickets include breastfeeding without formula or vitamin supplementation, very dark skin and . Before Acetylcholine M1/M3 receptors induce an increase in cyclic guanosine monophosphate (cGMP), which in turn opens cyclic nucleotide-gated ion channels (CNG). (b) Injected depolarizing, Summary of the target ion channels modulated by external calcium. increased responsiveness) due to the decreased interaction of calcium with sodium channels. Hypocalcemic seizure is uncommon, especially among adults. In type II vitamin Ddependent rickets, target organs cannot respond to calcitriol. Secondary hyperparathyroidism and hyperparathyroid bone disease can occur. Email: This article is distributed under the terms of the Creative Commons Attribution 3.0 License (, action potential, hypocalcemia, ion channel, neurophysiology, seizure, synaptic transmission, Ali F. E., Al-Bustan M. A., Al-Busairi W. A., Al-Mulla F. A. IV therapy should be continued until symptoms resolve and oral replacement can be initiated [2,41]. As the external calcium concentration is halved, threshold potential (63.3mV) almost equals the resting membrane potential (64mV), thus making the cells very likely to be excited. It manifests in childhood. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Seizures Associated With Bone Density Conservation Agents. If youre taking a medication that is causing your hypocalcemia, your healthcare provider may change it or adjust it in order to return your calcium levels to normal. Many different health conditions can cause hypocalcemia, and its often caused by abnormal levels of parathyroid hormone (PTH) or vitamin D in your body. Given the same magnesium concentration (2mM), a reduction of external calcium from 2 to 1mM increased action potential burst frequency from 28 to 171 Hz, a dramatic sixfold increase. Federal government websites often end in .gov or .mil. The patient had only signs of mild dehydration on physical exam and had an uneventful postictal recovery. National Library of Medicine Vitamin D deficiency, hypocalcemia, and severe hypophosphatemia occur. Affected patients have hypocalcemia, hyperphosphatemia Hyperphosphatemia Hyperphosphatemia is a serum phosphate concentration > 4.5 mg/dL (> 1.46 mmol/L). While multiple types of potassium channels contribute to AHP, it is the KCa channels that may fine tune the actual depth of the AHP (Sah, 1996). Clinical read more and often causes chronic tetany. Severe hypocalcemia (serum calcium < 7 mg/dL [< 1.75 mmol/L]) may cause hyperreflexia, tetany (paresthesias of the lips, tongue, fingers, and feet, carpopedal and/or facial spasms, muscle aches), or generalized seizures. Pseudohypoparathyroidism can occasionally be managed with oral calcium supplementation alone, but calcitriol at the above dose may be needed. According to this surface charge hypothesis, as more calcium binds to the outer surface, the transmembranous electric field takes on a more hyperpolarized nature. The age at which someone could develop hypocalcemia usually depends on the cause. Most of your bodys calcium is stored in your bones, but calcium is needed in your blood as well. T1 - Hypocalcemic seizures in neonates. official website and that any information you provide is encrypted The interval between adjacent action potential spikes (interspike interval) is a key factor that determines firing frequency (Han etal., 2007). When rat hippocampal slices were incubated in a low calcium solution for a prolonged duration of at least 60min, spontaneous epileptiform bursting appears on the extracellular field potential recording (Roper etal., 1992, 1993; Richardson and OReilly, 1995; Ghai etal., 2000). The institutionalized elderly are at particular risk because of decreased skin synthetic capacity, undernutrition, and lack of sun exposure. Physical examination was normal except for jitteriness. These data suggest an alternative sequential model: external calcium>CaSR>G-protein>KCa. Hypocalcemia also frequently accompanies colicky gastrointestinal symptoms, suggesting hyperexcitability in the vagal nerve system. If so, the ultimate effect on postsynaptic neurons will be quite complicated, depending on the relative weight of excitatory versus inhibitory inputs. It can also result from alterations in vitamin D metabolism as occur with certain drugs (eg, phenytoin, phenobarbital, rifampin) or from decreased formation in the skin due to lack of exposure to sunlight. Arch Intern Med. Hypocalcemia. This dramatic firing rate could be partially explained by an increase in resting membrane potential and a decrease of firing threshold. In vitamin D deficiency, osteomalacia or rickets may be present, usually with typical skeletal abnormalities on x-ray. (2005), Endogenous RGS proteins enhance acute desensitization of GABA(B) receptor-activated GIRK currents in HEK-293T cells, Multiple roles of calcium ions in the regulation of neurotransmitter release, Phillips C. G., Harnett M. T., Chen W., Smith S. M. (2008), Calcium-sensing receptor activation depresses synaptic transmission, Epileptiform activity in the dentate gyrus during low-calcium perfusion and exposure to transient electric fields, Roper S. N., Obenaus A., Dudek F. E. (1992), Osmolality and nonsynaptic epileptiform bursts in rat CA1 and dentate gyrus, Roper S. N., Obenaus A., Dudek F. E. (1993), Increased propensity for nonsynaptic epileptiform activity in immature rat hippocampus and dentate gyrus, Ca(2+)-activated K+ currents in neurones: Types, physiological roles and modulation, Neurotransmitter release: The last millisecond in the life of a synaptic vesicle, Tsai P. L., Lian L. M., Chen W. H. (2009), Hypocalcemic seizure mistaken for idiopathic epilepsy in two cases of DiGeorge syndrome (chromosome 22q11 deletion syndrome), Tsourdi E., Rachner T. D., Gruber M., Hamann C., Ziemssen T., Hofbauer L. C. (2011), Seizures associated with zoledronic acid for osteoporosis, The Journal of Clinical Endocrinology & Metabolism, Vassilev P. M., Ho-Pao C. L., Kanazirska M. P., Ye C., Hong K., Seidman C. E., Brown E. M. (1997), Cao-sensing receptor (CaR)-mediated activation of K+ channels is blunted in CaR gene-deficient mouse neurons, Wang T., Wang J., Cottrell J. E., Kass I. S. (2004), Small physiologic changes in calcium and magnesium alter excitability and burst firing of CA1 pyramidal cells in rat hippocampal slices, Wegner L. H., De Boer A. H., Raschke K. (1994), Properties of the K+ inward rectifier in the plasma membrane of xylem parenchyma cells from barley roots: Effects of TEA, Ca2+, Ba2+ and La3+, Wise A., Green A., Main M. J., Wilson R., Fraser N., Marshall F. H. (1999), Calcium sensing properties of the GABA(B) receptor, Divalent cation modulation of a-type potassium channels in acutely dissociated central neurons from wide-type and mutant Drosophila, Yano S., Brown E. M., Chattopadhyay N. (2004), Zuhlke R. D., Pitt G. S., Tsien R. W., Reuter H. (2000), Ca2+-sensitive inactivation and facilitation of L-type Ca2+ channels both depend on specific amino acid residues in a consensus calmodulin-binding motif in the(alpha)1C subunit, http://www.creativecommons.org/licenses/by/3.0/, http://www.uk.sagepub.com/aboutus/openaccess.htm, Only indirect evidence, mechanism unknown. [5] The normal range of blood calcium is typically between 2.12.6mmol/L (8.810.7mg/dL, 4.35.2 mEq/L) while levels less than 2.1mmol/L are defined as hypocalcemic. An official website of the United States government. Many different health conditions can cause hypocalcemia, and it's often caused by abnormal levels of parathyroid hormone (PTH) or vitamin D in your body. 9500 Euclid Avenue, Cleveland, Ohio 44195 |, Important Updates + Notice of Vendor Data Event, (https://www.ncbi.nlm.nih.gov/books/NBK430912/). Counterintuitively, however, clinical observation has frequently documented hypocalcemias role in induction of seizures and general excitability processes such as tetany, Chvosteks sign, and bronchospasm. Trousseau sign is the precipitation of carpal spasm by reduction of the blood supply to the hand with a tourniquet or blood pressure cuff inflated to 20 mm Hg above systolic blood pressure applied to the forearm for 3 minutes. It is these processes that we theorize may help shed light on the calcium paradox and lead to further understanding of the mechanisms behind production of seizures through hypocalcemia. Response can be dramatic but may last for only a few hours. Elevated serum alkaline phosphatase in such patients may be a sign of rapid uptake of calcium into bone. The external calcium concentration is relatively constant unless affected by a significant organ malfunction such as severe renal function impairment, tumor lysis syndrome, hyperparathyroidism, hypoparathyroidism, or severe insufficient vitamin D or calcium intake. Seizures during the neonatal period have a broad differential diagnosis, many with a specific treatment and prognosis. Hypocalcemia is diagnosed by a total serum calcium concentration < 8.8 mg/dL (< 2.2 mmol/L). Chvostek and Trousseau signs are easily elicited at the bedside to identify latent tetany. AHP=afterhyperpolarization. [citation needed], Hypoparathyroidism is a common cause of hypocalcemia. Diagnosis of vitamin D deficiency and dependency Diagnosis Inadequate exposure to sunlight predisposes to vitamin D deficiency. Hypocalcemia is a common side effect of having your thyroid removed (thyroidectomy). Furthermore, decreasing calcium current significantly reduced AHP. In agreement with this hypothesis, reducing external Ca2+ from 2 to 1mM resulted in a 100% appearance of recurrent or continuous seizure-like activity (Isaev etal., 2012). Several different health conditions can cause hypocalcemia. Because only the maternal allele for GNAS1 is expressed in the kidneys, patients whose abnormal gene is paternal, although they have many of the somatic features of the disease, do not have hypocalcemia, hyperphosphatemia, or secondary hyperparathyroidism; this condition is sometimes described as pseudopseudohypoparathyroidism. The following treatments and medications are often used for hypocalcemia: Risk factors for developing hypocalcemia can include having: Unfortunately, theres nothing you can do to prevent hypocalcemia. However, Wang etal. Vomiting. Dosing of rhPTH 1-84 begins with 50 mcg subcutaneously once a day along with a decrease in vitamin D dosing by 50%. Most infants with hypocalcemia are asymptomatic; those who present with symptoms most commonly present with increased neuromuscular irritability or seizures [ 1] and less commonly with stridor, wheezing, or vomiting caused by laryngospasm, bronchospasm, or pylorospasm, respectively [ 2 ]. Therefore, clinicians are advised to check calcium in cases of Anti-epileptic drug (AED) refractory seizures. Nevertheless, several studies primarily addressing other biophysical issues have provided some clues. In transient hypoparathyroidism after thyroidectomy or partial parathyroidectomy, supplemental oral calcium may be sufficient: 1 to 2 g of elemental calcium/day may be given as calcium gluconate (90 mg elemental calcium/1 g) or calcium carbonate (400 mg elemental calcium/1 g). The electrophysiological literature conventionally use external and internal as they refer to the preparation of experimental bath solution or pipette solution. Infections can occur anywhere and are most common in skinfolds, digital read more , and X-linked recessive idiopathic hypoparathyroidism. External calcium inhibits NALCNs, shifts the voltage dependency of voltage-gated Na+ channels, stabilizes CNG channels, reduces inward current through AMPA channels, and depresses the release of excitatory neurotransmitters. First-time seizures in pediatric patients are often benign and require only an outpatient workup; some are dangerous. J Child Neurol. Most medical literature prefer to use extracellular or intracellular to emphasize the anatomical concept. Hypocalcemia is a lethal complication that can lead to arrhythmia, heart failure, and seizure [ 1 - 3 ]. Although rhPTH 1-34 also has been shown to be effective in treating chronic hypoparathyroidism, it is not approved for this use in the US. This site needs JavaScript to work properly. 2002). People who have mild hypocalcemia often have no symptoms (are asymptomatic). As demonstrated by Hille, changing external calcium concentration had no effect on delayed rectifier K+ channel (Kdr) activation. However, because low plasma protein can lower total, but not ionized, serum calcium, ionized calcium should be estimated based on albumin concentration. In this review, we use this nomenclature interchangeably. Physiological Reviews 84: 803833. Guided by this information, we then further analyze the relevant ion channels individually. However, evaluation of isolated hypocalcemia does not mandate ECG testing. Seizures. Differential diagnosis and mechanisms. Background The diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Causes include chronic kidney disease, hypoparathyroidism, and metabolic or respiratory acidosis. did not provide any further analysis on the ion channel mechanism that affects these intrinsic firing properties. Cureus. Vitamin D deficiency and dependency Vitamin D Deficiency and Dependency Inadequate exposure to sunlight predisposes to vitamin D deficiency. Type II pseudohypoparathyroidism is even less common than type I. This bursting is not dependent on synaptic transmission because excitatory transmission blockers (AP-5/DNQX) had been included in the bath solution (Roper etal., 1992). Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Branco T, Cardoso A, Baltazar A, Gonalves C, Santos VC. National Library of Medicine Hypocalcemia can be potentially life-threatening if its not diagnosed and treated in time. These seizures likely occur in patients with predisposing endocrinological abnormalities or renal insufficiency with overall poor calcium homeostasis. Hypocalcemia-induced seizures, in particular, have attracted much clinical attention. Hypocalcemia is a common, treatable cause of neonatal seizures. The site is secure. Your healthcare provider may find mild hypocalcemia incidentally (by chance) from routine blood tests or by testing for other conditions. The numerical definition of high or low calcium was not uniform among these studies. Clipboard, Search History, and several other advanced features are temporarily unavailable. Hypocalcemic seizures are a known complication of Rickets. For patients with renal failure, calcitriol or another vitamin D analog that does not require renal metabolic alteration (eg, alfacalcidiol, dihydrotachysterol) should be used. A reasonable estimation would be 1.0 to 1.3mM free calcium bathing the cells outside the cell membrane. KCa channels have an intracellular domain that binds to intracellular calcium. We report national incidence estimates, and the demographic and clinical features of cases. The calcium paradox described above partially arises from the concept of extracellular (external) calcium and intracellular (internal) calcium. Muscle cramps involving the back and legs are common. Case Rep Neurol. An Infant with Recurrent Hypocalcemic Seizures. 1979 Oct;139(10):1166-71. doi: 10.1001/archinte.139.10.1166. The need for large amounts of parenteral calcium usually does not fall until the alkaline phosphatase concentration begins to decrease. government site. Neonatal hypocalcemic seizures: case report and literature review. Healthcare professionals and researchers have not yet determined how common hypocalcemia is. A Rare Etiology of Hypocalcemic Seizures in Adulthood: Clues to Diagnosis from Facial Dysmorphism We report a 40-year-old male who presented with seizures due to hypocalcemia. ECG may show arrhythmia or heart block occasionally in patients with severe hypocalcemia. The resting membrane potential was increased from 67.5 to 64mV. Be sure to contact your healthcare provider if youre experiencing symptoms. Experimental evidence suggests that reducing Mg2+ concentration decreases neuronal firing threshold as well but to a much less extent compared with Ca2+ reduction (Wang etal., 2004). A term girl neonate with no apparent risk factors developed seizures on day 5 of life, consisting of rhythmic twitching of all extremities in a migrating pattern. The influx of Na+ and Ca2+ through CNG channels contributes to the depolarizing plateau (Kuzmiski and MacVicar, 2001). In this review, we analyze the data of these studies and propose an integrative model to explain this hypocalcemic paradox.
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