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RomanianJournalofOralRehabilitation Vol.6,No.3,JulyͲSeptember2014

HYPERCALCEMIA IN CHILDREN Smaranda Diaconescu, Nicoleta Gimiga, Claudia Olaru*, Marin Burlea “Grigore T. Popa" University of Medicine and Pharmacy - Ia܈i, Romania, Faculty of Medicine, Vth Pediatric Clinic, "Sf. Maria" Children's Hospital

*Corresponding author: Claudia Olaru, MD, PhD Student “Grigore T. Popa" University of Medicine and Pharmacy - Ia܈i, Romania; e-mail: [email protected]

ABSTRACT Hypercalcemia is less common in children than in adults, but is more likely to be clinically significant in younger patients as routine biochemical screening tests are rarely performed in children. The serum levels are maintained through the interplay of parathyroid, renal, and skeletal factors. The most common causes of hypercalcemia are primary ( or cancer) but a variety of unusual etiologies must be considered in children. The initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium. In most cases, hypercalcemia is due osteoclastic bone resorption, and the effective treatment is based on agents that inhibit or destroy osteoclasts . Parathyroid surgery is recommended for all children with primary hyperparathyroidism.

Keywords: hypercalcemia, pediatrics, parathyroid

Hypercalcemia is not a common pediatric regulatory hormones [2]. The three problem; the actual incidence in children is predominant sources of calcium and targets unknown, although it is less common than in for regulation are the bones, renal filtration adults. In adults, hypercalcemia is the primary and reabsorption, and intestinal absorption. malignancy-associated endocrine/ The major regulators of calcium levels are disorder; it is present in 5% of all (PTH) and vitamin D, malignancies, or in 15 per 100,000 total which target the bones, intestine, and patients [1]. The normal values of to increase serum calcium. Calcitonin, a more calcium in children varies from 8.5 to 10.3 minor player in regulation, decreases serum mg%. Hypercalcemia is considered, calcium by its effects on bone and kidney. depending on age, at the following values: premature -> 9 mg%, term newborn -> 10, 4 Etiology mg%, child / adolescent -> 10.4 mg% . Most Hypercalcemia is caused by either primary of the body calcium (98% is in the skeleton hyperparathyroidism or cancer in over 90% of and only 2% is in circulation; half of this one cases. The rest of the etiologies are numerous. is free calcium (ionized) Ca++, (2)Primary hyperparathyroidism is a physiologically active. 1% is fastened to the pathologic and unregulated excess of PTH rest of the serum proteins. Calcium leading to elevated calcium. Malignancy is absorption and regulation involve a complex the most common cause of hypercalcemia interplay between multiple organ systems and that leads to inpatient care. Other less

91 RomanianJournalofOralRehabilitation Vol.6,No.3,JulyͲSeptember2014 frequent etiologies are bone diseases, determining the etiology may be more granulomatous conditions, and diet. In the important than the electrolyte imbalance case of malignancy or granulomatous disease, itself.

Table 1. Calcium physiology

Hormone Efect Bone Gut Kidney

Ca reabsorbtion PTH K Ca L Po4 K Osteoclasts Indirect / Vit. D Po4 excretion K Ca K Po4 Vitamin D3 K Ca K Po4 Indirect action Indirect action absorbtion Inhibate Calcitonin L Ca L Po4 Indirect action Ca and Po4 excretion osteoclasts

Hyperparathyroidism: rare instances a parathyroid carcinoma may Primary hyperparathyroidism ranges in account for the condition. severity from very mild and asymptomatic, to Less common etiologies: severe disease complicated by the Vitamin D is a fat-soluble vitamin that consequences of bone loss, including can become toxic when excessive amounts fractures and osteitis fibrosa cystica (von are taken in over time. Self-dosing or is the Recklinghausen disease). Tertiary usual cause. Overdosing with 1,alpha- hyperparathyroidism occurs in chronic renal hydroxylated vitamin D metabolites failure. (alfacalcidol or calcitriol) can easily result in Malignancy: hypercalcemia and chronic administration Hypercalcemia may be associated with must be avoided or carefully monitored. malignancies in two ways: bony involvement Exaggerated supplementation with over-the- by the tumor may lead to massive osteoclastic counter products can also readily and activity (osteolytic lesions) when the calcium frequently lead to hypercalcemia. Vitamin D flux simply overwhelms homeostatic is also elevated in granulomatous disease mechanisms; a variety of tumors release such as , berylliosis, . PTH-related peptide acting on PTH receptors The mechanism is enhanced conversion of [3]. From 25% to 30% of patients with cancer vitamin D by macrophages. Endocrine will develop hypercalcemia at some point diseases such as can lead to over the course of their disease. Common hypercalcemia and almost always malignancies that can lead to hypercalcemia hypercalciuria as a consequence of rapid bone include: multiple myeloma, leukemia, lung turnover; another pathologic conditions are and breast cancer. When malignancies cause adrenal insufficiency, , hypercalcemia, the tumor is typically very acromegaly. Iatrogenic causes includes advanced. Malignancies which produce milk-alkali syndrome caused by excess hypercalcemia may be associated with dietary milk or alkali (e.g., because of multiple endocrine neoplasia (MEN) type 1 dyspepsia) or excess calcium supplementation and MEN type 2a or isolated familial (e.g., in postmenopausal women) [4]. Other hyperparathyroidism. There is an association drugs are lithium and vitamin A derivates, of primary hyperparathyroidism with used for acne treatment and that neurofibromatosis and von Hippel-Landau. In affect renal mechanisms and rapid bone

92 RomanianJournalofOralRehabilitation Vol.6,No.3,JulyͲSeptember2014 turnover, thus both causing hypercalcemia transient . that reverses when the drugs are stopped. Immobilization in adolescents and young Clinical presentation people (Paget disease) causes massive bone First, the clinician should take a history demineralization and hypercalcemia. Older detailing any bone pain to suggest patients can also be subject to this problem, malignancy in metastatic locations of the long but the robust state of bone mineralization in bones. A history of weight loss would young people means there is a much larger identify malignancy more likely than mobile calcium pool to create and sustain the hyperparathyroidism. History may also hypercalcemia. Excess bone metabolism of identify symptoms of high calcium such as any etiology can lead to hypercalcemia. renal stones (typical of hyperparathyroidism, Congenital causes: familial hypocalciuric lethargy), easy fatigue, confusion, depression, hypercalcemia can be confused with irritability, constipation, and hypercalcemia due to hyperparathyroidism as polyuria/polydipsia. Classic GI symptoms abnormal calcium sensing in the parathyroid may also be present (nausea, , glands and kidneys leads to mild elevation of abdominal pain, peptic ulcer, ). PTH and reduced calcium excretion. Chronic symptoms are more consistent with Williams syndrome - is a rare hyperparathyroidism, whereas more recent neurodevelopmental disorder characterized onset of symptoms suggests malignancy. by a distinctive, "elfin" facial appearance, Symptoms from calcium elevation are along with a low nasal bridge, an unusually typically not found unless the calcium is cheerful demeanor and ease with strangers; above 12 mg/deciliter. Severe symptoms and developmental delay coupled with strong coma are likely to appear when calcium gets language skills and cardiovascular problems, above 13 mg/deciliter [5, 6]. such as supravalvular aortic stenosis and

Table 2. Clinical signs of Hypercalcemia Renal symptoms Nervous system Cardiac symptoms GI system Musculoskeletal system Renal stones CNS depressyon QT shortening Gastritis Arthralgia Polyuria Decreased reflexes Sinus tahycardia Pancreatitis Bone pain Nycturia Ventricular Constipation Spontaneous fractures Hematuria extrasystoles

Laboratory data plasma total calcium should be 8.5 to 10.5 The most common causes of mg/dl and the ionized calcium should be 4.6 hypercalcemia are primary to 5.1 mg/dl. The PTH is elevated in primary hyperparathyroidism and malignancy, hyperparathyroidism, despite elevated together accounting for 90% of cases. They calcium indicating a disconnect between the can be distinguished by ordering a serum regulating hormone and the regulated. In PTH level and a simultaneous repeat calcium malignancy, calcium is elevated either due to test. Total serum calcium is usually a humoral abnormality with a PTH-related satisfactory but if there is an elevated or peptide or due to bone destruction in markedly depressed plasma protein metastases. In cases of malignancy, the PTH concentration, the physiologically important might even be very low or barely detectable fraction is ionized calcium. Normal serum or since the elevated calcium should inhibit PTH

93 RomanianJournalofOralRehabilitation Vol.6,No.3,JulyͲSeptember2014 secretion. Hypercalcemia

Medication

IͲPTH PTHrP 

IͲPTH PTHrP  

High/N Low Low High Low/N Low/N

Primary Vit.D PTHrP Urinary 1,25 Endocrinolog hyperparathyroid intoxication, calcium24h dihydroxyvita ical ism Malignancy,  MilkͲalkali minD  

Figure 1. Laboratory work-up in hypercalcemia

Imaging Studies biophosphonates, calcitonin. Initial treatment Plain radiography may reveal of hypercalcemia involves hydration to demineralization, pathologic fractures, bone improve urinary calcium output. Isotonic cysts, and bony metastases. chloride solution is used, because Renal imaging (ultrasonography, CT increasing sodium excretion increases urography or intravenous pyelography) may calcium excretion. Addition of a loop find or stones. inhibits tubular reabsorption of calcium. Ultrasonography of the parathyroid glands Biophosphonates are studied mainly in adults is useful for hyperplasia or adenoma. A but the usage of some of them is approved in sestamibi nuclear scan may be helpful in children (etidronate and pamidronate). locating a parathyroid adenoma [1]. Calcitonin decrease skeletal reabsorption of calcium and inhibit renal reabsorption. Other Treatment therapeutic options include gallium nitrate, Treatment aims are the stabilization and mithramycin, or reduction of serum calcium levels by and new agents like adequate hydration with increased urinary calcimimetics (primarily indicated for chronic excretion of calcium, by inhibition of renal disease and secondary osteoclasts in bone, by interruption of the hyperparathyroidism) or calcitriol and other drugs associated with hypercalcemia and by vitamin D analogues, such as paricalcitol. In resolving the underlying cause. [1,6,7] summary, every patient with serum The therapeutic options for hypercalcemia calcium level superior to 12 mg % should includes rehydration and , underwent medical treatment, while values

94 RomanianJournalofOralRehabilitation Vol.6,No.3,JulyͲSeptember2014 above 14 mg% are considered an emergency prolonged healing.[7] No subtotal (hypercalcemic crisis). parathyroidectomy can be performed, or Surgical indications include serum calcium complete parathyroidectomy can be chosen levels above 12 mg% at any age, severe with reimplantation of a small amount of “acute” hyperparathyroidism, hypercalciuria tissue in the forearm in cases of renal (more than 400 mg/day), renal litiasis and hyperparathyroidism. In secondary impaired renal function, thinning of cortical hypercalcemia (majority of cases of bone in osteitis fibrosa cystica , low bone malignant origin), together with the treatment density, neuromuscular symptoms, age under of primary cause, administration of 50 yrs (including children and teenagers). biophosphonates, , corticoids, Surgical therapy aims to remove parathyroid mithramycin, calcitonin may be useful. [8] in hyperparathyroidism, to resect PTH- secreting tumor and to treat orthopedic CONCLUSIONS complications in bone metastases. Hypercalcemia is often asymptomatic. Hipercalcemia can be associated in children The most common causes of hypercalcemia with rare severe neonatal are primary hyperparathyroidism and hyperparathyroidism but also with familial or malignancy. The etiology of hypercalcemia in sporadic nonMEN or MEN cases determined children is age-dependent and includes a by adenomas, hyperplasias and even broad differential diagnosis. Although these carcinomas. Surgical excision i.e conditions are not common, it is nevertheless adenomectomy, subtotal or total important not to overlook them, as untreated parathyroidectomy (with autotransplant) hypercalcemia can have a profound impact on practiced early can provide quality and a child’s growth and development.

REFERENCES 1 Claudius IA, Fattal O ,Nakamoto J, Pitukcheewanont P: Pediatric Hypercalcemia. http://emedicine.medscape.com/article/920955-overview#a0199 2 [Guideline] Hawley C, Elder G. Calcium. Westmead NSW (Australia): CARI - Caring for Australasians with Renal Impairment; 2005 Oct. 3 Bennett MT, Sirrs S, Yeung JK, Smith CA. Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole. Leuk Lymphoma. Dec 2005;46(12):1829-31. 4 Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf). Nov 2005;63(5):566-76. 5 Hsu YH, Chen HI. Acute respiratory distress syndrome associated with hypercalcemia without parathyroid disorders. Chin J Physiol. Dec 2008;51(6):414-8. 6 Behrman RE, Kliegman R, eds. Nelson Textbook of Pediatrics. 16th ed. WB Saunders Co; 2000. 7 Shaw NJ, Bishop NJ. Bisphosphonate treatment of bone disease. Arch Dis Child. May 2005;90(5):494-9 8 McCay C, Furman WL: Hypercalcemia Complicating Childhood Malignancy. Cancer 2006, 72(1): 256-60

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