CHAPTER I INTRODUCTION Calcium deficiency means a condition of low level of calcium in the blood (hypocalcemia) which can make

the nervous system highly irritable causing tetany (spasms of the hands and feet, muscle cramps, abdominal cramps, and overly active reflexes). Hypocalcemia is defined as a total serum calcium concentration of less than 2.1 mmol/L (8.5 mg/dL) in children, less than 2 mmol/L (8 mg/dL) in term neonates, and less than 1.75 mmol/L (7 mg/dL) in preterm neonates (Singhal, 2010). Hypocalcemia in children may be asymptomatic or there may be a wide range of signs and symptoms. Because very young patients cannot accurately verbalize symptoms, they are more likely to present with signs such as weakness, feeding problems, facial spasm, jitteriness or seizures. In addition, features of conditions known to be associated with hypocalcemia may be identified (Dawrant, 2007). There are multiple causes of hypocalcemia in children, thus, diagnosis must follow a systematic approach. Since pediatric hypocalcemia can represent the first manifestation of a genetic disorder, a definitive diagnosis may eventually require further testing at a specialized centre (Dawrant, 2007). Once diagnosis of hypocalcemia has been made, a systematic workup that includes a panel of blood tests can help sort out what may otherwise be a confusing clinical picture. Hypocalcemia in children can be an early presentation of a genetic syndrome, and a systematic approach can facilitate referral for definitive diagnosis and treatment (Dawrant, 2007).

CHAPTER II PEDIATRIC CALCIUM DEFICIENCY 2.1 Risk Factor

Risk factors for calcium deficiency are factors that do not seem to be a direct cause of the disease, but seem to be associated in some way. Having a risk factor for calcium deficiency makes the chances of getting a condition higher but does not always lead to calcium deficiency. Also, the absence of any risk factors or having a protective factor does not necessarily guard you against getting calcium deficiency. Obesity or overweight is a serious condition. There are various other conditions for which obesity is a risk factor. Cholesterol as a risk factor for other medical conditions. High cholesterol is a serious condition. There are various other conditions for which cholesterol-related conditions are a risk factor. Because bone stores of calcium can be used to maintain adequate blood calcium levels, short-term dietary deficiency of calcium generally does not result in significantly low blood calcium levels. But, over the long term, dietary deficiency eventually depletes bone stores, rendering the bones weak and prone to fracture. A low blood calcium level is more often the result of a disturbance in the body's calcium regulating mechanisms, such as insufficient PTH or vitamin D, rather than dietary deficiency. When calcium levels fall too low, nerve and muscle impairments can result. Skeletal muscles can spasm and the heart can beat abnormallyit can even cease functioning. Toxicity from calcium is not common because the gastrointestinal tract normally limits the amount of calcium absorbed. Therefore, short-term intake of large amounts of calcium does not generally produce any ill effects aside from constipation and an increased risk of kidney stones. However, more severe toxicity can occur when excess calcium is ingested over long periods, or when calcium is combined with increased amounts of vitamin D, which increases calcium absorption. Calcium toxicity is also sometimes found after excessive intravenous administration of calcium. Toxicity is manifested by abnormal

deposition of calcium in tissues and by elevated blood calcium levels (hypercalcemia). However, hypercalcemia is often due to other causes, such as abnormally high amounts of PTH. Usually, under these circumstances, bone density is lost and the resulting hypercalcemia can cause kidney stones and abdominal pain. Some cancers can also cause hypercalcemia, either by secreting abnormal proteins that act like PTH or by invading and killing bone cells causing them to release calcium. Very high levels of calcium can result in appetite loss, nausea , vomiting, abdominal pain, confusion, seizures, and even coma.

2.2

Etiology

Overall, one of the most common causes of hypocalcemia is renal failure, which results in hypocalcemia because of inadequate 1-hydroxylation of 25hydroxyvitamin D and hyperphosphatemia due to diminished glomerular filtration (Singhal, 2010). The causes of hypocalcemia can be classified by the child's age at presentation. The first classification is early neonatal hypocalcemia (within 48-72 h of birth). The possible causes are prematurity, birth asphyxia, diabetes mellitus in the mother, intrauterine growth retardation (IUGR). In premature infants, the possible mechanisms include poor intake, decreased responsiveness to vitamin D, increased calcitonin, and hypoalbuminemia leading to decreased total but normal ionized calcium (Singhal, 2010). In infants with birth asphyxia, delayed introduction of feeds, increased calcitonin production, increased endogenous phosphate load, and alkali therapy all may contribute to hypocalcemia (Singhal, 2010). The presence magnesium depletion in the mother with diabetes mellitus causes hypomagnesemic state in the fetus. This hypomagnesemia induces functional hypoparathyroidism and hypocalcemia in the infant. A high incidence of birth asphyxia and prematurity in infants of diabetic mothers are also contributing factors (Singhal, 2010). Infants with IUGR may have hypocalcemia if they are also preterm or have had perinatal asphyxia (Singhal, 2010).

The second classification is late neonatal hypocalcemia (3-7 d after birth, though occasionally as late as age 6 week). The possible causes are exogenous phosphate load, magnesium deficiency, transient hypoparathyroidism of newborn, hypoparathyroidism due to other causes and gentamicin uses. Exogenous phospate load-related hypocalcemia is most commonly seen in developing countries. The identified cause is feeding with phosphate-rich formula or cows milk. Whole cows milk has 7 times the phosphate load of breast milk (956 vs 140 mg/L in breast milk) (Singhal, 2010). The third classification is hypocalcemia in infants and children. The major causes are hypoparathyroidism, abnormal vitamin D production or action, and hyperphosphatemia (Singhal, 2010).

2.3

Epidemiology

The incidence of neonatal hypocalcemia varies in different studies. Hypocalcemia occurs in as many as 30% of infants with very low birth weight (<1500 g) and in as many as 89% of infants whose gestational age at birth was less than 32 weeks. A high incidence is also reported in infants of mothers with diabetes mellitus and in infants with birth asphyxia. No variation is reported across national boundaries. However, late-onset hypocalcemia is more common in infants in developing countries where babies are fed cow's milk or formulas containing high amounts of phosphate than in countries where infants are fed human milk or formulas containing low amounts of phosphate.

2.4

Pathophysiology

Calcium absorption is dependent upon the calcium needs of the body, the foods eaten, and the amount of calcium in the foods eaten. Vitamin D from diet or exposure to the ultraviolet light of the sun increases calcium absorption. Calcium absorption tends to decrease with increased age for both men and women. More than 99% of total body calcium is stored in the bones and teeth where it functions to support their structure. The remaining 1% is found throughout the body in

blood, muscle, and the fluid between cells. Because of its biological importance, calcium levels are carefully controlled in various compartments of the body. The three major regulators of blood calcium are parathyroid hormone (PTH), vitamin D, and calcitonin. PTH is normally released by the four parathyroid glands in the neck in response to low calcium levels in the bloodstream (hypocalcemia). PTH acts in three main ways, it causes the gastrointestinal tract to increase calcium absorption from food, it causes the bones to release some of their calcium stores, and it causes the kidneys to excrete more phosphorous, which indirectly raises calcium levels. Vitamin D works together with PTH on the bone and kidney and is necessary for intestinal absorption of calcium. Vitamin D can either be obtained from the diet or produced in the skin when it is exposed to sunlight. Insufficient vitamin D from these sources can result in rickets in children and osteomalacia in adults, conditions that result in bone deformities. Calcitonin, a hormone released by the thyroid, parathyroid, and thymus glands, lowers blood levels by promoting the deposition of calcium into bone. Most dietary calcium is absorbed in the small intestine and transported in the bloodstream bound to albumin, a simple protein . Because of this method of transport, levels of albumin can also influence blood calcium measurements. Calcium is deposited in bone with phosphorous in a crystalline form of calcium phosphate.

2.5 Clinical Manifestation

The symptoms of hypocalcemia may vary depending on age. In newborns there may be no specific symptoms found while later, there may be possibilities of vomiting, abdominal distension, and poor feeding as early signs of hypocalcemia. Earliest newborns may be premature, birth asphyxia may occur, and congenital heart disease may be found. Symptoms experienced in children are not as far as those experienced by the adults. Often the earliest symptoms of hypocalcemia in children are paresthesias, tingling sensation around the mouth and lips, and in the extremities of the hands and feet. Additionally, petechias which appear as one-off spots become confluent and appear as purpura in some parts of the body. Tetany and signs of nerve irritability will be found it further calcium deficiency happens. Usually carpopedal and generalized tetany all over the body shows an unrelieved and strong contraction of the hands and muscles of the body. Further, latent tetany showing signs of trousseau latent tetany shows carpal spasm by inflating the blood pressure cuff and maintaining the cuff pressure above systolic. Also Chvostek's sign odservable by tapping of the inferior portion of the zygoma will produce facial spasms. Tendons of children are usually hyperactive during reflexes. There may be some serious life threatening clinical manifestation found in calcium deficiency, although hypocalcemia is already an emergency condition. Such condition such as laryngospasm, cardiac arrhythmias, and apnea is a dangerous complication of calcium deficiency. Cardiac arrhythmias may develop and ECG changes including intermittent QT prolongation on the echocardiogram will be shown if further hypocalcemia occurs, it may lead to a ventricular fibrillation that is a serious problem.

2.6

Diagnosis and Differential Diagnosis

There is a few methods must be used to diagnosis calcium deficiency (hypocalcemia) in paediatrics. Adequate information is important for accurate diagnosis. Firstly, a full history about the patients general health and diet should be questioned such as is there any eating disorders, exposure to mercury, including infantile acrodynia excessive dietary magnesium, as with supplementation. Prolonged use of medications or laxatives containing magnesium Chelation therapy for metal exposure, particularly EDTA, absent parathyroid hormone (PTH). The degree of balance between nutrient intake and nutrient requirement is referred to as nutritional status. As with all aspects of assessment, several factors can affect the health status of a person. For nutrition assessment, the physiologic, psychosocial, developmental, cultural, and economic aspects of the individuals life must be considered. The health practitioner needs to determine whether the patient has optimal nutrition or undernutrition. Besides this, physical examination or some clinical findings must be done to confirm the diagnosis. For this case, clinical findings such as weakness, fatigue, muscle cramping and spasm (difficulty speaking may indicate laryngeal spasm), paresthesias (perioral or fingertip), abdominal pain, nausea or vomiting, irritability, and depression delirium, psychosis, and seizures which is caused by severe hypocalcemia. Skin exam may reveal patchy hair loss, dry and/or scaly skin, hyperpigmentation, brittle nails, and mucocutaneous candidiasis. Trousseau's sign-Carpal spasms upon inflation of a blood pressure cuff for 2 to 3 minutes. Chvostek's sign-Tapping of cranial nerve VII (anterior to ear) causes twitching of facial muscles, cardiac arrhythmias, decreased myocardial contractility (may lead to CHF), hypotension, vitiligo, alopecia, nail fungal infection, vital signs, growth parameters, facial dysmorphism (DiGeorge syndrome, PHP IA), skeletal deformities (bowed legs, widened wrists/ankles, rachitic rosary, frontal bossing) is also considered. Other than that, we must also enquire about patients with post surgical hypoparathyroidism or chronic renal insufficiency, or who have been given phosphate. Laboratory evaluation should be guided by history and physical examination. Renal failure, cell lysis syndromes, hypomagnesemia or hypermagnesemia, and acute pancreatitis can be diagnosed or excluded using measurements of serum

creatinine, creatine kinase, magnesium, and amylase levels. A serum magnesium concentration lower than 1.0 mg/dL should be considered significant and corrected. In the absence of these conditions, disorders affecting the production or action of PTH or vitamin D should be considered. The immunoreactive PTH (iPTH), 25-hydroxyvitamin D, and 1,25-hydroxyvitaminvitamin D levels need to be determined and the results are often delayed 2 to 7 days. Futhermore, laboratory or biochemistry finding is important to contribute to the diagnosis. Thus some laboratory testing, such as complete blood count (CBC) and calcium levels. A serum calcium level less than 8.5 mg/dL or an ionized calcium level less than 1.0 mmol/L is considered hypocalcemia. Analysis for ionized level must be performed rapidly with whole blood to avoid changes in pH and anion chelation. Blood should be drawn in an unheparinized syringe for best result. Falsely depressed levels can be seen with heparin, oxalate, citrate, or hyperbilirubinemia. Serum magnesium levels may be low in patients with hypocalcemia. Severe hypomagnesemia (0.46 mmol/L) causes hypocalcemia by impairing the secretion and action of parathormone (PTH). Serum electrolyte and glucose levels, seizures and irritability in newborns and children can be associated wih hypoglycemia and sodium abnormalities. Low bicarbonate levels and acidosis may be associated with Fanconi syndrome and renal tubular acidosis. Phosphorus levels estimating the phosphate level is essential to establish the etiology of hypocalcemia. Phosphate levels are increased in cases of exogenous and endogenous phosphate loading and renal failure. Levels are usually high in patients with hypoparathyroidism. Levels are low in cases of vitamin D abnormalities and rickets. The imaging studies include, chest radiography to evaluate thymic shadow, which may be absent in patients with DiGeorge syndrome. Ankle and wrist radiography, evaluate for evidence of rickets. Changes appear at an early stage in the radius and ulna, which is the distal ends are widened, concave, and frayed. Other tests, electrocardiography, which show a prolonged QTc (>0.4 s), a prolonged ST segment, and T-wave abnormalities and may be observed. Malabsorption workup, total lymphocyte and T-cell subset analyses, findings are decreased in patients with DiGeorge syndrome. Karyotyping to assess for 22q11 and 10p13 deletion.

Maternal and family screening, helpful in familial forms of hypocalcemia, such as those caused by activating mutations of the calcium-sensing receptor. Accurate identification of nutritional problems allows for earlier intervention. Calcium deficiency is often misdiagnosed as other disease. This is due to the similarities in the way the condition presents itself. Among those diseases are hydrofluoric hyperglycemic acid burns, hypernatremia, coma, hypercalcemia, hyperosmolar nonketotic hyperkalemia, hyperparathyroidism,

hypermagnesimia and hyperphosphatemia.

2.7

Treatment

Dietary calcium requirements depend in part upon whether the body is growing or making new bone or milk. Requirements are therefore greatest during childhood, adolescence, pregnancy, and breastfeeding. Recommended daily intake (of elemental calcium) varies accordingly 400 mg for infants 06 months, 600 mg for infants 612 months, 800 mg for children 110 years, 1,200 mg for ages 1124 years, and 800 mg for individuals over 24 years of age. Pregnant women require additional calcium (RDA 1,200 mg). Many experts believe that elderly persons should take as much as 1,500 mg to help prevent osteoporosis , a common condition in which bones become weak and fracture easily due to a loss of bone density. Dairy products, meats, and some seafood (sardines, oysters) are excellent sources of calcium. Spinach, beet greens, beans, and peanuts are among the best plant-derived sources. Calcium absorption is affected by many factors, including age, the amount needed, and what foods are eaten at the same time. CALCIUM SUPPLEMENT SUPPLEMENT ELEMENTAL CALCIUM BY WEIGHT Calcium carbonate 40% Most commonly used COMMENT

 Less well absorbed in persons with decreased stomach acid (e.g., elderly or those on antiacid medicines) Natural preparations from oyster shell or bone meal may contain contaminants such as lead Least expensive Calcium citrate 21% Better absorbed, especially by those with decreased stomach acid May protect against kidney stones More expensive. Calcium phosphate 38% or 31% Tricalcium or dicalcium phosphate Used more in Europe Absorption similar to calcium carbonate Calcium gluconate 9% Used intravenously for severe hypocalcemia Well absorbed orally, but low content of Calcium glubionate 6.5% Available as syrup for children Low content elemental calcium.

Calcium lactate

13%

Well absorbed, but low content elemental calcium.

Source : Gregory, Philip J. (2000) "Calcium Salts." Prescriber's Letter.

In general, calcium from food sources is better absorbed than calcium taken as supplements. Children absorb a higher percentage of their ingested calcium than adults because their needs during growth spurts may be two or three times greater per body weight than adults. Vitamin D is necessary for intestinal absorption, making Vitamin Dfortified milk a very well-absorbed form of calcium. Older persons may not consume or make as much vitamin D as is optimal, so their calcium absorption may be decreased. Vitamin C and lactose (the sugar found in milk) enhance calcium absorption, whereas meals high in fat or protein may decrease absorption. Excess phosphorous consumption (as in carbonated sodas) can decrease calcium absorption in the intestines. High dietary fiber and phytate (a form of phytic acid found in dietary fiber and the husks of whole grains) may also decrease dietary calcium absorption in some areas of the world. Intestinal pH also affects calcium absorptionabsorption is optimal with normal stomach acidity generated at meal times. Thus, persons with reduced stomach acidity (e.g., elderly persons, or persons on acid-reducing medicines) do not absorb calcium as well as others do. Calcium supplements are widely used in the treatment and prevention of osteoporosis. Supplements are also recommended, or are being investigated, for a number of conditions, including hypertension , colon cancer , cardiovascular disease, premenstrual syndrome, obesity , stroke , and preeclampsia (a complication of pregnancy). There are several forms of calcium salts used as supplements. They vary in their content of elemental calcium, the amount effectively absorbed by the body, and cost. Whatever the specific form, the supplement should be taken with meals to maximize absorption. Medical care

General medical care in patients with hypocalcemia involves stabilization with management of the patient's airway and breathing if seizures occur. Anticonvulsants are commonly administered before hypocalcemia is confirmed in a new patient. Seizures usually do not respond to the usual antiseizure medications until calcium is intravenously administered. Treatment of an asymptomatic patient with hypocalcemia remains controversial, especially in neonates. Some authorities suggest that treating such patients is unnecessary. In contrast, most clinicians agree that hypocalcemia should be treated promptly in any symptomatic neonate or older child because of its serious implications for neuronal and cardiac function. Intravenous treatment is usually indicated in patients having seizures, those who are critically ill, and those who are planning to have surgery. Oral calcium therapy is used in asymptomatic patients and as follow-up to intravenous calcium therapy. In certain conditions like pancreatitis and rhabdomyolysis, full correction of hypocalcemia should be avoided. After the primary condition is resolved, these patients may develop hypercalcemia due to the release of complexed calcium. In cases with concurrent acidemia, hypocalcemia should be corrected first. Acidemia increases the ionized calcium levels by displacing calcium from albumin. If acidemia is corrected first, it decreases ionized calcium levels. Those patients should be given a diet high in calcium and low in phosphate is required in most instances. Infants drinking regular cow's milk or evaporated milk must be given humanized infant formula instead. Patients with renal failure should be given a low-solute low-phosphate formula, such as Similac PM 60/40.

2.8

Complication

Children who do not consume sufficient quantities of calcium generally will experience growth-related problems including bone deformation. Children also can develop Rickets, a condition that leads to softening and weakening of the

bones. It cause by a lack of vitamin D, calcium, or phosphate that makes failure of osteoid to calcify in adults is called osteomalacia. Children that are faced with calcium deficiency are not going to grow properly and they are not going to have strong and healthy bones. This is very important for small children as they learn to crawl and walk because you do not want your child to injure themselves. They may also suffer from a lack of an appetite and they may get teeth later than other children. When they do get teeth, they may be decayed. Your child may eventually have respiratory or intestinal complications if these symptoms are not taken care of. Young girls that are suffering from calcium deficiency symptoms are going to have other complications such as developing into puberty at a late time or having complications with their menstrual cycle. They may also suffer from severe cramping. In addition, a child who refuses to eat foods, or drink beverages, that are rich in calcium, including milk, may be experiencing a complication associated with sensory input which will lead to mood disorders.

2.9

Prognosis

Prognosis is dependent on the etiology of hypocalcemia but is generally good. The prognosis for correcting hypocalcemia is excellent. However, the eye damage that may result from chronic hypocalcemia cannot be reversed.