Hypocalcemia PDF

HYPOCALCEMIA PREPARED BY: SARA HENNAWI LECTURER OF PEDIATRIC, PORTSAID UNIVERSITY DEFINITION Decreased total serum calcium level below 8.5 mg/dL (corrected for albumin) or serum calcium level below 4.65 mg/dL (1.16 mmol/L) Corrected total calcium level =...

HYPOCALCEMIA PREPARED BY: SARA HENNAWI LECTURER OF PEDIATRIC, PORTSAID UNIVERSITY DEFINITION Decreased total serum calcium level below 8.5 mg/dL (corrected for albumin) or serum calcium level below 4.65 mg/dL (1.16 mmol/L) Corrected total calcium level = measured total calcium level + (0.8 × [4 − measured albumin level in g/dL])  Total serum calcium level below - Total serum calcium level of 8 7.6 mg/dL, to 8.5 mg/dL - Symptomatic at any level - Asymptomatic below the reference range Mild Severe CA METABOLISM AND FUNCTION 99% of total body Ca is stored in bone, and serum levels constitute less than 1%. Serum calcium is present in two forms: free (ionized); about 50% and bound form; either bound to proteins (40%) or complexed (10%) with bicarbonate, citrate, and phosphate.  Calcium in the serum is critical to many important biologic functions, including the following: 1- Calcium messenger system by which extracellular messengers regulate cell function 2- Activation of several cellular enzyme cascades 3- Smooth muscle and myocardial contraction 4- Nerve impulse conduction 5- Secretory activity of exocrine glands MAGNESIUM Approximately 50% of magnesium is found in bone and 50% in muscle and other soft tissues. As much as half of the magnesium in bone is not sequestered in the mineral phase but is freely exchangeable with the extracellular fluid and therefore may serve as a buffer against changes in extracellular magnesium concentration. PHOSPHATE METABOLISM Approximately 85% of phosphate is located in the mineral phase of bone, whereas the remainder is found in inorganic or organic form throughout the extracellular and intracellular compartments. The need for the large amounts of phosphate incorporated into cellular constituents during cell proliferation explains why phosphate levels in the blood are regulated by growth factors, such as insulin-like growth factor 1 (IGF1), in addition to regulation by hormones of bone mineralization. Phosphate plays a particularly prominent role as the key substrate or recognition site in numerous kinase and phosphatase regulatory cascades REGULATION OF SERUM CA CONT: REGULATION AND ACTIONS OF PTH ETIOLOGY: EARLY ONSET NEONATAL HYPOCALCEMIA Occurs within 48-72 hours of birth 1- Prematurity: inadequate nutritional intake, decreased responsiveness of parathyroid hormone to vitamin D, increased calcitonin level. 2- Birth asphyxia: Delayed introduction of feeds, increased calcitonin production, increased endogenous phosphate load. 3- Infants of a diabetic mother: Magnesium depletion in mothers with diabetes mellitus causes a hypomagnesemic state in the fetus, which induces functional hypoparathyroidism and hypocalcemia in the infant. 4- Intrauterine growth restriction: Infants with intrauterine growth restriction may develop hypocalcemia because of decreased transplacental passage of calcium. ETIOLOGY: LATE-ONSET NEONATAL HYPOCALCEMIA Occurs 3-7 days after birth, although occasionally it is seen as late as age 6 weeks 1- Exogenous phosphate load: most commonly seen in developing countries, when the neonate is fed with phosphate-rich formula or cow's milk. 2- Vitamin D deficiency: vitamin D insufficiency or deficiency and hypomagnesemia. 3- DiGeorge syndrome is a primary immunodeficiency disorder, characterized by cellular (T-cell) deficiency, characteristic facies, congenital heart disease and hypocalcemia ETIOLOGY: HYPOCALCEMIA IN INFANTS AND CHILDREN 1- Hypoparathyroidism Post surgical hypoparathyroidism: most common cause of chronic hypocalcemia Transient hypoparathyroidism : if parathyroid gland function recovers within 12 months after parathyroid surgery. Permanent hypoparathyroidism is defined as hypoparathyroidism persisting 12 months after onset Aplasia or hypoplasia of parathyroid gland -eg DiGeorge syndrome, Haploinsufficiency of the transcription factor GATA3 causes the syndrome of HDR. Autoimmune parathyroiditis (Autoimmune polyendocrine syndrome type 1) Infiltrative lesions -Hemosiderosis, Wilson disease, thalassemia Idiopathic causes  Genetic Parathyroid Disorders 1- Disorders of Parathyroid Gland Formation Tbx1 is a transcription factor whose loss in the 22q11 deletion syndrome (DS), also called DiGeorge syndrome I or velocardiofacial syndrome, is most likely the cause of the hypoparathyroidism that is often seen in this syndrome. CHARGE syndrome is a group of rare disorders with phenotypic overlap between 21q11DS and HDR (see later) and is caused by heterozygous mutations in SEMAE3 or CHD7.  Haploinsufficiency of the transcription factor GATA3 causes the syndrome of HDR. (hypoparathyroidism, sensorineural deafness and renal disease )  Kenny-Caffey syndrome type 1, (hypoparathyroidism, extreme short stature, mental retardation, and dysmorphism), due to mutations in the chaperone protein TBCE; required for the proper folding of α tubulin and the formation of α-β tubulin heterodimers. Autosomal-dominant Kenny-Caffey syndrome type 2, characterized by short stature, hypoparathyroidism, and osteocraniostenosis, is caused by mutations in FAM111A, a gene of unknown function with protease motifs. Hypoparathyroidism in association with mitochondrial myopathies such as mitochondrial trifunctional protein deficiency and Kearns-Sayre syndrome  Activating mutations in the CaSR cause autosomal-dominant hypocalcemia type 1 (ADH1) associated with inappropriately normal PTH levels. This syndrome can also be seen in pati Disorders of Parathyroid Activating mutations in Hormone Secretion the CaSR cause autosomal-dominant hypocalcemia type 1 (ADH1) associated with inappropriately normal PTH levels. This syndrome can also be seen in pa Activating mutations in the CaSR cause autosomal-dominant hypocalcemia type 1 (ADH1) associated with inappropriately normal PTH levels. This syndrome can also be seen in patien 2- Disorders of Parathyroid Hormone Secretion Activating mutations in the CaSR cause autosomal-dominant hypocalcemia type 1 (ADH1) associated with inappropriately normal PTH levels. ADH2 has been shown to be caused by gain-of-function mutations of the G protein subunit α 11 (GNA11). 60 The clinical syndrome is variable; patients can present with hypocalcemia and seizures, some with asymptomatic hypocalcemia. Hypercalciuria is a severe problem because it is exaggerated by the calciuric effect of the activated CaSR in the kidney. Pseudohypoparathyroidism (PHP) was first documented by Albright in 1942 and is a disease of PTH resistance leading to hypocalcemia and hyperphosphatemia, similar to patients  Impaired secretion of PTH from the parathyroid glands by profound hypomagnesemia can lead to functional hypoparathyroidism and target organ resistance to PTH. Pseudohypoparathyroidism (PHP) was first documented by Albright in 1942 Refers to a group of heterogeneous disorders defined by targeted organ (kidney and bone) unresponsiveness to PTH. It is characterized by: Hypocalcemia Hyperphosphatemia Elevated PTH concentrations  Type 1 is caused by Variants of the GNAS1 gene, which encodes the alpha subunit of a GTP-binding protein (Gs, or G protein), which couples to the PTH receptor in a cyclical manner. G protein's inability to activate adenyl cyclase upon the binding of PTH to its receptor. Activation of adenyl cyclase is required for signal transduction that produces the end-organ response to PTH MECHANISM OF ACTION OF PTH  Patients with PHP type 1a have a constellation of findings known as Albright hereditary osteodystrophy (AHO), which includes : round facies, obesity short stature, short fourth metacarpal bones, subcutaneous calcifications, and developmental delay. In addition, the PTH resistance of the renal tubule leads to hyperphosphatemia, hypocalcemia, and secondary hyperparathyroidism and hyperparathyroid bone disease (osteitis fibrosa  GNAS1 is imprinted in humans so that expression of the allele for a specific tissue is dependent on whether the allele is maternally or paternally inherited;therefore, the disease manifestations also differ depending on the parent of origin Pseudo-pseudohypoparathyroidism – By contrast to patients with maternally transmitted variants that, those with paternally transmitted variants have the phenotype of AHO but with normal serum calcium concentrations and without renal tubular resistance to PTH.  Type 1b – Patients with the PHP type 1b disease have hypocalcemia but do not have the phenotypic abnormalities of AHO. This rare autosomal dominant disorder appears to be caused by methylation defects or variants that affect the regulatory elements of GNAS1, rather than variants in GNAS1 itself. Type 1b is maternally transmitted  Type 1c – PHP type 1c refers to a subgroup of cases in which coupling of the G protein to the PTH receptor is aberrant. The ability to stimulate adenyl cyclase remains intact but is no longer coupled to the binding of PTH and its receptor. Patients with PHP type 1c are usually phenotypically similar to those with PHP type 1a. Patients with PHP type 2 do not have the features of AHO. They have normal or even elevated urinary cAMP concentrations in response to exogenous PTH administration but without a concomitant increase in phosphate excretion Due to variants in the PRKAR1A gene (protein kinase, cAMP-dependent, regulatory, type1, alpha), which encodes the catalytic subunit of adenylate cyclase and incorporates a phenotype of multiple hormone resistance with acrodysostosis  3- Abnormal vitamin D production or action can be caused by the following: Vitamin D deficiency: Dietary insufficiency and maternal use of anticonvulsants. Acquired or inherited disorders of vitamin D metabolism Resistance to actions of vitamin D Liver disease: Liver disease can affect 25-hydroxylation of vitamin D; certain drugs (eg, phenytoin, carbamazepine, phenobarbital, isoniazid, and rifampin) can increase the activity of P-450 enzymes, which can increase the 25-hydroxylation and also the catabolism of vitamin D.  4- Hyperphosphatemia can result from the following: Excessive phosphate intake from feeding cow milk or infant formula with improper (low) calcium to phosphate ratio Excessive phosphate intake caused by inappropriate use of phosphate-containing enemas Excessive phosphate or inappropriate Ca:P ratio in total parenteral nutrition Increased endogenous phosphate load caused by anoxia, chemotherapy, or rhabdomyolysis Renal failure  5- Drug induced Bone-active agents: Bisphosphonates, denosumab Cinacalcet Phenytoin Fluoride toxicity Chemotherapy agents: Cisplatin and others  6- Other causes of hypocalcemia in infants and children include the following: Malabsorption syndromes Alkalosis: Respiratory alkalosis is caused by hyperventilation; Metabolic alkalosis occurs with the administration of bicarbonate, diuretics, or chelating agents, such as the high doses of citrates taken in during massive blood transfusions.  Pancreatitis Pseudohypocalcemia (ie, hypoalbuminemia): Serum calcium concentration decreases by 0.8 mg/dL for every 1 g/dL fall inconcentration of plasma albumin. “Hungry bones syndrome:" Rapid skeletal mineral deposition is seen in infants with rickets or hypoparathyroidism after starting vitamin D therapy.  A clue to long-standing hypocalcemia when associated with hyperphosphatemia (e.g., PTH deficiency or resistance) is ectopic calcifications in the basal ganglia and other soft tissues. Cataract formation can also be a feature. Chronic hypocalcemia, when associated with hypophosphatemia, as in vitamin D deficiency, is associated with growth plate abnormalities in children (rickets) and defects in the mineralization of new bone (osteomalacia) in adults. These findings are not seen in the hypocalcemia of hypoparathyroidism. CLINICAL PICTURE Clinical manifestations range from asymptomatic to life-threatening, depending on severity of calcium deficiency and rate at which calcium level falls 1- Asymptomatic in mild and chronic hypocalcemia 2- Symptoms of acute, severe hypocalcemia (Low calcium levels decrease the threshold of excitation of neurons) include the following:  Perioral and digital paresthesias Muscle cramps Wheezing Seizure  Signs of acute, severe hypocalcemia Positive Trousseau sign ( Carpal spasm elicited by inflation of a blood pressure cuff to 20 mm Hg above systolic blood pressure for 3 minutes) Positive Chvostek sign (Twitching of circumoral muscles in response to tapping of facial nerve anterior to ear) May be present in up to 10% of population with normal calcium levels 1 May be completely absent in chronic hypocalcemia Tetany DIAGNOSTIC WORK UP 1- Total and ionized serum calcium levels To confirm true hypocalcemia. A decrease in total calcium can be associated with low serum albumin concentration and abnormal pH. 2- Serum magnesium levels Patients with hypocalcemia may not respond to calcium therapy if hypomagnesemia is not corrected. Also severe hypomagnesemia (0.46 mmol/L) causes hypocalcemia by impairing the secretion and action of parathormone (PTH). 3- Serum electrolyte and glucose levels Seizures and irritability in newborns and children can be associated with hypoglycemia and sodium abnormalities.  4- Phosphorus levels Phosphate levels are increased in cases of exogenous and endogenous phosphate loading and renal failure and are usually high in patients with hypoparathyroidism. Phosphate levels are low in cases of vitamin D abnormalities and rickets.  5- Parathormone levels Indicated if hypocalcemia persists in the presence of normal magnesium and normal or elevated phosphate levels. Low PTH levels suggest hypoparathyroidism; serum calcium rises in response to PTH challenge. PTH levels are elevated in patients with vitamin D abnormalities and pseudohypoparathyroidism, and calcium levels do not rise in response to PTH challenge. 6- Vitamin D metabolite (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) levels These may be assessed, along with hormone concentrations, to eliminate uncommon causes of hypocalcemia (e.g., malabsorption, disorders of vitamin D metabolism). 7- Urine calcium, magnesium, phosphorus, and creatinine levels  7- Urine calcium, magnesium, phosphorus, and creatinine levels Should be assessed in patients with suspected renal tubular defects and renal failure. Urine should also be evaluated for pH, glucose, and protein. A urine calcium-to-creatinine ratio of more than 0.3 on a spot sample in presence of hypocalcemia suggests inappropriate excretion. 8- Serum alkaline phosphatase levels Elevated in patients with rickets.  ECG Indicated for all patients with severe hypocalcemia Acute hypocalcemia causes lengthening of ST segment and prolongation of QT interval QT prolongation can lead to ventricular arrhythmias  10- Imaging studies Chest radiography - Evaluate for 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 (the distal ends are widened, concave, and frayed)  Treatment 1- Correct hypocalcemia Severe hypocalcemia: serum calcium less than 1.9 mmol/L (7.6 mg/dL) or any level of hypocalcemia associated with severe symptoms Medical emergency Monitor ECG Initiate IV calcium gluconate infusion; alternatively calcium chloride may be used via central line Dose: 100 to 200 mg/kg/dose (Max: 2 g/dose) IV every 6 hours as needed as determined by serum calcium concentrations and patient response. Alternatively, 8 to 13 mg/kg/hour continuous IV infusion may be administered if symptoms recur after initial IV calcium replacement. Titrate dose according to serum calcium concentrations.  Mild hypocalcemia: symptomatic patients with serum calcium level greater than 1.9 mmol/L (7.6 mg/dL) Begin oral calcium supplementation:100 mg/kg/day elemental calcium PO in 3 to 4 divided doses.  If hypocalcemia is due to vitamin D deficiency For infants: 25 to 125 mcg (1,000 to 5,000 International Units) PO once daily or 1,250 mcg (50,000 International Units) PO once weekly for at least 6 weeks, then 10 to 25 mcg (400 to 1,000 International Units) PO once daily. Children and Adolescents: 50 to 150 mcg (2,000 to 6,000 International Units) PO once daily then 15 to 25 mcg (600 to 1,000 International Units) PO once daily or 1,250 mcg (50,000 International Units) PO once monthly.  - Treat chronic renal disease if present. - Replace magnesium if hypocalcemia is accompanied by hypomagnesemia 3- Recombinant human parathyroid hormone is an option for treatment of refractory hypocalcemia due to hypoparathyroidism.  Prevention Some causes of hypocalcemia can be prevented, as follows: Vitamin D deficiency Ensure adequate calcium and vitamin D intake Adequate sun exposure  Adverse effect of drugs Monitor patients who receive treatment with phosphate or calcium chelators Postoperative hypoparathyroidism after thyroid surgery Test for and treat vitamin D deficiency preoperatively with high-dose vitamin D supplementation Meticulous surgical technique to preserve parathyroid glands Postoperative parathyroid hormone measurement predicts need for postoperative calcium  Calcium gluconate 10% IV: 100-200 mg/kg (1-2 ml/kg) over 5-10 minutes Brand name (available here) :Calcionate ampoule 10 ml: Composition: 500 mg calcium gluconate (44.5 mg elemental calcium). 342 mg calcium levulinate (44.8 mg elemental calcium). Dilution to max dilution 50mg/ml in NS, glucose 5%. Moniter heart rate , extravasation.  Calcium chloride 10% IV (271 mg elemental Ca ) Dose: 10-20 mg/kg (0.1-0.2ml/kg) Dilute to max. concentraton 20mg/ml