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HYPOCALCEMIA. Hasan AYDIN , MD Yeditepe University Medical Faculty Department of Endocrinology and Metabolism. Overview of Calcium Balance. Etiolog y. Decreased GI Absorption Poor dietary intake of calcium Impaired absorption of calcium Vitamin D deficiency
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HYPOCALCEMIA Hasan AYDIN, MD Yeditepe UniversityMedicalFaculty Department of EndocrinologyandMetabolism
Etiology Decreased GI Absorption Poor dietary intake of calcium Impaired absorption of calcium Vitamin D deficiency Poor dietary intake of vitamin D Malabsorption syndromes Decreased conversion of vit. D to calcitriol Liver failure Renal failure Low PTH Hyperphosphatemia Decreased Bone Resorption/Increased Mineralization Low PTH ( hypoparathyroidism) PTH resistance ( pseudohypoparathyroidism) Vitamin D deficiency / low calcitriol Hungry bones syndrome Osteoblastic metastases Increased Urinary Excretion Low PTH Thyroidectomy I131 treatment Autoimmune hypoparathyroidism PTH resistance Vitamin D deficiency / low calcitriol
Parathyroid Related Disorders • Absence of the parathyroid glands or of PTH • Congenital • DiGeorge’s syndrome • X-linked or autosomally inherited hypoparathyroidism • Autoimmune polyglandular syndrome type I • PTH gene mutations • Postsurgical hypoparathyroidism • Infiltrative disorders • Hemachromatosis • Wilson’s disease • Metastases • Hypoparathyroidism following radioactive iodine thyroid ablation • Impaired secretion of PTH • Hypomagnesemia • Respiratory alkalosis • Activating mutations of the calcium sensor • Target organ resistance • Hypomagnesemia • Pseudohypoparathyroidism (Type I and II)
Vitamin D Related Disorders • Vitamin D deficiency • Dietary absence • Malabsorbtion • Accelerated loss • Impaired enterohepatic recirculation • Anticonvulsant medications • Impaired 25-hydroxylation • Liver disease • Isoniazid • Impaired 1α-hydroxylation • Renal failure • Vitamin D dependent rickets type I • Oncogenic osteomalcia • Target organ resistance • Vitamin D dependent rickets type II • Phenytoin
Other Causes • Excessive deposition in to the skeleton • Osteoblastic malignancies • Hungry bone syndrome • Chelation • Foscarnet • Phosphate infusion • Infusion of citrated blood products • Infusion of EDTA containing contrast agents • Fluoride • Neonatal hypocalcemia • Prematurity • Asphyxia • Diabetic mother • Hyperparathyroid mother • HIV infection • Drug therapy • Vitamin D deficiency • Impaired PTH responsiveness • Critical illness • Pancreatitis • Toxic shock syndrome • Intensive care unit patients
Clinical Features • Signs and symptoms depend on • Level of serum calcium • Age at onset and duration • Level of serum magnesium and potassium • Accompanying disturbances in acid-base homeostasis • Sometimes only symptoms of underlying disorder
Symptoms and Signs • Systemic • Confusion • Weakness • Mental retardation • Behavioral changes
Symptoms and Signs • Neuromuscular • Parestesias • Psychosis • Seizure • Carpopedal spasm • Chvostek’s and Trousseau’s signs • Depression • Muscle cramps • Parkinsonism • Irritability • Basal ganglia calcifications
Syptoms and Signs • Cardiac • Prolonged QT interval • T wave changes • Congestive heart failure • Ocular • Cataracts
Syptoms and Signs • Dental • Enamel hypoplasia of teeth • Defective root formation • Failure of adult tooth to erupt • Respiratory • Laryngospasm • Bronchspasm • Stridor
Chvostek’s Sign • Elicited by tapping over facial nerve causing twitching of ipsilateral facial muscles
Trousseau’s Sign • Carpal spasm in response to inflation of BP cuff to 20 mm Hg above SBP for 3 min
Evaluation of Hypocalcemia • History: • Paresthesias/ cramping • Tetany • Carpopedal spasm • Laryngospasm • Seizures
PhysicalExamination • Signs of hypocalcemia: • Chvostek sign • Trousseau sign • Hyper-reflexia • Dysmorphism (Di George Syndrome, PHP) • Dental abnormalities • Chronic mucocutaneous candidiasis • Rickets
Investigations • Serum calcium (ionic), phosphate, magnesium • Ionized Ca is physiologically active • 0.1 increase in pH increases iCa by 3-8% • 10 g/L decrease in albumin increases iCa by 0.2 • iPTH • Serum urea and creatinine levels • Vitamin D levels (if available) • Genetic studies (if necessary)
Approach to low serum calcium PTH Level Low High Mg level Phosphate Low High High Low Hypo magnesemia Hypo parathyroid Creatinine 25 OH Vit D High Normal Low Normal Renal Failure PHP 1,25 OH Vit D Nutrition Malabsorption Liver disease Vit D Dep Rickets Vit D Res Rickets
Treatment • Symptomatic: • Parenteral Ca • 10% CaCl2: 10 cc ampoules contains 360 mg of elemental Ca • 10% Ca gluconate: 10 cc ampoules contains 93 mg of elemental Ca • Recommended dose: 100-300 mg of elemental Ca over 10-20 min followed by an infusion of 0.5-2 mg/kg/h
Treatment • Side effects: • Nausea • Vomiting • Flushing • Hypertension • Bradycardia, heart block (patients should be monitored)
Treatment • Asymptomatic • Oral Ca supplementation • 1-4 g/day in divided doses • If patient has concurrent hypomagnesemia, Careplacement alone will not correct hypocalcemia unless Mg is also replaced (2-4 g IV for symptomatic patients)
Acute Management Of Hypocalcemia • Frank Tetany • 10-20 ml calcium gluconate (93 mgf elemental Ca/10 ml) for 10 min. • Ongoing severe hypercalcemia • 10 ampul of 10 ml calcium gluconate infused over 8-10 hours (in saline or dextrose) • When due to hypomagnesemia • 1-2 gram of magnesium sulfate (8-16 mEq) q6h, for several days
DevelopmentalAbnormalities • DiGeorge Syndrome • Parathyroid dysplasia, thymic hypoplasia, immune deficiency, cardiac defects, craniofacial malformations, mental retardation • Deletion on long arm of chromosome 22 • Kenny Caffey Syndrome • Parathyroid aplasia, medullary stenosis of long bones, growth retardation • Barakat syndrome • Hypoparathyroidism, nerve deafness, renal dysplasia
Disorders of 25-OH D Metabolism • Hepatic and hepatobiliary disease • Impairement of synthesis • Particularly in biliary cirrhosis • Gastrointestinal disorders • Malabsorption and disruption of enterohepatic circulation of vitamin D • Protein wasting syndrome • Drugs • Increased conversion of 25 OH D to inactive metabolites
Disorders of 1,25-OH D Metabolism • Vitamin D dependent rickets type I • Vitamin D dependent rickets type II • Vitamin D resistant rickets and osteomalacia • Hypercalciuric hypophosphatemic rickets • Tumor induced osteomalacia
Vitamin D Dependent Rickets Type I • Autosomal recessive • Inactivating mutations on chromosome 12 • Circulating levels of 1,25 (OH) D are low • Treatment with calcitriol 0,5-3 mcg/day
Vitamin D Dependent Rickets Type II • Target organ resistance to calcitriol • Markedly elevated plasma levels of 1,25 (OH) D • Sporadic and autosomal recessive • Alopecia, epidermal cysts, oligodentia • Low 24,25 (OH)2D3 and 24 (OH)-25-hydroxylase • Treatment with massive doses of vitamin D (10-20 mg/day) or 1,25 (OH)D (6 mcg/kg/day)
Vitamin D Resistant Rickets and Osteomalacia • Sporadic or familial • X-linked hypophosphatemic VDRR • Hypophosphatemia, normocalcemia, normal PTH, hyperphophaturia • 25 (OH)D normal, 1,25 (OH)D low/normal • Treatment with administration of phosphorus supplements and vitamin D
Tumor Induced Osteomalacia • Release of humoral factors affecting renal phosphate reabsorption, and formation of 1,25 (OH)2D • Bone pain, muscle weakness, recurrent pathological fractures, pseudofractures • Hypophosphatemia, hypocalcemia, elevated ALP, PTH vary • Surgery of tumor • Treatment with phosphorus + vitamin D
Hypoparathyroidism • Clinically • Symptomsof neuromuscular hyperactivity • Biochemically • hypocalcemia, • hyperphosphatemia, • diminished to absent circulating iPTH.
Etiology • Surgical hypoparathyroidism(most common) • Familial hypoparathyroidism • Idiopathichypoparathyroidism • Functionalhypoparathyroidism
Functional Hypoparathyroidism • long periods of hypomagnesemia • selective gastrointestinal magnesium absorption defects • generalized gastrointestinal malabsorption • alcoholism. • Serum PTH low • Hypocalcemia • Mg is required for PTH release • Mgis probably also required for the peripheral action of PTH
Classification • 5 categories based primarily on the concentration of serum calcium. • Grades 1 with no hypocalcemia, • Grades 2 inconstant hypocalcemia • Grades 3 serum calcium is below 8.5 mg/dl • Grades 4 serum calcium is below 7.5 mg/dl • Grades 5 serum calcium is below 6.5 mg/dl • Clinical manifestations of hypoparathyroidism depend upon the severity and chronicity of the hypocalcemia.
Treatment • Physiologic replacement of PTH. • Pharmacologic doses of vitamin D • (ergocalciferol or its more potent analog dihydrotachysterol, in combination with oral calcium administration) • Diets low in phosphate (restriction of dairy products and meat) and oral aluminum hydroxide gels
Etiology of Pseudohypoparathyroidism • abnormal target tissue responses • receptor binding of the hormone • final expression of the cellular actions of PTH • resistance to several other hormones (vasopressin, glucagon). • secretion of a biologically inert form of PTH, • circulating inhibitors of PTH action, • an intrinsic abnormality of PTH receptors, • autoantibodies to the PTH receptor,
Pseudohypoparathyroidism • Rare familial disorder • Target tissue resistance to PTH, • Hypocalcemia, hyperphosphatemia • Increased parathyroid gland function, • Short stature and short metacarpal and metatarsal bones.
PsHP Type Ia (Albright Syndrome) • Hypoparatrhyroidism, short stature, round facies, obesity, brachydactily, neck webbing, sc calcifications • Defect in the function of Gs protein • TSH, Glucagon, Gonadotropin resintance • Autosomal dominant • Intermittant hypocalcemia, elevated PTH, low urine Ca
Pseudopseudohypoparathyroidism • developmental defects • without the biochemical abnormalities of pseudohypoparathyroidism. • lack evidence of PTH resistance • 50% reduction in Gs alpha function • Autosomal dominant
Pseudoidiopathic hypoparathyroidism • Structurally abnormal form of PTH present • Fail to respond to own PTH • Normal response to exogenous PTH