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HYPOCALCEMIA Hasan AYDIN, MD Yeditepe University Medical Faculty
Department of Endocrinology and Metabolism
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Overview of Calcium Balance
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Etiology Decreased GI Absorption Increased Urinary Excretion
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
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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 Pseudohypoparathyroidism (Type I and II)
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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
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Other Causes Excessive deposition in to the skeleton Chelation
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
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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
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Symptoms and Signs Systemic Confusion Weakness Mental retardation
Behavioral changes
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Symptoms and Signs Neuromuscular Parestesias Psychosis Seizure
Carpopedal spasm Chvostek’s and Trousseau’s signs Depression Muscle cramps Parkinsonism Irritability Basal ganglia calcifications
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Syptoms and Signs Cardiac Ocular Prolonged QT interval T wave changes
Congestive heart failure Ocular Cataracts
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Syptoms and Signs Dental Respiratory Enamel hypoplasia of teeth
Defective root formation Failure of adult tooth to erupt Respiratory Laryngospasm Bronchspasm Stridor
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Chvostek’s Sign Elicited by tapping over facial nerve causing twitching of ipsilateral facial muscles
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Trousseau’s Sign Carpal spasm in response to inflation of BP cuff to 20 mm Hg above SBP for 3 min
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Differential Diagnosis
Ca PO4 PTH 25-Vit D Calcitriol Hypoparathyroidism ↓ ↑ N Pseudohypoparathyroidism ↓N Liver disease Renal disease
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Evaluation of Hypocalcemia
History: Paresthesias/ cramping Tetany Carpopedal spasm Laryngospasm Seizures
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Physical Examination Signs of hypocalcemia:
Chvostek sign Trousseau sign Hyper-reflexia Dysmorphism (Di George Syndrome, PHP) Dental abnormalities Chronic mucocutaneous candidiasis Rickets
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Investigations Serum calcium (ionic), phosphate, magnesium iPTH
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)
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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
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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: mg of elemental Ca over min followed by an infusion of mg/kg/h
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Treatment Side effects: Nausea Vomiting Flushing Hypertension
Bradycardia, heart block (patients should be monitored)
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Treatment Asymptomatic Oral Ca supplementation
1-4 g/day in divided doses If patient has concurrent hypomagnesemia, Ca replacement alone will not correct hypocalcemia unless Mg is also replaced (2-4 g IV for symptomatic patients)
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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
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SPECIFIC CAUSES OF HYPOCALCEMIA
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Developmental Abnormalities
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
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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
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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
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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
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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)
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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
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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
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Hypoparathyroidism Clinically Biochemically
Symptoms of neuromuscular hyperactivity Biochemically hypocalcemia, hyperphosphatemia, diminished to absent circulating iPTH.
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Etiology Surgical hypoparathyroidism (most common)
Familial hypoparathyroidism Idiopathic hypoparathyroidism Functional hypoparathyroidism
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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 Mg is probably also required for the peripheral action of PTH
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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.
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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
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PTH Resistance Syndromes
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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,
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Pseudohypoparathyroidism
Rare familial disorder Target tissue resistance to PTH, Hypocalcemia, hyperphosphatemia Increased parathyroid gland function, Short stature and short metacarpal and metatarsal bones.
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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
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Pseudopseudohypoparathyroidism
developmental defects without the biochemical abnormalities of pseudohypoparathyroidism. lack evidence of PTH resistance 50% reduction in Gs alpha function Autosomal dominant
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Pseudoidiopathic hypoparathyroidism
Structurally abnormal form of PTH present Fail to respond to own PTH Normal response to exogenous PTH
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