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ECF Diet 0.5-1.5 gr 10% complexed citrate, sulphate Resorption 0.3-0.5 g Formation 0.3-0.5 g calcium 8.5–10.5 mg/dl Bone 1000 g Filtration 5-7gr 40-45 % Absorption ionized 0.25-0.5gr 40-45 % albumin bound Secretion 0.1-0.2gr Feces 0.35-0.6gr • Total body Ca Reabsorption 1 to 1.5 kg 4.9-6.7gr • 99%- skeleton 98% • 0.1% ECF 0.15-0.3 g/24h • rest intracellular Calcium • • • • • • • An essential intracellular and extracellular cation Extracellular calcium is required to maintain normal biological function of nervous system, the musculoskeletal system, and blood coagulation Intracellular calcium is needed for normal activity of many enzymes Preservation of the integrity of cellular membrane Regulation of endocrine and exocrine secretory activities Activation of compliment system Bone metabolism Calcium (Ionized) - Roles • • • • • In bone: calcium salts provide structural integrity of the skeleton ( mineralization) Regulation of neuromuscular contractility Regulation of activity of many enzymes Cofactor in coagulation process ( factors VII, IX, X and prothrombin) Cellular activities: second messenger, mediating the effects of membrane signals on release or secretory products (neurotransmitters, amylase, insulin, aldosteron) Calcium and Albumin • • • 40-45% of circulating calcium is bound to albumin Change in serum albumin change in measured total serum calcium concentration Calcium is bound to carboxyl groups in albumin, this binding is highly pH dependent • • • Acute acidosis binding ionized calcium Acute alkalosis binding ionized calcium • These changes are not reflected at the total calcium A shift of 0.1 pH unit produces a change in ionized calcium of 0.04 to 0.05 mmol/L ( 0.16-0.2 mg/dl) Calcium and Albumin • • • • • At pH 7.4 each g/dl of serum albumin binds 0.8 mg/dl of calcium Serum calcium should be “corrected” according to serum albumin level Normal level of serum albumin is 4 g/dl Change of 1 g/dl in serum albumin serum calcium 0.8 mg/dl in total Example: A patient with total serum calcium 7.5 mg/dl albumin 2 mg/dl, has corrected serum calcium of 9.1 mg/dl Disorders of Calcium Metabolism • Hypercalcemia • Hypocalcemia Serum Calcium >10.4 mg/dl Serum Calcium < 8.5 mg/dl Causes of Hypercalcemia Parathyroid related I. Primary hyperparathyroidism Solitary adenoma Hyperplasia MEN II. Lithium therapy Malignancy related I. Solid tumor with metastasis (breast) II. Solid tumor with humoral mediation of hypercalcemia (lung, kidney) III. Hematologic malignancies (multiple III. Familial Hypocalciuric myeloma, lymphoma, Hypercalcemia (FHH) leukemia) Causes of Hypercalcemia Vitamin D related I. Vitamin D intoxication II. 1,25(OH)2D; sarcoidosis and other granulomatous diseases III. Idiopathic hypercalcemia of infancy Associated with high bone turnover I. Hyperthyroidism II. Immobilization III. Thiazides IV. Vitamin A intoxication Associated with renal failure I. Severe secondary hyperparathyroidism II. Aluminum intoxication III. Milk- alkali syndrome Diagnosis of Hypercalcemia Serum Ca Measure serum albumin or ionized calcium Albumin corrected calcium normal Medical history and medication use history Measure PTH PTH or N Check calciuria PTH Check 1,25(OH)2D3 Malignancy Diagnosis of Hypercalcemia Check calciuria Urine Ca Urine Ca / N FHH Primary HPT Check 1,25(OH)2D3 1,25(OH)2D3 Granulomatous diseases (Sarcoidosis), Lymphoma Primary Hyperparathyroidism Incidence 42/100 000 Age > 40 1/200; 1/1000 X 3.5 after introduction of routine serum calcium testing 80% single gland involvement – adenoma 20% multiple gland involvement – hyperplasia <2% carcinoma MEN Hyperparathyroidism Serum Calcium Primary Secondary Tertiary Serum Plasma PTH Phosphorus / Normal / Normal / Normal / Normal / / Normal / Clinical Manifestations • CNS - Cognitive difficulties, apathy, drowsiness, obtundation or even coma • GI - Anorexia, nausea, vomiting, constipation and rarely acute pancreatitis • CVS - Hypertension, A-V nodal delay, shortened QT interval, enhanced sensitivity to digitalis, compete heart block, ventricular arrhythmias • RENAL- Loss of concentrating ability, polyuria, polydipsia, nephrolithiasis and occasionally nephrocalcinosis, nocturia Bone and Joint Manifestations in Primary Hyperparathyroidism • • • Osteoporosis Diffuse bone pain without osteitis fibrosa cystica Osteitis fibrosa cystica Diffuse demineralization Subperiostal bone resorption Phalanges Lamina dura Distal clavicles • Cystic lesions Brown tumors Cysts Deformities, Fractures, Pain Arthritic symptoms Resorption of articular bone Periarticular metastatic calcification Pseudogout Gout Treatment When is surgery indicated in PHPT patients ? Guidelines for Surgery NIH Consensus 1990 NIH Consensus 2002 Serum 1 – 1.6 mg/dl > upper 1 mg/dl > upper limit of Calcium limit of normal normal Urine > 400 mg/24h > 400 mg/24h Calcium by 30 % compared by 30 % compared CCT with age matched with age matched 2 SD of gender, T score (– 2.5) at any BMD age, race matched site Age < 50 < 50 Patients for whom medical surveillance is either not desirable or not possible Femoral Neck BMD Change in PHPT Patients Silverberg et al NEJM Other Considerations • Neuropsychological disturbances • Weakness and easy fatigability • Depression • Intellectual weariness • Increased sleep requirements Improved by surgery • Onset of Menopause • Increased bone loss 99mTc- sestamibi Parathyroid Scan 20 min 3 hours 90% sensitivity in parathyroid tissue detection Patients’ Monitoring Goal – early detection of: • • • • • Worsening of hypercalcemia Renal impairment Loss of bone mass Stones Fractures Guidelines for Monitoring NIH Consensus 1990 NIH Consensus 2002 Serum Calcium Urine Calcium x2 year x2 year x1 year Not recommended CCT x1 year Not recommended, s-cr Abdom. X-Ray, US x1 year Not recommended x1 year (forearm) x1 year (3 sites: lumbar spine, hip, forearm) BMD General Measures • Hydration • Adequate Mobility • Diet neither restrictive nor excessive in calcium • Adequate vitamin D status • Prompt medical attention for the possibility of worsening of hypercalcemia (intercurrent illness accompanied by risk of dehydration) Calcium-sensing Receptor • • • A member of the G protein-coupled receptor family Contains seven hydrophobic helices that anchor it in the plasma membrane. The large (~600 amino acids) extracellular domain critical to interactions with extracellular calcium Large (~200 amino acids) cytosolic tail. Inactivating Mutations in Calcium Sensing Receptor • Inactivating mutation – Familial hypocalciuric hypercalcemia (FHH) heterozygous Calcium set point serum calcium Urinary calcium reabsorption urinary calcium – Neonatal severe hyperparathyroidism (NSHPT) – homozygous -מחלה קטלנית אם לא מבצעים כריתה של בלוטות ה parathyroid Hypercalcemia of Malignancy • • • • • Lung, breast, and prostate cancer frequently invade skeleton and destroy bone tissue Breast and lung cancer also cause hypercalcemia of malignancy (HCM), without invading skeleton Multiple myeloma has skeletal complications in virtually 100% of cases Damage to skeleton usually late in course of disease Bone damage associated with considerable worsening in patient’s quality of life PTHrP-PTH related peptide • גן על כרומוזום 12 • הגן מצוי ברקמות עוברים :סחוס ,לב ,זקיקי שיערות, אפיתל • הגן ל PTHrP -מבוטא ברקמות של מבוגר :חשוב להתפתחות רקמת שד ,ריכוז גבוה בחלב מוטציה בעכבר הומוזיגוטים מוטציה לטלית פגמים בהתפתחות העצם והסחוס הטרוזיגוטים תקינים PthrP Induced Hypercalcemia Squamous cell carcinoma Islet cell tumor (pancreas) Adult T cell leukemia Renal cell carcinoma Breast carcinoma Paracrine Effect of Bone Resorbing Substances Malignant cells travel through bloodstream & invade bone Release substances into immediate area: • PTHrP • TGF- (transforming growth factoralpha) • IL-1 (interleukin-1) • TNF (tumor necrosis factor) • IL-6 (interleukin-6) Cause osteoclast activation andlocal bone destruction & can lead to hypercalcemia Plasma Cell Myeloma Skeletal Metastasis Treatment Hydration Furosemide Bisphosphonates Calcitonin Glucocorticoids Dialysis Hydration • First step in the management of severe hypercalcemia - Isotonic saline • Usually serum calcium by 1.6-2.4mg/dl • Hydration alone rarely leads to normalization in severe hypercalcemia • Rate of IV saline based on severity of hypercalcemia and tolerance of CVS for volume expansion, if possible achieve urine output of 300 ml/hr Loop Diuretics • Facilitate urinary excretion of calcium – By inhibiting calcium reabsorption in the thick ascending limb of the loop of Henle. • Guard against volume overload – Volume expansion must precede the administration of furosemide, because the drug’s effect depends on delivery of calcium to the ascending limb. Needs frequent measurement of electrolytes and water Bisphosphonates • • • • • Structurally related to pyrophosphate Bind to hydroxyapatite in bone and inhibit the dessolution of crystals Great affinity for bone and their resistance to degradation Extremely long half life in bone Poor GI absorption < 1% Pamidronate • Inhibits osteoclast function • 60mg to 90 mg IV over 24hr • 70% to 100% of patients had serum • • calcium within 24 hrs, 2/3rd of this group had normal serum calcium within 7 days Adverse effects: – mild transient in temp (<2deg C) – transient leukopenia – small in s phosphate level Excreted by kidney dose adjustment Relative Potencies of Bisphosphonates Potency relative to pamidronate disodium in vivo (hypercalcemic rat), linear scale Potencies of Bisphosphonates 900 847 800 700 600 500 400 300 200 100 0.05 1.00 2.77 7.44 35.90 olpadronate alendronate risedronate 43.60 0 clodronate pamidronate disodium ibandronate ZOMERA® (zoledronic acid) 1. Green JR, Müller K, Jaeggi KA. Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res. 1994;9:745-751. Zoledronic Acid (ZOMERA) • Zoledronic acid belongs to a new class of highly • potent bisphosphonates Heterocyclic, nitrogen-containing bisphosphonate composed of: • A core bisphosphonate moiety • An imidazole-ring side chain containing 2 critically positioned nitrogen atoms OH O N P N OH O OH P HO OH Glucocorticoids • Inhibit the growth of neoplastic lymphoid tissue • Counteract the effects of vitamin D Functionally Based Classification of Hypocalcemia I. PTH absent A. Hereditary hypoparathyroidism B. Acquired hypoparathyroidism Autoimmune Post surgical C. Hypomagnesemia Functionally Based Classification of Hypocalcemia III. PTH overwhelmed A. Severe acute hyperphosphatemia 1. Tumor lysis 2. Acute renal failure 3. Rhabdomyolysis B. “Hungry bone syndrome” after parathyroidectomy Functionally Based Classification of Hypocalcemia II. PTH ineffective A. Chronic renal failure B. Active vitamin D lacking 1.Dietary intake or sunlight 2.Defective metabolism Anticonvulsant therapy Vitamin D dependent rickets type I C. Active vitamin D ineffective 1.Intestinal malabsorption 2.Vitamin D dependent rickets type II D. Pseudohypoparathyroidism Differential Diagnosis of Hypocalcemia Correct calcium for albumin: Ca = measured Ca + 0.8 for each mg/dl albumin below 4.0 Hypovitaminosis D Manifestations of Acute Hypocalcemia • • • CNS – Psychiatric disturbances – Seizures Neuromuscular – Tremor, twitching, movement disorders – Positive Chvostek and Trousseau signs – Carpopedal spasm – Tetany Cardiac – Q-T prolongation on ECG – Ventricular Arrhitmia – Heart block ECG in Hypocalcemia • Sinus rhythm with diffuse T wave inversion • T waves -inverted, but of relatively normal width • QT prolongation (The corrected qtc is 560 ms ) • Prolongation is in the ST segment rather than the T waves Carpopedal Spasm Treatment of Acute Hypocalcemia Calcium Repletion • • • • Promptly correct symptomatic or severe hypocalcemia with cardiac arrhythmias or tetany with parenteral administration of calcium salts Administer 1-2 ampules 10% calcium gluconate (93 mg/10 mL) in 50-100 mL of D5W over 5-10 minutes then NS with 15 mg/kg of calcium Each 10 cc ampule of 10% calcium gluconate contains 1 gm of calcium gluconate but less than 100 mg of calcium then therefore, if want to give 15 mg/kg calcium to 70 kg pt, have to give 10 amps Measure serum calcium every 4-6 hours to maintain serum calcium levels at 8-9 mg/dL Treatment of Acute Hypocalcemia • Patients with cardiac arrhythmias or patients on digoxin therapy need continuous ECG monitoring during calcium replacement because calcium potentiates digitalis toxicity. • In case of extreme emergency: Calcium chloride 10% solution (273 mg/10-mL ampule) delivers higher amounts of calcium and has advantages when rapid correction is needed, but it is very irritating when administered intravenously and probably only should be administered centrally. Treatment of Acute Hypocalcemia • Identify and treat the cause of hypocalcemia and taper the infusion. • Start oral calcium and vitamin D treatment early. Patients with postparathyroidectomy hungry bone disease, especially those with osteitis fibrosa cystica, can present with a dramatic picture of hypocalcemia. Activating Mutation • Familial hypercalciuric hypocalcemia the opposite of what is seen with inactivating mutations Calcium set point serum calcium Urinary calcium reabsorption Urinary calcium