Importance of Calcium CALCIUM DISORDERS. Hypercalcaemia. Calcium homeostasis. Effects on total calcium

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1 CALCIUM DISORDERS Reto Neiger Klinik für Kleintiere (Innere Medizin) Justus-Liebig Universität Giessen Importance of Calcium Bone formation and resorption, Enzymatic reactions, Membrane transport and stability, Blood coagulation, Nerve conduction, neuromuscular transmission, Muscle contraction, vascular smooth muscle tone, Hormone secretion, Control of hepatic glycogen metabolism, Cell growth and division Etc. Calcium homeostasis Hypercalcaemia Parathyroid gland PTH PTH 1,25(OH) 2D 3 Kidney P, Positive effects Negative effects Total calcium > 3.0 mmol/l Ionised Ca ++ > 1.42mmol/l (Ettinger 7th Edition) Calcium homeostasis 50% ionised calcium 40% bound calcium (Albumin) 10% complex calcium Bone Ca2+ ECF Intestine Guestimation for ionised Ca ++ : Total calcium/ 2 Depending on albumin and ph Alkaline ph = bidning to albumin = ion. Ca ++ Acidic ph = binding to albumin = ion Ca ++ Effects on total calcium Drugs Falsely low due to Anti epileptic drugs, glucocorticoids Phosphate containing enemas EDTA, Citrate Falsely high due to Oestrogen, Progesterone, Testosterone Parenteral calcium substitution Oral phosphate binder Laboratory problems Falsely low due to hyperbilirubinaemia Falsely high due to dehydration and lipaemia 1633 dogs Measuring of ionised Ca ++ in relation to total calcium and total protein as well as albumin Total protein calculated ion. Ca ++ (mg/dl) = total calcium (mg/dl) (0.4 x TP (mg/dl)) Sensitivity: 83% Specificity: 80% Albumin calculated ion. Ca ++ (mg/dl) = total calcium (mg/dl) - Albumin (mg/dl) Sensitivity: 82% Specificity: 82% ionised Ca ++ can not be reliably calculated Speificity for dogs with CKD: 63% 1

2 Ionized Calcium Clinical signs of I-Stat Nova AVL Omni Etc. PU/PD Anorexia Vomiting Constipation Weakness, lethargy Muscle twitching Seizures Therapy of Treat clinical signs, not primarily laboratory values! Infusion with 0.9%NaCl Furosemide 2-3x daily 2-4mg/kg Prednisolone 2x daily 1-2mg/kg if severe: 1-4 meq/kg sodium bicarbonate iv 4-6 IU/kg calzitonine sc additionally Ca-poor diet (k/d u/d s/d) Oral phosphate binder Biphosphonates (Pamidronate iv/ Fossamax po) Causes of Hypercalcaemia Non-pathologic Growing animal (depending on size) Laboratory error (lipaemia) Transient Hyperproteinaemia Haemoconcentration Pathological Pathological Hypercalcaemia Malignancy-associated Hyper-Ca of malignancy Lymphoma Anal sac adenocarcinoma Thymoma Carcinomas (lung, ) Bone marrow osteolysis Multiple myeloma Myeloproliferative dzs Leukaemia Hyperparathyroidism Adenoma, adenocarcinoma 1 bone marrow tumour Non malignancy-associated Chronic renal disease Acute, chronic Granulomatous dzs Blastomycosis, Aspergillosis Hypervitaminosis D Plants, Rodenticides, human psoriasis drugs Skeletal lesions Osteomyelitis, etc. Hypoadrenocorticism Idiopathic Hypercalcaemia of Malignancy PTH ATP PTHrP camp PTH/PTHrP Receptor N-Terminus of PTH or PTHrP Lymphoma Anal-sac adenocarcinoma Thymoma Carcinoma (lung, pancreas,..) 2

3 Osteolytic Hypercalcaemia Multiple myeloma Myeloproliferative diseases (Leukaemia,...) Lymphoma Endocrinology 131:1157; 1992 Cut-off: ionized Ca ++ > 1.33 mmol/l mean: 1.6 mmol/l Causes of 58 % tumour 78 % Lymphoma 11 % Carcinoma 6 % Anal sac adenocarcinoma 17 % kidney disease 13 % hyperparathyroidism 5 % hypoadrenocorticsm 4% granulomatous disease 3 % Vitamin D intoxication Ionised Ca ++ higher in LSA and anal sac carcinoma than in other diseases Not possible to make a diagnosis based on ionised calcium Total calcium and calculated ionised Ca ++ are not useful find ionised Diagnostic approach in animal with Confirm (laboratory error, lipaemia, transient form) If possible, measure ionized Ca² + Re-evaluate signalment and physical examination (including rectal exam) Rule out renal disease If masses present (also lymphnodes) fine needle aspirate and cytology Diagnostic plan in animals with CBC Biochemistry Renal parameters incl. phosphate Urinalysis + UPC PTH & PTHrP X-ray thorax tumour, granulom. dzs, bones X-ray abdomen osteolysis, urolithiasis Ultrasound abdomen osteolysis, tumour, urolithiasis Ultrasound parathyroid gland prim. hyperparathyroidism ACTH stimulation test hypoadrenocorticism Cyto lymph nodes ± bone marrow Lymphoma 3

4 28 healthy dogs 25 dogs with LSA 17 normocalcaemic 8 hypercalcaemic 9 dogs with primary hyperparathyroidism 7 dogs with carcinoma of anal glands Mellanby et al Vet Record 2006;159: first report in dogs Mean age: 9.3 Jahre Coon hound over represented (4/29) History: PU/PD (62%) Lethargy (48%) GI signs (24%) Muscle twitching (13%) Pathology: 85% Adenoma 14% Hyperplasia 1% Carcinoma commonly only 1 gland affected Age distribution of 78 dogs with primary hyperparathyroidism. The mean age at the time of diagnosis was 10.5 years. (From Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, ed 3, Philadelphia, 2004, Saunders.) 3 dogs with of malignancy All correct negative 12 dogs with primary hyperparathyroidism 6 Hyperplasia 5 falsely negative 1 falsely positive 6 Adenoma 5 falsely negative 1 correct positive Sensitivity for hyperplasia: 0% Sensitivity for adenoma : 25% Specificity: 50% Own study (Kreissl et al) scintigraphy of parathyroid galnds in hypercalcaemic dogs ion. Ca >1.59 mmol/l 3 dogs: Dachshund 12 years mc: PU/PD, constipation, incrased weight Hyperplasiae Mixed breed 13 years m: Serendipidous Parathyroid adenocarcinoma Mixed breed 6 years m: PU/PD, lethargy, weight loss Adenoma 4

5 Treatment of prim. Hyperparathyroidism Post operative complications Hypocalcaemia PTH from other glands must resume Surgery: parathyroidectomy (commonly + thyroidectomy) Clinical signs: Panting Ultrasound guided ethanol injection Restless Risk of leakage Poor success in our hands Benign neglect In case when no clinical signs? Twitching / seizures Rubbing of face Shaking of jaw Biting into paws Postoperative: Control of Ca up to 7 days post operatively 17/19 dogs normocalcaeic between 24h 6 days post OP normokalzämisch Median 36h Higher Ca-values preoperatively resulted in lower Cavalues post-operatively Signalment Symptoms & duration Pre-operative PTH, PTHrP Ion. Ca ++ Total calcium No value of these parameters regarding postoperative hypocalcaemia Pre-operative PTH Pre-operative ion. Ca ++ post operative decrease of ion. Ca ++ within first 24h no value of these parameters regarding postoperative hypocalcaemia Therapy for Therapy for Treat underlying disease (Chemotherapy, etc.) Aggressive therapy only needed if Ca (mg/dl) x P (mg/dl) product > Treat if: azotaemia, cardiac or neurologic problems, weakness, dehydrated No cut-off calcium value exist when therapy for hypercalcemia important Initial Considerations Fluids (0.9% sodium chloride) Furosemide Sodium bicarbonate Glucocorticoids Secondary Considerations Bisphosphonates Calcitonin Tertiary Considerations Mithramycin Ethylenediamine tetraacetic acid Peritoneal dialysis, homodialysis Future Considerations Calcium channel blockers Calcium receptor agonists 5

6 Treatment Dose Indication Comments 0.9% NaCl ml/kg/d Mod severe Caution in cardiac patients Furosemide 2-4 mg/kg q8-12h Dito Volume expansion before use Na-Bicarbonate 1 meq/kg iv slow infusion Only in severe Prednisolone 1-2 mg/kg/d Mod severe Calcitonin 4-6 IU/kg SQ q8-12h Clodronate mg/kg in a 4- hr IV infusion Mithramycin 25 µg/kg IV in 5% dextrose over 2-4hr Vit-D Intoxication Severe Unresponsive Hypercal of Malig. Sodium EDTA mg/kg/hr Severe Close monitoring, short lived Establish diagnosis before use! May have short action, ± vomiting Nephrotoxicity? Nephrotoxicity, Thrombocytop. Nephrotoxicity Prognosis Histopathological diagnosis (adenoma / carcinoma) difficult Surgical evaluation important 19 dogs 1 year survival: 72% 2 years survival: 37% 3 years survival: 30% 6