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Practical Clinical Pathology Calcium Disorders in the Dog & Cat
Wendy Blount, DVM
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Ionized Calcium The active form of calcium When is it important?
When verifying hypercalcemia Rarely needed of total calcium is normal or low
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Calcium – Danger Values
>15-16 mg/dl = acute renal failure, cardiac failure <7 mg/dl = tetany Depends on blood pH Lower pH masks clinical signs Ca can be 1 mg/dl and iCa 0.1 mml/L higher in juvenile dogs & Cats
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Errant Values False hypercalcemia False hypocalcemia Dehydration
Hyperlipidemia Drugs/toxins: vitamin D, cholecalciferol, estrogen, progesterone, testosterone, anabolic steroids, acetaminophen, hydralazine, oral phosphorus binders False hypocalcemia Increased bili Hypoalbuminemia (correct for this) Drugs: anticonvulsants, glucocorticoids, phosphates (Kphos or Fleet enema)
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DDx Hypercalcemia H = Hyperparathyroidism (1°, 3°, hyperplasia), HHM, houseplants, hyperthyroidism (cats) A = Addison's disease, aluminum, vitamin A R = Renal disease, raisins/grapes (dogs) D = Vitamin D toxicosis (granulomatous dz), drugs, Dovonex®, dehydration, diet I = Idiopathic (cats), infectious, inflammatory, iatrogenic (IV, phosphorus binders, calcipotriene) O = Osteolytic (osteomyelitis, immobilization, local osteolytic hypercalcemia, osteodystrophy, osteoporosis, bone infarct) N = Neoplasia (HHM and LOM), nutritional (acidifying diet, vitamin D) S = Spurious, schistosomiasis, salts of calcium, supplements
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DDx Hypercalcemia Very Common Causes - malignancy
HHM – Humoral Hypercalcemia of Malignancy Osteolysis Less Common but Important Causes Primary hyperparathyroidism Hypoadrenocorticism Acute and chronic renal failure Hypervitaminosis D Idiopathic feline hypercalcemia
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Symptoms of Hypercalcemia
PU-PD + urinary incontinence Calcium blocks ADH (nephrogenic DI) Weakness, lethargy CNS depression Muscle weakness, muscle wasting Anorexia, weight loss Water intake MAY also decrease Decreased drinking + PU = dehydration Vomiting, diarrhea, constipation Ileus, pancreatitis Shivering, twitching, stiff gait
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Consequences of Hypercalcemia
Soft tissue mineralization Increased risk if Ca x P = 60 nephrotoxicity Urolithiasis Calcium oxalate (cats > dogs) Calcium phosphate (dogs with primary hyperparathyroidism)
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Diagnosing Hypercalcemia
Rule out lab artifact Fasting prevents lipemia, which gives false + No hemolysis – also gives false + Confirm hypercalcemia is real Ionized calcium Follow reference lab handling guidelines Altered by temperature, pH and CO2
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Diagnosing Hypercalcemia
Look for tumors Rectal/perineal/vaginal exam, LN/mammary palpation, palpate long bones Imaging – chest rads, GlobalFAST®, abdominal US/rads, bone rads FNA – LN (even if small?), liver, spleen CBC, panel, UA, lytes, fecal, FeLV/HW test Sample bone marrow if cytopenias Hypercalcemia panel to Michigan
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Diagnosing Hypercalcemia
MSU Hypercalcemia panels Allow blood to clot in RTT for minutes before collecting serum Malignancy Panel PTH, PTHrp, iCa – EDTA plasma and serum Parathyroid Panel PTH & iCa - serum Vitamin D Panel PTH, 25-hydroxyVitD & iCa - serum
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Diagnosing Hypercalcemia
Diagnostic Chart 16 conditions and 10 blood parameters Ca-Phos Chart - Willard Feldman and Nelson – Diagnostic Algorithms Algorithm of Tests for Hypercalcemia Diagnostic Algorithm – Sick Hypercalcemic Dog Diagnostic Algorithm – Well Hypercalcemic Dog Willard – Diagnostic Algorithm Hypercalcemia
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Happy 6 year old SF GSD – Seeing Eye Service Dog PU-PD for 2-3 weeks
CBC, panel, lytes – Ca 13.2 mg/dl UA – USG 1.008 HW Test – negative Chest x-rays, abdominal US – NSAF FNA Liver and spleen showed no significant pathology Urine culture – negative Ionized calcium mildly elevated PTH, PTHrp normal
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Happy ACTH stim - normal No response to amoxicillin 750 mg
PO BID x 4 weeks Rx prednisone 1 mg/kg PO SID x 14 days, then 0.5 mg/kg PO SID x 14 days, then 0.5 mg/kg PO QOD x 14 doses PU-PD resolved calcium normalized 6 months later – enlarged lymph nodes FNA Cytology – large cell lymphoma Elected euthanasia Owner never paid her bill at TAMU
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Ronald Sayers - Forney TX
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Hypercalcemia of Malignancy
aka Pseudohyperparathyroidism aka HHM (humoral hypercalcemia of malignancy) HHM is most common cause of hypercalcemia in the dog and cat 67% of dogs with hypercalcemia have cancer 33% of cats with hypercalcemia have cancer Dogs with HHM most often have Anal sac adenocarcinoma LSA ( L-asparaginase check Ca in 48 hours) multiple myeloma Cats with HHM most often have LSA or SCC Other carcinomas (lung, mammary, nasal, pancreas, testicle, thymus, thyroid), hepatoma and melanoma
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Hypercalcemia of Malignancy
90% of dogs with anal sac tumors get HHM >50% are hypercalcemic at diagnosis 10-35% of dogs with LSA have HHM 15-20% of dogs with multiple myeloma have HHM Cats with LSA and HHM are most likely to have cranial mediastinal lymphoma >90% of dogs with LSA and HHM have enlarged lymph nodes HHM can be intermittent
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Hypercalcemia of Malignancy
Some tumors release PTH-rp Parathyroid hormone related protein Stimulates osteoclastic bone resorption Increases renal tubular reabsorption of calcium Made in low amounts by normal tissues Thought to regulate calcium transport during gestation and lactation Other humoral factors are involved in HHM Bony invasion can contribute to HHM
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Hypercalcemia of Malignancy
Diagnosis If concurrent azotemia, it can be difficult to distinguish HHM from renal hypercalcemia Hypercalcemia can cause nephrotoxicity Marked azotemia and mild hypercalcemia is more consistent with renal disease Marked hypercalcemia with mild azotemia is consistent with HHM Phosphorus often high with renal disease Phosphorus often low with HHM iCa++ high with HHM iCa++ normal to low with renal failure
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Sunshine 18 year old mixed terrier PU-PD for 2-3 weeks
CBC, panel, lytes – Ca 14.6 mg/dl UA – USG 1.003 HW Test – negative Chest x-rays, abdominal US
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Sunshine 18 year old mixed terrier PU-PD for 2-3 weeks
CBC, panel, lytes – Ca 14.6 mg/dl UA – USG 1.003 HW Test – negative Chest x-rays, abdominal US
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Sunshine 18 year old mixed terrier PU-PD for 2-3 weeks
CBC, panel, lytes – Ca 14.6 mg/dl UA – USG 1.003 HW Test – negative Chest x-rays, abdominal US
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Sunshine 18 year old mixed terrier PU-PD for 2-3 weeks
CBC, panel, lytes – Ca 14.6 mg/dl UA – USG 1.003 HW Test – negative Chest x-rays, abdominal US Enlarged perihilar lymph nodes Peribronchiolar pattern Urine culture – negative Ionized calcium elevated PTH low, PTHrp normal
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Sunshine Owner brings in a large bag of several dozen supplements at
each office visit, and talks about them at length We go through all of them, add up the Vitamin D, and it is about 10x the recommended dose All supplements with Vitamin D are discontinued Hypercalcemia and PU-PD resolve Treated empirically for respiratory infection and perihilar lymphadenopathy resolved
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Vitamin D Toxicosis Vitamin D increases calcium absorption in the GI tract & bone resorption Acute or chronic 1-2 weeks for steady state for supplements Symptoms as soon as hrs, peak in 2-3 days for cholecalciferol Weakness, anorexia lethargy first Then recumbency, hematemesis, bloody diarrhea, azotemia, shock Can present as normocalcemia with hyperphosphatemia
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Vitamin D Toxicosis Calcipotriene, calcipotriol House Plants
Eczema creams Trade names Dovonex®, Davionex®, Psorcutan® House Plants Cestrum diurnum day blooming jessamine Solanum malacoxylon and other nightshades Trisetum flavescens oat grasses
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Vitamin D Toxicosis Chronic toxicity results in soft tissue mineralization Endocardium, vasculature, tendons, kidneys, lung Cholecalciferol - Bromethalin trade names Quintox®, Rampage®, Muritan®, TomCat® 2 mg/kg causes hypercalcemia 4-6 mg/kg causes illness As little as 10 mg/kg can be lethal
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Doc 3 year old CM Standard Poodle CC – vomiting, weight loss,
drinking massive amounts of water, anorexia CBC – PCV 28% Panel – calcium 15 mg/dl (not lipemic) UA – SG 1.005 Urine culture – negative
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Doc DDx hypercalcemia Rectal exam - normal
Malignancy Primary hyperparathyroidism Granulomatous inflammation Hypervitaminosis D Addison’s Disease Rectal exam - normal Chest x-rays and abdominal US – normal Reticulocytes - <50,000/ul
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Doc PTH – low Ionized calcium – high PTHrP – negative ACTH stimulation
Pre ACTH cortisol – 0.8 ug/dl Post ACTH cortisol – 1.1 ug/dl
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Hypoadrenocorticism Degree of hyperkalemia is usually correlated with hypercalcemia usually moderate mg/dl Ionized calcium - usually normal Azotemia can be marked Distinguish from acute oliguric renal failure Moderately concentrated urine Or PU-PD Can resemble cholecalciferol toxicity Response to therapy markedly better for Addison’s
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Scooter 4 year old female dachshund Was fine 3 days ago
Lethargic and would not eat day before yesterday Today is really, really sick – weak and can not stand well Exam - 5-8% dehydrated, weak pulses, passing raspberry jam stools CBC – HCT high normal Panel – phosphorus 8.5 mg/dl, Ca 11.8 mg/dl Lytes, fecal – NSAF, UA – USG 1.032
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Scooter DDx: HGE Addison’s Disease Bromethalin Toxicity
Treated with fluids, ampicillin, enrofloxacin, single injection dexamethasone 0.2 mg/kg Scooter continued to deteriorate and died within 48 hours Owner put out Rampage® Rat Bait last week
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Mike Ward- Nacogdoches TX
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Renal Secondary HyperPTH
Hypercalcemia caused by ARF/CRF is usually mild mg/dl CRF can also result in normocalcemia or hypocalcemia ARF can show hypercalcemia during recovery, when moving from oliguric to polyuric
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Samantha 12 year old spayed female Labrador Retriever Mix
Has suffered from a gradual onset of lethargy, weakness, anorexia, and vomiting for several weeks, 5 pound weight loss. Has not eaten for several days Exam Salivating reluctant to rise and walk generalized muscular weakness Bladder easily expressed when lifted
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Samantha CBC, panel, lytes – Ca 14.2 UA – SG 1.010 Chest x-rays – NSAF
Abdominal x-rays and ultrasound Enlarged sublumbar lymph nodes Ionized calcium – moderately elevated PTH low, PTHrp 0 Started enrofloxacin PO BID, pending urine culture Prednisone 40 mg/m2 daily for 2 weeks, then every other day Samantha markedly improved within 1 week
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Samantha Mycoplasma cultured from Urine 3 weeks later
Sensitivity indicated doxycycline was a better choice, so switched to that for 6 weeks total Hypercalcemia, PU-PD, GI signs, weakness and sublumbar lymphadenopathy resolved and did not return Samantha was euthanized due to unresectable soft tissue sarcoma on a rear limb 2 years later, at 14 years of age
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Infectious/Inflammatory Disease Causing Hypercaclemia
Bacterial/fungal osteomyelitis Granulomatous disease Immune mediated Fungal Parasitic - schistosomiasis Mycobacterium spp. Mycoplasma spp. FIP
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Buster 12 year old neutered male dog
Has been drinking more water for several weeks, off and on, appetite sometimes off CBC, panel, UA – Ca 13.7 mg/dl Exam – 4-5mm nodule in the right anal sac FNA – anal sac carcinoma Chest x-rays, abdominal US - NSAF Surgery – right anal sacculectomy PU-PD resolved, appetite returned to normal Deramaxx PO daily Owner also treated with Neoplasene® and other supplements Rxed by holistic vet
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Buster 18 months later Cries out in pain when he tries to get up
Thoracic radiographs – 3 views
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Buster 18 months later Cries out in pain when he tries to get up
Thoracic radiographs – 3 views
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Buster 18 months later Cries out in pain when he tries to get up
Thoracic radiographs – 3 views Metastatic neoplasia to lungs Neck pain likely due to bone metastasis Owner elected euthanasia The Story of Buster
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Feline Idiopathic Hypercalcemia
Any age cat Long haired cats may be predisposed Mild hypercalcemia mg/dl Symptoms Half are asymptomatic GI symptoms, anorexia/weight loss nephrocalcinosis Azotemia and/or uroliths develop with time 10-15% have uroliths at diagnosis
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Primary Hyperparathyroidism
Diagnosis Parathyroid mass not usually palpable in dogs Sometimes palpable in cats Ultrasound or CT can find Hypoechoic mass dorsal to the trachea Normal parathyroid glands are <2mm to undetectable with HHM PT tumors are usually 4-8mm, but can be >2cm
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Hypercalcemia Primary hyperPTH Secondary hyperPTH
Neoplasia of the parathyroid gland produces excess PTH (usually benign) Secondary hyperPTH Systemic disease results in high PTH Renal dz, Adrenal neoplasia (functional) Diet low in Ca, low in Vit D, high in phos Tertiary HyperPTH – chronic untreated 2ndary HyperPTH results in parathyroid hyperplasia and continued PTH secretion
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Pattern Recognition - Panel
Hypercalcemia + azotemia Addison’s CRF HHM, Hypervitaminosis D Hypercalcemia + hypophosphatemia HHM primary hyperPTH – systemically well P can be lower half of normal range
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Pattern Recognition - Panel
Hypercalcemia + hyperphosphatemia Commonly Addison’s, renal failure Cholecalciferol (bromethalin), calcipotriene Less commonly Tumor osteolysis Calcitriol therapy Feline idiopathic hypercalcemia Severe dehydration Hyperthyroidism Raisin and grape toxicity Rarely Tertiary HyperPTH Aluminum toxicity
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Pattern Recognition – MSU
Hypercalcemia + high PTH Primary & tertiary hyperPTH Renal failure (moderate hypercalcemia) Less commonly feline idiopathic hypercalcemia Hypercalcemia + High PTHrp Reliable tumor marker False positive with renal failure
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Pattern Recognition – MSU
Hypercalcemia + high vitamin D HHM Cholecalciferol & calcitriol toxicity Primary hyperPTH Less commonly feline idiopathic hypercalcemia
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DDx Hypocalcemia Common Less common but important
Puerperal tetany (pariparturient hypocalcemia) Hypoalbuminemia PLE, PLN Vasculitis, exudative lesions Sepsis, SIRS Pancreatitis – cPL in the dog; ultrasound in the cat Ethylene glycol toxicity Less common but important Renal failure - acute > chronic Primary hypoparathyroidism Post feline thyroidectomy
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DDx Hypocalcemia Rare Hypomagnesemia Rhabdomyolysis
Tumor lysis syndrome Nutritional secondary hyperparathyroidism Low calcium, high phos diets Hypovitaminosis D Phosphate containing enemas Anticonvulsant medications Sodium bicarbonate administration Laboratory error – EDTA plasma or blood
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Terry Ray - Kilgore TX
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Parathyroid Hormone (PTH)
Centrifuge ASAP & ship frozen overnight Azotemia can interfere with assay Drugs that decrease calcium can increase PTH DDx High PTH Renal failure (secondary renal hyperparathyroidism) Primary & Tertiary hyperparathyroidism Mid-normal to increase PTH in the hypercalcemic patient indicates Primary hyperPTH Secondary nutritional hyperparathyroidism Secondary adrenal hyperparathyroidism Hypocalcemia
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Parathyroid Hormone (PTH)
DDx Low PTH Primary hypoparathyroidism Undetectable PTH in the hypercalcemic patient indicates Primary hypoPTH Spontaneous disease is rare More common after bilateral thyroidectomy Hypercalcemia except in the face of renal failure Kidneys eliminate PTH
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Summary PowerPoints Vet Handouts .pptx – Calcium Disorders
.pdfs – 1 and 6 slides per page Vet Handouts Chew - Hypercalcemia Diagnostic Chart Feldman & Nelson – Hypercalcemia Tests Feldman & Nelson – Hypercalcemia Sick Pet Feldman & Nelson – Hypercalcemia Well Pet Feldman & Nelson - Hypocalcemia Willard – Calcium and Phosphorus Chart Willard – Hypercalcemia Willard - Hypocalcemia
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Summary Laboratory Information Client Handouts Short Story
Michigan State U – Endocrinology submission form MSU – endocrinology reference ranges MSU – Test Fees Client Handouts Hypercalcemia Hypocalcemia Parathyroid Tumors Short Story The Story of Buster
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Summary Hidden Slides Why do we care about calcium?
Normal calcium values Pathophysiology hypercalcemia and kidneys Addison’s and hypercalcemia Primary hyperparathyroidism Pattern recognition Hypercalcemia of malignancy Vitamin D toxicosis, photos of toxic plants Renal secondary hyperparathyroidism Feline idiopathic hypercalcemia Primary hyperparathryoidism Treatment of feline idiopathic hypercalcemia Treatment & Ultrasound primary hyperparathyroidism Rare causes of hypercalcemia Treatment of hypercalcemia
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Acknowledgements Edward Feldman. Canine & Feline Endocrinology, 4th Edition. Ch 15 – Hypercalcemia and Primary Hyperparathryoidism. Richard Nelson. Small Animal Clinical Diagnosis by Laboratory Methods, 5th Edition. Ch 8 – Endocrine, Metabolic and Lipid Disorders. Eds. Michael Willard, Harold Tvedten.
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