Download - Calcium Homeostasis and Hypocalcemia
Calcium Homeostasis and Hypocalcemia
Marie E. Kerl DVM, MPHDiplomate, ACVIM (SAIM), ACVECC
Chief Medical Officer, VCA Inc.
Calcium
• Skeletal support • Vital intra- and extracellular functions
• iCa: Bone formation & resorption, cell growth & division, membrane transport & stability, enzymatic reactions, nerve conduction, muscle contraction, hormone secretion, hepatic glycogen metabolism, blood coagulation… among other things
• ECF iCa: Regulates cell function by binding to cell membrane calcium-sensing receptors
• Intracellular iCa: Messengers to transport cell surface signals to interior
Normal Adult Ca++ distribution• Plasma Ca++ = 10 mg/dl = 5 mEq/l = 2.5 mmol/l
• (mg/dl x 0.2495 = mmol/l)
Total diffusible 1.34 mmol/l
Ionized 1.18
Complexed to HCO3-, Citrate, etc. 0.16
Total non-diffusible (Protein-bound) 1.16 mmol/l
Bound to albumin 0.92
Bound to globulin 0.24
Total plasma calcium 2.50 mmol/l
Typical adult intake of 25 mmol Ca++ (1000 mg)(Ganong Review of Medical Physiology 23rd Ed.)
Extracellular Fluid35 mmol
GI Tract
Glomerular Filtrate250 mmol
Exchangeable:100 mmol
Stable:27,200 mmol
Diet: 25 mmol
Feces: 22.5 mmol
Absorption:15 mmol
Secretion:12.5 mmol
Reabsorption:247.5 mmol
Urine: 2.5 mmol
Accretion:7.5 mmol
Rapid exchange: 500 mmol
Reabsorption:7.5 mmol
Bone
(99% of total body Ca++ in bone)
Calcium HomeostasisCholecalciferol
25 (OH) Cholecalciferol (Calcidiol) (30 ng/ml)
(Calcitriol) (0.3 ng/ml)
Ca++,PO4 -
PTH
Ca++
Ca++, calcitriol (-) feedback 7-dehydrocholesterol
+ sunlight= PreVitD3 = Cholecalciferol (Vit D3)
1, 25 (OH)2 Cholecalciferol
Ca++
Calcitonin:Inhibits bone
resorption
Management of GI Ca++ Luminal surface
Basolateral surface
transient receptor potential vanilloid type 6 (TRPV6)
Image: Ganong 26th Ed. Note: Ca++ uptake still occurs without TRVP6 and Calbindin (huh?)
Kidneys
• Renal hydroxylation of Vitamin D catalyzed by renal 1-ahydroxylase in the proximal tubular cells• 1-a hydroxylase activity
• Stimulated by PTH• Increased with low Ca, Phos• Inhibited with increased Ca, Phos (Renal 2o hyperparathyroidism)
• If 1-a hydroxylase activity is low, 24-hydroxylase catalyzes formation of 24,25 (OH)2 Vit D
Newcomers to Renal Ca-Phos Management• Fibroblast Growth Factor 23
• Bone-derived hormone that promotes urinary phosphorous excretion and lowers 1,25 (OH)2 Vit D3
• Klotho proteins• a klotho and b klotho• Distal convoluted tubules
Kuro-o, M. The Klotho proteins in health and disease. Nature Reviews: Nephrology, Jan 2019, 27-44
CPP = Calciprotein particles
Renal 2o hyperparathyroidism – then and now
Graphic courtesy of Dr. C. Langston
Parathyroid Hormone: Chief Cells of PT Gland
• Linear polypeptide, MW of 9500, 84 AA residues• Prepro PTH – 115 AA residues, to Pro PTH – 90-AA polypeptide• Removal of 6 residues from amino terminal to get PTH
• Plasma t-1/2 = 10 minutes• 3 Receptors:
• # 1 binds PTH or PTHrP (many tissues)• # 2 binds PTH only, in brain, placenta, pancreas• CPTH receptor binds 24, 25 (OH)2 cholecalciferol
• Principal stimulus for release: Hypocalcemia• Minor effects: epinephrine, isoproterenol, dopamine secretin
• Calcitriol inhibits PTH synthesis
35 – 84 AA1 – 34 AA
Amino-terminal Midrange and carboxyl-terminal
PTH Receptor Detail:
Image: Ganong 26th Ed.
Mechanisms of HypocalcemiaCholecalciferol
25 (OH) Cholecalciferol (Calcidiol) (30 ng/ml)
(Calcitriol) (0.3 ng/ml)
Ca++,PO4 -
PTH
Ca++
Ca++, calcitriol (-) feedback 7-dehydrocholesterol
+ sunlight= PreVitD3 = Cholecalciferol (Vit D3)
1, 25 (OH)2 Cholecalciferol
Ca++
Calcitonin:Inhibits bone
resorption
Also… Acute Ca++ Complexing ~55%
~10%
~35%
Ionized Calcium Ca++
Complexed Calcium:Ca-citrateCa-lactate
Ca-bicarbonateCa-phosphate
Protein Bound Calcium
Question 5
• Muscle tremors/ fasciculations• Seizures • Tetany• Status epilepticus• Facial rubbing • Paw chewing• Behavior changes
• Panting/ Pyrexia• Lethargy• Depression• Anorexia• Third eyelid prolapse (Cats, not dogs)• Posterior lenticular cataracts• Tachycardia• PU/PD• Hypotension• Respiratory arrest• Death
• List your 3 favorite clinical signs of hypocalcemia in the chat
Common Causes of Hypocalcemia
Hypoalbuminemia (ionized usually normal)
Chronic renal failure (ionized usually normal)
Puerperal tetany (“eclampsia”)
Acute renal failure
Acute pancreatitis
Idiopathic (usually mild, not clinical)
iCa stabilizes nerve cell membranes, As ECF iCadecreases, the nervous system becomes more excitable due to increased neuronal membrane permeability. Nerve fibers discharge spontaneously.
Uncommon/ Rare Causes of HypoCa++
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714612/pdf/fvets-06-00276.pdf
• Retrospective study identified electrolyte abnormalities at presentation• Non-pathologic hyper Ca++ : Dogs = 44%, Cats = 24.2%• Dogs: Critical illness 17.4%, Kidney injury 10.4%, Toxicity 7.5% (Citrate in
transfusion, Furosemide, EG intox (1 case)• Cats: Kidney injury (21.6% - 2/3 were AKI), UO 15.1%, Critical illness 14.7%,
Toxicity 8.4%• Cats had overall higher rate of hypocalcemia compared to dogs
Ionized Hypocalcemia of Critical Illness• Ionized hypocalcemia is very common in critical illness, occurring in over
half of critically-ill people (21, 22), 16–24% of critically-ill dogs (23–25) and 59–93% of cats with septic peritonitis (26, 27). The mechanisms by which critical illness and hypocalcemia are associated are poorly understood and are likely multifactorial. Alterations in parathyroid hormone, vitamin D deficiency, hypomagnesemia and tissue accumulation have all been proposed (3). Critically ill patients may also be predisposed to developing hypocalcemia due to concurrent disease processes or treatments, such as blood transfusions, aggressive intravenous fluid therapy, concurrent kidney injury or pancreatitis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714612/pdf/fvets-06-00276.pdf
Hypocalcemia of Critical IllnessCholecalciferol
25 (OH) Cholecalciferol (Calcidiol) (30 ng/ml)
(Calcitriol) (0.3 ng/ml)
Ca++,PO4 -
PTH
Ca++
Ca++, calcitriol (-) feedback 7-dehydrocholesterol
+ sunlight= PreVitD3 = Cholecalciferol (Vit D3)
1, 25 (OH)2 Cholecalciferol
Ca++
Calcitonin:Inhibits bone
resorption
Bottom Line on HypoCa++ in the ER
• POC testing for Ionized Ca has become common for ER (YAY!)• HypoCA++ often seen• Usually reflective of another underlying condition and does not need
to be treated as a primary disease• Most clinical causes of biochemical hypocalcemia are readily apparent
• Question: Treat or monitor?
Rational Clinical Approach: Diagnosing Underlying Cause• Look for obvious or life-threatening things first
• Lactating?• Ethylene glycol/ other drugs• Acute renal failure• Severe pancreatitis (Cats especially)
• Measure ionized calcium• Measure PTH when persistently hypocalcemic,
handle sample appropriately, use a good lab• Need simultaneous iCa to interpret PTH• Consider Vit D
• Don’t forget about magnesium!
Question: Respond on the slide with “annotate”, or in the chat• When should you treat hypocalcemia when occurring with with renal
failure?
• Concerns?
“Marley” 7yo M/C Basenji
• Presented for evaluation of seizures of 1 month duration, treated with phenobarbital and levothyroxine (low t4). Seems much worse past few days• Physical exam:
• Demented, dull• Remainder of exam normal• Generalized ataxia• Phenobarbital effect?
Marley, Initial ChemistryTest Result Ref rangeBUN 19 8-28 mg/dl
Creatinine 1.0 0.6-1.9 mg/dl
Na+ 144 143-152 mEq/L
K+ 4.3 3.4-4.9 mEq/l
Cl- 110 108-117 mEq/l
Albumin 2.6 2.9-4 g/dl
Ca++ 4.4 9.2-11.3 mg/dl
iCa 0.56 1.13-1.37 mmol/l
Phosphorous 7.5 2-5 mg/dl
Marley: Further Tests• PTH 8.1 pmol/L (2-13 ref range)• iCa 0.6 mmol/l• What is your interpretation of this PTH result? (Post in chat)• Vitamin D: 89 nmol/L (20-50 ref range)• Diagnosis: Primary hypoparathyroidism• Treatment?• Seizure disorder?
Endocrine 101:“Primary” = Failure of the gland producing the hormone• Idiopathic• Iatrogenic• Cervical trauma• How do these forms influence your clinical response?
Hypocalcemic Tetany: Acute TreatmentRaise your hand if you have treated eclampsia!• Calcium gluconate (10%, 23%)• 1 ml/kg IV 10% slowly to effect (0.5 mL/kg IV 23%)• Monitor heart rate/ EKG – discontinue administration if bradycardic• Treat hyperthermia if necessary• Calcium chloride may be used, but irritating if perivascular• Other things?
• Eclampsia – Break cycle of puppies nursing (24 hours) and improve oral Ca++ intake for bitch
• Don’t forget about magnesium!
Drug Preparation Elemental CA++ Dose Comment
Ca++ gluconate 23% 21.4 mg/ml 1. 0.5-1.5ml/kg slow IV to effect, or
2. 5-15mg/kg/hr IV, or 3. 1-2 ml/kg diluted
1:1 with saline SQ tid
1. Stop IV infusion if bradycardic
2. Maintain Ca++
3. May give SQ
Ca++ chloride 10% 27.2 mg/ml 5-15 mg/kg/hr IV Extremely caustic perivascluarly
”Jessie”: 6 YO F/S Yorkie
• Chronic small bowel diarrhea for months with occasional vomiting, muscle wasting• Recently developed ascites with pure transudate• Primary care DVM bloodwork: Panhypoproteinemia,
hypocholesterolemia• Presented tonight to ER for acute onset tetany• iCa = 0.6 mmol/l• What’s the mechanism? (Post in chat)
Question (Use stamping tool)10% Calcium Gluconate contains X mg/ml of elemental calcium.a) 100 mg/mLb) ~50 mg/mLc) ~25 mg/mLd) ~10 mg/mL
Managing Persistent Hypocalcemia• Idiopathic or iatrogenic hypoparathyroidism
most common reason• Continuous IV Calcium
• 60-90 mg/kg/day elemental Ca++
• 10% Calcium gluconate contains 9.4 mg/ml elemental calcium• 10 kg dog would need
• 75 ml/day 10% CaGluconate (70mg/kg/day dose)• Maintenance fluids: 480-600 ml/day
• SQ Ca++ ?
Vitamin D Preparations• Bioavailability, onset, duration
• Ergocalciferol (Over-the counter)• Cholecalciferol• Calcitriol (most bioavailable)
• Must formulate calcitriol• Calcitriol dose
• 20-30 ng/kg/day for 3-4 days• 5-15 ng/kg/day maintenance
• Regulate Ca++ to low-normal
Preparation Daily Dose Time until Maximum Effect
Time to Resolve Toxicity
Vitamin D2(ergocalciferol)
Initial: 4000-6000 U/kg/dayMaintenance: 1000-2000 U/kg once daily to once weekly
5-21 days 1-18 weeks
Dihydrotachysterol25 OH vitamin D3
Initial: 0.02-0.03 mg/kg/dayMaintenance: 0.01-0.02 mg/kg q24-48 hrs
1-7 days 1-3 weeks
1,25 (OH)2vitamin D3(calcitriol)
Initial: 20-30 ng/kg/day x 3-4 daysMaintenance: 5-15 ng/kg/day
1-4 days 2-7 days
May not need additional oral Ca++ supplement once Vitamin D supplementation is on board
Oral Calcium Supplementation• Many types• Calcium carbonate most bioavailable• 25-50 mg/kg/day divided of elemental calcium• Binds phosphorous, therefore more renal
production of calcitriol• Oral calcium supplements generally not effective
alone
Duration of Treatment• Eclampsia: one time treatment
(hopefully)• Primary hypoparathyroidism:
Lifelong therapy• Iatrogenic: up to 3 months, or
lifelong• Hypovitaminosis D – Depends on
treatment response to primary GI disease