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