HYPOCALCEMIA  

Terri  L.  Paul  MD  FRCPC  Cert  Endo  Endocrinology  &  Metabolism  

Western  University  

Faculty/Presenter  Disclosure  •  Faculty:  Terri  Paul  

•  Rela0onships  with  commercial  interests:*  –  Grants/Research  Support:  Amgen,  Lilly,  Novar0s    –  Speakers  Bureau/Honoraria:  Amgen,  Lilly,  AbboF  –  Consul0ng  Fees:  N/A  –  Other:  N/A  

Disclosure  of  Commercial  Support  •  This  program  has  received  financial  support  from  Eli  Lilly/  Boehringer  

Ingelheim,  Novo  Nordisk,  Pfizer,  Sanofi,  Astra/BMS,  Merck,  NovarPs,  Serono/EMD,  Jannssen  in  the  form  of  an  Unrestricted  EducaPonal  Grant    

•  This  program  has  not  received  in-­‐kind  support  from  any  commercial  organizaPon    

•  Poten0al  for  conflict(s)  of  interest:  

Terri  Paul  has  received  funding  from  Amgen,  Lilly,  NovarPs  supporPng  this  program.  

•  Mi0ga0ng  Poten0al  Bias  •  PresentaPon  had  been  developed  independently  by  Dr.  Paul  

with  no  input  from  supporPng  industry.    

 

Calcium Regulation Bone

Releases calcium &

phosphorus

Increased blood calcium

Increases absorption of dietary calcium &

phosphorus

Small and

Large Bowel

Liver

Kidney

Sunlight or diet

Vitamin D

Parathyroids Sense low blood Ca & increases PTH secretion

↑ PTH

Calcitrol (1,25(OH)2D)

Calcitrol (1,25(OH)2D)

25(OH)D

♦  Increases calcitrol formation ♦  Decreases excretion of calcium ♦  Increases excretion of phosphorus

D.  Hanley  

Calcium  Homeostasis  

Total serum Ca 2.12-2.62 mmol/l Ionized Ca 1.1-1.3 mmol/l (50%) Protein bound Ca 0.9-1.1 mmol/l (40%) Complexed Ca 0.18 mmol/l (10%) Change in Albumin of 1 gm/l causes a

change in Ca of 0.02 mmol/l

Calcium  Homeostasis  

Change in Albumin of 1 gm/l causes a change in Ca of 0.02 mmol/l

So if Ca of 2.0 with albumin of 20, what is

actual Ca? Ca = Serum Ca + [0.02 X (Normal Albumin

– Patient Albumin)]

Calcium  Homeostasis  

Change in Albumin of 1 gm/l causes a change in Ca of 0.02 mmol/l

So if Ca of 2.0 with albumin of 20, what is

actual Ca? Ca = Serum Ca + [0.02 X (Normal Albumin

– Patient Albumin)] 2.0 + [0.02 X (40-20)] = (20 X 0.02) + 2.0 = 2.4

Hypocalcemia

Hypocalcemia  Serum Calcium< 2.12 mmol/L Results from: •  Failure to secrete PTH •  Failure to respond to PTH •  Deficiency of Vitamin D •  Failure to respond to Vitamin D •  Rarely, acute complexation of Ca

Symptoms  of  Hypocalcemia  

Acute:  •  Severe  Hypocalcemia      Tetany  –  parasthesias,  carpo-­‐pedal    

 spasm,  laryngeal  spasm,  convulsions  •  Mild  Hypocalcemia      Chvostek’s  and  Trousseau’s  signs  

 bradycardia,  impaired  cardiac  contracPlity,    and  prolongaPon  of  the  QT  interval  

Symptoms  of  Hypocalcemia  

Chronic: •  Neuropsychiatric symptoms –

papilledema, confusion, lassitude •  Catarcts •  Dry skin, brittle nails •  Basal cell ganglia calcification

EPology  of  Hypocalcemia  

PTH Deficient : low Ca, high phosphate, low PTH

•  Hypoparathyroidism •  Surgical  •  Idiopathic  (polyglandular  endocrinopathies)  

PTH Resistant: low Ca, high phosphate, high PTH

•  Vitamin D deficiency •  Pseudohypoparathyroidism: Inherited,  two  forms  1a  or  b  and  2,  lack  of  response  to  PTH  

 

Pseudohypoparathyroidism  •  Type 1a, resistance to

PTH (GNAS1 mutation) in kidney and bone

•  Round facies, short stature, short metacarpal and metatarsal bones (Albright’s hereditary osteodystrophy)

•  Pseudopseudohypo-parathyroidism has same phenotype but no PTH insensitivity

EPology  of  Hypocalcemia  

Vitamin D Deficient: low Ca, low phosphate, high PTH More common than PTH disorders

•  Malabsorption – fat soluble vitamin •  Renal failure, liver failure •  Drugs (phenytoin) •  Diet (rare) •  Lack of exposure to sun •  Rickets, osteomalacia

EPology  of  Hypocalcemia  Minor: •  Hypoalbuminemia •  Hypomagnesemia – ETOH, malabsorption •  Pancreatitis •  Inappropriate ADH secretion •  Tumor lysis, rhabdomyolosis, sepsis •  Massive transfusion

Hypoparathyroidism Vitamin D deficiency

Calcium Low Low

Phosphate High Low

Alk Phos Normal High

PTH Low High

Treatment of Hypocalcemia  

•  Management  of  hypocalcemia  depends  upon  the  severity  and  acuity  of  symptoms.    

•  In  paPents  with  acute  symptomaPc  hypocalcemia,  intravenous  calcium  gluconate  is  the  preferred  therapy,  

•  Chronic  hypocalcemia  is  treated  with  oral  calcium  and  vitamin  D  supplements.  

Treatment of Hypocalcemia

Acute: •  Calcium gluconate

10  mls  of  a  10%  soluPon  IV  over  10  minutes  Followed  by  20-­‐80  mls  over  8  hours  in  NS  

Chronic: •  Vitamin D: 0.5 mg/day (50,000IU) or

1,25 diOH (calcitriol) 0.25 -0.05 mcg BID

•  Calcium supplements

Calcium  infusion  in  Severe  Hypocalcemia    

•  IV  Calcium  infusion  in  severe  hypocalcemia  calcium  (1  to  2  g  of  calcium  gluconate,  equivalent  to  90  to  180  mg  elemental  calcium,  in  50  mL  of  5  percent  dextrose)  can  be  infused  over  10  to  20  minutes.    

•  The  calcium  should  not  be  given  more  rapidly,  because  of  the  risk  of  serious  cardiac  dysfuncPon,  including  systolic  arrest.    

•  This  dose  of  calcium  gluconate  will  raise  the  serum  calcium  concentraPon  for  only  two  or  three  hours;  as  a  result,  it  should  be  followed  by  a  slow  infusion  of  calcium  in  paPents  with  persistent  hypocalcemia.  

Calcium  infusion  in  Severe  Hypocalcemia    

•  Either  10  percent  calcium  gluconate  (90  mg  of  elemental  calcium  per  10  mL)  or  10  percent  calcium  chloride  (270  mg  of  elemental  calcium  per  10  mL)  can  be  used  to  prepare  the  infusion  soluPon  

•  Calcium  gluconate  is  usually  preferred  because  it  is  less  likely  to  cause  Pssue  necrosis  if  extravasated.  

•  An  IV  soluPon  containing  1  mg/mL  of  elemental  calcium  is  prepared  by  adding  11  g  of  calcium  gluconate  (equivalent  to  990  mg  elemental  calcium)  to  normal  saline  or  5  percent  dextrose  water  to  provide  a  final  volume  of  1000  mL.    

•  This  soluPon  is  administered  at  an  iniPal  infusion  rate  of  50  mL/hour  (equivalent  to  50  mg/hour).    

•  The  dose  can  be  adjusted  to  maintain  the  serum  calcium  concentraPon  at  the  lower  end  of  the  normal  range  (with  the  serum  calcium  corrected  for  any  abnormaliPes  in  serum  albumin  as  noted  above).    

•  PaPents  typically  require  0.5  to  1.5  mg/kg  of  elemental  calcium  per  hour.  

Calcium  infusion  in  Severe  Hypocalcemia    

 The  infusion  should  be  prepared  with  the  following  consideraPons:  •  The  calcium  should  be  diluted  in  dextrose  and  water  or  saline  

because  concentrated  calcium  soluPons  are  irritaPng  to  veins.  •  The  intravenous  soluPon  should  not  contain  bicarbonate  or  

phosphate,  which  can  form  insoluble  calcium  salts.  If  these  anions  are  needed,  another  intravenous  line  (in  another  limb)  should  be  used.  

Intravenous  calcium  should  be  conPnued  unPl  the  paPent  is  receiving  an  effecPve  regimen  of  oral  calcium  and  vitamin  D.  

Calcitriol,  in  a  dose  of  0.25  to  0.5  mcg  twice  daily,  is  the  preferred  preparaPon  of  vitamin  D  for  paPents  with  severe  acute  hypocalcemia  because  of  its  rapid  onset  of  acPon  (hours).    

Treatment  of  Hypoparathyroidism  

Goals  of  therapy  are  to    •  Relieve  symptoms  •  Maintain  the  serum  calcium  concentraPon  in  the  low-­‐normal  range  2.0  to  2.1  mmol/L  

•  Aiainment  of  higher  values  is  not  necessary  and  is  usually  limited  by  the  development  of  hypercalciuria  due  to  the  loss  of  renal  calcium  retaining  effects  of  PTH  

Oral  calcium  

•  1500  to  2000  mg  of  elemental  calcium  given  as  calcium  carbonate  or  calcium  citrate  daily,  in  divided  doses.    

•  Calcium  carbonate  is  40  percent  elemental  calcium,  so  that  1250  mg  of  calcium  carbonate  contains  500  mg  of  elemental  calcium.    

•  The  dose  of  elemental  calcium  is  listed  on  most  supplement  labels.    

•  Calcium  carbonate  is  the  least  expensive,  it  may  be  less  well-­‐absorbed  in  older  paPents  and  those  who  have  achlorhydria.  These  paPents  do  beier  with  calcium  citrate  

Treatment  of  Hypoparathyroidism  

•  The  iniPal  dose  of  calcitriol  is  typically  0.25  to  0.5  mcg  twice  daily.  

•  Major  side  effects  are  hypercalcemia  and  hypercalciuria,  which,  if  chronic,  can  cause  nephrolithiasis,  nephrocalcinosis,  and  renal  failure.    

•  Hypercalciuria  is  the  earliest  sign  of  toxicity  and  can  develop  in  the  absence  of  hypercalcemia  

Treatment  of  Hypoparathyroidism  •  Aker  iniPaPng  therapy,  serum  and  urinary  calcium  should  be  measured  frequently  (two-­‐week  intervals)    

•  Then  every  six  months  to  one  year  once  a  stable  dose  is  achieved.  

•  Hypercalciuria  and,  if  present,  hypercalcemia  usually  resolve  in  a  few  days  aker  cessaPon  of  therapy  in  paPents  treated  with  calcitriol.    

•  In  contrast,  recovery  is  slower  in  paPents  treated  with  vitamin  D,  but  can  be  accelerated  by  a  short  course  of  glucocorPcoid  therapy  

Treatment  of  Hypoparathyroidism  

•  Some  paPents  with  hypoparathyroidism  require  a  thiazide  diurePc  (25  to  100  mg  daily),  with  or  without  dietary  sodium  restricPon,  to  decrease  urinary  calcium  excrePon    

Treatment of Hypocalcemia Compound Trade Name Potency vs

D3 Onset action

days Offset action

D3 cholecalciferol

25,000- 100,000 U

1 10-14 Weeks to months

D2 ergocalciferol

25,000- 100,000 U

1 10-14 Weeks to months

Dihydrotachy-sterol

Hytackerol 5-10 4-7 7-21 days

Calcifediol 25OHvitD3

Calderol 10-15 7-10 weeks

*Alphacalcidiol 1aOHvit D3

One-alpha 0.25-2 ug/d

1000 1-2 2-3 days

*Calcitriol 1,25diOHvitD3

Rocaltrol 0.25-2 ug/d

1000 1-2 2-3 days

Recombinant  PTH  therapy  

•  Hypoparathyroidism  is  one  of  the  few  remaining  hormonal  insufficiencies  for  which  hormone  replacement  therapy  is  unavailable  

•  Recombinant  human  parathyroid  hormone  (teriparaPde)  is  not  approved  for  the  treatment  of  hypoparathyroidism  because  of  high  cost  and  the  necessity  for  twice  daily  injecPons.  

•  However  it  has  been  shown  to  normalize  serum  calcium  while  maintaining  normocalciuria  

Hypoparathyroidism  and  Pregnancy  

•  Calcitriol  requirements  decrease  during  lactaPon    •  Serum  calcium  concentraPons  should  be  measured  frequently  during  late  pregnancy  and  lactaPon  in  women  with  hypoparathyroidism  who  may  have  a  rise  in  serum  calcium,  requiring  a  decrease  in  calcitriol  dose.    

•  The  requirement  for  calcitriol  will  return  to  antepartum  levels  with  cessaPon  of  lactaPon  

Vitamin  D  deficiency  

•  NutriPonal  vitamin  D  deficiency  is  typically  treated  with  50,000  internaPonal  units  of  vitamin  D2  or  D3  weekly  for  six  to  eight  weeks  

•  Followed  by  rouPne  vitamin  D  replacement  of  1000-­‐2000  IU  daily  

Pseudohypoparathyroidism      •  The  long-­‐term  treatment  pseudohypoparathyroidism  is  similar  to  the  treatment  of  hypocalcemia  caused  by  other  forms  of  hypoparathyroidism.  

•  PaPents  with  pseudohypoparathyroidism  infrequently  develop  hypercalciuria  with  calcium  and  vitamin  D  therapy.    

•  Goal  of  treatment  with  calcium  and  vitamin  D  is  to  maintain  normocalcemia    

•  A  typical  starPng  dose  of  calcitriol  is  0.25  mcg  twice  daily.  

•  Approximately  1  to  2  gm  of  elemental  calcium  daily  (in  divided  doses)  is  recommended  

Hypomagnesemia  •  Hypomagnesemia  induces  resistance  to  parathyroid  

hormone  (PTH)  and  diminishes  PTH  secrePon  •  MalabsorpPon,  chronic  alcoholism,  and  cisplaPn  therapy  

are  most  common  causes  •  If  the  serum  magnesium  concentraPon  is  low,  2  g  (16  meq)  

of  magnesium  sulfate  should  be  infused  as  a  10  percent  soluPon  over  10  to  20  minutes,  followed  by  1  gram  (8  meq)  in  100  mL  of  fluid  per  hour.    

•  Persistent  hypomagnesemia,  as  occurs  in  some  paPents  with  ongoing  gastrointesPnal  (eg,  malabsorpPon)  or  renal  losses,  requires  supplementaPon  with  oral  magnesium,  typically  300  to  400  mg  daily  divided  into  three  doses