HYPERCALCEMIA

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HYPERCALCEMIA

• SYED NASRAT IMAM, MD
• The Chicago Medical School
• Chicago, IL

Syed Nasrat Imam, MD
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CALCIUM

• An essential intracellular and extracellular
  cation
• Extracellular calcium is required to maintain
  normal biological function of nervous system, the
  musculoskeletal system, and blood coagulation
• Intracellular calcium is needed for normal
  activity of many enzymes
• Preservation of the integrity of cellular
  membrane
• Regulation of endocrine and exocrine secretory
  activities
• Activation of compliment system
• Bone metabolism

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CALCIUM

• Respiratory alkalosis and elevated pH cause
  increase in the binding of calcium and lowers
  ionized calcium. Decrease in pH has the opposite
  effect. As a general rule a shift of 0.1 pH unit
  produces a change in ionized calcium of 0.04 to
  0.05 mmol/L
• Chelators such as citrate may transiently
  decrease ionized calcium
• Total body Ca -1 to 1.5 kg, 99- skeleton, 0.1
  ECF , rest intracellular.
• One gram per deciliter of albumin binds
  approximately 0.8 mg/dl of calcium

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FORMULA

• 0.8 for each gm of Albumin
• 0.16mg/dl for each gm of globulin.
• (Uca/Pca) (Ucr/Pcr) FEca
  lt1 - Familial hypocalciuric hypercalcemia, FEca
  gt2 - primary hyperparathyroidism
• ?? in pH will ?? protein bound Ca by 0.12mg/dl
• 80-90 of protein bound Ca is bound to Albumin.
• Increase in serum pH of 0.1 may cause decrease in
  ionized Ca of 0.16mg/dl
• Calcium Protein bound - 40 Complexed - 13
  Ionized fraction - 47

FEca
Uca/Pca x Pcr/Ucr
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CLINICAL MANIFESTATIONS

• GI- Anorexia, Nausea, Vomiting, Constipation and
  rarely acute Pancreatitis.
• CVS- Hypertension, shortened QT interval, and
  enhanced sensitivity to digitalis.
• RENAL- Polyuria, Polydipsia, and occasionally
  Nephrocalcinosis.
• CNS- Cognitive difficulties, Apathy, Drowsiness,
  Obtundation, or even Coma.

Most common symptom is probably nocturia
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SYMPTONS

• More than 50 of all patients with primary
  hyperparathyroidism are asymptomatic when
  hypercalcemia is first discovered.
• Diagnostic Finding Frequency ()
  Likelihood Ratio
  In Primary HPT
  In Malignancy Finding nt Finding
  -nt Renal Calculi 29 4
  7.3 0.74 Peptic Ulcer 13
  10 1.3
  0.97 Hypertension 49 25 2
  0.68 Polyuria 22 29 0.76
  1.1 Mental status change 23 33 0.7
  1.1 GI Distress 25 34 0.74
  1.1 Muscular weakness 32 36 0.89
  1.1 Bone Pain 28 58 0.48
  1.7 Constipation 19 58 0.33
  1.9 Weight Loss 19 64 0.30
  2.3 Anorexia 19 64 0.30
  2.3 Fatigue 31 73 0.42 2.6

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SIGNS
Band keratopathy The deposition of Ca as
corneal opacities is usually sign of long
standing hypercalcemia -most commonly associated
with primary hyperparathyroidism. Calcium
deposition begins near the limbus at the 3 9
oclock position, presumbly because there is less
friction from the lids near the limbus because
the tear film is most alkaline in the most
exposed area, band running across the cornea from
the 3 to 9 oclock position
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SIGNS
Bony tenderness Hyperactive tendon reflexes
Tongue fasciculations Hypercalcemia in pregnant
female may cause hypocalcemia in her neonates by
suppressing the fetal parathyroid. Hypercalcemia
- small dec. in GFR - due to hemodynamic effects
hyposthenuria (a loss of renal concentrating
abilities)
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COMPLICATIONS Sinus bradycardia Increase in
the degree of a heart block Cardiac
arrhythmia HTN Pancreatitis PUD
Nephrolithiasis Accelerated vascular
calcification
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CALCIUM HOMEOSTASIS
THREE HORMONE AND THREE ORGAN

• PTH
• ACTIVATED VITAMIN D
• CALCITONIN
• BONE
• KIDNEY
• SMALL INTESTINE

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THREE HORMONES

• PTH (84 amino acid)
• Actions on Bone Actions on Kidney
  Actions on GI
• Parathyroid cells are unusual in the respect
  that hormone degradation rather than synthesis is
  adjusted according to physiological demand. As
  much as 90 can be destroyed within the chief
  cells.
• If blood levels of ionized calcium drop by as
  little as 0.1 mg/dl, secretion of PTH is
  stimulated
• Half-life of PTH is minutesKidney reacts
  quickly to changes in PTH and is responsible for
  minute to minute adjustments of blood calcium.
• PTH acts directly on distal portion of the
  nephron to decrease urinary excretion of calcium
  mediated by cAMP.
• PTH powerfully inhibits tubular reabsorption of
  phosphate and thus increases the amount excreted
  in the urine, mainly in proximal tubules
• PTH stimulates the renal enzyme that converts vit
  D to its active form but has no direct effects on
  intestinal transport of calcium or phosphate.
• Action of PTH to increase 1,25(OH)2D is blunted
  in hyperphosphatemia

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• ACTIONS OF PARATHYROID HORMONE
• The principal regulator of calcium concentration
  in extracellular fluid
• Increases the calcium concentration and
  decreases the phosphate concentration in the
  blood.
• Bone responds in 2-3 hours 1st phase to small
  increases of PTH. PTH?Receptors on surface
  osteocytes? intervention of GTP binding
  protein?activates adenylate cyclase?Increases
  permeability to of osteocytes to calcium in
  surrounding bone fluid compartment?Calcium enters
  cytosol and then extruded to ECF compartment on
  other side of bone membrane and shifts
  equilibrium to solubilization
• 2nd phase- becomes evident about 12 hours later
  characterized by widespread resorbtion of both
  mineral and organic components of matrix.
  Osteoclastic activity predominates
• Activity of all bone cell types is increased by
  PTH but only osteocytes and osteoblasts have
  receptors for PTH. Activation of and
  recruitment of osteoclasts must be accomplished
  indirectly by some paracrine or endocrine signal
  produced by osteocytes and osteoblasts

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VITAMIN D

• Activated Vit D
• GI - increase Ca absorption.
• Bone - increase Ca mobilization.
• Kidney - increase reabsorption within the distal
  tubule.
• Deficiency of vitamin D severely impairs
  intestinal transport of both calcium and
  phosphorous
• Mineralization of osteoid occurs spontaneously
  when adequate amounts of calcium and phosphorous
  are available
• 1,25(OH)2D3 increases the number and activity of
  osteoclasts but osteoblasts have the receptors
• Effect on calcium absorption in the distal
  nephron Regulation- Hydroxylation of carbon 1
  by cells in the proximal tubules of the kidney
  which converts a nearly inactive precursor to a
  highly active hormone is stimulated primarily by
  PTH and by low phosphate concentrations.
  1,25(OH)2D3 inhibits hydroxylation of carbon in
  the kidney and carbon 25 in the liver and
  stimulates hydroxylation of carbon 24 which
  diverts precursor to a degradative pathway.

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• CALCITONIN ( 32 amino acid )
• Parafollicular cells of the Thyroid gland in
  response of hypercalcemia
• Decrease osteoclast activity.
• Stimulating a distal tubular - mediated
  calciuresis.
• Other hormones affecting calcium balance - many
  including prostaglandins that mobilize calcium,
  various growth factors, growth hormone,
  somatomedins, thyroid hormones(decrease skeletal
  mass), gonadal hormones which help maintain bone
  mass, adrenal cortical hormones

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TARGET ORGAN

• Small intestine approx. 40 absorbed, 50 of
  that - excreted into bile and other intestinal
  secretions. So only 20 of the total amount of Ca
  ingested daily is available to circulate between
  bone and extracellular fluid.
• Kidney Glumerulus filters out the Ca that is
  not bound to protein.
• Proximal tubule - approx. 50 to 70 is
  reabsorbed, Ca reabsorption mirrors Na
  reabsorption.
• Ascending limb of the loop of henle - approx.
  30 to 40 reabsorbed
• Distal nephron - about 10 reabsorbed. PTH and
  activated Vit D increases Ca absorption during
  Ca deficient states.
• Normally kidney excretes approx. 200 mg /day of
  Ca to maintain homeostasis. During states of
  severe Ca depletion, the Kidney can decrease
  urinary excretion to 50mg /day or less.

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CALCIUM REGULATION
_
PTH

_

1,25(OH)2 D3


CALCITONIN

_
ECF Pool of Calcium
GI Tract
BONE
URINE
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ETIOLOGY
Approx. 80 of all cases are caused by
Malignancy or Primary Hyperpathyroidism

• T Thiazide, other drugs - Lithium
• R Rabdomyolysis
• A AIDS
• P Pagets disease, Parental nutrition,
  Pheochromocytoma, Parathyroid disease

• V Vitamins
• I Immobilization
• T Thyrotoxicosis
• A Addisons disease
• M Milk-alkali syndrome
• I Inflammatory disorders
• N Neoplastic related disease
• S Sarcoidosis

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HYPERPARATHYROIDISM
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HYPERPARATHYROIDISM

• STONES,
• BONES,
• GROANS, AND
• MOANS

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Syed Nasrat Imam, MD
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PARATHYROIDECTOMY

• A serum calcium gt 12mg/dl
• Hypercalciuria gt 400mg/d
• Presence of sign and symptoms--S,B,G,M
• Markedly reduced cortical bone density
• Hypercalcemia causing decreased GFR
• Patient age under 50 years?
• NIH consensus development conference
  recommendation

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TREATMENT OPTION

• Gallium nitrate.
• Steroids.
• IV Phosphate.
• Dialysis.
• Others.

• Hydration.
• Furosemide.
• Bisphosphanate.
• Calcitonin.
• Mithramycin.

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HYDRATION

• First step in the management of severe
  hypercalcemia. --isotonic saline.
• Usually reduces - 1.6-2.4mg/dl.
• Hydration alone rarely leads to normalization in
  severe hypercalcemia.
• Rate of IV saline based on severity of
  hypercalcemia and tolerance of CVS for volume
  expansion.

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LOOP DIURETICS

• Facilitate urinary excretion of calcium
• By inhibiting calcium reabsorption in the thick
  ascending limb of the loop of Henle.
• Guard against volume overload
• Volume expansion must precede the administration
  of furosemide, because the drugs effect depends
  on delivery of calcium to the ascending limb.
  Needs frequent measurement of lytes and water

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• CALCITONIN Not as effective as
  bisphosphonate, tachyphylaxis quickly occurs and
  limits therapeutic efficacy
• MITHRAMYCIN Toxic effect limits its use,
  reserved for difficult cases of hypercalcemia
  that are related to malignancy
• GALLIUM NITRATE Need to infuse it over 5
  days, nephrotoxity limits its use, not used
  frequently
• CORTICOSTEROIDS For myeloma, lymphoma,
  Sarcoidosis, or vit D toxicity decrease GI
  absorption, 200-300mg hydrocort for upto 5 days,
  slow response limits its use
• HEMODIALYSIS Zero or low calcium bath, In
  selected condition, eg-hypercalcemia complicated
  by renal failure

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BISPHOSPHONATE

• Structurally related to pyrophosphate. P-C-P
  bound is a back bone that renders them resistant
  to phosphates. They bind to hydroxyapatite in
  bone and inhibit the dessolution of crystals.
  Their great affinity for bone and their
  resistance to degradation account for their
  extremely long half life in bone.
• Poor GI absorption- lt10
• ETIDRONATE PAMIDRONATE CLODRONATE
• Etidronate- 7.5mg/kg iv over 4 hr for 3-7 days,
  S. ca begins to decrease within 2 days after
  first dose. Response better if pt well hydrated
  before t/t. Oral to prevent recurrent
  hypercalcemia.. Adverse effect-increase s. cr,
  phosphate, long term use-impair bone formation,
  osteomalacia,

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PAMIDRONATE

• Inhibits osteoclast function
• The most potent bisphosphonate.
• 60mg to 90 mg IV over 24hr.
• 70 to 100 of patients had decreased s. calcium
  within 24 hr of t/t, 2/3rd of this group had
  normal s cal within 7 days.
• Adverse effect- mild transient increase in
  temp(lt2deg C), transient leukopenia, small
  reduction in s phosphate level.
• Excreted by kidney- dose adjustment.

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MITHRAMYCIN

• An inhibitor of RNA synthesis in osteoclasts
• IV 25 microgram/kg over 4-6 hr.
• Begins to decrease in 12hr, maxm in 48-72 hr.
• Duration of normocalcemia ranges from a few days
  to several wks. Depending on the extent of
  ongoing bone resorption.
• Adverse effect- Nausea- can be mini- by slow iv.
  Avoid extravasation-cellulitis.Hepatotoxic- in
  20 pt. Nephrotoxic- increase s. cr, proteinuria.
  Thrombocytopenia.
• Contraindication-liver, kidney dysfunction,
  thrombocytopenia, or any coagulopathy.

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GALLIUM NITRATE

• Inhibit bone resorption by adsorbing to and
  reducing the solubility of hydroxyapatite
  crystals.
• Adverse effect- Nephrotoxity, hypophosphatemia,
  small reduction in Hb concentration.
• Clinical experience limited.

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OTHERS

• GLUCOCORTICOIDS- inhibiting the growth of
  neoplastic lymphoid tissue, counteracting the
  effects of vitamin D.
• PHOSPHATE- Can lower rapidly and profoundly, but
  very dangerous. Restricted to pt with extreme,
  life threatening hypercalcemia in whom all other
  measure failed. Hyperphosphatemia and azotemia
  are contraindications.
• AMIFOSTINE(WR-2721) PG

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CHOICE OF AGENT

• Mild (lt3 mmol/l)-Hydration with saline.
• Moderate(gt3.5mmol/l) with moderate symptoms-
  Bisphosphonate.
• Severe life threatening( gt4mmol/l) - Saline
  Calcitonin mithramycin,alternatively
  bisphosphonate, if steroids sensitive
  steroids. Hypercalcemia secondary to
  malignancy- survival after the appearance of
  hypercalcemia is very poor - median of 3 months.

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REFERENCES

• Recognizing hypercalcemia The 3-hormone,
  3-organ rule-Gregory W. Rutecki, MD and
  Frederick C. Whittier, MD, The journal Of
  Critical Illness. Vol 13, no. 1.Jan 1998
• Management Of Acute Hypercalcemia, John P.
  Bilezikian, MD, The New England Journal Of
  Medicine,vol 326, No 18, April 30, 1992.
• Cecils Text Book Of Internal Medicine
• Harrisons Principle Of Internal Medicine.
• Renal and Electrolyte Disorders, Vth edition,
  Robert W. Schrier.
• Potts Jt, ed. 1991 NIH Consensus Development
  Conference Statement on Primary
  Hyperparathyroidism. J Bone Miner Res.
  19916s9-s13
• Mallette LE. The Hypercalcemia. Semin Nephro.
  199212159-190.
• Edelson GW, Kleenehoper M. Hypercalcemic crisis.
  Med Clin North Am. 19957979-92

Syed Nasrat Imam, MD