Calcium,

the greatest case report ever told

Joel M. Topf, M.D.

Attending Nephrologist
Cell: 248.470.8163
1
www.pbfluids.blogspot.com
 Introduction
The perfect case report for calcium

The patient I am using for this chapter on

Calcium and Phosphorous is a real patient
who was admitted to St John Hospital and
Medical Center in 2005. While usually
residents can learn one or two aspects of
medicine from any single admission. This
patient taught the team about 20 lessons on
electrolytes and metabolic bone disease.
The interesting case of M.M. is a poignant
reminder of the unspoken contract be-
tween residents and patients, “I’ll treat you
and at the same time I will learn the craft
of medicine.” Every talented physician
owes more of his knowledge to scores of
patients than to Tinsley Harrison, Burton
“Bud” Rose or the residents of Wash U.
This chapter is dedicated to the patients and
to the debt of knowledge we owe them.

Case Report 4

Calcium Balance 5
Total body calcium 5
Physiology of Calcium Regulation 7

Hypercalcemia 10
Primary hyperparathyroidism 10
Hypercalcemia of malignancy 11
Granulomatous disease 12
Milk-alkali syndrome 12
Symptoms of Hypercalcemia 12
Treatment of hypercalcemia 13

2
Hyperparathyroidism 14
Primary vs Secondary vs. Tertiary hyperparathyroidism 14

Renal Osteodystrophy 16
Treating secondary hyperparathyroidism/ROD 18
Treatment options 19

Hypocalcemia 20
Etiologies: 20
Tissue deposition 21
Increased renal loss 21
Decreased intake and mobilization of skeletal reserves 21
Hypocalcemia of critical illness 22
Consequences of hypocalcemia 23
Treatment 24

3
 Case Report
Routine admission for trauma or something more
A 26 year old African American dialysis patient, MM, with a history of non-
compliance and anti-social behavior presents with knee pain. X-rays showed avul-
sion of the patellar tendon. The patient had been on dialysis for 3 years due to re-
flux nephropathy induced FSGS. Past medical history was otherwise unremark-
able. No old records were available in the hospital
information system.
Initial labs:
Ca: 10.8 Phos: 6.6 PTH: 1012 Albumin: 2.8
A call to his dialysis unit reveals that over the last
four months his calcium has been between 10 and
11, his phos has been floating between 4.8 and 7.8.
The albumin has been falling from 4.0 to 3.0. His
most recent PTH was 880.
Questions: What is this patientʼs adjusted cal-
cium? What is the most common cause of
hypercalcemia in hospitalized patients. Among
outpatients? What is this patientʼs diagnosis?

4
 Calcium Balance
Total body calcium
Calcium is distributed in the body among two main
compartments. Ninety-nine percent of total body cal-
cium is stored in bone and teeth with 1% distrubuted
in solution between the intracellular compartment
and extracellular compartment. The intracellular con-
centration of calcium is very low, typically being one
ten thousandths the concentration of the extracellu-
lar calcium. The normal extracellular calcium is:
8.4-10.4.
Calcium in the serum is 45% ionized, 40% protein
bound (mainly albumin) and 15% complexed to ani-
ons, such as phosphate, bicarbonate and citrate.
Ionized calcium is the physiologically active fraction
and the fraction which is actively regulated by the
body. Changes in albumin and phosphorous may
alter the total calcium and briefly change the ionized
calcium but the regulatory mechanisms will bring the
ionized calcium back to its preset point even if it
leaves patients with an abnormal total calcium.
Though the
adjusted calcium compensates for
Adjusting calcium for albumin changes in albumin, other factors
which affect ionized calcium are phos-
An adjusted calcium compen-
phorous and pH.
sates for an abnormal albumin.
The adjusted calcium gives the Increasing pH (alkalosis) decreases
clinician an idea of what the total the ionized calcium and decreased pH
calcium would be if the albumin (acidosis) increases the ionized cal-
was 4. cium. The higher hydrogen ion concen-
tration displaces calcium from albumin,
CaAdj = Ca + [ (4 – Albumin) x 0.8]
increasing the fraction which is ionized.

5
This behavior was demonstrated in a controlled
trial of bicarbonate for lactic acidosis. Though 1.4
there was no survival benefit from treating the
Normal
acidosis, the investigators did find a drop in the
ionized calcium. (Cooper, DJ et al, Ann Intern 1.2 Range
Med 1990;112:492-8.)

1.0 Saline

Bicarbonate
0.8
Before After

Questions: In the following patients will they behave as if they have hyper-
calcemia, hypocalcemia or eucalcemia.
45 y.o. patient being treated for Burkittʼs Lymphoma
Ca: 8.8 Phos 16.4 Albumin 4.0 pH 7.4
 hypercalcemia  hypocalcemia "  eucalcemia

8 y.o. with congenital nephrotic syndrome (Finnish type)

Ca: 6.2 Phos 3.5 Albumin 1.2 pH 7.4
 hypercalcemia  hypocalcemia "  eucalcemia

28 y.o. getting pimped on the nephrology service and hyperventilat-

ing
Ca: 8.6 Phos 4.4 Albumin 4.0 pH 7.8
 hypercalcemia  hypocalcemia "  eucalcemia

Patients with altered phosphorous and pH will have an altered relationship of

ionized calcium and total calcium. There is no validated way to adjust for
changes in phosphorous and pH so these patients need to have a measured
ionized calcium.

6
Physiology of Calcium Regulation
Total body calcium, like all electrolytes is regulated by balancing intake and
excretion. The primary difference is the massive skeletal calcium store which
can absorb excess calcium or replenish a calcium deficit. The skeletal store
is slow and can safely be ignored in acute hospitalized patients but when
looking at long-term out-patient management it needs to be addressed.
The regulation of calcium is controlled by adjusting the absorption (via 1,25
dihydroxyvitamin D), excretion (via PTH) of calcium into and out of the body
and regulating the movement of calcium into and out of the bone (via PTH
and 1,25 dihydroxyvitamin D).

Ionized calcium is measured at the cell membrane of the parathyroid chief

cell by a transmembrane
protein logically called the
Calcium Sensing Receptor
(CaSR). Increases in cal-
cium at the CaSR surpress
the production and release
of PTH while decreases in
Ca stimulate the production
and release of PTH.

7
In addition to calcium, PTH is regulated by magnesium and 1,25 dihydroxyvi-
tamin D. High magnesium and 1,25 dihydroxyvitamin D both suppress PTH.
PTH acts to raise calcium by:
1. Minimizing urinary calcium excretion by increasing calcium resorption in
the thick ascending limb of the loop of Henle and distal convoluted tubule
2. Stimulating the conversion of 25-hydroxyvitamin D to 1,25-
dihydroxyvitamin D (calcitriol) by the kidney
3. In conjunction with calcitriol, mobilizing calcium and phosphorous from
bone
Note that the first two mechanisms depend on functioning kidneys.

Vitamin D is ingested or synthesized in the skin. In order for vitamin D to be-

come metabolically activate it must be hydroxylated, first in the liver and then
in the kidney, to form 1,25 dihydroxyvitamin D. 1,25 dihydroxyvitamin D in-

8
creases dietary absorption of calcium and phosphorous and is active in bone
metabolism and renal handling of calcium.

Holick MF. N Engl J Med. 2007 Jul 19;357(3):266-81

9
 Hypercalcemia
MM had an adjusted calcium of 11.8. The differential diagnosis of hypercal-
cemia is long but, as residents, you should have 4 diagnosis on the tip of
your tongue:
1. Primary hyperparathyroidism
2. Hypercalcemia of malignancy
3. Granulomatous diseases
4. Milk-Alkali syndrome

Primary hyperparathyroidism
Primary hyperparathyroidism is the number one cause of outpatient hyper-
calcemia. It is due to autonomous oversecretion of PTH by a benign ade-
noma of the parathyroids. The adenoma does not respond to the typical
negative feedback for PTH secretion such as increased calcium or 1,25 di-
hydroxyvitamin D. Patients have increased Ca and PTH, and decreased
phosphorous. Despite the increased reabsorption of urinary calcium they
have increased urinary calcium and often present with kidney stones. Treat-
10
 ment is surgical removal of the func-
Indications for parathyroidec- tioning adenoma.
tomy in primary HPTH
Hypercalcemia of malignancy
Serum Ca ≥1.0 mg/dL above the
upper limit of normal Hypercalcemia of malignancy in the
number one cause of hypercalcemia
Hypercalciuria (urinary Ca > 400 among hospitalized patients. There are
mg/day three different mechanisms for hyper-
Creatinine Cl decreased by 30% calcemia:

Osteoporosis (T score <-2.5) 1. Humoral hypercalcemia. Here a

normal hormone used in cartilage for-
Age less than 50 years mation is produced out of control. This
Periodic follow-up anticipated to protein, PTH related protein (PTHrP),
be difficult has PTH like properties due to the fact
that the first 13 amino acids are almost
identical. Like PTH, PTHrP increases
calcium reabsorption in the distal tubule and decreases phosphorous
reabsorption in the proximal tubule. It also promotes skeletal mobilization
of calcium. The primary difference from PTH is that it does not stimulate
the production of 1,25 dihydroxyvitamin D. It is produced in non-
metastatic solid tumors. PTH and phosphorous are low while calcium
and PTHrP are elevated.
2. Direct invasion of the bone causing increased osteoclast activity is seen
primarily non-small cell lung cancer and breast cancer following bone
metastasis. Multiple myeloma can also cause bone invasion and cause
hypercalcemia by this mechanism. These patients will have increased
calcium and decreased PTH, PTHrP and variable phosphorous.
3. Increased and unregulated hydroxylation of 25 hydroxyvitamin D. Hodg-
kinʼs and non-hodgkinʼs lymphoma cause activation of the storage form
of vitamin D outside of the normal regulation by the kidney and PTH.
These patients will have suppressed PTH, increased Ca and phospho-
rous and increased 1,25 vitamin D levels.

11
Granulomatous disease
This cause of hypercalcemia is identical to the third mechanism of hypercal-
cemia of malignancy. Unregulated
production of 1,25 vitamin D. Causes of unregulated produc-
tion of 1,25 dihydroxyvitamin D
Milk-alkali syndrome
• sarcoidosis
An interesting cause of hypercalcemia
is milk-alkali syndrome. The syndrome • tuberculosis
consists of renal failure, hypercalce- • Hodgkin lymphoma
mia and metabolic alkalosis. It is due
to ingestion of alkali and calcium and • non-Hodgkin's lymphoma
is now most often seen in woman tak- • berylliosis
ing calcium carbonate for osteoporo-
sis. • coccidioidomycosis
• histoplasmosis
Symptoms of Hypercalcemia
Mild hypercalcemia is associated with • candidiasis
relatively mild, non-specific symptoms. • Crohn's disease
Patients with primary hyperparathy-
roidism are generally asymptomatic • Langerhans-cell histiocytosis
but may complain of weakness, fa- • silicone-induced granulomas
tigue, anorexia, depression, vague
abdominal pain and constipation. • cat-scratch disease
Gastrointestinal side effects become • Wegener's granulomatosis
more severe at higher calcium levels.
Hypercalcemia has been associated • Pneumocystis carinii pneumonia
with increased gastrin secretion and
may predispose patients to peptic ulcers. Severe hypercalcemia can cause
pancreatitis. The hypothesized mechanism is inappropriate activation of tryp-
sinogen within the pancreatic parenchyma.
Hypercalcemia can cause multiple forms of renal dysfunction:
Long-standing hypercalcemia predisposes patients to nephrolithiasis.
Hypercalcemia causes nephrogenic diabetes insipidis by reducing sodium
reabsorption in the thick ascending limb of the loop of Henle and decreasing
the renal response to ADH. These changes predispose patients to volume
depletion.
Hypercalcemia also causes renal insufficiency. Primarily this is due to volume
deficiency but calcium induced vasoconstriction reduces renal blood flow. If
the hypercalcemia is long standing, calcification and ischemia results in irre-
versible renal insufficiency.

12
Mental status changes from mild confusion to psychosis or coma can occur
in severe cases of hypercalcemia. Mental status impairment can persist for
one to two days following correction of hypercalcemia.
Shortened QT-interval occurs with hypercalcemia and is generally consid-
ered a benign finding. Bradycardia, responsive to atropine, has been re-
ported.

This is representation of
the thick ascending limb of
the loop of Henle. The ba-
solateral side has CaSR
that respond to increases in
serum calcium by shutting
down the ROMK channel.
This decreases the positive
tubular charge which drives
the reabsorption of Ca, Mg
and Na. This is partly re-
sponsible for the nephro-
genic DI in hypercalcemia.

Treatment of hypercalcemia
The best treatment for hypercalcemia is to correct the underlying etiology. In
situations where this is not possible or specific hypocalcemic therapy is
needed, the treatment should focus on the three legs of calcium physiology:
calcium reabsorption in the kidney, calcium mobilization by the bones and
calcium absorption by the gut.
Calcium reabsorption is generally tied to sodium reabsorption so that inter-
ventions that reduce sodium reabsorption also reduce calcium reabsorption.
The most effective way to do this is to infuse saline. Saline also treats the
volume depletion found with hypercalcemia. Following volume repletion, loop
diuretics can further reduce calcium reabsorption. The goal of therapy is a
brisk diuresis of 250-300 mL/hr; however this may be difficult to achieve and
poses significant risk to patients. Significant hypercalcemia usually requires
additional therapy.
In hypercalcemia due to granulomatous diseases conservative therapy con-
sists of minimizing sun exposure, avoiding supplemental vitamin D and dis-
couraging calcium rich diets. Corticosteroids are highly effective in granulo-
matous disorders. If prednisone 40-60 mg/day for two weeks fails to correct
the calcium you probably have the wrong diagnosis. Chloroquine and hy-
droxychloroquine can be used as steroid-sparing agents.

13
The bisphosphonates are effective at correcting hypercalcemia of malig-
nancy regardless of the etiology. Pamidronate and zolendronate are com-
monly used to treat hypercalcemia of malignancy.
Salmon calcitonin can rapidly lower serum calcium by inhibiting osteoclastic
bone resorption. It also increases renal excretion of calcium. It can be given
IV or SQ and reduces serum calcium by 1-2 mg/dL within hours of admini-
stration. Unfortunately, it only works in just over half of patients with hyper-
calcemia of malignancy and tachyphylaxis is common after 2-3 days.

Hyperparathyroidism
Primary vs Secondary vs. Tertiary hyperparathyroidism
We have already talked about primary hyperparathyroidism, which causes
hypercalcemia. The other two forms of hyperparathyroidism are secondary
and tertiary hyperparathyroidism.
Secondary hyperparathyroidism is an increase in PTH due to a low calcium.
This increase in PTH is physiologic rather than pathologic. While short term
secondary hyperparathyroidism is adaptive, long term increases in PTH
cause a variety of problems. This long term secondary hyperparathyroidism
is found in chronic kidney disease:
1. Decreased GFR results in increased serum phosphorous
2. Increased serum phosphorous decreases the ionized calcium
3. Decreased ionized calcium triggers an increase in PTH
4. Increased PTH decreases phosphorous absorption in the proximal tubule
returning serum phosphorous to normal.
5. The increased PTH is enhanced by de-
creased production of 1,25 dihydroxyvita-
min D by the decreased renal mass. 1,25
vitamin D normally inhibits PTH release
from the parathyroid gland
6. The end result is a normal phosphorous at
the expense of an increased PTH
This system works with ever increasing PTH
as the GFR falls. The cycle can be interrupted
by decreasing the phosphorous load either by
diet or use of phosphorous binders.
Unfortunately this neat little system of increasing PTH in exchange for a
normal Phos completely fails when the patient progresses to ESRD. At this
point regardless how high the PTH is, the kidney is unable to excrete the
14
phosphorous. Patients are left with increased phosphorous and ever increas-
ing PTH.

This is representation of
the relative size increase
seen in hyperparathyroid-
ism. A change from 40 mg
to 1,000 mg

Long standing secondary hyperparathyroidism causes hypertrophy of the

parathyroid gland. This initially manifests as simply an increase in size of the
gland. Often the gland can increase from 40 mg to 1000 mg. Later the char-
acter of the gland can change to a nodular appearance. This nodularity is
associated with a decrease in responsiveness to the normal regulation of
PTH secretion. In essence the secretion of PTH ceases to be secondary to
hypocalcemia, hyperphosphatemia and low vitamin D. The secretion be-
comes autonomous in much the same way as in patients with primary hyper-
parathyroidism. A sign of this transition is hypercalcemia. This transition is
called tertiary hyperparathyroidism and like primary hyperparathyroidism it is
treated by surgery.

Type of Calcium Phos Treatment

HPTH

Primary High Low Surgery

Secondary Low to High in CKD Decrease phos load,

normal Active vitamin D,
Low in other
Calcimimetics
types of 2° HPTH

Tertiary High Normal to high Surgery

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 Renal Osteodystrophy
Bone disease due to renal disease

MM was admitted. The hypercalcemia was relatively asymptomatic. The ortho

service did an open reduction and internal fixation of the avulsed patellar tendon.
On the nephrology service we determined that his avulsion with minimal trauma
was due to osteitis fibrosa cystica. On further questioning, the patient reports dif-
fuse bone pain and severe itching.
Renal osteodystrophy (ROD) are skeletal disorders seen in CKD or ESRD
patients. The bone pathology in ROD comes in two basic flavors, high turn-
over disease with increased osteoblast activity and low-turn over disease
where there is a lack of osteoclast activity. Both conditions are bad for the
bones. The specific pathologies are below:
1. Osteitis fibrosa cystica - due to secondary hyperparathyroidism with
concomitant increase in resorption of bone. This condition leads to
increase in bone pains, fractures and skeletal deformities.

2. Osteomalacia – due to Vitamin D Deficiency which results in low

bone turnover in combination with increased volume of unmineral-
ized bone (osteoid)

16
 3. Adynamic bone disorder – due to PTH levels less than target which
results in low bone turnover.

4. Mixed osteodystrophy – mixed elements of both high and low bone

turnovers.
Regardless of the specific bone pathology found, renal osteodystrophy re-
sults in weak bones, bone pain and other extra-osseous manifestations of
diease:
• Anemia
• Itching (uremic pru-
ritis)
• Myopathy
• Increased Ca x
Phos product
• Calciphylaxis
• Vascular calcifica-
tion

17
Treating secondary hyperparathyroidism/ROD
Prevention and management of ROD revolves around maintenance of cal-
cium, phosphate and PTH balance. Researchers are just beginning to per-
form prospective studies to look at the proper target levels of calcium, phos-
phorous and PTH. For now physicians are relying on opinion based guide-
lines.
The National Kidney Foundation has created the K/DOQI guidelines.
Phosphorous
➡ Stage 3 and 4: 2.7 to 4.6
➡ Stage 5 and Dialysis: 3.5 to 5.5
Calcium
➡ Stage 3 and 4: keep the calcium within the “normal” range
➡ Stage 5 and Dialysis: 8.4 to 9.5
★ Intervene to lower the calcium when the Ca rises above 10.2
★ Do not intervene for a low calcium unless the patient is clinically
symptomatic
Calcium Phosphorous product
➡ Stage 3 to 5: less than 55
intact PTH
➡ Stage 3: 35-70
➡ Stage 4: 70-110
➡ Stage 5 and Dialysis: 150-300
The Kidney Disease Improving Global Outcomes (KDIGO) recommendations
are international consensus guidelines that purport to provide more evidence
based, rather than opinion based, guidelines. The Metabolic Bone Disease
Guidelines have not yet been published but the draft recommendations were
opened for public opinion in July 2008.
Phosphorous
➡ There is insufficient data to recommend specific targets. Extremely
abnormal values should be avoided.
➡ When the phosphorous is elevated it should be lowered.
Calcium
➡ There is insufficient data to recommend specific targets. Extremely
abnormal values should be avoided.
18
 ➡ Avoid hypercalcemia.
➡ Unknown what risk, if any, of moderate-degree hypocalcemia
intact PTH
➡ Avoid PTH levels < 2 or > 9 times the upper limit of normal for the as-
say being used. For the intact PTH used in the hospital this means
keep the PTH between 150 and 675
➡ Values that are persistently increasing or decreasing within 2-9X the
upper limit should also be addressed
KDIGO does not address calcium phosphorous product as an end-point.

Treatment options
Decrease Phosphorous Absorption
Controlling phosphorous can help patients get the Phos, the Ca-Phos prod-
uct and PTH to goal. There are two strategies for lowering the phosphorous,
decreasing the phosphorous in the diet and decreasing phosphorous ab-
sorbed from the diet. All dialysis patients are advised to ingest no more than
800 mg of phosphorous per day. High phosphorous foods include dairy prod-
ucts, whole grains, and nuts.
Phosphorous binders are effective at lowering the absorption of phospho-
rous. The current options are sevelamer, calcium carbonate, calcium acetate,
and lanthium carbonate. These medications need to be administered with
food to be effective.
The primary side effects are all GI related. There is a concern that the cal-
cium containing binders may promote vascular calcification by increasing the
calcium burden and suppressing the PTH. This has been shown in two un-
blinded trials (Treat To Goal and RIND) but use of sevelamer failed to reduce
mortality in the pivotal DCOR trial.
Intact PTH
In addition to using phosphorous binders to lower PTH, activated vitamin D
(1,25 dihydroxyvitamin D and its synthetic analogs) and cinacalcet can lower
the intact PTH.
The parathyroid gland uses 1,25 dihydroxyvitamin D as a negative inhibitor to
decrease the release of PTH. In renal failure the kidneys do not produce di-
hydroxyvitamin D so this negative feedback for PTH release is lost. Providing
exogenous vitamin D lowers the PTH. The primary problem with vitamin D is
that in addition to lowering PTH they increase the GI absorption of both cal-
cium and phosphorous. The synthetic analogs of dihydroxyvitamin D, pari-
calcitol (Zemplar) and doxercalciferol (Hecterol) have less GI activity and so
are less prone to cause hypercalcemia and hyperphosphatemia.
19
Cinacalcet (Sensipar) is the only commercially available member of a novel
class of medications called the calcimimetics. Cinacalcet binds the calcium
binding receptor and makes it bind calcium more tightly. This makes the re-
ceptor behave like the serum calcium level is significantly higher than it actu-
ally is. This perceived elevation in calcium inhibits the release of PTH. In
clinical trials cinacalcet reduces PTH, calcium and phosphorous. Cincalcet
was approved based on the ability to get patient to the K/DOQI bone and
mineral guidelines.
If patients have increased calcium and hyperparathyroidism they have terti-
ary hyperparathyroidism. Tertiary hyperparathyroidism is treated by parathy-
roidectomy, the last method of reducing PTH.
Per the K/DOQI guidelines: Parathyroidectomy should be recommended in
patients with severe hyperparathyroidism (persistent serum levels of intact
PTH >800 pg/mL [88.0 pmol/L]), associated with hypercalcemia and/or hy-
perphosphatemia that are refractory to medical therapy.
Per Up to Date: Main indications for parathyroidectomy are:
• Severe hypercalcemia
• Progressive and debilitating hyperparathyroid bone disease
• Pruritus that does not respond to medical or dialytic therapy
• Progressive extra-skeletal calcification or calciphylaxis
• Otherwise unexplained symptomatic myopathy
MM goes for a parathyroidectomy due to the bone pain, persistent hyperpara-
thyroidism and hypercalcemia. Following the surgery MM develops hypocal-
cemia, hypokalemia and hypomagnesemia. He is diagnosed with severe hungry
bone syndrome. His total calcium falls as low as 5 mg/dL. He is started on a
calcium drip.

Hypocalcemia
Is it pathology or physiology
Etiologies:
Hypocalcemia is a pervasive finding among acutely ill patients. Various stud-
ies have found a prevalence of 70-90% among patients in the ICU. Hypocal-
cemia occurs when calcium leaves the vascular space faster than it is re-
pleted. It can leave the vascular space by either by renal losses or deposition
in the bones or soft tissues. Repletion normally occurs through diet or mobili-
zation of skeletal stores.

20
Tissue deposition
Acute deposition in the tissues occurs with acute hyperphosphatemia as
seen with tumor lysis syndrome or with pancreatitis in which the calcium is
absorbed by free fatty acids produced by the increase in lipase. Citrate expo-
sure can also do this and occurs with blood transfusions, continuous dialysis
and plasmapheresis. Liver disease, renal failure and hypothermia all de-
crease the metabolism of citrate and contribute to this risk.
Hungry bone syndrome is a special case of tissue deposition, where long-
standing hyperparathyroidism (primary, secondary or tertiary) has demineral-
ized large amounts of the bone leaving osteoid. When the PTH is removed
the bone begins to rapidly remineralize and can absorb tens of grams of cal-
cium. The hypocalcemia can persist for months.

Increased renal loss

Renal loss of calcium is due to hypoparathyroidism. Decreased PTH is pri-
marily due to surgical intervention on the neck which can stun the parathyroid
glands (usually temporarily). Additionally high magnesium levels can trigger
the CaSR and suppress release of PTH. The release of PTH, like insulin, is a
magnesium dependent process, so hypomagnesemia can also suppress
PTH release and decrease end-organ PTH responsiveness.
In addition to the increased renal losses, the loss of PTH prevents the mobili-
zation of skeletal reserves.

Decreased intake and mobilization of skeletal reserves

Acute hypocalcemia with vitamin D deficiency occurs because of the inability
to mobilize skeletal reserves of calcium.
Vitamin D deficiency is very common with a Interpreting 25-OH Vitamin
measured prevelance among nursing home D levels
patients of 40-100%. Pre-adolescent white
• 30-40 ng/mL: optimal
girls have a 50% rate of insufficiency (Sulli-
van SS, Rosen CJ, et al. J Am Diet Assoc • 20-29 ng/mL: insufficient
2005; 105:971-974.). Even among health
• <20 ng/mL: deficient
conscious (daily vitamin and glass of forti-
fied milk plus weekly salmon) adults the
rate of deficiency was 32% (Tangpricha V, Pearce EN, et al. Am J Med
2002;112:659-662.).
Increased hepatic metabolism of vitamin D occurs in patients on phenytoin
and phenobarbital. The nephrotic syndrome is commonly associated with
hypocalcemia, though most of this is due to hypoalbuminemia. Ionized hy-
pocalcemia occurs with the nephrotic syndrome and may be due to the loss
of 25-hydroxyvitamin D and its binding protein in the urine. Decreased activa-
tion of 25-hydroxyvitamin D occurs with renal failure and hypoparathyroidism.

21
Hypocalcemia of critical illness
Hypocalcemia is a pervasive disorder in the ICU. While hypocalcemia was
thought to be limited to patients with sepsis, Zivin et al. have shown hypocal-
cemia to be frequent in all patients with severe illness.(Zivin JR, Gooley T, et
al. Am J Kidney Dis 2001 37:689-698.) Despite careful assessment however,
a definitive etiology can be found in less than half of the patients. Some
authors believe that ICU associated hypocalcemia (ICU-H) is an adaptive,
beneficial, response to critical illness as it may prevent intracellular hypercal-
cemia and associated tissue damage.
This concept of adaptive hypocalcemia gained credence initially from in-vitro
studies that showed that intracellular calcium was a mediator of injury. Addi-
tionally calcium infusions enhanced reperfusion injury. In vitro evidence came
from a series of studies on septic rats that showed that the correction of hy-
pocalcemia improved hemodynamics but increased mortality.

Ca BP

Ca
Induce
sepsis
Ca BP

• Zaloga G, Sager A, Black KW, Low dose calcium administration increases mor-
tality during septic peritonitis in rats., Circulatory Shock (1992) 37:226-229.
• Malcolm D, Zaloga G, Holaday J, Calcium administration increases the mortal-
ity of endotoxic shock in rats., Critical Care Med (1989) 17:900-903.

22
One other cautionary tale
about the consequences of
calcium replacement comes
from a 2008 article. (Bolland
MJ, Barber PA, et al. Brit
Med J 2008; 336: 262-6) This
was an additional analysis of
a 5 year study of calcium
supplementation in post-
menopausal women to look
at fracture risk and BMD.
This paper however looked
at the randomized cohort to
see if their was a risk of in-
creased cardiovascular
events.

Consequences of hypocalcemia
The primary manifestation of hypocalemia is neuromuscular irritability. This
can range from perioral numbness and acral paresthesias to severe tetany
and seizures.
Tetany can cause laryngospasm or bronchospasm resulting in respiratory
failure. The classic signs of latent tetany are Trouseauʼs sign (carpal spasm
after inflation of a blood pressure cuff on the arm for 3 minutes) and Chvos-
tekʼs sign (facial spasm induced by tapping on the facial nerve at the temple).
The sensitivity of both is poor and the specificity of Chvostekʼs is particularly
poor (a partial Chvostekʼs sign is found in 25% of eucalcemic individuals).
Acute hypocalcemia can cause heart failure. Even modest hypocalcemia can
precipitate heart failure and hypotension in patients with latent cardiac dam-
23
age. The classic electrocardiogram findings of hypocalcemia are bradycar-
dia, prolonged QT interval and inversion of the T wave. The electrocardio-
gram is not sensitive and may be normal during life threatening hypocalce-
mia.
Hypotension can occur following loss of vascular tone. In one ICU study de-
creased ionized calcium correlated with decreased mean arterial pressures.
Digitalis acts by increasing intracellular calcium. Hypocalcemia is a cause of
digitalis resistance. Patients can sometimes tolerate toxic digitalis levels with
concurrent hypocalcemia. Correction of this protective hypocalcemia can
precipitate symptomatic digitalis toxicity.

Treatment
Unique to calcium among all electrolyte disorders is the theory that hypocal-
cemia may be an adaptive response to critical illness and because of this,
the treatment of ICU associated hypocalcemia (ICU-H) is controversial. Care
must be made not to extrapolate this controversy to patients in which the eti-
ology of their hypocalcemia is understood (e.g. acute hypoparathyroidism,
tumor lysis syndrome, acute renal failure). Patients with chronic hypocalce-
mia and myocardial dysfunction should be given a trial of calcium supple-
mentation.
Calcium should be repleted in cases of seizures, tetany, laryngospasm and
hyperkalemia. Among asymptomatic patients, the risk of significant clinical
symptoms rises as the ionized calcium falls below 3 mg/dL and treatment is
warranted in these patients.
National guidelines call for active treatment of patients with hungry bone
syndrome.
Mild hypocalcemia can be treated with increases in oral calcium of 1000 mg/
day.

Calcium Elemental Pill Size

Preparation Calcium

Calcium carbonate 250 mg 650 mg

Calcium gluconate 90 mg 1000 mg

Calcium citrate 200 mg 950 mg

Calcium lactate 60 mg 300 mg

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Acute symptomatic hypocalcemia should be treated with IV calcium. Two
forms of IV calcium are available: calcium gluconate and calcium chloride.
The chloride preparation has more calcium but is sclerosing to the veins and
should only be used in patients with central access.

Calcium Elemental Calcium per gram

Preparation (ampule)

Calcium gluconate 94 mg

Calcium chloride 272 mg

(equivalent to 3 amps of Ca Gluconate)

Symptomatic patients should get 1-2 ampules of calcium gluconate followed

by a calcium infusion. I use 5 grams of calcium gluconate in 500 mL of D5W
and run this at 10-100 mL/hour to normalize the calcium.
Following the parathyroidectomy
M.M. lingered on the floor for days
on a calcium infusion, receiving regu-
lar potassium and magnesium sup-
plements. He never had symptomatic
hypocalcemia. Then Alonzo Mourn-
ing came to the hospital on a promo-
tional tour for Johnson and John-
son. As part of the tour he met M.M.
and actually spent 15 minutes alone
with the patient talking to him. I was
Alonzo’s physician guide and about
10 minutes after I left the ward with
him I received a frantic call from my
fellow that M.M. was stridorous and
in respiratory distress. We gave an
amp of calcium gluconate, increased
calcium drip and transferred him to
the ICU. The ABG done in the ICU
showed: 7.46 / 24 / 88. Our conclu-
sion was that M.M. hyperventilated in response to meeting Alonzo and devel-
oped respiratory alkalosis. This lowered his ionized calcium and precipitated
the symptomatic hypocalcemia.

25
Notes
Notes
 Joel M. Topf, MD
Nephrology
248.470.8163
http://pbfluids.blogspot.com/