vitamin d deficiency diagnosed

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American Family Physicians

January 15, 2005 Table of Contents

Undiagnosed Vitamin D Deficiency in the Hospitalized Patient

DAVID LYMAN, M.D., M.P.H., Greene Valley Developmental Center,
Greeneville, Tennessee

Related Editorial

Vitamin D deficiency among hospitalized patients may be more
widespread than realized. Vague musculoskeletal complaints in these
chronically ill patients may be attributed to multiple underlying
disease processes rather than a deficiency in vitamin D. However, the
failure to diagnose an underlying deficiency places the patient at
risk for continued pain, weakness, secondary hyperparathyroidism,
osteomalacia, and fractures. The causes of hypocalcemia and
hypophosphatemia in the chronically ill patient are many, and the
patient may respond to simple replacement therapy. Elderly
hospitalized patients with ionized hypocalcemia and hypophosphatemia,
with or without an elevated parathyroid hormone level, are most likely
deficient in vitamin D. Initiating treatment during hospitalization is
reasonable once the diagnosis has been confirmed by finding a low
25-hydroxyvitamin D level. Treatment with high doses of vitamin D is
safe. Unfortunately, some hospital formularies continue to provide
multivitamin supplements that contain less vitamin D than currently is
recommended. (Am Fam Physician 2005; 71:299–304. Copyright© 2005
American Academy of Family Physicians.)

Patients with severe vitamin D deficiency and hypocalcemia present
with classic findings of neuromuscular irritability, including
numbness, paresthesias, muscle cramps, laryngospasm, Chvostek’s sign,
Trousseau’s phenomenon, tetany, and seizures.1 By contrast, patients
with mild vitamin D deficiency present with more subtle complaints
such as muscle weakness or pain. Finding only a modest reduction in a
patient’s calcium or phosphate level should not reassure the physician
that all is well. When vitamin D deficiency is the cause of
hypocalcemia or hypophosphatemia, replacing calcium or phosphate alone
does not restore the body to homeostasis.2,3

Strength of Recommendations

---------------------------------------------------------------------

Key clinical recommendation

Label

References

Daily vitamin D supplementation of 800 to 1,000 IU is a reasonable
dose for adults.

C

2,9,10

Levels of 25-hydroxyvitamin D should be maintained above 32 ng per mL
(80 nmol per L) to maximize bone health.

C

11

In patients with severe vitamin D deficiency (serum levels of below 8
ng per mL with hypocalcemia), 50,000 IU of vitamin D should be given
daily for one to three weeks, followed by weekly doses of 50,000 IU.

C

2,7

After repletion of body stores, 800 IU of vitamin D daily or 50,000 IU
of vitamin D once or twice monthly is adequate maintenance therapy.

C

2,10

Patients with no sun exposure, malabsorption, or those taking
antiepileptic drugs may require larger maintenance doses of vitamin D
(i.e., up to 50,000 IU one to three times weekly).

C

2,7

In critically ill patients, albumin-adjusted calcium levels
underestimate true or ionized hypocalcemia. Therefore, measured
ionized calcium levels are recommended, particularly in patients who
are being treated in an intensive care unit.

B

12

If calcium supplementation alone fails to maintain normal serum
levels, the patient is vitamin D deficient or resistant and may
benefit from a trial of calcitriol (Rocatrol).

C

5

If the vitamin D deficiency is severe, the patient will require 90
mmol per L in the first 24 hours: 6 mL of K2PO4 added to each liter of
fluid and given at 200 mL per hour (1 mL of K2PO4 is equal to 4 mEq of
potassium and 3.0 mmol per L or 93 mg of phosphate).

C

14

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A = consistent, good-quality patient-oriented evidence; B =
inconsistent or limited quality patient-oriented evidence; C =
consensus, disease-oriented evidence, usual practice, opinion, or case
series. See page 225 for more information.

Ionized hypocalcemia has been found in 15 to 50 percent of patients
being treated in intensive care units (ICUs) and is associated with
increased mortality and disease severity.4,5 However, chronically ill
patients only rarely develop true tetany and hemodynamic instability.5,6

Prolonged asymptomatic hypocalcemia from deficient vitamin D
production or absorption stimulates the release of parathyroid hormone
(PTH). If vitamin D is not provided, secondary hyperparathyroidism
develops with increased bone turnover and decreased bone
mineralization.2 The adult patient with severe vitamin D depletion
develops osteomalacia and presents with localized bone pain,
antigravity muscle weakness, difficulty rising from a chair or
walking, and pseudofractures.3,7

Illustrative Cases

Two hospitalized chronically ill patients with unrecognized vitamin D
deficiency, hypocalcemia, and hypophosphatemia are presented below.

CASE 1

An elderly black woman was readmitted to the hospital from a nursing
home because of progressive weakness. She had been discharged two
weeks earlier following a four-month hospitalization for severe
chronic obstructive pulmonary disease. During her previous hospital
stay, she required prolonged mechanical ventilation through a
tracheostomy tube and total, or central, parenteral nutrition (CPN).
She was discharged to the nursing home on low-flow oxygen therapy. On
readmission, she had a weak cough and required vigorous tracheal
suctioning through her tracheostomy tube. Depressed levels of serum
calcium and phosphate resistant to vigorous oral and intravenous
replacement were noted on both hospital admissions. Before she was to
return to the nursing home, her 25-hydroxyvitamin D level was 7 ng per
mL (17 nmol per L; normal: 8 to 38 ng per mL 20 to 95 nmol per L),
and her PTH level was 161 pg per mL (17 pmol per L; normal: 9.5 to
49.4 pg per mL 1.0 to 5.2 pmol per L). Vitamin D and calcium
supplementation was to begin in the nursing home.

CASE 2

An elderly black man was transferred to the hospital from an
extended-care facility because of progressive weakness, hypokalemia,
and congestive heart failure. On admission, his potassium level was
2.2 mEq per L (2.2 mmol per L), digoxin was 1.6 ng per mL (2.0 nmol
per L), magnesium was 1.1 mEq per L (0.55 mmol per L; normal: 1.3 to
2.0 mEq per L 0.65 to 1.00 mmol per L), phosphorus was 2.3 mg per dL
(0.74 mmol per L; normal: 2.5 to 4.5 mg per dL 0.81 to 1.45 mmol per
L), and calcium was 6.9 mg per dL (1.72 mmol per L; normal: 8.4 to
10.2 mg per dL 2.10 to 2.55 mmol per L). He was in chronic atrial
fibrillation with an ejection fraction of 12 percent and a therapeutic
prothrombin time.

At the time of admission, he was diuresed and given potassium,
magnesium, and calcium. Before discharge, the on-call physician noted
that the patient’s serum calcium and phosphorus levels were still low,
and that his ionized calcium level was 3.9 mg per dL (0.97 mmol per L;
normal: 4.5 to 5.3 mg per dL 1.12 to 1.32 mmol per L). The patient
was thin, dyspneic, and had a positive Chvostek’s sign. The clinical
diagnosis of vitamin D deficiency was made. Oral vitamin D
supplementation was initiated in a dosage of 50,000 IU three times
weekly.

One week after the patient was discharged from the hospital, the
reference laboratory reported that his 25-hydroxyvitamin D level was 6
ng per mL (15 nmol per L). PTH levels were not obtained.

Risk Factors for Developing Vitamin D Deficiency

Vitamin D deficiency is common. The results of a 1998 study8 reported
a 57 percent prevalence of vitamin D deficiency in 290 patients
admitted to a hospital in Massachusetts. The investigators found that
assessment of common clinical risk factors through a multivariate
model failed to identify many patients with vitamin D deficiency.8

The vitamin D–deficient patients presented in the two illustrative
cases in this article were elderly, chronically ill, and mal-nourished
with a poor vitamin D intake. Furthermore, these patients had no
exposure to the sun. To produce a similar amount of vitamin D as
persons with lightly pigmented skin, persons with darkly pigmented
skin require three to six times more sun exposure.7

For the patient in case 1, the daily multivitamin supplement infused
into the CPN provided only 200 IU of vitamin D (an amount thought to
be adequate until recently). In 1997, based on the assumption that
young and middle-aged adults were exposed to more sunlight than older
adults, new dietary intakes of vitamin D were recommended as follows:
200 IU daily for children and adults 50 years and younger, 400 IU
daily for adults 51 to 70 years of age, and 600 IU daily for adults
older than 70 years. However, vitamin D supplementation was thought to
have such a large margin of safety that 800 to 1,000 IU daily is not
an unreasonable dose for all adults.2,9,10

Other disease states and characteristics not present in the
illustrative cases but associated with the development of vitamin D
deficiency include significant renal or hepatic disease, history of
gastric resection or bypass, malabsorption, and use of certain
medications such as anticonvulsants.7 To remain normocalcemic,
patients treated with phenytoin (Dilantin) or phenobarbital require
two to five times the recommended daily amount of vitamin D.3

Vitamin D Metabolism and Physiology

Vitamin D is absorbed from the small intestine and is produced in the
skin. Dietary vitamin D2 comes from yeasts and plants; fish and
cod-liver oil are good sources of vitamin D3, which also is made in
the skin.3 In the skin, 7-dehydrocholesterol is converted to
3-cholecalciferol (or vitamin D3) after exposure to ultraviolet B
radiation.2,9 Vitamins D2 and D3 are equipotent in humans, and
together are called “vitamin D.”3 Vitamins D2 and D3 are bound to the
vitamin D–binding protein and transported to the liver, where
25-hydroxylation of vitamin D produces 25-hydroxyvitamin D, or
calcidiol.

Calcidiol is the major circulating form of vitamin D. Although
biologically inert, the 25-hydroxyvitamin D level most accurately
reflects body stores.2,3,9 Under the influence of PTH,
25-hydroxyvitamin D is further hydroxylated in the kidneys to
1,25-dihydroxyvitamin D or calcitriol, the hormonally active form of
vitamin D. Calcitriol facilitates calcium absorption in the intestines
and is required for the efficient utilization of dietary calcium.3,10
1,25-dihydroxyvitamin D also is thought to inhibit cellular growth,
stimulate insulin secretion, and activate the immune system.10

The ICU patient with multiorgan failure has decreased hepatic
production of 25-hydroxyvitamin D and reduced renal synthesis of
1,25-dihydroxyvitamin D.3,4 PTH levels increase in response to
decreasing 1,25-hydroxyvitamin D levels and impaired dietary calcium
absorption. In the kidneys, PTH induces phosphaturia and increases
tubular reabsorption of calcium.2,7 High levels of PTH also activate
osteoclasts in bone to provide essential calcium, resulting in
osteopenia and osteoporosis. As both hypocalcemia and hypophosphatemia
worsen, the calcium-phosphate product is no longer adequate to
mineralize bone properly. Osteoblasts deposit a poorly mineralized
collagen, a rubbery matrix that provides inadequate skeletal support.
Painful osteomalacia (rickets, in children) is caused by the
activation of periosteal sensory pain fibers deformed by weakened and
poorly calcified bones.10

Diagnosis and Treatment

VITAMIN D DEFICIENCY

The findings of muscle weakness and pain on physical examination are
nonspecific, and often are misdiagnosed as fibromyalgia.10 The most
sensitive test to diagnose vitamin D deficiency is the serum
25-hydroxyvitamin D level.2,3,7 PTH levels are normal in early or mild
vitamin D deficiency.2 Only later do the findings of prolonged
secondary hyperparathyroidism present (i.e., osteomalacia,
osteoporosis).

If the vitamin D deficiency is mild (8 to 15 ng per mL 20 to 37 nmol
per L), patients should be given 800 IU of vitamin D with 1,500 mg of
elemental calcium daily.2 Alternatively, serum 25-hydroxyvitamin D
levels should increase from less than 15 ng per mL to 25 to 40 ng per
mL (62 to 100 nmol per L) after eight weekly doses of 50,000 IU of
vitamin D. With no additional vitamin D, adequate levels will be
sustained for only two to four months.3 Current recommendations are
that patient levels be maintained above 32 ng per mL (80 nmol per L)
to maximize bone health.11

In patients with severe vitamin D deficiency (serum levels of below 8
ng per mL with hypocalcemia), 50,000 IU of vitamin D should be given
daily for one to three weeks, followed by weekly doses of 50,000 IU.2,7
After repletion of body stores, 800 IU of vitamin D daily or 50,000 IU
of vitamin D once or twice monthly is adequate maintenance therapy.2,10
However, patients with no sun exposure or malabsorption, and those
taking antiepileptic drugs may require larger maintenance doses of
vitamin D (i.e., up to 50,000 IU one to three times weekly).2,7 Table
13,8,10 lists other treatment options.

TABLE 1
Causes and Management of Vitamin D Deficiency

---------------------------------------------------------------------

Causes

Management

Lack of adequate sunlight or chronic sunscreen

Ultraviolet lamp or increased sun exposure† use

Total (central) parenteral nutrition

400 to 800 IU of vitamin D orally per day, or 20 to 25 IU of vitamin D
per kg intravenously per day

Vitamin D–deficient diet

Usually 1,500 to 5,000 IU of vitamin D2 orally per day,  or 50,000 IU
of vitamin D2 orally per week  or 10,000 to 50,000 IU of vitamin D2
intramuscularly per month

Fat malabsorption

25-hydroxyvitamin D, 20 to 30 mcg per day

Cirrhosis, nephrotic syndrome, renal failure, gastric or small bowel
resection, rifampin, chronic corticosteroids, anticonvulsants

1,25-dihydroxyvitamin D, 0.15 to 0.5 mcg daily‡

---------------------------------------------------------------------

— Whole body exposure to a minimal erythemal dose of sunlight is
equal to 10,000 to 75,000 IU of oral vitamin D.

†—In a Boston study, exposure of hands, face, and arms to sunlight for
five to 15 minutes daily between 11 a.m. to 2 p.m. provided adequate
vitamin D.

‡—In cases of liver failure or nephrotic proteinuria, levels of
25-hydroxyvitamin D may be low; replacement may suffice. In cases of
renal failure with normal or elevated 25-hydroxyvitamin D levels and
ionized hypocalcemia, 1,25-dihydroxyvitamin D replacement is required.
The dose should be carefully adjusted to normalize calcium, phosphate,
and 25-hydroxyvitamin D levels.

Information from references 3,8, and 10.

HYPOCALCEMIA

In critically ill patients, albumin-adjusted calcium levels
underestimate true or ionized hypocalcemia. Therefore, measured
ionized calcium levels are recommended, particularly in patients who
are being treated in an ICU.12 Serum phosphate levels are elevated in
most cases of hypocalcemia. However, patients deficient in vitamin D
usually have low phosphate levels. Many disease processes can cause
ionized hypocalcemia; Figure 11–14 may help focus the evaluation.

Classification and causes of ionized hypocalcemia.

 

---------------------------------------------------------------------

Figure 1

Classification and causes of ionized hypocalcemia.

Information from references 1 through 14.

Asymptomatic patients with ionized calcium levels higher than 3.2 mg
per dL (0.8 mmol per L) can be closely monitored without therapy.
Treatment can be considered if symptoms develop or the ionized calcium
level falls below 3.2 mg per dL.5 This cautious approach to calcium
replacement is supported by a few case reports and animal studies that
suggest mortality is increased when hypocalcemia is corrected in the
setting of sepsis.4,5,13

There are no prospective studies on humans that support the use of
calcium supplementation in asymptomatic ICU patients with
hypocalcemia.4 However, hypocalcemia should be aggressively corrected
if the patient develops tetany, seizures, QT prolongation,
bradycardia, or hypotension refractory to pressors, or in the
mechanically ventilated patient where hypocalcemia is associated with
decreased diaphragmatic function.4,5

Patients with severe or symptomatic hypocalcemia should be treated
with intravenous calcium gluconate, which has 90 mg of elemental
calcium in each 10-mL ampule and is less irritating to the veins than
calcium chloride.5 A bolus of 100 to 180 mg of elemental calcium given
over five to 10 minutes will raise the calcium level for one to two
hours. An infusion of 15 mg per kg of elemental calcium over four to
six hours will increase the serum levels by 2 to 3 mg per dL (0.50 to
0.75 mmol per L).5 Calcium levels should be checked every two to four
hours, and serum calcium levels should be maintained in the low normal
range. When calcium levels stabilize, oral supplementation should
begin at a dosage of 1 to 4 g of elemental calcium daily. If calcium
supplementation alone fails to maintain normal serum levels, the
patient is vitamin D deficient or resistant and may benefit from a
trial of calcitriol (Rocatrol).5

HYPOPHOSPHATEMIA

The patient described in case 1 required prolonged intubation and
ventilatory support during her previous one-month hospitalization.
Mechanical ventilation, theophylline, corticosteroids, and beta2
agonists can cause hypophosphatemia.14 Other causes of
hypophosphatemia in the hospitalized patient include protein
malnutrition, malabsorption, diabetic ketoacidosis, respiratory
alkalosis, sepsis, antacid phosphate binders, and vitamin D
deficiency.6 Because hypophosphatemia and hypocalcemia decrease
diaphragmatic function, serum calcium and phosphorous levels must be
closely monitored in all patients who require mechanical ventilation.13,14

Symptoms of hypophosphatemia may range from fatigue and irritability
to seizures and acute respiratory failure.14 Mild hypophosphatemia
(phosphate level higher than 1 mg per dL 0.50 mmol per L) may be
treated orally with sodium or potassium phosphate (e.g.,
Neutra-Phos-K, one packet twice daily).6 In non–life-threatening
situations (e.g., when using CPN) the patient may require 30 mmol per
L or less per day of sodium or potassium phosphate for homeostasis.
This is achieved by adding 2 mL of phosphate solution (K2PO4) to each
liter of fluid given at 200 mL per hour.14

Severe hypophosphatemia (phosphate level below 0.5 mg per dL 0.15
mmol per L) requires intravenous treatment with sodium or potassium
phosphate.6 In the critically ill patient, phosphorous is infused
slowly to prevent tetany, hypotension, and hypocalcemia.6,14 If the
deficiency is severe, the patient will require 90 mmol per L in the
first 24 hours: 6 mL of K2PO4 is added to each liter of fluid and
given at 200 mL per hour (1 mL of K2PO4 is equal to 4 mEq of potassium
and 3.0 mmol per L or 93 mg of phosphate).14

The safety of faster infusion rates (i.e., 15 to 45 mmol per L over
one to three hours) has recently been demonstrated and may be
preferred.6 However, the vitamin D–depleted patient may present with
refractory hypophosphatemia. In the absence of hypercalcemia or
hypercalciuria, and after 25-hydroxyvitamin D levels have been drawn,
the patient may benefit from a trial of calcitriol (0.25 to 0.50 mcg
orally or via feeding tube) to decrease renal phosphate losses.6

---------------------------------------------------------------------

The Author

DAVID LYMAN, M.D., M.P.H., is the medical director of the Greene
Valley Developmental Center in Greeneville, Tenn. He received his
medical degree and his master of public health degree from the
University of Michigan Medical School, Ann Arbor. He completed a
residency in family medicine at the University of Colorado Health
Sciences Center, Denver, and a faculty development fellowship in
family medicine at the University of North Carolina at Chapel Hill,
Chapel Hill.

Address correspondence to David Lyman, M.D., M.P.H., Greene Valley
Developmental Center, 4850 E. Andrew Johnson Hwy., Greeneville, TN
37744 (e-mail: dlymanmdmph@yahoo.com). Reprints are not available from
the author.

The author indicates that he does not have any conflicts of interest.
Sources of funding: none reported.

REFERENCES

1. Kapoor	M, Chan GZ. Fluid and electrolyte abnormalities. Crit
Care Clin.	2001;17:503–29.

2. Thomas	MK, Demay	MB. Vitamin D deficiency and disorders of
Vitamin D	metabolism.	Endocrinol Metab Clin North Am. 2000;29:611–27.

3. Holick MF. Vitamin D: photobiology, metabolism, mechanism of
action, and clinical applications. In: Favus MJ, ed. Primer on the
metabolic bone diseases and disorders of mineral metabolism. 5th ed.
Washington, D.C.: American Society for Bone and Mineral Research,
2003; 129–37.

4. Carlstedt  F, Lind  L.  Hypocalcemic syndromes. Crit Care Clin.
2001;17:139–53.

5. Vasa  FR, Molitch  ME.  Endocrine problems in the chronically
critically ill patient. Clin Chest Med. 2001;22:193–208.

6. Mechanick  JI, Brett  EM.  Endocrine and metabolic issues in the
management of the chronically critically ill patient. Crit Care Clin.
2002;18:619–41.

7. Yew  KS, DeMieri  PJ.  Disorders of bone mineral metabolism. Clin
Fam Pract. 2002;4:525–65.

8. Thomas  MK, Lloyd-Jones  DM, Thadhani  RI, Shaw  AC, Deraska  DJ,
Kitch  BT, et al.  Hypovitaminosis D in medical inpatients. N Engl J
Med. 1998;338:777–83.

9. Nieves  JW.  Calcium, vitamin D, and nutrition in elderly adults.
Clin Geriatr Med. 2003;19:321–35.

10. Holick MF.	Vitamin D deficiency: what a pain it is editorial.
Mayo Clin Proc.	2003;78:1457–9.

11. Binkley  N, Krueger  D, Cowgill  CS, Plum  L, Lake  E, Hansen  KE,
et al.  Assay variation confounds the diagnosis of hypovitaminosis D:
a call for standardization. J Clin Endocrinol Metab. 2004;89:3152–7.

12. Slomp  J, van der Voort  PH, Gerritsen  RT, Berk  JA, Bakker  AJ.
 Albumin-adjusted calcium is not suitable for diagnosis of hyper- and
hypocalcemia in the critically ill. Crit Care Med. 2003;31:1389–93.

13. Pingleton  SK.  Nutrition in chronic critical illness. Clin Chest
Med. 2001;22:149–63.

14. Miller	DW, Slovis CM.	Hypophosphatemia in the emergency
department	therapeutics. Am	J Emerg Med. 2000;18:457–61.

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