PENELITIAN
Penelitian dan profesional celana
Hiperkalsemia Disebabkan oleh iatrogenik
Hypervitaminosis A
KARAN Bhalla, MD; DAVID M. ENNIS, MD, FACP; ELIZABETH D. ENNIS, MD, FACP
ABSTRAK
Vitamin toksisitas A menghasilkan ragam klinis Manifesta-tions
yang melibatkan berbagai jaringan dan sistem. Hiperkalsemia
kadang-kadang dapat dikaitkan dengan tingkat vitamin A yang
tinggi, tetapi jarang terjadi. Dalam laporan ini kami
menggambarkan pasien yang menerima komersial disiapkan en-
TERAL pemberian susu formula selama 2 tahun. Ia
mengembangkan hiperkalsemia asymp-tomatic dan memiliki
kadar vitamin A serum beberapa kali lipat di atas normal.
Selanjutnya, feed enteral custom-made digunakan yang berisi
jumlah diabaikan vitamin A. Beberapa bulan kemudian, kadar
vitamin A berkurang secara substansial dan kadar serum kalsium
kembali normal.
J Am Diet Assoc. 2005; 105: 119-121.
V itamin A toxicity is a well-described medical condi-tion
with a multitude of potential presenting symp-toms and signs.
Skeletal pain, hair loss, anorexia, pseudotumor cerebri, liver
disease, and psychiatric com-plaints have been described (1).
Hypercalcemia is a rare but known complication of vitamin A
toxicity. This report describes a 74-year-old man receiving
commercially available enteral feeding for 2 years who was
found to have unexplained hypercalcemia with toxic serum levels
of vitamin A. Subsequently, a custom-made enteral for-mula
lacking vitamin A was devised and used for feeding. A gradual
reduction in the vitamin A level was noted, along with
normalization of serum calcium levels. This is the first reported
case of iatrogenic hypervitaminosis A and hypercalcemia
produced by a commercially available
enteral nutrition product.
K. Bhalla is a chief medical resident and instructor,
D. M. Ennis is a member of the teaching faculty in med-icine and
transitional year residency training programs, and E. D. Ennis
is the vice president of medical educa-tion and research, and
program director of the internal medicine residency program,
all at Baptist Health Sys-tem, Birmingham, AL.
Address correspondence to: Karan Bhalla, MD, Bap-tist
Health System, 840 Montclair Rd, Suite 317, Bir-mingham, AL
35213. E-mail: karan.bhalla@bhsala.com
Copyright © 2005 by the American Dietetic
Association.
0002-8223/05/10501-0010$30.00/0 doi:
10.1016/j.jada.2004.10.006
© 2005 by the American Dietetic Association
CASE REPORT
The patient described in this report was initially admitted to our
hospital in June 2001 with multiple cranial nerve palsies and
bilateral lower extremity weakness. On further evaluation
including cerebrospinal fluid analysis, a diagno-sis of Miller-
Fisher variant of Guillain-Barré syndrome was made. Eight days
after admission, the patient suffered re-spiratory arrest secondary
to a bronchial mucous plug and was emergently intubated.
During the arrest, he experi-enced considerable anoxic brain
injury. We were unable to wean him from the ventilator, and
given the poor prognosis for neurologic recovery, a tracheostomy
and percutaneous endoscopic gastrostomy (PEG) were
performed. He subse-quently received Pulmocare enteral formula
(Ross Products, Columbus, OH) via his PEG tube and remained
ventilator-dependent. His corrected serum calcium levels during
this admission ranged between 8.9 and 9.4 mg/dL (serum cal-
cium corrected for albumin level using the formula, cor-rected
calcium serum calcium 0.8 [4 serum albumin]). He was
subsequently discharged to a nursing home, where he received
Pulmocare as continuous enteral feeding.
The patient was then readmitted 2 years later with chief
complaints of fever, pneumonia, and dehydration. At the time of
admission, his corrected serum calcium level was 11.5 mg/dL
(normal 8.5 to 10.3 mg/dL). A systematic evaluation of this
patient’s unexplained hy-percalcemia was undertaken. Initially,
the patient was aggressively hydrated and then diuresed with
intrave-nous furosemide, which enhances calcium excretion by
the kidneys. However, on subsequent evaluation his cor-rected
serum calcium level remained persistently ele-vated, ranging
between 11.2 and 14.5 mg/dL. The patient then received
intravenous pamidronate, a drug that in-hibits bone resorption
and reduces serum calcium levels.
Past medical, social, and family histories were re-viewed. In
addition to his vegetative state, the patient had hypertension,
diabetes mellitus, and chronic kidney disease. His baseline
creatinine clearance was 45 mL/ min. There was no family
history of hypercalcemia, para-thyroid surgery, or living relatives
with symptoms sug-gestive of hypercalcemia. Review of
medications revealed no current or past use of thiazides, lithium,
aluminum, or calcium carbonate– containing antacids or vitamin
A or D supplements; these medications could elevate calcium
levels. Additionally, the patients’ family and staff denied use of
skin emollients containing vitamin A or D, which also can rarely
increase calcium levels.
Intact parathyroid hormone level (PTH) was low at 4 pg/mL
(normal 14 to 72 pg/mL) and phosphorus level was normal at 4.1
mg/dL (normal 2.5 to 4.7 mg/dL). Thyroid-stimulating hormone
level was 5.92 IU/mL (nor-
Journal of the AMERICAN DIETETIC ASSOCIATION
119
mal 0.35 to 5.50 IU/mL), and free T4 was 0.7 ng/dL (normal 0.9
to 1.8 ng/mL). A Cortrosyn (Amphastar Pharmaceuticals Inc,
Rancho Cucamonga, CA) stimula-tion test was performed to
diagnose subclinical adrenal insufficiency, and results were
normal. Multiple myeloma is a common cause of hypercalcemia
in elderly patients, and we excluded this condition by performing
serum and urine immuno-electrophoresis.
The patient underwent a computed tomography scan of his
chest and abdomen that revealed bilateral pleural effusions and
patchy areas of infiltrate within the left upper lobe. Tuberculosis
can occasionally cause hypercal-cemia and reactivation disease
can present in the upper lobe of lungs. To further evaluate the left
upper lobe infiltrate, fiberoptic bronchoscopy was performed,
which revealed extensive purulent secretions. Washings from the
affected lobe were cultured, but no acid-fast bacilli were present.
Additionally, a purified protein derivative skin test result was
negative, essentially ruling out tu-berculosis. A radionuclide
bone scan was performed and revealed increased uptake of the
isotope in the left shoul-der, elbow, and wrist, in both hips, and
also in the pelvis. This pattern was suggestive of a metastatic
malignancy, which could explain the hypercalcemia. A bone
marrow aspirate and biopsy was performed, which revealed nor-
mochromic, normocytic anemia and was negative for
granulomas, acid-fast bacilli, fungi, and hematologic or
metastatic cancer. Additionally, the level of PTH-related protein,
which is elevated in many cancer-associated hy-percalcemia, was
undetectable.
After the above exhaustive search, vitamin levels were
measured. The 25-hydroxy vitamin D level was 21 ng/mL
(normal 8 to 38 ng/mL), and the 1,25-hydroxy vitamin D level
was 10 pg/mL (normal 22 to 67 pg/mL). The serum vitamin A
level was dramatically elevated at 2,347 mg/L (normal 360 to
1,200 mg/L).
During this evaluation, the patient continued to receive
Pulmocare enteral feeding. This formula contains 2,840 IU of
vitamin A per 8 fl oz; thus the patient had been receiving 15,523
IU of vitamin A on a daily basis for the prior 34 months. The
dietary reference intake for vitamin A in adults is 3,000 IU per
day. Subsequently a special enteral feed was devised using the
following ingredients: 60 mL vegetable oil, 300 mL unsweetened
applesauce, 60 mL in-stant mashed potatoes, 300 mL powdered
skim milk, 12 scoops of Promod (Ross Products) and 1,000 mL
of water. This formula provided 1,966 kcal, 102 g protein, and
only 152 IU vitamin A per day. One month later the vitamin A
level had decreased to 2,055 mg/L, but the patient remained
mildly hypercalcemic. He was later discharged from the hospital
and continued to receive the special enteral for-mula at a nursing
home. Two months after the initiation of special enteral feed, the
vitamin A and serum calcium levels normalized. The vitamin A
level was 1,060 mg/L, and the corrected serum calcium level was
9.6 mg/dL.
DISCUSSION
In 1953, Shaw and Niccoli (2) first described hypercalce-mia as a
complication of vitamin A therapy. Since that time, only 10
additional patients have been reported with this unique
association. Hypercalcemia in the setting of vitamin A toxicity
has been described in anecdotal re-ports, and is seen in three
groups of patients. The first
120 January 2005 Volume 105 Number 1
Parathyroid related
Primary hyperparathyroidism
Solitary adenoma
Multiple endocrine neoplasia
Lithium therapy
Familial hypocalciuric hypercalcemia
keganasan terkait
Padat tumor dengan metastasis (payudara)
Padat tumor dengan mediasi humoral dari
hiperkalsemia (paru-paru, ginjal)
keganasan hematologi (multiple myeloma,
limfoma, leukemia)
Terkait dengan gagal ginjal
Parah hiperparatiroidisme sekunder dan tersier
aluminium keracunan
sindrom susu-alkali
Vitamin D terkait
1,25 (OH)2D3 sarkoidosis dan penyakit
granulomatosa lainnya hiperkalsemia idiopatik dari
bayi
insufisiensi adrenal
Terkait dengan pergantian
tulang yang tinggi
hipertiroidisme
imobilisasi
tiazid
Vitamin A keracunan
Angka. Klasifikasi penyebab hiperkalsemia.
kelompok pasien adalah mereka yang menerima terapi asam
retinoat all-trans untuk pengobatan akut promyelocytic leuke-mia
(3). Kelompok kedua adalah pasien hemodialisis yang
mengkonsumsi suplemen gizi yang mengandung dosis pharmaco-
logika vitamin A (4). Lastly, a handful of case reports describe
hypercalcemia in association with inges-tion of massive doses of
vitamin A (5-11). This publication describes the first reported
case of vitamin A toxicity caused by enteral feeding using
commercially available tube-feed formula.
Whenever hypercalcemia is confirmed, a definitive di-agnosis
must be established. The Figure lists the causes of
hypercalcemia, simplified and arranged to reflect com-mon
pathophysiologic mechanisms. Although hyperpara-thyroidism, a
frequent cause of asymptomatic hypercal-cemia, is a chronic
disorder in which disease manifestations, if any, are expressed
only over a matter of months or years, hypercalcemia also can be
the earliest clue to the presence of malignancy, the second-most-
com-mon cause of hypercalcemia in the adult population. Hy-
perparathyroidism and malignancy account for more than 90% of
all cases of hypercalcemia.
The differential diagnosis of hypercalcemia in the pa-tient
described in this article, after careful review, in-cluded
immobilization or vitamin A toxicity. Immobiliza-tion is rarely
associated with hypercalcemia in the absence of associated
disease in adults. The mechanism involves a relative change in
bone turnover rate favoring resorption over bone formation, and
is seen with sudden loss of weight-bearing ability. Thus,
immobilization can cause hypercalcemia only in situations in
which underly-ing diseases associated with high bone turnover,
such as Paget disease, coexist. In this patient, a normal alkaline
phosphate level excluded the diagnosis of Paget disease.
 It is not clear exactly how vitamin A influences bone
metabolism. Increased PTH activity is probably not in-duced by
the vitamin (6). Belanger and colleagues (12) found increased
osteoblastic activity with a definite in-crease in periosteal bone
apposition in rats fed large doses of vitamin A. Tissue culture of
animal bones in the presence of excessive vitamin A has resulted
in marked bone resorption. Vitamin A probably acts directly on
bone to stimulate osteoclastic resorption and/or inhibit osteo-
blastic formation. In certain circumstances, such as im-
mobilization or dehydration, this could result in hyper-calcemia.
Hyperparathyroidism and
malignancy account for more than
90% of all cases of hypercalcemia.
The patient in this report was receiving 2,840 IU of vitamin A
per 8 fl oz of Pulmocare. This is substantially higher compared
with other commonly used formulas, such as Jevity (Ross
Products) 1.5 cal 1,185 IU/8 fl oz, Nepro (Ross Products) 1,000
IU/8 fl oz, and Osmolite (Ross Products) 1,190 IU/8 fl oz.
However, 55% of the vitamin A in Pulmocare is in the form of
beta carotene, which has not been shown to be as toxic as
preformed vitamin A. Thus, our patient was effectively receiving
approximately 7,000 IU of preformed vitamin A per day, which
is considerably higher than the recommended daily maximum.
Previous studies have not shown this level of daily vitamin A
intake to cause hypercalcemia. We pos-tulate that extremely high
dietary intake of the vitamin, in addition to immobilization and
chronic kidney disease, resulted in hypercalcemia in this patient.
Additionally, we have shown a temporal relationship of
decreasing vitamin A levels and resolving hypercalcemia. In the
absence of other etiologies, we think that high dietary intake of
vitamin A, in the setting of immobilization and renal failure, can
cause hypervitaminosis and subsequent hypercalcemia.
All patients described in published literature have had
resolution of their hypercalcemia after withdrawal of vi-tamin A,
as did our patient. Additionally, if needed, ad-ministration of 100
mg cortisone or its equivalent per day leads to rapid
normalization of calcium levels (6). The
nonspecific and protean manifestations of hypervitamin-osis A
involve a wide variety of tissues and systems. Our patient had a
very unusual manifestation, hypercalce-mia. Early recognition of
the syndrome can result in a gratifying response to potentially
critical medical compli-cations.
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