Journal of Pediatric Gastroenterology and Nutrition
`9:400-403 © 1989 Raven Press, Ltd., New York
`
`Case Report
`Hypocalcemia Complicating Deferoxamine Therapy in an
`Infant with Parenteral Nutrition-Associated Aluminum
`Overload: Evidence for a Role of Aluminum in the Bone
`Disease of Infants
`
`Gordon L. Klein, Wayne R. Snodgrass, M. Pamela Griffin, *Naney L. Miller, and
`*Allen C. Alfrey
`
`Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, and *Medic시 and Research
`Services, VA Medical Center, and Department of Medicine, University of Colorado School of Medicine,
`Denver, Colorado, U.S.A,
`
`Summary: Aluminum (Al) contaminates total parenteral
`nutrition (TPN) solutions given to infants, and high levels
`of Al have been demonstrated in their bone, serum, and
`urine. However, it is uncertain whether Al at current lev­
`els of contamination of TPN solutions is harmful to bone.
`We report an 8-month-old infant who developed os-
`teopenic bone disease while receiving TPN, which did not
`respond to large amounts of calcium, phosphate, and vi­
`tamin D?. Serum and urine Al levels were greatly elevated
`and fel| after a short course of deferoxamine. However,
`
`shortly after treatment began, serum calcium levels feH in
`the absence of hypercalciuria. We postulate that chela­
`tion of Al from this patient's bone permitted increased
`bone calcium uptake. This would suggest that Al at cur­
`rent levels of contamination of TPN solutions may impair
`bone calcium uptake and thus contribute to the pathogen­
`esis or exacerbation of TPN-related osteopenia. Key
`Words; Total parenteral nutrition一Aluminum contamina­
`tion——
`
`Aluminum (Al) has been associated with low-
`tumover bone disease in adults receiving chronic
`total parenteral nutrition (TPN) (1,2). In 1985 Sed-
`man and colleagues (3) demonstrated that infants
`receiving intravenous therapy had bone Al levels
`10-fold greater than controls and that the sources of
`Al were primarily calcium and phosphate salts, but
`also heparin and albumin. These findings have sub­
`sequently been confirmed (4). However, it is not
`certain that the quantity of Al inadvertently infused
`during TPN therapy is sufficient to account for the
`bone demineralization seen in infants receiving
`TPN. We report the case of an infant who devel-
`
`Address correspondence and reprint requests to Dr. G. L.
`Klein at Department of Pediatrics, University of Texas Medical
`Branch, Galveston, TX 77550-2776, U.S.A.
`
`oped Al overload while receiving long-term nutri­
`tional support with TPN. Use of deferoxamine to
`treat the Al overload did not result in roentgeno-
`graphic improvement but produced a hypoealcemic
`response, which suggests that Al at current levels of
`contamination of TPN solutions may contribute to
`the bone demineralization complicating TPN treat­
`ment.
`
`CASE REPORT
`
`The patient was an 8-month-old girl bom at 25
`weeks of gestation, weighing 620 g. At 7 weeks she
`developed necrotizing enterocolitis and underwent
`partial bowel resection. She was managed by a
`combination of TPN and enteral feedings but by age
`
`400
`
`1
`
`EXELA 2010
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00086
`
`

`

`ALUMINUM IN INFANT BONE DISEASE
`
`401
`
`4 months necrotizing enterocolitis recurred, this
`time with intestinal perforation. She underwent co­
`lon resection and ileostomy and was treated exclu­
`sively with continuous TPN for 24 h/day. At age 7
`months she was noted to have osteopenia, perios­
`teal resorption, and cupping on x-ray film, sugges­
`tive of rickets (Fig. 1). Results of an initial biochem­
`ical evaluation were compatible with nutritional
`rickets (Table 1).
`The TPN solution contained elemental calcium
`33-36 mg/kg/day, phosphorus 31-40 mg/kg/day,
`copper 30 p,g/kg/day, and vitamin 叫 5(jtg/day. This
`was the maximum amount that could be added to
`the solution without calcium phosphate precipita­
`tion. The patient was given supplemental vitamin
`叫 125 |xg i.m. each week beginning 6 weeks prior to
`diagnosis and therapy for aluminum overload and
`was maintained on this dose throughout her course.
`This was done even though the patient had no bio­
`chemical evidence of vitamin D deficiency because
`of a previous report that rickets occurring in infants
`receiving chronic TPN therapy improved following
`high-dose vitamin D supplementation (5).
`As part of the evaluation, serum Al concentration
`was found to be 182 |xg/L (normal <10 卩g/L) (2) and
`urinary Al/creatinine 0.7 |xg/mg [normal 0.06 士 0,08
`(SD) |xg/mg] (3). The TPN solution initially con­
`tained 229 fxg Al/L, providing the patient with 22
`卩Lg/kg/day. Because of these high Al levels and be­
`cause no additional calcium or phosphate eould be
`added to the TPN solution, she was given deferox­
`amine, an agent used to chelate Al from bone in
`patients with dialysis osteomalacia (6). The purpose
`
`TABLE 1. Initial evaluation of patient with total
`parenteral nutrition-associated metabolic bone disease
`
`Value
`
`Normal range (ref.)
`
`Serum parameter
`Total calcium (mg/dl)
`
`Ionized calcium (mg/dl)
`Phosphorus (mg/dl)
`Magnesium (mg/di)
`Creatinine (mg/이)
`Albumin (g/dl)
`Parathyroid hormone
`(ng/ml) (midregion assay)
`25-Hydroxyvitamin D
`(&/ml)
`
`1,25-Dihydroxyvitamin D
`
`(pg/mi)
`Aluminum (jig/L)
`
`Copper (pLg/dl)
`Urine parameter
`Calcium/creatinine (mg/mg)
`Al/crealinine (pig/mg)
`TmP/GFR* (mg/dl)
`
`8.5
`
`4.82
`3.7
`2.1
`
`0.6
`2.8
`
`3.5
`
`20
`
`150
`182
`121
`
`9.0-11.5
`(with normal albumin)
`4.50-5.50
`4.0-7.0
`1.8-3.0
`
`<1.0
`3.0-5.0
`
`<1
`
`9-52
`
`14-«〇
`<10
`110-175
`
`0.013
`0.70
`3.4
`
`0.12 ± 0.02a (10)
`0.055 ± 0.0460 (3)
`
`4.2-8.0(11)
`
`“ SD.
`b Based on a constant infusion of phosphate per day and no
`
`oral intake.
`
`of this treatment was to attempt to improve the
`bone mineralization. During this therapeutic trial,
`all nutrients came exclusively from TPN.
`
`METHODS
`
`Calcium, phosphorus, and creatinine levels in se­
`rum and urine were analyzed by standard auto­
`mated methods; ionized calcium levels in serum
`were ascertained by ion-selective electrode analysis
`
`FIG. 1. Roentgenograph of femurs, illustrating osteopenia and periosteal resorption.
`
`J Pediatr Gastroenterol Nutr, Vol. 9, No. 3, 1989
`
`2
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`

`

`402
`
`G, L. KLEIN ET AL,
`
`pectedly, total serum calcium levels fell by the
`fourth dose of deferoxamine and reached 6.5 mg/dl
`with serum ionized c이cium 3.95 mg/dl by the be­
`ginning of the third week of therapy (Fig. 2). During
`this time she continued to receive calcium in her
`TPN, 33-36 mg/kg/day, as w이 1 as the phosphorus
`and vitamin D doses mentioned above. Thereafter,
`serum calcium levels fluctuated but remained low.
`Urinary c지cium/creatinine was low initially (Table
`1) (10) and did not change significantly when re­
`peated durin응 week 3, 0.04 mg/mg. Serum levels of
`PTH and 1,25-dihydroxyvitamin D did not change
`from baseline following reevaluation during the
`third week of deferoxamine therapy. Deferoxamine
`therapy was discontinued by week 6 owing to re­
`peated episodes of gram-negative bacterial sepsis
`and difficulty in maintaining central venous cathe­
`ters. No roentgenographic improvement was seen.
`The patient was ultimately discharged, receiving
`parenteral nutrition at home. She subsequently died
`at home and permission for an autopsy was refused.
`
`DISCUSSION
`Our patient developed sustained hypocalcemia in
`response to deferoxamine given to reduce the body
`burden of Al incurred as a result of chronic TPN
`therapy. The cause of the hypocalcemia is uncer­
`tain, but it occurred despite constant calcium infu­
`sion in the TPN solution and sustained elevation of
`serum levels of PT너 and 1,25-dihydroxyvitamin D,
`hormones that should increase bone resorption to
`sustain serum calcium lev이s (11). Urine c이cium
`excretion did not increase during deferoxamine
`therapy and ostomy calcium output was not mea­
`sured. The affinity of deferoxamine for calcium is
`substantially lower than that for aluminum,
`Ka = 1〇2 VS. I〇2* (12). Inasmuch as deferoxamine
`did not increase urinary c이cium excretion and at
`least 70% of deferoxamine is excreted in the urine
`(12), it is unlikely that deferoxamine therapy in­
`creased ostomy calcium excretion. Although uri­
`nary calcium/creatinine may vary over the course of
`a day, the patient received a continuous infusion of
`calcium in the TPN solution and received nothing
`by mouth. Thus, conditions were such as to mini­
`mize any variability that might occur. However, the
`lack of elevated urinary calcium excretion is con­
`sistent with this patient's hyperparathyroidism.
`One can speculate that if calcium excretion was
`not increased, a likely explanation for the low se­
`
`using a Radiometer A-1 electrode. Serum levels of
`magnesium were determined colorimetrically on an
`Ektachem 400 (Kodak, Rochester, NY, U.S.A.)
`and albumin levels were determined by serum pro­
`tein electrophoresis on a cellulose-acetate gradient.
`Serum levels of 25-hydroxy- and 1,25-
`dihydroxyvitamin D were performed at Mayo Med-
`ic시 Laboratories (Rochester, MN, U.S.A.) using
`dual-cartridge extraction and a radioreceptor assay,
`with interassay variations of 10 and 15%, respec­
`tively (7). Analyses of sera for immunoreactive
`parathyroid hormone (PTH) levels were performed
`utilizing an antibody to the midmolecular region,
`with intraassay variation of 5% and interassay vari­
`ation of 10% (8). Aluminum levels were determined
`utilizing flameless atomic absorption spectroscopy
`as previously described (9).
`
`RESULTS
`
`The patient was given deferoxamine 20 mg/kg i.v.
`over 2 h 3 evenings during week 1, but the dose was
`reduced to 10 mg/kg once weekly thereafter. Peak
`serum Al during the first week of therapy was 73
`|xg/L and this level fell over 6 weeks to 26 p,g/L (Fig.
`2). Urine Al/creatinine rose by 〜350% 24 h follow­
`ing each administration of deferoxamine. Unex-
`
`了アノ，匕ソノノノ/ノ///7アフノノノソ Z777ア"ノノノノ•〃アア”7ソ ノノソ ノノノノソ〃アノノノノ ,ノノノノ■〃〃ノノノノノブ〃 KE
`
`； DEFEROXAMINE
`: 20 mg/kgZdose 10 mg/kg
`
` .
`
`〇
`
`2
`
`3
`
`WEEKS OF DEFEROXAMINE
`
`
`
`5
`
`6
`
`E
`
`EC
`
`Ti
`
`E
`
`200
`
`6
`
`100 -
`
`〇
`
`FIG. 2. Serial serum lev이s of cal이um (total and ionized),
`
`albumin, parathyroid hormone (PTH), phosphorus, and alu­
`minum during the course of deferoxamine therapy. Arrows
`indicate days on which deferoxamine was given. Each circle
`represents an individual determination. Normal serum levels
`are defined by the hatched areas.
`
`J Pediatr Gastroenterol Nutr. Vol. 9, No. 3, /989
`
`3
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`

`

`ALUMINUM IN INFANT BONE DISEASE
`
`403
`
`rum calcium would be deposition in the patient's
`demineralized bone, the chief repository of body
`calcium. It is known from previous studies that Al
`accumulates at the mineralization front of bone
`both in infants (4) and in adults (1) receiving TPN
`therapy. Administration of deferoxamine to our pa­
`tient resulted in a significant increase in urinary Al
`and a fall in serum Al. This would suggest chelation
`of Al from bone, one of the major repositories of
`parenterally administered Al (1-5). Chelation of Al
`from bone followed by increased bone calcium de­
`position suggests that Al deposited in bone may im­
`pair bone calcium uptake.
`Reduction of serum calcium has also been de­
`scribed during deferoxamine treatment for AI-
`associated dialysis osteomalacia (6,13-16), includ­
`ing a preliminary report of a series of 51 patients
`(16). Lack of roentgenographic improvement in our
`patient may be explained by a duration of deferox­
`amine therapy of <4 months, the minimum needed
`to show improvement in dialysis patients (6), the
`constant resupply of Al in the TPN solution, and
`lack of adequate provision of calcium and/or phos­
`phate.
`Inadequate provision of calcium and/or phos­
`phate in TPN solutions has been most frequently
`implicated in the pathogenesis of what may well be
`multifactorial metabolic TPN-related bone disease
`in infants (17-19). Lack of calcium and/or phos­
`phate may have been a primary pathogenic factor in
`the bone demineralization observed in our patient.
`However, the amount of Al received by our pa­
`tient in her TPN solution is similar to amounts pre­
`viously reported to result in bone Al accumulation
`in infants 10-fold greater than in normal infants
`(3,4). Thus, Al in amounts currently contaminating
`TPN solutions may contribute to the pathogenesis
`or exacerbation of TPN-related bone disease in in­
`fants.
`
`Acknowledgment: We are grateful to Nancy Alcock,
`Ph.D., Department of Preventive Medicine and Commu­
`nity Health, University of Texas Medical Branch at
`Galveston, for the determination of serum copper con­
`centration and to Wilma Nance and Rosa Jaramillo for
`manuscript preparation.
`
`REFERENCES
`
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`ciated with low bone formation in patients receiving chronic
`
`parenteral nutrition. Ann Intern Med 1983;98:910-4.
`
`2. Klein GL, Alfrey AC, Miller NL, et al. Aluminum loading
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`
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`
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`4
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