PRIMER Metabolic complications

PRIMER

Metabolic complications of parenteral nutrition

in adults, part 2
IMAD F. BTAICHE AND NABIL KHALIDI
Acid–base disturbances
Most acid–base disturbances in
patients receiving PN therapy are re-
lated to the patients’ underlying con-
ditions rather than to the PN compo-
nents. However, excessive chloride
salts in PN solutions may cause met-
abolic acidosis,150 and excessive ace-
tate salts may cause metabolic alkalo-
sis.151 The management of acid–base
disorders relies mainly on correcting
the underlying problem. Altering the
chloride-to-acetate ratio in PN solu-
tions may help to correct minor
acid–base abnormalities. For exam-
ple, because acetate is converted to
bicarbonate at a 1:1 molar ratio, high
acetate levels in PN help correct the
bicarbonate deficit accompanied by
losses from diarrhea and fistulas.
Conversely, increasing the chloride
content of PN may help correct met-
abolic alkalosis, such as occurs in pa-
tients with gastric fluid losses or un-
dergoing diuretic therapy.
Liver complications
The overall frequency of PN-
associated liver complications ranges
from 7.4% to 84%.152 Some 15–40%
Purpose. Common metabolic complica-
tions associated with parenteral nutrition
(PN) are reviewed, and the consequences
of overfeeding and variables for patient
monitoring are discussed.
Summary. Although PN is a lifesaving
therapy in patients with gastrointestinal
failure, its use may be associated with
metabolic, infectious, and technical com-
plications. The metabolic complications
associated with PN in adult patients
include hyperglycemia, hypoglycemia,
hyperlipidemia, hypercapnia, refeeding
syndrome, acid–base disturbances, liver
complications, manganese toxicity, and
metabolic bone disease. These complica-
tions may occur in the acute care or chron-
ic care patient. The frequency and severity
of these complications depend on patient-
and PN-specific factors. Proper assess-
ment of the patient’s nutritional status;
tailoring the macronutrient, micronutri-
ent, fluid, and electrolyte requirements on
the basis of the patient’s underlying dis-
of adult patients receiving long-term
PN therapy may develop end-stage
liver disease.153 The wide variation in
the reported frequency is the result of
heterogeneity in the population
studied, the duration and composi-
eases, clinical status, and drug therapy;
and monitoring the patient’s tolerance of
and response to nutritional support are es-
sential in avoiding these complications.
Early recognition of the signs and symp-
toms of complications and knowledge of
the available pharmacologic and nonphar-
macologic therapies are essential to prop-
er management. PN should be used for
the shortest period possible, and oral or
enteral feeding should be initiated as soon
as is clinically feasible. The gastrointestinal
route remains the most physiologically ap-
propriate and cost-effective way of pro-
viding nutritional support.
Conclusion. PN can lead to serious compli-
cations, many of which are associated with
overfeeding. Close management is neces-
sary to recognize and manage these
complications.
Index terms: Electrolytes; Manganese;
Minerals; Nutrition; Toxicity
Am J Health-Syst Pharm. 2004; 61:2050-9
tion of PN, and the liver complica-
tions reported in the studies.154 Mild
to moderate elevation of liver en-
zymes is commonly seen within two
weeks after starting PN,155,156 but liver
enzymes return to normal after PN is

IMAD F. BTAICHE, PHARM.D., BCNSP, is Clinical Assistant Professor, MI 48109-0008 (imadb@umich.edu).

Department of Clinical Sciences, College of Pharmacy, University
of Michigan (UM), and Clinical Pharmacist, University of Michi-
gan Hospitals and Health Centers (UMHHC), Ann Arbor. NABIL
KHALIDI, PHARM.D., FASHP, is Clinical Associate Professor, Depart-
ment of Clinical Sciences, College of Pharmacy, UM, and Associate
Director of Pharmacy Services, UMHHC.
Address correspondence to Dr. Btaiche at the Department of Phar-
macy Services, University of Michigan Hospitals and Health Centers,
UH B2 D301, Box 0008, 1500 East Medical Center Drive, Ann Arbor,
This is article 204-000-04-010-H01 in the ASHP Continuing Edu-
cation System; it qualifies for 3.0 hours of continuing-education
credit. See page 2058 or http://ce.ashp.org for the learning objectives,
test questions, and instructions.
Part 1 of this article appeared in the September 15, 2004, issue.
Copyright © 2004, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/04/1001-2050$06.00.

2050 Am J Health-Syst Pharm—Vol 61 Oct 1, 2004


discontinued.157 With long-term PN,
severe liver complications may oc-
cur, such as steatosis, steatohepatitis,
cholestasis, and cholelithiasis. Al-
though PN-associated cholestasis
and hepatic steatosis can coexist, ste-
atosis is more common in adults,
while cholestasis is more common in
children. Distinctive histopathologi-
cal findings have been described in
patients with PN-associated liver
dysfunction. These include peripor-
tal inflammation, bile duct prolifera-
tion, portal bridging, canalicular and
intralobular cholestasis, pigmented
Kupffer cells, pseudoacinar forma-
tion, portal–portal bridging, fatty
droplets, pericellular and portal fi-
brosis, and cirrhosis.158,159
Hepatic steatosis and steatohepa-
titis. The administration of excessive
carbohydrate calories can cause he-
patic steatosis and steatohepatitis.
Hepatic steatosis describes fat accu-
mulation in the hepatocytes, essen-
tially in the form of triglycerides and
cholesterol esters.160 Steatohepatitis is
an advanced liver disease that is
marked by severe hepatic inflamma-
tion that may rapidly progress to liv-
er fibrosis and cirrhosis.161 Fat accu-
mulation in the liver is the result of
an imbalance between liver fat syn-
thesis and secretion.162,163 Although
hepatic steatosis is primarily the re-
sult of excessive dextrose infusion,164
other factors may also contribute, in-
cluding lipid overfeeding42 and defi-
ciencies in specific nutrients, such as
carnitine,165,166 choline,167,168 and es-
sential fatty acids.169,170 Patients with
hepatic steatosis are mostly asymp-
tomatic. However, steatosis should
be suspected when hepatomegaly,
malaise, and abdominal discomfort
occur.152
Dextrose and lipid balance. Glu-
cose conversion to fat or de novo li-
pogenesis is presumably the result of
an increased insulin:glucagon ratio in
response to dextrose overfeeding.171
Excess calories157,172 and an imbal-
ance in the carbohydrate:lipid ratio173
can both cause hepatic steatosis in
PRIMER
PN patients. Hepatic steatosis oc-
curred in 53% of patients who re-
ceived only dextrose infusions, com-
pared with 17% of patients who
received mixed lipid and dextrose so-
lutions (30% and 70% of nonprotein
calories, respectively).173 Accumula-
tion of fat in the liver was also report-
ed in patients who received amino
acid and carbohydrate mixtures, but
not in patients whose PN also includ-
ed lipid emulsions.174 In isolated case
reports, patients who received lipid-
free PN developed hepatic steatosis,
possibly as a result of essential fatty
acid deficiency. Hepatic steatosis re-
solved following lipid supplementa-
tion.169,170 However, the role of fatty
acid deficiency in the development of
steatosis remains uncertain, since
fatty liver occurs even with adequate
lipid supplementation. Nonetheless,
excessive lipid infusion should be
avoided, as it may also cause hepatic
steatosis. Fat overload syndrome
characterized by hypertriglyceri-
demia, fever, hepatosplenomegaly,
coagulopathy, and multiorgan dys-
function occurred with lipid emul-
sion dosages of >4 g/kg/day.175,176
These dosages, however, exceeded
the maximum recommended lipid
dosages of 1 g/kg/day in adults and 3
g/kg/day in children.
Carnitine deficiency. The role of
carnitine deficiency in the pathogen-
esis of hepatic steatosis is less clear.
Carnitine is an amine that transports
LCTs across the mitochondrial
membrane for oxidation. The im-
provement in fat metabolism with
carnitine supplementation has led to
the suggestion that carnitine plays a
role in mobilizing hepatic lipid
stores and thus could prevent steato-
sis. In animal studies, carnitine sup-
plementation reduced liver fat accu-
mulation.177 In humans, carnitine
deficiency is mostly described in pre-
mature neonates because of their lim-
ited carnitine stores and their
reduced ability to synthesize car-
nitine from methionine and lysine.178
Carnitine deficiency is rare in adults,
Am J Health-Syst Pharm—Vol 61 Oct 1, 2004
Metabolic complications
because carnitine is ubiquitous in the
diet. One severely cachectic patient
developed carnitine deficiency that
was associated with elevated liver en-
zymes, hepatomegaly, and steatosis;
the problems responded to carnitine
supplementation.179 Carnitine sup-
plementation has also been reported
to prevent alcohol-induced hepatic
steatosis.180 Carnitine is not routinely
included in PN formulations. Car-
nitine supplementation in PN has
been shown to enhance ketogenesis
and fat metabolism in infants,181 re-
duce hepatocyte fatty infiltration,165
and reverse hyperbilirubinemia.166
However, the effects of carnitine in
preventing PN-associated liver toxic-
ity have not been replicated in other
studies. Although carnitine supple-
mentation for one month normal-
ized plasma and liver carnitine levels
in patients receiving PN, it did not
improve hepatic steatosis.182
Choline deficiency. The role of
choline deficiency in the pathogene-
sis of hepatic steatosis is also incon-
clusive. Choline, a quaternary amine
that is ubiquitous in the diet and is
derived in vivo from methionine me-
tabolism, is essential in the synthesis
of phospholipids and other compo-
nents of cell membranes. Phosphati-
dylcholine is a byproduct of choline
and is a substrate in lipoprotein syn-
thesis. It has been proposed that re-
duced phosphatidylcholine synthesis
as a result of choline deficiency leads
to abnormal lipoprotein production
and promotes triglyceride accumula-
tion in the liver, causing hepatocyte
distortion.183,184 Because choline is
present in most foods, choline defi-
ciency is rare. Although the methion-
ine precursor is supplied in the ami-
no acid mix in PN, choline deficiency
has been reported in patients receiv-
ing long-term PN therapy.167,168 This
is possibly due to methionine being
metabolized differently when given
intravenously rather than enteral-
ly.185 So far, limited data on the ef-
fects of choline supplementation in
reversing steatosis in PN recipients
2051
 PRIMER Metabolic complications
are available.168,186 A pilot study of 15
adult patients with hepatic steatosis
receiving PN at home found that in-
travenous choline chloride supple-
mentation at 2 g/day for up to 24
weeks was safe and effective in reduc-
ing the degree of hepatic steatosis.187
More research is still needed to clari-
fy the role of choline in liver disease
and to support any recommendation
for routine choline supplementation
in PN. Studies are under way to test
the role of choline supplementation
in preventing and treating PN-
associated liver disease in adults.185
Hepatic steatosis and steatohepati-
tis. Hepatic steatosis can be reversed if
a portion of the carbohydrates is re-
placed by lipid calories.188,189 In one
study, replacing one third of carbo-
hydrate calories in PN with lipid calo-
ries resulted in a 50% reduction in in-
sulin secretion and improved glucose
control. 190 Avoiding carbohydrate
overfeeding lowers insulin levels and
minimizes the extent of carbohydrate
conversion to fat in the liver.188 Mon-
itoring liver function during PN is
recommended. However, liver en-
zymes may not be sensitive indica-
tors of hepatic steatosis, since they
correlate poorly with the degree of
fatty infiltration.191 Avoiding over-
feeding and providing a balanced PN
regimen are essential in preventing
hepatic steatosis. A balanced PN reg-
imen should provide 20–30% of total
calories from lipids, 50–60% from
dextrose, and the remaining 10–20%
from amino acids.
Cholelithiasis. PN-associated
cholelithiasis is the result of de-
creased gallbladder contractility dur-
ing fasting. In the absence of oral in-
take or enteral stimulation, there is
decreased secretion of cholecystoki-
nin (CCK), a peptide hormone se-
creted in the duodenum in response
to meals that induces gallbladder
contractility. A distended gallbladder
and an absence of gallbladder con-
tractions were reported in patients
receiving PN during prolonged fast-
ing, but not in enterally fed pa-
2052 Am J Health-Syst Pharm—Vol 61 Oct 1, 2004
tients.192 Bile accumulation in the
biliary tract facilitates cholesterol
gallstone formation193 and calcium
bilirubinate precipitation in a form
of sludge.194 Biliary sludge, gallstones,
and hyperviscous and tenacious bile
were found during surgical proce-
dures to relieve refractory cholestasis
in PN-dependent patients.195,196
Patients with short-bowel syn-
drome are at increased risk of
cholelithiasis and biliary sludge.197
This is due to several factors, includ-
ing impaired bile flow during fast-
ing, disrupted enterohepatic cycling
with ileal resection, and canalicular
accumulation of toxic bile compo-
nents, such as lithocholic acid.198,199
Twenty-three percent of patients
who received PN for a mean of 13.5
months developed cholecystitis and
gallstones.200 Gallbladder complica-
tions were significantly more fre-
quent among PN recipients with
ileal disease (Crohn’s disease or con-
ditions requiring ileal resection)
(40%) than among patients without
ileal disease (25%). Among the pa-
tients with ileal disease, acalculous
and calculous cholecystitis occurred
in 32% of PN recipients, compared
with 6% of a series of similarly de-
fined patients who did not receive
PN. Prolonged fasting, ileal disease
and resection, and the use of narcot-
ics and anticholinergics were corre-
lated with an increased risk of gall-
bladder complications. The duration
of PN therapy was not, however,
correlated with the occurrence of
gallbladder disease.
The best approach to preventing
cholelithiasis is early initiation of
oral or enteral feeding, even in small
amounts, to stimulate CCK secre-
tion, bowel motility, and gallbladder
emptying. Cholecystectomy may be
indicated in patients with cholecysti-
tis. Injections of cholecystokinin
octapeptide (CCK-OP) to induce
gallbladder contractions and reduce
biliary sludge have yielded mixed re-
sults and caused gastrointestinal in-
tolerance in some patients. 201,202
Treatment or prophylaxis with CCK-
OP is uncommon and requires fur-
ther evaluation.
Cholestasis. PN-associated chole-
stasis (PNAC) is less common in
adults than in children. Factors pre-
disposing patients to PNAC include a
long duration of PN, overfeed-
ing,161,203 short-bowel syndrome,204,205
bowel rest, bacterial transloca-
tion,203,206 and frequent sepsis.207 Lim-
ited data have also implicated excess
methionine,208 phytosterols in lipid
emulsions,209 and taurine deficiency
(in children)210 in causing liver inju-
ry, but their effects remain uncertain.
Patients with PNAC may show
increased serum liver aminotrans-
ferase, alkaline phosphatase, bili-
rubin, and γ -glutamyltransferase
levels. 211,212 An elevated alkaline
phosphatase concentration is com-
mon in patients with PNAC and in-
dicates biliary-tract damage. Howev-
er, alkaline phosphatase may also be
elevated in bone disease and is
not a sensitive or specific marker of
liver disease. Although elevated se-
rum bilirubin is uncommon early in
PN in adult patients, long-term PN
may be associated with increased
bilirubin when cholestasis occurs. A
serum conjugated bilirubin concen-
tration of ≥2 mg/dL is considered
the most sensitive marker of cho-
lestasis. Jaundice may also occur, de-
pending on the severity of the
clinical presentation.213
PNAC is reversible if PN is dis-
continued before irreversible liver
damage occurs. The underlying dis-
order requiring bowel rest and re-
sulting in a lack of gut stimulation
that made PN a necessity is a major
predisposing factor for cholestasis.
Bowel rest leads to increased intesti-
nal permeability,214 alteration in gut
hormone secretion,215 reduction in
bile flow, decreased excretion of bile
salts, bacterial overgrowth, bacterial
and endotoxin translocation from
the gut, and impaired intestinal im-
munologic mechanisms. 216,217 Be-
cause of the detrimental effects of

bowel rest, early initiation of enteral
or oral feedings and weaning the pa-
tient from PN seem best to prevent
PNAC.204 Other methods of prevent-
ing PNAC include avoiding over-
feeding,87 using balanced sources of
calories,218 cyclic PN infusion,219 and
avoiding or treating sepsis.207
Pharmacologic measures can also
be undertaken to prevent PNAC, im-
prove bile flow, provide symptomat-
ic relief of cholestasis, and reduce the
toxic insult to the liver. Ursodiol has
been shown to improve bile flow and
reduce the clinical signs and symp-
toms of cholestasis.220 However, at 6–
15 mg/kg/day, ursodiol yielded
mixed and limited results. Ursodiol
is available only in an oral dosage
form, and its absorption may be lim-
ited in patients with intestinal resec-
tions. Also, the beneficial effects of
ursodiol at usual dosages may be less
than adequate to displace the toxic
bile acids that are believed to accu-
mulate and cause liver injury. CCK-
OP has been used investigationally in
infants to induce gallbladder con-
traction and improve bile flow.221,222
This approach reduced serum biliru-
bin levels and improved the clinical
signs of cholestasis. However, experi-
ence with CCK-OP therapy in adults
is limited, and its long-term effects
on the liver are unknown.
Oral antibiotics, such as metro-
nidazole, gentamicin, and neomycin,
have been used to reduce intesti-
nal bacterial overgrowth during
prolonged bowel rest and in short-
bowel-syndrome patients. Treating
bacterial overgrowth reduces the
population of bacteria translocating
across the intestinal wall and the pro-
duction of hepatotoxic endotox-
ins.223 Patients with short-bowel syn-
drome and end-stage liver disease
may benefit from combined liver and
bowel transplantation. Early referral
of short-bowel-syndrome patients at
high risk of liver complications for
bowel transplantation may be an op-
tion before irreversible liver damage
occurs.224
PRIMER
Manganese toxicity
Manganese is a trace element that
serves as a coenzyme in multiple
chain reactions and is required for
mucopolysaccharide production and
cartilage, bone, and connective tissue
formation. The recommended dos-
age of manganese supplementation
has ranged from 0.08 to 0.5 mg/day.
Typically, manganese is supplied in
the PN solution at a daily dose of 0.5
mg as part of a multiple-trace-
element additive. Since manganese is
primarily eliminated via biliary ex-
cretion, patients with biliary obstruc-
tion or cholestasis may accumulate
manganese to potentially toxic lev-
els.225,226 Manganese accumulation
has been mainly reported to cause
neurotoxicity, especially in cholestat-
ic patients receiving PN.225,227,228 A
possible association between manga-
nese accumulation and liver toxicity
has also been suggested.229
Neurotoxicity is the most com-
monly reported toxicity of manga-
nese accumulation in patients receiv-
ing PN. Magnetic resonance imaging
(MRI) revealed deposition of manga-
nese in the basal ganglia of PN-
dependent patients.230 Patients who
showed neurologic abnormalities
with high blood manganese levels
had brain abnormalities on MRI im-
aging.231 Reported neurologic symp-
toms related to manganese toxicity
included parkinsonian symptoms,
including muscle rigidity, tremor,
gait, and mask-like facies,232 as well as
neuropsychiatric disorders, such as
headache,233 confusion, somnolence,
and weakness. 234 The neurologic
signs and symptoms were reversed
after manganese was removed from
the PN solution.233,235
The effects of manganese on the
liver are less clear. It has been postu-
lated that manganese may cause
hepatotoxicity by affecting the biliary
canalicular membrane. 236,237 Al-
though a correlation was found be-
tween elevated blood manganese
concentrations and increased liver
enzymes, there is no firm evidence
Am J Health-Syst Pharm—Vol 61 Oct 1, 2004
Metabolic complications
that hypermagnesemia causes cho-
lestasis.238,239 In one study of children
who received PN for more than two
weeks, a significant correlation was
found between whole-blood manga-
nese concentrations and elevated
plasma aspartate aminotransferase
and bilirubin levels.229 Manganese
and bilirubin levels decreased after
reduction or discontinuation of
manganese supplementation. On the
other hand, another study showed
no significant difference in the fre-
quency of cholestasis between two
groups of infants who received either
large or small amounts of manganese
in PN.240 However, blood manganese
concentrations were not measured in
all infants in the study.
Patients with hypermagnesemia
may or may not exhibit signs and
symptoms of manganese toxicity.
Abnormally elevated serum manga-
nese levels have been reported in pa-
tients receiving long-term home PN
without noticeable symptoms of tox-
icity.241 Since hypermagnesemia may
occur even in the absence of cho-
lestasis, it is possible that the current
practice of manganese supplementa-
tion in PN at 0.5 mg/day may exceed
the daily requirement or that PN ad-
ditives may be a possible source of
manganese contamination.242,243 To
date, no clear relationship has been
established between blood manga-
nese levels and neurologic or liver
abnormalities. Also, whole-blood or
serum manganese levels may not
necessarily reflect tissue stores. 226
Nonetheless, periodic measurements
of blood manganese concentrations
provide a safety tool for monitoring
manganese status. Restricting man-
ganese in cholestatic patients receiv-
ing PN is warranted to prevent its
accumulation.
Metabolic bone disease
Metabolic bone disease, including
osteomalacia, osteopenia, and os-
teoporosis, has been reported in pa-
tients receiving long-term PN.244,245
The actual frequency of metabolic
2053
 PRIMER Metabolic complications
bone disease in PN patients is un-
known, but reports suggest that 40–
100% of patients receiving long-term
PN may have some degree of bone
demineralization. Many patients
with metabolic bone disease are
asymptomatic, and the diagnosis is at
times incidental. Symptomatic pa-
tients have bone pain, back pain, and
fractures. Radiologic techniques
commonly used in diagnosing bone
disease include bone mineral density
testing and quantitative computed
tomography.246 Biochemical markers
of metabolic bone disease may in-
clude increased serum alkaline phos-
phatase levels, low to normal plasma
parathyroid hormone (PTH) levels,
hypercalcemia, hypocalcemia, hyper-
calciuria, normal serum 25-hydrox-
yvitamin D levels, and low serum
1,25-dihydroxyvitamin D levels.247,248
PN-related factors that predispose
patients to metabolic bone disease
include deficiencies of calcium,
phosphorus, and vitamin D249,250; vi-
tamin D toxicity251; aluminum toxic-
ity252,253; and amino acid and hyper-
tonic dextrose infusions. 245 Other
non-PN-related factors, such as cor-
ticosteroid therapy and metabolic ac-
idosis, may contribute to bone loss.
Corticosteroids inhibit bone forma-
tion and cause osteoporosis by re-
ducing osteoblast proliferation and
type I collagen synthesis, increasing
renal calcium excretion, and inhibit-
ing vitamin D-dependent calcium
absorption.254,255 Chronic metabolic
acidosis may cause bone demineral-
ization by affecting the bone buffer-
ing systems or impairing vitamin D
metabolism.256
Calcium deficiency. Calcium de-
ficiency in PN recipients is a major
cause of metabolic bone disease. Hy-
pocalcemia occurs as a result of de-
creased calcium intake or increased
urinary calcium excretion or both.
Solubility problems with calcium
and phosphate limit the amounts of
calcium and phosphorus that can be
supplemented with PN and still
avoid calcium and phosphate precip-
2054 Am J Health-Syst Pharm—Vol 61 Oct 1, 2004
itation. Factors that cause hypercalci-
uria include excessive calcium and
inadequate phosphorus supplemen-
tation,257 amino acids in PN solu-
tions,258 cyclic PN infusion,259 and
chronic metabolic acidosis.256
Several studies have correlated
amino acid intake with urinary calci-
um excretion.248,258,260 In one study,
mean ± S.D. urinary calcium elimi-
nation increased from 287 ± 46 mg/
day to 455 ± 58 mg/day when amino
acids were increased from 1 to 2 g/
kg/day.260 Although the exact mecha-
nism of protein-induced hypercalci-
uria is unknown, it could be related
to an increased glomerular filtration
rate or increased excretion of sul-
fates, ammonia, and urinary titrat-
able acidity that decreases renal
calcium reabsorption. Alternatively,
acidosis may contribute to bone loss.
In renally impaired patients who de-
veloped osteomalacia with chronic
hyperchloremic metabolic acidosis,
treatment with oral bicarbonate re-
sulted in improvement in the signs
and symptoms of bone disease.256
Adequate amounts of acetate and
chloride should be provided in PN
solutions to maintain a normal acid–
base balance. Patients with short-
bowel syndrome who have signifi-
cantly elevated lactic acid levels also
developed osteomalacia, bone pain,
and bone fractures, which led to the
conclusion that lactic acidosis in
these patients could have contribut-
ed to metabolic bone disease.261
Cyclic PN infusion has also been
shown to increase urinary calcium
losses. In one study, urinary calcium
excretion increased by 18% and 28%
when PN was infused over 18 or 12
hours, respectively, compared with
24-hour PN infusion.259 About 80%
of urinary calcium loss occurred dur-
ing PN cycling that resulted in a neg-
ative calcium balance. However, an-
other study showed that, although
urinary calcium excretion increased
during cyclic PN infusion, total mean
daily urinary calcium excretion was
not significantly affected.258
Aluminum toxicity. Aluminum
toxicity causes osteomalacia in pa-
tients receiving long-term PN thera-
py.262 Excess aluminum is mainly
found as a contaminant of multivita-
min, trace-element, and calcium and
phosphate salt products.263 Because
the kidneys are the main route of alu-
minum elimination, premature in-
fants with inefficient kidney function
and patients with renal failure are at
higher risk of aluminum toxicity.
Aluminum may exert its toxic effects
on the bones by impairing calcium
bone fixation,262 reducing PTH secre-
tion, or inhibiting the conversion of
25-hydroxyvitamin D to the active
1,25-dihydroxyvitamin D. 253,263,264
FDA has been investigating the alu-
minum contamination problem of
intravenous products since 1986. In
2000, FDA issued a rule specifying
acceptable aluminum concentrations
in large-volume intravenous prod-
ucts. The rule states that for large-
volume intravenous products used in
PN, the package insert section under
“precautions” should indicate that
the product contains aluminum at a
concentration no higher than 25 µg/
L. Because the toxic effects of alumi-
num occur at the microgram level,
FDA has defined a possible safe up-
per limit for parenteral aluminum
intake as <4–5 µg/kg/day.265 Adher-
ing to these limits requires an exten-
sive effort by manufacturers to re-
duce aluminum contamination in
the intravenous products used in the
making of PN solutions.
Vitamin D toxicity. Typical
vitamin D supplementation in adult
PN solutions is 200 IU/day. It has
been suggested that vitamin D in the
multivitamin mix added to the PN
solution may be toxic to the bones.
The withdrawal of vitamin D from
PN was associated with improve-
ment in the clinical and biochemical
indices of bone demineralization in
PN-dependent patients. Also, posi-
tive calcium balance,266 subsidence of
bone pain, fracture healing, and de-
creased calciuria and phosphaturia251

occurred after vitamin D removal. A
two-year follow-up examination of
patients for whom vitamin D was
withheld from PN formulations
showed normal bone histomor-
phometry despite a reduction in se-
rum 25-hydroxyvitamin D concen-
trations.251 Withdrawal of vitamin D
from PN for 4.5 years also resulted in
improvement in mineral content
in the lumbar vertebrae and normal-
ization of serum PTH and 1,25-
dihydroxyvitamin D concentra-
tions.267 Although vitamin D toxicity
has been suggested as a cause of met-
abolic bone disease, vitamin D defi-
ciency also results in bone loss. To
date, data on vitamin D excess and
bone disease remain controversial. It
has been suggested that a trial course
of vitamin D omission from PN solu-
tions may be warranted in PN recipi-
ents who show reduced serum
1,25-dihydroxyvitamin D and PTH
concentrations and normal serum 25-
hydroxyvitamin D concentrations.267
Prevention and treatment. To
prevent metabolic bone disease in
patients receiving PN, it is essential
to provide sufficient calcium and
phosphorus to improve bone miner-
alization.268,269 Although removal of
vitamin D from PN solutions has
been suggested for selected patients,
the role of vitamin D in causing bone
disease at the current dosage of 200
IU/day is inconclusive. Also, it is im-
practical for compounding pharma-
cies to remove vitamin D from the
intravenous multivitamin mix. Rou-
tine monitoring of serum vitamin D,
calcium, and phosphorus levels is
recommended. However, insofar as
aluminum is concerned, pharmacy
policies should be established to reg-
ularly monitor aluminum levels in
PN solutions. PN recipients with sus-
pected metabolic bone disease
should have their serum aluminum
concentrations measured to rule out
aluminum toxicity.
Theoretically, the use of bisphos-
phonates is a potential but unproven
therapy for metabolic bone disease,
PRIMER
although they are used to decrease
bone resorption in postmenopausal
osteoporosis. Patients undergoing
long-term PN therapy should be en-
couraged to perform regular low-
intensity exercises that may help in-
crease lumbar spine bone density.
Patients receiving home PN therapy
should receive bone-density mea-
surements yearly and whenever met-
abolic bone disease is suspected.246
Conclusion
PN can lead to serious metabolic
complications, many of which are as-
sociated with overfeeding. Close
monitoring is necessary to recognize
and manage these complications.
References
150. Richards CE, Drayton M, Jenkins H et al.
Effect of different chloride infusion rates
on plasma base excess during neonatal
parenteral nutrition. Acta Paediatr.
1993; 82:678-82.
151. Eliahou HE, Feng PH, Weinberg U et al.
Acetate and bicarbonate in the correc-
tion of uraemic acidosis. BMJ. 1970;
4:399-401.
152. Kelly DA. Liver complications of pediat-
ric parenteral nutrition—epidemiology.
Nutrition. 1998; 14:153-7.
153. Chan S, McCowen KC, Bistrian BR et al.
Incidence, prognosis, and etiology of
end-stage liver disease in patients receiv-
ing home parenteral nutrition. Surgery.
1999; 126:28-34.
154. Btaiche IF, Khalidi N. Parenteral
nutrition-associated liver complications
in children. Pharmacotherapy. 2002;
22:188-211.
155. Grant JP, Cox CE, Kleinman LM et al.
Serum hepatic enzyme and bilirubin ele-
vations during parenteral nutrition. Surg
Gynecol Obstet. 1977; 145:573-80.
156. Nanji AA, Anderson FH. Sensitivity
and specificity of liver function tests in
the detection of parenteral nutrition-
associated cholestasis. J Parenter Enteral
Nutr. 1985; 9:307-8.
157. Sheldon GF, Petersen SR, Snaders R. He-
patic dysfunction during hyperalimenta-
tion. Arch Surg. 1978; 113:504-8.
158. Payne-James JJ, Silk DB. Hepatobiliary
dysfunction associated with total
parenteral nutrition. Dig Dis. 1991;
9:106-24.
159. Baker AL, Rosenberg IH. Hepatic com-
plications of total parenteral nutrition.
Am J Med. 1987; 82:489-97.
160. Zamir O, Nussbaum MS, Bhadra S et al.
Effect of enteral feeding on hepatic ste-
atosis induced by total parenteral nutri-
tion. JPEN J Parenter Enteral Nutr. 1994;
18:20-5.
Am J Health-Syst Pharm—Vol 61 Oct 1, 2004
Metabolic complications
161. Powell EE, Cooksley WG, Hanson R et
al. The natural history of nonalcoholic
steatohepatitis: a follow-up study of
forty-two patients for up to 21 years.
Hepatology. 1990; 11:74-80.
162. Fong DG, Nehra V, Lindor K et al. Meta-
bolic and nutritional considerations in
nonalcoholic fatty liver. Hepatology.
2000; 32:3-10.
163. Hall RI, Grant JP, Ross LH et al. Patho-
genesis of hepatic steatosis in the
parenterally fed rat. J Clin Invest. 1984;
74:1658-68.
164. Lowry SF, Brennan MF. Abnormal liver
function during parenteral nutrition: re-
lation to infusion excess. J Surg Res.
1979; 26:300-7.
165. Palombo JD, Schnure F, Bistrian BR et
al. Improvement of liver function tests
by administration of L-carnitine to a car-
nitine-deficient patient receiving home
parenteral nutrition: a case report. J
Parenter Enteral Nutr. 1987; 11:88-92.
166. Worthley LI, Fishlock RC, Snoswell AM.
Carnitine deficiency with hyperbiliru-
binemia, generalized skeletal muscle
weakness and reactive hypoglycemia in a
patient on long-term total parenteral
nutrition: treatment with intravenous
L -carnitine. J Parenter Enteral Nutr.
1983; 7:176-80.
167. Sheard NF, Tayek JA, Bistrian BR et al.
Plasma choline concentrations in hu-
mans fed parenterally. Am J Clin Nutr.
1986; 43:219-24.
168. Buchman AL, Dubin MD, Moukarzel
AA et al. Choline deficiency: a cause of
hepatic steatosis during parenteral nutri-
tion that can be reversed with intrave-
nous choline supplementation. Hepatol-
ogy. 1995; 22:1399-403.
169. Richardson TJ, Sgoutas D. Essential fatty
acid deficiency in four adult patients
during total parenteral nutrition. Am J
Clin Nutr. 1975; 28:258-63.
170. Reif S, Tano M, Oliverio R et al. Total
parenteral nutrition-induced steatosis:
reversal by parenteral lipid infusions.
JPEN J Parenter Enteral Nutr. 1991;
15:102-4.
171. Li S, Nussbaum MS, Teague D et al. In-
creasing dextrose concentrations in total
parenteral nutrition (TPN) causes alter-
ations in hepatic morphology and plas-
ma levels of insulin and glucagon in rats.
J Surg Res. 1988; 44:639-48.
172. Campos AC, Oler A, Meguid MM et al.
Liver biochemical and histological
changes with graded amounts of total
parenteral nutrition. Arch Surg. 1990;
125:447-50.
173. Zagara G, Locati L. Role of total
parenteral nutrition in determining liver
insufficiency in patients with cranial in-
juries. Glucose vs glucose + lipids. Min-
erva Anestesiol. 1989; 55:509-12.
174. Tulikoura I, Huikuri K. Morphological
fatty changes and function of the liver,
serum free fatty acids, and triglycerides
during parenteral nutrition. Scand J Gas-
troenterol. 1982; 17:177-85.
175. Kollef MH, McCormack MT, Caras WE
2055
 PRIMER Metabolic complications
et al. The fat overload syndrome: suc-
cessful treatment with plasma exchange.
Ann Intern Med. 1990; 112:545-6.
176. Heyman MB, Storch S, Ament ME. The
fat overload syndrome. Report of a case
and literature review. Am J Dis Child.
1981; 135:628-30.
177. Tao RC, Peck GK, Yoshimura NN. Effect
of carnitine on liver fat and nitrogen bal-
ance in intravenously fed growing rats. J
Nutr. 1981; 111:171-7.
178. Schmidt-Sommerfeld E, Penn D. Car-
nitine and parenteral nutrition of the
neonate. Biol Neonate. 1990; 58(suppl
1):81-8.
179. Karpati G, Carpenter S, Engel AG et al.
The syndrome of systemic carnitine defi-
ciency. Clinical, morphologic, biochem-
ical, and pathophysiologic features. Neu-
rology. 1975; 25:16-24.
180. Sachan DS, Rhew TH, Ruark RA. Ame-
liorating effects of carnitine and its pre-
cursors on alcohol-induced fatty liver.
Am J Clin Nutr. 1984; 39:738-44.
181. Helms RA, Mauer EC, Hay WW et al.
Effect of intravenous L-carnitine on
growth parameters and fat metabolism
during parenteral nutrition in neonates.
J Parenter Enteral Nutr. 1990; 14:448-53.
182. Bowyer BA, Miles JM, Haymond MW et
al. L-carnitine therapy in home parenter-
al nutrition patients with abnormal liver
tests and low plasma carnitine concen-
trations. Gastroenterology. 1988; 94:434-
8.
183. Lombardi B, Pani P, Schlunk FF.
Choline-deficiency fatty liver: impaired
release of hepatic triglycerides. J Lipid
Res. 1968; 9:437-46.
184. Yao ZM, Vance DE. The active synthesis
of phosphatidylcholine is required for
very low density lipoprotein secretion
from rat hepatocytes. J Biol Chem. 1988;
263:2998-3004.
185. Buchman AL. Choline deficiency during
parenteral nutrition in humans. Nutr
Clin Pract. 2003; 18:353-8.
186. Buchman AL, Dubin M, Jenden D et al.
Lecithin increases plasma free choline
and decreases hepatic steatosis in long-
term parenteral nutrition patients. Gas-
troenterology. 1992; 102(4, pt. 1):1363-
70.
187. Buchman AL, Ament M, Sohel M et al.
Choline deficiency causes reversible he-
patic abnormalities in patients receiving
parenteral nutrition: proof of a human
choline requirement: a placebo-
controlled trial. JPEN J Parenter Enteral
Nutr. 2001; 25:260-8.
188. Nussbaum MS, Li S, Bower RH et al.
Addition of lipid to total parenteral nu-
trition prevents hepatic steatosis in rats
by lowering the portal venous insulin/
glucagon ratio. JPEN J Parenter Enteral
Nutr. 1992; 16:106-9.
189. Buzby GP, Mullen JL, Stein TP et al. Ma-
nipulation of TPN caloric substrate and
fatty infiltration of liver. J Surg Res. 1981;
31:46-54.
190. Meguid MM, Akahoshi MP, Jeffers S et
al. Amelioration of metabolic complica-
2056 Am J Health-Syst Pharm—Vol 61 Oct 1, 2004
tions of conventional total parenteral
nutrition. A prospective randomized
study. Arch Surg. 1984; 119:1294-8.
191. Sax HC, Talamini MA, Brackett K et al.
Hepatic steatosis in total parenteral nu-
trition: failure of fatty infiltration to cor-
relate with abnormal serum hepatic en-
zyme levels. Surgery. 100:697-704.
192. Jawaheer G, Pierro A, Lloyd DA et al.
Gall bladder contractility in neonates: ef-
fects of parenteral and enteral feeding.
Arch Dis Child. 1995; 72:F200-2.
193. Gurll NJ, Meyer PD, DenBesten L. The
effect of cholesterol crystals on gallblad-
der function in cholelithiasis. Surg Fo-
rum. 1977; 28:412-3.
194. Allen B, Bernhoft R, Blanckaert N et al.
Sludge is calcium bilirubinate associated
with bile stasis. Am J Surg. 1981; 141:51-
6.
195. Cooper A, Ross AJ, O’Neill JA et al. Res-
olution of intractable cholestasis associ-
ated with total parenteral nutrition fol-
lowing biliary irrigation. J Pediatr Surg.
1985; 20:772-4.
196. Rintala R, Lindahl H, Pohjavuori M et al.
Surgical treatment of intractable
cholestasis associated with total
parenteral nutrition in premature in-
fants. J Pediatr Surg. 1993; 28:716-9.
197. Caniano DA, Starr J, Ginn-Pease ME.
Extensive short-bowel syndrome in neo-
nates: outcomes in the 1980s. Surgery.
1989; 105:119-24.
198. Hofmann AF. Defective biliary secretion
during total parenteral nutrition: proba-
ble mechanisms and possible solutions. J
Pediatr Gastroenterol Nutr. 1995; 20:
376-90.
199. Palmer RH, Ruban Z. Production of bile
duct hyperplasia and gallstones by litho-
cholic acid. J Clin Invest. 1966; 45:1255-
67.
200. Roslyn JJ, Pitt HA, Mann LL et al. Gall-
bladder disease in patients on long-term
parenteral nutrition. Gastroenterology.
1983; 84:148-54.
201. Sitzman JV, Pitt HA, Steinborn PA et al.
Cholecystokinin prevents parenteral nu-
trition induced biliary sludge in humans.
Surg Gynecol Obstet. 1990; 170:25-31.
202. Doty JE, Pitt HA, Porter-Fink V et al.
Cholecystokinin prophylaxis of par-
enteral nutrition-induced gallbladder
disease. Ann Surg. 1985; 201:76-80.
203. Colomb V, Goulet O, Rambaud C et al.
Long-term parenteral nutrition in chil-
dren: liver and gallbladder disease.
Transplant Proc. 1992; 24:1054-5.
204. Cavicchi M, Beau P, Crenn P et al. Prev-
alence of liver disease and contributing
factors in patients receiving home
parenteral nutrition for permanent in-
testinal failure. Ann Intern Med. 2000;
132:525-32.
205. Ito Y, Shils ME. Liver dysfunction asso-
ciated with long-term total parenteral
nutrition in patients with massive bowel
resection. JPEN J Parenter Enteral Nutr.
1991; 15:271-6.
206. Pierro A, van Saene HK, Donnell SC et
al. Microbial translocation in neonates
and infants receiving long-term
parenteral nutrition. Arch Surg. 1996;
131:176-9.
207. Beath SV, Davies P, Papadopoulou A et
al. Parenteral nutrition-related cholesta-
sis in postsurgical neonates: multivariate
analysis of risk factors. J Pediatr Surg.
1996; 31:604-6.
208. Moss RL, Haynes AL, Pastuszyn A et al.
Methionine infusion reproduces liver
injury of parenteral nutrition cholesta-
sis. Pediatr Res. 1999; 45:664-8.
209. Clayton PT, Whitfield P, Iyer K. The role
of phytosterols in the pathogenesis of
liver complications of pediatric
parenteral nutrition. Nutrition. 1998;
14:158-64.
210. Cooper A, Betts JM, Pereira GR et al.
Taurine deficiency in the severe hepatic
dysfunction complicating total parenter-
al nutrition. J Pediatr Surg. 1984; 19:462-
5.
211. Beale E, Nelson R, Bucciarelli R et al.
Intrahepatic cholestasis associated with
parenteral nutrition in premature in-
fants. Pediatrics. 1979; 64:342-7.
212. Benjamin DR. Hepatobiliary dysfunc-
tion in infants and children associated
with long-term total parenteral nutri-
tion: a clinico-pathologic study. Am J
Clin Pathol. 1981; 76:276-83.
213. Vileisis RA, Inwood RJ, Hunt CE. Lab-
oratory monitoring of parenteral
nutrition-associated hepatic dysfunction
in infants. J Parenter Enteral Nutr. 1981;
5:67-9.
214. Deitch EA, Winterton J, Li M et al. The
gut as a portal of entry for bacteremia.
Role of protein malnutrition. Ann Surg.
1987; 205:681-92.
215. Aynsley-Green A. Plasma hormone con-
centrations during enteral and parenter-
al nutrition in the human newborn. J
Pediatr Gastroenterol Nutr. 1983; 2(sup-
pl 1):S108-12.
216. Alverdy JC, Aoys E, Moss GS. Total
parenteral nutrition promotes bacterial
translocation from the gut. Surgery.
1988; 104:185-90.
217. Go LL, Healy PJ, Watkins SC et al. The
effect of endotoxin on intestinal mucosal
permeability to bacteria in vitro. Arch
Surg. 1995; 130:53-8.
218. Buchmiller CE, Kleiman-Wexler RL,
Ephgrave KS et al. Liver dysfunction and
energy source: results of a randomized
clinical trial. JPEN J Parenter Enteral
Nutr. 1993; 17:301-6.
219. Hwang TL, Lue MC, Chen LL. Early use
of cyclic TPN prevents further deteriora-
tion of liver functions for the TPN pa-
tients with impaired liver function.
Hepatogastroenterology. 2000; 47:1347-
50.
220. Hofmann AF. Pharmacology of ursode-
oxycholic acid, an enterohepatic drug.
Scand J Gastroenterol. 1994; 29(suppl
204):1-15.
221. Rintala RJ, Lindahl H, Pohjavuori M.
Total parenteral nutrition-associated
cholestasis in surgical neonates may be
reversed by intravenous cholecystokinin:

a preliminary report. J Pediatr Surg.
1995; 30:827-30.
222. Teitelbaum DH, Han-Markey T,
Schumacher RE. Treatment of
parenteral nutrition associated
cholestasis with cholecystokinin-
octapeptide. J Pediatr Surg. 1995; 30:
1082-5.
223. Vanderhoof JA, Langnas AN, Pinch LW
et al. Short bowel syndrome. J Pediatr
Gastroenterol Nutr. 1992; 14:359-70.
224. Beath SV, Needham SJ, Kelly DA et al.
Clinical features and prognosis of chil-
dren assessed for isolated small bowel or
combined small bowel and liver trans-
plantation. J Pediatr Surg. 1997; 32:459-
61.
225. Taylor S, Manara AR. Manganese toxici-
ty in a patient with cholestasis receiving
total parenteral nutrition. Anaesthesia.
1994; 49:1013. Letter.
226. Hambidge KM, Sokol RJ, Fidanza SJ et
al. Plasma manganese concentrations in
infants and children receiving parenteral
nutrition. J Parenter Enteral Nutr. 1989;
13:168-71.
227. Reynolds P, Kiely E, Meadows N. Man-
ganese in long term paediatric parenteral
nutrition. Arch Dis Child. 1994; 71:527-
8.
228. Alves G, Thiebot J, Tracqui A et al. Neu-
rologic disorders due to brain manga-
nese deposition in a jaundiced patient
receiving long-term parenteral nutri-
tion. JPEN J Parenter Enteral Nutr. 1997;
21:41-5.
229. Fell JM, Reynolds AP, Meadows N et al.
Manganese toxicity in children receiving
long-term parenteral nutrition. Lancet.
1996; 347:1218-21.
230. Kafrista Y, Fell J, Long S et al. Long term
outcome of brain manganese deposition
in patients on home parenteral nutri-
tion. Arch Dis Child. 1998; 79:263-5.
231. Takagi Y, Okada A, Sando K et al. On-off
study of manganese administration to
adult patients undergoing home
parenteral nutrition: new indices of in
vivo manganese level. JPEN J Parenter
Enteral Nutr. 2001; 25:87-92.
232. Fitzgerald K, Mikalunas V, Rubin H et
al. Hypermanganesemia in patients re-
ceiving total parenteral nutrition. JPEN J
Parenter Enteral Nutr. 1999; 23:333-6.
233. O’Donnell K, Radigan A. Hypermanga-
nesemia in an acute care setting. Nutr
Clin Pract. 2003; 18:374-6.
234. Nagatomo S, Umehara F, Hanada K.
Manganese intoxication during total
parenteral nutrition: report of two cases
and review of the literature. J Neurol Sci.
1999; 162:102-5.
235. Mirowitz SA, Westrich TJ. Basal ganglial
signal intensity alterations: reversal after
discontinuation of parenteral manga-
nese administration. Radiology. 1992;
185:535-6.
236. Plaa GL, De Lamirande E, Lewittes M et
al. Liver cell plasma membrane lipids in
manganese-bilirubin-induced intrahe-
patic cholestasis. Biochem Pharmacol.
1982; 31:3698-701.
PRIMER
237. Ayotte P, Plaa GL. Hepatic subcellular
distribution of manganese in manganese
and manganese-bilirubin induced
cholestasis. Biochem Pharmacol. 1985;
34:3857-65.
238. Alastair F, Jawhari A. Manganese toxici-
ty and parenteral nutrition. Lancet. 1996;
347:1774. Letter.
239. Jawhari A, Ong C, Wood S et al. Hyper-
manganesemia and TPN: a cause for
cholestasis? Gastroenterology. 1995;
108:A732. Abstract.
240. Beath SV, Gopalan S, Booth IW. Manga-
nese toxicity and parenteral nutrition.
Lancet. 1996; 347:1773-4.
241. Siepler JK, Nishikawa RA, Diamantidis
T et al. Asymptomatic hypermagne-
semia in long-term home parenteral nu-
trition patients. Nutr Clin Pract. 2003;
18:370-3.
242. Kurkus J, Alcock NW, Shils ME. Manga-
nese content of large-volume parenteral
solutions and of nutrient additives. J
Parenter Enteral Nutr. 1984; 8:254-7.
243. Pluhator-Murton MM, Fedorak RN,
Audette RJ et al. Trace element contami-
nation of component solutions. JPEN J
Parenter Enteral Nutr. 1999; 23:228-32.
244. The TS, Kollee LA, Boon JM et al. Rick-
ets in a preterm infant during intrave-
nous alimentation. Acta Pediatr Scand.
1983; 72:769-71.
245. Kien CL, Browning C, Jona J et al. Rick-
ets in premature infants receiving
parenteral nutrition: a case report and
review of the literature. J Parenter Enter-
al Nutr. 1982; 6:152-6.
246. Buchman AL, Moukarzel A. Metabolic
bone disease associated with total
parenteral nutrition. Clin Nutr. 2000;
19:217-31.
247. Shike M, Shils ME, Heller A et al. Bone
disease in prolonged parenteral nutri-
tion: osteopenia without mineralization
defect. Am J Clin Nutr. 1986; 44:89-98.
248. De Vernejoul MC, Messing B,
Modrowski D et al. Multifactorial low
remodeling bone disease during cyclic
total parenteral nutrition. J Clin Endo-
crinol Metab. 1985; 60:109-13.
249. Prestridge LL, Schanler RJ, Shulman R et
al. Effect of parenteral calcium and
phosphorus on mineral retention and
bone mineral content in very low birth
weight infants. J Pediatr. 1993; 122:761-
8.
250. Leape LL, Valaes T. Rickets in low birth
weight infants receiving total parenteral
nutrition. J Pediatr Surg. 1976; 11:665-
74.
251. Shike M, Sturtridge WC, Tam CS et al. A
possible role for vitamin D in the genesis
of parenteral nutrition-induced meta-
bolic bone disease. Ann Intern Med.
1981; 95:560-8.
252. Koo WW, Kaplan LA, Horn J et al.
Aluminum on parenteral nutrition
solution—sources and possible alterna-
tives. J Parenter Enteral Nutr. 1986;
10:591-5.
253. Ott SM, Maloney NA, Klein GL et al.
Aluminum is associated with low bone
Am J Health-Syst Pharm—Vol 61 Oct 1, 2004
Metabolic complications
formation in patients receiving chronic
parenteral nutrition. Ann Intern Med.
1983; 98:910-4.
254. Adler RA, Rosen CJ. Corticosteroids and
osteoporosis. Endocrinol Metab Clin
North Am. 1994; 23:655-70.
255. Lukert BP, Raisz LG. Glucocorticoid-
induced osteoporosis: pathogenesis and
management. Ann Intern Med. 1990;
112:352-64.
256. Cunningham J, Fraher LJ, Clemens TL et
al. Chronic acidosis with metabolic bone
disease. Am J Med. 1982; 73:199-204.
257. Larchet M, Garabedian M, Bourdeau A
et al. Calcium metabolism in children
during long-term total parenteral nutri-
tion: the influence of calcium, phospho-
rus, and vitamin D intakes. J Pediatr
Gastroenterol Nutr. 1991; 13:367-75.
258. Lipkin EW, Ott SM, Chesnut CH III.
Mineral loss in the parenteral nutrition
patient. Am J Clin Nutr. 1988; 47:515-23.
259. Wood RJ, Bengoa JM, Sitrin MD et al.
Calciuric effect of cyclic versus continu-
ous total parenteral nutrition. Am J Clin
Nutr. 1985; 41:614-9.
260. Bengoa JM, Sitrin MD, Wood RJ et al.
Amino acid-induced hypercalciuria in
patients on total parenteral nutrition.
Am J Clin Nutr. 1983; 38:264-9.
261. Karton MA, Rettmer R, Lipkin EW et al.
D-lactate and metabolic bone disease in
patients receiving long-term parenteral
nutrition. J Parenter Enteral Nutr. 1989;
13:132-5.
262. Vargas JH, Klein GL, Ament ME et al.
Metabolic bone disease of total parenter-
al nutrition: course after changing from
casein to amino acids in parenteral solu-
tions with reduced aluminum content.
Am J Clin Nutr. 1988; 48:1070-8.
263. Koo WW, Kaplan LA, Bendon R et al.
Response to aluminum in parenteral nu-
trition during infancy. J Pediatr. 1986;
109:883-7.
264. Klein GL. Metabolic bone disease of to-
tal parenteral nutrition. Nutrition. 1998;
14:149-52.
265. Food and Drug Administration. Alumi-
num in large and small volume
parenterals used in total parenteral nu-
trition. Fed Regist. 2000; 65:4103-11.
266. Shike M, Harrison JE, Sturtridge WC et
al. Metabolic bone disease in patients re-
ceiving long-term total parenteral nutri-
tion. Ann Intern Med. 1980; 92:343-50.
267. Verhage AH, Cheong WK, Allard JP et
al. Increase in lumbar spine bone miner-
al content in patients on long-term
parenteral nutrition without vitamin D
supplementation. JPEN J Parenter Enter-
al Nutr. 1995; 19:431-6.
268. Sloan GM, White DE, Brennan MF. Cal-
cium and phosphorus metabolism dur-
ing total parenteral nutrition. Ann Surg.
1983; 197:1-6.
269. Wood RJ, Sitrin MD, Cusson GJ et al.
Reduction of total parenteral nutrition-
induced urinary calcium loss by increas-
ing the phosphorus in the total parenter-
al nutrition prescription. J Parenter
Enteral Nutr. 1986; 10:188-90.
2057