SPECIAL REPORTS AND REVIEWS Hepatobiliary Complications of Total Parenteral Nutrition EAMONN
M. M. QUIGLEY,*
JON L. SHAFFER,*
*Section of Digestive Diseases and Nutrition, Department of Internal Medicine, and “Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska: and *Division of Gastroenterology, Department of Medicine, Manchester University School of Medicine, Hope Hospital, Salford, England
The relationships between various hepatobiliary disorders and the administration of total parenteral nutrition (TPN) were reviewed and, in particular, the role of TPN in their pathogenesis was critically evaluated. Several clinical and pathological entities including steatosis, steatohepatitis, cholestasis, and cholelithiasis have been commonly linked to TPN, and instances of chronic decompensated liver disease have been reported. However, it is concluded that it is often difficult to extricate the effects of TPN on hepatobiliary function from many other hepatotoxic factors that may be operative in these patients. Thus, whereas considerable evidence exists to support a role fro carbohydrate or calorie excess in TPN solutions in the pathogenesis of steatosis, a loss of enteric stimulation and not TPN per se may be the primary factor in the development of cholestasis, biliary sludge, and gallstones. The apparent predilection of infants to TPN-related cholestasis may be based on the relative immaturity of the neonatal biliary excretory system.
steatosis The third
on the other.
on the newappear
and on adults
The first two appear
on one hand
to be the
to be common
TPN-Related Hepatic Dysfunction in Adults Most studies that have attempted to define the incidence of hepatic dysfunction in adults receiving TPN
have relied primarily
in a selected
minority’5~‘6~‘8~‘“~23; only a few
most of the patients studied.17*24,33 Though enzyme abnormalities were certainly
he advent of total parenteral nutrition (TPN) has independent survival of permitted long-term many infants and adults with intestinal failure.’ With
25% to 100%. This may be due, first, to the fact that
of the requirements
elements, and advances in catheter design and placement techniques, the metabolic and septic complications
problems recede, the specter of serious TPN-related hepatic dysfunction and disease has emerged to haunt those who care for these patients.5-12 The delineation of TPN-related liver disease and the definition of its incidence continue to be hampered by the frequent presence in these patients of other conditions, which of themselves may be associated with disordered hepatic function.‘3,‘4 Considerable evidence from both clinical studies ments to suggest a role for a number of disorders of
has accrued, nevertheless, in man and animal experiTPN in the pathogenesis of the liver and biliary system
mon in all studies,
the data are not consistent,
different populations were being dominated by “surgical” by
levels has varied
studied; some series cases,24,26,30 and others
ease.22*23,27,29,31 Several series included
a highly heterog-
enous patient population,‘5-‘s*23*28 rendering interpretation near impossible given the known influence of such factors as pre-existing hepatic dysfunction,20J”~30 sepsis,3o and the presence of cancer*’ or Crohn’s disease3’ on the incidence of liver enzyme abnormalities during TPN. Second, the composition of TPN solutions has changed considerably over the past 20 years. Of considerable relevance to liver injury has been the Abbreviations used in this paper: TPN, total parenteral nutrition. 0 1993 by the American Gastroenterological Association 0016~5085/93/$3.00
HEPATOBILIARY COMPLICATIONS OF TPN
Table 1. Hepatobiliary
Disorders Reported in Patients on TPN
Adults Steatosis Steatohepatitis Cholestasis Fibrosis Micronodular cirrhosis Phospholipidosis Biliary sludge Chole/ithiasis and its complications Acalculous cholecystitis Infants Cholestasis Fibrosis Cirrhosis Hepatocellular carcinoma Biliary sludge Abdominal pseudotumor (distended Cholelithiasis and its complications
these authors suggested that steatosis was an early, often transient effect of TPN with cholestasis ing later and usually persisting
as long as TPN
the many complicating
actual relationship histological
to the clinical
study has provided important
ized, controlled patients
on the true
frequency of “liver test” abnormalities
NOTE. The more common disorders are italicized.
differences34 render extrapo-
patients who frequently
indirect and circumstantial. have provided considerable
insights into the pathophysiology
what is the
abnormalities ? For many clinical
tions, evidence remains Though animal models
of TPN to these biochemical
in one group of
receive TPN. In this random-
trial, 61.5% of those carefully matched inflammatory
ceived TPN developed elevated serum levels of biliru-
overall reduction in total calories supplied coupled with the introduction of lipid solutions as a standard
bin and/or liver enzymes compared with only 6.2% of
those who received enteral nutrition.31
of TPN formulations.22-31
The time course of these enzyme abnormalities
been more consistent; peak enzyme levels usually occurring between 1 and 4 weeks following initiation of TPN.‘5~17*20~21~26*2”-31 Various that
dase 28,30,31alanine transaminase, 15,18,23aspartate trans-
were not, however,
steatosis, cholestasis, mains undefined.
figured more prominently
appear to be non-
specific; transaminase and alkaline phosphatase elevations are more indicative of either steatosis or cholestasis, respectively.
is less common,
occurring between 0%28 and 46%.16 Enzyme elevations are usually mild and often transient, and most series report either a fall or an actual normalization elevated
TPN-Related Hepatlc Dysfunction in Infants hepatic complication
and the frequency
or other pathologic
amit5ase,29 and alkaline phosphatase16,17v22*32 are the most sensitive indicators of TPN-related hepatic Though
steatosis has been the most common of TPN in adults, cholestasis
in children.5,35-56 Because
the principal indication for TPN has been the short bowel syndrome, due either to congenital abnormalities or necrotizing
ing TPN have been young infants. Indeed, reports of hepatic complications of TPN have been virtually confined to low birth weight, premature infants. The precise incidence of hepatic dysfunction in this population remains poorly defined and has varied from as low as 7.4%54 to as high as 84%.46 The interpretation of
these findings suggest that elevated liver
the pediatric literature
is similarly complicated
enzymes should not be interpreted as evidence of permanent hepatic dysfunction or histological damage,
frequent assumption, dence, that abnormal
often without supportive evienzyme or bilirubin levels are
few studies have correlated
indicative of dysfunction and/or damage. In one large study from the 1970’s, Postuma et al. described an elevation of bilirubin within 2 weeks of initiating TPN in 34% of 92 mostly preterm infants44,
enzyme changes with ei-
ther formal tests of hepatic synthetic or excretory function on the one hand or histological change on the other. The possibility that at least some of these instances of liver enzyme elevations may simply reflect enzyme induction cannot, therefore, be dismissed. In those studies in which a liver biopsy was included, the predominant hepatic histological abnormality in patients with elevated enzymes was steatosis.‘5-‘8,24,33 In two studies, biopsies were performed at
elevations of alkaline phosphatase and serum glutamic oxaloacetic transaminase were observed usually after 4 to 6 weeks in a similar percentage. The most prominent feature on liver biopsy was cholestasis. Within approximately 4 weeks of discontinuation of TPN, liver tests had returned to normal in most infants. In a
Bell et al., who
as a serum
dL, noted a much lower incidence
level 2 1.5 mg/
lestasis of 7.4% among 624 infants.54 Cholestasis was detected in almost two thirds of these cases within 14 days of initiating within
the first week.54 The definition
with the primary
or bile acids
the high mortality disease
in these infants
is less well-defined than that in adults. Available dence suggests that cholestasis, once developed, sists as long as TPN
content.67*68 They concentrations hepatic which,
that the infusion and amino
and the synthesis
in fatty acid oxidation.“8
in turn, promoted
a direct corre-
of total calories
in the liver. In a series
et al. showed
the rate-limiting If, in addition,
is a relative carbohydrate-to-nitrogen imbalance caused by either inadequate or mis-matched amino acid content
of the infusion,63,69-7’
in rats fed both lipidTPN
Hall et al. have
suggest that the develop-
ries are converted
Clinical-Pathological Syndromes of TPN-Related Hepatobiliary Dysfunction
effects of excess calories
sis may be impaired
form of dextrose or glucose and an impairment in the hepatic secretion of triglyceride.‘0~“~‘6~17~2’~24*26~57-68
most other studies have relied on hyperbil-
levels of gamma may
lar or centrilobular.‘5-‘8,24,33
cholestasis, the highest incidence rates being from highly selected autopsy series.38,43,46 irubinemia,
tosis, fat deposition
was less striking,
in those rats administered TPN solutions that included lipid. These authors further suggested that lipid supplementation
incidence appears to have decreased with the addition to TPN solutions of lipid as a calorie source accompa-
fatty acid oxidation, and increasing peripheral tissue triglyceride lipolysis. 6’ Although this concept has been supported by some clinical observations in man,57,72
inflammation, cholestasis, or hepatocyte necrosis was a common occurrence during administration of TPN to adults (Figure 1). 6,‘0,“,‘6-‘9,24,33 Although its
nied by an associated reduction in the amount of glucose or dextrose infused,24T26 steatosis remains the most frequently documented pathological correlate of abnormal liver enzymes in relation to TPN in adults. ‘5-‘8*24,33Even in patients with striking enzyme elevations, steatosis may be the sole pathological abnormality.29 Clinically, steatosis is rarely symptomatic, although occasionally it has been reputed to cause right upper quadrant discomfort and hepatic tenderness. Modest elevations of transaminases, accompanied less frequently by elevated alkaline phosphatase and bilirubin levels, are the biochemical correlates of steatosis; peak enzyme levels occur within 2 weeks of beginning TPN and can usually be expected to return to normal despite continuation of the same infusion. On histological examination, fat accumulation is initially periportal in distribution; with more severe stea-
lipid supplementation zyme abnormalities.73 Further trose-based
may prevent uptake,
trial failed to show any effect of on the frequency for an effect
comes from the studies of Li et al. By adding glucagon, which inhibits fatty acid synthesis and enhances hepatic release of fatty acids, to TPN solutions, they prevented the development of steatosis in their rat mode1.66 Several other components of dextrose-based TPN solutions have been incriminated in the pathogenesis of steatosis and include the induction of essential fatty acid”” and carnitine deficiency,78-85 impaired hepatic drug oxidation,*” and the absence of an as yet uncharacterized, water-soluble “protective factor” present in the normal diet (Table 2).65,80,87
HEPATOBILIARY COMPLICATIONS OF TPN
Figure 1.. Photomicrograph of liver showing macrovasicular steatosis and hepatocellular ballooning, which developed dunng TPN in an infant (H&E; original magnification X50).
The development could, and
lead to impaired
in association deficient
acid deficiency genesis
as well as lipidthat
does not play a major role in the patho-
As will be discussed
in an animal a relationship
zymes, histological steatosis, concentration of lithocholic
The balance of evidence indicates benign, reversible and nonprogressive
to the pathogenesis tion”’ and steatosis
cent study has failed to show a significant in hepatic
TPN patients following administration of carnitine, despite normalization of plasma carnitine levels.” Steatosis
may also result from lipid excess,63*9s96 be-
cause provision of more than 50% of calories as lipid may cause direct deposition of exogenous fatty acids in the liver. Recently Grant and Snyder have provided evidence to suggest that the addition of L-glutamine to TPN solutions may not only prevent the intestinal mucosal atrophy associated with the loss of oral intake but may also inhibit TPN-related steatosis.97 Li et al., confirming this protective effect of L-glutamine on the development of steatosis related to the infusion of hypertonic dextrose solutions, suggested that this effect was
inappropriate to the steatosis
and an increased biliary acid.” The relevance of
primary carnitine deficiency and steatosis,” it has been proposed that carnitine deficiency may also be relevant
et al. have
this observation to TPN-related remains to be determined?
Given the important role of carnitine in lipid metabolism’” and of the documented association between
of TPN-related hepatic dysfuncin particular.78-85 However, a re-
may also be mediated
that steatosis consequence
to the delivery
load in a manner
that may accompany
is a of of an
Several modifications to TPN solutions have resulted in a significant fall in the incidence of steatosis. This seems to have been achieved
to the patient’s required energy needs and by using balanced glucose, amino acid, and lipid solutions, which include 10%30% of nonprotein calories in the form of lipid.
Cholestasis Histological examination of liver biopsies taken early in the course of TPN-related cholestasis in infants revealed mild-to-severe, principally centrilobular, cholestasis with little evidence of inflammation or necrosis and no evidence of fat accumulation (Figure 2). Individual hepatocytes showed mild-to-moderate
2. Patient Factors and TPN-Related Effects Proposed to Contribute
to the Pathophysiology
on TPN TPN Effects
Cholestasis in children
Gallbladder disease and gallstones
with an increase
Starvation Protein-calorie malnutrition Glucose intolerance
Calorie excess Carbohydrate excess Carbohydrate-nitrogen
Immaturity of biliary secretory system Absence of oral intake (loss of enteric stimulation) Sepsis Major surgery (especially GI) Disturbed enterohepatic circulation Small intestinal bacterial overgrowth Hypoxia Absence of oral intake (loss of enteric stimulation) Sepsis lleal disease or resection Short bowel syndrome Inflammatory bowel disease Malignant disease Bacterial overgrowth Lithocholate toxicity Fasting -+ loss of enteric stimuli + gallbladder stasis and impaired bile flow
Amino acid excess Prolonged duration
in cytoplasmic 46,48*49Dahms
logical features of TPN-associated cholestasis may be confused with neonatal hepatitis, extrahepatic biliary obstruction, and biliary atresia.49 Electron-microscopic features have included increased mitochondrial size, dilated rough endoplasmic reticulum, the presence of collagen fibers in the space of Disse, and glassy homogenous material in hepatocyte cytoplasm. 39*49The latter was thought to represent proteinaceous fluid within hypertrophied and confluent smooth endoplasmic reticulum. The elucidation of the pathogenesis of cholestasis in
Low energy-to-nitrogen ratio Contrnuous administration Bacterial translocation L-glutamine deficiency Copper in TPN solubon Lipid Content Lithocholate toxicity
samples featured scattered foci of hepatocyte necrosis and bile duct proliferation; no evidence of fat accumulation was seen. These authors stressed that the histo-
Essential fatty acid deficiency Carnitine deficiency lmparred drug oxidation Absence of dietary “protective factor” L-glutamine deficiency Lipid excess Serine deficiency Methionine deficiency Taurine deficiency Selenium, Vitamin E deficiency TPN contaminants (sodium bisulphite, aluminum) Bacterial translocation L-glutamine deficiency Lithocholate toxicity
one half of the biopsy
Minor or controversial
in 11 infants
of their jaundice revealed severe cholestasis accompanied by portal inflammation and mild portal and perifibrosis.
glycogen and and Halpin
who developed jaundice within 1.5 and 3 weeks after beginning TPN.49 Biopsy samples taken at the height
the frequent such as sepsis, small
it does appear
certain factors are consistently associated with a high incidence of TPN-related cholestasis (Table 2). These include
low birth weight, sepsis, a failure to
initiate oral nutrition, and the presence of gastrointestinal conditions that require surgery. 7,36,37,41,43,45,47,49-56,100-103 Based on multivariate analyses of their large data set, Bell et al. noted that the development of cholestasis was also associated with intracranial hemorrhage and the presence of a patent ductus arteriosus.54 They suggested that this relationship was based on the hypoxia common to both of these conditions.54 The high incidence of TPN-related cholestasis in the very young may be based on the physiology of bile secretion in the neonate. In premature infants bile salt pool size, synthesis, and intestinal concentration are all low in comparison to full term infants,io4 suggesting a relative immaturity of the biliary secretory system. In immature animals, hepatic mitochondrial function
Figure 2. Photomicrograph of liver showing intracellular and canalicular cholestasis, which developed during prolonged TPN. (H&E; original magnification X50).
may also be more sensitive perturbations,
including TPN.“’ Together,
work of Vileisis et al. who compared the effects of two
effect of amino
iological factors may set the stage for the development
logical expression may then be precipitated constituents prolonged monal
not only by
of TPN solutions but also by the effects of fasting
and neural stimulation
tion9”*lo3 and by coexistent
by decreased of hepatic
sepsis. “I6 Loss of oral intake is a common,
though not inevita-
ble accompaniment of TPN administration in this age group. As will be reviewed later, this factor alone, through its effects on bile flow and secretion, major factor in TPN-related
may be a
It is in this
only in protein
in 82 in-
that the inci-
dence of cholestasis was directly related to the volume of amino acids infused. They noted, first, that cholestasis was observed only in infants who received TPN for longer than 2 weeks and, second, that the interval to onset of jaundice was shorter and the peak bilirubin level higher in those infants receiving
the TPN solu-
the higher protein content (3.6 tion with g-kg-‘. day-’ vs. 2.3 g. kg-’ - day-‘).loo Brown et al. have recently proposed that avoidance of amino acidcontaining
context that there has been a common failure to make a distinction between hepatobiliary pathology associated
mature neonates.io3 While these studies invoked protein or amino acid
with TPN and directly related to TPN.
excess, others pointed to a role for deficiencies of specific amino acids in the pathogenesis of cholestasis.
loss of enteral stimulation
The primacy of a over direct TPN toxicity is,
of course, difficult to establish in humans; trials com-
namely Travasol (Travenol Canada Inc., Mississauga, Ontario) and Vamin (Pharmacia Canada Inc., Dorval,
flaunted as conclusive
evidence of direct TPN hepato-
toxicity, cannot, by their very nature, resolve this issue. With regard to the role of TPN solutions per se, animal studies have implicated amino acids in the induction of cholestasis.‘02~‘07-‘09 Studies of Black et al. in the human neonate suggested an early, direct, and independent effect of amino acid infusions on the hepatocyte canalicular membrane.“’ Further support for
used amino acid solutions,
Quebec), Belli et al. observed impaired bile flow only in rats administered Travasol.“’ Furthermore, cholestasis could be reversed by the addition of serine, a standard constituent of Vamin.“’ They concluded, therefore, that the inclusion of methyl donor amino acids such as serine (or, perhaps, methionine112) in TPN formulations protects against cholestasis. Others have proposed a role for taurine deficiency
acid in the mature
or in the adult,
sumes this status in the preterm levels of activity sulfinic
tation in both
and taurine Its benefits
been shown to impair bile flow and induce cholestasis in animals.12’ Enhanced colonic absorption of lithocholate tween
has also been postulated.“” lithocholate-induced
also been emphasized.
The similarities damage
changes three studies
have also been incrimistudies
et al. have
aluminum, as a TPN contaminant, in the etiology of cholestasis.140 However, these mechanisms are unlikely to be relevant to modern TPN solutions. Recently, jaundice and cholestasis have been reported in a change
in lipid emulsion;
4 adult patients
these effects were mediated
by the differences
the two emulsions
to be related Sheldon
et al. found
whereas steatosis was almost universal in those with abnormal biopsies within 5 days of beginning TPN, cholestasis and periportal inflammation were more
pathogenesis of cholestasis. Manginello and Javitt suggested that the occurrence of cholestasis in infants on TPN was related not to the duration of administration or composition of TPN solutions but rather to the presence of sepsis. 45 The similarity of the light and electron-microscopic appearances of TPN-associated liver disease to that associated with endotoxin have also been pointed out, 133 but until recently there was little convincing evidence of portal endotoxemia in association with TPN. Recent studies suggest TPN may impair intestinal mucosal immunity’34 and
15*17,‘8,23,27 and tends
The pathogenesis TPN
ministration did not prevent the development of abnormal liver enzymes in rats on TPN.13’ Others have
caused by TPN-related selenium.131,‘32
both by strucand by the devel-
suggested that cholestasis and hepatocellular may be related to peroxidative free radical
the latter.136 Gluta-
loss of oral intake
lipid particle size, or lecitchin would not be defined.14’
reported a decreased incidence of TPN-related hepatic dysfunction in patients who were pretreated with either oral metronidazole127-12* or gentamicin.129 In a animal
an effect on gut immunity.
cells. 139This schema whereby
not only to attenuate
and leads to an in-
plasia 13* but also to prevent TPN-related depletion of Immunoglobulin (Ig) A-producing gut lamina propria
of bile salts may contribute
has been advoof the en-
oral and intravenous
to be mediated
Fiber supplementation mine
of fiber.136,‘37 TPN-related
liver injury. Intestinal stasis and colonization of the small intestine by colonic-type bacteria promotes inbile salt deconjugation
in the intestinal
In some clinical
plain the predilection
and in adult
bile acid secretion
come as no surprise,
wall. 135-137In these animal
due to their low
bile flow and protect
in the neonate
has been shown
bile acid conjugate
of the mecha-
nisms proposed in children are variably invoked (Table 2). Thus, Messing et al. correlated the occurrence of cholestasis with the duration of TPN, continuous rather than cyclic administration of infusions, a low energy-to-nitrogen ratio of the infusate, and the presence of distal ileal disease and sepsis.23 Other studies have also shown an apparent association between TPN-related cholestasis in adults and either inflammatory bowel disease2’*“’ or the short bowel syndrome.142 Nanji and Anderson, in contrast, found the incidence of cholestasis not related to the duration of TPN or
of sepsis but rather
process; cholestasis with hematological patients
to the underlying
was observed malignancies
in all and bile duct one
In one of
that directly approached the issue of of TPN-related cholestasis in adults,
et al., based on an association
levels of lithocholic
of inflammatory TPN-related
acid in bile from a group
bowel disease patients liver
role by lithocholate.” The pathophysiology of TPN-associated cholestasis remains uncertain, and a direct role for TPN has not been
in 87% of patients but in only 56% of
the few studies the pathogenesis elevated
in the other of TPN.
of jaundice half.
the liver, either intestine,
showed fibrosis Though
with the small
The gross and microscopic
at the time of transplantation
for this lesion being based on the rela-
of their biliary
tive immaturity dence
the possibility, supported by a considerable body of evidence 44,46-49*143that TPN-related cholestatic syndromes may progress to chronic and irreversible liver disease remains a major concern. Most authorities agree, therefore, that TPN should be discontinued once cholestasis has developed. This may, in practice, be very difficult to accomplish in some patients such as those with the short bowel syndrome and chronic intestinal pseudo-obstruction. It is for these unfortunate individuals that new approaches are urgently needed. Recent reports indicate that small bowel transplantation may soon prove a realistic option in these most difficult
Chronic Liver Disease Long-term administration of TPN in both infants and adults may be accompanied by the development of chronic, and indeed, irreversible liver dis-
case report noma
of cholestasis, hepatocellular
to evaluate; that
to speculate supervene
et a1.i5’ They described
lated to TPN. effect of TPN TPN solutions
at this in-
subsequently died from when aged 26 months. The significance unreasonable
at 3 weeks of age, following
in figure 3A and B respectively. alarming
child who began TPN development
liver disease associated
the case reported
to TPN are
of decompensated TPN-reRecently, transplantation of
immunological consequences of a lack of enteral stimulation may be the primary factors, the predilection of infants
alone or in combination
liver disease and cholestasis
rare nowadays, instances lated cirrhosis still occur.
but the child carcinoma of this single
it is, however, hepatocellular
in the context
A possible carcinogenic or mutagenic has not been shown, the influence of on hepatic nucleic acid turnover failing
to show any effect on DNA synthesis.‘51 Similarly, effects on hepatic regeneration have been inconsis152,153
ease. 6,9-11,32,142,143,146,147 Benjamin described pathological evidence of wellestablished periportal fibrosis and portal-portal bridging in 8 of 15 infants who received TPN for >60 days and who came to either liver biopsy or autopsy4*: indeed, 5 showed cirrhosis. Cohen and Olsen reported the development of bile duct proliferation in 64% of
11 infants in their series who had been on TPN for >3 weeks; both infants maintained on TPN for more than 90 days showed hepatic fibrosis, and one infant developed a micronodular cirrhosis after 5 months of receiving TPN.46 TPN was continued in 1 of the 11 infants with TPN-associated cholestasis reported by Dahms and Halpin; this infant died from chronic liver disease at the age of 5.5 months.49 Of further concern was the persistence, in their series, of architectural ab-
in one study.‘54 Bowyer et al. provided the best data regarding the incidence of liver dysfunction in adults on long-term TPN.‘43 Of 60 patients maintained on TPN for an
Long-term TPN administration may produce parallel effects in the liver and in other organs in infants. Similarly striking changes in phosphoglyceride composition in both liver and brain, characterized by a relative excess of linoleic, and deficiency of linolenic, acids have been shown
average of 29 months, 9 (15%) had persistent liver enzyme abnormalities over periods ranging from 8 to 95 months. All of these patients also had evidence of gallbladder disease; 5 required cholecystectomy. Liver biopsies revealed steatohepatitis in 8, centrilobular fi-
Figure 3. (A) Gross photograph of an explanted nodular clrrhotic liver from a l-year-old male infant who had been on TPN from birth for the short bowel syndrome and developed decompensated liver disease requiring transplantation. (B) Photomicrograph of liver from Figure 3A showing bridgmg fibrosis and cirrhosis (Masson’s Trichrome stain; original magnification X 100).
brosis in 3, cholestasis in 3, and early nodular regeneration in 1. Three of these patients went on to develop severe symptomatic liver disease, and 1 died from portosystemic encephalopathy. Further instances of steatohepatitis reported’55-‘56 and Figure 4 depicts features year-old
of another case. Craig patient on long-term
have also been the histological
et al. described a 63TPN who developed
moderate fatty changes and pericellular fibrosis after 16 months and who developed an alcoholic-type steatohepatitis. The patient subsequently died from a myocardial infarction and at autopsy was found to have an established micronodular cirrhosis.‘55 It is clear, therefore, that chronic TPN-related liver disease, though more common in children, also occurs in adults.
HEPATOBILIARY COMPLICATIONS OF TPN
Figure 4. Photomicrograph
of liver showing hepatocellular ballooning, individual hepatocyte necrosis, and inflammation representing steatohepatitis. Patient had been on home TPN for the short bowel syndrome. (H&E; original magnification X50).
of some oral intake
In infants, chronic liver disease appears to be a direct consequence of prolonged cholestasis and must be
factors, proposed be repeated,
may not include
effect of TPN.
the early institution
hypophosphatemia,15* all been proposed
and lithocholate but are not supported
TPN in adults is liver phospholipidosis.‘59 This lesion, which is similar to that described in certain lysosomal storage diseases,
posits and multilamellar lysosomes in hepatocytes, Kupffer cells, and portal macrophages. These deposits are thought to reflect intra hepatic accumulation of phospholipids
in the TPN
of solutions, of oral feedings.
tal has been suggested
by the provision
ever a beneficial
data. A further
may be minimized
The pathophysiology of the steatohepatitis-type lesion seen in adults is poorly understood. Relationships to of carnitine,8’s5
In infants, function
of food, and the omis-
and, in particular, Oral phenobarbicholestasis16’;
effect has not been consistent.‘6’
Dlsorders of the Gallbladder and Biliary Tree In Association with TPN Acalculous
gallbladder distension, and gallstones have all been reported in association with TPN in both children and adults.8~‘0~“~23~‘43~‘62-‘70 In a careful, prospective study,
tions. The relationship of such deposits to the development of other hepatic pathologic changes following
Messing et al. reported a progressive increase in the incidence of biliary sludge from 6%, following 3 weeks
of TPN to 50% at 4-6 weeks and 100% at 6-13 weeks.‘67 It is not surprising, therefore, that the incidence of gallstone formation is also significantly associated with the duration of TPN. Thus, 9 of a group of 21 children on chronic TPN who developed gallstones
has not yet been defined.
Prevention of TPN-RelatedLiver Disease How can TPN-related liver injury be prevented? For adults, Bowyer et al. have suggested the following measures: avoidance of excess caloric loads by accurate measurement and prediction of energy requirements, cycling of TPN during the day, the early
had been on TPN for an average of 30 months,“’ whereas 21 of 60 adults who developed gallstones had been on TPN for at least 24 months.‘65 Not surprisingly, disease or resection in the distal ileum promotes
GASTROENTEROLOGY Vol. 104. No. 1
QUIGLEY ET AL.
in these patients.‘66
On a diag-
ative in these patients.
nostic note, Warner et al. have drawn attention to the limitations of hepatobiliary isotope scans in patients
tion to amino
a 36% incidence
in a group
not to have acute cholecys-
as a consequence
to the bedside
is far from
ate such complications.
Of relevance of TPN
several on bile
of both cholestasis
that during TPN administration, bile is not 179~180~182 Lirussi et al., indeed, showed
was increased, choleresis.
posed the presence within
biliary did not
bile acid concentration result
of a relative
in an appropriate these authors
recent report by Lindor and Burnes of reversal vere TPN-related cholestasis by ursodeoxycholic suggests that choleresis
of bile acids The of seacid
by the oral administra-
than initia prerequi-
In both infants of bile
as a consequence factor
bile flow and sustain
by TPN. system in
may be the primary
may be exacerbated
of the biliary
lack of oral intake
rats. 182In the same study, bile acid pool size was found was unchanged.
flow and gallbladder
to be increased,
yet bile acid synthesis
may set the stage for cholestasis.
of this data
of TPN in many circumstances,
to or exacerbate
can cause steatosis, Similarly,
TPN may contribute
site for the institution
to the pathogenesis
and cholelithiasis, effects
acid excess, the extrapolation
in this patient
titis.“’ A recent report suggests, however, that the administration of intravenous morphine will substantigraphy
Bacterial translocation related to gut mucosal hypoplasia and impaired mucosal immunity’“’ provides another mechanism whereby loss of oral induce hepatic injury. An understanding of TPN
intake might of the effects and biochem-
istry has led to the development
of TPN formulations,
tion of bile salt preparations may be beneficial in this context.‘84 Along with impaired bile flow, gallbladder stasis appears to be an important contributor
theless, examples of chronic and even decompensated liver disease continue to occur in relation to long-term TPN administration. It has not been established that
to the development of cholelithiasis TPN8*‘79,‘85; Cano et al. demonstrated
in relation to impaired gall-
bladder emptying in parenterally fed patients during both continuous and cyclic infusions.lg5 Clinical and experimental studies indicate that such stasis may indeed be prevented by the administration of exogenous cholecystokinin (CCK)‘86*‘87 or by stimulating nous release of CCK through periodic pulsed of large volumes
occurred in infants requiring long-term parenteral nutrition for the short bowel syndrome. It is in these rare, but unfortunate, individuals tation of the small intestine prove
that combined transplanand liver may eventually
acids’** or by the provision
of small amounts of enteral nutrition.‘*” Therefore, TPN provides an important example of the development of cholelithiasis based, not on cholesterol supersaturation, but on biliary and gallbladder stasis consequent on loss of enteral stimulation by oral nutrients (Table 2). 168*169TPN-related cholestasis may have a similar basis.
Conclusions It is often difficult and perhaps inappropriate to extricate the effects of TPN on hepatobiliary function from many other hepatotoxic factors that may be oper-
References Pettit SH, ShafferJL. Nutrition: supplemental, enteral and parenteral. In: Turnberg LA, ed. Clinical Gastroenterology. Oxford: Blackwell Scientific, 1989:356-384. Jeejeebhoy KN, Langer B, Tsallas G. Total parenteral nutritron at home: studies in patients surviving four months to five years. Gastroenterology 1976;7 1:943-953. Dudrick SJ, O’Donnell JJ, Englert DM, Matheny RG, Blume ER, Nutt RE, Hickey MS, Barroso AO. 100 patient-years of ambulatory home total parenteral nutrition. Ann Surg 1984; 199:770781. Giner M, Curtas S. Adverse metabolic consequences of nutritional support: macronutrients. Surg Clin North Am 1986;66: 1025-1047.
HEPATOBILIARY COMPLICATIONS OF TPN
5. Peden VH, Witzleben CL, Skelton MA. Total parenteral nutrition. J Pediatr 1971;78:180-181. 6. Erlrnger S. Les consequences hepatiques et biliares de I’alimentahon parenterale. Gastroenterol Clin Biol 1982;6:67 l672. 7. Hughes CA, Talbot IC, Ducker DA, Harran MJ. Total parenteral nutrition in infancy: effect on the liver and suggested pathogenesis. Gut 1983;24:241-248. 8. Holzbach RT. Gallbladder stasis: consequence of long-term parenteral hyperalimentation and risk factor for cholelithiasis. Gastroenterology 1983;84: 1055- 1058. 9. Whrtington PF. Cholestasis associated with total parenteral nutrition in infants. Hepatology 1985;5:693-696. 10. Roy CC, Belli DC. Hepatobiliary complications associated with TPN: An enigma. J Am Coll Nutr 1985;4:651-660. 11. Baker AL, Rosenberg IH. Hepatic complications of total parenteral nutrition. Am J Med 1987;82:489-497. 12. Sax HC, Bower RH. Hepatic complications of total parenteral nutrition. JPEN 1988;12:615-618. 13. Jeejeebhoy KN. Hepatic complications of total parenteral nutrition: need for prospective investigation. Hepatology 1988;8: 428-429. 14. Quigley EMM, Zetterman RK. Hepatobiliary complications of malnutrition and malabsorption. Semin Liver Dis 1988;8:2 18228. 15. Grant JP, Cox CE, Kleinman LM, Maher EM, Pittman MA, Tangrea JA, Brown JH, Gross E, Beazley RM, Jones RS. Serum hepatic enzyme and bilirubin elevations during parenteral nutntion. Surg Gynecol Obstet 1977; 145573-580. 16. Messing B, Bitoun A, Galian A, Mary J-Y, Goll A, Bernier JJ. La steatose hepatique au tours de la nutrition parenterale depend-elle de I’apport calorique glucidique? Gastroenterol Clin HI01 1977;1:1015-1025. 17. Sheldon GF, Petersen SR, Sanders R. Hepatic dysfunction during hyperalimentation. Arch Surg 1978; 113:504-508. 18. L.indor KD, FlemingCR, Abrams A, Hirschkorn MA. Liverfunction values in adults receiving total parenteral nutrition. JAMA 1979;241:2398-2400. 19. Reines HD, Queener B, Rodman G. Problems encountered with hyperalimentation in critically ill patients. Southern Med J 1979;72: 1524- 1526. 20. MacFadyen BV, Dudrick SJ, Baquero G, Gum ET. Clinical and biological changes in liver function during intravenous hyperalimentation. JPEN 1979;3:438-443. 21. I_owry SF, Brennan MF. Abnormal liver function during parenteral nutrition: relation to infusion excess. J Surg Res 1979;26:300-307. 22. Fouin-Fortunet H, Le Quernec L, Erlinger S, Lerebours E, Colin R. Hepatic alterations during total parenteral nutrition In patients with inflammatory bowel disease: a possible consequence of lithocholate toxicity. Gastroenterology 1982;82: 932-937. 23. Messing B, De Oliveira FJ, Galian A, Bermer JJ. Cholestase au tours de la nutrition parenterale totale: mise en evidence de facteurs favorisants; association a une lithiase vesiculaire. Gastroenterol Clin Biol 1982;6:740-747. 24. Tulikoura I, Huikuri K. Morphological fatty changes and function of the liver, serum free fatty acids and triglycerides during parenteral nutrition. Stand J Gastroenterol 1982; 17: 177- 185. 25. Wagman LD, Burt ME, Brennan MF. The impact of total parenteral nutrition on liver function tests in patients with cancer. Cancer 1982;49: 1249- 1257. 26. Meguid MM, Akahoshi MP, Jeffers S, Hayashi RJ, Hammond WG. Amelioration of metabolic complications of conventional total parenteral nutrition. Arch Surg 1984; 1 19: 1294- 1298. 27. Nanji AA, Anderson FH. Cholestasis associated with parenteral nutrition develops more commonly with hematologic malig-
nancy than 8:325.
Nanji AA, Anderson FH. Sensitivity and specificity of liver function tests in the detection of parenteral nutrition-associated cholestasis. JPEN 1985;9:307-308.
Bengoa JM, Hanauer SB, Sitrin MD, Baker AL, Rosenberg IH. Pattern and prognosis of liver function test abnormalities during parenteral nutrition in inflammatory bowel disease. Hepatology 1985;5:79-84.
Robertson JFR, Garden OJ, Shenkin A. Intravenous and hepatic dysfunction. JPEN 1986; 10: 172- 176.
Abad-Lacruz A, Gonzalez-Huix F, Esteve M, Fernandez-Banares F, Cabre E, Boix J, Acero D, Humbert P, Gassull MA. Liver function test abnormalities in patients with inflammatory bowel disease receiving artificial nutrition: a prospective randomized study of total enteral nutrition vs. total parenteral nutrition. JPEN 1990;14:618-621.
Clarke PJ, Ball MJ, Kettlewell MGW. Lrver function tests in patients receiving parenteral nutrition. JPEN 199 1; 15:54-59.
33. Jacobson S, Ericsson JLE, Obel A-L. Histopathological and ultrastructural changes in the human liver during complete intravenous nutrition for seven months. Acta Chir Stand 1971; 173:335-349. 34.
Friday KE, Lipkin EW. Long-term parenteral nutrition in unrestrained non-human primates: an experimental model. Am J Ckn Nutr 1990;5 1:470-476.
Driscoll JM Jr, Heird WC, Schullinger JN, Gongaware RD, Winters REV. Total intravenous alimentation in low-birth weight infants: a preliminary report. J Pediatr 1972;81: 145.
36. Touloukian RJ, Downing SE. Cholestasis associated with longterm parenteral hyperalimentation. Arch Surg 1973;106:5862. 37. Touloukian RJ, Seashore JH. Hepatic secretory obstruction with total parenteral nutrition in the infant. J Pediatr Surg 1975; 10:353-360. 38.
Rager R, Finegold MJ. Cholestasis fants: is parenteral alimentation 1975;86:264-269.
Rodgers BM, Hollenbeck JI, Donnelly WH, Talbert JL. Intrahepatic cholestasis with parenteral alimentation. Am J Surg 1976;131:149-155.
Bernstein J, Chang C-H, Brough AJ, Heidelberger KP. Conjugated hyperbilirubinemia in infancy associated with parenteral alimentation. J Pediatr 1977;90:361-367.
Sondheimer JM, Bryan H, Andrews W, Forstner GG. Cholestatic tendencies in premature infants on and off parenteral nutrition. Pediatrics 1978;62:984-989.
Brown MR, Putnam TC. Cholestasis associated with central intravenous nutrition in infants. NY State J Med 1978;78:27-30.
Beale EF. Nelson RM, Bucciarelli RL, Donnelly WH, Eitzman DV. lntrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics 1979;64:342-347.
Postuma R, Trevenen CL. Liver disease in infants receiving total parenteral nutrition. Pediatrics 1979;63: 1lo- 1 15.
Manginello FP, Javitt NB. Parenteral nutrition and neonatal cholestasis. J Pediatr 1979;94:296-298.
Cohen C, Olsen MM. Pediatric total parenteral nutrition. Liver histopathology. Arch Pathol Lab Med 198 1; 105: 152- 156.
in immature newborn inresponsible? J Pediatr
Pereira GR, Sherman MS, Di Giacomo J, Ziegler M, Roth K, Jacobowski D. Hyperalimentation-induced cholestasis: increased incidence and severity in premature infants. Am J Dis Child 198 1; 135:842-845. 48. Benjamin DR. Hepatobiliary dysfunction in infants and children associated with long-term total parenteral nutrition. A clinicopathologic study. Am J Clin Pathol 198 1;76:276-283. 49. Dahms BB, Halpin TC. Serial liver biopsies in parenteral nutn-
tion-associated cholestasis 1981;81:136-144. 50.
GASTROENTEROLOGY Vol. 104, No. 1
QUIGLEY ET AL.
of early infancy. Gastroenterology
Hodes JE, Grosfield JL, Weber TR, Schreiner RL, Fitzgerald JF, Mirkin LD. Hepatic failure in infants on total parenteral nutrition (TPN): clinical and histopathologic observations. J Pediatr Surg 1982; 17463-468.
51. Pallares R, Sitges-Serra A, Fuentes J, Sitges-Creus A, Guardia J. Cholestasis associated with total parenteral nutrition. Lancet 1983; 1:758-759. 52. Cano M, Gerolami A. lntrahepatic cholestasis during total parenteral nutntion. Lancet 1983; 1:985. 53. Case records of the Massachusetts General Hospital. Case 121984. N Engl J Med 1984;310:774-781. 54.
Bell RL, Ferry GD, Smith EO, Shulman RJ, Christensen BL, Labarthe DR, Wills CA. Total parenteral nutrition-related cholestasis in infants. JPEN 1986; 10:356-359. Kubota A, Okada A, Nezu R, Kamata S, lmura K, Takagi Y. Hyperbrlirubinemia in neonates associated with total parenteral nutrition. JPEN 1988; 12:602-606. Drongowski RA, Coran AG. An analysis of factors contributing to the development of total parenteral nutrition-induced cholestasis. JPEN 1989; 13:586-589. McDonald ATJ, Phillips MJ, Jeejeebhoy KN. Reversal of fatty liver by intralipid in patients on total parenteral nutrition (abstr). Gastroenterology 1973;64:A 199. Koga Y, lkeda K, lnokuchi K. Effect ofcomplete parenteral nutrrtion using fat emulsion on liver. Ann Surg 1975; 18 1: 186- 190. Kaminski DL, Adams A, Jellinek M. The effect of hyperalimentation on hepatic lipid content and lipogenic enzyme activity in rats and man. Surgery 1980;88:93100. Buzby GF, Mullen JL, Stein TP, Rosato EF. Manipulation of TPN caloric substrate and fatty infiltration of the liver. J Surg Res 1981;3 1:46-54. Hall RI, Grant JP, Ross LH, Coleman RA, Bozovic MG, Quarfordt SH. Pathogenesis of hepatic steatosis in the parenterally fed rat. J Clin Invest 1984;74: 1658- 1668. Sax HC, Talamini MA, Brackett K, Ftscher JE. Hepatic steatosis in total parenteral nutrition: failure of fatty infiltration to correlate with abnormal serum hepatic enzyme levels. Surgery 1986; 100:697-702. Keim NL. Nutritional effects of hepatic steatosis Induced by parenteral nutrition in the rat. JPEN 1987; I 1:18-22. Shulman RJ, Fiorotto ML, Sheng H-P, Finegold MJ, Garza C. Liver composition and histology in growing infant miniature pigs given different total parenteral nutrition fuel mixes. JPEN 1987; 11:275-279. Burgess P, Hall RI, Bateman DN, Johnston IDA. The effect of total parenteral nutrition on hepatic drug oxidation. JPEN 1987; 11:590-593. Li S, Nussbaum MS, McFadden DW, Gapen CL, Dayal R, Fischer JE. Addition of glucagon to total parenteral nutrition (TPN) prevents hepatic steatosis in rats. Surgery 1988; 104:350-357. Campos AC, Oler A, Meguid MM, Chen T-Y. Liver biochemtcal and histological changes with graded amounts of total parenteral nutrition. Arch Surg 1990; 125:447-450. Meguid MM, Chen T-Y, Yang Z-J, Campos ACL, Hich DC, Gleason JR. Effects of continuous graded total parenteral nutrition on feeding indexes and metabolic concomitants m rats. Am J Physiol 199 1;260:E 126-E 140. Chang G, Silvis SE. Fatty liver produced by hyperalimentation of rats. Am J Gastroenterol 1974;62:4 1O-4 18. Goodgame JT, Lowry SF, Brennan MF. Body weight changes and nutritional adequacy in the parenterally alimented rat. J Surg Res 1978;4:520-526. lkeda Y, Soda S, Okada A, Kawashima Y. Are hepatomegaly and jaundice attributable to “glucose overload?” Acta Char Stand 1979;(Suppl494): 170- 172.
72. Reef S, Tano M, Oliverio R, Young C, Rossi T. Total parenteral nutrition-induced steatosis: reversal by parenteral lipid infusion. JPEN 1991;15:102-104. 73. Tayek JA, Bistrian B, Sheard NF, Zeisel SH, Blackburn GL. Abnormal liver function in malnourished patients receiving total parenteral nutrition: a prospective randomized study. J Am Coll Nutr 1990;9:76-83. 74. Langer B, McHattie JD, Zohrab WJ, Jeejeebhoy KN. Prolonged survival after complete small-bowel resection using intravenous alimentation at home. J Surg Res 1973; 15:226-233. 75. Fleming CR, Smith LM, Hodges RE. Essential fatty actd deficiency in adults receiving total parenteral nutrition. Am J Clin Nutr 1976;29:976-983. 76. Barr LH, Dunn GD, Brennan MF. Essential fatty acid deficiency during total parenteral nutrition. Ann Surg 198 1; 193:304-3 1 1. 77. Keim NL, Mares-Perlman JA. Development of hepatic steatosis and essential fatty acid deficiency in rats with hypercaloric, fatfree parenteral nutrition. J Nutr 1984;114:1807-1815. 78. Schiff D, Chan G, Seccombe D, Hahn P. Plasma carnrtine levels during intravenous feeding of the neonate. J Pediatr 1979;95: 1043- 1046. 79. Penn D, Schmidt-Sommerfeld E, Wolf H. Carnitine deficiency in premature infants receiving total parenteral nutrition. Early Hum Dev 1980;4:23-34. 80. Tao RC, Yoshimura NN. Carnitine metabolism and its application to parenteral nutrition. JPEN 1980;4:469-486. 81. Penn D, Schmidt-Sommerfeld E, Pascu F. Decreased tissue carnitine concentrations in newborn infants receiving total parenteral nutrition. J Pediatr 1981;98:976-978. 82. Hahn P, Allardyce DB, Frohlich J. Plasma carnitine levels during total parenteral nutrition of adult surgical patients. Am J Clin Nutr 1982;36:569-572. 83. Worthley LI, Fishlock RC, Snoswell AM. Carnitine deficiency with hyperbilirubinemia, generalized skeletal muscle weakness and reactive hypoglycemia in a patient on long-term total parenteral nutrition: treatment with intravenous L-carnitine. JPEN 1983;7:176-180. 84. Bowyer BA, Fleming CR, llstrup DM, Burnes JU, Nelson J, Reek S. Plasma carnitine levels in patients receiving home parenteral nutrition. Am J Clin Nutr 1986;43:85-91, 85. Palombo JD, Schnure F, Bistrian BR, Buchanan LM, Blackburn GL. Improvement of liver function tests by administration of LCarnitine to a carnitine-deficient patient receiving home parenteral nutrition: a case report. JPEN 1987; 1 1:88-92. 86. Knodell RG, Whitmer DI, Holman RT. Influence of hyperalimentation on rat hepatic microsomal fluidity and function. Gastroenterology 1990;98: 1320- 1325. 87. Whalen GF, Shamberger RC, Perez-Atayde A, Folkman J. A proposed cause for the hepatic dysfunction associated with parenteral nutrition. J Pediatr Surg 1990;25:622-626. 88. Sinclair AJ, Collins FD. Fatty livers in rats deficient in essential fatty acids. Biochim Biophys Acta 1968; 152:498-5 10. 89. Seifter S, Englard S. Energy metabolism. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The liver: biology and pathobiology. 2nd ed. New York: Raven, 1988:279-3 15. 90. Karpati G, Carpenter S, Engel AG, Walters G, Allen J. Rothman S, Klassen G, Mamer OA. The syndrome of systemic carnitine deficiency: clinical, morphologic, biochemical and pathophysiologic features. Neurology 1975;25: 16-24. 91. Tibboel D, Delemarre FMC, Przyrembel M, Bos AP, Affourtn MJ, Mollenaar JC. Carnitine deficiency in surgical neonates receiv1. ing total parenteral nutrition. J Pediatr Surg 1990;25:418-42 92. Bowyer BA, Mile JM, Haymond MW, Fleming CR. L-Carnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentrations. Gastroenterology 1988;94:434-438. 93. Stein TP, Buzby GP, Leskiw MJ, Giandomenico AR, Mullen JL.
HEPATOBILIARY COMPLICATIONS OF TPN
Protein and fat metabolism in rats during replebon with total parenteral nutrition. J Nutr 198 1; 1 1 1: 154- 165. Meurling S, Roos KA. Liver changes in rats on continuous and intermittent parenteral nutrition with and without fat (Intralipid 20%). Acta Chir Stand 1981;147:475-480.
free total parenteral 1052:71-77.
Biophys Acta 1990;
Cooper A, Betts JM. Pereira GR, Ziegler MM. Taurine deficiency in the severe hepatic dysfunction complicating total parenteral nutnbon. J Pediatr Surg 1984;19:462-466.
Boelhouwer RU, King WW, Kingsnorth AN, Weening JJ, Young VR, Malt RA. Fat-based (intralipid 20%) versus carbohydratebased total parenteral nutrition: effects on hepattc structure and function in rats. JPEN 1983;7:530-533. 96. Martins FM, Wennberg A, Meurling S, Kihlberg R, Lindmark L. Serum lipids and fatty acid composition of tissues in rats on total parenteral nutrition (TPN). Lipids 1984; 19:728-737. 97. Grant J, Snyder P. Use of L-glutamine in TPN. J Surg Res 1988;44:506-5 13. 98. Li S. Nussbaum MS, McFadden DW, Zhang F-S, LaFrance RJ, Dayal R, Fischer JE. Addition of L-glutamine to total parenteral nutrition and its effects on portal insulin and glucagon and the development of hepatic steatosis In rats. J Surg Res 1990;48:42 l-426.
Rigo J, Senterre J. Is taurine essential for neonates? nate 1977;32:73-76.
Dorvil NP, Yousef IM, Tuchweber B, Roy CC. Taurine prevents cholestasls induced by lithocholate acid sulfate in guinea pigs. Amer J Ckn Nutr 1983;37:22 l-232.
Belli DC, Roy CC, Fournier L-A, Tuchweber B, Giguere R, Yousef IM. The effect of taurine on the cholestatic potential of sulfated lithocholate and its conjugates. Liver 199 1; 1 1: 162- 169.
Okamoto E. Rassin DK, Zucker CL, Salen GS, Heird WC. Role of taurine in feeding the low birth-weight infant. J Pediatr 1984; 104:936-940.
Wang W-Y, Liaw K-Y. Effect of a taurine-supplemented diet on conjugated bile acids In blliary surgical patients. JPEN 199 1; 15:294-297.
Guertin F, Roy CC, Lepage G, Perea A, Giguere R, Yousef I, Tuchweber B. Effect of taurine on total parenteral nutrition-associated cholestasis. JPEN 199 1; 15:247-25 1.
Cooke RJ, Whitington PF, Kelts D. Effect of taurine supplementation on hepatic function during short-term parenteral nutrition in the premature infant. J Pediatr Gastroenterol Nutr 1984;3:234-238.
Palmer RH, Hruban Z. Production of bile duct hyperplasia and gallstones by lithocholic acid. J Clin Invest 1964;45: 12551267.
Hunt RD, Leveille GA, Sauberlich HE. Dietary bile acids and lipid metabolism. Ill. Effects of lrthocholic acid in mammalian specles. Proc Sot Exp Biol Med 1964; 115:277-280.
Miyai K, Pnce VM, Fisher MM. Bile acid metabolism in mammals. Ultrastructural studies on the intrahepatic cholestasis induced by lithocholate and chenodeoxycholic acids in the rat. Lab Invest 197 1;24:292-302.
Palmer RH. Bile acids, liver injury and liver disease. Arch Intern Med 1972; 130:606-6 17.
Fischer CD, Cooper NS, Rothschild MA, Mosbach EH. Effect of dietary chenodeoxycholic acid and lithocholic acid in the rabbit. Am J Dig Dis 1974; 19:877-886.
Kakis G, Yousef IM. Mechanism of choke acid protection in lithocholate-induced intrahepatic cholestasis in rats. Gastroenterology 1980;78: 1402- 14 1 1,
Capron J-P, Gineston J-L, Herve M-A, Braillon A. Metronidazole in prevention of cholestasis associated with total parenteral nutrition. Lancet 1983; 1:446-447.
Kubota A, Okada A, lmura K, Kawamara H, Nezu R, Kamata S, Takagi S. The effect of metronidazole on TPN-associated liver dysfunction in neonates. J Pediatr Surg 1990;25:618-621.
Spurr SG, Grylack LJ, Mehta NR. Hyperalimentation-associated neonatal cholestasis: effect of oral gentamicin. JPEN 1989; 13:633-636.
Freund HR, Muggia-Sullam M, LaFrance R, Enrione EB, Popp MB, Bjornson HS. A possible beneficial effect of metronidazole in reducing TPN-associated liver function derangements. J Surg Res 1985;38:356-363. Berger HM, Den Ouden AL, Calame JJ. Pathogenesis of liver damage during parenteral nutrition: is lipofuscin a clue? Arch Dis Child 1985;60:774-776.
Gleghorn EE. Merritt RJ, Henton DM, Neustein HM, Landing B, Sinatra FR. A subacute rabbit model for hepatobiliary dysfunction during total parenteral nutrition. J Pediatr Gastroenterol NtJtr 1989;9:246-255. 100. Vileisis RA, lnwood RJ, Hunt CE. Prospective controlled study of parenteral nutrition-associated cholestatic jaundice: effect of protein intake. J Pediatr 1980;96:893-897. 101. Fouin-Fortunet H, Hemet J, Ducastelle T. Galmiche JP, Lerebours E, Colin R. Alterations hepatiques au tours de la nutrition parenterale exclusive prolongee dans les enterocolites cryptogenetiques. Etudes clinique, histologtque et ultrastructurale. Gastroenterol Clin Biol 198 1;5: 145- 154. 102. Lilly JR, Sokol RJ. On the bile sludge syndrome or is total parenteral nutrition cholestasts a surgical disease? Pediatrics 1985;76:992-993. 103. Brown MR, Thunberg BJ, Golub L, Maniscalo WM, Cox C, Shapiro DL. Decreased cholestasis with enteral Instead of intravenous protein in the very low-birth weight infant. J Pediatr Gastroenterol Nutr 1989;9:2 l-27. 104. Watkins JB, Szczepanik P, Gould JB, Klein P, Lester R. Bile salt metabolism in the human premature infant. Gastroenterology 1975;69:706-7 13. 105. Katayama T, Tanaka M, Tanaka K, Asumumak, Uemoto S, Okamura R, Utsunomiya M, Fujita S, Ueda J, Tanaka A, Ozawa K. Alterations in hepatic mitochondrial function during total parenteral nutrition in immature rats. JPEN 1990; 14:640-645. 106. Nakai H, Landing BM. Factors in the genesis of bile stasis in infancy. Pediatrics 1961;27:300-307. 107. Presig R, Rennert 0. Biliary transport and cholestatic effects of amino acids (abstr). Gastroenterology 1977;73: 1240. 108. King WW, Boelhouwer RU, Kingsnorth AN, Ross JS, Young VR, Malt RA. Nutritional efficacy and hepatic changes during intragastric, intravenous and pre-hepatic feeding in rats. JPEN 1983;7:443-446. 109. Merritt RJ, Sinatra FR, Henton DH, Neustein H. Cholestatic effect of intraperitoneal administration of tryptophan to suckling rat pups. Pediatr Res 1984; 18:904-907. 110. Black DD, Suttle EA, Whitington PF, Whitington GL, Korones SD. The effect of short-term total parenteral nutrition on hepatic function in the human neonate: a prospective randomized study demonstrating alteration of hepatic canalicular function. J Pediatr 198 1;99:445-449. 111. Belli DC, Fournier L-A, Lepage G, Yousef I, Weber AM, Tuchweber B, Roy CC. Total parenteral nutrition-associated cholestasis in rats: comparison of different amino acid mixtures. JPEN 1987; 11:67-73. 112. Masumi A, Aoi S, Shiga J, Tsukada K. Heat-shock proteins and nuclear hypertrophy in the liver of rat infused with methionine-
Berger HM. The pathogenesis of cholestasis in parenteral nutntion. JPEN 1985;9:524. Utili R, Abernathy CO, Zimmerman HJ. Cholestatic effects of Escherichia Co11endotoxin on the isolated perfused rat liver. Gastroenterology 1976;70:248-253. Alverdy JA, Chi HS, Sheldon GS. The effects of parenteral nutri-
QUIGLEY ET AL.
tion on gastrointestinal immunity: stimulation. Ann Surg 1985;202:68
GASTROENTEROLOGY Vol. 104, No. 1
the importance l-684.
135. Alverdy JC, Aoys F, Moss GS. Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 1988; 104:185-190. 136. Spaeth G, Specian RD, Berg RD, Deitch EA. Bulk prevents bacterial translocation induced by the oral administration of total parenteral nutrition solution. JPEN 1990; 14:442-447. 137. Spaeth G, Berg RD, Specian RD, Deitch EA. Food without fiber promotes bacterial translocation from the gut. Surgery 1990; 108:240-247. 138. Souba WW, Klimberg VS, Plumley DA, Salloum RM, Flynn TC, Bland KI, Copeland EM. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990;48:383-39 1. 139. Alverdy JA, Aoys E, Weiss-Carrington P, Burke DA. The effect of glutamine-enriched TPN on gut immune cellularity. J Surg Res 1992;52:34-38. 140. Klein GL, Sedman AB, Heyman MB, Marathe G, Battifora MA, Worral JL, Horst RL. Hepatic abnormalities associated with aluminum loading in piglets. JPEN 1987; 1 1:293-297. 141. Gerard-Boncompain M, Claude1 JP, Gaussorgues P, Salord F, Sirodot M, Chevallier M, Robert D. Hepatic cytolytic and cholestatic changes related to a change of lipid emulsions in four longterm parenteral nutrition patients with short bowel. JPEN 1992; 16~78-83. 142. Stank0 RT, Nathan G, Mendelow H, Adibi SA. Development of hepatic cholestasis and fibrosis in patients with massive loss of intestine supported by prolonged parenteral nutrition. Gastroenterology 1987;92: 197-202. 143. Bowyer BA, Fleming CR, Ludwig J, Petz J, McGill DB. Does longterm home parenteral nutrition in adult patients cause chronic liver disease? JPEN 1985;9:11-17. 144. Purdum PP, Kirby DF. Short bowel syndrome: a review of the role of nutrition support. JPEN 199 1; 15:93- 10 I. 145. Vanderhoof JA, Langnas AN, Pinch LW, Thompson JS, Kaufman SS. Short bowel syndrome and intestinal transplantation. J Pediatr Gastroenterol Nutr 1992; 14:359-370. 146. Salvian AJ, Allardyce DB. Impaired bilirubin secretion during total parenteral nutrition. J Surg Res 1980;28:547-555. 147. Ito Y, Shils ME. Liver dysfunction associated with long-term total parenteral nutrition in patients with massive bowel resection. JPEN 1991;15:271-276. 148. Williams JW, Sankary HN, Foster PF, Loew JM, Goldman GM. Splanchnic transplantation. An approach to the infant dependent on parenteral nutrition who develops irreversible liver disease. JAMA 1989;26 1: 1458- 1462. 149. Grant D, Wall W, Zhong R, Mimeault R, Sutherland F, Ghent C, Duff J. Experimental clinical intestinal transplantation: initial experience of a Canadian Center. Transplantation Proceedings 1990;22:2497-2498. 150. Vileisis RA, Sorensen K, Gonzalez-Crussi F, Hunt CE. Livermalignancy after parenteral nutrition. J Pediatr 1982; 100:88-90. 151. Aoi S, Wen L-T, Kuwahata T, Tsukada K. Alteration in the ribonucleic acids in rat liver induced by a methionine-free total parenteral nutrition solution. J Nutr 1987; 1 17:673-677. 152. Rigotti P, Peters JC, Tranberg K-G, Fischer JE. Effects of aminoacid infusions on liver regeneration after partial hepatectomy in the rat. JPEN 1986; 10: 17-20. 153. Kirvela 0, Takala J. Postoperative parenteral nutrition with high supply of branched-chain amino acids: effects on nitrogen balance and liver protein synthesis. JPEN 1986; 10:574-577. 154. Martinez M. Ballabriga A. Effects of parenteral nutrition with high doses of linoleate on the developing human liver and brain. Lipids 1987;22: 133- 138. 155. Craig RM, Neumann T, Jeejeebhoy KN, Yokoo H. Severe hepatocellular reaction resembling alcoholic hepatitis with cirrhosis
after massive small bowel resection and prolonged total parenteral nutrition. Gastroenterology 1980;79: 13 1- 137. 156. Freund U. Liver disease after TPN. Gastroenterology 1982;82: 164- 165. 157. Burt ME, Hanin I, Brennan MF. Choline deficiency associated with total parenteral nutrition. Lancet 1980;2:638-639. 158. Nanji AA, Anderson FH. Relationship between serum phosphate and parenteral nutrition-associated increase in serum glutamic-oxaloacetic transaminase. Am J Clin Nutr 1984;39:860862. 159. Degott C, Messing B, Moneau D, Chazouilleres 0, Paris Columbell JF, Lebec D, Potet F, Feldmann G. Benhamou JP. Liver phospholipidosis induced by parenteral nutrition: histologic, histochemical and ultrastructural investigations. Gastroenterology
1988;95:183-191. 160. South M, King A. Parenteral nutrition-associated
cholestasis: recovery following phenobarbitone. JPEN 1987; 1 1:208-209. 16 1. Gleghorn EE, Merritt RJ, Subramanian N, Ramos A. Phenobarbital does not prevent total parenteral nutrition-associated cholestasis in non-infected neonates. JPEN 1986; 10:282-283. 162. Anderson JL. Acalculous cholecystitis-a possible complication of parenteral hyperalimentation. Report of a case. Med Ann DC 1972;4 1:448-450. 163. Peterson SR, Sheldon GF. Acute acalculous cholecystitis: a complication of hyperalimentation. Am J Surg 1979; 138:8 14817. 164. Barth RA, Brasch RC, Filly RA. Abdominal pseudotumor in childhood: distended gallbladder with parenteral hyperalimentation. Am J Roentgen01 198 1; 136:34 l-343. 165. Pitt HA, King W, Mann LL, Roslyn JJ, Benquist WE, Ament ME, Den Besten L. Increased risk of cholelithiasis with prolonged total parenteral nutrition. Am J Surg 1983; 145: 106- 1 12. 166. Roslyn JJ, Pitt HA, Mann LL, Ament ME, Den Besten L. Gallbladder disease in patients on long-term parenteral nutrition. Gastroenterology 1983;84: 148- 154. 167. Messing B, Bories C, Kunstlinger F, BernierJJ. Does total parenteral nutrition induce gallbladder sludge formation and lithiasis? Gastroenterology 1983;84: 10 12- 10 19. 168. Carey MC, Cahalane MJ. Whither biliary sludge? Gastroenterologv 1988;95:508-523. 169. Afdhal NH, Smith BF. Current concepts on the pathogenesis of cholesterol gallstones. Viewpoints on Digestive Diseases
1990;22:13-18. 170. Arad I, Peleg 0, Udassin R, Zamir 0, Goldberg M, Lebensart P. Gallbladder distention in premature neonates receiving parenteral nutrition. J Perinat Med 1989; 17:337-340. 171. Roslyn JJ, Berquist WE, Pitt HA, Mann LL, Kangarloo H, Den Besten L, Ament ME. Increased risk of gallstones in children receiving total parenteral nutrition. Pediatrics 1983;7 1:784789. 172. Warner BW, Hamilton FN, Silberstein EB, Gaskill M, Teague D, Bower RH, Fischer JE. The value of hepatobiliary scans in fasted patients receiving total parenteral nutrition. Surgery 1987;
102:595-599. 173. Flancbaum L, Alden SM. Morphine cholescintigraphy. Surg Gynecol Obstet 1990; 17 1:227-232. 174. Hamilton RF, Davis WC, Stephenson DV, Magee DF. Effects of parenteral hyperalimentation on upper gastrointestinal tract secretions. Arch Surg 197 1; 102:348-352. 175. Van Der Linden W, Nakayama F. Effect of intravenous fat emulsion on hepatic bile: increased lithogenicity and crystal formation. Acta Chir Stand 1976; 142:40 l-406. 176. Gimmon Z, Kelley RE, Simko V, Fischer JE. Total parenteral nutrition increases bile lithogenecity in the rat. J Surg Res 1982;32:256-263. 177. Cano N, Marteau C, DiConstanzo J, Martin J, Richieri JP, Mas JC, Crotte C, Gerolami A. Etude de la composition biliare sous nutri-
totale chez I’homme.
lnnis SM, Boyd MC. Cholesterol and bile acid synthesis during total parenteral nutrition with and without lipid emulsion in the rat. Am J Clin Nutr 1983;38:95-100.
Doty JE, Pitt HA, Porter-Fink V, Den Besten L. The effects of intravenous fat and total parenteral nutrition on biliaty physiology. J Parenteral Enteral Nutr 1984;8:265-268.
180. lnnis SM. Hepatic transport of bile salt and bile composition following total parenteral nutrition with and without lipid emulsion in the rat. Amer J Clin Nutr 1985;4 1: 1283- 1288.
Muller EL, Grace PA, Pitt HA. The effect of parenteral nutrition on biliary calcium and bilirubin. J Surg Res 1986;40:55-62.
Lirussi F, Vaja S, Murphy GM, Dowling RH. Cholestasis of total parenteral nutrition: bile acid and bile lipid metabolism in parenterally nourished rats. Gastroenterology 1989;96:493-502.
183. Das JB. Ghosh S, Cosentino CM, Ansari GG. Hepatic organic anion transport kinetics and bile flow during short-term total parenteral nutrition in the rabbit. Proc Sot Exp Biol Med 1990; 195:274-278.
Lindor KD, Burnes J. Ursodeoxycholic acid for the treatment of home parenteral nutrition-associated cholestasis. A case report. Gastroenterology 199 1; 10 1:250-253.
185. Can0 N, Cicero F, Ranieri F, Martin J, DiCostanzo T. Ultrasonographic study of gallbladder motility during total parenteral nutrition. Gastroenterology 1986;9 1:3 13-3 17. 186. Doty JE, Pitt HA, Porter-Fink V, Denbesten L. Cholecystokinin prophylaxis of parenteral nutrition-induced gallbladder disease. Ann Surg 1985;20 1:76-80. 187. Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170:25-31. 188. Nealon WH. Upp JR, Alexander RW, Gomez G, Townsend CR, Thompson JC. Intravenous amino acids stimulate human gallbladder emptying and hormone release. Amer J Physiol 1990;259:G 173-G 178. 189. Cohen IT, Meunier K, Hirsh MP. The effects of enteral stimulation on gallbladder bile during total parenteral nutrition in the neonatal piglet. J Pediatr Surg 1990;25: 163- 167. 190. Deitch EA, Xu D, Qi L, Specian RD, Berg RD. Protein malnutrition alone and in combination with endotoxin impairs systemic and gut-associated immunity. JPEN 1992; 16:25-31.
Received October 11, 1991. Accepted August 27, 1992. Address requests for reprints to: Eamonn M. M. Quigley, M.D., University of Nebraska Medical Center, 600 South 42nd Street, Omaha, Nebraska 68198-2000.