Hepatobiliary complications of total parenteral nutrition

Hepatobiliary complications of total parenteral nutrition

GASTROENTEROLOGY 1993;104:286-301 SPECIAL REPORTS AND REVIEWS Hepatobiliary Complications of Total Parenteral Nutrition EAMONN M. M. QUIGLEY,* MIC...

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GASTROENTEROLOGY

1993;104:286-301

SPECIAL REPORTS AND REVIEWS Hepatobiliary Complications of Total Parenteral Nutrition EAMONN

M. M. QUIGLEY,*

MICHAEL

N. MARSH,*

JON L. SHAFFER,*

and

RODNEY

S. MARKIN’

*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.

(Table

1). Three

dromes

dominate.

differing

effects

born

infant

Thus,

of parenteral

steatosis The third

mation

and

and

liver

cholelithiasis,

on the other.

injury

namely appear

the

on the newappear

steatohepatitis

syndrome,

syn-

to reflect

nutrition

syndromes

of TPN-related

adults.

clinical

and on adults

cholestatic

young,

both

distinctive

The first two appear

on one hand

whereas

hallmark

apparently

to be the

in

the

very

predominate

in

biliary

sludge for-

to be common

in

groups.s-”

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

liver

enzymes

performed studies

on elevated

and bilirubin.‘5-32

in a selected

included

serum

Liver

levels of

biopsies

were

minority’5~‘6~‘8~‘“~23; only a few

histological

data

from

either

all or

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

incidence

refinements

25% to 100%. This may be due, first, to the fact that

T

standing

in infusion

solutions,

of the requirements

a greater

for vitamins

under-

and trace

elements, and advances in catheter design and placement techniques, the metabolic and septic complications

of TPN

have become

less frequent.‘”

As these

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,

of abnormal

enzyme

different populations were being dominated by “surgical” by

cancer20,21,25,27

or

comand the

levels has varied

from

studied; some series cases,24,26,30 and others

inflammatory

ease.22*23,27,29,31 Several series included

bowel

dis-

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

January 1993

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

varying

intervals

following

initiation

287

of TPN15,17*23;

these authors suggested that steatosis was an early, often transient effect of TPN with cholestasis ing later and usually persisting

superven-

as long as TPN

was

continued.‘6T22 Given

the many complicating

actual relationship histological

dysfunction,

interspecies

to the clinical

study has provided important

of TPN-related

ized, controlled patients

with

liver

difficult.

One recent

information

on the true

frequency of “liver test” abnormalities

NOTE. The more common disorders are italicized.

situa-

differences34 render extrapo-

situation

patients who frequently

and

indirect and circumstantial. have provided considerable

insights into the pathophysiology

gallbladder)

what is the

abnormalities ? For many clinical

tions, evidence remains Though animal models

lation

factors,

of TPN to these biochemical

in one group of

receive TPN. In this random-

trial, 61.5% of those carefully matched inflammatory

bowel

disease who

re-

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

component

those who received enteral nutrition.31

of TPN formulations.22-31

The time course of these enzyme abnormalities

has

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

the

levels

of

studies

gamma

have

glutamyl

suggested transpepti-

dase 28,30,31alanine transaminase, 15,18,23aspartate trans-

were not, however,

performed

steatosis, cholestasis, mains undefined.

dysfunction.

figured more prominently

glutamyl transpeptidase

during TPN,

elevations

gamma

appear to be non-

specific; transaminase and alkaline phosphatase elevations are more indicative of either steatosis or cholestasis, respectively.

Hyperbilirubinemia

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

enzyme

levels

despite

of these

continuance

of

TpN_l!il7,20,21,29-31

change

of re-

TPN-Related Hepatlc Dysfunction in Infants hepatic complication

common

and the frequency

or other pathologic

amit5ase,29 and alkaline phosphatase16,17v22*32 are the most sensitive indicators of TPN-related hepatic Though

Liver biopsies

Although

steatosis has been the most common of TPN in adults, cholestasis

has

in children.5,35-56 Because

the principal indication for TPN has been the short bowel syndrome, due either to congenital abnormalities or necrotizing

enterocolitis,

most children

receiv-

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,

Although

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

by the

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

288

more

QUIGLEY

ET AL.

recent

series,

lated cholestasis

GASTROENTEROLOGY

Bell et al., who

as a serum

defined

bilirubin

dL, noted a much lower incidence

TPN-re-

level 2 1.5 mg/

of TPN-related

cho-

lestasis of 7.4% among 624 infants.54 Cholestasis was detected in almost two thirds of these cases within 14 days of initiating within

TPN

and

in more

than

the first week.54 The definition

at least

in part,

explain

the wide

one

employed range

Although liance

tine”

has recently

ral history

tests

of TPN-related

be more

indicators.”

common

than

tests. Given

of TPN-related

and that

transpeptidase

with the primary

that re-

may underestimate

cholestasis

glutamyl sensitive

suggested

Cholestasis reflected

cholestasis

serum

or bile acids

process,

may

by “rou-

the high mortality disease

the

often

the natu-

in these infants

is less well-defined than that in adults. Available dence suggests that cholestasis, once developed, sists as long as TPN

eviper-

of steatosis

Under

fat accumulation

evidence

TPN

conditions,

is primarily

related

delivered

to

in the

excess carbohydrate

of elegant

Meguid

studies,

between

the proportion

as TPN

content.67*68 They concentrations hepatic which,

of glucose

of acylglycerol

from

carnitine

enzyme

admin-

and triglyceride

that the infusion and amino

lipogenesis

glucose

insulin

release

and the synthesis

while

inhibiting

acyltransferase,

in fatty acid oxidation.“8

of high

acids promoted

by stimulating

in turn, promoted

chondrial

steatosis

proposed

fat deposition

a direct corre-

of total calories

and hepatic

calo-

in the liver. In a series

et al. showed

mito-

the rate-limiting If, in addition,

there

is a relative carbohydrate-to-nitrogen imbalance caused by either inadequate or mis-matched amino acid content

of the infusion,63,69-7’

hepatic

leading

indeed

of triglyceride

there-

triglyceride shown

ac-

impaired

in rats fed both lipidTPN

lipid accumulation

synthe-

secretion,

to intrahepatic

Hall et al. have

secretion

lipoprotein

and triglyceride

and carbohydrate-containing

of

panlobu-

suggest that the develop-

to triglyceride

hepatic without

during

the former

cumulation.

Steatosis Hepatic

studies

ries are converted

fore, restricted,

Clinical-Pathological Syndromes of TPN-Related Hepatobiliary Dysfunction

either

effects of excess calories

sis may be impaired

is administered.43,44*49

to become

form of dextrose or glucose and an impairment in the hepatic secretion of triglyceride.‘0~“~‘6~17~2’~24*26~57-68

istered

laboratory

associated

ment

and animal

the combined

lation

be more

therefore

Clinical

most other studies have relied on hyperbil-

levels of gamma may

derived

extends

No. 1

lar or centrilobular.‘5-‘8,24,33

Whitington

on conventional

incidence

may,

in reported

cholestasis, the highest incidence rates being from highly selected autopsy series.38,43,46 irubinemia,

half

tosis, fat deposition

Vol. 104,

solutions.”

was less striking,

Intrahowever,

in those rats administered TPN solutions that included lipid. These authors further suggested that lipid supplementation

of TPN

solutions

formerly

by decreasing

hepatic

triglyceride

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-

one recent

randomized

lipid supplementation zyme abnormalities.73 Further trose-based

evidence TPN

may prevent uptake,

steatosis promoting

trial failed to show any effect of on the frequency for an effect

solutions

of liver

of glucose

on triglyceride

en-

or dexsecretion

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

January 1993

HEPATOBILIARY COMPLICATIONS OF TPN

289

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

of essential

in turn,

lead to impaired

triglyceride

secretion

Others,

however,

in association deficient

solutions

acid deficiency genesis

reporting

with

fatty

mediated

through

formation

tion.”

hence,

steatosis.*’

lated benefits

the occurrence

of steatosis

mucosal

and,

lipid-containing, have

acid deficiency

lipoprotein

suggested

as well as lipidthat

essential

fatty

does not play a major role in the patho-

of steatosis.6’-63

the stimulation

As will be discussed

described

in an animal a relationship

Gleghorn

between

zymes, histological steatosis, concentration of lithocholic

The balance of evidence indicates benign, reversible and nonprogressive

to the pathogenesis tion”’ and steatosis

TPN,

cent study has failed to show a significant in hepatic

lipid

accumulation

amelioration

in carnitine-deficient

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

related

carbohydrate

liver

en-

and an increased biliary acid.” The relevance of

primary carnitine deficiency and steatosis,” it has been proposed that carnitine deficiency may also be relevant

is directly

on gut

et al. have

elevated

this observation to TPN-related remains to be determined?

which

by effects

integrity. model

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-

secre-

these glutamine-re-

may also be mediated

and immunological

Finally,

of glucagon

later,

steatosis

in humans

that steatosis consequence

to the delivery

load in a manner

that may accompany

diabetes

is a of of an

analgous mellitus.

Several modifications to TPN solutions have resulted in a significant fall in the incidence of steatosis. This seems to have been achieved

by tailoring

caloric

intake

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

290

QUIGLEY

Table

GASTROENTEROLOGY

ET AL.

2. Patient Factors and TPN-Related Effects Proposed to Contribute

to the Pathophysiology

Vol. 104,

of Hepatoblliary

No. 1

Dysfunction

on TPN TPN Effects

Patient factors

Complication Steatosis

Cholestasis in children

Cholestasis

in adults

Gallbladder disease and gallstones

swelling

with an increase

lipofuscin

accumulation.

performed

a detailed

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

histological

study

Approximately

Decreased

these

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

imbalance

of TPN

Low energy-to-nitrogen ratio Contrnuous administration Bacterial translocation L-glutamine deficiency Copper in TPN solubon Lipid Content Lithocholate toxicity

infants

disturbed

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

Altered

bile flow

presence

one half of the biopsy

Minor or controversial

-

of TPN

in 11 infants

of their jaundice revealed severe cholestasis accompanied by portal inflammation and mild portal and perifibrosis.

Duration

glycogen and and Halpin

who developed jaundice within 1.5 and 3 weeks after beginning TPN.49 Biopsy samples taken at the height

portal

Major

bacterial

has proved

of other

difficult,

complicating

enterohepatic overgrowth.

bile composition

given

factors

circulation Nevertheless,

and

the frequent such as sepsis, small

bowel

it does appear

that

certain factors are consistently associated with a high incidence of TPN-related cholestasis (Table 2). These include

prematurity,

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

January

1993

HEPATOBILIARY

COMPLICATIONS

OF TPN

291

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,

to disruption

by various

a cholestatic

including TPN.“’ Together,

these phys-

work of Vileisis et al. who compared the effects of two

effect of amino

iological factors may set the stage for the development

TPN solutions,

of TPN-related

the development

cholestasis.”

Its clinical

and morpho-

logical expression may then be precipitated constituents prolonged monal

not only by

of TPN solutions but also by the effects of fasting

(accompanied

and neural stimulation

tion9”*lo3 and by coexistent

by decreased of hepatic

hor-

bile secre-

disease processes

such as

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

cholestasis.

may be a

It is in this

fants.“’

Their

differing

acids comes

only in protein

of cholestatic

observations

jaundice

indicated

from the

content,

on

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

solutions

may prevent

cholestasis

in pre-

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-

Comparing

paring

namely Travasol (Travenol Canada Inc., Mississauga, Ontario) and Vamin (Pharmacia Canada Inc., Dorval,

TPN

with

flaunted as conclusive

enteral

nutrition,

though

often

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

two commonly

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

292

in

QUIGLEY

the

ET AL.

etiology

fants.l13

GASTROENTEROLOGY

of TPN-induced

Though

not

acid in the mature

cholestasis

considered

infant

an essential

or in the adult,

sumes this status in the preterm levels of activity sulfinic

of hepatic

acid decarboxylase.‘14

been shown

to promote

lithocholate

toxicity.

tation in both

low-birth

with

should

in TPN

on TPN

and taurine Its benefits

terohepatic

situations,

circulation

was promoted

ministration

opment

pa-

to ex-

to cholestasis

glutamine shown

plasma nism

to

droxylation

of lithocholic

acid

of chenodeoxycholic

(by 7a-dehy-

acid),

which

has

been shown to impair bile flow and induce cholestasis in animals.12’ Enhanced colonic absorption of lithocholate tween

has also been postulated.“” lithocholate-induced

models

and

TPN-related

also been emphasized.

liver

The similarities damage

histological

122-126Indeed,

be-

in animal

changes three studies

against

Not

all studies

deficiencies

incriminate

TPN-related

hepatic

solutions

Thus,

has

been

gut hypo-

TPN-solution nated

another

alone

could

mechaexplain

cholestasis. contaminants

in cholestasis.

Thus,

of tryptophan

by sodium

tabolites.15”09

bisulfite

Klein

have also been incrimistudies

have suggested

in TPN

solutions

may produce

et al. have

cholestatic

suggested

that

contamia role

mefor

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;

whether

4 adult patients

these effects were mediated

following

by the differences

have

between

the two emulsions

ad-

damage damage

Cholestasis

may

administration.i5*”

in sodium

Thus,

oleate

purification

occur

in adult

to be related Sheldon

content, processes

patients

on

to long-term

et al. found

that

whereas steatosis was almost universal in those with abnormal biopsies within 5 days of beginning TPN, cholestasis and periportal inflammation were more

of Vitamin

E and

common

solutions

in the

adults

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

also

15*17,‘8,23,27 and tends

thereafter.”

The pathogenesis TPN

overgrowth.136,137

have

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-

provides

TPN

suggested that cholestasis and hepatocellular may be related to peroxidative free radical

pre-

the latter.136 Gluta-

loss of oral intake

subsequent

metronidazole

ad-

was

TPN-associated

lipid particle size, or lecitchin would not be defined.14’

study, however,

and

TPN-related

of TPN

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

transloca-

an effect on gut immunity.

cells. 139This schema whereby

nated

production

may inhibit

enrichment

traluminal creased

mucosa

not only to attenuate

degradation

and leads to an in-

gut

plasia 13* but also to prevent TPN-related depletion of Immunoglobulin (Ig) A-producing gut lamina propria

uncertain.12’

of bile salts may contribute

through

bacterial

bacterial

also protect

dysfunction

has been advoof the en-

may

the

oral and intravenous

to be mediated

intestinal

Fiber supplementation mine

No. 1

of fiber.136,‘37 TPN-related

against

liver injury. Intestinal stasis and colonization of the small intestine by colonic-type bacteria promotes inbile salt deconjugation

addition

of small

across

solutions135-‘37

is thought

It

perturbations

of TPN

by the

studies,

in the intestinal

invoked

bacteria

by both

tural changes

de-

however,

tion

translocation

disorders.“’

supplementation remain,

is

supplemen-

infants

of

and has

that taurine

has been

of pre-term

cated.“’

In some clinical

therefore,

solutions,

plain the predilection

taurine

and in adult

of hepatobiliary

translocation

vented

bile acid secretion

infants”’

come as no surprise,

ficiency,

and cysteine

taurine

to promote

promote

wall. 135-137In these animal

as-

due to their low

bile flow and protect

weight

a variety

amino

in the neonate

‘15*‘i6Indeed,

has been shown

in-

taurine

Furthermore,

bile acid conjugate

tients

infant

cystathionase

the principal

in

Vol. 104,

is poorly

of TPN-associated

understood,

and many

cholestasis

in

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

January

HEPATOBILIARY

1.993

presence

of sepsis but rather

process; cholestasis with hematological patients

with

to the underlying

was observed malignancies

inflammatory

bowel

disease

normalities tinuation

disease.”

fibrosis

in all and bile duct one

In one of

the height

that directly approached the issue of of TPN-related cholestasis in adults,

mately

Fouin-Fortunet

et al., based on an association

persistent

levels of lithocholic

of inflammatory TPN-related

between

acid in bile from a group

bowel disease patients liver

dysfunction,

who developed

suggested

a “toxic”

role by lithocholate.” The pathophysiology of TPN-associated cholestasis remains uncertain, and a direct role for TPN has not been

established.

The

hormonal,

10 infants

in 87% of patients but in only 56% of

the few studies the pathogenesis elevated

in the other of TPN.

COMPLICATIONS

morphological,

and

months

Thus,

of jaundice half.

and

some,

ballooning.

the liver, either intestine,

biopsies

several

of TPN

showed fibrosis Though

related

successfully

with the small

performed

children.14*,i4”

The gross and microscopic

liver removed

at the time of transplantation

preterm

for this lesion being based on the rela-

other

of their biliary

stitution

tive immaturity dence

of cholestasis

attributable

system.

While

to TPN

the inci-

has fallen,54

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

cases.‘44-145

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-

infant

who underwent

are presented

Perhaps chronic

the most

and later.

example

by Vileisis

fibrosis

Discontinuation

apparent

clinical

case report noma

could

in infancy

is a

enterocolitis.

395

days

was accompanied

by

of cholestasis, hepatocellular

to evaluate; that

the

Cholestasis

documented

of TPN

to speculate supervene

of irreversible

et a1.i5’ They described

were

remission

is difficult

lated to TPN. effect of TPN TPN solutions

an-

at this in-

with TPN

subsequently died from when aged 26 months. The significance unreasonable

of a

from

at 3 weeks of age, following

of necrotizing

periportal

features

in figure 3A and B respectively. alarming

child who began TPN development

in these

this procedure

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

dis-

Although

alone or in combination

has been

lobular

in others.49

liver disease and cholestasis

rare nowadays, instances lated cirrhosis still occur.

at

in approxi-

cholestasis,

it persisted

discon-

and periportal

proliferation liver

293

performed

portal

discontinuation

hepatocyte in

chronic

revealed

mild hepatocellular

resolved

following

biopsies

Follow-up

following

array,

liver

OF TPN

but the child carcinoma of this single

it is, however, hepatocellular

in the context

not carci-

of cirrhosis

re-

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

tent.

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

in infants

receiving

intralipid

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-

294

QUIGLEY

GASTROENTEROLOGY

ET AL.

Vol. 104,

No. 1

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.

January 1993

HEPATOBILIARY COMPLICATIONS OF TPN

295

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).

resumption

of some oral intake

In infants, chronic liver disease appears to be a direct consequence of prolonged cholestasis and must be

sion,

in patients

assumed

from

TPN

to result

factors, proposed be repeated,

from

prolonged

to induce

exposure

cholestasis

may not include

to those

which,

a direct

it must

effect of TPN.

anced

the

infusion

solutions,

of excessive

deficiencies

and taurine,‘15

tinuous

toxicity22

the early institution

hypophosphatemia,15* all been proposed

choline,15’

and lithocholate but are not supported

have

by consistent

amino

consequence

of long-term

(>18

months)

TPN in adults is liver phospholipidosis.‘59 This lesion, which is similar to that described in certain lysosomal storage diseases,

features

cytoplasmic

phospholipid

de-

posits and multilamellar lysosomes in hepatocytes, Kupffer cells, and portal macrophages. These deposits are thought to reflect intra hepatic accumulation of phospholipids

from

fat emulsions

in the TPN

solu-

of copper

of chronic

for neonatal

dysof bal-

in particular,

cyclic rather

of solutions, of oral feedings.

tal has been suggested

hepatic

by the provision

the avoidance,

acid loads,

administration

ever a beneficial

data. A further

incidence

may be minimized

The pathophysiology of the steatohepatitis-type lesion seen in adults is poorly understood. Relationships to of carnitine,8’s5

cholestasis,

solutions.‘43

In infants, function

of food, and the omis-

with persistent

than

con-

and, in particular, Oral phenobarbicholestasis16’;

how-

effect has not been consistent.‘6’

Dlsorders of the Gallbladder and Biliary Tree In Association with TPN Acalculous

cholecystitis,

biliary

sludge,

striking

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

long-term

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

TPN

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

296

GASTROENTEROLOGY Vol. 104. No. 1

QUIGLEY ET AL.

gallstone

development

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

have

on TPN

of gallbladder

carbohydrate-lipid

on TPN

tion to amino

by reporting

nonvisualization

a 36% incidence

in a group

were subsequently

proven

of patients

who

not to have acute cholecys-

clearly

steatosis

as a consequence

to the bedside

is far from

ate such complications.

the diagnostic

Of relevance of TPN

Impaired

several on bile

bile

flow

however,

of both cholestasis

studies flow

has

ing.‘74~‘75~‘80~‘82~‘83 The

of cholescin-

have examined

and

been

balance

the

composition.““‘*” a

consistent

of evidence

suggests,

that during TPN administration, bile is not 179~180~182 Lirussi et al., indeed, showed

cholesterol

saturation

indices

in their

TPN-fed

which tractility,

Furthermore,

though

was increased, choleresis.

this

To explain

posed the presence within

biliary did not

bile acid concentration result

these results,

of a relative

the enterohepatic

in an appropriate these authors

stagnation

circulation

in TPN.‘83

recent report by Lindor and Burnes of reversal vere TPN-related cholestasis by ursodeoxycholic suggests that choleresis

induced

pro-

of bile acids The of seacid

by the oral administra-

than initia prerequi-

excretory

of enteric

and

In both infants of bile

as a consequence factor

of

in the

sludge, gallstones,

and cholesta-

pharmacological

maneuvers,

bile flow and sustain

may ultimately

by TPN. system in

stimulation

may be the primary

of biliary

stimulate

occurs,

rather

may be exacerbated

of the biliary

contractility

lack of oral intake

rats. 182In the same study, bile acid pool size was found was unchanged.

which

the absence

Nutritional

In many

dysfunction

Thus, malnutrition,

flow and gallbladder

to be increased,

yet bile acid synthesis

straightforward.

may set the stage for cholestasis.

development

in rela-

of this data

of TPN in many circumstances,

immaturity

and adults,

sis.

excess or

to or exacerbate

can cause steatosis, Similarly,

calorie

and cholestasis

hepatobiliary

TPN may contribute

infants

find-

supersaturated. lower

where

site for the institution

to the pathogenesis

and cholelithiasis, effects

specificity

group.‘73

of both

acid excess, the extrapolation

tially

in this patient

studies

by TPN,

of either

imbalance

situations

increase

experimental

the induction,

titis.“’ A recent report suggests, however, that the administration of intravenous morphine will substantigraphy

Although

shown

prevent

gallbladder

con-

these complications.

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

solutions

on hepatic

physiology

intake might of the effects and biochem-

istry has led to the development

of TPN formulations,

which

of hepatobiliary

function

minimize

the incidence

in general

and steatosis

in particular.

dysNever-

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

these

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

of amino

endogeinfusions

instances

Though TPN,

cirrhosis most

reflect

direct

may rarely

instances

TPN-hepatotoxicity.

occur

of TPN-related

in adults

on home

cirrhosis

have

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

an important

that combined transplanand liver may eventually

therapeutic

alternative.

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-

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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.