Increased Risk of Gallstones in Children Receiving Total Parenteral Nutrition

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Increased

Risk of Gallstones

in Children

Receiving

Total

Parenteral

Nutrition

Joel

J. Roslyn,

MD, William

E. Berquist,

MD, Henry

A. Pitt, MD,

Linda

L. Mann,

RN, Hooshang

Kangarloo,

MD,

Lawrence

DenBesten,

MD, and Marvin

E. Ament,

MD

From the Departments of Pediatrics, Surgery, and Radiology, UCLA School of Medicine,

Los Angeles, and Surgical Service, Veterans Administration Medical Center, Sepulveda, California

ABSTRACT. Twenty-one children receiving long-term total parenteral nutrition were prospectively evaluated for the presence of gallstones. Using ultrasonography, nine children (43%) were found to have cholelithiasis, and five have since undergone cholecystectomy. Only children with ileal disorders or previous resection devel-oped stones. In the select group of patients with ileal disorders or previous resection, the prevalence of stones was 64%, nearly twice that which has been observed in similarly defined adults not receiving total parenteral nutrition. Data from this study suggest that the prolonged administration of parenteral nutrition significantly en-hances the risk of gallstone formation already imposed

by a previous ileal resection or disorder. Periodic ultra-sonograms provide a safe and accurate means of

moni-toring high-risk patients during and after prolonged total

parenteral nutrition therapy. Pediatrics 1983;71:784-789; parenteral nutrition, gallbladder stasis, gallstones.

Gallbladder disease is not commonly considered in the differential diagnosis ofchildren with abdom-inal complaints because it occurs so infrequently. Unlike adults, children with cholelithiasis and/or cholecystitis may not complain of symptoms refer-able to the biliary tract. Therefore, awareness of a predisposition to gallbladder disease and early rec-ognition of the signs and symptoms of cholecystitis in children maintained on long-term TPN is of great significance. For these reasons, the present study was undertaken to determine prospectively the prevalence of gallbladder disease in our pedi-atric patients receiving long-term TPN.

METHODS

Study Population

An increased incidence of acalculous and calcu-bus cholecystitis has been observed in adults main-tamed on long-term total parenteral nutrition (TPN).’ Anecdotal reports have also suggested that children receiving TPN may develop biliary stasis2

and cholelithiasis.3 However, a possible cause-and-effect relationship between TPN and gallstone dis-ease has not been critically evaluated in a large pediatric population. As increasing numbers of chil-dren are receiving prolonged courses of parenteral nutrition, an etiologic relationship between TPN and gallbladder disease has assumed new signifi-cance.

Received for publication June 10, 1982; accepted July 26, 1982.

Reprint requests to (H.A.P.) 77-130 Center for the Health

Sci-ences, UCLA School of Medicine, Los Angeles, CA 90024.

784

PEDIATRICS Vol. 71

No. 5 May

1983

A prospective analysis was conducted of all chil-dren receiving a prolonged course of parenteral nutrition at the UCLA Medical Center from Janu-ary 1981 through December 1981. Patients included in this study were <15 years of age and were main-tamed on parenteral nutrition for three or more months. Twenty-one children met these criteria

and form the basis for this report. It was assumed

that no patient had gallbladder disease prior to initiation ofparenteral nutrition. Children fulfilling these criteria underwent abdominal ultrasonogra-phy between January and December 1981.

The study group consisted of 12 boys and nine girls. Their ages ranged from 8 months to 14 years,

with a mean of 45.6 months. Nine of these children

(42%) were <2 years of age at the time of

evalua-tion. The diagnosis and indication for parenteral

nutrition for the 21 children are shown in Table 1.

Small bowel malrotation or volvulus occurred in six children, pseudoobstruction in four, necrotizing

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785

TABLE 1. Diagnosis and Indication for Total

Paren-teral Nutrition (TPN)

Diagnosis

Malrotation, volvulus

Idiopathic pseudoobstruction

Necrotizing enterocolitis Crohn’s disease Intestinal atresia

Inflammatory bowel disease, unclassified Chromosome anomaly

Vasculitis, unclassified Combined immunodeficiency TPN Indication

Short bowel syndrome

Failure to thrive Obstruction Malabsorption

Active Crohn’s disease

No. of Patients

(N

=

21)

terocolitis in three, inflammatory bowel disease in three, and intestinal atresia in two; in the three

remaining children miscellaneous diagnoses were

given. The justification for parenteral nutrition was

listed as short bowel syndrome in 11 children,

fail-ure to thrive in five, obstruction in three, and malabsorption and active Crohn’s disease in one child each.

The length of time that patients received TPN varied from 3 to 168 months and averaged 20.8

months. Although all of these children were

hospi-talized for long periods, they received the majority of their TPN as outpatients. Parenteral nutrition

solutions provided calories with hypertonic glucose,

protein, and fat emulsions. Protein was supplied in

the form of casein hydrolysates or amino acid

so-lutions. The concentration used was 3% in the

former and 2% in the latter. Either 10% Intralipid or 10% Liposyn was administered on a regular basis to all 21 children. Trace metals and vitamins were

also included in standard solutions, and electrolytes

were added according to needs of individual

pa-tients.

Gallbladder Assessment

Ultrasonography was used as the primary

diag-nostic modality in this study for gallstone detection.

Gray-scale and, in particular, real-time ultraso-nography have been shown to provide an effective

means of diagnosing gallstones and cholecystitis in

the pediatric population.4’5 Patients were

consid-ered to have gallbladder disease only if they had definite gallstones shown by ultrasonography.4 The

finding of biliary sludge was not accepted as a

positive study. Because of our study population’s

age and the presence of malabsorption in most of

our patients, oral cholecystography was not

consid-ered to be an appropriate diagnostic modality.

Analysis

of Prevalence

and Risk Factors

Two thirds of the children studied had

preexist-6 ing ileal disease or had undergone extensive small

4 bowel resection. Whereas adults with ileal disease

are thought to have a predisposition to gallstone

2 formation,6’7 reliable data on the prevalence of

gall-1 stones in children with similarly defined problems

1 are not available. In order to assess the effect of

1 total parenteral nutrition on the incidence of

gall-1 bladder disease in patients already at risk, we

com-11 pared the prevalence of gallstones in our children

5 receiving TPN with that reported in an autopsy

3 study8 and in adults with ileal disorders.7

1 In addition to prevalence data, several potential

1 risk factors were analyzed for an associated

in-creased incidence of gallstones. The factors ana-lyzed included (1) length of time patients received TPN, (2) duration of time patients had severely limited or no oral intake during TPN, (3) history of an ileal disorder, and (4) levels of total bilirubin, alkaline phosphatase, SGOT, and SGPT, prior to

and during TPN administration.

Statistical

Analysis

Data were expressed as means ± SD. The

mci-dence of gallbladder disease in our TPN patients was compared with that expected in ileal disorder patients by

x2

analysis. This statistical test was also employed to determine whether other clinical

and laboratory factors were associated with an

in-creased risk of gallbladder disease in our hyperali-mentation patients.

RESULTS

Gallbladder

Disease

Prevalence

Prevalence data for children receiving prolonged parenteral nutrition are shown in Table 2. Of 21 children studied, nine (43%) were found by ultra-sound to have gallstones. Eight children had

nu-merous echogenicities indicating multiple

gall-stones noted on ultrasound; one patient had a

sol-itary stone. The incidence of gallbladder disease in boys and girls was 58% and 22%, respectively. The mean age of the nine patients developing gallstones was 52.3 months, compared with 45.6 months for the entire study population. The youngest patient to develop stones was an 8-month-old child with intestinal atresia who had been receiving parenteral nutrition since shortly after birth.

Of

14 children with an ileal disorder or a previous terminal ileal resection nine (64%) had gallbladder

(3)

;

70 p<.O1 vs Normal Children

C’, 60 + p< .O5vs Adult rleal Dis. Ui

z

g

*

U)

:1

Li

0 Ui U z Ui 0 U

z .1% [43#{176}/q

*P< .01.

t Prolonged fasting or massive small bowel resection.

786 TOTAL PARENTERAL

NUTRITION

AND GALLSTONES

disease. In comparison, none of the seven children with an intact ileum developed gallstones (P < .01).

Comparative gallstone incidence data are presented in the Figure. The incidence of gallbladder disease in children <15 years of age is reported to be <1%.8

The observed incidence of 43% in our 21 children

receiving TPN is striking (P < .01). When

com-pared to an adult ileal disorder population with a mean age of>40 years,7 children with ileal resection who received TPN had a significantly greater (P <

.05)

incidence of gallstone disease (64% v 32%).

Five of the nine children with documented gall-stones have undergone cholecystectomy. All pa-tients who required operations had episodic emesis, intermittent jaundice, and significant abdominal tenderness on physical examination. In one child the clinical picture was compatible with biliary tract disease, but other diagnoses were thought more likely, and surgery was delayed. When cholecystec-tomy was finally undertaken, identification of the gallbladder was so difficult, as to preclude its safe removal. This patient subsequently developed an opportunistic pulmonary infection and died. Post-mortem examination revealed acute and chronic cholecystitis, cholelithiasis, and a pericholecystic abscess secondary to gallbladder perforation.

Risk Factors

The association of multiple factors with the de-velopment of gallbladder disease in children receiv-ing parenteral nutrition is shown in Table 3. The mean time on TPN for the 21 patients studied was

20.8 months. Children developing gallstones had been maintained on TPN more than twice as long as their counterparts who did not have stones de-tected by ultrasound (P < .01). Two children, aged 8 months and 14 years, had stones detected 8 months after initiation of TPN. For the remaining

seven children with stones, the minimal length of time on TPN was 20 months (average 36 months). In contrast, the average time on TPN in children without gallstones was 14 months. Only one of these 12 children without gallstones had been receiving

TPN for >20 months.

Of 21 children receiving prolonged TPN, 11 either took oral supplements or had periods of

TABLE 2. Prevalence of Gallstones in Children

Receiv-ing Total Parenteral Nutrition (TPN)

No. of No. with Gallstone

Patients Gallstones Prevalence

(%)

Total 21 9 43

Males/Females 12/9 7/2 58/22

Ileal disorder 14 9 64

Nonileal disorder 7 0 0

Normal Children Adult Children

Children onTPN Ileal Ileal Dis.

Expected Observed Disorder + TPN

Figure. Incidence of gallstones observed in 21 children receiving total parenteral nutrition (TPN) compared with that expected in normal children8 and gallstone preva-lence observed in 14 children with ileal disorders (Dis) who received TPN compared with that reported in adults with similarly defined ileal disorders who had not re-ceived TPN.7

TABLE 3. Analysis of Risk Factors in Children Receiv-ing Total Parenteral Nutrition (TPN)

With Without Gallstones Gallstones

(N=9) (N=12)

Mean TPN time (mo) 30.1 13.9*

Gallbladder stasist (%) 89 42*

Ileal resection (%) 89 42*

Ileal disorder (%) 100 42*

substantial oral intake. When children who formed

stones and children who did not form stones were compared, there was no significant difference re-garding the amount of oral intake or the duration of fasting. Four of the nine patients developing

gallstones fasted during their courses of TPN. The

remaining five patients with gallstones took oral supplements; however, four of these patients had undergone extensive small bowel resections result-ing in duodenocolonic or proximal jejunocolonic anastomoses. In these four patients the oral

feed-ings may not have been effective in stimulating

gallbladder contractions. Thus, eight of the nine children who developed gallstones may have been at increased risk because of prolonged gallbladder stasis (Table 3). The incidence of gallstones in patients receiving either Intralipid or Liposyn was not significantly different.

A history of previous ileal resection was an out-standing risk factor in stone formation in children receiving TPN. Gallstones were not detected in any child who had not undergone ileal resection.

Gall-stones formed in eight patients who had prior distal

small bowel resections and in a ninth patient with

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787

Crohn’s disease involving the terminal ileum. Of 13 patients with a previous ileal resection, eight (62%)

were found to have gallstones a mean of 31 months

after resection and 33 months after starting TPN.

For the five patients with ileal resection who had

negative ultrasound studies the average time on TPN was 21 months. Most children had some ele-vation of their serum total bilirubin, alkaline phos-phatase, or serum transaminase levels, which were

above pre-TPN levels. There was, however, no

sig-nificant difference in these laboratory values be-tween patients with and without gallstones.

Gallstone

Confirmation

Five of the nine children who were determined by ultrasonography to have gallstones have had the presence of stones documented at surgery or at

postmortem examination. In four children the

stones were jet black and appeared to be pigment stones. In the fifth child the gallbladder was filled

with orange clay-like material which contained

three 4-mm diameter firm areas which were black

when sections were studied. Analysis by infrared

spectroscopy of the stones from this fifth child and from three of the other children showed that they consisted mainly of calcium bilirubinate. Choles-terol content by weight was <20%. Neither the oxylate nor citrate content of these stones was determined.

DISCUSSION

The present study represents the first prospective analysis of the prevalence of gallstones in a large number of children receiving prolonged parenteral nutrition. In an age group that virtually never has cholelithiasis, nine of 21 children (43%), with a

mean age of <4 years, developed gallstones

follow-ing the institution of parenteral nutrition. Analysis of multiple factors revealed that increased length of time on TPN, aberrant eating patterns, and prior

ileal resection were associated with a significantly increased incidence of gallstones in children receiv-ing TPN.

These data provide further evidence that the prolonged administration of parenteral nutrition induces cholelithiasis and cholecystitis, as

previ-ously suggested by anecdotal reports3’9 and by a

retrospective analysis of our adult TPN patients.’

The enhanced risk of gallstones among long-term

TPN patients results from a combination of factors that promote gallbladder stasis and alter normal hepatic metabolism. Within the total population of

patients receiving TPN, those at greatest risk are

patients who have ileal disorders or who have undergone a prior terminal ileal resection.

Under normal circumstances, gallstone

forma-tion in children is a rare phenomenon. In a

retro-spective study, Andrassy et al’#{176}reported that

chil-then <15 years old accounted for only 0.72% of all

the cholecystectomies performed at an individual center. The prevalence of gallstones in children is

not known, although autopsy data put this figure

at <0.1%.8 Reports examining cholecystitis in

chil-dren suggest that in most instances congenital

an-omalies, hemolytic anemias, and/or infection are

the important etiologic factors’#{176} and that acalculous

cholecystitis is more common than calculous dis-ease.”2 In the present series of 21 children receiv-ing prolonged TPN, the incidence of gallstones was astoundingly high in comparison with previous re-ports. Furthermore, none of our children with gall-stones had any evidence of hemolytic anemia or

extrahepatic biliary anomalies, and all had

calcu-bus cholecystitis.

Anecdotal reports’3 suggest that children who

have .had an ileal resection or disorder are at

in-creased risk for gallstone formation. This

phenom-enon has been documented in adults.6’7 However,

data are not available on the incidence of gallstones

in children with ileal disorders or ileal resection. In

adults with ileal disorders studied by Heaton and

Read7 the observed incidence ofgallstones was 32%. Although the number of our patients studied was only 14, the 64% incidence of gallstones suggests that the prolonged administration of parenteral nutrition favors the expression and development of

gallstone disease in children who are already at risk

because of ileal disorders.

The pathogenesis of gallstones in children receiv-ing TPN is not clear, but information gleaned from

the present study may help to clarify the issue.

Length of time that a patient receives TPN is an important factor in stone formation. Children de-veloping stones had been maintained on TPN more

than twice as long as those without evidence of

cholelithiasis. Seventy-eight percent of children

with stones had received TPN for a minimum of 20

months, and 67% had been receiving TPN for a

minimum of 30 months. In contrast, patients

with-out stones received TPN a mean of 14 months, and

only 8% were maintained on TPN >30 months. Of

the six patients receiving TPN for >30 months,

five (83%) had cholelithiasis. These data suggest a

direct correlation between length of time on TPN and stone formation.

The prolonged administration of TPN is associ-ated with fasting and aberrant eating patterns. TNP is also used for patients with massive bowel resections who have ineffective food-stimulated gallbladder emptying. Fasting and abnormal eating

patterns remove the physiologic, neural, and

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788 TOTAL

PARENTERAL

NUTRITION

AND

GALLSTONES

monal stimuli that regulate gallbladder emptying,

resulting in biliary stasis. In patients with extensive proximal small bowel resections, (duodeno- or je-junocolostomies) cholecystokinin release may be

impaired, leading to altered gallbladder contraction and biliary stasis. In the present study, eight of

nine children with gallstones had biliary stasis

sec-ondary to fasting or an interruption in the food-cholecystokinin-gallbladder contraction pathway.

Stasis of bile within the gallbladder is a vital factor

in the pathogenesis of gallstones and has been

reported in children receiving TPN.2 During pe-nods of fasting, the stimulus for gallbladder con-traction is absent, and the sphincter of Oddi re-mains closed. This situation results in hepatic bile preferentially moving into the gallbladder and

de-creased gallbladder emptying. The net effects are

sequestration of bile salts within the gallbladder and an early expansion of the bile salt pool. When

experimental animals maintained on TPN for ten

days were compared with control animals,’4 the ratio of labeled bile acids in gallbladder compared with hepatic bile was reduced, suggesting that the proposed mechanism for TPN-induced stasis is

cor-rect. Ultrasound and in vivo studies have confirmed

the evolution from bile stasis to sludge to calcium bilirubinate stones.’5 These observations support

the hypothesis that fasting during TPN leads to

gallbladder stasis which, in turn, results in biliary

sludge and, ultimately, noncholesterol gallstone for-mation.

The alternative interpretation of our data is that the prolonged exposure to the TPN solution, itself a potentially lithogenic substance, is a critical factor in stone formation. This hypothesis seems less likely to be an important etiologic factor for several reasons. One study in rats, a species without a gallbladder, suggests that the intravenous admin-istration of parenteral nutrition increases hepatic bile lithogenicity.’6 However, the applicability of an animal model without a gallbladder to humans with an intact gallbladder is questionable. In compari-son, a recent study in the prairie dog, an excellent model for human gallstone formation, showed that the saturation index of gallbladder and hepatic bile decreased significantly after ten days of TPN ther-apy.’4 Furthermore, the finding of pigment stones in children receiving TPN suggests that in this clinical setting, the degree of cholesterol saturation of bile may not be pertinent.

Traditionally, ileal resection has been thought to predispose to cholesterol gallstone formation.’3 The presumed mechanism was interruption of the nor-mal enterohepatic circulation leading to a decreased bile salt pool size, increased hepatic bile

lithogenic-ity, cholesterol precipitation and, ultimately,

cho-lesterol stone formation. Our observation that

non-cholesterol gallstone formation occurs in children with ileal disorder who are maintained on TPN

confirms the recent observations by Heubi and

associates.’7 However, the exact mechanism whereby ileal resection promotes noncholesterol calcium bilirubinate stone formation remains to be elucidated.

The frequency with which cholelithiasis is

ob-served in children receiving TPN mandates consid-eration of cholecystitis as a diagnosis in a child receiving TPN who experiences abdominal symp-tomatology. In this situation it may be particularly difficult to make the clinical diagnosis of

cholecys-titis as symptoms frequently overlap those of

TPN-induced liver disease as well as those of other gas-trointestinal disorders. They key to clinical

diag-nosis is a high index of suspicion. Surveillance

programs designed to screen for asymptomatic

gall-stones in patients receiving TPN are advised.

Ultrasonography is a safe and effective means

of diagnosing cholelithiasis. Children receiving

TPN who are found to have gallstones and have any symptoms suggestive of cholecystitis should undergo early cholecystectomy. Studies are

cur-rently underway in our institution to evaluate the

feasibility of gallstone prophylaxis in TPN patients.

SUMMARY

In the present study, we have prospectively eval-uated 21 children receiving long-term TPN and found a 43% incidence of gallstones. Analysis of multiple factors revealed that increased length of time on TPN, aberrant eating patterns, and prior ileal resection were associated with a significantly increased incidence of gallstones. Our data suggest that the administration of TPN favors the early clinical expression of noncholesterol gallstone for-mation in children already at high risk. Surveillance

programs for stone detection are advised and early

cholecystectomy should be considered. Studies to evaluate gallstone prophylaxis in high-risk patients receiving TPN are currently underway.

ACKNOWLEDGMENT

This work was supported, in part, by a Veterans Administration research grant.

REFERENCES

1. Roslyn JJ, Pitt HA, Mann L, et al: Long-term total paren-teral nutrition induces gallbladder disease. Gastroenterology 1981;80:1264.

2. Barth RA, Brasch RC, Filly RA: Abdominal pseudo tumor

in childhood: Distended gallbladder with parenteral hyper-alimentation. AJR 1981;136:341

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ARTICLES 789

3. Whitington PF, Black DD: Cholelithiasis in premature in-fants treated with parenteral nutrition and furosemide. J Pediatr 1980;97:647

4. Greenberg M, Kangarloo H, Cochran ST, et al: The ultra-sonographic diagnosis of cholecystitis and cholelithiasis in children. Radiology 1980;137:745

5. Billeaud C, Cadier L, Demarquez JL, et al: Gallbladder and biliary tract detected by echotomography in children on total parenteral nutrition. JPEN 1980;4:603

6. Hill GL, Mair WSJ, Goligher JC: Gallstones after ileostomy and ileal resection. Gut 1975;16:932

7. Heaton KW, Read AE: Gallstones in patients with disorders of the terminal ileum and disturbed bile salt metabolism. Br

Med J 1969;3:494

8. Newman H, Northup J, Rosenblum M, et al: Complications

of cholelithiasis. Am J Gastroenterol 1968;50:476

9. Petersen SR, Sheldon GF: Acute acalculous cholecystitis: A complication of hyperalimentation. Am J Surg 1979;138:814 10. Andrassy BA, Treadwell TA, Ratner JA, et al: Gallbladder

disease in children and adolescents. Am J Surg 1976;132:19

11. Dutta T, George V, Sharma GD, et al: Gallbladder disease in infancy and childhood. Prog Pediatr Surg 1975;8:109 12. Pieretti R, Auldist AW, Stephens CA: Acute cholecystitis in

children. Surg Gynecol Obstet 1975;140:16

13. Pellerin D, Bertin P, Nihoul-Fedete C, et al: Cholelithiasis and ileal pathology in childhood. J Pediatr Surg 1975;10:35

14. Doty JE, Pitt HA, Porter-Fink V, et al: The pathophysiology of gallbladder disease induced by total parenteral nutrition. Gastroenterology 1982;82:1046

15. Allen B, Bernhoft R, Blanckaert N, et al: Sludge is calcium

bilirubinate associated with bile stasis. Am J Surg

1981;141:51

16. Gimmon Z, Kelley RE, Simko V, et al: Total parenteral

nutrition (TPN) solution increases lithogenicity of bile in

the rat. J Surg Res 1982;32:256

17. Heubi JE, Soloway RD, Balistreri WF: Biliary lipid com-position in healthy and diseased infants, children, and young adults. Gastroenterology 1982;82:1295

WILLIAM

T. GRANT

FOUNDATION

FACULTY SCHOLARS

AWARDS

Each year, the William T. Grant Foundation makes awards to five young

research workers in the field of children’s mental health. Institutions where the Scholars work receive $150,000, plus indirect costs for partial support for the Scholars for five years. The purpose of the award is to protect the research time of the Scholars during the critical early years of their careers. Preference is given to Scholars working in the field of the Foundation’s principal interest-understanding how school age children cope with stresses which may lead to failure to fulfill their potential.

Awards for 1983 were made to:

Ronald G. Barr, MD, Assistant Professor of Pediatrics, McGill University

(Montreal)

Gregory K. Fritz, MD, Assistant Professor of Psychiatry, Stanford University

School of Medicine

Helen Orvaschel, PhD, Assistant Professor of Psychiatry, Western

Psychi-atric Institute and Clinic, University of Pittsburgh

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Elaine F. Walker, PhD, Assistant Professor of Clinical Psychology, Cornell University

The Foundation plans to make the awards annually. Deadlines for applications

are July 1 of each year. Information on application procedures is available from

the Foundation.

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1983;71;784

Pediatrics

Lawrence DenBesten and Marvin E. Ament

Joel J. Roslyn, William E. Berquist, Henry A. Pitt, Linda L. Mann, Hooshang Kangarloo,

Increased Risk of Gallstones in Children Receiving Total Parenteral Nutrition

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