Total
Parenteral
Nutrition
Cholestasis:
A Cause
of Mechanical
Biliary
Obstruction
MAJ Robert
W. Enzenauer,
MC, USA, CPT Jill S. Montrey,
MC, USA,
COL
Peter
J. Barcia,
MC,
USA,
and
LTC
Joseph
Woods,
MC,
USA
From the Departments of Pediatrics, Surgery, and Pathology, Trip/er Army Medical Center, Honolulu
ABSTRACT.
In a
newborn baby with Hirshsprung’sdis-ease obstructive jaundice developed following prolonged
parenteral nutrition. At laparotomy, thick inspissated
bile was flushed from the biliary tree and prompt reso-lution of the jaundice followed. To our knowledge, this is the first reported case in which inspissated bile appeared to be a complication of total parenteral nutrition.
Me-chanical obstruction must be recognized as an extreme in the spectrum of total parenteral nutrition cholestasis.
Pediatrics 1985;76:905-908; totalparenteral nutrition
cho-lestasis, inspissated bile syndrome, bile sludge syndrome.
Inspissated
bile
syndrome was described by Ladd’in 1935 as a category of obstructive jaundice caused
by
a
plug of inspissated bile obstructing thecorn-mon
bile duct.2,3
Now,
however,
there
is no
univer-sal agreement that the syndrome even exists.4 We present
a patient
who had cholestatic
jaundice
fol-lowing prolonged total parenteral nutrition.
Inspis-sated bile was flushed from the biliary tree, and resolution of the jaundice followed. To our knowl-edge, this is the first reported case in which the
inspissated
bile syndrome
appeared
to be a
compli-cation of total parenteral nutrition. We propose
that
this
mechanical
obstruction
in the biliary
tree
must
be recogized
as an extreme
in the spectrum
of
total parenteral nutrition cholestasis. Its recogni-tion is important because mechanical intervention
may
be required
for resolution.
Received for publication Nov 13, 1984; accepted March 28, 1985. The opinions or assertions contained herein are the private
views of the authors and are not to be construed as official as
reflecting the views of the Department of the Army or the Department of Defense.
Reprint requests to (R.W.E.) 621 Bunker Hill Rd, Clarksville,
TN 37042.
PEDIATRICS (ISSN 0031 4005). Copyright (C 1985 by the
American Academy of Pediatrics.
CASE
REPORT
The patient was an 11-day-old male infant
air-evacu-ated to Tripler Army Medical Center (TAMC) from the
Marshall Islands for treatment of intestinal obstruction.
Prenatal history was unremarkable and a spontaneous
vaginal delivery was uneventful. Birth weight was 7 lb 7 oz (3,380 g). At 12 hours of age, signs and symptoms of intestinal obstruction developed. Clinical and pathologic findings confirmed a diagnosis of Hirshsprung’s disease
and a sigmoid colostomy was performed in the normally
innervated colon. Total parenteral nutrition was begun on the second postoperative day. Persistent feeding in-tolerance prompted a variety of studies that revealed a mechanical small bowel obstruction requiring lysis of
adhesions on the 30th day of life. Parenteral nutrition
was continued. Two weeks later, small enteral feedings
were begun, but necrotizing enterocolitis developed
man-ifested by temperature instability, abdominal distention, vomiting, and hyperbilirubinemia (total bilirubin, 14.7
mg/dL; direct bilirubin, 9.7 mg/dL). Stools were positive
for both guiac and reducing substances. Abdominal ra-diographs revealed dilated loops of bowel with air-fluid levels and intramural air. Stool cultures grew heavy
Kieb-siella pneumoniae.
A 10-day
course
of antibiotics
(ampi-cillin, kanamycin, and cefadyl), nasogastric suction, and continued parenteral hyperalimentation resulted in im-provement of all clinical and laboratory parameters ex-cept the jaundice and hyperbilirubinemia. Stools were acholic. Oral feedings were begun. Abnormal liver func-tion tests were consistent with cholestatic jaundice (seeFigure).
The infant had received eight RBC transfusions during his hospital course. Tests for hepatitis B surface antigen
were negative on three occasions. Serum a1-antitrypsin
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TOTAL
PARENTERAL
NUTRITION
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went exploratory laparotomy with intraoperative chole-cystogram and liver biopsy to rule out biliary atresia. At
operation, a dark green liver and a large gallbladder filled with bile were noted. The bile was the consistency of “sludge,” like thick molasses. The gallbladder and extra-hepatic biliary tree were both lavaged clear of the
thick-ened
bile and
manually
emptied
into the duodenum; anormal, clear biliary tract was then demonstrated radio-graphically, although an initial cholangiogram revealed incomplete filling of the biliary system, presumably due to the very thick bile.
Postoperatively, the hyperbilirubinemia and abnormal
liver function tests rapidly returned to normal. Stools
became normal. The infant’s course thereafter was un-complicated. The infant was discharged at 4 months of
age,
weighing
3,290 g. Follow-up at 18 months of agerevealed
a thriving
baby
with
normal
liver function
tests.
PATHOLOGIC
FINDINGS
The liver biopsy specimen showed marked cen-trolobular and diffuse intracellular and canalicular
cholestasis. Feathery degeneration of hepatocytes was widespread and focally associated with collec-tions of neutrophiles, giant cell transformation, and
bile-containing Kupffer cells. Bile duct
prolifera-tion and bile plugs in the portal bile ducts were not
present.
DISCUSSION
There is controversy about the existence of the
inspissated bile syndrome. Inspissated bile
syn-drome was originally described as cholestasis caused by inspissation of bile in neonates with
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www.aappublications.org/news
severe Rh hemolytic disease.57 However, studies of
the liver biopsies taken at the time of surgery have led many observers to abandon the term
“inspis-sated bile” and call most cases “hepatitis with
res-olution
coincident
with
surgery.”’#{176}
Only
a few
authors have proposed that inspissated bilesyn-drome
is
not
a
specious
disease
but
possibly
a
distinct clinical entity.” Lilly’2 reported an infantwith inspissated bile plug, requiring surgical
extrac-tion
of
the
impacted,
firm,
green,
biliary
calculi.
Benson’3
described
an
infant
with
this
condition
who
recovered
following
irrigation
of
the
biliary
tree
and
removal
of the
inspissated
biliary
material.
Rickham and Lee’#{176}described five patients in whom
operative
cholangiography
was
performed.
A small
catheter was inserted into the gallbladder and
con-siderable
pressure
had
to
be
exerted
in
order
to
inject contrast medium into the gallbladder. Thegallbladder
and
bile
ducts
became
distended
until
there was a sudden release of pressure and free flow
of contrast
material
into
the
duodenum.
The
biliary
tree was radiographically normal, and the jaundice resolved immediately postoperatively. Liver biopsy
specimens were normal in
these
five
patients.
A number
of
factors
are
known
to
modify
bile
production.’4 Additionally, specific conditions ap-pear to predispose a sick neonate to the
develop-ment
of
cholestatic
jaundice.
Prolonged
periods
without
oral
feedings
causes
cholestasis
and
a
de-crease in the bile acid pooi,’52’ partially from lack of bacterial colonization in the intestinal tract.22’23 The hepatic enzyme system is immature. In the mature newborn infant, the cholate pool and
secre-tory
rate
are
about
50% of adult values,24 andpre-mature infants have an even smaller output of bile
acids.25 Prehepatic hyperbilirubinemia is often present due to other factors.
Total parenteral nutrition has been associated with obstructive jaundice in infants.22’2632 The etiology is unknown, but some authors believe that
it is caused by interference with the hepatocellular enzymes controlling bile excretion.3#{176} The most prominent findings in liver biopsies in these pa-tients has been intracellular and canalicular
chole-stasis. Other pathologic findings are bile duct pro-liferation, fibrosis, and portal inflammation with
eosinophils.22’2932 More recently, increased mci-dence of gallbladder disease has been documented
in patients
receiving
long-term
total
parenteral
nu-trition.21’3336 The liver biopsy results in our patient are similar to the findings described in infants treated with total parenteral nutrition. Because of
the
pathologic
findings
and
the
clinical
history,
we
believe that the prolonged total parenteral nutrition was largely responsible for the mechanical biliary obstruction in our patient.
Cholestasis associated with total parenteral nu-trition encompasses a wide spectrum. It is generally
mild, with asymptomatic hepatic enzyme eleva-tions, which are totally reversible with the cessation of the total parenteral nutrition, and requires no intervention. However, the cholestasis can progress to actual mechanical obstruction in the biliary tree.
Our
patient
presented
with
“inspissated
bile
syn-drome” as a manifestation of this mechanical ob-struction. Mechanical flushing of the biliary tree intraoperatively successfully reversed the condition in our patient. It is doubtful that the inspissated bile, already formed, would have cleared without
surgical intervention.
No specific means have been proposed to prevent total parenteral nutrition-associated cholestasis in critically ill neonates requiring prolonged hyperal-imentation. Obviously, the duration of total par-enteral nutrition administration should be limited
whenever
possible.
When
actual
mechanical
ob-struction develops, percutaneous catheterization of
the
gallbladder
and
biliary
tree,
hitherto
used
as a
diagnostic tool in infants,37’ could be a therapeutic tool if the condition were recognized preoperatively. Prophylactic or therapeutic cholecystectomy incritically ill infants requiring long-term total par-enteral nutrition would not be reasonable because of prohibitive operative morbidity and mortality.39 Daily infusion of cholecystokinin-octapeptide has prevented total parenteral nutrition-induced
gall-bladder
stasis
in laboratory
animals.4#{176}It is
conceiv-able that intermittent administration of parenteral cholecystokinin could help evacuate the biliary tree and prevent actual mechanical obstruction.
Appro-priate clinical trials are indicated.
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