Abbreviations
CMC: Critical micellar concentration
MCT: Medium chain triglycerides
EHA: Extrahepatic biliary atresia
PIBD: “Paucity of intrahepatic bile ducts”
PHC: Post-hepatitic cirrhosis
(Revision received November 1; accepted for publication November 8, 1971.)
Supported in part by U.S. Public Health Crant FR-69, the Jessica Nyc and the Justine
Lacoste-Beaubien Funds.
ADDRESS FOR REPRINTS: (C.C.R.) H#{243}pitalSainte-Justine, 3175 Ste. Catherine Road, Montreal 250, P.Q.
PEnIAnucs, Vol. 50, No. 1, July 1972
THE
MALABSORPTION
ASSOCIATED
WITH
CHRONIC
LIVER
DISEASE
IN CHILDREN
Andr#{233}eWeber, M.D., and Claude C. Roy, M.D.
From the Departments of Pediatrics, H#{244}pitaZSainte-Justine, University of Montreal,
and the University of Colorado Medical Center, Denver, Colorado
Montreal, P.Q.;
ABSTRACT. The malabsorption associated with chronic liver disease was studied in 23 children, all except two of whom had evidence of cirrhosis. There were 14 patients with extrahepatic biiary atresia, four with “paucity of intrahepatic bile ducts,” and five with post-hepatitic cirrhosis. Ste-atorrhea (>5 gm /24 hr) was documented in the
14 patients tested while on a normal diet. No
evidence of pancreatic or small bowel mucosal
disease could be found.
While basal duodenal bile salt concentrations
were found to be below the critical micellar
concentration (CMC) in only two of the four
cases of post-hepatitic cirrhosis tested, a poor re-sponse to pancreozymin clearly separated all the
four from normal control subjects. The 10 children with end stage cirrhosis excreted significantly (P < .001 ) more fat (21.4 ± 6.6) in their stools than did the others (10.9 ± 2.1). Even though a medium chain triglyceride (MCT) supplemented low fat diet was associated with a drop in fecal
fat, it had no effect on the severe malnutrition
of decompensated extrahepatic biliary atresia;
whereas, in conjunction with cholestyramine, it
led to a resumption of weight gain and a
con-comitant amelioration of liver function in patients
with “paucity of intrahepatic bile ducts” and in
those with post-hepatitic cirrhosis. Pediatrics, 49: 73, 1972, MALABSORPTION, BILE SALTS, ExTRA-HEPATIC BILIARY ATRESIA, CIRRHOSIS.
T
HE malnutrition which, almostinvari-ably, accompanies advanced cirrhosis
relates not only to anorexia but also to
ste-atorrhea.’ Since the pathogenesis of the fat
malabsorption remains unclear and since
there is evidence that malnutrition may, in
turn, aggravate the cirrhotic process,2 a
clinical study was undertaken in children with chrome liver disease and cirrhosis to determine the nature and extent of the
ma!-absorption, and its response to a low fat
diet supplemented with medium chain
tri-glycerides
(
MCT) and to cholestyramine. PATIENTS AND METHODSA total of 23 children were studied. All had an exploratory laparotomy, operative
cholangiogram, and liver biopsies.
Subse-quent progression of the liver disease was
assessed at postmortem in six, at the time
of liver transplantation in four, or through
percutaneous liver biopsies when
coagula-tion studies permitted in six. Based on the
anatomical and pathological criteria of
Ta-ble I, 14 patients had extrahepatic biliary
atresia (EHA), four had “paucity of
in-trahepatic bile ducts” (PIBD), and five
post-hepatitic cirrhosis (PHC).
The important clinical findings are
sum-marized in Table II. Patients 15 and 17,
both with PIBD, were the only cases
with-out cirrhosis. Ascites (10/23) refers to a
distended abdomen with a decreased tym-panitic note and a shifting dullness. Varices
TABLE I
CLASSIFICATION OF CLINICAL MATERIAL
Ez1rahepaic Biliary Atre,ia (14)
“Paucity of Intrahepatic
Bite Duct? (4)
Post Hepaiitic
Cirrhosis (5)
Atretic biiary tract Normal biliary tract Normal hiliary tract
Proliferated bile Rare to absent bile Normal or proliferated
ducti ducts bile ducta
Cirrhosis vaing degree of
pa-renchymal damage
Cirrhosis
course of barium meals, which were carried
out in all patients and indicated intestinal
mairotation in three children
(
Numbers 5,8, and 13). One of them
(
Number 8) suf-fered from repeated bouts of acute abdomi-nal distension. The hernias noted in sixwere diagnosed before the appearance of
abdominal distension secondary to ascites
or to massive hepatosplenomegaly. They
occurred exclusively in EHA. Two children
with EHA
(
Numbers 10 and 14) had aCushingoid facies, thin extremities, and
some degree of truncal obesity. In addition,
they were the only patients standing above
the 50th percentile for weight after the first
6
months of life. The occurrence of patho-logical fractures in Patient 14 and of aper-forated duodenal ulcer in Patient 10 would
also support hyperadrenocorticism.
How-ever, this diagnosis could not be confirmed
in the laboratory. Patients without ascites did not have the propensity for respiratory infections manifest in the ones with abdom-ma! distension.
The laboratory data in Table III were obtained at the time of the investigation for
malabsorption. The prothrombin times
were drawn 24 hours after the intramuscu-lar injection of 5 mg of vitamin K. Bilirubin, SGOT, alkaline phosphatase, proteins,
cho-lesterol, carotene, and tocopherol were
de-termined on fasting plasma samples.
Patients were either on a normal diet or on a low fat diet supplemented with me-dium chain triglycerides (Portagen* and medium chain triglyceride out ).
Gastroin-testinal intolerance to Portagen in normal
dilution was particularly high in infants. Abdominal distension, flatulence and
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76
rhea were common problems, quickly
re-solved by feeding equal parts of skimmed milk and Portagen in the dilution
recom-mended by the manufacturer. Despite the
much improved taste of this preparation, a few toddlers refused it. Medium chain
tri-glyceride
(
MCT) oil was added to pureedfruit and vegetables and used for cooking.
In addition to the MCT diet,
cholestyra-mines (6 to 12 gm/day) was administered
to the four patients with PIBD and to three
of
the ones with PHC. No patient receivedantibiotics which could have modified fat
absorption during the 2 weeks preceding
the stool collection. Stool fat and fecal
chy-motrypsin determinations were carried out
on stools collected between two charcoal
markers administered 72 hours apart. The Van de Kainer method3 was used for fecal lipid assays. Since the validity of this method has been questioned when used for
the assessment of the effect of MCT on
steatorrhea,4 14 collections were reassayed
with a high degree of efficiency using a
technique which extracts MCT.5 The values
obtained were essentially the same. Fecal
chymotrypsin was measured with a
modifi-cation6 of the Haverback assay.7 Values
were expressed in milligrams per 72 hours per kilogram of body weight.
Duodenal juice was collected through a
Levine tube positioned in the 3rd portion of
the duodenum. Twenty-minute collections were obtained before and after the I.V. in-jection of pancreozymin 1.5 Unit/kg. The
samples were kept frozen until assayed for
total bile salt concentration. Duplicate sam-ples were homogenized in 100% methanol and .1 ml was used for the enzymatic
deter-mination with 3-hydroxysteroid
dehy-drogenase.II’8 Prior extraction of lipids was not deemed necessary since identical results
a Portagen: Mead Johnson and Co., Evansville,
Indiana.
f M.C.T. oil: Drew Chemical Co., Boonton, New Jersey.
Questran: Mead Johnson and Co., Evansville, Indiana.
§Boots Pure Drug, Nottingham, England. IIWorthington Biochemical Company, Freehold, New Jersey.
were obtained in several samples where ex-traction was carried out.
RESULTS
Absorption of water soluble substrates was not routinely studied. However, a
D-xylose absorption test was normal in six
pa-tients. The upper GI series with small
bowel follow through did not show any pat-tern of malabsorption except for a mild
in-crease in the size of mucosal folds when
low albumin levels were present. Further-more, autopsy findings in 10 patients failed to demonstrate any significant changes in the villous pattern, lamina propria lacteals, or intestinal epithelial cells. Pancreatic
function assessed by fecal chymotrypsin in
19 patients proved to be well within or
above the normal range (Table III). All patients tested on a normal diet had
steatorrhea
(
Fig. 1)
.
The mean fatexcre-tion in nine cases of EHA was 13.7 gm
(range 7.3 to 21.2) versus 20.5 gm (range 11.8 to 31.4) in five patients with PIBD and
PHC. Because of ascites and
hypopro-thrombinemia
(
< 70%) after intramuscular vitamin K (Tables II and III), 10 patientswere considered to be in the
decompen-sated stage of their cirrhosis and 13 to be
compensated. This classification correlated well with the clinical condition of the pa-tients and their growth. In fact, 9 of 13 chil-dren with a severe growth lag
(
< 3rdper-centile) were in the decompensated group.
The degree of liver failure bore little rela-tionship to bilirubin or albumin levels.
As shown in Figure 1 and Table IV, the
steatorrhea on a normal diet was more
se-vere (21.4 ± 6.6) in the decompensated than
(
10.9 ± 2.1)
in the compensatedgroup. With the use of a low fat diet
sup-plemented with MCT, the steatorrhea
de-creased and the difference between the
two groups was abolished. It should be
mentioned, however, that in one patient
with PHC (Number 21
),
the use of thespecial diet with cholestyrainine twice led
to an increase in fat excretion
(
11.8 to 17.6 and 14.4 gm/24 hours).F,
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Fic. 2. The effect of a low fat diet supplemented
with MCT in three children with extrahepatic
biliary atresia. The solid lines correspond to the 3rd and the 50th percentiles.
10
1S 1$
14
11 10 Is Is 4 II 10 5 S 4 I
COMPENSATED UVE DISEASE NEPATIC OSCOMPENIATION
NOINAL DIIT IA
IPtCIAI. DIII IS
NOINAL DIET ZA
IPICIAI. DIET 5
Fic. 1. Stool fat in grams per 24 hours according to the stage of the liver disease (I and 11) and
the diet (A and B).
with MCT was associated with a drop in fat excretion in all except one patient, its effect
on the weight of those with EHA was much
less convincing. Figure 2 illustrates three of the weight curves obtained. Whether on a normal or on the special diet, infants with
EHA grew relatively well until they
reached the decompensated stage of their
disease. However, Patient R.W. (Fig. 2)
does seem to show a steeper weight curve
in
response to MCT until his cirrhosisbe-comes decompensated. The other patients (D.B. and M.R.
)
show the invariable and intractable flattening of their weight curve associated with end-stage cirrhosis. Incon-trast, two of the four patients with PIBD
who were followed after having been
placed on the special diet and cholestyra-mine showed prompt acceleration of their
weight curve. This observation was also
made in two of the three children with
PHC who were similarly treated and
followed for some time. In fact, the three
patients shown in Figures 3 and 4 were
ini-tially placed in the group with decompen-sated cirrhosis. After 6 to 12 months of
ther-apy, liver function improved to the point
where clinical evidence of decompensation had disappeared.
Total bile salt concentrations in duodenal
juice are shown in Figure 5. Control
pa-tients without any evidence of hepatic
dis-ease, all had basal concentrations above the
“critical micellar concentration”
(
CMC)
of2mM and a brisk increase in concentration
after I.V. pancreozymin. One patient with
PIBD and cirrhosis had a post-stimulation bile salt concentration of 1.5 while a second
one without cirrhosis showed a good
al-though late response since the
post-pan-creozymin concentration recorded (30.7)
was obtained from a specimen collected 20 to 40 minutes after the injection. Basal duodena! bile salt concentrations were be-low the CMC in only two of four cases of PHC. However, the lower
post-pancreozy-mm concentrations clearly separated these
four patients from the 10 values obtained in controls.
DISCUSSION
Approximately 50% of adult cirrhotics2,9,b0 and the large majority of children with
cirrhosis exhibit steatorrhea.1’ The etiology
of fat malabsorption associated with
TABLE IV
STATISTICAL ANALYSIS OF FAT ExcurrloN ACCORDING
TO THE STAGE OF THE Llvmt DISEASE (I AND II)
AND THE Divr (AAND B)
in
adults appears to be poorly correlated with the extent and severity of the liver damage.12In the six patients in whom they were
performed, D-xylose absorption tests were
normal. Admittedly, this test does not
nec-essarily rule out an abnormal absorption of
monosaccharides through the intestinal cell
and the portal system since significant por-tacaval shunting of D-xylose could have
compensated for its decreased intestinal
transport.13 However, a study using
poly-ethylene glycol as a nonabsorbable marker
has failed to demonstrate a significant dif-ference in D-xylose absorption between cir-rhotic patients and controls.14 Norma!
ab-sorption of this pentose together with
malabsorption of lipid strongly suggests that the underlying defect does not involve the intestinal epithelial cell.
Defects in the intralumina! phase of fat
digestion may be responsible for the
ste-atorrhea associated with chronic liver
disease. A relative degree of exocrine
pan-creatic insufficiency and pancreatic mor-phological changes have been described in adult alcoholic cfrrhoti&#{176} and in children with severe malnutrition.15 In the present study, pancreatic function assessed by fecal
chymotrypsin was normal even in cases
where malnutrition was particularly severe. The results confirm recent evaluation by test meals of the pancreatic contribution to lipid absorption in adult cirrhosis.1#{176}
The exact role of bile salts in the malab-sorption associated with liver disease is dif-ficult to define. As expected, bile salts were
practically absent in the duodenal juice of
EHA. The few determinations carried out
in PHC showed basal values overlapping
with those of controls but significantly lower post-pancreozymin levels than those obtained in children without any hepatic
disease. However, the fact that
post-pan-creozymin bile salt concentrations in PHC
were far above the critical micellar concen-tration is in accord with data suggesting
that duodenal bile salt concentrations in
adult cirrhotics are no lower than those in
Comon4 SMistic Significance
Analysis of variance by ranks H =20 .1 P< .001
IAvsIB U P=.001
IIAvsHB U=0 P(.001
IAvsIIA U=1 P=.001
IBvsIIB U=z P>.05
A Kruskal-Wallis H Test and Mann-Whitney U test.
cholecystectomized patients.17 However, in
two recent reports where the administration of test meals permitted the measurement of the proportion of fat in micellar solution, decreased bile salts were thought to be a
significant factor contributing to the
ste-atorrhea of both acute18 and chronic liver
disease.16 Since our patients were studied in the fasting state, it is entirely possible that bile salt concentrations below the critical
concentration for micelle formation would
have been found later in the day when a
certain percentage of the pool is thought to
become unavailable for secretion in the
duodenum because of impaired liver func-tion.16
All patients studied on a normal diet had
steatorrhea. That this was more severe in
paucity of bile ducts and post-hepatitic cir-rhosis than with extra-hepatic atresia
con-firms the lack of correlation between the
degree of biliary obstruction and the
amount of fat excreted in the stools.U Since,
however, a good correlation was recently
established between stool fat and the
intes-tinal transport of labeled cholic acid of
in-fants with intrahepatic cholestasis,1#{176} our
re-sults might have been different had more
patients been studied, with less age discrep. ancy between the extra-hepatic atresia group and the others. Fat malabsorption was further reflected by studies of fat
solu-ble vitamins A, D, E, and K. Carotene
C. R
6
4
2
I
MCT 04 Cholestyromine
i 2 3 4 5
e
7yeorsLJ
Cholestyromins
I 2
MCT +
Cholsstyron*Ins
Kg
22
20 I 8
16 14 12
I0
8
FIG. 3. Weight response to MCT and cholestyramine in a patient with PIBD The 3rd and 50th percentile lines for girls are shown.
were determined. The relationship between vitamin E deficiency and the anemia,
retic-ulocytosis and abnormally large number of
platelets exhibited by some of the patients has previously been documented in infants
and children2o and in premature 21
Since vitamin D is not absorbed from the gut in the absence of bile,22 it is not
surpris-ing that four patients
(
Numbers 5, 6, 19,and 21
)
developed clinical and biochemical evidence of rickets while on a normalpro-phylactic dose of vitamin D.
Hypopro-thrombinemia was almost invariably
pres-ent but responded to parenteral vitamin K in 13 patients.
The observation that, on a normal diet
largely made up of long chain fatty acids,
patients we have called decompensated
cir-rhotics exhibit more steatorrhea than those
lCq
16
‘4 12
I0 8
6
with hepatic compensation has not been
previously reported. It suggests a correla-tion between liver function, clinical
condi-tion, and degree of fat malabsorption. A
possible explanation is that, as portal
hyper-tension increases, long chain fatty acid
ab-sorption is further impaired. The portal
hy-pertension associated with most forms of
cirrhosis is of the post-sinusoidal type,
ye-nous outflow from the liver is obstructed, and the resultant elevation of intrahepatic pressure leads to dilatation of hepatic lym-phatics23 and a marked increase in thoracic duct lymph flow and pressure.24
Conceiv-ably ascites and portal hypertension might
produce edema or vascular and lymphatic
alterations.25 In fact, edema of the bowel
wall, dilatation of mesenteric lymphatics,
weeping of lymph from the surface of the
Age in years
3
FIG. 4. Effect of MCT and cholestyramine therapy in two children with
DUODEPIAL BILE SALT CONCENTRATION (ml IIiMoIss/L)
70
SI
5.
54 52 44 42 40 32 30 25 25 24 22
20 Is
IS ‘4 2 I0
S
S 4 2
81
gut and mesentery are often noted at
lapa-rotomy in adult cirrhotics.26 While autopsy
revealed no significant morphological
changes in the small bowel of 10 patients in
this report, the data on fat excretion
never-theless suggest that elevated portal venous and/or thoracic duct lymph pressure associ-ated with end-stage cirrhosis may be re-sponsible for the enhanced fat malabsorp-tion of the decompensated stage.
Replacement of dietary long chain fats
by medium chain ones considerably
re-duces steatorrhea in children with chronic
liver disease.11’27 This occurred in our
pa-tients to such an extent that the significant difference in fat excretion of the
compen-sated and the decompensated groups
disap-peared. Diets low in fat or containing MCT
decrease the lymph volume normally
in-creased during the digestion and absorption of long chain fats28 since the former are
transported from the gut mainly via the
portal vein.29 It is known that portacaval
shunting brings about a dramatic drop in
both lymph flow and pressure.3#{176} Adult
cir-rhotics with surgical portacaval shunts
ex-crete signfficantly less long chain fat in
their stools even though their absorption rate of a medium chain fatty acid
(
octanoic acid) does not differ significantly from that observed in cirrhotics without shunts.#{176} We therefore suggest that, as portal hyperten-sion increases beyond a certain point,ab-sorption of long chain fats is adversely
af-fected because of a functional disorder in
the lymphatic circulation.
Recent work11’2 suggests that medium
chain triglycerides in chronic obstructive jaundice are beneficial not only by reducing
steatorrhea but also by increasing growth.
In the present study, the invariable de-crease of steatorrhea with that special diet had no effect on the weight of patients with
extrahepatic biliary atresia who had signs
of hepatic decompensation. In fact, the
place of medium chain triglycerides in the
treatment of these children even in the
compensated stage of their disease is in
doubt, since our experience shows that they grow relatively well even without the
spe-r “--
L
I#{149}Pre poncrsozymin I
I. Post poncreozymin
S
i
#{149}::
#{149}J#{149}:.
: #{149}Controls E.H.A. PI.B.D. PH.C.
FIG. 5. The values shown correspond to the
con-centration of bile salts in 20-minute specimens
taken before and after pancreozymin I.V. (1.5
unit/kg). In eight cases, two 20-minute postpan-creozymin specimens were collected. The values were usually lower in the second 20-minute col-lection except for the value of 30.7 found in one
patient with PIBD.
cia! diet. Cholestyramine, a nonabsorbable resin which binds bile salts in the intestinal lumen and sequesters them in stools, leads to a decreased bile salt pool by interfering with their extrahepatic circulation, and
in-duces steatorrhea when long chain fats are
fed.3’ However, when medium chain
tri-glycerides are given, steatorrhea is
abol-ished.32 The increase in steatorrhea
ob-served in one patient with post-hepatitic
cirrhosis (Fig. 4) receiving both medium
chain triglycerides and cholestyramine
sug-gests that inordinate amounts of long chain triglycerides were still being fed.
Neverthe-less, acceleration of growth was noted only
after cholestyramine was added to medium
chain triglycerides. It would suggest that
82
bile ducts” or post-hepatitic cirrhosis. The
remarkable improvement of liver function
and the prompt acceleration of weight
re-ported by others’3 in cases of “paucity of
in-trahepatic bile ducts” treated with choles-tyramine is confirmed by the present study. This therapy is also suggested in patients with post-hepatitic cirrhosis, since excellent
results were obtained in two such children
initially classified as being in the decom-pensated stage of their disease.
SUMMARY
In a clinical study of 23 children with
chronic liver disease, steatorrhea and
ma!-absorption of fat soluble vitamins were
present even in the absence of cirrhosis. The severity of the steatorrhea bore little
relationship to the degree of biliaiy
ob-struction; however, it was significantly
in-creased in patients with signs of hepatic decompensation
(
ascites,hypoprothrom-binemia after vitamin K). Despite a
de-crease in steatorrhea, a low fat diet supple-mented with medium chain triglycerides did not help the severe malnutrition associ-ated with the decompensated stage of
ex-trahepatic biliary atresia. The patients with
either “paucity of intrahepatic bile ducts”
or post-hepatitic cirrhosis who were
followed for some time after having been placed on the special diet in conjunction with cholestyramine responded favorably in terms of nutrition and liver function.
REFERENCES
1. Silverberg, M., and Davidson, M.: Nutritional requirements of infants and children with liver disease. Amer. J. Clin. Nutr., 23:604,
1970.
2. Baraona, E., Orrego, H., Fernandez, 0., Ame-nabar, E., Maldonado, E., Tag, F., and Sail-nas, A.: Absorptive function of the small in-testine in liver cirrhosis. Amer. J. Dig. Dis., 7:318, 1962.
3. Van de Kamer, J. H., ten Bokkel Huininck, H., and Wejers, H. A.: Rapid method for the determination of fat in feces. J. Biol. Chem., 177:347, 1949.
4. Saunders, D. R.: Medium chain triglycerides and the Van de Kamer method. Castroenter-ology, 52:135, 1967.
5. Jeejeebhoy, K. N., Ahmad, S., and Kozak, C.:
Determination of fecal fats containing both medium and long chain triglycerides and fatty acids. Clin. Biochem., 3: 157, 1970. 6. Bonin, A., Lasalle, R., Brosseau, M., Truteau,
M., and Roy, C. C.: Fecal chymotrypsin: A
reliable index of exocrine pancreatic func-tion. Cystic Fibrosis Club, Atlantic City, May 1970.
7. Haverback, B. J., Dyce, B. J., Gutentag, P. J.,
and Montgomery, D. W. : Measurement of
trypsin and chymotrypsin in stool: A diag-nostic test for pancreatic exocrine insuffi-ciency. Gastroenterology,
44:588,
1963.
8. Iwata, T., and Yainasaki, K.: Enzymatic deter-mination and thin layer chromatography of bile acids in blood. J. Biochem. (Tokyo), 56:
424, 1964.
9. Linscheer, W. C., Patterson, J. F., Moore, E. W., Clermont, R. J., Robins, S. J., and Chal-mers, T. C.: Medium and long chain fat ab-sorption in patients with cirrhosis. J. Clin. Invest., 45:1317, 1966.
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Acknowledgment
The authors wish to thank Doctors Tom Stan
