GASTROENT EROLOGY
1
Copyright © 1972 by The Willia ms & Wilkins Co.
PROGRESS IN GASTROENTEROLOGY
THE ENTEROHEPATIC CIRCULATION
R. HERMON DOWLING, M.D., M R
. .e.p.
Department of Medicine, Royal Postgraduate Medical School,
Hammersmith Hospital, London, England
Any substance secreted in bile which is
reabsorbed from the intestine and returns
to the liver to appear once again in bile
may be said to undergo an enterohepatic
circulation (EHe) . Accepting this defini-
tion, the list of endogenous and exogenous
substances with an EHe is formidable.
The lipids in bile, cholesterol, phospho-
lipids, and bile salts, provide examples of
endogenous substances which all undergo
enterohepatic circulations but with widely
differing efficiencies (assuming that 100%
absorption and reexcretion is the most ef-
ficient EHe). Of these biliary lipids, the
EHe of bile salts is the most important
but since individual molecules of both cho-
lesterol and lecithin, the principal phos-
pholipid in bile, may also circulate from
bile to intestine and back to the liver and
bile, they may be considered as having
an EHe. Based on studies with labeled
cholesterol, an EHe for cholesterol was
postulated in 1952 1 and later by other
authors. 2-~ Endogenous biliary cholesterol
is probably mainly absorbed in the je-
junum 5 and of this reabsorbed fraction, a
small percentage may reappear in bile hav-
ing followed the circuitous route of lym-
phatic transport, systemic circulation,
hepatic artery, liver, ~md bile. However,
there are many intermediate pools in
which the individual cholesterol molecule
may become sidetracked on the way and
cholesterol, therefore, does not undergo
Received July 27, 1971.
Address requests for reprints to: Dr. R. Hermon
Dowling, Department of Medicine, Royal Postgradu-
ate Medical School, Hammersmith Hospital, Ducane
Road, London W12, England.
122
Vol. 62, No.
Printed in U.S.A .
the "bulk" enterohepatic circulation of
bile salts.
Phospholipids, the other major lipid
class in bile, resemble cholesterol in that a
small percentage of biliary lecithin, which
passes into the intestine, may find its way
back to the bile. However, it differs from
cholesterol in that it is digested in the in-
testinal lumen by pancreatic phospho-
lipase to lysolecithin, and after absorp-
tion, is reesterified by the intestinal epi-
thelium. A small percentage may find its
way back to the bile. However, Saunders 6
has recently shown convincingly that,
quantitatively, the EHe of phospholipids
is insignificant.
Other endogenous substances with an
EHe include bile pigments,7 vitamin B 12,
a small percentage of which recycles each
day, 8 folic acid,9, 10 and many estrogenic
sterols. II, 12
Examples of ex, ~enous substances which
undergo an EHe include many drugs such
as flufenamic acid,13 digitalis glycosides, 14
and glutethimide,15 although the concept
of an EHe for this last drug has recently
been challenged. 16
This review discusses the normal physi-
ology of the EHe of bile salts both in ex-
perimental animals and in man. (Differ-
ent aspects of the bile salt EHe have been
reviewed recently in this journaP7. 18 and
elsewhere. 19-21) The applied physiology
of an interrupted EHe is discussed in de-
tail since the altered bile salt metabolism
of patients with ileal dysfunction may play
a major role in the pathogenesis of diar-
rhea, renal calculi, and gallstone forma-
tion, from which ileectomy patients may
January 1972 PROGRESS IN GASTROENTEROLOGY
suffer. However, the role played by bile
salts in regulating synthesis and secretion
of biliary cholesterol and phospholipids is
only briefly mentioned.
It is now well established that the body
conserves the bile acids by reabsorption
from the intestine and that the bulk of this
reabsorption is by active transport from
the ileum. However, it is also known that
other parts of the intestine, namely the
stomach,2 2 jejunum, 23-26 and colon 27 -31
may absorb bile acids by passive processes.
The normal bile salt EHC in man may be
summarized as follows. A 3- to 5-g bile salt
pool consisting of both primary bile salts
(synthesized in the liver from cholesterol)
and secondary bile salts (resulting from
bacterial conversion of primary bile acids
in the intestine) circulates from liver to
bile (with intermittent storage and concen-
tration in the gallbladder), to intestine, to
portal blood, and back to liver about six to
10 times per day.3 2, 33 Between 2 and 5%
of the total circulating bile salts (or about
20 to 25% of the total bile salt pool34) es-
cape reabsorption to appear in the feces
giving a fecal bile salt excretion of approxi-
mately 200 to 600 mg per day.3 5.38 In the
steady state, since synthesis must equal
loss, hepatic bile salt synthesis is there-
fore 200 to 600 mg per day. Quantitatively,
fecal excretion is normally the only route
for bile salt loss from the EHC (about 2%
of the total daily bile salt loss is accounted
for by urinary and skin excretion 38).
It has been estimated (in the rat) that at
anyone time about 85% of the circulating
bile salts are present in the intestinal lu-
men, about 10 to 12% in the gut wall, and
only 3 to 5% in the liver. 27
Function of Bile Salts in the
Intestinal Lumen
The EHC of bile salts ensures an eco-
nomic conservation of these "biological de-
tergents." Furthermore, the localization
of the major transport site to the ileum
presumably means that once the bile salt
micelle has delivered its complement of
lipolytic products to the small bowel epi-
thelium, it may be reutilized to solubilize
other lipids. If this concept is correct, then
123
as chyme is propelled along the intestine,
the bile salts provide a shuttle service be-
tween the oil water interface of emulsified
fat droplets where hydrolysis of dietary
fat by pancreatic lipase takes place, and
the intestinal epithelium of the upper small
bowel, where fat absorption is thought to
occur.32, 39
Th~ simple concept of bile salts shuttl-
ing between emulsified fat in the bowel
lumen and the microvillous membrane is
still unproven, since at present it is not
known exactly how monoglyceride and
fatty acid molecules are absorbed from
the micelle at the brush border of the ab-
sorptive epithelium. It seems likely, how-
ever, that fat molecules passively diffuse
across the membrane, thereby disturbing
the thermodynamic equilibrium of the
micelle and creating vacancies for further
lipid molecules to be solubilized.
Hepatic Component of the
Bile Salt EHC
Quite apart from bile salt synthesis, the
liver has two other roles in bile salt meta-
bolism. It both conjugates any free bile
salts which are delivered to it and it
"clears" or secretes the bile salts into the
bile by an active mechanism . This clear-
ance is extremely efficient. In the dog,
O'Maille et al. 40 found that 92% of labeled
taurocholate given intravenously was
cleared in one passage through the liver.
The glycine conjugate, glycocholate, which
is not a naturally occurring bile salt in the
dog, was cleared equally rapidly.
Bile salt conjugation. Normally there
are no free or deconjugated bile salts in
bile. Both newly synthesized and presum-
ably also recycled bile acids, which have
been deconjugated by intestinal bacteria
before their reabsorption, must therefore
be conjugated with the amino acids gly-
cine or taurine before they are secreted
in bile. To take cholic acid as an example,
in the presence of adenosine triphosphate,
the free bile acid is activated by coenzyme
A to form cholyl CoA which, in turn, com-
bines with the amino acid glycine to form
glycocholate (or in the case of taurine, to
form taurocholate). This conjugation
124 PROGRESS IN GASTROENTEROLOGY Vol. 62, No.1

step-peptide linkage at the carboxyl Choleretic effect of bile salts. The active
group of the bile acid-must also be effi- transport of bile salts by the liver is the
cient since when O'Maille and colleagues 4o major, but not the sole, factor regulating
injected free cholic acid, rather than its the volume of bile secreted. 52 At zero bile
glycine conjugate, intravenously, 79% was salt secretion, the liver still secretes a
cleared by the liver in one circulation. watery bile-the so-called "bile salt-inde-
Normally, there are two factors which pendent fraction."53 The concept of a bile
regulate the choice of amino acid for bile salt-independent fraction was derived
salt conjugation 41, 42-first, a species dif- from studies where bile volume was plotted
ference, and second, the availability of on the ordinate with bile salt secretion on
the sulfur-containing amino acid taurine the abcissa. When this is done, a straight
or its precursors cystine, cysteine, and line is found 54-57 and by extrapolation this
methionine. Considering the species dif- line does not go through the origin but in-
ference, bile acids in the rat are almost ex- tersects the ordinate. The bile salt-inde-
clusively conjugated with taurine while in pendent fraction does not apply to all
the rabbit glycine conjugates predominate. species, since in the dog the linear rela-
Bremer 43 showed that the hepatic micro- tionship between bile volume and bile salt
somes of the rat selectively conjugated bile excretion passes close to zero. 55
acids with taurine while those of the rabbit In much the same way, there appears to
used glycine. be a relationship between the secretion
Although in man the glycine conjugates rates for bile salts and phospholipids and
normally predominate, the glycine to tau- those for bile salts and cholesterol in bile.
rine (G: T) ratio being approximately 2 or The intimate relationship between bile
3: 1,44-48 the human liver conjugates bile salts, phospholipids, and cholesterol has
acids preferentially with taurine. 49 In fact, been shown in isolated perfused livers of
after feeding taurine in doses from 3 to rats 58 . 59 and dogs 60 and by bile fistula tech-
15 g per day for 5 days, Sjova1l 44 showed niques in monkeys 61 and in man. 62 In fact,
that the normal G: T ratio became in- Nilsson and Schersten 63 have shown, by
verted so that 96% of the bile acids pres- in vitro studies using human liver slices,
ent became conjugated with taurine. The that bile acids regulate phospholipid syn-
usual dietary intake of taurine or its pre- thesis.
cursors in man is such that it is normally in Hepatic bile acid synthesis and its con-
relatively short supply. In contrast, gly- trol. The steps involved in hepatic bile acid
cine, which is involved in many metabolic synthesis and the way in which this syn-
pathways, is freely available. Conjugation thesis is regulated have been the subject
with bile acids is the only specific route of recent studies by Shefer et al. 64-65 The
for taurine catabolism. liver synthesizes both cholesterol and bile
The factors regulating the choice of acids-cholesterol being synthesized from
amino acid for bile acid conjugation are acetate along the hydroxymethylglutarate
particularly important when the entero- CoA, mevalonate, cholesterol pathway. In
hepatic circulation is interrupted-for ex- turn, cholesterol is catabolized to 7a-hy-
ample by ileal dysfunction. Whether a bile droxy cholesterol and bile acids. A de-
acid is conjugated with glycine or taurine tailed account of this complex pathway is
will influence its physical state in the gut beyond the scope of this review, but
and hence its rate of reabsorption from briefly, an a-OH group is added in the 7
areas of the intestine other than the ileum. position, the spatial orientation of the
The question of which amino acid is used OH group in the 3 position (common to all
for conjugation may also be important in primary mammalian bile acids) changes
the genesis of hyper oxaluria and urinary from (3 to a. The Ll5 double bond of the
oxalate stone formation. 50, 51 This, and cholesterol molecule is reduced, bile acids
other aspects of the broken EHC are dis- being fully saturated, and in the case of
cussed later. cholic acid, a further OH group is added in
January 1972 PROGRESS IN GASTROENTEROLOGY
the 12 position before the side chain of the
27-carbon atom cholesterol molecule is
shortened by 3 carbon atoms. 66
Hepatic bile acid synthesis is regulated
by feedback inhibition exerted by the
amount of bile acids returning to the liver.
This was shown by Bergstrom and Daniels-
son 67 who reinfused bile acids into the
distal end of the common bile duct in the
bile fistula rat. By so doing, they were able
to inhibit the rebound or compensatory
increase in synthesis which is seen after
the EHC is broken by fistula diversion of
bile. These studies were confirmed by
She fer et al.,64 who returned bile salts to
the EHC by duodenal infusion and quan-
titated the amount of bile acid needed to
inhibit the rebound increase in synthesis.
They then extended these studies to de-
fine, with labeled precursors, at which
step in the acetate to bile acid pathway,
the regulation of bile acid synthesis took
place. They concluded that 7a-hydroxy
cholesterol was the rate-limiting step, and
that 7a-hydroxylase was the rate-limiting
enzyme. This confirms earlier studies by
Danielsson et al. 68 Danielsson 69 has sug-
gested that the major pathway for cholic
acid formation from cholesterol is by this
7a hydroxylation step although the bile
acid may also follow a less important path-
way through 26 OH cholesterol. 70
The enzyme cholesterol 7a-hydroxylase
is the first unique enzyme in bile acid bio-
synthesis and in recent years it has been
extensively studied. It may be increased
(up to 6-fold) when the EHC is broken
with a bile fistula 68 or after feeding cho-
lestyramine. 71 The enzyme is produced by
the endoplasmic reticulum 71 but, unlike
other microsomal enzymes such as cyto-
chrome P450, Boyd et al. 71 found that it
was not significantly induced by pheno-
barbitone. However, it has been suggested
recently that small doses of phenobarbi-
tone in the primate do significantly in-
crease bile salt synthesis. 72 Furthermore,
this key enzyme in bile acid synthesis is
believed to undergo a circadian rhythm
with maximal acitivity in late afternoon.
This diurnal variation is, in part at least,
under hormonal controp3 since it is in-
125
hibited by hypophysectomy and/or adrena-
lectomy.74
The factors regulating the secretion of
bile and the passage of bile acids from
liver and gallbladder into the intestine
are complex. Food is of major importance
in stimulating both bile volume and bile
salt secretion 75 -78 presumably because, to-
gether with gastric acid, it stimulates
cholecystokinin, glucagon, and secretin re-
lease from duodenal mucosa. In turn,
these polypeptide hormones stimulate the
liver to secrete a watery bile rich in bicar-
bonate 75. 79-85 and in the case of cholecysto-
kinin, provoke gallbladder contraction.
Gastrin, like secretin and glucagon, stimu-
lates the hepatocytes to secrete a bicar-
bonate rich watery bile. 86 -87
Intestinal Bile Acid Absorption
Intestinal bile acid transport may be
summarized as follows: (1) Active transport
from ileum alone, which is the major route
for bile salt reabsorption. (2) Passive ab-
sorption from stomach, jejunum, ileum,
and colon. (a) passive monomer diffusion-
diffusion of individual bile salt molecules
when the intraluminal bile salt concentra-
tion is below the critical micellar concen-
tration (rare) or diffusion of single mole-
cules which always coexist in equilibrium
with the molecular aggregates of bile salt
molecules-the micelles. (b) passive mi-
cellar diffusion.
These passive processes may be in the
ionic or non ionic form but since the trans-
port of charged particles is inhibited by the
electrical gradient in the intestine, non-
ionic diffusion is more important.
Active Ileal Transport
The active transport of bile salts in the
ileum has been repeatedly demonstrated
in the last decade, 18, 20, 88-92 since Baker
and Searle 93 confirmed earlier studies by
von Tappeiner 94 by showing in vivo, that
bile acids were absorbed from the ileum
in the rat. The localization of active bile
salt transport to the ileum has also been
shown for hamsters, 92. 95 rabbits, 95, 96
dogs 89, 95 and many other species includ-
126 PROGRESS IN GASTROENTEROLOGY
ing Leghorn chickens, King pigeons, mice,
squirrel monkeys, and spider monkeys. 95
The comparative efficiency of active ileal
transport for different bile acids was re-
ported by Lack and Weiner,90 who found
that the dihydroxy bile acids (deoxy- and
chenodeoxycholic acid) were absorbed less
efficiently than the trihydroxy bile acid
(cholic acid) and that the taurine conjug-
ates were transported more rapidly than
the glycine conjugates. Furthermore,
Heaton and Lack 97 showed that there was
mutual inhibition of transport of glycine
and taurine conjugates. The quantitative
significance of these findings in terms of
the EHC in man has yet to be evaluated.
Passive Absorption
Influence of physical properties on bile
acid absorption. Passive bile acid diffusion
may be either from the ionized or from the
nonionized form, which in turn depends on
the prevailing pH and the dissociation con-
stant (pKa) of the individual bile acid.
Thus, at normal intestinal pH levels of
5.0 to 7.0 98 ,103 a greater proportion of free
bile acids with pKa's of 5.0 to 6.3 will be
in the protonated (or nonionized) form than
the glycine-conjugated bile acids (pKa's
4.3 to 5.2) while the stronger taurine-con-
jugated bile acids (pKa's 1.8 to 1.9) are al-
most entirely in the ionized form. 104 Since
passive bile acid absorption by non ionic
diffusion is at least 5 to 6 times greater
than diffusion of charged particles,24 free
bile acids are absorbed more rapidly from
extra-ileal sites than glycine conjugates
while the ionized taurine conjugates are
almost totally dependent on the active
transport site in the ileum for their re-
absorption. 25
The physical properties of the different
types of bile acids are therefore of con-
siderable importance in determining not
only their rates of absorption, but also
their own solubility in the intestinal lu-
men 104 and their capacity to solubilize
other lipids in the small bowel. However,
bile acids do not have fixed critical mi-
cellar concentrations (CMC's), dissocia-
tion constants (pKa's), and lipid-solubi-
lizing capacities. The CMC of an individ-
ual bile acid in vitro is not constant but is
Vol. 62, No . 1
related to pH, temperature, and counter
ion concentration. 105, 106 The pKa is
related to bile acid concentration 107 and
perhaps to a limited extent to counter ion
concentration 104. 108 while the ability of
a given bile acid to solubilize cholesterol,
for example, is greatly altered by the pres-
ence of other lipids such as phospholipids
which expand the micelle, 105, 109 thereby
enhancing its lipid-solubilizing capac-
ity.105, 110·112 Furthermore, the CMC of a
bile acid depends to a certain extent on
the method used to measure it. 105. 108 There
is, therefore, no simple magical figure for a
bile salt CMC below which concentration
lipolytic products are not solubilized and
above which fat solubilization and absorp-
tion proceeds satisfactorily. In general,
however, once the CMC is exceeded, the
greater the bile salt concentration, the
greater is the amount of fat solubilized.
This concept is illustrated by the findings
of Badley et aI., 113 who showed that in pa-
tients with chronic liver disease, those
with steatorrhea had intraluminal bile
salt concentrations of less than 4 J1moles
per ml while those with normal fecal fat
excretion had bile salt concentrations ex-
ceeding 6 J1moles per ml-a concentration
found in control subjects and comparable
to other reported normal values. 44 • 47, 103,
114, 115 Based on their studies of intra-
luminal bile salt concentrations in liver
disease, Badley et al. 116 suggested that
the term "critical physiological concen-
tration" rather than CMC was more rele-
vant in clinical investigation. The relation-
ship between physicochemical properties
of bile salts and their function has been
fully reviewed elsewhere. 19, 105
Quantitative significance of extra-ileal
bile salt absorption. The quantitative sig-
nificance of passive absorption from extra-
ileal sites is controversial. Although bile
salts can be absorbed at a particular rate
by passive diffusion, this does not mean
that they are necessarily absorbed at that
rate under physiological conditions. Con-
versely, although active bile acid transport
is confined to the ileum, this does not mean
that the distal small bowel is the sole site
for bile salt transport. While the role of
passive extra-ileal bile salt absorption may
January 1972 PROGRESS IN GASTROENTEROLOGY
be less important for the normal EHC, it
assumes greater significance in clinical
situations where EHC is broken. For
example, extra-ileal bile salt absorption is
of considerable importance in ileal dysfunc-
tion, following cholestyramine, lignin, or
neomycin treatment where bile acids are
complexed or precipitated in the intesti-
nal lumen, and in the blind loop syndrome
when bacterial deconjugation renders bile
acids vulnerable to premature absorption
by diffusion 25 or perhaps to precipitation
at normal intestinal pH, as was postulated
recently on ·the basis of in vitro titration
studies. 104 Bile acid precipitation may
certainly occur in patients with intestinal
stasis since bile acid enteroliths have been
found in patients with jejunal diverticu-
losisl17-120 and in other examples of the
blind loop syndrome.121-123 However, the
quantitative significance of bile acid pre-
cipitation as a mechanism for conjugated
bile salt deficiency in the blind loop syn-
drome has yet to be established.
Bile Acid Transport to the Liver
Following their absorption, bile acids
are transported to the liver in the portal
veinl24-126 bound to albumin and to a
lesser extent to other proteins. 127 -128 In
1955, Sjovall and Akesson 125 showed that
although oral 14C-taurocholate could be
recovered in the bile, none was found in
lymph, suggesting that it was absorbed by
another route-presumably by the portal
vein. More recently, Reinke and Wilson 129
showed that although the concentration of
bile acid carrier protein was only twice as
high in lymph as in blood, portal blood
flow was 280 times that of lymph. The dif-
ference in flow rates, therefore, is the
principal factor governing bile acid trans-
port by the portal route.
In the rat, as much as 36% of bile acids
in the portal blood may be in the free
form.130 However, the rat is coprophagic
and much higher concentrations of bac-
teria capable of deconjugating bile salts
are found in the normal rat jejunum when
compared with man. It is unlikely, there-
fore, that such a high percentage of un-
conjugated bile salts would be found in
human portal blood.
127
Serum Bile Acids
In man, the concentration of individual
bile acids in the systemic circulation is
normally very low, the total serum bile
acids ranging from 2 to 4 Jlmoles per
liter131-about one-thousandth that found
in the intestinal lumen. In serum, bile acids
are normally in the conjugated form, but in
intestinal diseases such as the blind loop
syndrome and in patients with intestinal
resection, there are elevated concentra-
tions of total bile acids in the systemic cir-
culation, largely due · to the presence of
free bile acids. 132 Since free bile acids are
cleared by the liver almost as efficiently
as are the conjugated forms, 40. 133 the
mechanism for the raised levels of serum
free bile acids in conditions of intestinal
stasis is not clear. The explanation may be
that free bile acids are more avidly bound
to albumin in the serum with a resultant
differential hepatic clearance rate between
the bound free and the unbound con-
jugated biles acids. 128
High levels of bile acids in the serum of
patients with obstructive jaundice, intra-
hepatic cholestasis, pruritis, and jaundice
of pregnancy have been known for some
time.134-136 However, in this situation the
mechanism for high serum bile acid con-
centrations is different from that in the
blind loop syndrome since in the chole-
static disorders there is impaired hepatic
uptake, the mean normal half-life of in-
travenously 14C-cholic acid of 12.6 min in-
creasing to 45_min. 133
While difficult to document accurately
for technical reasons, there are also in-
creased quantities of bile acids in the skin
of patients with obstructive jaundice 137
which are thought to cause the pruritis by
irritation of sensory nerve endings. A rough
correlation was found between the severity
of itching and the quantity of bile acid re-
covered from the skin. 137 Why high levels
of serum bile acids in patients with the
blind loop syndrome or ileal resection
should not cause itching similar to that
seen in obstructive jaundice is not clear.
It may be that only conjugated bile acids
are capable of causing itching as opposed
to the free form which is found in the
serum of the blind loop patient.
128 PROGRESS IN GASTROENTEROLOGY
Role of Bacteria
The principal actions of intestinal bac-
teria on bile salts may be summarized as
follows: (1) deconjugation-removing
taurine and glycine from the conjugated
bile salts; (2) 7a dehydroxylation-remov-
ing the OH group from the 7 position of
the primary bile salts, cholate and cheno-
deoxycholate, producing deoxycholate and
lithocholate respectively; (3) oxidation of
the hydroxyl groups to produce keto bile
acids; (4) epimerization with changes in
the spatial orientation of a-hydroxyl
groups to the f3 position.
The liver in man synthesizes two pri-
mary bile acids, the trihydroxy cholic acid
and the dihydroxy chenodeoxycholic acid.
However, analysis of human bile shows
that roughly one-quarter to one-third of
the total bile acids are secondary bile
acids-deoxycholic acid and occasionally
trace amounts of lithocholic acid. These
secondary bile acids are the result of
bacterial enzymatic 7 a dehydroxylation of
the primary bile acids. Thus, removal of
the hydroxyl group from the 7 position of
cholic acid produces the secondary
dihydroxy bile acid deoxycholic acid
while lithocholic acid (a monohydroxy bile
acid) is formed by 7 a dehydroxylation of
chenodeoxycholic acid.
When the primary bile salts are pre-
vented from coming in contact with in-
testinal bacteria, for example, by diversion
of bile with a fistula 138 or when the com-
mon bile duct is occluded by a stone, 139
deoxycholate rapidly disappears from the
circulation.
Norman 140 has shown in vitro that be-
fore bacteria remove the hydroxyl (OH)
group from the 7 position, deconjugation
must first occur. The deconjugating en-
zyme seems to be widely distributed
among anaerobic intestinal bacteria such
as Bacteroides, Veillonella, Bifodobac-
teria (anaerobic lactobacilli) 141- 144 and
some strains of clostridiae, 142, 145 but
dehydroxylating enzymes seem much less
common. 140
Sites of secondary bile acid formation
and absorption. The concentrations of
anaerobic organisms increase to concen-
Vol. 62, No.1
trations of 10 7 to 10 9 per ml in the distal
ileum-concentrations similar to . those
found in the colon and in feces. 146, 147 It
is likely, therefore, that deoxycholate and
lithocholate are formed in the lower ileum
as well as in the colon. Lithocholate is
extremely insoluble and has a very high
critical micellar temperature (CMT or
"Krafft" point).148 Because of these
physical properties, it does not form
micelles at body temperature, is poorly
absorbed, and as a result, it is quantita-
tively unimportant in the normal EHC of
bile salts. Where deoxycholate is absorbed
to enter the EHC is largely an open ques-
tion, although available evidence suggests
that it is absorbed from the colon. Again,
although deoxycholate can be absorbed
from the cecum and colon, this does not
necessarily mean that this is its normal
site of absorption. Nor would studies with
ileal intubation answer the question, since
intraluminal deoxycholate concentrations
at this site are the net result of both rates
of formation and rates of absorption. How-
ever, the limited available evidence sug-
gests that although deconjugation may
occur normally in the ileum, 149 dehydroxyl-
ation of the liberated cholate does not
occur until the large bowel. 150
In patients with ileostomy following
proctocolectomy for ulcerative colitis, the
ileal effluent contains high concentrations
of bacteria-lOS to 10 8 per ml 143 capable
of salt deconjugation 142, 151 and in fact, free
bile salts may be demonstrated in the ef-
effluent.143 Although many of these same
bacteria are also capable of dehydroxyla-
tion in vitro, no deoxycholate is present
either in ileal effluent or in bile. If the find-
ings in ileostomy patients may be extrapo-
lated to the normal EHC, deoxycholate
must be passively reabsorbed from the
colon.
The secondary bile acids produced by
bacterial action, deoxycholate and litho-
cholate, make up the bulk of bile acids
excreted in the feces. 35 , 36 However, in
addition to deconjugation and dehydroxyl-
ation, bacteria can also oxidize the hy-
droxyl groups to yield keto groups and
other metabolites. In fact, about 19 differ-
January 1972 PROGRESS IN GASTROENTEROLOGY
ent types of bile acid have been identified
in human feces. 35 , 152
Effects of Interruption of the EHe
Studies on the effects of interruption of
the EHC have been among the most in-
teresting developments of applied gastro-
intestinal physiology in recent years.
The EHC may be interrupted either
when bile salts are prevented from reach-
ing the intestine, as in obstructive jaun-
dice, or when intestinal absorption is
blocked by intraluminal events such as
bile acid binding by drugs-for example
cholestyramine l53 , 154 and lignin,155 or by
bile acid precipitation as in the Zollinger-
Ellison syndrome 156 or following neomycin
treatmentt l5 , 157, 158 and perhaps also in
the blind loop syndrome. 104 Intestinal
malabsorption may also interrupt the EHC,
for example in patients with resection,
bypass, or disease of the ileum (including
Crohn's disease,159 celiac disease, 160-161
and tropical sprue 162).
Ileal disease, resection, and bypass.
Since the ileum is the major site for bile salt
reabsorption, ileal disease or resection
should cause bile salt malabsorption, and
in 1965 this was clearly demonstrated in
dog. 16 3 These authors fed isotopic tauro-
cholate to animals with a cannula in the
gallbladder and showed that the percent-
age of recovery oflabeled material was sim-
ilar in controls and in dogs with proximal
resection (48%), but only 3% was recovered
from ileectomized dogs. Since then, in-
creased fecal bile salt excretion and/or
markedly shortened half-lives of isotopic
bile salts have been repeatedly demon-
strated both in experimental animals and
in man. 29 , 47, 48, 159,164-172 As a result,
many, but not all, of these patients have
intraluminal bile salt deficiency in the je-
junal lumen_ 47. 165, 166. 169
The bile salt concentrations in the je-
junal lumen of ileectomized patients may
vary throughout the day_ It has been sug-
gested that, during an overnight fast of
about 12 hr, the maximal rates of hepatic
bile salt synthesis may reconstitute the
bile salt pool which, in the absence of food-
stimulated cholecystokinin release, is
129
stored in the gallbladder. In response to
breakfast, therefore, the gallbladder con-
tracts to produce normal jejunal bile salt
concentrations. In the absence of an in-
tact ileum, however, the bile salt pool is
malabsorbed on the first enterohepatic
cycle and even with maximal synthesis, in
the relatively limited period of time be-
tween meals, the bile salt pool cannot be
restored. As a result, the intraluminal bile
salt concentrations are depleted after the
mid-day and evening meals. 169
This diurnal variation in jejunal bile salt
concentration after ileal resection is illus-
trated by the results of a study in our labo-
ratory (R. H. Dowling and C. B. Campbell,
1971, unpublished observations) (fig. 1) .
After an overnight fast, in a patient with a
massive distal small bowel resection, je-
junal bile salt concentrations in response
to a test meal were normal and the amount
9.00 A. M. (Fasti ng) 3. OO P. M. I Fed)
INTRA- 1Jl moles 7.8-9 . 5
concentrat ion 2 0 - 2 8
Range . .
LUM INAL 1m!.
BI LE ~-----+-------I
SALTS mmoles
2. 006 0.651
100
80
DISTR IBUTION
Of
INTRA-LUM INAL 60
FAT
40
20
FIG. 1. Diurnal variation in intraluminal bile salt
concentrations after ileal resection. Jejunal bile salt
concentrations and phase distribution of fat aspirated
from the intestinal lumen over three half-hour peri-
ods, following a test meal in a patient with a massive
distal small bowel resection (14 inches jejunum re-
maining, anastomosed to midtransverse colon). The
study was performed initially after an overnight fast
and repeated 1 week later in midafternoon (see text) .
(R. H. Dowling and C. B. Campbell, unpublished ob-
servations) .
130 PROGRESS IN GASTROENTEROLOGY
of fat in the micellar phase of ultracentri-
fuged intestinal aspirates was also nor-
mal. I15 However, on a second occasion 1
week later, when the study was repeated
after breakfast, mid-morning snack, and
lunch, there was intraluminal bile salt
deficiency with reduced fat in the micellar
phase and a corresponding expansion of
the oil phase. Furthermore, the total
amount of bile salt aspirated during the
three 1/2-hr periods of the study (a crude
measure of the bile salt pool) was normal
during the early morning study, but
markedly diminished at 3:00 PM.
The observation that ileal resection may
produce jejunal bile salt deficiency pro-
vided one possible explanation for the
apparent paradox that while fat absorp-
tion normally occurs in the jejunum, 32. 39
removal of the ileum produces a greater
degree of malabsorption than does resec-
tion of a comparable length of jejunum. 17 3
Other factors such as the adaptive ability
of the ileum to increase its absorptive
capacity and differential rates of transit
through jejunum and ileum also account
for the paradoxical steatorrhea after
ileectomy. 174, 175
The bile salt deficit which follows ileal
resection leads to impaired micelle forma-
tion and reduced absorption of fat and par-
ticularly of sterols such as cholesterol and
the fat soluble vitamins whose absorption
is dependent on bile salts to a much greater
extent than dietary triglycerides, which
may be absorbed even in the absence of
bile salts. 176, 177
In patients with ileal dysfunction, there
sometimes is a discrepancy between bile
salt malabsorption with shortened half-
lives of isotopic bile salts, and normal con-
centrations of bile salts in the jejunum. In
the absence of a normal ileum, the jejunal
bile salt concentration depends, on one
hand, on increased bile salt loss in the
feces due to malabsorption, and, on the
other hand, on the ability of extra-ileal
sites to partially maintain the EHC,
coupled with the adaptive increase in
hepatic bile salt synthesis.
Compensatory increase in hepatic bile
salt synthesis. The precedent that the
liver is capable of a compensatory increase
in bile salt synthesis after ileal resection
Vol. 62, No . 1
is well established from studies where
there has been a broken EHC from other
causes. After creating a bile fistula in rats,
for exam pIe, Eriksson 178 found a 10- to 20-
fold increase in hepatic bile salt synthesis,
which was later confirmed by others,64, 65.
67, 179, 180 although in Myant and Eder's
experiments, 181 there was only a 4- to
5-fold increase in synthesis. Similar in-
creases in hepatic bile salt synthesis have
been found after feeding cholestyramine
to mice l82 and to man. 183. 184 However, it
should be stressed that synthesis normally
contributes such a small fraction to the
total circulating bile salts, that even a 10-
to 20-fold increase in synthesis is usually
totally inadequate to compensate for the
increased fecal loss which follows ileal
resection.
Recently, detailed studies of the adap-
tive increase in hepatic bile salt synthesis
were made in the rhesus monkey, com-
paring the long term effects of mechanical
interruption of the EHC with varying de-
grees of ileal resection. 172 Bile from a
chronic bile fistula was returned to the in-
testine through an electronic stream
splitter, which diverted varying percent-
ages of bile to the exterior, thus providing
controlled interruption of the EHC.57 The
rhesus monkey can only compensate for
20% interruption of the EHC by a 4- to
5-fold increase III hepatic bile salt
synthesis.
Assuming that steady state kinetics
exist in patients with ileal resection and
that fecal bile salt excretion matches
hepatic synthesis, a similar degree of com-
pensation was calculated for patients with
complete external biliary fistulae by Carey
and Williams, 185 who estimated that the
human liver could compensate for 16% in-
terruption of the EHC.
Extra-ileal bile 'salt absorption. The
partial conservation of the EHC by bile
salt diffusion from extra-ileal sites was sug-
gested by studies in the rhesus monkey
which showed that the more extensive the
distal small bowel resection, the greater
was the deficit in bile salt secretion. 172
Following ileal resection, the individual
contributions by the residual jejunum and
colon in bile acid reabsorption have not
yet been documented. However, recent
January 1972 PROGRESS TN GASTROENTEROLOGY
studies from our laboratory 18sa suggest
that, per unit length, the jejunum is 2 to 3
times more effective than the colon in bile
acid absorption. It also seems likely that a
small adaptive increase in bile acid absorp-
tion occurs in the residual jejunum after
removal of the ileum, comparable to the
compensatory increase in glucose absorp-
tion seen after ileectomy,l74 although no
such adaptive change is seen in the colon.
Furthermore, following proximal small
bowel resection, active bile salt transfer
by the residual ileum becomes supranor-
mal. 185a
Bile salt markers for the broken EHC.
The physiological markers of a broken
EHC may be summarized as follows. De-
pending on the magnitude of bile salt loss
due to ileal malabsorption, and the degree
of success in restoring the EHC by the
adaptive increase in hepatic bile salt syn-
thesis and by extra-ileal bile salt reabsorp-
tion, there mayor may not be intraluminal
bile salt deficiency. There is, however,
increased fecal bile salt excretion and
therefore increased hepatic bile salt syn-
thesis. In turn, hepatic 7 a-hydroxylase
activity is increased 68. 71 while 12a-
hydroxylase activity is suppressed. As a
result, the ratio of chenodeoxycholate to
cholate in both blood and bile is in-
creased. 186 Again, if cholic acid is pre-
vented from contact with intestinal micro-
organisms, as occurs, for example, with a
bile fistula, . the secondary bile acid,
deoxycholic acid, disappears from the
EHC and is no longer found in duodenal
aspirates. 186, 187 Finally, the G:T bile salt
ratio increases from the normal 2 or 3:1 44 - 47
to between 12 and 20:1. 47 , 51,169, 188
There are two possible mechanisms for
the increased G : T ratio. First, the in-
creased hepatic bile salt synthesis rate
rapidly drains the limited stores of taurine
while the ubiquitous glycine is freely avail-
able. Second, in ileal dysfunction at least,
there are theoretical reasons for postulat-
ing selective wasting "f taurine-conjugated
bile acids. Because of their low pKa's, at
prevailing intestinal pH levels (5.0 to 7.0)
the taurine conjugates are almost entirely
in the ionized form and as such are unavail-
able for passive non ionic diffusion. In con-
trast, a considerable percentage of the
131
glycine-conjugated bile acids are in the
nonionized form at these pH levels and so
their EHC is partially conserved by je-
junal reabsorption. The quantitative con-
tribution of each of these mechanisms
is unknown, but depletion of taurine stores
is probably the more important factor.
Certainly the fractional catabolic rate of
labeled glycocholate was the same as that
of taurocholate when the turnover of these
two isotopes was compared in patients
with ileal dysfunction. 188 However, a com-
parable study with the glycine and taurine
conjugates of chenodeoxycholic acid is
needed, since the passive diffusion of
dihydroxy bile salts is greater than that of
cholic acid. 20
Clinical Consequences of the Broken
EHC in Ileal Dysfunction
Depletion of bile salts: steatorrhea and
gallstone formation. The spillover of unab-
sorbed bile salts into the colon of patients
with ileal dysfunction is thought to be an
important factor in the pathogenesis of
watery diarrhea from which many of these
patients suffer. 189, 190 The resultant intra-
luminal bile salt deficiency contributes to
the steatorrhea of the ileectomized pa-
tient. Furthermore, the depletion of biliary
bile salts may jeopardize cholesterol solu-
bility in bile, thereby predisposing choles-
terol gallstone formation ,
Bile salt diarrhea in the broken EHC.
The cathartic action of excessive amounts
of bile salts in the colon, which results from
ileal disease, has been emphasized re-
cently.189, 190 Bile salts, particularly the
dihydroxy bile salts, inhibit water, sodium,
chloride, and bicarbonate absorption and
promote potassium secretion.190-192 The
cathartic effect of excessive amounts of
bile salts in the colon may also be related
to accelerated motility, which has been
shown in the dog,193 in the guinea pig,194
and in man. 19S
Although patients with ileal dysfunction
may have an intraluminal bile salt defi-
ciency, replacement therapy with exoge-
nous bile salts has not been successful in
controlling their diarrhea. In fact, although
fecal fat excretion may be improved, the
diarrhea is usually aggravated,164, 166, 196
132 PROGRESS IN GASTROENTEROLOGY
presumably because malabsorption of
exogenous bile salts simply compounds
the cathartic or cholerheic load of endoge-
nous material already spilling into the
colon. 189 The apparent paradox of further
reducing the available bile salts by feeding
a bile acid-sequestering agent, cholestyra-
mine l97 may in fact improve the patient's
diarrhea. 198·201 Lignin, a derivative of wood
pulp, also binds bile acids both in vitro, 155
and in the intestinal lumen. 202 It is said to
selectively bind free bile acids and there-
fore theoretically its principal effect should
be in the colon after bacteria have decon-
jugated the malabsorbed conjugates. If
true, this would leave the conjugated bile
salts free to promote micelle formation in
the jejunum. 203 This hypothesis has not
been supported in man,204 and lignin
seems to have a similar but less effective
bile acid-binding capacity than cholestyra-
mine. 205 Its sole advantage, therefore, is
probably that it is more palatable than
cholestyramine, which, in spite of refine-
ments in preparation, still has a somewhat
fishy odor.
Complications to treatment with cho-
lestyramine have been recorded, however,
including nausea, vomiting, constipation,
and fecal impaction,154 acidosis due to
increased bicarbonate loss in the stool,206
intestinal obstruction,207 and hemorrhage
from hypoprothrombinemia. 208 In spite of
these rare complications, a therapeutic
trial with cholestyramine is always worth-
while in an attempt to control the diarrhea
of patients with ileal disease or resection-
preferably in the controlled environment
of a metabolic unit. Hofmann and Poley l99
have suggested that patients with short
lengths of ileum resected (less than 100
cm) who have watery diarrhea are the pa-
tients most likely to benefit from choles-
tyramine therapy, even at the expense of a
modest increase in fecal fat. However, in
the author's experience, response to treat-
ment with this drug is variable and unpre-
dicatable and is not dependent on the
extent of the resection.
Treatment of hypercholesterolemia by
breaking the EHC. Since bile acid syn-
thesis represents the major catabolic path-
way for cholesterol,209. 210 many attempts
Vol. 62, No.1
have been made to promote the excretion
(and hence the synthesis) of bile acids in
the management of hypercholesterolemia.
The methods used have included ileal
resection and bypass, 211-215 and treatment
with bile acid-sequestering (cholestyra-
mine) and precipitating (neomycin) drugs.
Although such treatment undoubtedly
does increase both bile acid and neutral
sterol excretion in the feces, unfortunately
such interruption of the EHC also stimu-
lates hepatic cholesterol synthesis and as
a result, the initial lowering of serum cho-
lesterollevels is not always maintained. 196
Oxalate metabolism in the broken EHC.
An intriguing consequence of bile salt mal-
absorption and the attendant increase in
G: T bile salt ratio is the occurrence of
hyperoxaluria and renal calculi from which
the patient with ileal disease or resection
may suffer. 50. 51. 216.217 The proposed mech·
anism for the hyperoxaluria is as follows.
Colonic bacteria deconjugate the malab-
sorbed glycine-conjugated bile acids and
some of the liberated glycine is further
converted by bacterial enzymes to gly-
oxalate which is absorbed, oxidized in the
liver to oxalic acid, and excreted by the
kidneys to produce hyperoxaluria. Since
glycine is thought to be the substrate for
this form of secondary hyperoxaluria, and
since it has been known for some time that
the G: T ratio may be reversed by feeding
taurine,44 Dowling et al. 5I fed taurine to
one of their ileal resection patients and
abolished the hyperoxaluria-a finding
which has subsequently been confirmed. 217
Why some but not all patients with ileal
dysfunction should develop hyper-
oxaluria is not at present clear.
Radiorespirometry in the broken EHC
and in the blind loop syndrome. Most
isotopic bile salts studies use material
labeled with 14C in the carboxyl position
but l4C-glycine labeled glycocholate is
now commercially available (Radiochemi-
cal Centre, Amersham, Bucks., England).
Using this isotope, Hofmann et al. 50
showed that in patients with a broken
EHC due to ileal dysfunction, in addition
to the glycine -> glyoxalate -> oxalic acid
pathway, some of the glycine may be con-
verted to l4CO 2' By trapping expired
January 1972 PROGRESS IN GASTROENTEROLOGY
14C0 2 in hyamine, Hofmann and his
colleagues 5 0 were able to measure cumu-
lative breath excretion of 14C0 2 with a
liquid scintillation counting technique.
Over a 12-hr period, 2 ileal resection pa-
tients excreted 31 and 36% of the isotope,
compared with a mean of 8.4% (range
3.6 to 13.2%) in 5 normal controls.
The bacterial catabolism of glycine may
well be analogous to the formation of in-
dican from dietary tryptophan. Raised
levels of urinary indican excretion are
found both in patients with the blind loop
syndrome where excessive numbers of
colonic bacteria attack normal dietary
tryptophan in the small bowel, and also in
malabsorption where the normal colonic
flora attacks tryptophan which has spilled
into the large bowel. 218 By the same
analogy, the increased G: T ratio in p?-
tients with intestinal stasis 219 may pro-
vide the glycine substrate for oxalate
formation and hyperoxaluria in the stag-
nant loop syndrome. This hypothesis has
yet to be confirmed, but two recent stud-
ies have suggested that by monitoring
expired radioactivity after oral HC-glycine
labeled glycocholate, a marked increase in
14C0 2 production is found in the breath of
patients with the blind loop syn-
drome.220.221 The development of a
simple breath monitoring test after an oral
isotopic dose of glycine-labeled glyco-
cholate to diagnose ileal dysfunction or in-
testinal stasis offers tempting possibilities.
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