PERSPECTIVES IN CLINICAL HEPATOLOGY

Ursodeoxycholic Acid in Cholestatic Liver

Disease: Mechanisms of Action and
Therapeutic Use Revisited
Gustav Paumgartner and Ulrich Beuers
Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver
diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of
cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of
the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of
bile and, possibly, decrease of the concentration of hydrophobic bile acids in the
cholangio- cytes; (2) stimulation of hepatobiliary secretion, putatively via Ca2 - and
protein kinase C- dependent mechanisms and/or activation of p38MAPK and
extracellular signal-regu- lated kinases (Erk) resulting in insertion of transporter molecules
(e.g., bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular
membrane of the hepatocyte and, possibly, activation of inserted carriers; (3)
protection of hepatocytes against bile acidinduced apoptosis, involving inhibition of
mitochondrial membrane permeability transition (MMPT), and possibly, stimulation
of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves
serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis,
and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (1320 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but
effects on disease progression must be further evaluated. Anticholestatic effects of
UDCA have also been reported in intrahepatic cholesta- sis of pregnancy, liver disease of
cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host
disease. Future efforts will focus on definition of additional clinical uses of UDCA, on
optimized dosage regimens, as well as on further elucidation of mechanisms of action of
UDCA at the molecular level. (HEPATOLOGY 2002;36:525-531.)
rsodeoxycholic acid (UDCA; 3 , 7 -dihydroxy-5 -cholanic acid) is a hydrophilic bile
acid that is increasingly used for the treatment
of
various cholestatic disorders.1,2 It is normally present in
human bile, albeit in a low concentration of only
about
3% of total bile acids. It is the major bile acid in
black

Abbreviations: UDCA, ursodeoxycholic acid; PBC, primary biliary cirrhosis;

PSC, primary sclerosing cholangitis; Bsep, rat bile salt export pump; BSEP, human
bile salt export pump; CA, cholic acid; TUDCA, tauroursodeoxycholic
acid; [Ca2 ]i, cytosolic free calcium; PKC, protein kinase C; MAPK, mitogenactivated protein kinase; CFTR, cystic fibrosis transmembrane regulator; Erk,
extracellular signal-regulated kinase; MMPT, mitochondrial membrane
permeability transition; PFIC, progressive familial intrahepatic cholestasis; GG
, -glutamyltranspepti- dase; Mrp2, rat multidrug resistance associated protein
2; MRP2, human multi- drug resistance associated protein 2.
From the Department of Medicine II, Klinikum Grosshadern, University of
Munich, Munich, Germany.
Received February 26, 2002; accepted July 26, 2002.
Address reprint requests to: Gustav Paumgartner, M.D., F.R.C.P., Klinikum
Grosshadern, University of Munich, Marchioninistr. 15, 81377 Munich, Germany. E-mail: Gustav.Paumgartner@med2.med.uni-muenchen.de; fax: (49) 897095 7609.

Copyright 2002 by the American Association for the Study of Liver Diseases.
0270-9139/02/36030002$35.00/0
doi:10.1053/jhep.2002.36088

bears bile, which has been used in Chinese traditional

medicine for the treatment of liver diseases.3 First
reports on the effects of UDCA in patients with liver
diseases came from Japan as early as 1961.3 Since 1989, a
number of controlled trials on the use of UDCA in
primary biliary cirrhosis (PBC) and primary sclerosing
cholangitis (PSC) were published in the Western
literature.4 To date, UDCA is widely used for the
treatment of PBC for which it is the only drug approved
by the U.S. Food and Drug Administration (FDA).

Pharmacokineti
cs

UDCA capsules and tablets contain crystals of the

acid form, which are poorly soluble at pH
7. The
pKa of UDCA is 5.1, and the solubility of its
protonated form is
9 mol/L. After oral administration of pharmacologic
doses (10-15 mg/kg/d), UDCA is absorbed by
dissolu- tion-limited passive nonionic diffusion
mainly in the small intestine and to a small extent in
the colon.5 Since the critical micellization pH for
UDCA is close to pH 8, dissolution of UDCA in the
proximal jejunum occurs by solubilization in mixed
micelles of other bile acids.5 Thus,
525

HEPATOLOGY,
526
PAUMGARTNER
Vol. 36, No.
AND
3, 2002
BEUERS

administration of UDCA with a meal may enhance

ab- sorption. In patients with cholestasis and decreased
biliary secretion of endogenous bile acids, absorption of
UDCA may be decreased. UDCA is taken up from the
portal blood into the liver with a first pass extraction
of about
50%,5 conjugated mainly with glycine and to a
lesser extent with taurine, and actively secreted into
bile. Al- though conjugates of UDCA appear to be the
active spe- cies mediating the pharmacologic effects of
UDCA in cholestatic liver disease, conjugation even in
the choles- tatic liver is so efficient that it apparently
suffices to ad- minister the unconjugated molecule.
The degree of UDCA enrichment in bile following
chronic ingestion correlates with the daily administered
dose. A daily dose of 13 to 15 mg/kg UDCA causes an
enrichment of ap- proximately 40% to 50% in biliary
bile acids of patients with PBC. Beyond a certain
dose, which has not been adequately defined, additonal
enrichment does not occur because of both the inability
of UDCA to inhibit bile acid synthesis and the
epimerization of UDCA to chenodeoxy- cholic acid.5
UDCA conjugates are absorbed mainly from the distal
ileum, where they compete with endogenous bile acids
for active transport, and undergo enterohepatic
circulation. Nonabsorbed UDCA conjugates pass into
the colon, are deconjugated, and converted to
lithocholic acid by intestinal bacteria. Because of its
low aqueous solubility, most of the lithocholic acid
formed remains insoluble in the colonic content. The
fraction of litho- cholic acid returning to the liver
undergoes sulphation that in turn leads to excretion via
the feces. Even in pa- tients with cholestatic liver
disease, less than 5% of the dose of UDCA is found as
conjugates and metabolites in the urine, showing that
renal elimination represents a mi- nor pathway of
UDCA elimination.5

Mechanisms of Action of
UDCA
The mechanisms underlying the beneficial effects of
UDCA in cholestatic disorders are increasingly being
unraveled. Experimental evidence suggests three
major mechanisms of
action:
protection
of
cholangiocytes against cytotoxicity of hydrophobic bile
acids, stimula- tion of hepatobiliary secretion, and
protection of hepato- cytes against bile acidinduced
apoptosis. One or all of these mechanisms may be of
relevance in individual cho- lestatic disorders and/or
different stages of the cholestatic liver disease.

Protection of Cholangiocytes
Against
Cytotoxicity of Bile
Acids

PAUMGARTNER
HEPATOLOGY,
AND September
BEUERS 2002
526

Hydrophobic bile acids damage cell membranes at

high micromolar to millimolar concentrations in
vitro.

527 PAUMGARTNER
HEPATOLOGY,
Vol. 36, No.
AND
3, 2002

BEUERS
Conjugates
of UDCA counteract the effects of hydrophobic bile acids.6,7 Modulation by UDCA of the
structure and composition of mixed phospholipid-rich
micelles in bile have been implicated for the membrane
protecting effects of UDCA.7 Since high concentrations
of bile acids are only present within the biliary lumen,
the relevance of these in vitro findings appears to be
restricted to the biliary tree.
Phospholipids in bile, by formation of mixed
micelles with bile acids, protect cholangiocytes against
membrane damage induced by hydrophobic bile acids.
The mdr2- knockout mouse that lacks the ability to
secrete phos- pholipids into bile develops a chronic
nonsuppurative cholangitis resembling human chronic
cholestatic liver disease.8 Enrichment of bile with
UDCA renders bile more hydrophilic and less
cytotoxic. Feeding of UDCA decreases the degree of
cholangiocellular injury, portal inflammation, and
ductular proliferation in these ani- mals.8 Likewise, in
patients with PBC and PSC under treatment with
UDCA, the inflammatory reaction around bile ducts
was reported to be less severe.9-13
UDCA feeding prevented ductular proliferation thought
to be induced by hydrophobic bile acids also in bile
duct ligated rats.14 Interestingly, the effects of
UDCA on cholangiocytes were apparently mediated
by Ca2 - and protein kinase C(PKC )
dependent mechanisms. Ca2 - and PKC -dependent

PAUMGARTNER
HEPATOLOGY,
AND September
BEUERS 2002
527

mechanisms have previ- ously been shown to

contribute to the anticholestatic ac- tion of UDCA
conjugates in hepatocytes15-17 as outlined below. Thus, it
is attractive to speculate that UDCA con- jugates may
protect cholangiocytes against bile acid injury by
stimulating basolateral secretion and decreasing the
cholangiocellular concentration of hydrophobic bile acids, a concept brought forward by A. F. Hofmann a decade ago.5

Stimulation
Secretion

of

Hepatobiliary

The disturbance common to all forms of cholestasis is

an impairment of bile formation. This results in
retention of bile acids and other potentially toxic biliary
constitu- ents in the liver, which leads to liver cell injury
with fur- ther impairment of bile formation and
hepatocellular apoptosis.
Experimentally, UDCA stimulates biliary secretion of
bile acids and other organic anions (e.g., bilirubin
glucu- ronides, glutathione conjugates) and prevents
cholestasis induced by hydrophobic bile acids in rat
liver.17,18 In line with these observations, UDCA
stimulates biliary secre- tion of bile acids in patients
with PBC and PSC19 and decreases serum levels of
bilirubin9,10,12,20,21 and endoge- nous bile acids22 in
these patients. Thus, beneficial effects

of UDCA in cholestasis may be related to the

enhanced elimination of toxic compounds from the
hepatocytes.
The secretory capacity of the hepatocyte is
determined by the number and activity of carrier proteins
in the apical membrane and may be regulated both on a
transcriptional and posttranscriptional level. It has
recently been shown that UDCA stimulates the
expression of transporter pro- teins for biliary secretion
in the hepatocyte23 and the tar- geting and insertion of
transporter
molecules
into
the
canalicular
membrane.17,24 The effect of UDCA on mRNA and
protein levels may be important for long- term
regulation, whereas effects on the insertion of transporters into the canalicular membrane and on carrier
activity may also determine short-term regulation of
se- cretion. By up-regulation of synthesis, apical
insertion, and activation of the bile salt export pump
(Bsep) and the conjugate export pump (Mrp2), UDCA
might enhance bile salt dependent and bile salt
independent bile flow.
Up-regulation of Synthesis of Transporter
Proteins. The transcriptional regulation of canalicular
transporter proteins by UDCA and cholic acid (CA) has
recently been addressed.23 In hepatocytes of mice fed a
UDCA- or CA- supplemented diet, both UDCA and
CA up-regulated Bsep and Mrp2 mRNA. Since this
effect was not specific for UDCA, its role for the
anticholestatic action of UDCA remains unclear.
Apical Insertion of Transporter Proteins. In cholestasis, vesicle-mediated targeting of proteins to the canalicular membrane is impaired. Experimental
evidence suggests that the taurine conjugate of UDCA
(TUDCA), by a complex network of signals, stimulates
hepatobiliary vesicular exocytosis and insertion of
carrier proteins into the apical membrane of the
hepatocyte.15-17,24-26 As re- cently shown in cholestatic
rat liver, TUDCA signifi- cantly enhances the
density of the conjugate export pump, Mrp2, in
canalicular membranes and thereby stimulates
secretion of potentially toxic compounds.17
Cytosolic free calcium [Ca2 ]i seems to be critical for
TUDCA-induced exocytosis in the model of the
perfused
rat liver.15 TUDCA, but not the trihydroxy bile acid taurocholic acid acid, induces a sustained elevation of [Ca2 ]
15,27
TUDCA also selectively
i in isolated hepatocytes.
in- duces translocation of the Ca2
-sensitive
-isoform of PKC (a key mediator of regulated
exocytosis) to hepato- cellular membranes, and
activates membrane-bound PKC.16,28
Inhibition of
PKC
by the PKC inhibitor bisindolylmaleimide-I
markedly impairs TUDCA-in- duced secretion of the
model Mrp2 substrate dinitrophenyl-S-glutathione in experimental cholestasis, which
strongly supports the concept that TUDCA exerts anti-

Fig. 1. Experimental model of TUDCA-induced stimulation

of hepato- cellular secretion. TUDCA, taken up into the
hepatocyte by the Na - taurocholate cotransporting
polypeptide (Ntcp), stimulates apical vesicular exocytosis
and insertion of key canalicular transporters such as the
conjugate export pump, Mrp2, and the bile salt export
pump, Bsep, via Ca2
- and PKC
-dependent
mechanisms15,17 or via activation of p38MAPK and Ras-,
Raf-, Erk-1/2 dependent mechanisms24,26 (for de- tails, see
text).

Canalicular bile acid secretion may be increased by

TUDCA via alternative signaling pathways independent
of PKC in normal liver.24,26 Activation of the small GTPbinding protein Ras and the mitogen-activated protein
kinases (MAPK), extracellular signal-regulated kinase
(Erk)-1 and Erk-2, on one hand and the Ras/Rafinde- pendent p38MAPK on the other hand mediate
TUDCA- induced bile acid secretion in the perfused
rat liver.24,26
TUDCA induced a transient and concentration-dependent activation of p38MAPK and of Erk-2. This was
accom- panied by enhanced insertion of Bsep into the
canalicular membrane and by an increase of
taurocholic acid excre- tion.24
Thus, UDCA
conjugates may improve the im- paired secretory
capacity of the cholestatic liver by modulating
complex intracellular signaling cascades including
calcium, PKC , and different MAPK (Fig. 1).
Activation/Inactivation of Transporter Proteins.
Phosphorylation/dephosphorylation of transporter proteins at their site of action may be a third mechanism
by which UDCA modulates apical secretion in
hepatocytes. The mouse Bsep is phosphorylated by
PKC .29 Recent evidence indicates that the transport
capacity of the Bsep is increased via PKC -mediated
phosphorylation,29 a process inhibited by PKC .30
Since taurolithocholic acid has been shown to
selectively translocate PKC
to cana- licular
31
membranes, it is attractive to speculate that cholestatic
(e.g.,
taurolithocholic
acid)
and
anticholestatic (e.g., TUDCA) bile acids, by differential
modulation of PKC isoforms,17,31 directly affect
transporter activity in the canalicular membrane.29,30
Cholangiocytes contribute to bile formation by secreting an HCO3 -rich fluid. In cystic fibrosis, Cl -dependent HCO3 secretion is typically impaired due to a

cholestatic effects, at least in part, by Ca2 - and PKC dependent mechanisms.17

mutation of the CFTR gene, which encodes for a Ca2 independent Cl channel. UDCA is known to stimulate

HCO 3 secretion in rat and in man. It has been

speculated
that UDCA may stimulate cholangiocyte HCO3 secretion by Ca2 -dependent mechanisms via activation of a
Ca2 -dependent Cl channel and concomitant stimulation of Cl /HCO3 exchange via the anion exchanger 2.
UDCA directly increases [Ca2 ]i in cholangiocytes and
induces membrane binding of Ca2 -dependent PKC ,14
mechanisms similar to those observed in hepatocytes.15,16,27,28,32 UDCA conjugates also indirectly increase [Ca2 ]i in cholangiocytes possibly by stimulation
of biliary ATP secretion, which then may induce Ca2 dependent Cl secretion via apical P2Y ATP receptors.33
Interestingly, anion exchanger 2 expression and
bicarbon- ate secretion are impaired in patients with
PBC and are up-regulated after treatment with
UDCA.34,35 Thus,
stimulation of cholangiocellular HCO3 secretion may
contribute to the anticholestatic effect of UDCA at least
in certain biliary diseases in which HCO3 secretion is
impaired.

Protection Against Bile Acid

Induced
Apoptosis
Apoptosis is a major form of hepatocyte cell death in
cholestatic liver diseases such as PBC.1 It has been attributed to the action of accumulating hydrophobic bile
acids in cholestatic liver cells.1 In rat hepatocytes,
glycoche- nodeoxycholic acid or glycodeoxycholic acid
induce apo- ptosis by ligand-independent activation of
the Fas death receptor,36 followed by activation of
caspase 8 and the proapoptotic molecule Bid. Bid
chaperones another pro- apoptotic molecule, Bax, to
the
mitochondrial
membrane.
Thereby,
mitochondrial membrane permeability transition
(MMPT) is induced, which causes a sudden increase in
permeability of the inner mitochondrial mem- brane to
ions. MMPT is then followed by mitochondrial
swelling, release of cytochrome c to the cytosol, interaction of cytochrome c with the apoptotic proteaseactivat- ing factor 1, subsequent activation of caspase
9, and apoptotic cell death.1 Antiapoptotic effects of
UDCA have been shown in vitro and in vivo in the
rat.37,38 They were associated with a reduction of the
MMPT and of mitochondrial cytochrome c release.1,38
A recent study showed that UDCA, via activation of
the epidermal growth factor receptor and MAPK,
induces a survival sig- nal in hepatocytes that may
contribute to the antiapop- totic effect.39 Although
intriguing, the impact of antiapoptotic mechanisms
for the beneficial effects of UDCA in cholestatic
liver disease remains unclear at present.
A number of other potential sites of action of
UDCA in chronic cholestatic liver disease have been

as reversal of aberrant expression of HLA class I molecules

on hepatocytes
has been observed, but appears to be
secondary to the anticholestatic effect of UDCA. In vitro
studies suggested direct immunomodulating effects of
UDCA on cytokine secretion of peripheral monocytes;
the physiologic relevance of these studies, however, has
been questioned due to methodological concerns.41

Therapeutic Uses and Efficacy

Primary
Biliary Cirrhosis. This chronic
cholestatic liver disease may be regarded as a model
disease for UDCA therapy. It starts with an
inflammatory lesion of interlobular bile ducts of
unknown etiology, which results in bile duct
destruction, fibrosis, and finally cirrhosis.
Since the cause of the disease is unknown, therapy must
aim at inhibiting the underlying pathogenetic processes to
delay the progession of the disease.
Randomized, double-blind, placebo-controlled trials
discussed. Modulation of cell-mediated immunity by
UDCA such

on the use of UDCA in PBC have shown that UDCA at

doses of 13 to 15 mg/kg/d improves serum liver
chemis- tries including bilirubin, an important
prognostic marker in PBC,9-11,20 the Mayo risk
score,20
and liver his- tology.9,11 It may delay
progression of the disease to severe fibrosis or cirrhosis.42
A combined analysis of three of the largest trials
including 548 patients found that treatment with
UDCA in a dosage of 13 to 15 mg/kg/d was associ- ated
with a marked decrease in serum bilirubin and all
other serum markers of cholestasis and that the time
taken to liver transplantation or death was increased in
patients treated for up to 4 years.43 No apparent
survival benefit was seen within the first 2 years of
treatment. A Swedish multicenter, double-blind,
randomized trial conducted for 24 months including
116 patients concluded that UDCA in a dosage of 7.7
mg/kg/d is of little benefit in PBC.44 A meta-analysis of

8 randomized trials showed no difference between

UDCA and placebo in the effects on incidence of
death, liver transplantation, and death or liver
transplantation.45 It must be considered that this
analysis evaluated treatment given up to 24 months in 6
studies and for a mean of 24 and 63.6 months in 2
studies. A benefit of UDCA, as shown in the
combined analysis with the extended follow-up of 4
years mentioned above,43 may not have been detectable
in the meta-anal- ysis. Two of the trials included in the
meta-analysis used dosages of UDCA (7.7 and 10
mg/kg/d) that are now generally considered to be too
low. Clearly, trials with longer duration would be
needed to reach a statistically valid assessment of the
therapeutic efficacy of UDCA in PBC.
Primary Sclerosing Cholangitis. This chronic cholestatic liver disease of unknown cause is characterized by

chronic periductal inflammation of intrahepatic and

ex- trahepatic bile ducts leading to obliterative fibrosis,
duct loss, and biliary cirrhosis.
Although several randomized controlled trials showed
that UDCA in a dosage of 13 to 15 mg/kg/d improved
serum liver chemistries and bilirubin, an important
prog- nostic marker of PSC, none of these studies
showed an effect on
disease progression or
12,13,21
transplant-free sur- vival.
Even the largest of these
studies was probably too small and the follow-up
period too short to allow evaluation of survival.21
Recently, Mitchell et al.46 pre- sented a small
randomized trial suggesting that treatment of PSC with
a high dosage (20 mg/kg/d) may have a positive
effect on histologic stage, cholangiographic appearance, and projected survival. Thus, therapy of patients with PSC with high doses of UDCA is
promising, but must be evaluated by large, controlled
trials. One may speculate that in patients with PSC
absorption of UDCA is decreased due to an impaired
alkalinization of bile by the diseased biliary epithelium.
Therefore, a higher dos- age of UDCA may be required
for therapeutic success. If there is no response to UDCA
treatment, the presence of a dominant bile duct stricture
should be excluded.47
Intrahepatic Cholestasis of Pregnancy. This
choles- tatic disorder affecting pregnant women during
the third trimester has been shown to respond to
UDCA treat- ment. In small controlled trials, UDCA
improved pruri- tus and serum liver chemistries,
including serum bilirubin and transaminases, and
diminished the number of prema- ture deliveries.48 In
an uncontrolled study, it has been shown that an
increased dosage of UDCA (1.5 to 2.0 g/d;
20-25 mg/kg/d) improves biochemical liver tests such as
transaminases and serum bilirubin in intrahepatic cholestasis of pregnancy. An effect on fetal or maternal outcome, however, remains to be proven.49 No side effects
of UDCA have been reported in children or women
treated during pregnancy. UDCA may be considered a
safe treat- ment of intrahepatic cholestasis of pregnancy
in the third trimester, but further controlled trials are
needed before treatment of intrahepatic cholestasis of
pregnancy with this drug can be generally
recommended.
Liver Disease in Cystic Fibrosis. This genetic disorder is caused by mutations of the CFTR (cystic fibrosis
transmembrane conductance regulator) gene, which
re- sult in the secretion of viscous bile. This may lead to
the formation of bile duct plugs, biliary obstruction,
focal biliary fibrosis, and focal biliary cirrhosis.
In a randomized, double-blind, placebo-controlled
trial for 1 year, UDCA improved biochemical markers
of cholestasis, nutritional status, and general
condition.50
Histologic improvement has been reported as well.51

However, the prognostic significance of these findings

remains unclear. A higher dosage of UDCA (20 mg/kg/d)

appears to be more effective than a lower dosage (10 mg/
kg/d) because the intestinal absorption of UDCA and, as
a consequence, enrichment of bile with UDCA may be
impaired when pancreatic insufficiency is present.52
UDCA appears to be an effective and safe treatment in
cholestatic liver disease of cystic fibrosis. However, its
effect on survival has yet to be proven.
Progressive Familial Intrahepatic Cholestasis. Progressive familial intrahepatic cholestasis (PFIC)
represents a group of autosomal recessive inherited
disorders of childhood in which cholestasis usually
presents in the neonatal period or the first years of life
and leads to death from liver failure at ages ranging from
infancy to adoles- cence. They are caused by defective
transporters of the canalicular membrane, namely
FIC1 (PFIC 1), BSEP (PFIC 2), and MDR3 (PFIC
3). Although children with PFIC 1 or PFIC 2 are
characterized by a normal serum
-glutamyltranspeptidase (GGT), children suffering
from PFIC 3 have high serum GGT.
Patients with PFIC have been treated with UDCA
(20-30 mg/kg/d) for periods of 2 to 4 years.53 Twentysix children had normal serum GGT and 13 children
had high serum GGT. In the group as a whole,
alanine transaminase and GGT decreased significantly,
and nu- tritional state, as evidenced by weight gain,
improved. Liver function tests normalized in about

40% and im- proved in 20% to 30% of the patients.

No adverse effects of UDCA were seen. The factors
responsible for response to UDCA are not yet clear.
Response may be related to the type and/or location of
the mutation in the responsible gene, e.g., to residual
activity of BSEP or FIC in patients with normal serum
GGT. In patients with elevated serum GGT with a
partial defect of MDR3 and residual phos- pholipid
concentrations in bile, UDCA administration may be
sufficient to reduce the bile acid toxicity in bile below a
critical threshold. In contrast, nonresponders may have a
complete defect in phospholipid secretion.
Chronic Graft-Versus-Host Disease. Graft-versushost disease involving the liver may cause cholestasis. A
randomized, placebo-controlled trial showed that prophylactic administration of UDCA in patients undergoing bone marrow transplantation with a preparative
regimen of busulfan plus cyclophosphamide decreased
the incidence of hepatic complications.54
Drug- and Parenteral NutritionInduced Cholestasis. Small case series suggest that UDCA treatment
may be beneficial in some of these disorders.1
Although UDCA has been used for the treatment of
cholestatic liver diseases in Western medicine for more
than a decade, the underlying mechanisms of its
anticho- lestatic effects are only now being unraveled.
Future ef-

forts will focus on definition of clinical uses of UDCA

beyond those established so far, on optimized dosage regimens, as well as on further elucidation of potential
mech- anisms of action of UDCA. Among these, the
suggestion that UDCA induces cytochrome P450 3A4
(CYP3A4), a bile acid, drug-, and cholesterolmetabolizing enzyme,55 and the speculation that UDCA
decreases cholangiocel- lular concentrations of
hydrophobic bile acids (see above), appear of special
interest.

Reference
s
1. Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid mechanisms
of action and clinical use in hepatobiliary disorders. J Hepatol 2001;35:
134-146.
2. Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis:
potential mechanisms of action and therapeutic applications. HEPATOLOGY 1998;28:1449-1453.
3. Hagey LR, Crombie DL, Espinosa E, Carey MC, Igimi H, Hofmann AF.
Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas,
and related carnivores. J Lipid Res 1993;34:1911-1917.
4. Leuschner U, Fischer H, Kurtz W, Guldutuna S, Hubner K, Hellstern A,
Gatzen M, et al. Ursodeoxycholic acid in primary biliary cirrhosis:
results of a controlled double-blind trial. Gastroenterology
1989;97:1268-1274.
5. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic
drug. Scand J Gastroenterol Suppl 1994;29(Suppl 204):1-15.
6. Guldutuna S, Zimmer G, Imhof M, Bhatti S, You T, Leuschner U. Molecular aspects of membrane stabilization by ursodeoxycholate. Gastroenterology 1993;104:1736-1744.
7. Heuman DM, Bajaj RS, Lin Q. Adsorption of mixtures of bile salt
taurine conjugates to lecithin-cholesterol membranes: implications for
bile salt toxicity and cytoprotection. J Lipid Res 1996;37:562-573.
8. Van Nieuwkerk CM, Elferink RP, Groen AK, Ottenhoff R, Tytgat GN,
Dingemans KP, Van Den Bergh Weerman MA, et al. Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. Gastroenterology 1996;111:165-171.
9. Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter,
controlled trial of ursodiol for the treatment of primary biliary cirrhosis.
UDCA-PBC Study Group. N Engl J Med 1991;324:1548-1554.
10. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM,
Ghent CN, Michieletti P, et al. The Canadian multicenter double-blind
random- ized controlled trial of ursodeoxycholic acid in primary biliary
cirrhosis. HEPATOLOGY 1994;19:1149-1156.
11. Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A,
Berenguer J, et al. Long-term effects of ursodeoxycholic acid in primary
biliary cirrhosis: results of a double-blind controlled multicentric trial.
UDCA-Cooperative Group from the Spanish Association for the Study
of the Liver. J Hepatol 2000;32:561-566.
12. Beuers U, Spengler U, Kruis W, Aydemir U, Wiebecke B, Heldwein W,
Weinzierl M, et al. Ursodeoxycholic acid for treatment of primary
scleros- ing cholangitis: a placebo-controlled trial. HEPATOLOGY
1992;16:707714.
13. Stiehl A, Walker S, Stiehl L, Rudolph G, Hofmann WJ, Theilmann L.
Effect of ursodeoxycholic acid on liver and bile duct disease in primary
sclerosing cholangitis. A 3-year pilot study with a placebo- controlled study
period. J Hepatol 1994;20:57-64.
14. Alpini G, Baiochchi L, Glaser S, Ueno Y, Marzioni M, Francis H,
Phinizy JL, et al. Ursodeoxycholate and tauroursodeoxycholate inhibit
cholangio- cyte growth and secretion of BDL rats through activation of
PKC alpha. HEPATOLOGY 2002;35:1041-1052.
15. Beuers U, Nathanson MH, Isales CM, Boyer JL. Tauroursodeoxycholic
acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca
mechanisms defective in cholestasis. J Clin Invest 1993;92:2984-2993.
16. Beuers U, Throckmorton DC, Anderson MS, Isales CM, Thasler W,
Kul- lak-Ublick GA, Sauter G, et al. Tauroursodeoxycholic acid activates
pro-

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

tein kinase C in isolated rat hepatocytes. Gastroenterology 1996;110:

1553-1563.
Beuers U, Bilzer M, Chittattu A, Kullak-Ublick GA, Keppler D, Paumgartner G, Dombrowski F. Tauroursodeoxycholic acid inserts the apical
conjugate export pump, Mrp2, into canalicular membranes and
stimulates organic anion secretion by protein kinase C-dependent
mechanisms in cholestatic rat liver. HEPATOLOGY 2001;33:1206-1216.
Kitani K, Ohta M, Kanai S. Tauroursodeoxycholate prevents biliary protein excretion induced by other bile salts in the rat. Am J Physiol 1985;
248:G407-G417.
Jazrawi RP, de Caestecker JS, Goggin PM, Britten AJ, Joseph AE,
Maxwell JD, Northfield TC. Kinetics of hepatic bile acid handling in
cholestatic liver disease: effect of ursodeoxycholic acid. Gastroenterology
1994;106:
134-142.
Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh
PA, Harrison JM, et al. Ursodeoxycholic acid in the treatment of
primary biliary cirrhosis. Gastroenterology 1994;106:1284-1290.
Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary
Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med
1997;336:691-695.
Poupon RE, Chretien Y, Poupon R, Paumgartner G. Serum bile acids in
primary biliary cirrhosis: effect of ursodeoxycholic acid therapy. HEPATOLOGY 1993;17:599-604.
Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Pojer C, Zenz R,
Lammert F, et al. Effects of ursodeoxycholic and cholic acid feeding on
hepatocellular transporter expression in mouse liver. Gastroenterology
2001;121:170-183.
Kurz AK, Graf D, Schmitt M, Vom Dahl S, Haussinger D. Tauroursodesoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats. Gastroenterology
2001;121:
407-419.
Haussinger D, Saha N, Hallbrucker C, Lang F, Gerok W. Involvement of
microtubules in the swelling-induced stimulation of transcellular taurocholate transport in perfused rat liver. Biochem J 1993;291:355-360.
Schliess F, Kurz AK, vom Dahl S, Haussinger D. Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by
tauroursode- oxycholate in rat liver. Gastroenterology 1997;113:13061314.
Bouscarel B, Fromm H, Nussbaum R. Ursodeoxycholate mobilizes intracellular Ca2 and activates phosphorylase a in isolated hepatocytes. Am J
Physiol 1993;264:G243-G251.
Stravitz RT, Rao YP, Vlahcevic ZR, Gurley EC, Jarvis WD, Hylemon PB.
Hepatocellular protein kinase C activation by bile acids: implications for
regulation of cholesterol 7 alpha-hydroxylase. Am J Physiol 1996;271:
G293-G303.
Noe J, Hagenbuch B, Meier PJ, St-Pierre MV. Characterization of the
mouse bile salt export pump overexpressed in the baculovirus system.
HEPATOLOGY 2001;33:1223-1231.
Noe JA, Meier PJ, St-Pierre MV. Functional characterization of the
phos- phorylation of the bile salt export pump by protein kinase C
[abstract]. HEPATOLOGY 2001;34(Part 2):255A.
Beuers U, Probst I, Soroka C, Boyer JL, Kullak-Ublick GA, Paumgartner
G. Modulation of protein kinase C by taurolithocholic acid in isolated
rat hepatocytes. HEPATOLOGY 1999;29:477-482.
Beuers U, Nathanson MH, Boyer JL. Effects of tauroursodeoxycholic
acid on cytosolic Ca2
signals in isolated rat hepatocytes.
Gastroenterology
1993;104:604-612.
Nathanson MH, Burgstahler AD, Masyuk A, Larusso NF. Stimulation of
ATP secretion in the liver by therapeutic bile acids. Biochem J 2001;358:
1-5.
Medina JF, Martinez A, Vazquez JJ, Prieto J. Decreased anion exchanger 2
immunoreactivity in the liver of patients with primary biliary
cirrhosis. HEPATOLOGY 1997;25:12-17.
Prieto J, Garcia N, Marti-Climent JM, Penuelas I, Richter JA, Medina JF.
Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology 1999;117:167-172.

36. Faubion W, Guicciardi M, Miyoshi H, Bronk S, Roberts P, Svingen P,

Kaufmann S, et al. Toxic bile salts induce rodent hepatocyte apoptosis
via direct activation of Fas. J Clin Invest 1999;103:137-145.
37. Benz C, Angermuller S, Tox U, Kloters-Plachky P, Riedel HD, Sauer P,
Stremmel W, et al. Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes. J Hepatol 1998;28:99106.
38. Rodrigues C, Fan G, Wong P, Kren B, Steer C. Ursodeoxycholic acid
may inhibit deoxycholic acid-induced apoptosis by modulating
mtiochondrial transmembrane potential and reactive oxygen species
production. Mol Med 1998;4:165-178.
39. Qiao L, Yacoub A, Studer E, Gupta S, Pei XY, Grant S, Hylemon PB, et
al.
Inhibition of the MAPK and PI3K pathways enhances UDCA-induced
apoptosis in primary rodent hepatocytes. HEPATOLOGY 2002;35:779-789.
40. Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and
class II major histocompatibility complex molecules in primary biliary
cirrhosis: effect of ursodeoxycholic acid. HEPATOLOGY 1990;11:12-15.
41. Bergamini A, Dini L, Baiocchi L, Cappannoli L, Falasca L, Bolacchi F,
Capozzi M, et al. Bile acids with differing hydrophilic-hydrophobic properties do not influence cytokine production by human monocytes and
murine Kupffer cells. HEPATOLOGY 1997;25:927-933.
42. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The
effect of ursodeoxycholic acid therapy on liver fibrosis progression in
primary biliary cirrhosis. HEPATOLOGY 2000;32:1196-1199.
43. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R,
Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;
113:884-890.
44. Eriksson LS, Olsson R, Glauman H, Prytz H, Befrits R, Ryden BO,
Ein- arsson K, et al. Ursodeoxycholic acid treatment in patients with
primary biliary cirrhosis. Scand J Gastroenterol 1997;32:179-186.
45. Goulis J, Leandro G, Burroughs A. Randomised controlled trials of
ursode- oxycholic-acid therapy for primary biliary cirrhosis: a metaanalysis. Lancet
1999;354:1053-1060.
46. Mitchell SA, Bansi DS, Hunt N, von Bergmann K, Fleming KA,
Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid
in primary sclerosing cholangitis. Gastroenterology 2001;121:900-907.

47. Stiehl A, Rudolph G, Kloters-Plachky P, Sauer P, Walker S. Development

of dominant bile duct stenoses in patients with primary sclerosing
cholan- gitis treated with ursodeoxycholic acid: outcome after
endoscopic treat- ment. J Hepatol 2002;36:151-156.
48. Palma J, Reyes H, Ribalta J, Hernandez I, Sandoval L, Almuna R,
Liepins J, et al. Ursodeoxycholic acid in the treatment of cholestasis of
pregnancy: a randomized, double-blind study controlled with
placebo. J Hepatol
1997;27:1022-1028.
49. Mazzella G, Nicola R, Francesco A, Patrizia S, Luciano B, Anna M, Giuliana S, et al. Ursodeoxycholic acid administration in patients with
cho- lestasis of pregnancy: effects on primary bile acids in babies and
mothers. HEPATOLOGY 2001;33:504-508.
50. Colombo C, Battezzati PM, Podda M, Bettinardi N, Giunta A. Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a doubleblind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis. HEPATOLOGY 1996;23:1484-1490.
51. Lindblad A, Glaumann H, Strandvik B. A two-year prospective study
of the effect of ursodeoxycholic acid on urinary bile acid excretion and
liver morphology in cystic fibrosis- associated liver disease. HEPATOLOGY
1998;
27:166-174.
52. van de Meeberg PC, Houwen RH, Sinaasappel M, Heijerman HG,
Bijlev- eld CM, Vanberge-Henegouwen GP. Low-dose versus high-dose
ursode- oxycholic acid in cystic fibrosis-related cholestatic liver disease.
Results of a randomized study with 1-year follow-up. Scand J
Gastroenterol 1997;32:
369-373.
53. Jacquemin E, Hermans D, Myara A, Habes D, Debray D, Hadchouel M,
Sokal EM, et al. Ursodeoxycholic acid therapy in pediatric patients
with progressive familial intrahepatic cholestasis. HEPATOLOGY
1997;25:519523.
54. Essell JH, Schroeder MT, Harman GS, Halvorson R, Lew V, Callander N,
Snyder M, et al. Ursodiol prophylaxis against hepatic complications
of allogeneic bone marrow transplantation. A randomized, double-blind,
pla- cebo-controlled trial. Ann Intern Med 1998;128:975-981.
55. Bodin K, Bretillon L, Aden Y, Bertilsson L, Broome U, Einarsson C,
Diczfalusy U. Antiepileptic drugs increase plasma levels of 4betahydroxy- cholesterol in humans: evidence for involvement of cytochrome
p450 3A4. J Biol Chem 2001;276:38685-38689.