Current Clinical Pharmacology, 2007, 2, 155-177 155

Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid in Cholestatic

Liver Diseases
Davide Festi1,*, Marco Montagnani1, Francesco Azzaroli1, Francesca Lodato1, Giuseppe Mazzella1,
Aldo Roda2, Anna Rita Di Biase3, Enrico Roda1, Patrizia Simoni1 and Antonio Colecchia1

1
Departments of Internal Medicine and Gastroenterology and 2of Pharmaceutical Sciences, University of Bologna and
3
Department of Pediatrics, University of Modena, Italy

Abstract: Ursodeoxycholic acid (UDCA), previously used for cholesterol gallstone dissolution, is currently considered
the first choice therapy for many forms of cholestatic syndromes. Many mechanisms and sites of action have been pro-
posed for UDCA, but definitive data are still missing regarding the key points of its efficacy and optimal dosage in order
to achieve a sustained clinical effect. Among the suggested mechanisms of action of UDCA, changes in bile acid pool
composition, hepatocyte membrane protection, immunomodulatory effects and bicarbonate-rich hypercholeresis have
been extensively studied. However, recent evidence indicate that UDCA is a potent intracellular signalling agent that
counterbalances impaired biliary secretion, inhibits hepatocyte apoptosis and protects injured cholangiocytes against toxic
effects of bile acids. It is clear that the relative contribution of these mechanisms to the anticholestatic action of UDCA
depends on the type and stage of the liver injury. Available clinical evidence suggest that UDCA treatment has to be initi-
ated as early as possible and that higher doses could be more efficacious in inducing and maintaining clinical remission of
cholestatic diseases. The future availability of UDCA derivatives will possibly enhance the chances to effectively treat
chronic cholestatic diseases.

Key Words: Bile secretion, apoptosis, liver cirrhosis, nuclear receptors, intestinal absorption, transport systems, ursodeoxy-
cholic acid, cholestatic liver diseases.

INTRODUCTION enterohepatic circulation of bile acids and the main physiol-

Ursodeoxycholic acid (UDCA; 3
,7-dihydroxy-5-
cholanoic acid) is a dihydroxy bile acid, which is normally
present in human bile, although at low concentrations (about
1-3% of total bile acids) [1]. It represents the major bile acid
of the bile of black bears [2] and it has been used for centu-
ries in traditional Chinese medicine as a remedy for liver
diseases. In modern medicine, UDCA has been employed as
a litholytic agent in place of chenodeoxycholic acid since
1975, when Makino et al. [3] documented its ability to re-
duce biliary cholesterol supersaturation, the main biochemi-
cal defect in cholesterol gallstone disease. Since that pre-
liminary report, several clinical studies have identified UDCA
as the best therapeutic agent in the medical treatment of cho-
lesterol gallstones [4]. In 1985, Leuschner et al. [5] first re-
ported the potential use of UDCA as a hepatoprotective
agent in chronic active hepatitis and, subsequently, Poupon
et al. [6] suggested UDCA administration in chronic cho-
lestatic liver diseases. Today, UDCA is used for the treat-
ment of different chronic cholestatic liver diseases, such as
primary biliary cirrhosis (PBC), primary sclerosing cholangi-
tis (PSC), intrahepatic cholestasis of pregnancy (ICP) and
pediatric cholestasis [7].
The aim of the present article is to review the available
evidence regarding the therapeutic role of UDCA in chronic
cholestatic liver diseases, after a short introduction on the
*Address correspondence to this author at the Department of Internal Medi-
cine and Gastroenterology, Policlinico S. Orsola-Malpighi, Via Massarenti
9, 40138 Bologna, Italy; Tel/Fax: +39-051-6364123;
E-mail: davide.festi@unibo.it
ogic concepts of the bile acid transport system.
Bile Acid Transport Systems and the Modulatory Role of
Ursodeoxycholic Acid
Bile acids enable the intestinal absorption of lipids and
fat-soluble vitamins [8]. Moreover, new findings on the in-
teraction between bile acids and nuclear receptors have re-
newed interest in the role of bile acids as regulators of lipid
homeostasis [9]. Bile acids are secreted by hepatocytes into
the biliary system and successively reach the intestinal lu-
men, where they are absorbed and recirculated back to the
liver via the portal blood. These physiological events realize
the entero-hepatic circulation of bile acids [10], which is
maintained mainly through active transport systems located
in the terminal ileum and in the liver [11]. Bile acids trans-
port kinetics in the liver [12] and in the intestine [13, 14]
have been characterized in vivo using animal models and in
vitro using membrane vesicles.
Bile acids are taken up via the basolateral sodium-
taurocholate cotransporter (NTCP) and organic anion trans-
port proteins (OATPs) at the basolateral membrane of the
hepatocyte [12]. The hepatocyte intracellular transport of
bile acids has not yet been completely elucidated (Fig. 1).
Following uptake across the basolateral membrane, bile ac-
ids bind to the cytosolic protein 3
-hydroxysteroid dehydro-
genase in rodents and to the hepatic bile acid binding protein
(HBAB) in the human liver. Vesicular trancytosis is possibly
involved in the transport of bile acids across hepatocytes, as
is suggested by its strong association with organelles, but
this mechanism is probably restricted to UDCA and litho-
cholic acid [15]. Canalicular secretion is the rate limiting

1574-8847/07 $50.00+.00 ©2007 Bentham Science Publishers Ltd.

156 Current Clinical Pharmacology, 2007, Vol. 2, No. 2 Festi et al.

Fig. (1). Hepatobiliary transport systems.

The figure represents the major hepatobiliary bile acids (BA) transport systems. Na+/taurocholate cotransporter (NTCP) and organic anion
transporting proteins (OATPs) represent the basis for import into hepatocytes of BA which are then secreted into bile by the bile salt export
pump (BSEP). The Multidrug Resistance Protein 2 (MRP2) transports bilirubin, reduced glutathione (GSH), sulphated BA and various or-
ganic anions (OA) into bile while phospholipids (Pl) are secreted by multidrug resistance 3 protein (MDR3). The multidrug resistance-related
proteins 3 and 4 (MRP 3 & 4) are basolateral efflux transporters for BA and OA. Familial Intrahepatic cholestasis 1 protein (FIC1) is an
aminophospholipid (amino-Pl) flippase maintaining the canalicular membrane physiological inner/outer asymmetry. In cholangiocytes, the
apical sodium-bile acid transporter (ASBT) is located at the apical membrane, where it allows bile acid active uptake. In the basolateral
membrane of cholangiocytes, Ost
/ and MRP3 enable bile acid extrusion into the pericanalicular plexus, from which bile acids recirculate
back to hepatocytes (chole-hepatic shunt). In the apical membrane of cholangiocytes, the cystic fibrosis transmembrane conductance regula-
tor (CFTR) is possibly responsible for chloride secretion and maintainance of fluid balance across epithelium.

step in the blood-to-bile transport of bile acids. A specific patic cholestasis and in benign recurrent intrahepatic cho-
canalicular membrane bile salt export pump (BSEP) has lestasis [17]. FIC1 is an aminophospholipid flippase with
been cloned and characterized [16-18]. BSEP is an ABC- regulatory function in the secretory processes, derived from
type transmembrane protein, responsible for ATP-dependent its role in maintaining the canalicular membrane asymmetry
transport of monovalent bile acids into bile, which in turn between the inner and the outer layer [24, 25].
drives the bile acid-dependent bile flow. In the mouse model,
The terminal ileum is the intestinal site where the apical
UDCA can both prevent and reduce the Bsep down-
sodium-bile acid cotransporter (ASBT) [13, 14] is located,
regulation caused by DCA, explaining one of the mecha-
accounting for the active absorption of glycine and taurine-
nisms responsible for UDCA’s protective role in the treat-
conjugated bile acids [14]. The correct functioning of ASBT
ment of cholestatic liver disease [19]. The multidrug resis-
has been demonstrated to be necessary for adequate bile acid
tence protein 2 (MRP2) which works as bilirubin conjugate
export pump, is also a divalent bile acid transporter [20] reabsorption [26, 27], allowing more than 90% of these
molecules to be recirculated back to the liver via the portal
which allows the biliary excretion of bile acids with two
blood [14]. In addition to the ileal active transport, ionic and
negative charges, such as sulfated tauro- or glycolithocholic
non-ionic passive diffusion of bile acids occurs across the
acid. MRP2 also mediates the canalicular excretion of re-
small intestinal and colonic epithelia [14], accounting for the
duced glutathione (GSH) [21] and organic anions, such as
absorption of unconjugated and, to a lesser extent, glycine-
divalent amphipathic conjugates with glutathione, glucuro-
nate, and sulfate [22, 23]. Another transporter involved in conjugated dihydroxy bile acids [28, 29]. Furthermore, in
vitro experiments using brush border membrane vesicles
bile acid secretion is familial intrahepatic cholestasis 1 (FIC1),
indicate the presence of a facilitated transport system for
a P-type ATPase mutated, in progressive familial intrahe-
Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid
unconjugated bile acids in the jejunum [13, 30]. Studies us-
ing intestinal brush border membrane vesicles showed that
UDCA is capable of reducing both the putative jejunal facili-
tated and the ileal active bile acid uptake [13].
Additional transport systems are involved in bile acid
transport through the enterocyte [28]: the cytosolic ileal bile
acid binding protein (I-BABP) [31, 32] and an heteromeric
organic solute transporter (OST
-OST) which has been
recently characterized as the ileal basolateral bile acid and
sterol carrier [33, 34].
In addition to hepatocytes and ileocytes, other cells pro-
vided with specialized bile acid transport systems are located
along the biliary tree and in the kidney. Large and medium
sized rat cholangiocytes express both Asbt (identical to the
ileal transporter) and a truncated form of the same protein (t-
Asbt) [35, 36]. ASBT is located at the apical membrane of
cholangiocytes where it accounts for the active sodium cou-
pled bile acid uptake. Furthermore, nonionic diffusion may
also contribute to bile acid apical uptake in cholangiocytes
[8]. A sodium-independent transport system mediates the
basolateral efflux of bile acids from cholangiocytes into the
peribiliary plexus [37] and MRP3 has been identified as the
basolateral efflux pump [38-41]. In rodents, t-Asbt [36] and
Oatp3 [12] have been proposed as basolateral bile acid efflux
pumps. More recently, Ost
/, which are selectively local-
ized in the basolateral plasma membrane of the epithelial
cells with bile acid and sterol absorption capacity, have been
identified as an important basolateral transport system in
cholangiocytes [33]. The cholangiocyte transport systems are
supposed to realize a chole-hepatic shunt [42] which should
allow a constant bile acid recycling to the hepatocytes, and
could explain the hypercholeretic effect of certain bile acids
[42, 43]. This system is also supposed to be important in the
adaptation to chronic extrahepatic cholestasis [44, 45]. More-
over, bile acids can activate intracellular signalling pathways
and modulate cholangiocyte secretion, proliferation and sur-
vival [35]. Since bile acid-dependent biliary flow is the main
physiologic choleretic mechanism, the chole-hepatic shunt
could help biliary secretion during the inter-prandial period,
when the intestinal uptake cannot provide a sufficient bile
acid supply through the portal circulation. Similarly to cho-
langiocytes, the gallbladder epithelial cells also express
ASBT, MRP2 and OATP-A, which are located in the apical
membrane and mediate sodium-dependent and –independent
uptake [35]. MRP3 has been identified as a basolateral bile
acid transporter in gallbladder epithelial cells [39, 40].
In addition to the hepatic, intestinal and cholangiocyte
transport, bile acid uptake systems are located in the apical
and basolateral membranes of the proximal renal tubular
cells. ASBT is expressed in the proximal renal tubular cells,
where it is located in the apical membrane and is responsible
for the uptake of bile acids from glomerular filtrate, mini-
mizing the urinary loss under normal conditions [34, 46].
MRP2 is also located in the apical membrane, where it me-
diates the excretion of organic anions and sulphated/glucu-
ronidated bile acids under normal conditions and during cho-
lestasis, respectively [47, 48]. Basolateral output from the
proximal renal tubular cells is provided by Mrp3 and Ost
/
[33].
Current Clinical Pharmacology, 2007, Vol. 2, No. 2 157
MECHANISMS OF ACTION OF URSODEOXY-
CHOLIC ACID IN CHOLESTASIS
Since the first report of UDCA efficacy in liver diseases
[5], different mechanisms of action have been suggested [49]
to explain its therapeutic effects: changes in bile acid pool
composition, hepatocyte membrane protective effects, im-
munomodulatory effects and bicarbonate-rich hypercholere-
sis. Furthermore, recent evidence indicate that UDCA is a
potent intracellular signalling agent which induces stimula-
tion of impaired biliary secretion, inhibits hepatocyte apop-
tosis and may protect injured cholangiocytes against the
toxic effects of bile acids [50] (Fig. 2). Although it is not
clear which of these mechanisms has a primary role in the
therapeutic action in cholestasis, it is likely that the effects
mainly depend on the specific cholestatic liver disease and
the stage of the disease itself [51].
In fact, cholestatic diseases can differ with respect to the
primary site of bile secretory impairment: in patients with
PBC, PSC and liver disease associated with cystic fibrosis
biliary secretion from both hepatocytes and cholangiocytes
may be impaired, while in patients with ICP and drug-
induced and sepsis-associated cholestasis, the predominant
defect is related to bile secretion from the hepatocytes [52].
Furthermore, the stage of the disease may influence UDCA
therapeutic action. In the early stage of PBC, when the dam-
age is mainly related to a toxic effect of bile acids, the pri-
mary therapeutic mechanism is towards the protection of
injured cholangiocytes and subsequently the excretory func-
tion. In the later stage of the disease, stimulation of biliary
secretion is crucial for preventing retention of hydrophobic
bile acids and other toxic substances in the hepatocytes.
When bile acids are retained within the hepatocyte, the inhi-
bition of bile acid-induced hepatocyte apoptosis represents
another important protective mechanism [51] (Fig. 2).
Effect of Ursodeoxycholic Acid on Transport Proteins
and Metabolic Pathways
In the course of cholestasis, bile acids, bilirubin and other
cholephils accumulate in the liver and blood, while their
concentration in the intestinal lumen is reduced [7]. In turn,
adaptive protective mechanisms determine profound changes
in the transporter and enzyme expression [7, 24, 41, 53].
Adaptive changes also occur during UDCA administration in
rodents [54, 55], but an additional role of UDCA on these
adaptive mechanisms in the course of cholestasis has not yet
been proven. In the hepatocyte, UDCA induces transcrip-
tional and post-transcriptional changes, leading to enhanced
expression and function of canalicular and basolateral trans-
porters. In mice, the expression of genes for the canalicular
transporters Bsep (monovalent bile acids transporter) and
Mrp2 (divalent bile acids and anionic conjugate transporter)
are enhanced by UDCA administration [19, 54]. The expres-
sion of genes for basolateral bile acid efflux pumps, Mrp3
and Mrp4, is also enhanced by UDCA in mice [55]. Post-
transcriptional mechanisms, such as vesicular exocytosis and
targeting of the transporters to the canalicular membrane, are
induced by UDCA in rodents, through mechanisms involv-
ing calcium-dependent PKC-
and MAP-kinases [51, 56,
57]. In patients with PBC, UDCA improves the excretory
function [58] and the expression of MRP2 has been shown to
158 Current Clinical Pharmacology, 2007, Vol. 2, No. 2
Fig. (2). Cholestatic liver diseases: pathogenetic mechanisms and mechanisms of action of ursodeoxycholic acid. BSEP function can be in-
hibited by estrogens. BSEP function and targeting to the canalicular membrane can be inhibited by cyclosporin (CyA).
UDCA= ursodeoxycholic acid; BSEP= Bile Salt Export Pump; PFIC= progressive familial intrahepatic cholestasis; PBC= primary biliary
cirrhosis; PSC= primary sclerosing cholangitis.
be increased during treatment with UDCA [59]. In PBC pa-
tients, UDCA treatment also upregulates the chloride-bicar-
bonate anion exchanger AE2, which is present in the apical
membrane of both hepatocytes and cholangiocytes, improv-
ing the hepatobiliary bicarbonate secretion [60-62].
In primary human hepatocytes, UDCA stimulates CYP3A4
expression [63, 64], which may increase hydroxylation and a
more efficient renal excretion of bile acids. On the other
hand, reduced expression of CYP7A1 has been shown after
UDCA treatment in primary human hepatocytes [65, 66],
and this could reduce the synthesis and accumulation of
more hydrophobic, potentially toxic bile acids.
The effect of UDCA on the expression of bile acid trans-
porters also operates in different cell types. For example, bile
acid efflux pumps are upregulated by UDCA both in the
proximal renal tubule (Mrp2 and Mrp4) and in the enterocyte
(Mrp2 and Mrp3) [55], protecting them from the intracellular
and systemic accumulation of more hydrophobic and toxic
bile acids. Similarly, the apical and basolateral efflux pumps
(Mrp2 and Mrp3, respectively) are upregulated by UDCA in
the murine enterocytes [55].
Interaction of Ursodeoxycholic Acid with Nuclear Recep-
tors
The growing knowledge about nuclear receptor activity
in bile acid homeostasis has opened a new field of interest
for both physiology and pharmacology research. The nuclear
receptors involved in bile acid metabolism and transport,
with a possible pivotal involvement in the adaptive responses
to cholestasis, are: farnesoid X receptor (FXR), short het-
erodimer partner (SHP), pregnane X receptor (PXR), vitamin
D receptor (VDR), constitutive androstane receptor (CAR),
and peroxisome proliferator-activated receptor-alpha (PPAR-

) [11].
Festi et al.
Among these nuclear receptors, FXR is considered the
primary intracellular bile acid sensor [67]. In the hepatocyte,
bile acids activate FXR which in turn, after induction of SHP
gene transcription, represses bile acid synthesis. Moreover,
FXR induces different target genes encoding bile acids and
phospholipid canalicular transport proteins, while repressing
the hepatocyte basolateral sodium-bile acid cotransporter
(NTCP). In the ileal enterocyte, FXR represses ASBT ex-
pression and induces the transcription of I-BABP, OST
/,
and the fibroblast growth factor 19 (FGF 19), the enterocyte
derived factor that mediates repression of the hepatic bile
acid synthesis.
Recently, it has been demonstrated that UDCA is able to
activate the glucocorticoid receptor [68] which, in turn,
transactivates the ASBT gene (SLC10A2) [69]. In the liver,
the NTCP gene (SLC10A1) is also activated by the gluco-
corticoid receptor and by the PPAR- coactivator-1
, and
suppressed by bile acids via a SHP- dependent mechanism
[70].
Protection of Cholangiocytes Against Toxic Effects of
Hydrophobic Bile Acids
The biliary tree is the anatomic compartment in which
bile acids reach the highest concentration (millimolar range).
Therefore, the protective effect of UDCA from the detergent
damage caused by the more hydrophobic bile acids is maxi-
mal for cholangiocyte and hepatocyte apical membranes. In
chronic cholestatic liver diseases, UDCA accumulates in bile
during the treatment, enhancing the hydrophilic/hydrophobic
ratio in bile acid pool composition [7, 71]. This change in the
hydrophilic/hydrophobic balance of bile acid pool is consid-
ered an important factor for the protection of the biliary epi-
thelium from the detergent effect of more hydrophobic bile
acids [7, 71]. Moreover, UDCA treatment increases the bil-
iary secretion of phospholipids [7, 71], which in turn con-
Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid
tribute to the formation of mixed micelles, protecting the
cholangiocytes from the detergent effect of bile acids. In
vitro studies demonstrate that UDCA protects cholesterol
rich membranes from the detergent damage induced by the
more hydrophobic bile acids, and this mechanism seems to
be dependent primarily on the altered structure and composi-
tion of the simple and mixed micelles [72, 73].
Ursodeoxycholic Acid and Apoptosis
Among the various properties assigned to UDCA, the
inhibition of apoptosis is one of the most recent. This sug-
gestion comes from the observation that UDCA was protec-
tive against cholestasis and the toxicity induced by hydro-
phobic bile acids, such as deoxycholic acid (DCA) and che-
nodeoxycholic acid (CDCA) [73-75].
Hydrophobic bile acids are able to induce apoptosis [76]
by a ligand independent activation of the Fas death receptor
[77, 78]. Fas activation then triggers intracellular signal
transduction pathways, among which is the activation of
caspase 8 and Bid [77] leading to Bax translocation to the
mitochondria, with disruption of the mitochondrial mem-
brane permeability [79]. The subsequent mitochondrial swel-
ling determines cytochrome-C release, followed by the acti-
vation of apoptotic protease activating factor 1 (APAF-1)
and the downstream caspases (9, 3, 6 and 7), finally leading
to apoptotic cell death [80].
In vitro studies have shown that UDCA is capable of
protecting hepatocyte from apoptosis induced by a variety of
different stimuli, including hydrophobic bile acids [81, 82].
UDCA diminishes Fas-ligand induced apoptosis preventing
cytochrome-C release from the mitochondria, probably by
modulating the mitochondrial membrane permeability transi-
tion and the production of reactive oxygen species [81-86].
Another line of evidence suggests that UDCA in its taurine
conjugated form protects against hydrophobic bile salt in-
duced apoptosis through the activation of survival pathways
(PI3K, p38, ERK MAPK) even though this latter possibility
is still uncertain [87, 88]. Together with the in vitro experi-
ments are the in vivo observations that UDCA administration
prevents the increase of apoptotic hepatocytes in rats fed
DCA [82] and reduces DNA fragmentation and bcl-2 expres-
sion in biliary epithelial cells of patients with PBC [89].
However, the real relevance of apoptosis in cholestasis is not
well defined [90, 91].
In virtue of its anti-apoptotic properties, UDCA has also
been proposed as an additional treatment for viral hepatitis
[92]. This concept might be supported by an improved re-
sponse rate to interferon-alfa in non responder patients with
hepatitis C virus (HCV)-related chronic hepatitis [93] even
though in vitro studies using co-cultures of Fas-Ligand ex-
pressing fibroblasts and primary mouse hepatocytes have
shown a modest efficacy of UDCA in protecting from Fas
induced apoptosis [86].
PHARMACOKINETICS AND PHARMACODYNAM-
ICS OF URSODEOXYCHOLIC ACID
UDCA is administered orally in its protonated unconju-
gated form and is solubilized at a pH greater than 8 in the
proximal jejunum in mixed micelles of endogenous bile ac-
Current Clinical Pharmacology, 2007, Vol. 2, No. 2 159
ids and phospholipids [1]. Unconjugated UDCA is absorbed
by passive diffusion throughout the intestinal tract and the
rate and amount absorbed is related to the effective solubili-
zation of the drug in the intestinal content, which is en-
hanced when it is administered with a meal (high pH) and
may be decreased in patients with cholestasis owing to a
reduced biliary and pancreatic secretion, which result in a
relatively acidic pH [94]. After intestinal absorption, UDCA
is taken up from the portal blood by the hepatocytes in their
sinusoidal domain via specific bile acid transporters. The
first-pass clearance is up to 60-70% and a relatively low
amount spill in the systemic circulation. In hepatocytes,
UDCA is conjugated mainly with the aminoacid glycine and,
to a lesser extent, with taurine and it is secreted in bile only
as conjugated by BSEP, the canalicular bile acid transport
protein [1, 12]. Unconjugated UDCA is also secreted by the
hepatocytes in bile, where it is actively reabsorbed by cho-
langiocytes. The chole-hepatic shunt of UDCA is linked to
increased biliary bicarbonate secretion [42].
In the intestinal lumen, glycoconjugated - UDCA is reab-
sorbed by both active and passive transport mechanisms,
while tauroconjugated -UDCA is absorbed in the terminal
ileum by active transport mechanism [1, 12]. Like other en-
dogenous bile acids, UDCA conjugates undergo an efficient
enterohepatic circulation [1]. The unabsorbed fraction of
UDCA and of UDCA conjugates enter the colon, where,
after bacterial deamidation and dehydroxilation of conju-
gates, they are mostly converted into lithocholic acid (LCA)
by intestinal bacteria and eliminated in feces [1]. Only small
amounts of LCA are reabsorbed by the colonic mucosa, sul-
phated in the liver and secreted into bile [1].
During chronic administration, UDCA becomes the pre-
dominant bile acid and this enrichment in the bile acid pool
seems to be dependent on the dose administered [95, 96].
Bioavailability of Ursodeoxycholic Acid
In the last 20 years, UDCA has been widely used for cho-
lesterol gallstone dissolution [94] and more recently for cho-
lestatic liver disease treatment [4, 97]. However, clinical
studies have demonstrated that, at a daily dose of 10-15
mg/kg, UDCA could have a limited therapeutic efficacy due
to its poor intestinal absorption and to a relatively high pH
(up to 8.4) necessary to go in solution as a ionized salt [96].
Experimental studies conducted on humans have demon-
strated that the orally administered drug is poorly absorbed,
with almost 50% being eliminated in the stools [98]. Intesti-
nal absorption is further impaired in patients affected by cho-
lestatic liver disease, due to the relatively low pH of their
intestinal content caused by a decreased biliary secretion [94,
99]. This defect could be overcome by the use of higher
doses of UDCA. Studies have shown that in PBC patients
high doses (up to 30 mg/kg day) produce higher biliary en-
richment in UDCA [95, 100, 101]. In turn, these data suggest
that the increase of the conventionally used therapeutic doses
may be of benefit in treating cholestatic liver diseases. Alter-
natively, drug formulations could be optimized to increase
UDCA intestinal absorption.
It has been recently shown that UDCA’s effectiveness in
the treatment of cystic fibrosis-related cholestatic liver dis-
160 Current Clinical Pharmacology, 2007, Vol. 2, No. 2
ease, PBC and PSC increases at a raised dose (i.e. 30-50
mg/kg) [62, 100-102]. At this dose, biliary UDCA accumula-
tion reaches 55-70% of the total bile acid pool, which is sig-
nificantly higher than the amount (30-40%) reached after
administration of the conventional daily dose of 10-15 mg/kg
[95]. These data underline the importance of UDCA pharma-
ceutical preparations and indicate that, since its intestinal
absorption is incomplete, either the conventionally used
therapeutic dose needs to be increased or the drug formula-
tion needs to be further optimized.
Few accurate studies are available regarding UDCA
pharmacokinetics and bioavailability in humans. In the first
(and still the most comprehensive) study, Parquet et al. [103]
demonstrated that, when administered to fasting subjects,
UDCA is poorly absorbed because of its low solubility in
gastro-intestinal contents (21-50% of the ingested doses
were recovered in the solid form). In fact, the profile of
plasma concentrations paralleled the amount of soluble
UDCA present in the intestinal lumen; as a consequence, the
bioavailability of the drug varies with its progressive solubi-
lization along the gastrointestinal tract. To overcome these
problems, the authors [103] proposed multiple daily admini-
strations to improve absorption.
UDCA’s solubility in water (8
mol/L) is much lower
than that of other physiological dihydroxy bile acids, such as
CDCA or DCA. UDCA has a relatively high critical micellar
concentration when compared with other dihydroxy bile ac-
ids such as CDCA and according to its pKa of 5, which is
similar to that of endogenous bile acids, it produces a rela-
tively high critical micellizzation pH (CMpH) of 8.4, which
is the pH required to the drug to be dissolved in a micellar
solution. The CMpH of the endogenous dihydroxy bile acid
is much lower, i.e. 7. UDCA therefore requires an alkaline
pH to form a micellar solution [104-106], and this accounts
for its slow dissolution rate and the loss of the molecule in
the solid form.
A recently comprehensive serum level study involving
four UDCA formulations indicated the importance of formu-
lation optimization for efficient intestinal absorption and
high bioavailability [107].
To facilitate UDCA solubilization, Roda et al. [106] de-
veloped an enteric coated formulation of UDCA sodium salt
which released the active ingredient only at a pH higher than
5.5; gastroprotection prevented protonation by the gastric
juice and allowed UDCA sodium salt release only in the
duodenum, where it quickly dissolved, leading to enhanced
absorption with respect to conventional formulations [108],
from 50% to almost 90% of the administered dose. Other
improved formulations were based on the formation of inclu-
sion complexes of UDCA with cyclodextrins or polyethylene
glycol (PEG), which enhanced the solubility of the proto-
nated form [109-111]. In addition, the effect of different ex-
cipients on UDCA wet ability and also the effect of solid-
state structure (i.e. crystalline, amorph, micronised) were
investigated in vitro [112]. A duodenal release formulation
[113] has been developed by modifying the gastric delivery
time of a gastro-resistant tablet sinking in the stomach. Be-
cause of its sinking capacity, the tablet was released in the
duodenum only at the end of the gastric phase of digestion,
Festi et al.
following the fate of the solids. Therefore, since UDCA was
released when the pH was high because of a sustained biliary
secretion, its solubilization was greatly facilitated, thus im-
proving bioavailability.
Various formulations have also been developed which
modulate the kinetics of UDCA release [114]. The first de-
layed release preparation was developed and reported in
1983 by Sama et al. [115]: a gelatin capsule containing three
small tablets, each with a different Eudragit coating which
provided therapeutic UDCA levels over a long period to-
gether with good bioavailability. Nevertheless, few data are
available concerning the rationale of the drug design and the
increased efficacy of such formulations [116]. In order to
allow selection of the most efficient formulation, especially
in cost-benefit terms, it is important to provide data about its
relative intestinal absorption, release kinetics, and serum
levels. Therefore, a comparative study of pharmacokinetics
and bioavailability of the most representative formulations is
important. Recently a comparative study has been reported
[117]. The results obtained indicate that the pharmacokinet-
ics of commercially available oral UDCA formulations can
be highly variable. The effect of the intestinal pH is a limit-
ing factor regarding UDCA solubility, since the molecule
requires a relatively alkaline pH for the formation of the
soluble salt. An elevated intestinal pH is driven by the extent
of biliary and pancreatic secretions, which are influenced by
the meal hormones and could be impaired in cholestatic liver
diseases. In addition gastric emptying, gallbladder contrac-
tion, biliary secretion, and the overall motility of the gastro-
intestinal tract associated with food intake play a major role
in determining the serum concentration-time curve.
In conclusion, the new enteric coated formulations above
discussed generally enhance the intestinal absorption of the
drug from 50% to 90-95% of the administered dose.
Metabolism
When administered orally, the absorbed UDCA is effi-
ciently metabolized in the liver. Like other endogenous bile
acids UDCA is mainly conjugated in C-24 position with gly-
cine, (glycoursodeoxycholic acid, GUDCA) and to a less
extent with taurine (tauroursodeoxycholic acid, TUDCA).
Only in this form UDCA is secreted and accumulated in bile.
The only forms of UDCA in a steady-state condition are
these forms, with a glycine /taurine ratio of 5-10 /1.
The unabsorbed fraction of UDCA and of UDCA conju-
gates enter the colon, where, after bacterial deamidation of
the conjugated form, are mostly dehydroxylated and con-
verted into LCA, and to a less extent, in a 7-oxo derivative
by intestinal bacteria and excreted in faeces [1]. Only small
amounts of LCA are reabsorbed by the colonic mucosa, sul-
phated in the liver and secreted into bile [1].
During chronic administration, UDCA becomes the pre-
dominant bile acid and it is present mainly as GUDCA and
this enrichment in the bile acid pool seems to be dependent
on the dose administered: usually from 30-50% of total bile
acids at a dose of 10 mg/Kg/day to 50-70 % at higher doses
of 20-30 mg/Kg/day [95].
Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid
URSODEOXYCHOLIC ACID IN CHRONIC CHO-
LESTATIC LIVER DISEASES
Primary Biliary Cirrhosis
UDCA is the first choice treatment for PBC at a dose of
13-15 mg/Kg/day [118]. The first report of UDCA efficacy
dates back to 1987 when Poupon et al. [6] reported a signifi-
cant improvement in biochemical parameters [gamma-
glutamyltranspeptidase (
GT), alkaline phosphatases (ALP),
and alanine aminotransferase (ALT) and bilirubin] in PBC
patients treated with the drug over a period of two years (Ta-
ble 1). These results were later confirmed by a double blind
controlled trial [119] which opened the way to many trials
investigating the efficacy of UDCA in PBC. In fact, a series
of trials followed which confirmed the efficacy of UDCA in
improving biochemical cholestasis in PBC patients [58, 120-
130]. Furthermore, studies evaluating the effect of UDCA on
histology have reported that UDCA administration delays
the histologic progression of the disease [125, 126, 131-133].
The combined analysis of three large trials have also sug-
gested that UDCA treatment of up to four years prolongs
transplantation free survival [134]. However, meta-analyses,
each of which involved more than a thousand patients, found
no difference between UDCA and the placebo with respect
to transplantation free survival or death [135, 136]. These
meta-analyses have been criticized by experts in the field
because they involved many studies of short duration and
used low doses of UDCA [137]. A wide range of UDCA
dosages have been used in PBC and few studies have inves-
tigated doses higher than those recommended [95, 100, 118,
138-140]. Despite some differences among the studies,
higher doses of UDCA, up to 30 mg/Kg/day, have proven to
be well tolerated and to induce greater improvements in bio-
chemical data of the patients. However, the short duration of
those studies does not allow any evaluation on long term
benefits from higher doses in incomplete responders PBC
patients, particularly those without an advanced disease. The
recommended dosage will remain 13-15 mg/Kg/day for all
patients until longer randomized controlled trials show a
significant benefit from higher doses of UDCA in partial
responders.
Another important aspect influencing the efficacy of
UDCA is the stage of the disease. Patients in stage III-IV of
the disease are likely to have limited or no benefit from
UDCA administration. A long term prospective randomized
trial showed no demonstrable effect on the long term out-
come or survival of PBC patients treated with UDCA stan-
dard dose [141]. This result was certainly due in part to 65%
of the stage III-IV patients. In fact, recently, three long term
studies have shown that UDCA administration improves
liver biochemistry and survival free of liver transplantation
(OLT) as well as delays histological progression in early
stage patients [142-144]. Furthermore, two of these studies
[142, 144] show that patients in the early stages with a com-
plete response to UDCA achieve a survival comparable to
that of a control population, in line with previous suggestions
by Poupon [145]. There is no doubt that UDCA is now the
first choice treatment for PBC at the accepted dosage of 13-
15 mg/Kg/day [118]; however, there is still a minority of
patients who will not respond to standard treatment and on
Current Clinical Pharmacology, 2007, Vol. 2, No. 2 161
the basis of the autoimmune nature of the disease, a number
of different combinations with immune regulatory drugs
have been used. Combination with classical steroids (predni-
sone and prednisolone) seemed to add something to mono-
therapy with UDCA with regard to improvement in liver
function tests and liver histology [146, 147]. However, side
effects related to steroid treatment [148, 149] have limited its
long term use among clinicians. More appealing is the asso-
ciation of UDCA with budesonide, a glucocorticoid with a
very high first pass metabolism [150], which has been shown
to possess fewer side effects than conventional glucocorti-
coids in patients with inflammatory bowel disease [151]. In
fact, budesonide has been shown to improve liver histology
and biochemical parameters of liver function at the cost of
lower steroid related side effects [152, 153]. More recently, a
three year randomized trial with 6 mg/day of bude-sonide has
confirmed previous results of efficacy in terms of biochemis-
try and liver histology with a mild systemic glucocorticoid
effect evident after two years [154]. Similarly to UDCA,
budesonide has also been shown to be effective in the early
stages of PBC, while an unfavourable pharmacokinetic pro-
file and the development of significant side effects discour-
age its use in stage IV PBC patients [155].
Bezafibrate may represent another option for combina-
tion therapy. This association was proposed after the obser-
vation that ALP, gamma-GT and IgM were decreased by its
administration in patients with hypercholesterolemia [156].
The mechanisms at the basis of its efficacy in PBC patients
are not well known. Laboratory data for a series of Japanese
studies with a limited number of patients [156-161], includ-
ing a small prospective randomized crossover trial [158],
have shown that the combination of 600 mg/day of UDCA
with bezafibrate is more effective than low dose UDCA
monotherapy. However, whether the combination has any
added benefit over standard dose UDCA in PBC is still un-
known.
Colchicine was proposed in the past as an adjunct to
UDCA in view of its immunomodulatory and anti-fibrotic
properties [162, 163]. However, it does not seem to be supe-
rior to a placebo according to a recent Cochrane systematic
review of randomized clinical trials [164], and the longest
double blind placebo-controlled trial of the combination
therapy in PBC patients has failed to find any added benefit
over UDCA monotherapy [165].
Methotrexate added to UDCA, as well, has no effect on
the course of PBC, as shown by the more recent randomized
controlled trials [166, 167].
A randomized, placebo controlled trial has reported the effi-
cacy on both biochemistry and liver histology of a triple
combination of azathioprine and prednisolone with UDCA
after a 1 year of treatment in PBC patients [168]. To the
best of our knowledge, no further studies on triple therapy in
PBC patients have been published, even though results were
promising.
Intrahepatic Cholestasis of Pregnancy
ICP is a disease typical of the third trimester of preg-
nancy. It is benign for the mother, but potentially harmful for
the foetus and usually presents with pruritus associated with
162 Current Clinical Pharmacology, 2007, Vol. 2, No. 2
Table 1. Studies on UDCA for the Treatment of Primary Biliary Cirrhosis
First Author Treatment Schedule
UDCA monotherapy
Poupon [6] UDCA 13-15 mg/kg
b.w./day
Leuschner [119] UDCA 10 mg/Kg b.w./day
Poupon [58] UDCA 13-15 mg/kg
b.w./day
Lindor [121] UDCA 13-15 mg/Kg
b.w./day
Poupon [130] UDCA 13-15 mg/kg
b.w./day
Heathcote [122] UDCA 14 mg/kg b.w./day
Combes [124] UDCA 10-12 mg/Kg
b.w./day
Van Hoogstraten [100] UDCA 10 mg/Kg b.w./day
vs 20 mg/Kg b.w./day in
non responders to 10
mg/Kg b.w./day
Angulo [126] UDCA 13-15 mg/kg
b.w./day
Degott [132] UDCA 13-15 mg/kg
b.w./day
Combes [131] UDCA 10-12 mg/Kg
b.w./day
Poupon [145] UDCA 13-15 mg/Kg/day
Van Hoogstraten [128] 10 mg/Kg b.w./day
Angulo [138] UDCA 5-7 mg/Kg b.w./day
vs 13-15 mg/Kg b.w./day
vs 23-25 mg/Kg/day
Verma [140] UDCA 0, 300, 600, 900
and 1200 mg/Kg b.w./day
Type of Study
Prospective observational
Double blind controlled trial
Multicenter, double blind placebo
controlled
Randomized placebo controlled
Multicenter, double blind placebo
controlled + open label extension
Multicenter double blind placebo
controlled
Randomized, double blind pla-
cebo controlled
Multicenter Randomized con-
trolled open
Cohort study
Double blind placebo controlled
Randomized double blind placebo
controlled
Cohort study
Cohort study
Randomized open
Observational Crossover
Festi et al.
Lenghth of the Study Results
2 years Improved biochemistry
6 months Improved biochemistry
2 years Improved biochemistry, Mayo
Risk Score, antimitochondrial-
antibody titer and histology
except for fibrosis
2 years Delayed progression of disease
2 + 2 years Reduced progression and need
for liver transplantation
2 years Improvement of biochemical
parameters
2 years Histology favourably affected
by ursodiol in stage I and II
patients
6 months Significant Improvement in
liver biochemistry with higher
dosages
High dose well tolerated with
greater biliary enrichment
5-9 years UDCA delays progression to
cirrhosis
2 – 4 years UDCA delays progression of
liver fibrosis
2 years No significant differences in
florid duct lesions between the
placebo and the treated arm
6 years Longer transplantation free
survival in patients treated with
UDCA
2 - 5 years Improved liver biochemistry
Bilirubin the best predictor for
prognosis
Five year treatment failure of
27% and transplantation free
survival of 79%
1 year No significant differences be-
tween standard and high dose
for biliary enrichment and liver
biochemistry
No side effects or toxicity for
any dose
each dose for 8 weeks Higher doses better than the low
with a 4 week washout ones with no significant differ-
between doses ences between the 900 and 1200
doses
Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid Current Clinical Pharmacology, 2007, Vol. 2, No. 2 163

(Table 1. Contd….)

First Author Treatment Schedule Type of Study Lenghth of the Study Results

Pares [120] UDCA 14-16 mg/Kg/day Multicenter double blind placebo 3.4 years Improved biochemical parame-
controlled ters and portal inflammation;
UDCA prevented histological
stage progression; no signifi-
cant effect on death or time to
liver transplantation

Corpechot [125] UDCA 13-15 mg/Kg Randomized double blind placebo 2 + 2 years UDCA delays progression of
b.w./day controlled + open label extension liver fibrosis

Angulo [139] UDCA 28-32 mg/Kg Observational 1 year No significant improvement

b.w./day in incomplete from baseline
responders to 13-15 High dose well tolerated
mh/Kg/dat

Roda [95] UDCA 15 mg/Kg b.w./day Crossover observational 6 months Improved liver tests with higher
vs 30 mg/Kg/day dosages in early stage PBC

Jorgensen [127] UDCA 13-15 mg/Kg Retrospective up to 12 years UDCA of most benefit when
b.w./day instituted in early stage disease

Papatheodoridis [141] UDCA 12-15 mg/kg Prospective randomized con- 12 years No significant effect on long
b.w./day trolled term outcome and survival

Siegel [129] UDCA 13-15 mg/Kg Randomized controlled 4 years Significant weight gain in
b.w./day vs placebo treated patients in the first year
of treament

Combes [123] UDCA 10-12 mg/Kg Open label extension of previous 2 + 2 years No significant differences in
b.w./day randomized double blind placebo time to liver transplantation or
controlled survival

Pares [144] UDCA 15 mg/kg b.w./day Cohort study 7.5 years Survival of good responders at 1
year comparable to control
population, suboptimal survival
in non responders

ter Borg [142] UDCA 13.3 mg/Kg Cohort study 10 years Survival of responders compa-
b.w./day rable to matched general popu-
lation

UDCA + Colchicine

Vuoristo [162] UDCA 12-15 mg/kg Multicenter double blind placebo 2 years UDCA superior to colchicine
b.w./day or Colchicine 1 controlled
mg/day or placebo

Poupon [163] UDCA 13-15 mg/kg Multicenter double blind placebo 2 years No significant differences
b.w./day + Colchicine 1 controlled
mg/day, 5 days per week

Battezzati [165] UDCA 8.8 mg/kg b.w./day Double blind placebo controlled 10 years No added benefit of colchicine
+ Colchicine 1 mg/day to UDCA

UDCA + Methotrexate

Kaplan [167] MTX 15 mg per week or Randomized controlled 10 years No improvement in survival
colchicine 0.6 mg twice compared to UDCA alone
daily + UDCA 12-15
mg/kg b.w./day

Combes [166] UDCA 15 mg/kg b.w./day Multicenter, double blind placebo 7.6 years No added effect of methotrexate
for at least 6 months + controlled
MTX 15 mg/m2 body sur-
face area (maximum dose
20 mg) once a week
164 Current Clinical Pharmacology, 2007, Vol. 2, No. 2 Festi et al.

(Table 1. Contd….)

First Author Treatment Schedule Type of Study Lenghth of the Study Results

UDCA + Steroids (Budesonide, Prednisone, Prednisolone)

Angulo [152] UDCA 13-15 mg/kg Observational on suboptimal 1 year Transitory improvement in
b.w./day + Budesonide 9 responders to UDCA biochemistry, increase in Mayo
mg/day Risk Score, steroid related side
effects

Leuschner [153] UDCA 10-15 mg/kg Prospective double blind 2 years Improved biochemistry and
b.w./day + Budesonide 9 histology
mg/day vs UDCA 10-15
mg/kg b.w./day + placebo

Rautiainen [154] UDCA 15 mg/kg b.w./day Randomized controlled 3 years Combination treatment im-
+ Budesonide 6 mg/day vs proved liver histology
UDCA 15 mg/kg b.w./day UDCA alone effective mainly
on biochemistry

Wolfhagen [147] UDCA 10 mg/Kg b.w./day Retrospective 1 year Combined treatment improved
+ prednisone 10 mg/day symptoms and biochemistry to a
larger extent than either treat-
ment alone

Leuschner [146] UDCA 10 mg/Kg b.w./day Randomized placebo controlled 9 months Improved biochemistry and
+ prednisolone 10 mg/day histology with the combination
compared to monotherapy

UDCA + Bezafibrate

Nakai [156] bezafibrate 400 mg/day + Randomized open label 1 year Improved biochemistry with
UDCA 600 mg/day vs combination treatment
UDCA 600 mg/day

Kurihara [160] bezafibrate 400 mg/day vs Randomized open label 1 year Improved biochemistry with
UDCA 600 mg/day both treatments

Ohmoto [161] bezafibrate 400 mg/day Observational 1 year Improved biochemistry with
added to UDCA 600 combination treatment
mg/day

Kanda [159] bezafibrate 400 mg/day + Open label controlled 1 year Improved biochemistry with
UDCA 600 mg/day vs combination treatment
UDCA 600 mg/day

Ikatura [158] Bezafibrate 400 mg/day ± Prospective randomized crossover 6 months + 6 months Improved biochemistry with the
UDCA 600 mg/day combination

Akbar [157] bezafibrate 400 mg/day ± Open label 1 year Improvement of liver function
UDCA dose not stated in tests
the paper Reduced nitrite production by
dendritic cells

UDCA + Prednisone + Azathioprine

Wolfhagen [168] UDCA 10 mg/Kg/day + Randomized placebo controlled 1 year Improved biochemistry and
Prednisone 30 tapered to 10 histology
mg/day + Azathioprine 50
mg/day

elevation of transaminases and serum bile salts [169]. The pruritus called for the development of an effective treatment.
presence of a high percentage of preterm deliveries as well The first report of UDCA efficacy in ICP was published in
as adverse effects of the disease on the foetus (i.e. stillbirths, 1991 showing an improvement in serum bile salts and pruri-
intrapartum foetal distress) and a sometimes severe maternal tus with the treatment [170]. This preliminary observation
Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid
was later confirmed by other groups [171-176] and by two
randomized, double blind controlled trials which confirmed
that UDCA, both at low and standard dose, is effective in
attenuating ICP pruritus and improving maternal transa-
minases and serum bile salts (Table 2) [177, 178]. Further-
more, deliveries occurred closer to term in treated mothers
compared to controls receiving placebo [177]. This impor-
tant observation has been confirmed by our group [179] and
by a retrospective evaluation of UDCA on a twelve year ex-
perience by a Chilean group [180].
The efficacy of UDCA in the treatment of ICP has also
been compared to other proposed treatments such as cho-
lestyramine, dexamethasone and S-Adenosyl-L-Methionine
(SAMe) [181-184]. Cholestyramine is a bile acid binding
resin that may be effective in reducing pruritus in patients
with ICP [185]; however a major drawback is given by its
capacity of binding vitamin K possibly leading to coagulo-
pathies. In fact, severe fetal intracranial hemorrhage has been
described with its use [186]. This observation, coupled to the
evidence that UDCA is significantly superior to cholestyra-
mine both on pruritus and biochemical parameters in patients
with ICP, should discourage further use of the resin in this
condition. Dexamethasone was first proposed in an observa-
tional study on 10 patients on the basis of its theoretical ca-
pability of reducing the fetoplacental estrogen production
[187]. A recent randomized controlled trial has shown that
dexamethasone is ineffective in ICP, while UDCA improved
biochemical parameters irrespective of disease severity [182].
SAMe has positive effects on bile secretion and increases the
bioavailability of sulphates for the conjugation of bile acids.
A recent randomized prospective comparative study of UDCA,
SAMe and a combination of the two drugs has shown that
UDCA and the combination treatment led to a significant
improvement in biochemical parameters compared to SAMe
monotherapy [183]. The authors observed a faster decrease
of serum concentrations of bile acids and transaminases
compared to UDCA monotherapy, suggesting a possible
synergistic effect [183]. However, this data, combined to
previous evidence from a randomized double blind placebo
controlled trial showing that SAMe monotherapy does not
improve ICP [188], does not support the use of SAMe in
routine clinical practice.
No published study until now has reported any adverse
effect of UDCA on the foetus; on the contrary its administra-
tion has resulted in deliveries closer to term and a higher
infant weight as compared to those born from controls, sug-
gesting that treatment may be beneficial for the foetus [177,
180]. Furthemore, the observation that UDCA reduces pri-
mary bile acids levels in colostrum and its presence in breast
milk is less than 0.01% of the dose administered to the
mother supports the safety of its use [189].
The mechanisms underlying UDCA efficacy in ICP are
still unclear, even though some hypotheses can be made. It is
likely that the efficacy regarding pruritus results from im-
provement of cholestasis achieved by the increased biliary
secretion [140], while the more fascinating aspect is how
UDCA may be beneficial in eliminating adverse foetal ef-
fects. We know that elevated bile acids may induce vasocon-
striction of the umbilical artery [190], leading to foetal an-
Current Clinical Pharmacology, 2007, Vol. 2, No. 2 165
oxia and uterine contractions [191]. Thus the accumulation
of bile acids in the foetal compartment (amniotic fluid, cord
blood) during ICP [179] may have an important role in the
pathophysiology of the disease and adverse foetal effects.
Functional evidence for bile acid transport through the hu-
man placenta has been described [192, 193]. Placental bile
acid transport is impaired by cholestasis and restored by
UDCA [194, 195] and is probably mediated by MRP iso-
forms [196]. In line with data from experimental animals
[197] we have recently shown that UDCA administration
results in an up-regulation of Mrp2 human placenta [198].
These data, coupled with evidence that UDCA administra-
tion reduces bile acid accumulation in the foetal compart-
ment in ICP [179], suggest that the positive effect of UDCA
might come not only from improved maternal biliary secre-
tion but also from improved extrusion of bile acids from the
foetal compartment, which might include a positive effect on
foetal liver function (secretion into meconium). These hy-
potheses await further demonstrations.
Primary Sclerosing Cholangitis
PSC is a chronic cholestatic liver disease causing in-
flammation and obliterative fibrosis of intra and/or extrahe-
patic bile ducts. It is usually progressive, leading to bile sta-
sis, fibrosis, cirrhosis and end-stage liver disease with an
estimated median survival time from diagnosis to death of 12
years [199-201]. The target cell involved in disease onset
and progression is the cholangiocyte which interacts with
other cells (immunocytes, macrophages, stellate cells) in
response to injury; the reactive cholangiocyte seems to play
a crucial role in liver damage and repair [200]. The patho-
genesis of PSC is unknown; a genetic predisposition is
shown by the increased risk of disease development in sib-
lings [202] and the association with specific alleles of the
major histocompatibility complex (MHC) [203] but it seems
that the inheritance of PSC is complex. Immune dysregula-
tion seems to play an important role [204-206] in disease
development. The prevalence of PSC is 8.5 cases per 100.000
people in Western Countries, with 70-80% of patients with
concomitant inflammatory bowel disease (IBD), mostly ul-
cerative colitis (UC) [207]. The risk of developing cholan-
giocarcinoma is increased in patients with PSC [208, 209]
and it seems that the risk of colorectal cancer is higher in
those with PSC and UC than in those with UC alone [210,
211].
UDCA has been used in PSC since the early 1990s (Ta-
ble 3); initial small studies demonstrated biochemical and in
some cases histological improvement in patients treated with
low doses of UDCA (10 to 15 mg/Kg/day) [212-214] with
no relevant side effects. Later, Lindor et al. [215] conducted
a larger study on 105 patients with a median follow-up of 2.2
years; this study showed good results with regard to liver
function tests but no improvement in symptoms or in histol-
ogy was demonstrated. A meta-analysis of six randomised
controlled trials of UDCA for the treatment of PSC failed to
show significant differences to the placebo in terms of death,
treatment failures, liver histology or cholangiographic dete-
rioration [216]. However the authors state that the studies
had a low methodological quality, with small samples and a
short follow-up.
166 Current Clinical Pharmacology, 2007, Vol. 2, No. 2 Festi et al.

Table 2. Studies on UDCA for the Treatment of Intrahepatic Cholestasis of Pregnancy

First Author Treatment Type of Study Results

UDCA monotherapy

Palma [176] 1 g/day Observational open Improved biochemistry

No adverse effects on the foetus

Floreani [171] 450 mg/day Observational open Improved pruritus and biochemistry

Diaferia [177] 600 mg/day vs placebo Randomized double blind pla- Improved pruritus and biochemistry
cebo controlled Lower rate of prematurity

Palma [178] 1g/day Randomized double blind pla- Improved pruritus and biochemistry
cebo controlled Lower rate of prematurity
Higher birthweight in infants from treated mothers
No adverse effects on the foetus

Nicastri [184] UDCA 600 mg/day vs SAMe Randomised placebo controlled Improved biochemistry and parameters in all groups
800 mg/day vs UDCA + SAMe Combination more effective on bile salts
800 mg/day vs placebo

Brites [189] UDCA 14 mg/Kg b.w./day vs Observational UDCA decreases endogenous bile acids in colostrum
no treatment

Brites [173] UDCA 14 mg/Kg b.w./day vs Observational open label Improved biochemistry
no treatment

Serrano [194] UDCA 1g/day vs no treatment Observational open label UDCA improves pruritus and biochemical parameters
Improved bile acid transport through the placenta

Berkane [172] 10 mg/Kg/day Observational open Improved pruritus and biochemistry

Mazzella [179] UDCA 1.5-2 g/day vs observa- Observational Improved pruritus and biochemistry
tion Reduced accumulation of bile acids in the foetal
compartment
No adverse effects on the foetus

Laifer [174] UDCA 600-1200 mg/day Retrospective Improved pruritus and biochemistry

Zapata [180] UDCA 15 mg/Kg/day vs his- Observational retrospective on Improved pruritus and biochemistry
torical controls 12 years Lower rate of prematurity
Higher birthweight in treated group
No adverse effects on the foetus

Kondrackiene [181] UDCA 8-10 mg/Kg/day vs Randomized open label UDCA is safe and more effective than cholestyramine
cholestyramine 8 g/day Improved pruritus and biochemistry
Lower rate of prematurity

Glantz [182] UDCA 1 g/day vs dexametha-
sone 12 mg/day followed vs
placebo
Randomized double blind pla-
cebo controlled
UDCA improved pruritus and biochemistry
Dexamethasone had no effect on pruritus and ALT and
was less effective than UDCA in reducing bile acids and
bilirubin
No adverse effects on the foetus

Binder [183] SAMe 500 mg x 2/day i.v. for
14 days and then per os vs
UDCA 250 mg x 3/day vs
combination of both drugs at
the same dosage
Prospective randomized open All treatments improved pruritus
label Combined and UDCA monotherapy improved serum
concentrations of bile acids and transaminases compared
to SAMe monotherapy
No adverse effects on the foetus

Liu [175] UDCA 900 mg/day vs Randomized open label Improved biochemistry
10%glucos+Vitamin C+Inosine Lower rate of prematurity, foetal asphixya and meconium
staining in amniotic fluid with UDCA
Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid Current Clinical Pharmacology, 2007, Vol. 2, No. 2 167

Table 3. Studies on UDCA for the Treatment of Primary Sclerosing Cholangitis

Author N Drug Treatment Type of Study Treatment Period Results

UDCA 10 mg/kg body Improved biochemistry, fa-

O’Brien [212] 12 Open-label, pilot 2.5 years
weight/day tigue and pruritus

Prospective, randomized,
UDCA 13-15 mg/kg body Improved biochemistry and
Beuers [213] 14 double-blind, placebo- 1 year
weight/day histology
controlled

Double-blind, placebo-
Stiehl [214] 20 UDCA 750 mg/day 3 months Improved biochemistry
controlled

UDCA 13-15 mg/kg body Randomized, double-blind,

Lindor [215] 105 2 years Improved biochemistry
weight/day placebo-controlled

UDCA 25-30 mg/kg body Improvement of biochemistry

Harnois [101] 30 Open-label, pilot 1 year
weight/day and Mayo Risk Score

Improved biochemistry, fibro-

UDCA 20 mk/kg body Randomized, double-blind,
Mitchell [102] 26 2 year sis and cholangiographic ap-
weight/day placebo-controlled
pearances

No differences in biochemis-
UDCA 17-23 mg/kg body Randomized, placebo-
Olsson [217] 219 5 years try, survival, symptoms, qual-
weight/day controlled
ity of life

Trials based on high-dose UDCA schedules were con-
ducted in the early 2000’s. The hypothesis was that larger
doses would be needed to provide a sufficient enrichment of
bile acids in cholestasis [95]. Two small studies comparing
high-dose UDCA (20-30 mg/Kg/day) vs placebo or standard
doses (13-15 mg/Kg/day) suggested a better efficacy of these
dose regimens, with improvement in liver enzymes, cholan-
giographic features, liver fibrosis and survival [101, 102].
The treatment was well tolerated in both studies. Again, a
larger prospective placebo-controlled study [217], conducted
on 219 patients, failed to show a significant difference in
terms of survival or cholangiocarcinoma prevention, although
there was a tendency to an improved survival in the treat-
ment group and the study was insufficient to give statisti-
cally significant results.
When a major bile duct stricture is present, UDCA alone
is not efficacious; therefore, a combined endoscopic and
medical treatment in these cases is required. In an 8 years
follow-up study of patients treated with UDCA in combina-
tion with endoscopic dilatation of strictures, survival was
significantly higher in treated patients when compared to the
calculated survival without treatment [218].
Some studies suggested that UDCA may be helpful in
preventing colorectal cancer in patients with associated IBD
[219, 220]. This hypothesis was then confirmed by clinical
studies: in a cross sectional study, patients treated with
UDCA showed a decreased prevalence of colonic dysplasia
(OD, 0.18, 95% CI, 0.05 to 0.61; p= 0.005) [221]; in a pro-
spective study of 52 patients with PSC and UC patients
treated with UDCA had a relative risk of 0.26 for dysplasia
or cancer (95% CI 0.06-0.92; p= 0.034) when compared to
patients treated with a placebo [222].
In conclusion, UDCA has been extensively used in the
treatment of PSC with good results in terms of liver test im-
provement, but there is no conclusive evidence that it may
lead to an improvement in histology and survival, although a
trend toward a statistically significant benefit is present.
Combined endoscopic and UDCA treatment is necessary
when a major bile duct stricture is present. When PSC is
associated with UC, UDCA may have beneficial effects in
reducing the risk of colorectal cancer development.
PEDIATRIC AND INHERITED INTRAHEPATIC
CHOLESTASIS
Pediatric cholestatic liver diseases represent one of the
major causes of death for children and although the true
prevalence is unknown, it is estimated that roughly 15000
children /yr are hospitalised for liver disease in the USA,
about 1 each 2500 live birth, the major disorders being rep-
resented by biliary atresia, metabolic diseases and intrahe-
patic cholestasis [223].
Intrahepatic cholestasis is a heterogeneous spectrum of
cholestatic diseases characterized by specific syndromes
with different clinical features and clinical outcomes ranging
from benign forms, known as benign recurrent intrahepatic
cholestasis (BRIC), to more severe diseases, indicated as
PFIC (progressive familial intrahepatic cholestasis), requir-
ing OLT. The pathogenetic basis of these disorders is still
partially unknown and only future genetic and molecular
insight can permit us to better define and classify them with
the aim of carring out more specific and efficacious thera-
peutic strategies. However, over the past 30 yrs significant
progress has been made in differentiating the various syn-
dromes from the idiopathic neonatal hepatitis spectrum. Spe-
cifically, substantial progress has been made in subcategoris-
ing the different forms of the disease. In fact, the report of a
single topic conference, sponsored by the American Associa-
tion for the Study of the Liver has recently been published
168 Current Clinical Pharmacology, 2007, Vol. 2, No. 2
[224]. The new proposed classification subdivides pediatric
intrahepatic cholestasis into: a) disorders of membrane
transport and secretion which include disorders of canalicu-
lar secretion (PFIC type 2, BRIC2, PFIC type 3 and cystic
fibrosis) and complex or multiorgan disorders (PFIC type 1,
Bylers disease, BRIC type 1); b) disorders of bile acid syn-
thesis and conjugation; c) disorders of embryogenesis
(Alagille syndrome, Caroli’s disease etc); d) unclassified
(idiopatic neonatal hepatitis).
On the basis of the evolving knowledge in terms of clas-
sification, morphological and clinical findings and the main
molecular pathogenetic mechanisms of bile formation, new
therapeutic approaches will be investigated. In particular,
agonists and antagonists of nuclear hormone receptors are
particularly promising drugs [225, 226].
Up to now, UDCA is the only medical treatment for most
pediatric cholestatic syndromes and, in some of these, it rep-
resents the bridge therapy for OLT.
Familial Intrahepatic Cholestasis
Rare inherited forms of cholestasis are the consequence
of mutations in the canalicular transport systems [25] and
can produce mild to severe hepatic injury, leading to cirrho-
sis and liver failure. Mutations of three genes encoding for
three different proteins located at the hepatocyte canalicular
membrane are responsible for the development of these cho-
lestatic syndromes. PFIC type 1 (also known as Bylers dis-
ease) is caused by mutations in the ATP8B1 gene (ATP8B1),
resulting in dysfunction of an aminophospholipid flippase
(FIC-I) whose activity is essential for bile acid secretion. A
mild cholestatic form presenting as BRIC1, is associated
with ATP8B1 mutations too.
PFIC type 2 is the consequence of mutations in the
ABCB11 gene (ABCB11), which encodes for the canalicular
bile acid transporter (BSEP). Mutations of ABCB11 are as-
sociated both with progressive (PFIC type 2) and benign
(BRIC2) cholestatic syndromes. Unlike BRIC1, BRIC2 is
often associated with gallstones [227].
PFIC type 3 is the consequence of mutations of the
ABCB4 gene (ABCB4), which resuls in a dysfunctional
phosphatidylcholine flippase and leads to defective biliary
phospholipid secretion. In these patients, bile acid secretion
is maintained. The consequence of maintained bile acid se-
cretion, in the absence of a sufficient concentration of biliary
phospholipids, is a damage to the apical membrane of the
cholangiocytes, with consequently high
GT activity, which
distinguishes this form from PFIC/BRIC type 1 and type 2.
ABCB4 mutations can be associated with either progressive
or milder phenotypes [25]. Moreover, ABCB4 mutations
have been found to be associated with anti-mitochondrial
antibodies negative PBC and with intrahepatic cholesterol
gallstones [228, 229].
The best strategy for the treatment of PFIC has not been
completely established and probably depends on the type of
PFIC, the severity of the disease at diagnosis, and mainly on
the penetrance of gene defects. OLT is considered to be a
definitive therapeutic strategy, with a survival rate of about
92 % at five years [230]. However, it is difficult to establish
Festi et al.
the best timing for OLT since in some patients the transplant
is performed because of a poor quality of life rather than end
stage liver disease. Furthermore, in some patients, after OLT
peculiar severe complications can occur, such as severe non-
alcoholic steatohepatitis [231] and intractable diarrhoea [232,
233], with an overall morbidity and mortality of about 10-15
% at one year. The most important medical treatment is rep-
resented by the use of UDCA together with standard nutri-
tional support. The mechanism of action is not completely
clear and it could depend on the degree of the gene defect
penetrance and the type of PFIC. In fact, in patients with
PFIC type 3 with partial defect of MDR3 and a residual
phospholipid concentration in bile, UDCA administration
could be an effective treatment. From a clinical point of view
some studies have demonstrated that chronic UDCA admini-
stration can improve biochemical parameters and alleviate
pruritus [234, 235]. The most important and convincing
study [236] demonstrated in 39 children (26 with normal

GT and 13 with high
GT) treated with 20-30 mg /Kg/day
of UDCA for 2-4 yrs a significant decrease of ALT and
GT
levels and an improved nutritional state, with corresponding
improvement of hepatosplenomegaly and pruritus. Moreover
it has been recently shown [230] that UDCA efficacy is re-
lated to early initiation of the therapy, low penetrance of the
genetic defect and less severe pre-existing liver damage
Liver Disease in Cystic Fibrosis
CF is a multi-organ autosomal recessive disorder, affect-
ing roughly 1/ 2500 newborn worldwide, caused by a muta-
tion in the gene encoding the cystic fibrosis transmembrane
conductance regulator (CFTR), which plays a key role in
maintaining fluid balance across the epithelium [237]. In CF,
the CFTR mutations are associated with an epithelial secre-
tory defect, with reduced luminal hydration and progressive
luminal obstruction in different organs (sweat gland, pan-
creas, liver, lung).
Hepatobiliary involvement ranges from 18 to 37% [238,
239] and represents the third cause of death in CF, account-
ing for about 2.3% of overall mortality [240]. In the hepato-
biliary system, CFTR is expressed only in the cholangiocytes
and gallbladder epithelium, but not in the hepatocytes [241].
Thus the primary event into the development of biliary cir-
rhosis is the bile duct cell injury [242] due to a long-standing
impairment in the ductular bile flow. For these reasons the
hepatobiliary disease in CF is considered the first inherent
liver disease resulting from an alterated secretory function of
the biliary epithelium; accumulation of potentially toxic
compounds, such as hydrophobic bile acids, and eventually
common bile duct compression by pancreatic fibrosis or sec-
ondary sclerosing cholangitis may represent additional fac-
tors [243].
The spectrum of hepatic manifestations ranges from as-
ymptomatic elevation of the liver function tests (10-35 %), to
neonatal cholestasis (2%), hepatic steatosis/ steatohepatitis
(20-60%), focal biliary cirrhosis (11-70%) and multilobular
biliary cirrhosis (5-15 %); focal biliary cirrhosis being con-
sidered the specific hepatic lesion of CF which can result in
multilobular cirrhosis and liver failure [244]. In recent years
the improved life expectancy in patients with CF due to im-
proved management of lung and pancreatic manifestations of
Clinical Efficacy and Effectiveness of Ursodeoxycholic Acid
the disease prompted to focus on the increasing importance
of the hepatobiliary disorder. At present, UDCA is the only
approved drug for hepatobiliary disease in CF. It has been
suggested that UDCA can replays the hydrophobic bile acids
and stimulates Cl- secretion through a Ca++ dependent Cl-
channel [245] or by a mechanism of ATP secretion different
from the CFTR [246].
Early uncontrolled studies [247-249] and two RCTs [250,
251] showed an improvement in the biochemical and the
nutritional status of the patients treated with UDCA at a dose
of 15 mg/kg/day. An improvement on liver histology was
also documented [61]. Evidence suggests that higher UDCA
doses (20-30 mg/Kg/day) are more efficacious than standard
doses (5-15 mg/Kg/day) [248, 252].
Although UDCA is the only drug accepted for the treat-
ment of hepatobiliary disease in CF, its effectiveness on the
natural history of liver disease in CF has yet to be defined
[253]. In particular, its effect on the complications of liver
disease (variceal hemorrage, portal hypertension), on the
need for OLT or on overall survival are unknown. Thus it is
necessary to design adequate RCTs to justify the long- term
use of UDCA. Additional points to be elucidated are repre-
sented by the preventive effect of UDCA in either high risk
subjects or asymptomatic patients for hepatobiliary disease.
Alagille Syndrome
Alagille syndrome (AGS) is an autosomal dominant dis-
order, clinically defined by the presence of at least three of
the following major features: chronic cholestasis, congenital
heart disease, peculiar faces, butterfly- like vertebrae and
posterior embryotoxon [254]. AGS occurs in about 1/10000
live births and is caused by mutations in the Jag1 gene,
which encodes a protein belonging to a family of ligands of
the Notch receptor [255, 256]. Mutation of Jag1 were identi-
fied in about 94% of the subjects with AGS [257]. Notch 2
mutations can also be present in patients without Jag1 muta-
tions, confirming that AGS is a heterogeneous disorder
[258].
Jag1 is involved in cell differentation and regulation of
biliary epithelium development [255, 256] and its mutation
leads to bile duct paucity with an increased portal tract to
bile duct ratio. Hepatic manifestation in ASG are present in
the majority of children, mainly in the first three months of
life, with a wide clinical spectrum ranging from mild cho-
lestasis to jaundice, pruritus and to progressive liver failure.
Jaundice is present as a result of conjugated bilirubin associ-
ated with high serum levels of bile acids, tryglicerides and
cholesterol, and with typical xanthomas. The management of
liver disease in AGS is more difficult than in other cho-
lestatic pediatric diseases because of the presence of serious
extrahepatic manifestations, conditioning the survival. OLT
represents the treatment of choice in end stage liver disease,
in severe hypercholesterolemia and in diffuse xanthomas,
with a survival rate of about 80% at 5 years [259]. This rela-
tively low survival rate is due to the multisystemic disease
involvement.
UDCA in AGS, unlike other cholestatic syndromes, has
no efficacy on the biochemical and histological parameters,
or on survival, but it can be utilized as a symptomatic drug,
Current Clinical Pharmacology, 2007, Vol. 2, No. 2 169
mainly on pruritus, although results are conflicting [234,
260, 261].
Biliary Atresia
Biliary atresia is the most common neonatal cholestatic
disorder, with a prevalence ranging from 1/8000 in Far East
countries (Asian populations) to 1/18000 in European popu-
lations (European countries), with female predominance
[262]. The disease is characterized by progressive inflamma-
tory cholangiopathy evolving toward sclerosing fibrosis,
involving early the extrahepatic biliary tree, and eventually
later the intrahepatic biliary tree. For the two different forms
of the disease, i.e the fetal (20%) and the post-natal (80%),
genetical, environmental (viral infection?), immunological
and embryological factors have been hypothesized [263].
The treatment of choice of biliary atresia in children
younger than 3 months is the portoenterostomy (Kasai’s op-
eration) that allows an efficacious bile flow, with an im-
provement of serum bilirubin levels, jaundice and liver en-
zymes. However, most of the patients will progress to cir-
rhosis [263]. After Kasai’s operation, the survival rate at 20
yrs is less than 20% with native liver [264]; thus Kasai’s
operation should be considered a bridge treatment to OLT. In
fact OLT is the definite treatment, with survival rate of about
84 % at 10 years [265].
UDCA has been employed after Kasai’s operation, in
order to delay progression to cirrhosis, although to date no
randomized clinical trial has been performed. Preliminary
reports [266] and a more recent study [267] demonstrated an
improvement of biochemical parameters as well as an in-
crease of body weight. However, neither an increase of the
patients’ survival time nor a reduction of the need for OLT
were observed on the caution. On the contrary a combined
therapy with UDCA together with steroids and antibiotics
has been suggested to be able to reduce the need of early
OLT [268].
URSODEOXYCHOLIC ACID IN DIFFERENT CLINI-
CAL SETTINGS
Besides therapeutic use in chronic cholestatic syndromes
and in gallstone disease, UDCA use has been proposed for
prevention of colon carcinoma in PSC patients [198,199],
reduction of liver complications in the graft versus host dis-
ease [269, 270], decrease of rejection after liver and heart
transplantation [271, 272], and treatment of bile reflux gas-
tritis [273, 274]. Among the above mentioned clinical set-
tings, the most promising seems to be UDCA use in preven-
tion of colon carcinoma, which starts from observations in
the in vitro and animal models showing that UDCA exerts
antineoplastic effects on colonic mucosa [275-277]. Besides
the proposed UDCA prevention on colon carcinoma in PSC
patients with concomitant ulcerative colitis [221, 222], a
reduced recurrence of colorectal adenoma has been demon-
strated in PBC patients treated with UDCA, as compared to
controls [278]. Finally, the results of a recent phase-III study
in patients who had undergone removal of a colorectal ade-
noma demonstrate that UDCA treatment is associated with a
statistically significant reduction in recurrence of adenomas
with high-grade dysplasia [279], supporting the possible role
of this bile acid in the chemoprevention strategies.
170 Current Clinical Pharmacology, 2007, Vol. 2, No. 2 Festi et al.

DEVELOPMENT OF UDCA-DERIVATIVES FOR GSH = Reduced glutathione

CLINICAL USE IN HEPATOBILIARY DISEASES
FIC1 = Familial intrahepatic cholestasis 1
Although UDCA is an effective agent in different cho-
ASBT = Apical sodium-bile acid cotransporter
lestatic liver diseases, its physico-chemical characteristics
and biotransformation routes may limit the potential thera- I-BABP = Ileal bile acid binding protein
peutic efficacy. For this reason, efforts have been performed
to identify UDCA derivatives with improved efficacy. OST
-OST = Heteromeric organic solute transporter
-

The C23 (C24-nor) homolog of UDCA, nor-ursodeoxy- CYP = Cytochrome p-450

cholic acid (nor-UDCA) has shown peculiar biotransforma- FXR = Farnesoid X receptor
tion and physiological properties in humans [280]. In par-
ticular, in human liver nor-UDCA is glucuronidated rather PXR = Pregnane X receptor
than amidated with glycline or taurine, with considerable VDR = Vitamin D receptor
renal elimination of the C23 glucuronide, which is its domi-
nant metabolite in humans [280]. Moreover, nor-UDCA oral CAR = Constitutive androstane receptor
administration in two volunteers induced a bicarbonate-rich PPAR-
= Peroxisome proliferators-activated recep-
hypercholeresis, with lower biliary secretion of phospholip- tor-alpha
ids and cholesterol [280]. Therefore, the hypercholeretic
properties of nor-UDCA suggest its potential benefit in cho- SHP = Small heterodimer partner
lestatic liver diseases.
DCA = Deoxycholic acid
Finally, it has recently been shown that nor-UDCA is CDCA = Chenodeoxycholic acid
superior to UDCA in the treatment of a mice model of scle-
rosing cholangitis [281]. APAF-1 = Apoptotic protease activating factor 1
CONCLUSIONS HCV = Hepatitis C virus
UDCA use in the treatment of chronic cholestatic dis- LCA = Lithocholic acid
eases is consolidated and growing evidence has been pro-
CMpH = Critical micellization pH
duced in the last years on its beneficial role not only in the
biochemical improvement but also in the long term remis- PEG = Polyethylenglycol
sion of cholestatic syndromes. The optimal safety profile and
a better knowledge of the optimal dose for inducing and GT = Gamma-glutamyltranspeptidase
maintaining disease remission in chronic cholestatic diseases ALP = Alkaline phosphatases
prompted to the common use of high doses UDCA in the
clinical practice. Further studies with well defined end points ALT = Alanine aminotransferase
(e.g. death or liver transplantation) are needed in order to OLT = Ortotopic liver transplantation
better clarify the long term efficacy of UDCA in PSC, while
the long term efficacy on major end points in PBC has been SAMe = S-Adenosyl-L-Methionine
clearly demonstrated. Pediatric cholestasis is also an impor- MHC = Major histocompatibility complex
tant field in which UDCA has achieved important therapeu-
tic results. Continuous advances in the fields of physiology IBD = Inflammatory bowel disease
and molecular biology have better clarified the mechanisms
UC = Ulcerative colitis
of different cholestatic syndromes and will possibly help in
the development of new UDCA derivatives with higher PFIC = Progressive familial intrahepatic cholestasis
therapeutic effectiveness.
BRIC = Benign recurrent intrahepatic cholestasis
ABBREVIATIONS
AMA = Antimitochondrial antibodies
UDCA = Ursodeoxycholic acid
CFTR = Cystic fibrosis transmembrane conductance
PBC = Primary biliary cirrhosis regulator
PSC = Primary sclerosing cholangitis AGS = Alagille syndrome
ICP = Intrahepatic cholestasis of pregnancy Used abbreviations: According to the conventional use of
abbreviations, upper case will be used to indicate human
NTCP = Na+/taurocholate cotransporter
proteins, while lower case (with upper case only for the first
OATPs = Organic anion transport proteins letter) will indicate proteins in rodents and non human spe-
cies in general.
HBAB = Hepatic bile acid binding protein
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Received: 05 January, 2007 Revised: 23 January, 2007
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Accepted: 22 February, 2007