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The Therapeutic Role of Ursodeoxycholic Acid in Digestive
Anthony Gamboa, Chenlu Tian, Julia Massaad, Preeti Reshamwala and Qiang Cai
Affiliation: Division of Digestive Diseases, School of Medicine, Emory University, Atlanta, GA, USA
Ursodeoxycholic acid (UDCA) makes up a small portion of the naturally occurring bile acid pool in humans, and the drug is effective in
several diseases. The mechanism of action involves the displacement of more toxic endogenous bile acids, direct protection of hepatocytes
against apoptosis, and stimulation of endogenous secretion of bile to alleviate cholestasis. The use of UDCA has been studied extensively in
primary biliary cirrhosis and cholelithiasis and there is evidence for its use in both diseases. There is also evidence against the use of UDCA in
primary sclerosing cholangitis (PSC). Several potential uses of UDCA warrant further investigation after initial studies have shown promise
including treatment for microlithiasis, intrahepatic cholestasis of pregnancy, total parenteral nutrition, chemoprophylaxis of colorectal cancer
in patients with ulcerative colitis and PSC, viral hepatitis, and in bone marrow transplantation. Ursodeoxycholic acid is generally well tolerated
with few adverse events, though minor weight gain is a common side effect.
Keywords: Ursodeoxycholic acid, primary biliary cirrhosis, primary sclerosing cholangitis, cholelithiasis, microlithiasis
Correspondence: Qiang Cai, Division of Digestive Diseases, School of Medicine, Emory University, 1365 Clifton Road, B1262, Atlanta, GA
30322, USA. Tel: 1-404-778-4857; Fax: 1-404-778-2578; e-mail: email@example.com
Ursodeoxycholic acid (UDCA) constitutes around 3% of the
total bile acid pool in humans. Bacteria modify another
naturally occurring bile acid, chenodeoxycholic acid, in the
gut to form UDCA. The UDCA is a primary bile acid found in
bears, and it was discovered in polar bears by Swedish and
Danish explorers in Greenland in the early 1900s. Later UDCA
was isolated from the black bear and given its current name
for being an isomer of deoxycholic acid.
The mechanism of action for UDCA is multifactorial. First,
UDCA is hydrophilic whereas many other bile acids are
hydrophobic and therefore more cytotoxic to hepatocytes. The
UDCA competes with dominant endogenous bile acids for
absorption in the terminal ileum, making the bile acid pool
Second, UDCA has a direct protective
effect on hepatocytes against bile acid-induced apoptosis.
Third, in cholestatic diseases, the retention of toxic bile acids
leads to cell injury. The UDCA counters this effect by
stimulating hepatocytes and bile duct epithelial cells to
secrete bile (Figure 1).
The UDCA is generally a well-
tolerated drug, but weight gain is a well-documented side
effect. Patients gain on average 2.2 kg in the first year of
treatment and their weight stabilizes thereafter.
PRIMARY BILIARY CIRRHOSIS
In primary biliary cirrhosis (PBC), an immune reaction
targets bile duct epithelium and destroys intrahepatic ducts.
Subsequent cholestasis leads to damage to hepatocytes and
can eventually result in cirrhosis in up to 25% of patients.
The UDCA at 1315 mg/kg/day is approved for treatment of
PBC by the United States Food and Drug Administration, and
UDCA is the only disease-modifying agent recommended by
the American Association for the Study of Liver Disease
(AASLD) for PBC.
Several trials show that UDCA improves
transplant-free survival, delays histologic progression of liver
disease, and improves biochemical markers of the disease.
Patients in early histologic stage of PBC (I or II) on liver
biopsy who are treated with UDCA have the best outcomes
and have been shown to have survival rates similar to control
populations without PBC.
In treated patients, survival rates
are better than rates predicted by the Mayo model.
When treating a PBC patient with UDCA, improvement in
transaminases and bilirubin levels is a favorable prognostic
factor. Transplant-free survival is best predicted biochemi-
cally by lower levels of alkaline phosphatase, aspartate
aminotransferase (AST), and bilirubin. Patients with lower
biochemical markers had a 10-year transplant-free survival
rate of 90% compared to 51% in patients with higher levels in
Despite an increase in the total number of liver
transplants over a 12-year period ending in 2006, the number
of transplants for PBC patients declined over the same time
period. This finding suggests that UDCA has been successful
as the primary treatment for PBC.
Ursodeoxycholic acid may also decrease the risk of devel-
oping esophageal varices in PBC patients. A prospective trial
following 180 patients with PBC for 4 years showed that 16%
of patients treated with UDCA developed esophageal varices
versus 58% of those given placebo.
This effect may be due
to delayed progression of advancing liver disease, as opposed
to a protective effect against portal hypertension.
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Several meta-analyses have shown conflicting results
regarding outcomes in PBC patients treated with UDCA.
Two meta-analyses showed no benefit on mortality or liver
Common criticisms of these analyses are
that they included studies with inadequate follow-up times
and small doses of UDCA.
Two other meta-analyses
demonstrated an improvement in survival with no liver
A 2006 meta-analysis requiring at least a
mid-dose of UDCA (10 mg/kg/day or more) and long-term
follow-up of at least 2 years showed an odds ratio of 0.65 for
liver transplant and 0.75 for death or liver transplant in
patients receiving UDCA versus placebo or no treatment.
Current AASLD guidelines recommend a dose of 1315 mg/
kg/day for PBC in patients with abnormal liver markers with a
cholestatic pattern, regardless of histological stage. Patients
with PBC but no elevation of liver markers are not advised to
Patients discontinuing UDCA tend to have liver
biochemical markers return to pretreatment values, therefore
treatment is continued indefinitely.
Patients awaiting trans-
plant may be treated with UDCA as well.
The recommended dose of 1315 mg/kg/day is based on a
study comparing low dose (57 mg/kg/day), standard dose
(1315 mg/kg/day), and high dose (2325 mg/kg/day) UDCA.
Maximum improvement in alkaline phosphatase, AST, the
amount of UDCA in bile, and Mayo risk score were seen with
the standard dose. There were no additional side effects with
this dose. The high dose did not have additional side effects
but also was not shown to be of any additional benefit.
The use of UDCA in combination with other medications
has been considered. A recent study suggests that patients
with suboptimal biochemical response to UDCA after 1 year
may derive benefit from a combination of UDCA, budesonide
(6 mg/day) and mycophenolate mofetil (1.5 g/day).
there is also evidence that UDCA is effective when combined
with corticosteroids in lowering serum biochemistries
in patients with PBC and autoimmune hepatitis overlap
PRIMARY SCLEROSING CHOLANGITIS
Initial studies of UDCA in primary sclerosing cholangitis
(PSC) showed improvement in biochemical markers, histo-
logical features, and clinical symptoms of pruritis and
However, in 1997 there was a larger randomized,
double-blind trial comparing UDCA with placebo in treating
PSC. The dose was 1315 mg/kg/day with a median follow-up
of 2.2 years. There was no difference between the treatment
and the placebo groups when examining the combined
outcome of death, need for transplant, histological progres-
sion, development of varices, ascites, encephalopathy, fati-
gue, or pruritis.
Later smaller studies suggested that higher doses may be
of more benefit. In three studies, doses ranging from 17 to
30 mg/kg/day improved serum biochemistries, cholangio-
graphic appearance, rate of liver fibrosis, or Mayo risk
Finally, a trial compared 10, 20, and 30 mg/kg/
day doses and the Mayo risk score was significantly better in
the high dose group.
Despite these successes with high dose UDCA, a rando-
mized, double-blind placebo-controlled trial of high dose
UDCA by Lindor et al looking at 150 patients with PSC
showed poorer outcomes among patients treated with
UDCA. Patients were given 2830 mg/kg/day of UDCA.
The study included long-term follow-up and measured the
following primary outcomes: development of cirrhosis,
varices, cholangiocarcinoma, liver transplantation, and
death. Thirty nine percent of patients in the UDCA group
reached one of the above endpoints by the end of the study
versus 26% in the placebo group. The UDCA group had
lower serum liver tests.
The authors offered several
explanations for the results. Higher doses may have allowed
more drugs to reach the colon with subsequent conversion
into hepatotoxic bile acids. High dose UDCA may also
inhibit the apoptosis of activated stellate cells, allowing for
more fibrinogenesis and liver disease. Finally, UDCA may
exacerbate hepatocyte necrosis in the setting of biliary
obstruction and PSC.
The AASLD gives a 1A recommendation (strong recom-
mendation with high quality evidence) against the use of
UDCA in patients with PSC.
As an editorial on the negative
study above points out, the role of UDCA for PSC remains
unclear. Low or medium dose UDCA for PSC could be
further evaluated in large trials with longer durations of
Figure 1. Mechanisms of action of UDCA. Ursodeoxycholic acid decreases
the cytotoxicity of bile by making the bile acid pool more hydrophilic. The
UDCA also directly inhibits apoptosis induced by hydrophobic bile acids.
Finally, UDCA stimulates secretion of bile, decreasing the retention of toxic
bile acids. Reprinted by permission from MacMillan Publishers Ltd: Beuers
U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in
Nat Clin Pract Gastroenterol Hepatol.
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Cholecystectomy is the treatment of choice for patients with
symptomatic cholelithiasis. However, in certain cases of
uncomplicated cholelithiasis, UDCA may be useful. A rando-
mized, double-blind placebo-controlled trial of 177 patients
with highly symptomatic gallstones awaiting cholecystectomy
showed that the rate of biliary colic, nonsevere biliary pain,
and analgesic intake were similar between the UDCA and
placebo groups over a 90-day follow-up period. This indicates
that UDCA does not have a role in alleviating biliary pain in
the short-term among patients awaiting cholecystectomy.
The UDCA may however be useful in longer-term treatment
of gallstones in patients not undergoing cholecystectomy. In
a nonrandomized cohort of 527 patients with uncomplicated
gallstones, UDCA was associated with decreased need for
cholecystectomy and decreased biliary pain. This was inde-
pendent of the analysis of gallstone dissolution.
Among patients with an intact gallbladder, recurrent acute
pancreatitis may occur less frequently when UDCA is used,
especially if microlithiasis may be playing a role.
with recurrent pancreatitis who will not undergo cholecys-
tectomy, performing a sphincterotomy is advised as well.
In certain populations, UDCA may effectively dissolve
cholesterol gallstones by solubilizing cholesterol in bile.
A meta-analysis showed that UDCA successfully dissolved
radiolucent stones in 37% of patients. The efficacy increased
with decreasing size of the stones.
Other analyses have
shown dissolution rates of 30%50%.
frequently return after dissolution with UDCA. Single stones
have the lowest rate of recurrence.
Recurrence rates have
been shown to be 12.5% in the first year and 61% by 11 years
in one study.
Patient selection is very important for successful dissolution
of gallstones with UDCA. Ideal candidates for UDCA therapy
should have a functioning gallbladder, their largest stone
should be ideally less than 5 mm and certainly less than 10
mm, and the stones should be of the cholesterol variety and
Ursodeoxycholic acid has been shown to reduce the
incidence of rapid weight loss induced gallstone formation
in patients undergoing gastric bypass. A randomized placebo-
controlled study using 600 mg daily for 6 months reduced the
incidence of gallstone formation over 6 years following
gastric bypass from 32% with placebo to 2% with UDCA.
Treatment of microlithiasis may include cholecystectomy,
endoscopic sphincterotomy, or UDCA. The UDCA can
prevent recurrence of acute ‘‘idiopathic’’ pancreatitis, which
is often caused by biliary sludge and microlithiasis in patients
with an intact gallbladder.
In a study of patients with
recurrent pancreatitis and cholesterol monohydrate crystals in
their bile, UDCA eliminated biliary microlithiasis and pre-
vented recurrence of pancreatitis over a 44-month period.
another small study, 4 out of 5 patients with biliary sludge
and microlithiasis treated with UDCA achieved long-term
relief from recurrent pancreatitis.
Because of the risk of
recurrence, however, cholecystectomy is routinely recom-
mended in patients with biliary sludge who have had acute
Many patients who undergo cholecystectomy for sympto-
matic gallstones continue to experience pain. Approximately
one-third of all patients undergoing cholecystectomy will
experience this postcholecystectomy syndrome. The patho-
physiology of postcholecystectomy syndrome has not been
clearly delineated, though several mechanisms have been
proposed including sphincter of Oddi dysfunction.
Microlithiasis has been identified in some patients who
have undergone cholecystectomy, and one study demon-
strates that it may be a cause of postcholecystectomy pain.
The UDCA may be useful for treatment in these cases. The
study looked at 118 patients with postcholecystectomy
syndrome, and 12 (10%) were found to have microlithiasis
on examination of their bile. These 12 patients were further
studied. In the first phase of the study, 6 patients received
UDCA and had a significant reduction in pain compared
to the untreated 6 patients. In the second phase, the other
6 patients were treated with UDCA and also experienced a
significant reduction in pain. The UDCA may be of benefit in
patients with postcholecystectomy pain and microlithiasis.
This study was limited by several factors including the small
sample size of 12 and the lack of placebo control. Bile
analysis was not performed after treatment to confirm the
resolution of microlithiasis as the reason for pain relief. Also,
the appropriate duration of treatment is not known. It is not
known whether endoscopic sphincterotomy is an effective
therapy in patients with microlithiasis and postcholecystect-
MISCELLANEOUS CHOLESTATIC DISEASES
Intrahepatic cholestasis of pregnancy (ICP) manifests as
pruritis with elevated serum bile acids in the second half
of pregnancy. It generally resolves after pregnancy with only
rare complications for the mother. Fetal complications are
more common and are associated with elevated maternal
serum bile acid concentrations. The mechanism of disease
involves improper biliary transport across the canalicular
Recent trials have evaluated the utility of UDCA in treating
ICP. In one study, patients received either UDCA at a dose of
810 mg/kg of body weight daily or cholestyramine. The
UDCA group had a decrease in serum aminotransferases,
serum bile acid levels, and pruritis. Babies in the UDCA group
were delivered significantly closer to term without adverse
events from UDCA.
In another trial comparing UDCA at
1 gm daily to dexamethasone, patients receiving UDCA
showed a decrease in serum alanine transaminase (ALT)
and bilirubin. In the women with the highest initial serum
bile acid levels, UDCA also decreased pruritis and serum bile
acid levels. There was no significant effect on fetal complica-
There have been no reports of fetal complications
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with maternal use of UDCA, but no study has been powered
to detect such events.
Patients on long-term total parenteral nutrition (TPN) are at
risk for hepatobiliary complications including cholesta-
A study of nine patients with cholestasis due to
TPN who were treated with UDCA at 10.612 mg/kg/day
showed a significant reduction in gamma-glutamyltransferase
(GGT) and ALT during treatment periods compared to
nontreatment periods. There was no significant difference
in bilirubin, AST, or alkaline phosphatase.
retrospective studies examining UDCA in pediatric popula-
tions receiving TPN showed improvements in liver biochem-
istries as well.
There is no evidence regarding the use of UDCA in the
treatment of hepatotoxic drug reactions. However, given the
benefit of UDCA in other cholestatic diseases, it is a
reasonable assumption that UDCA may be of benefit in
cholestatic drug hepatotoxicity with minimal risk to the
patient. A dose of 1315 mg/kg/day has been suggested.
BONE MARROW TRANSPLANTATION
Various hepatic complications are associated with hemato-
poietic cell transplantation including veno-occlusive disease,
hepatic graft-versus-host disease (GVHD), and liver
A prospective randomized trial examining pre-
vention of hepatic complications after allogeneic stem cell
transplantation suggests a role for UDCA. Patients received
either UDCA or placebo from the day preceding conditioning
until day 90 after transplantation. The UDCA group had
significantly lower serum bilirubin and ALT levels, a sig-
nificantly lower incidence of grade III or IV acute GVHD, and
improved overall survival at 1 year (71 vs 55%). There was no
difference in the incidence of veno-occlusive disease.
A small study examined the use of UDCA for the treatment
of hepatic GVHD. Twelve allogeneic bone marrow transplant
patients received 6 to 12 weeks of UDCA for treatment of
refractory GVHD. Results showed improvement in AST,
bilirubin, and alkaline phosphatase with approximately a
one-third decline in each. However, there is no evidence for
Ursodeoxycholic acid has been associated with improved
serum transaminases in patients with chronic hepatitis C
despite having no influence on the viral load. The mechanism
likely involves the cytoprotective effect of UDCA.
A trial in
1994 demonstrated that UDCA at a dose of 600 or 900 mg/day
for 16 weeks was associated with a 26% reduction in ALT and
a 50% reduction in GGT.
A recent large, double-blind trial
evaluated serum biochemical response to UDCA at either 150,
600, or 900 mg/day for 24 weeks in 596 patients with chronic
hepatitis C. This trial confirmed that 600 mg/day was the
preferred dose for maximal response in transaminases, but
serum GGT decreased significantly more in the 900 mg/day
group. This may be a reflection of the choleretic effect of
UDCA. There was no difference in adverse events among the
Progression of fibrosis in chronic hepatitis C has been
linked to serum transaminase levels.
However, trials of
UDCA have failed to show benefit in histological progression.
This may be due to the relatively short duration of follow-up
of the studies to date, which have been 6 to 12 months.
A recent Cochrane review of UDCA in viral hepatitis showed
an improvement in liver biochemistries for Hepatitis B and C.
The UDCA did not affect clearance of virus, and there was no
evidence to indicate improvement in outcomes such as
progression to cirrhosis or incidence of hepatocellular
NONALCOHOLIC FATTY LIVER DISEASE
Nonalcoholic fatty liver disease (NAFLD) includes hepatic
steatosis and nonalcoholic steatohepatitis (NASH), which can
progress to cirrhosis and hepatocellular carcinoma.
study suggested a role for UDCA in treating NASH.
However, a randomized controlled trial of 166 patients who
received either 1315 mg/kg/day of UDCA or placebo for 2
years showed no significant difference in serum liver
biochemistries or histology.
The authors of this study
suggest that perhaps the dose of UDCA used was not high
enough to detect a benefit. Another study using a fixed dose
of 1200 mg/day of UDCA versus placebo also failed to show a
benefit for serum transaminases.
Finally, a Cochrane review
with meta-analysis examined four randomized trials of UDCA
for NAFLD and was unable to detect a significant benefit for
mortality or biochemistries with UDCA.
CHEMOPROPHYLAXIS OF COLORECTAL
The use of UDCA in patients with ulcerative colitis (UC) and
PSC for chemoprevention of colorectal cancer has also been
investigated. A cross-sectional study of 59 patients with UC
and PSC revealed an odds ratio of 0.18 for the development of
colonic dysplasia in patients taking UDCA versus patients not
In another study, 52 patients with UC and
PSC received either UDCA for a median of 42 months or
placebo for a median of 40 months. The relative risk of
developing dysplasia or cancer was 0.26 for the UDCA group
compared to the placebo group.
Finally, a retrospective analysis compared 28 patients with
UC and PSC who were treated with UDCA for at least 6
months to 92 patients who did not receive UDCA. There was
no significant difference in the incidence of dysplasia or
Given the potential adverse outcomes in PSC
patients taking UDCA and the inconclusive evidence, the
AASLD recommends against the use of UDCA for chemo-
In cystic fibrosis patients with evidence of hepatic involve-
ment, UDCA was shown in an observational study to be
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associated with a delay in the progression of liver disease. No
solid evidence for its use in cystic fibrosis is available in the
form of randomized controlled trials.
Ursodeoxycholic acid is a well-tolerated and safe drug with
a wide range of potential clinical uses (Table 1). In PBC, the
evidence favors the use of UDCA as a disease-modifying agent
that improves transplant-free survival. The UDCA is useful for
dissolving gallstones and preventing symptoms in carefully
selected patients with cholelithiasis; namely, in patients with
small gallstones and a functioning gallbladder who are not
undergoing cholecystectomy. The UDCA is effective in
preventing cholelithiasis in patients who have undergone
gastric bypass surgery.
In PSC, the evidence is equivocal but suggests potential
harm from high-dose UDCA use. Finally, there is promise for
the potential use of UDCA in microlithiasis, cholestatic
diseases such as ICP and liver injury from TPN, as well as
in chronic viral hepatitis, bone marrow transplantation,
chemoprophylaxis in UC and PSC, and cystic fibrosis. More
research is warranted in these areas.
Disclosure: The authors declare no conflict of interest.
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Table 1. Potential Uses of UDCA
Conditions with evidence supporting use
Primary biliary cirrhosis
Conditions with some evidence supporting use requiring further investigation
Microlithiasis and pancreatitis
Microlithiasis and postcholecystectomy syndrome
Intrahepatic cholestasis of pregnancy
TPN-induced liver injury
Bone marrow transplantation and GVHD
Nonalcoholic fatty liver disease
Chemoprophylaxis of colorectal cancer for UC and PSC
Conditions with evidence against use
Primary sclerosing cholangitis
Conditions with theoretical benefit but no evidence
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