Journal of Hepatology
Volume 35, Issue 1 , Pages 134-146, July 2001

Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’☆

  • Konstantinos N Lazaridis
    • ,
  • Gregory J Gores
    • ,
  • Keith D Lindor

      Affiliations

    • There is no direct pharmaceutical company support for this work. However, Doctor Lindor has received research support from Axcan Pharma off and on since 1988 for clinical trials involving ursodeoxycholic acid.
    • There is no direct pharmaceutical company support for this work. However, Doctor Lindor has received research support from Axcan Pharma off and on since 1988 for clinical trials involving ursodeoxycholic acid.
    • Corresponding Author InformationCorresponding author. Tel.: +1-507-284-4823; fax: +1-507-284-0538

Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, 55905, USA

Article Outline

 

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1. Introduction and overview 

The use of ursodeoxycholic acid (UDCA) in the treatment of liver maladies originates in ancient Chinese folk medicine. Indeed, for centuries, the Chinese drug ‘yutan’ a powder preparation derived from dried bile of adult bears was utilized to alleviate hepatobiliary disorders [1].

In 1902, Hammarsten first reported the presence of an unknown bile acid in the bile of the polar bear that he called ‘ursocholeinic acid’ [2]. At that time, given the lack of knowledge on steroid compounds, Hammarsten was unable to describe the chemical structure of this novel bile acid. In 1927, Shoda was the first to define the chemical form of UDCA from the bile of the Chinese black bear [3]. Shoda named this bile acid urso-deoxycholic acid because of its initial discovery in the bile of the bear (called ‘ursus’ in Latin) and his belief that it was a chemical isomer of deoxycholic acid. In 1936, Iwasaki, defined the chemical structure of UDCA [4] and this led to its sufficient synthesis for use in clinical investigation.

In 1975, Makino reported the first prospective study of patients with gallbladder stones treated with UDCA demonstrating gallstone dissolution [5]. In 1985, Leuschner first observed improved liver tests of patients with chronic active hepatitis treated with UDCA for gallstone dissolution [6]. In 1987, Poupon suggested that long-term use of UDCA is safe and effective in patients suffering from primary biliary cirrhosis (PBC) [7]. Since then, a variety of studies have shown the beneficial effect of UDCA in liver disorders. In clinical practice today, UDCA possesses a defined role in treating patients with cholestatic liver diseases. Nevertheless, its exact mechanism(s) of action have not been completely elucidated despite many investigations. This review intends to outline the physicochemical and pharmacological properties of UDCA, focus on its proposed pathways of action and examine its use and efficacy in clinical practice.

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2. Physicochemical properties of ursodeoxycholic acid 

2.1. Chemical structure, characteristics and origin 

Bile acids are acidic steroids that are synthesized from cholesterol within the hepatocytes. UDCA represents a hydrophilic dihydroxy (i.e. 3α, 7β-dihydroxy-5β-cholan-24-oic acid) bile acid (Fig. 1). The solubility of its protonated form is ~ 9 μmol/l and it has a melting point of 203°C [8]. In humans, UDCA accounts for up to 4% of the bile acid pool and because it is not synthesized in the liver it likely originates in the colon by bacterial 7β epimerization of the primary bile acid chenodeoxycholic [1]. Following its formation, UDCA is passively absorbed by the colonic mucosa to enter the portal circulation and subsequently the pool of bile acids.

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  • Fig. 1. 

    Chemical structure of chenodeoxycholic acid and ursodeoxycholic acid. Chenodeoxycholic acid (left) and ursodeoxycholic acid (right) have different planar orientation of the 7-hydroxy group that causes the latter to become more hydrophylic.

2.2. Hydrophilic properties 

Natural bile acids in their protonated (or unionized) form are quite insoluble in water. In relation to the dominant bile acids in bile such as chenodeoxycholic and deoxycholic, UDCA is more hydrophilic. This property of UDCA is due to the hydrophilic groups as seen in Fig. 1. Indeed, the number, position, and orientation of the steroid hydroxyl group(s) define the hydrophilicity of a bile acid [1]. For example, the higher the number of hydroxyl groups the greater the hydrophilicity of a bile acid (i.e. trihydroxy bile acids are more hydrophilic than monohydroxy bile acids). The orientation (α or β) of the hydroxyl groups relative to each other determines the bile acid hydrophilicity in these planar molecules. For instance, a 7 α-hydroxylation (i.e. chenodeoxycholic acid) renders a bile acid less hydroplilic than a 7β-hydroxylation (i.e. ursodeoxycholic acid) given the 3 α-hydroxylation (Fig. 1).

2.3. Bioavalaibility, transport and metabolism 

Following oral administration, approximately 30 to 60% of UDCA is absorbed in the gut. The absorption occurs throughout the small intestine (~80%) and less in the colon (~20%) [9]. Oral absorption of UDCA is enhanced by bile acid solubilization suggesting that it should be taken during meals. In contrast, concurrent use of other medications such as activated charcoal, aluminium-containing antacids, cholestyramine and colestipol may diminish the intestinal uptake of UDCA due to intraluminal binding [10]. Accordingly, it is recommended to be administered 5 h apart from those agents such as cholestyramine that may interfere with its intestinal absorption [11]. Of note, the UDCA absorption and bioavailability can be decreased in advanced cholestasis [12]. After intestinal absorption, UDCA enters the portal circulation and then is taken up by the hepatocytes at their sinusoidal domain via specific bile acid transporters namely, NTCP and OATP [13]. Within the hepatocyte, UDCA is conjugated to glycine (mainly) or taurine [8] and is subsequently transported across their canalicular domain into the bile ducts via another bile acid carrier molecule, designated BSEP [13]. Following secretion into the biliary apparatus, UDCA reaches the small intestine and thereafter enters the enterohepatic circulation along with the other bile acids.

UDCA has a high first-pass metabolism approaching 70% which leads to its low blood level in the systemic circulation [14]. In bile, the UDCA concentration reaches a peak 1–3 h following per os administration [9]. The degree of UDCA enrichment in biliary bile following chronic ingestion correlates with its daily-administered dose. UDCA given at 8–10 mg/kg per day causes an expected enrichment of approximately 40% in biliary bile acids [8]. UDCA dose above 10–12 mg/kg per day does not further increase its proportion in bile due to its epimerization to chenodeoxycholic acid and the inability of inhibiting the hepatic synthesis of primary bile acids [8], [9]. In humans, the half-life of UDCA is 3.5 to 5.8 days [15] and the predominant route of elimination from the body is by the feces. In the colon, the unabsorbed UDCA undergoes mainly microbial conversion to lithocholic acid, which probably remains insoluble within the colonic content and is subsequently excreted via the feces [8]. However, in studies of healthy individuals and cholestatic patients treated with UDCA, UDCA conjugates were found increased in the urine of the latter group compared to normal subjects [16]. Indeed, in cholestatic patients the increased renal clearance of UDCA conjugates represents an important pathway of UDCA elimination [16].

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3. Pharmacological activities of ursodeoxycholic acid 

3.1. Cholesterol and bile acid metabolism 

UDCA therapy decreases the cholesterol secretion into bile as indicated by a decline in the cholesterol fraction of biliary lipids. Indeed, UDCA reduces the biliary cholesterol by 40–60%. These UDCA induced changes are greater compared to equal doses of chenodeoxycholic acid [15]. In humans, UDCA at 15 mg/kg per day does not suppress HMG CoA reductase in contrast to chenodeoxycholic acid [8]. Thus, it is likely that UDCA either decreases the intestinal absorption of cholesterol and/or increases its conversion to bile acids. Although the first is true based on human and animal studies the exact mechanism by which UDCA reduces cholesterol uptake in the gut is lacking [8].

Regarding its effect on bile acid metabolism, studies have shown that UDCA increases the metabolic conversion of cholesterol to bile acids in healthy individuals, patients with hyperlipidemia and in cholestatic liver diseases [8]. Nevertheless, UDCA has no notable effect on the total bile acid pool size. Following UDCA therapy, the UDCA in bile is enriched (accounting for 19–64% of biliary bile acids depending on daily dose). However, the reported changes in the concentration of the endogenous bile acids in bile are variable. For example, in patients with gallstones, UDCA treatment causes slight decline in biliary chenodeoxycholic, cholic and deoxycholic acid but no significant change in lithocholic acid [15]. In contrast, a study of PBC patients treated with UDCA reported a drop in the biliary concentration of cholic acid without notable changes of chenodeoxycholic and deoxycholic acid [17].

3.2. Phospholipid metabolism 

UDCA has no significant effect on biliary phospholipid output and concentration [15].

3.3. Serum lipids 

Patients with gallbladder stones receiving UDCA for stone dissolution fail to demonstrate a change in serum cholesterol including no significant changes in serum LDL and HDL levels [1], [15]. However, in a study involving non-cirrhotic patients with PBC, the total serum cholesterol, VLDL and LDL concentrations were considerably diminished following treatment with UDCA for 2 years [18]. Other investigators reported that UDCA appears to lower the level of triglycerides in serum by more that 10%, however, the clinical implications of this effect have not been evaluated [1], [15].

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4. Mechanisms of ursodeoxycholic acid action 

UDCA exerts its action(s) in liver through multiple possibly interrelated pathways including alterations of bile acid pool, choleresis, immune modulation effects and cytoprotection mechanisms as shown in an overview on Fig. 2 and explained in detail on the following pages.

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  • Fig. 2. 

    Overview of UDCA mechanisms of action. ‘The effects of UDCA in liver are multifaceted and interrelated. Indeed, each of these proposed mechanisms might have variable contribution in different hepatobiliary disorders’.

4.1. Expansion of hydrophilic bile acid pool 

In experimental models or cholestatic liver diseases bile acids accumulate within the liver, systemic circulation and peripheral tissues. In liver, the intracellular accumulation of hydrophobic (i.e. toxic) bile acids leads to an array of cell-damaging events ranging from increased cell-membrane fluidity and permeability to programmed-cell death (i.e. apoptosis) and necrosis [19]. The level and duration of liver exposure to hepatotoxic bile acids relate to the degree of cell damage. For example, a transient increase in bile acids inside the hepatocytes can cause reversible elevation of transaminases. However, during prolonged cholestasis, exposure of hepatocytes to toxic bile acids likely promotes liver fibrosis and cirrhosis [19].

It has been postulated that one of the main therapeutic mechanisms of UDCA in cholestatic liver diseases relates to displacement of the endogenous hepatotoxic bile by expansion of the hydrophilic bile acid pool (i.e. enrichment by UDCA). This protective function of UDCA may correlate with competitive displacement of endogenous (i.e. toxic) bile acids either at the level of ileal absorption or at the hepatocyte level (i.e. cell-plasma membrane, intracellular organelles, etc) [20]. Indeed, oral administration of UDCA may reduce the ileal absorption of endogenous bile acids by competitive inhibition at the level of terminal ileum [20]. However, competition of UDCA for the ileal uptake of more hydrophobic bile salts does not significantly alter the composition of the bile acid pool. Moreover, in the bile fistula rat model, intravenous infusion of conjugated UDCA improved the hepatotoxicity induced by toxic bile acids. It seems, therefore, likely that UDCA exerts its protective action at the level of the liver [19], [21]. UDCA being hydrophilic, displays no cell-membrane damage and/or subcellular destruction in humans or in vitro models up to a concentration of 500 μmol/l [19]. Furthermore, treatment with UDCA does not affect significantly the de novo bile acid synthesis in liver compared to the effects of bile acid binding resins that have been used in the past to ameliorate the intrahepatic consequences of cholestasis [6], [19].

The exact contribution of UDCA on ‘displacement’ of endogenous (i.e. hepatotoxic) bile acids as a mechanism in preventing liver damage remains unclear. Of interest, Beuers et al. have shown improvement in the liver blood tests of patients with cholestatic liver diseases following 1 month therapy with UDCA without a decline in the pool size and serum levels of the main endogenous hydrophobic bile acids [22]. In another study of patients with primary sclerosing cholangitis (PSC) treated with UDCA for 3 months, no change was noted before and after therapy in the pool size of bile acids and serum concentration of chenodeoxycholic acid [23]. Based on these observations, it is unlikely that UDCA improves the liver function of cholestatic patients simply by displacing endogenous bile acids from or expanding the hydrophilic bile acids in the bile acid pool.

4.2. Choleretic effect and hypercholeresis 

It is known that UDCA provokes the secretion of bile acids and other organic compounds in experimental models such as the isolated hepatocytes, isolated perfused rat liver, bile fistula rat model and cholestatic liver diseases [24]. The ‘choleretic effect’ of UDCA is considered comparable to, but lacking the hepatotoxicity of the endogenous bile acids. These properties make UDCA a useful choleretic drug for the treatment of cholestatic liver diseases. In fact, a study by Jazrawi et al. demonstrated that in patients with PBC and PSC, UDCA therapy improved the net and absolute hepatic excretory rates and transit time of a γ-labeled bile acid analog [25].

In cholestatic hepatocytes, vesicular exocytosis is impaired. Tauroursodeoxycholic acid (TUDCA) induces vesicular exocytosis at the canalicular domain of hepatocytes. Indeed, exposure of isolated rat hepatocytes to TUDCA at 5–50 μmol/l causes an increase of cytosolic free Ca2+ [(Ca2+)i] by mobilizing intracellular stores and increasing the influx of extracellular Ca2+ [26]. In the isolated perfused rat liver, TUDCA induces Ca2+ -dependent stimulation of vesicular exocytosis (Fig. 3) [27]. It has been proposed that induction of the Ca2+-dependent hepatocyte exocytosis is mediated by activation and translocation of α-PKC from cytosol to the plasma membrane [28]. Therefore, the mechanism of TUDCA-induced choleresis and subsequent cytoprotection in cholestasis may be related to the fact that it can promote apical exocytosis and thus create an increase in canalicular transport. This improvement in canalicular transport helps restore bile flow promoting the excretion of toxic hydrophobic bile salts from the hepatocyte. In another study it was suggest that TUDCA increases the canalicular bile acid transport via activation of the mitogen-activated protein (MAP) kinases [29].

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  • Fig. 3. 

    Effect of TUDCA on exocytic insertion of transport proteins into the canalicular domain of hepatocytes. TUDCA increases the intracellular Ca2+ [(Ca2+)i] by mobilizing intracellular stores and promoting influx of extracellular Ca2+. The elevated (Ca2+)i causes exocytic insertion of vesicles bearing transport proteins into the canalicular domain of hepatocytes (see text for details).

Other proposed mechanisms of UDCA-induced choleresis involve modulation of membrane transport proteins. For instance, the expression of the chloride-bicarbonate anion exchanger 2 (AE2) in biliary epithelia was found diminished in patients with PBC [30], [31]. Of interest, therapy of PBC patients with UDCA upregulated the expression of AE2 transporter compared to untreated patients [30], [31]. Moreover, in a bile duct cell-line, UDCA increased the intracellular Ca2+ [(Ca2+)i] causing activation of whole-cell Cl− channels [32]. This Cl− efflux could then promote bicarbonate movement into bile ducts [32]. It is apparent that further studies are needed to elaborate whether UDCA therapy affects the regulation of membrane carriers as a mechanism in improving cholestasis.

A specific UDCA induced, bicarbonate rich, ‘hypercholeresis’ has been reported in rodents [33]. The term ‘hypercholeresis’ was coined to describe a greater than expected choleresis for intravenously infused UDCA [33]. Hofmann proposed that the UDCA produced bicarbonate-rich hypercholeresis is achieved via a ‘cholehepatic shunt’ process [34]. In his proposed pathway, the unconjugated UDCA molecule is protonated within the canaliculus, is passively absorbed by biliary epithelia creating concurrently a bicarbonate anion within the bile ducts, and subsequently returns to hepatocytes via the periductural capillary plexus, a branch of the hepatic artery [34]. This ‘cholehepatic’ circulation of UDCA continues to induce ‘hepercholeresis’ till the bile acid is conjugated or metabolized [35], [36]. To date, the role of ‘cholehepatic shunt’ in cholestatic patients treated with UDCA remains unclear. In fact, no significant amounts of unconjugated UDCA were found in the bile of cholestatic patients treated with UDCA at therapeutic doses of 10–15 mg/kg per day [17]. It might, however, be argued that effective re-uptake of unconjugated UDCA by the biliary epithelia prevents its detection in bile samples. This statement could be supported by recent evidence that bile duct cells possess apical and basolateral bile acid transporters [37], [38], [39]. Nevertheless, UDCA bears protective effects on the liver extending beyond the proposed mechanisms of hydrophilic bile acid pool expansion, choleresis, or ‘hypercholeresis’. In fact, experimental studies have shown that UDCA may exert immunomodulatory activity and provides cytoprotection on isolated liver cells as described below.

4.3. Immunomodulatory properties 

UDCA has been suggested to be immunomodulatory for the humoral immune system [40]. However, these experimental findings should be viewed with caution. Indeed, the immunomodulating effects of bile acids on peripheral mononuclear cells in vitro may depend on the concentration of physiological protein used in cell-culture media as reported by Bergamini et al. [41]. Of interest, in patients with PBC UDCA treatment reduces the serum level of IgM class AMA antibodies [42] and IgG antibodies to pyruvate dehydrogenase [43]. Whether these changes in serum immunoglobulins of PBC patients treated with UDCA reflect a direct effect or an epiphenomenon are difficult to determine.

Regarding cell-mediated immunity, it is known that during cholestasis the major histocompatibility complex (MHC) class I and class II molecules are overexpressed in hepatocytes and biliary epithelia, respectively [44], [45]. Aberrant expression of MHC class I on hepatocytes may lead to their recognition and subsequent destruction by cytotoxic T lymphocytes. Of interest, Calmus et al. reported that MHC class I overexpression was not suppressed by either cyclosporin or corticosteroids [46]. The proposed mechanism of MHC class I induction in cholestasis involves at least a direct effect of bile acids on MHC class I mRNA transcriptional activation probably via protein kinase C and protein kinase A [47]. In patients with PBC, UDCA decreases the hepatocellular and biliary expression of MHC class I [48] and MHC class II [49] molecules, respectively. This suggests that UDCA might reduce the T-cell mediated hepatocellular damage. Podevin et al. have shown that bile duct ligation-induced cholestasis and bile acids in vitro can reduce the biological activity of interferon and render defective the natural killer (NK) cell [50]. Of interest, in PBC patients UDCA therapy reported to correct the defective natural killer (NK) cell activity by inhibiting prostaglandin E2 production [51]. Recently, Yamazaki et al. have demonstrated that in patients with PBC, 4-week treatment with UDCA reduces the peripheral blood eosinophils and inhibits the eosinophilic activation and degranulation [52].

Although UDCA may possess an array of interdependent immunomodulatory activities it is worth mentioning that cholestasis itself induces immunosuppression probably due to accumulation of hydrophobic bile acid within the liver as suggested by Calmus et al. [53]. To this end, the favorable action of UDCA in ameliorating liver damage during cholestasis may relate less to its proposed direct immunomudulating properties on liver cells but rather more to the effect of displacing the endogenous (i.e. hydrophobic) bile acids [53].

4.4. Cytoprotection 

The hepatoxicity of hydrophobic bile acids is dependent to direct interaction with the target liver cells (i.e. hepatocytes, cholangiocytes). The proposed mechanisms of bile acid-induced cell damage extend from simply binding to plasma membranes to the induction of apoptosis or even necrosis. The final injurious effect of bile acids on the hepatic epithelia depends on the balance between the degree of insult and the existing protective systems. UDCA offers cytoprotection in hepatic epithelia by a variety of pathways involving preservation/stabilization of cell structures (i.e. plasma membranes, mitochondria) and by induction of subcellular anti-apoptotic pathways as discussed below.

Heuman et al. have proposed that the protective effect of UDCA in opposing the hepatotoxicity of bile acids is achieved at the level of the liver [54]. Indeed, he reported that UDCA cytoprotection was related to its direct interaction with plasma membranes of hepatocytes [55]. Subsequently, it was proposed that UDCA provides membrane stability via a physicochemical effect by reducing the toxic bile salt disruption of cholesterol-rich model membranes [56]. More recent studies, using large unilamellar vesicles and mixtures of bile salt taurine conjugates revealed that UDCA does not directly stabilize membranes but rather prevents hydrophobic bile acid-induced membrane disruption by alteration of the structure and composition of mixed micelles [57].

It is evident, that UDCA possesses properties that prevent cell-membrane damage. To achieve this effect in isolated cells or whole organ (i.e. liver) a high concentration of UDCA, in the range of mM, is required. Thus, the membrane protective effects of UDCA are more relevant in cholangiocytes, the cells that line the intrahepatic bile ducts, where the concentration of bile acids is ~3–45 mM [58]. Although the presence of phospholipid-rich mixed micelles in canaliculi may be critical to avert damage on the apical domain of cholangiocytes by hydrophobic bile acids, the direct protective effect of UDCA on these cells can not be overstated. For example, in the mdr2 (−/−) knockout mice the canalicular phospholipid export pump, mdr2, is absent leading to development of chronic non-suppurative cholangitis due to deficient phospholipid protection of bile ducts [59]. Of interest, mdr2 (−/−) mice fed with UDCA displayed improvement in the chronic non-suppurative cholangitis compared to mdr2 (−/−) mice fed with control diet [59].

Experimental evidence supports the concept that bile salt cytotoxicity may be induced by mitochondrial dysfunction [60], [61]. Indeed, hepatocyte necrosis can be caused by induction of the mitochondrial membrane permeability transition (MMPT) [62]. The permeability transition is a phenomenon characterized by an abrupt permeability of the inner mitochondrial membrane to ions. This event results in mitochondrial swelling, depolarization of the mitochondrial membrane potential and uncoupling of oxidative phosphorylation [62]. The uncoupling of oxidative phosphorylation, if extensive, results in ATP depletion loss of cellular ion homeostasis and cellular death by necrosis. Furthermore, the associated mitochondrial swelling has also been linked to redistribution of cytochrome c from the intermembrane space to the cytosol. In the cytosol, cytochrome c interacts with APAF-1 (apoptotic protease-activating factor 1) to activate caspase 9 and subsequently to cause apoptosis. Thus, induction of the MMPT can be a critical step in cell death by either necrosis or apoptosis. In an in vitro study, glycochenodeoxycholic acid (GCDC), a toxic bile salt, induced the MMPT in a dose-dependent manner [63]. In the same work, UDCA inhibited the GCDC-induced MMPT and prevented hepatocyte necrosis following exposure to GCDC [63]. Thus, a mechanism of UDCA cytoprotection may relate to inhibition of bile salt-induced MMPT. In another study, UDCA reduced the deoxycholic acid-associated loss of the mitochondrial membrane potential (▵Ψm) and decreased the production of reactive oxygen species [64].

In hepatic epithelia, cell death takes place primarily through apoptosis rather than necrosis [65]. Apoptosis (the most common form of programmed cell death) is defined by distinct morphologic and biochemical cell alterations leading to internucleosomal degradation and the development of apoptotic bodies (i.e. nuclear fragments and cell organelles contained by plasma membrane). Apoptosis facilitates the selected elimination of senile, injured or diseased liver epithelia. For example, Harada et al. have reported enhanced apoptosis causing bile duct loss in patients with PBC [66]. Glycochenodeoxycholic and glycodeoxycholic bile acids can directly induce apoptosis in rat hepatocytes at concentrations comparable to those present in cholestasis. The bile salt-induced hepatocyte apoptosis entails activation of the Fas death-receptor and subsequent activation of caspase 8 followed by activation of Bid which leads to mitochondrial dysfunction by chaperoning Bax to mitochondrial membrane (Bid and Bax are pro-apoptotic molecules of the Bcl-2 family; Bax is thought to induce MMPT) (Fig. 4) [67]. To this end, in patients with PBC, the Fas-receptor was found upregulated in the small interlobular bile ducts and the Fas-ligand was present on cytotoxic lymphocytes infiltrating the portal tracts [66].

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  • Fig. 4. 

    Induction of hepatocyte-apoptosis by toxic bile salts via the Fas death-receptor. The bile salt-induced hepatocyte apoptosis entails activation of the Fas death-receptor and subsequent activation of caspase 8 followed by activation of Bid which leads to mitochondrial dysfunction via chaperoning Bax to mitochondrial membrane (see text for details). UDCA prevents bile salt-induced apoptosis in hepatocytes by intervening with mitochondrial dysfunction and release of cytochrome c.

Recently, Rodrigues et al. have demonstrated that feeding deoxycholic acid to rats or exposing it to primary rat hepatocytes induces apoptosis in the liver parenchyma and isolated hepatocytes, respectively [68]. Interestingly, it was noted that co-administration of UDCA with deoxycholic acid caused inhibition of hepatocyte apoptosis both in vivo and in vitro [68]. It was also shown that UDCA inhibits the induction of apoptosis in hepatocytes caused by non-membrane damaging agents such as ethanol, transforming growth factor-β1 (TGF-β1), anti-Fas antibody and okadaic acid [68]. These universal effects of UDCA in regulating a variety of apoptotic pathways may probably relate to modulation of mitochondrial membrane stability and function. Even though the exact mechanism of UDCA on inhibition of apoptosis and specifically on the MMPT is currently lacking, it has been proposed that UDCA action may attribute to binding to the pro-apoptotic protein Bax and thus preventing the translocation of the latter from cytosol to mitochondria where the initiation of critical pathways of apoptosis occur [64], [69].

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5. Clinical use and efficacy 

UDCA has been used for the treatment of cholestatic and other liver diseases. We review here the main studies conducted for these hepatic disorders and discuss the use of UDCA in clinical practice.

5.1. Adult cholestatic hepatic diseases 

5.1.1. Primary biliary cirrhosis (PBC) 

A multicenter controlled trial of patients with PBC by Poupon et al. demonstrated that UDCA therapy for 2-years leads to reduction of clinically overt disease, improvement of liver blood tests, Mayo risk score, and mean histologic score of liver biopsies in the treated group compared to placebo [42]. Subsequent studies have shown that UDCA delays the progression rate of PBC resulting in a decreased need for liver transplantation [70]. Lindor et al. reported a 2.6-fold lesser mortality or need for liver transplantation in the UDCA treatment group compared to patients receiving placebo (Fig. 5) [71]. Furthermore, a combined multicenter analysis revealed that long-term therapy with UDCA (13–15 mg/kg per day) improved the survival free of liver transplantation in PBC patients with moderate or severe disease [72]. To this end, Pasha et al. demonstrated that patients with PBC who take UDCA have a lower incidence of major complications and lower medical costs [73]. To improve the beneficial effect of UDCA in patients with PBC many combination treatment trials (i.e. UDCA plus other agents) have been conducted over the years. However, none of these studies has provided an additional favorable outcome compared to UDCA monotherapy [74], [75], [76], [77], [78].

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  • Fig. 5. 

    Comparison of proportion of patients with PBC surviving or requiring liver transplantation in the UDCA-treated, placebo group, and predicted group from the Mayo survival model using the intent-to-treat analysis. UDCA-treated group (____; n=89), placebo group (–-; n=91) and predicted group (~~~) using the Mayo risk model. (from Lindor et al. -ref. 71- with permission).

Of interest, a recent meta-analysis on published randomized, controlled trials of UDCA treatment for PBC, reported no difference between the placebo and UDCA group in the incidence of death, liver-related death, liver transplantation, death or liver transplantation and in the development of liver disease complications [79]. In our view, there are inherent limitations of meta-analysis in evaluating the randomized controlled trials of UDCA in patients with PBC. Indeed, the prolonged and unpredictable natural history of PBC, the lack of defined surrogate markers of disease progression and end-points of treatment in addition to the variable timing and listing for liver transplantation make the attempt of meaningful meta-analysis difficult [80]. Novel medical remedies are needed to advance our therapeutic armamentarium against PBC. In the interim, we concur with the recommendation of the American Association for the Study of Liver Diseases for using UDCA (13–15 mg/kg per day) in PBC patients given its potential beneficial effects, high tolerability and absence of significant side effects [81].

5.1.2. Primary sclerosing cholangitis (PSC) 

Initially, uncontrolled pilot [82], [83] and small placebo-controlled [84], [85] studies revealed promising effects of UDCA in patients with PSC. However, the largest, randomized, double-blind study by Lindor et al. involving 105 patients with PSC and using UDCA (13–15 mg/kg per day) over a median-follow-up of 2.2 years did not reveal clinically beneficial results [86]. Although treatment with UDCA improved the patients biochemical profile at 1 and 2 years compared to placebo, there was no significant difference between the groups in time to treatment failure including patients with early-stage disease and no improvement in time to liver transplantation [86]. The lack of notable clinical effect by UDCA in PSC patients may relate to the stage of disease, duration of treatment and probably other factors pertinent to disease process itself. Recently, Harnois et al. reported that treatment of PSC patients with high dose UDCA (25–30 mg/kg per day) for 1 year led to improved biochemistries and the Mayo risk score [87]. Thus, therapy of PSC patients with high doses UDCA (25–30 mg/kg per day) is promising. Nevertheless, additional studies are needed to further address the treatment role of high doses UDCA in PSC patients perhaps in the context of multi-drug experimental trials.

5.1.3. Intrahepatic cholestasis of pregnancy (ICP) 

ICP is a rare cholestatic entity of unknown etiology affecting pregnant women during the third trimester. ICP is characterized by severe pruritus, a cholestatic pattern of liver enzymes and is associated with an increased rate of fetal distress, premature delivery and perinatal mortality. Although the maternal prognosis is excellent following delivery the potential unfavorable effect on fetal health dictates medical intervention. In the first uncontrolled study by Palma et al. involving eight pregnant women with ICP, UDCA improved pruritus, cholestasis, and appeared to be safe for both the mothers and the babies before and after delivery [88]. Subsequently, in a double-blind study of 15 patients with ICP, UDCA (16 mg/kg per day) for a 3-week period improved pruritus and liver biochemistries in the treatment group compared to control [89]. Furthermore, in the UDCA group deliveries occurred at or near term compared to pregnant women receiving placebo in whom deliveries took place earlier including one stillbirth. Three months following the deliveries no adverse effects were noted in the mothers or babies [89]. It has been postulated that UDCA has a stimulatory effect on the biliary excretion of 3a-sulfoxed and disulfated steroids in ICP in addition to facilitating bile acid excretion [90]. Recently, Mazzella et al. reported that high dose UDCA (1.5–2.0 g/d) could be even more effective in treating ICP without posing toxic effects to the mothers and babies [91]. Thus, treatment of ICP with UDCA can be justifiable although additional studies are needed to further address its efficacy and safety profile in pregnant women and the newborn.

5.2. Pediatric cholestatic hepatic diseases 

5.2.1. Cystic fibrosis (CF) 

CF causes thick biliary secretions resulting in bile duct plugs and obstruction. Over time, the lesions lead to focal biliary fibrosis and subsequently to focal/multilobular cirrhosis [92]. Given the currently extended survival of patients with CF, the prevalence of hepatobiliary disease in these patients is expected to increase. Thus, therapy that attenuates the progression of liver disease in CF would be of benefit.

Uncontrolled studies noted improvement of hepatic function [93], [94] and nutritional status of patients with CF following therapy with UDCA [93]. In a double-blind trial, Colombo et al. had shown that UDCA (15 mg/kg per day) improved the biochemical and clinical parameters of CF in the treatment group within 1 year of follow-up [95]. Recently, it was reported that treatment of CF patients with UDCA (10–15 mg/kg per day) for 2 years causes improvement of liver histology [96]. The ideal dose of UDCA in CF has been the focus of two studies, which demonstrated that dose at 20 mg/kg per day provides greater improvement of liver biochemistries than lower doses [97], [98]. Overall, UDCA should be considered as potentially effective in CF patients. Whether UDCA affects the disease progression and survival of patients with CF is unknown and future studies should address these issues.

5.2.2. Progressive familial intrahepatic cholestasis (PFIC) 

PFIC or Byler's disease, a recessive inherited disorder, is characterized by pruritus, intrahepatic cholestasis with eventual progression to cirrhosis and hepatocellular failure ultimately causing death prior to adolescence. Jacquemin et al. treated 39 patients with PFIC using UDCA at 20–30 mg/kg per day for 2 to 4 years and demonstrated improvement on liver function and clinical status in these patients suggesting that UDCA should be considered in children with PFIC [99].

5.2.3. Bile-duct paucity syndromes 

These syndromes include biliary atresia, Alagille's syndrome and other syndromes of disappearing bile ducts. UDCA therapy should be as viewed beneficial in those patients in improving/stabilizing cholestasis prior to liver transplantation [100].

5.3. Other hepatic diseases 

5.3.1. Gallstone dissolution 

Investigators postulated that UDCA may dissolve cholesterol stones given its chemical and structural relationship to chenodeoxycholic acid, an agent that was studied extensively in the 1970’s for this purpose. In a pivotal study, Makino et al. first reported gallstone dissolution with UDCA [5]. Since then UDCA has been used in the treatment of gallbladder stones as an alternative to cholecystectomy [101]. The proposed mechanism of action involves unsaturation of bile by UDCA leading to gallstone dissolution by solubilizing cholesterol from the stone surface [9]. Candidates for UDCA treatment should have radiolucent gallstones less than 20 mm in diameter and a patent cystic duct. The recommended dose of UDCA for gallbladder stones is 8–10 mg/kg per day with higher doses not providing additional benefit in outcome [9]. A dissolution rate of 30 to 60% has been reported [15], [101]. Absence of or minimal change in gallstone diameter within 6 to 12 months of UDCA therapy represents a poor prognostic sign for dissolution [9]. Following complete dissolution UDCA should be continued for 3 additional months to confirm decomposition of microscopic stones that may escape ultasonography. Gallstone recurrence was reported to be 50 to 70% 12 years following successful treatment limiting the enthusiasm for this kind of therapy [102]. Low dose UDCA (300 mg/day) as maintenance therapy diminished the recurrence rate of gallstones over 90 years by almost 50% compared to a control group [102]. Today, UDCA can be useful in the treatment of selected type gallstones in patients at high risk for surgical interventions.

5.3.2. Biliary sludge 

The widespread use of ultrasound nowadays has led to the frequent description of biliary sludge in many patients. Sludge formation in the biliary system can be precipitated by rapid weight loss, pregnancy, total parenteral nutrition, ceftriaxone or octreotide therapy and bone marrow or solid organ transplantation [103]. Whether biliary sludge causes symptoms in all those individuals remains difficult to prove. Ros et al. have shown that in 13 patients with ‘idiopathic pancreatitis’ and gallbladder sludge, UDCA at 10 mg/kg per day eliminated the gallbladder ‘microlithiasis’ within 3 to 6 months. Also, maintenance therapy with UDCA (300 mg/day) prevented gallstone recurrence and more episodes of pancreatitis over a follow-up of 44 months [104]. Thus, UDCA may have a role in selected patients with biliary sludge particularly when surgical approaches are prohibited and therapy is necessary.

5.3.3. Graft versus host disease (GVHD) involving the liver 

GVHD following allogeneic bone marrow transplantation can involve the liver causing a cholestatic picture and veno-occlusive disease. Pilot studies have shown improvement of cholestasis in hepatic GVHD following short-term treatment with UDCA [105], [106]. Essell et al. in a randomized, placebo-controlled trial reported that prophylactic use of UDCA (600–900 mg/day) led to a decreased incidence of veno-occlusive disease in the treatment group (15%) compared to control (40%) [107]. While these findings are promising additional studies are required to define the long-term benefit of UDCA in patients with hepatic GVHD.

5.3.4. Liver allograft rejection 

Granted its proposed immunomodulatory properties, UCDA was suggested in the treatment of acute cellular rejection and supported by promising data of uncontrolled studies. Subsequently, four randomized, placebo-controlled trials tested UDCA as a prophylactic regimen in reducing the incidence of acute cellular rejection following liver transplantation [108], [109], [110], [111]. In three of these studies, UDCA failed to prevent acute cellular rejection in the treatment group compared to control [108], [109], [111]. Nevertheless, in one study, addition of UDCA in the immunosuppression regimen resulted in fewer episodes of acute cellular rejection, shorter hospital stay and better 90-day and 1 year survival [110]. At this point, the prophylactic use of UDCA in acute cellular rejection after liver transplantation remains to be established.

5.3.5. Drug-induced cholestasis 

Published case reports [112], [113] and small case-series [114], [115]) have shown the beneficial effect of UDCA in drug-induced cholestasis. Thus, an empiric trial of UDCA in cases of prolonged drug-induced cholestasis is reasonable. Controlled studies are required to validate the potential favorable effect of UDCA in drug-induced cholestasis. However, conduct of such trials is difficult given the variety of involved drugs and the isolated nature of these cases.

5.3.6. Total parenteral nutrition (TPN) induced cholestasis 

Although the pathogenesis of TPN-induced cholestasis remains obscure [116] it represents a clinical challenge particularly in premature infants and adults with history of Crohn's disease requiring long-term bowel rest. Lindor et al. first reported the satisfactory improvement of hyperbilirubinemia in a patient who presented with jaundice during TPN [117]. Subsequently, in a pilot study involving seven children on long-term TPN, it was demonstrated that UDCA at 30 mg/kg per day results in disappearance of the biochemical profiles and clinical signs of cholestasis [118]. Of interest, TPN-induced cholestasis in piglets appeared to improve following intravenous administration of UDCA for 3 weeks [119]. Given the lack of controlled studies in adults, we can justify UDCA treatment in patients with TPN-induced cholestasis perhaps in the context of experimental trial. Indeed, additional investigations are in demand to define for the practicing gastroenterologist the prophylactic use of UDCA in TPN-induced cholestasis.

5.3.7. Benign recurrent intrahepatic cholestasis (BRIC) 

This rare familial syndrome is characterized by recurrent episodes of cholestasis associated with jaundice, pruritus, fatigue, anorexia and weight loss that may persist 3 to 4 months with subsequent complete recovery. Although the experience with UDCA in BRIC is limited and controversial [120], [121] empiric treatment with UDCA should be considered.

5.3.8. Non alcoholic steato-hepatitis (NASH) 

NASH is characterized by histopathological findings of alcohol damage on liver biopsy despite the lack of alcohol abuse. The recent increased frequency in diagnosing NASH and its potential progression to cirrhosis have led investigators in a pilot study reporting that UDCA (13–15 mg/kg per/day) but not the lipid-lowering agent clofibrate improved the biochemical profile and hepatic steatosis of patients with NASH [122]. It is imperative that further studies should follow to address this promising finding. Indeed, randomized trials of UDCA in the treatment of NASH are ongoing.

5.3.9. Alcoholic liver disease 

UDCA protected the ethanol-induced damage in a human hepatocyte cell-line [123] and in rat liver mitochondria [124]. In a placebo-controlled cross-over study of patients with alcoholic cirrhosis, UDCA (15 mg/kg per day) for 4 weeks caused improvement of liver tests in the treatment group compared to control subjects [125]. Nevertheless, randomized, controlled trials are necessary to evaluate this preliminary report.

5.3.10. Chronic viral hepatitis 

Randomized, controlled studies for therapy of chronic hepatitis C involving either UDCA monotherapy [126] or in combination with interferon [127], [128] failed to consistently demonstrate a favorable virological response or histological improvement. Therefore, UDCA can not be recommended in the therapy of chronic hepatitis C.

5.3.11. Autoimmune hepatitis 

In a randomized, placebo-controlled trial of 37 patients with problematic steroid treated type 1 autoimmune hepatitis, UDCA in addition to corticosteroid therapy fox 6 months neither affected the clinical outcome and histological activity of the disease, nor facilitated a decrease in the dose of corticosteroids used [129]. Thus, UDCA treatment of type 1 autoimmune hepatitis is not supported.

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6. Summary 

UDCA exerts its beneficial effect in liver diseases through a diverse, probably, complementary array of mechanisms. The clinical use and efficacy of UDCA in PBC have been evident. UDCA may also have a place in the management of PSC, ICP, cystic fibrosis, PFIC and GVHD involving the liver, although, more studies are needed to further determine its therapeutic potential in these diseases and in other hepatobiliary disorders such as liver allograft rejection, drug and TPN-induced cholestasis, NASH, and alcoholic liver disease.

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Acknowledgements 

We are indebted to Dr Alan Hofmann for his valuable critiques in this manuscript.

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☆ This article concerns Drugs.

PII: S0168-8278(01)00092-7

Journal of Hepatology
Volume 35, Issue 1 , Pages 134-146, July 2001

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