Ursodiol for Hepatobiliary Disorders

Pharmacology

Oral administration of ursodiol (Actigall; Summit Pharmaceuticals, Summit, New Jersey) leads to enrichment of bile in a dose-dependent manner such that, at pharmacologic doses (10 to 15 mg/kg per day), it becomes the predominant biliary bile acid. About 30% to 60% of an oral dose of ursodiol is absorbed, although the percentage absorbed decreases with increasing dose [4, 5]. The proportion of ursodiol in bile plateaus at doses exceeding 10 to 12 mg/kg per day because of epimerization to chenodeoxycholic acid and because ursodiol does not inhibit hepatic synthesis of the primary bile salts [6].

Ursodiol is absorbed along the length of the jejunum and ileum by nonionic passive diffusion and is absorbed in the ileum by active transport mechanisms [4, 7]. Colonic absorption is also substantial and may account for as much as 20% of an ingested dose [8]. Even in patients who have had ileal resections, high oral doses (4 g/d) of ursodiol can increase the biliary concentration of ursodiol tenfold [9].

Once absorbed, ursodiol is efficiently taken up by the liver with first-pass clearance of more than 60% of the absorbed dose [2]. Therefore, in the absence of cholestasis or substantial liver disease, minimal levels of ursodiol appear in plasma [10]. In the liver, ursodiol is conjugated with either glycine or taurine and is rapidly secreted into bile. Peak bile concentrations of ursodiol are seen 1 to 3 hours after an oral dose [4]. Ursodiol excreted from the biliary tract is resorbed through the enterohepatic circulation or is metabolized to insoluble bile salts that are excreted in the feces. The biological half-life of ursodiol is 3.5 to 5.8 days in humans [2]. With discontinuation of the drug, serum and bile levels decline exponentially [10]. Other medications, such as cholestyramine, colestipol, charcoal, sucralfate, and antacids may impair the absorption of ursodiol, thereby decreasing its bioavailability.

Cholesterol Gallstones

Formation of Cholesterol Gallstones

The pathogenesis of cholesterol gallstones involves the failure to maintain cholesterol in solution in the bile [11-16]. Biliary cholesterol is normally solubilized by micelles and unilamellar cholesterol-phospholipid vesicles [11-15]. A prerequisite for the formation of cholesterol gallstones is bile that is supersaturated with cholesterol. In addition to supersaturation, an excess of nucleating factors or a deficiency of antinucleating factors or both lead to nucleation of solid cholesterol crystals [11-13, 17-19]. Gallbladder mucin, free calcium ions, and gallbladder stasis may also contribute to cholesterol crystal nucleation and stone growth [11-13, 15-17].

Bile Salt Therapy for Gallstones

Cholecystectomy is the treatment of choice for patients with symptomatic gallstones. For patients at high operative risk and for patients who wish to avoid surgery for personal reasons, the most widely used of the nonsurgical treatments is the bile salt ursodiol.

Chenodiol (Chenix; Solvay Pharmaceuticals, Marietta, Georgia) was the first bile salt reported to dissolve gallstones [11, 20-22]. It was extensively evaluated in the 1970s, particularly in the National Cooperative Gallstone Study [23] in which more than 900 patients were randomly assigned to receive placebo, low-dose chenodiol (375 mg/d), or high-dose chenodiol (750 mg/d) for up to 2 years [23]. In the high-dose group, 13.5% complete dissolution was noted, less than the 20% to 40% complete dissolution other investigators [24] achieved with higher doses. The major drawbacks of chenodiol are the dose-related side effects of diarrhea and an increase in serum aminotransferase levels. Chenodiol was not widely prescribed in the United States, and with the introduction of ursodiol in the late 1980s, it is now rarely used as monotherapy.

Ursodiol has also been studied as a gallstone dissolution agent [2, 3]. Its safety and ease of administration have made ursodiol the most common therapeutic alternative to cholecystectomy [21, 22, 25]. Ursodiol is also used after shock-wave lithotripsy to dissolve residual stone fragments in the gallbladder [22, 26, 27].

Ursodiol dissolves gallstones by solubilizing cholesterol from the stone surface. Ursodiol results in the conversion of supersaturated bile to unsaturated bile [21]. This desaturation of bile enhances the transport capacity of bile for cholesterol. Ursodiol results in biliary desaturation through several mechanisms, most of which are incompletely understood [21]. Despite somewhat conflicting results, decreased intestinal absorption of cholesterol probably occurs during ursodiol administration [2, 3]. This could be related to less effective micelle formation or to less efficient intestinal absorption from liquid crystals. Ursodiol may also decrease hepatic cholesterol synthesis by decreasing the activity of 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis [21]. Lastly, there is little, if any, negative feedback inhibition of hepatic bile salt synthesis by ursodiol, such that cholesterol continues to be converted to bile salts [21, 28]. In addition to biliary desaturation, ursodiol also has the unique property of promoting the formation of a liquid crystal mesophase of phospholipid plus cholesterol [21, 29]. Such liquid crystals can form even in the presence of bile that is supersaturated with cholesterol, which probably accounts for the observation that ursodiol may dissolve gallstones in the presence of supersaturated bile.

Proper patient selection is critical for optimizing gallstone dissolution with ursodiol. As already noted, cholecystectomy is the treatment of choice for patients with symptomatic gallstones. Patients with mild or infrequent episodes of biliary pain are the most appropriate candidates for ursodiol treatment. Asymptomatic patients with gallstones are not suitable candidates for therapy [30-32]. Ursodiol should not be used in the management of patients with acute gallstone complications, such as acute cholecystitis, bile duct obstruction, cholangitis, or gallstone pancreatitis.

Candidates for ursodiol therapy must have radiolucent gallstones and a patent cystic duct [22]. Although dissolution with ursodiol may occur in patients with nonvisualization of the gallbladder as determined by oral cholecystographic techniques, such instances have involved small numbers of patients and have not clearly defined the cause for nonvisualization. Nonvisualization of the gallbladder during the course of ursodiol therapy is, however, associated with a very low dissolution rate [22].

After the initiation of ursodiol therapy in patients with gallstones, the proportion of total biliary bile salts comprised by ursodiol increases within 1 to 2 weeks from 1% to a maximum of approximately 60% [21]. Although doses as low as 3 to 5 mg/kg per day have resulted in gallstone dissolution, the optimal dose is 8 to 10 mg/kg per day. Doses exceeding 10 mg/kg per day do not result in increased dissolution rates [2, 6, 21, 33-36].

Interestingly, with ursodiol therapy, symptoms such as pain, nausea, bloating, and vomiting may improve in some patients before actual gallstone dissolution [37-41]. The decrease in symptoms may be attributed to changes in gallbladder dimensions and to a resultant decrease in the likelihood of gallstones becoming impacted in the cystic duct [42]. Ursodiol leads to a reversible, dose-dependent increase in gallbladder volume within 2 days of starting treatment [42-44]. In addition, ursodiol therapy results in a decrease in gallbladder mucin, perhaps decreasing bile viscosity and improving bile flow [45].

The overall success rate for ursodiol in dissolving gallstones up to 20 mm in diameter ranges from 30% to 50% [2, 6, 33-36]. A meta-analysis of randomized trials with ursodiol [46] found that the dissolution rate was 37% for patients treated with ursodiol at doses of more than 7 mg/kg per day or of more than 500 mg/d for at least 6 months.

The mean rate of decrease in gallstone diameter during oral bile salt therapy is 1.0 mm/mo, whereas the median rate is 0.7 mm/mo [47]. The diameter of the stones is a more important determinant of dissolution than is the number of stones; the size of the largest stone is rate-limiting [2, 6, 33-36]. In the meta-analysis by May and colleagues [46], dissolution with ursodiol was observed in 48.5% of patients with stones smaller than 10 mm and in 28.8% of those with larger stones.

Factors other than gallstone size have been shown to affect the success of dissolution therapy. Stone buoyancy on oral cholecystography is highly correlated with successful dissolution [33, 35]. About 15% of gallstones are buoyant using oral cholecystographic techniques, and dissolution rates of up to 70% have been achieved with these types of stones [36]. Only cholesterol stones are buoyant, and these stones have a substantially lower content of calcium salts than do nonfloating cholesterol stones [48, 49].

Unsuccessful dissolution may, therefore, be related to stone composition including the presence of pigment stones or cholesterol stones that, although radiolucent, contain substantial amounts of calcium salts [50-52]. Other possible reasons for failure of gallstone dissolution include patient noncompliance, inadequate dosage for biliary desaturation, inadequate entry of desaturated bile into the gallbladder, or insufficient concentration of ursodiol within the gallbladder lumen because of impaired mucosal concentrating ability.

Dissolution of gallstones must be documented by ultrasonography. No or minimal decrease in stone diameter after 6 to 12 months of therapy is a poor prognostic sign; few of these patients ever have complete dissolution of their stones. Once stones or sludge is no longer seen on ultrasonography, therapy should still be continued for another 3 months because microscopic stones or crystals may still be present even when sonogram results are normal. These microscopic stones or crystals could then serve as nidi for stone re-growth.

After successful dissolution with ursodiol, recurrence of gallstones occurs in 50% to 70% of patients after 11 years of follow-up [53, 54]. A plateau is reached in the recurrence rate after 5 to 9 years. Patients who initially have multiple gallstones have a higher recurrence rate than do those with single stones [54]. The pathophysiology of gallstone recurrence is presumed to be similar to that of de novo formation of stones, although this has not been extensively studied. Once therapy with ursodiol is discontinued, bile reverts to its previous state of supersaturation within a few weeks unless a substantial change has occurred (such as substantial weight loss) in a patient's medical condition. Supersaturation alone appears to be a necessary, but not sufficient, condition for recurrence, as shown by the finding that 30% to 50% of patients do not re-form stones despite presumably supersaturated bile.

Maintenance low-dose ursodiol therapy (300 mg/d) decreases the recurrence rate of gallstones over 9 years by about 50% when compared with no treatment [54]. Maintenance therapy with ursodiol is advisable in the elderly or those at high risk for surgery.

Ursodiol for oral dissolution of gallstones is well tolerated. Diarrhea occurs in fewer than 2% of patients, is transient, and generally resolves despite continued therapy [2, 3]. Unlike chenodiol, ursodiol does not increase levels of serum low-density lipoproteins and rarely leads to increased levels of serum aminotransferases. Stone calcification has been reported in approximately 5% to 10% of patients receiving ursodiol. It is not clear whether this calcification simply reflects the natural history of gallstone disease, because 7% of patients receiving placebo develop stone calcification during a 2-year period [23].

Although bile acids may damage the gastric mucosal barrier, they differ in their ability to injure the gastric mucosa in relation to their hydroxylation and conjugation [55]. Rather than causing symptomatic bile acid-associated gastritis, ursodiol treatment has been shown to actually decrease the symptoms associated with bile reflux gastritis in patients with [56] and without [55] previous gastric surgery.

Limited data are available about the safety of ursodiol for gallstone dissolution in pregnant patients. Although the administration of lithocholic acid has been associated with toxicity in rat embryos [57], treatment with ursodiol has not been linked with teratogenicity in laboratory animals or in humans [58, 59]. Ursodiol has not been associated with maternofetal defects even when used in patients with intrahepatic cholestasis of pregnancy [60] in whom higher systemic levels of ursodiol would be expected. At the current time, however, pregnant patients requiring medical therapy for symptomatic cholesterol gallstones should be included in ongoing studies of the maternofetal effects of this medication.

Combination therapy with ursodiol and chenodiol (usually 5 to 7.5 mg/kg per day for each drug) for patients with gallstones has been evaluated [36] based on the rationale that chenodiol forms micelles more effectively, whereas ursodiol promotes liquid crystal formation. Although combination treatment may lead to slightly more rapid dissolution in some select patients, the overall dissolution rate is the same as with ursodiol monotherapy [34-36]. Moreover, patients receiving combination therapy have substantially more diarrhea [61].

Ursodeoxycholic Acid Combined with Extracorporeal Shock-Wave Lithotripsy for Treating Gallbladder Stones

Although not approved for the treatment of gallstones in the United States, extracorporeal shock-wave lithotripsy has been used in Europe in combination with ursodiol for the treatment of symptomatic gallbladder stones in patients with a patent cystic duct [22, 27, 62]. Lithotripsy may also be useful for patients with common duct or intrahepatic stones not amenable to treatment by other methods.

Fragmentation of gallstones into smaller particles by lithotripsy increases their surface area to volume ratio, facilitating subsequent dissolution by ursodiol [26]. Single radiolucent stones smaller than 20 mm in diameter respond most favorably to this treatment. The time to achieve complete clearance of the fragments is proportional to the initial stone number and size. Approximately 50% to 70% of patients with one stone smaller than 20 mm become free of stones after 6 months [22, 60]. Transient mild biliary pain occurs in 30% to 50% of patients after lithotripsy [22, 26], and duct obstruction by stone fragments is observed infrequently [26, 27]. The recurrence rate after successful lithotripsy appears to be similar to the rate after bile salt therapy alone [22].

Microlithiasis and Pancreatitis

In addition to its utility for the treatment of gallstones, ursodiol is also effective for the treatment of acute or recurrent pancreatitis associated with biliary microlithiasis (cholesterol monohydrate crystals, calcium bilirubinate granules, and calcium carbonate microspheroliths).

Biliary sludge is the term for the radiographic appearance of microlithiasis within bile that contains high concentrations of mucus and other proteins [63]. Biliary sludge has been observed in 5% of ambulatory patients being evaluated for abdominal pain [63, 64], 30% of patients recovering from nonbiliary abdominal surgery [65], and 100% of patients receiving total parenteral nutrition for 12 weeks [66].

Biliary sludge is highly associated with the presence of gallstones and is felt to be a precursor of gallstone formation. Gallstones form in 15% of ambulatory patients with biliary sludge [63] and in 43% of patients who develop sludge using total parenteral nutrition [66]. In patients with cholesterol gallstones, 92% have cholesterol crystals in collected bile [67].

Biliary microlithiasis has been implicated as a cause of acute and recurrent pancreatitis. Microlithiasis is present in approximately 70% of patients with “idiopathic” pancreatitis but not in patients with alcohol-related pancreatitis [68, 69]. The association of microlithiasis and pancreatitis is further supported by data showing that cholecystectomy or sphincterotomy prevents recurrent attacks of biliary pain and pancreatitis in patients with microlithiasis [68].

Treatment with ursodiol (10 mg/kg per day) successfully resolves biliary microlithiasis. Ros and colleagues [68] observed complete disappearance of biliary sludge after 3 to 6 months of ursodiol therapy in 8 of 16 patients in whom biliary drainage contained microlithiasis. These investigators [68] also showed, using serial bile analysis, that ursodiol successfully eliminated microlithiasis and prevented further attacks of pancreatitis in 8 of 13 patients with idiopathic pancreatitis and microlithiasis who were followed for a mean of 44 months. Although cholecystectomy is the treatment of choice for patients with acute or recurrent pancreatitis, intact gallbladders, and the finding of biliary sludge or microlithiasis, ursodiol is an acceptable therapeutic option for patients refusing or unable to have cholecystectomy. Whether ursodiol is effective for the treatment of patients after cholecystectomy who have pancreatitis and microlithiasis or for patients with biliary-type pain of unclear origin and the finding of gallbladder sludge or microlithiasis is the source of current investigation.

Cholestatic Liver Diseases

In addition to its efficacy in dissolving cholesterol gallstones and treating biliary microlithiasis, ursodiol improves biochemical markers of cholestasis and hepatocellular damage in patients with chronic liver diseases [70]. In 1985, Leuschner and colleagues [71] serendipitously noted improvement in serum aminotransferase levels in patients with chronic active hepatitis who were receiving ursodiol for gallstone dissolution. Since that landmark observation, the efficacy of ursodiol for the treatment of chronic cholestatic liver disorders has been studied extensively, particularly for patients with primary biliary cirrhosis (Table 1). Although the pathogeneses of the cholestatic disorders are distinct, clinicopathologically they are characterized by the accumulation of potentially hepatotoxic bile acids.

Several studies [72-75] have shown that hydrophobic bile acids induce cholestasis in laboratory animals and in humans. In patients with chronic cholestatic diseases, bile acid-mediated damage to hepatocytes and biliary epithelium might perpetuate cholestasis, thereby exacerbating hepatobiliary injury, and ultimately result in fibrosis and cirrhosis. Moreover, although diseases such as primary biliary cirrhosis and primary sclerosing cholangitis probably arise from immunologically mediated bile duct injury, cholestasis itself may result in further derangement in local immune function. For example, experimental bile duct ligation in rats induces changes in cell-mediated immunity and in HLA class I antigen expression on hepatocytes [76, 77].

Ursodiol may interrupt this cycle of hepatobiliary injury Figure 2 by three main mechanisms. First, ursodiol displaces the potentially hepatotoxic bile acids from bile and serum. Second, ursodiol diminishes the toxicity and cholestasis produced by other bile acids [78-81] and limits the injury and fibrosis after experimental bile duct ligation [82]. This may be mediated by the ability of ursodiol to stabilize hepatocyte plasma cell membranes [81, 83, 84]. Third, either directly or indirectly (by reducing cholestasis), ursodiol may ameliorate the immunologic aberrations observed in patients with cholestatic disorders.

In addition to its potential effect on pathogenesis, treatment with ursodiol relieves pruritus in some patients with cholestatic liver disease. The difficulty in quantifying this subjective complaint has hindered rigorous analysis of the effect of medical therapy on pruritus. Most trials incorporate a static analog scale describing the intensity of itching for one period of time but do not account for the differential patient threshold of symptom recognition or the intermittent occurrence and varying intensity of this complaint.

The mechanism mediating pruritus in patients with cholestatic disorders has not been conclusively determined. Bile salt deposition in the skin is the most commonly invoked theory [85], although the detergent action of certain bile salts on the hepatocyte membrane may release a pruritogen [86] or endogenous opiates (which accumulate in chronic liver disease) may mediate pruritus through central mechanisms [87]. The effect of ursodiol treatment on pruritus may be explained by alterations in the bile salt profile or by modulation of hepatocyte injury (the “hepatoprotective” effect).

Primary Biliary Cirrhosis

Most of the literature evaluating the use of ursodiol for the treatment of patients with chronic cholestatic liver disease focuses on primary biliary cirrhosis, a progressive cholestatic disorder characterized by destruction of the interlobular and septal bile ducts that leads to cholestasis and cirrhosis.

The pathogenesis of primary biliary cirrhosis is incompletely understood, although considerable evidence points to an immunologic origin. Patients with primary biliary cirrhosis have numerous immunologic abnormalities, including aberrant expression of major histocompatibility antigens on hepatocytes [88], circulating autoantibodies that recognize epitopes on the inner membrane of the mitochondria, increased levels of serum IgM, and decreased suppressor T-cell function [89]. A large percentage of patients with primary biliary cirrhosis also manifest other autoimmune disorders, such as keratoconjunctivitis sicca, progressive systemic sclerosis, and autoimmune thyroiditis [89].

Whatever the inciting event, interlobular and septal bile duct injury are associated with the accumulation of potentially toxic “endogenous” bile salts in hepatocytes and serum. Not only is the concentration of biliary and serum bile acids increased in patients with primary biliary cirrhosis compared with controls, but changes also occur in the patterns of conjugation and relative proportions of the individual bile acids [90-95]. In addition, analysis of liver biopsy specimens from patients with primary biliary cirrhosis shows aberrant expression of HLA class I and II molecules on hepatocytes and biliary epithelial cells, respectively [96]. It has not been determined whether these findings relate to the primary immunologic injury of primary biliary cirrhosis or are secondary to cholestasis itself.

The search for specific therapy for patients with primary biliary cirrhosis has centered primarily on immunosuppressive agents in an attempt to blunt the immunologic attack on bile ducts [89]. Although several of these agents have been associated with some improvement in biochemical tests and even histologic results, only colchicine and, possibly, azathioprine appear to improve survival without clinically significant adverse effects [97, 98].

Three randomized, placebo-controlled trials [91, 99, 100] and several nonrandomized^studies [90, 92-95] have evaluated the efficacy of ursodiol in the treatment of primary biliary cirrhosis (Table 2). Within a few weeks of initiating therapy in patients with primary biliary cirrhosis, the serum concentration of ursodiol increases 10- to 20-fold. However, because of a compensatory decrease in endogenous bile acids, the total concentration of serum bile acids remains the same or increases modestly [90-95, 101].

Improvements in laboratory markers of cholestasis and inflammation occur in parallel with changes in biliary and serum bile acids in patients with primary biliary cirrhosis who are treated with ursodiol. The studies [91, 92, 94, 99-101] cited above consistently show that treatment leads to statistically significant improvement in levels of serum alkaline phosphatase (range, 21% to 65%), aminotransferases (range, 44% to 68%), and γ-glutamyl transpeptidase (range, 45% to 78%) when compared with pretreatment levels. Additionally, in the largest trial to date, Poupon and colleagues [99] showed substantial improvements in serum bilirubin levels and Mayo Risk scores (a validated index predictive of survival in patients with primary biliary cirrhosis), as well as serum IgM levels and anti-mitochondrial antibody titer [99].

Ursodiol treatment has also been shown to decrease hepatocyte expression of HLA class I antigens in liver biopsy specimens from patients with primary biliary cirrhosis, although this may reflect improvements in the bile acid profile rather than showing a direct immunologic effect [96, 102].

Most studies show improvement in laboratory variables within the first few months, which plateau 3 to 6 months after initiating ursodiol therapy. Several investigators [93, 101] have observed that these laboratory improvements are maintained only during active treatment, with “relapses” noted shortly after ursodiol therapy is discontinued. In patients with advanced histologic stages of primary biliary cirrhosis or whose liver disease is complicated by hyperbilirubinemia (serum bilirubin levels greater than 34.2 mmol/L [2 mg/dL]), ursodiol may be less effective in improving biochemical variables and in decreasing concentrations of endogenous serum bile acids [95, 103].

The effect of ursodiol on symptoms in patients with primary biliary cirrhosis was less consistent than its effect on laboratory chemistry results. The controlled, double-blind studies have not shown statistically significant (P < 0.05) improvements in fatigue or pruritus in the intention-to-treat cohorts [91, 99, 100]. Battezzati and colleagues [100] found a statistically significantly lower pruritus score during treatment than they found at entry in the ursodiol and the placebo groups, perhaps reflecting the natural history of pruritus in patients with primary biliary cirrhosis. In several unblinded studies [93, 95, 101], however, ursodiol treatment was, in some patients, associated with a marked improvement in pruritus and a decreased need for cholestyramine. Moreover, ursodiol was well tolerated by patients with primary biliary cirrhosis, with few reported adverse effects.

To date, no trial has had sufficient follow-up to assess the effect of ursodiol therapy on survival in patients with primary biliary cirrhosis. Therefore, there has been much interest in whether, as an interim marker of clinical efficacy, ursodiol improves histologic results. Uncontrolled studies have shown decreased portal inflammation and piecemeal necrosis in serial biopsy specimens from individual patients with noncirrhotic primary biliary cirrhosis after 1 to 2 years of ursodiol treatment [93, 104]. These results were supported by the placebo-controlled trial by Poupon and colleagues [99], although this analysis did not include the patients who withdrew from the study or those who “failed” treatment. Although sustained improvement in portal inflammation and piecemeal necrosis might stem the histologic progression to fibrosis or cirrhosis or both, only one of the uncontrolled trials [92] to date has found any improvement in established fibrosis.

A crucial, unanswered question is whether the improvements in laboratory markers and histologic results seen with ursodiol treatment in patients with primary biliary cirrhosis reflect a genuine interruption in the natural history of the disease. In fact, the effect on laboratory tests in patients with primary biliary cirrhosis may wane after the first year of treatment with ursodiol [103, 105]. Of greater concern are case reports [106] of patients with primary biliary cirrhosis whose laboratory studies and symptoms dramatically improved while on ursodiol therapy, although histologic results showed their disease deteriorated. These data, coupled with the diminished response of patients with more advanced stages of primary biliary cirrhosis, suggest that ursodiol therapy may prove to be most beneficial for patients with earlier, perhaps more reversible disease.

Primary Sclerosing Cholangitis

Ursodiol improves biochemical markers of cholestasis and hepatocellular damage in patients with primary sclerosing cholangitis, another chronic cholestatic liver disease of uncertain pathogenesis. Primary sclerosing cholangitis is characterized by chronic inflammation, fibrosis, and destruction of the large intrahepatic and extrahepatic bile ducts and may result in cirrhosis and liver failure [107].

As in primary biliary cirrhosis, immunologic factors appear to be important in the pathogenesis of primary sclerosing cholangitis [107]. Patients with symptomatic primary sclerosing cholangitis often have increased serum IgM levels and modest increases of serum antinuclear and anti-smooth muscle antibodies [108]. Other immunologic abnormalities observed in patients with primary sclerosing cholangitis include aberrant expression of HLA antigens on bile ducts and hepatocytes and changes in the circulating T-cell number and function [109-111]. Although nearly 70% of cases occur in patients with ulcerative colitis, primary sclerosing cholangitis is also associated with thyroiditis, celiac sprue, and sarcoidosis. Genetic factors also appear to be important in the pathogenesis of primary sclerosing cholangitis. Certain HLA haplotypes that are associated with other autoimmune diseases are also prevalent in patients with primary sclerosing cholangitis [112, 113].

Although the exact pathogenesis of primary sclerosing cholangitis is still unclear, the bile acid profile in patients with this disorder resembles that seen in patients with primary biliary cirrhosis. Total serum bile acids are increased more than fivefold in patients with primary biliary cirrhosis when compared with healthy controls [114]. The major serum bile acid in patients with primary sclerosing cholangitis is cholic acid, in contrast with control subjects, who have predominantly chenodeoxycholic acid [114].

The early successes of ursodiol treatment for patients with primary biliary cirrhosis and the inability to affect the natural history of primary sclerosing cholangitis with other medical therapies [115] have prompted two pilot trials [114, 116] and one randomized, double-blind, placebo-controlled trial [110] of ursodiol for patients with primary sclerosing cholangitis.

At pharmacologic doses in patients with primary sclerosing cholangitis, ursodiol comprises approximately 50% of the total serum bile acids. Whether the total serum bile acid level remains the same or increases during treatment is controversial [110, 114]. Within 6 months of initiating ursodiol treatment, decreases compared with pretreatment levels were observed in levels of serum alkaline phosphatase (range, 36% to 67%), γ-glutamyl transpeptidase (range, 53% to 64%), and aminotransferase (range, 36% to 48%) [110, 114, 116]. O'Brien and colleagues [114] noted that when ursodiol is withdrawn, the laboratory results became abnormal again. Similar to that described for patients with primary biliary cirrhosis, hepatocyte expression of HLA class I antigens decreased in serial liver biopsy specimens from two patients with primary sclerosing cholangitis who were treated with ursodiol [110].

The effect of ursodiol on symptoms in patients with primary sclerosing cholangitis has been less consistent than its effect on biochemistry results. Fatigue and pruritus have not been statistically significantly influenced by treatment; however, for some individual patients, considerable improvement in symptoms has been described [114, 116]. In fact, in the open-label trial by O'Brien and colleagues [114], fatigue, pruritus, and diarrhea worsened after withdrawal of the medication and responded again when ursodiol was restarted. Still, pruritus has been newly observed in a few patients in both arms of the randomized, double-blind controlled series [110]. Otherwise, ursodiol has been exceptionally well tolerated in patients with primary sclerosing cholangitis, with few gastrointestinal adverse effects even in those patients whose primary sclerosing cholangitis was associated with ulcerative colitis [110].

Analysis of the effect on histologic results of treatment with ursodiol in patients with primary sclerosing cholangitis has been limited by the small numbers of patients studied. Beuers and colleagues [110], however, did observe improvement in a multiparametric histologic score during ursodiol treatment, primarily because of improvements in portal and parenchymal inflammation and in necrosis. To date, no trial has had sufficient power to assess the effect of ursodiol on survival in patients with primary sclerosing cholangitis.

Cystic Fibrosis

As more patients with cystic fibrosis reach adulthood, hepatic complications of this relatively common heritable disease are being increasingly recognized. As many as 20% of adolescents with cystic fibrosis develop chronic liver disease, characterized by extrahepatic and intrahepatic ductal abnormalities and by complications of portal hypertension [117-119]. Inspissated bile may promote focal biliary fibrosis, although an aberrant immunologic response to liver membrane antigens may also contribute to the cholestatic injury in cystic fibrosis [120]. Both mechanisms may be amenable to treatment with ursodiol.

In uncontrolled studies, ursodiol has led to dose-related, reversible normalization of serum aminotransferase levels and improvement of alkaline phosphatase levels in patients with cystic fibrosis [121]. Higher doses of ursodiol (up to 20 mg/kg per day) appear to be required to improve laboratory variables and to enrich biliary bile to the same degree as in patients with primary biliary cirrhosis or primary sclerosing cholangitis [121]. The hypothesis that the mechanism of action of ursodiol in cystic fibrosis-associated cholestasis derives at least in part from its choleretic properties is supported by improvements in results from serial scintigraphic studies obtained during treatment [122].

In patients with cystic fibrosis-associated cholestasis, weight gain and increased urinary creatinine excretion have been observed during ursodiol administration, but steatorrhea has not improved [122, 123]. The effect of ursodiol therapy on symptoms or on the natural history of the chronic liver disease in patients with cystic fibrosis has not yet been described. No statistically significant adverse effects attributable to ursodiol have been reported for patients with cystic fibrosis-associated liver disease.

Intrahepatic Cholestasis of Pregnancy

Although the pathogenesis of the intrahepatic cholestasis of pregnancy is unclear, clinically this disorder is recognized by intense pruritus, usually beginning in the second half of gestation. Biochemically, it is characterized by increases in levels of serum bile acids, aminotransferases, and (in severe cases) serum bilirubin [124]. Intrahepatic cholestasis of pregnancy is associated with an increased risk of fetal demise [124]. Typically, maternal pruritus and abnormal laboratory results disappear days to weeks after delivery [124]. Affected women may have flares of pruritus with subsequent pregnancies or when taking oral contraceptives [124].

The effect of ursodiol (1 g/d) has been studied in an open-label trial in eight Chilean patients with intrahepatic cholestasis of pregnancy who remained hospitalized until delivery [60]. Statistically significant improvements were observed in an analog pruritus score and in levels of serum alanine aminotransferase. In three patients, pruritus and abnormal laboratory results recurred 2 weeks after treatment with ursodiol was discontinued and again improved when the drug was resumed. This trial was not intended to answer whether ursodiol altered the clinical outcome of intrahepatic cholestasis of pregnancy. No adverse events were detected in either the mothers or the neonates during 5 months of follow-up after delivery [60]. Importantly, all patients received ursodiol in the second half of pregnancy, after fetal organ development was complete. At the current time, ursodiol is best reserved for use in pregnant women under the auspices of approved therapeutic trials.

Graft-versus-Host Disease

The liver is often one of the principal target organs in acute and chronic graft-versus-host disease [125]. Graft-versus-host disease results when immunocompetent donor T cells recognize as foreign the histocompatibility antigens of an immunocompromised recipient. Chronic cholestasis occurs in 80% of patients with chronic graft-versus-host disease. This graft-versus-host disease-associated chronic cholestasis may be characterized by increases in levels of serum alkaline phosphatase, aminotransferase, and bilirubin and by segmental disruption of small bile ducts [125]. Fibrosis, hyalinization of portal triads, obliteration of bile ducts, and centrilobular cholestasis may occur [8], which are evident in histologic specimens. Progression of chronic hepatic graft-versus-host disease to biliary cirrhosis has been reported [129].

Although additional immunosuppressive therapy is usually effective for the treatment of graft-versus-host disease, the hepatic manifestations may lag behind those of other organs [128]. The recognition that primary biliary cirrhosis and chronic hepatic graft-versus-host disease affect small bile ducts and appear to be perpetuated by immune-mediated mechanisms prompted Fried and colleagues [129] to do a short-term, open-label study to determine the efficacy of ursodiol treatment of refractory chronic hepatic graft-versus-host disease. Thirteen patients with chronic hepatic graft-versus-host disease who were unresponsive to immunosuppressive therapy were treated for 6 weeks with 10 to 15 mg/kg per day of ursodiol [129]. Levels of alkaline phosphatase, aspartate aminotransferase, and bilirubin showed statistically significant improvement during treatment; however, the abnormal laboratory results recurred after the discontinuation of therapy. Symptom scores remained unchanged throughout, but no adverse effects attributable to therapy were noted. The study was not designed to answer whether these changes can be sustained with long-term therapy or whether ursodiol alters the natural history of chronic hepatic graft-versus-host disease.

Acute Rejection after Transplantation

The incidence of acute rejection after orthotopic liver transplantation has been reported to be between 50% and 100% [130]. Major targets of hepatic allograft rejection include the epithelial cells of the bile duct and the endothelium of hepatic arteries and veins; hepatocytes seem less vulnerable [131]. Clinically, acute rejection may manifest as various degrees of cholestatic jaundice, increased levels of serum aminotransferase, or failure of hepatic synthetic function. The development of cyclosporine has been the single most important factor in decreasing the incidence of acute rejection after orthotopic liver transplantation [132]. Treatment of acute rejection, which occurs despite cyclosporine therapy, has focused on corticosteroids, antilymphocyte preparations, and more recently, FK-506 [133].

In an attempt to exploit the choleretic and the less well-defined, immunomodulatory effects of ursodiol, this medication has been used as adjuvant treatment after orthotopic liver transplantation to decrease the frequency and severity of rejection episodes. Compared with historical controls, patients treated with ursodiol (10 mg/kg per day) started during the first postoperative week show not only improved serum liver tests but also have substantially fewer episodes of acute rejection after orthotopic liver transplantation [134, 135]. An immunomodulatory basis for this effect is supported by data suggesting that treatment with ursodiol decreases cardiac allograft survival in rats [136].

Total Parenteral Nutrition-Associated Cholestasis

Abnormal liver function test results are also a well-recognized complication in patients receiving total parenteral nutrition [137]. Although levels of serum aminotransferase may increase transiently in the first few weeks after the start of therapy, levels of alkaline phosphatase and conjugated bilirubin typically peak after 2 to 4 weeks [138]. Liver biopsy specimens from adult patients maintained on long-term total parenteral nutrition may show steatohepatitis, centrilobular fibrosis, and cholestasis, although frank cirrhosis is quite rare [139].

The pathogenesis of total parenteral nutrition-associated cholestasis is not known. It has been variably attributed to loss of enteric stimulation; bacterial overgrowth; amino acid, fatty acid, and mineral deficiencies; and bile salt toxicity [138]. Impaired bile flow during total parenteral nutrition may be relevant to the pathogenesis of cholestasis and the increased incidence of biliary sludge and cholelithiasis associated with total parenteral nutrition [66, 138]. Based on the possible pathogenic factors implicated for patients with total parenteral nutrition-associated cholestasis, several medical therapies have been tried, although no treatment is reliably effective. In a single case report, Lindor and Burnes [140] described a patient with well-documented total parenteral nutrition-associated cholestasis in whom therapy with ursodiol (600 mg/d) was associated with normalization of liver function test results and with resolution of the symptoms of pruritus and malaise. Trials evaluating the efficacy of ursodiol for patients with total parenteral nutrition-associated cholestasis are ongoing.

Chronic Active Hepatitis

As previously noted, the first report [43] of a salutary effect of ursodiol in patients with liver disease described a decrease in serum aminotransferase levels in patients with chronic active hepatitis who had gallstone dissolution. Although bile acid retention is not a feature of chronic active hepatitis, ursodiol may exert a beneficial effect in this heterogeneous group of patients by virtue of its membrane-stabilizing or immunomodulatory effects.

Ursodiol has been evaluated in two randomized, double-blind trials [141, 142] and in one dose-response study [143] in patients with chronic active hepatitis, whose liver disease in many cases was probably caused by viruses. Levels of aminotransferases and γ-glutamyl transpeptidase showed statistically significant decreases after 1 month of ursodiol treatment [141]. This benefit was even observed in patients with cirrhosis or bridging necrosis or both [142]. As has been described in the patients with cholestatic disorders, laboratory variables relapsed within 3 months after discontinuation of treatment [142]. As a result of their short duration, these studies are insufficient to assess the effect of ursodiol on the progression of symptoms, histologic results, and survival in patients with chronic active hepatitis.

Conclusion

For patients with symptoms attributable to cholesterol gallstones who are not candidates for cholecystectomy, ursodiol is a safe and relatively effective medical option that is associated with few adverse effects. Ursodiol works primarily by desaturating bile, promoting the solubilization of cholesterol from the surface of gallstones. Dissolution with ursodiol is effective for approximately 30% to 50% of stones smaller than 20 mm in diameter, with the best results for small, buoyant stones. After successful dissolution, the anticipated 50% recurrence rate can be decreased by half with low-dose maintenance ursodiol therapy.

In addition to its ability to dissolve cholesterol gallstones, ursodiol improves biochemical markers of cholestasis and inflammation in patients with various chronic liver diseases; however, most of the data are for patients with primary biliary cirrhosis. In the various disorders studied, the beneficial effect has been limited to the periods of ursodiol treatment, with “relapses” evident after the medication is discontinued. In regard to pruritus, a substantial effect of ursodiol therapy is more convincing during treatment of intrahepatic cholestasis of pregnancy than for patients with other chronic liver diseases. Ursodiol therapy has been exceedingly well tolerated, with few adverse effects reported.

The precise mechanism by which ursodiol exerts its benefit in the different liver disorders is unclear. Its proven ability to displace potentially hepatotoxic bile acids from bile and serum is probably of greatest importance in the cholestatic diseases. The relative importance of the hepatoprotective and immunomodulatory effects of ursodiol needs to be further delineated.

Although many of the data about the use of ursodiol for the treatment of the cholestatic disorders are from uncontrolled studies, they have prompted the institution of randomized, controlled trials. Future studies will determine which subsets of patients benefit most from ursodiol treatment, as well as the effect of ursodiol therapy on histologic results and, ultimately, on morbidity and mortality.