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Journal of Pediatric Gastroenterology & Nutrition:
Invited Review

Bile Acid Therapy in Pediatric Hepatobiliary Disease: The Role of Ursodeoxycholic Acid

Balistreri, William F.

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Division of Pediatric Gastroenterology and Nutrition, Children's Hospital Medical Center, Cincinnati, Ohio, U.S.A.

Received March 11, 1996; revised July 1, 1996; accepted August 13, 1996.

Address correspondence and reprint requests to Dr. W. F. Balistreri at Division of Pediatric Gastroenterology and Nutrition, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, U.S.A.

Clinicians have been frustrated by their inability to effectively treat infants and children with severe hepatobiliary disease due to biliary atresia, “neonatal hepatitis,” or various forms of intrahepatic cholestasis, including cystic fibrosis-associated liver disease. Affected patients are plagued by persistent and progressive disability, dominated by poor weight gain and intractable pruritus. Current therapeutic modalities, aimed primarily at management of these consequences of cholestasis, have no durable effect. Directed therapy to halt the progression to end-stage liver disease is not available. The major hope for high quality of life and/or long-term survival in most affected patients is liver transplantation, which, unfortunately, will not be a solution for all cases.

There is increasing evidence that bile acids might be benefit as therapeutic agents in the management of chronic cholestatic diseases. Bile acids may be orally administered in two strategic applications-displacement therapy and/or replacement therapy: (a) A nontoxic bile acid, specifically, ursodeoxycholic acid (UDCA) might be used to displace endogenous bile acids, with the desired therapeutic goal being to decrease the intrahepatic concentration of these potentially cytotoxic bile acids that accumulate in the presence of cholestasis. Altering the composition of the bile acid pool will result in amelioration of clinical symptoms and biochemical findings. (b) Primary bile acids, specifically, cholic acid (CA), might be used to replace a depleted bile acid pool that results from defective biosynthesis or defective conservation. The desired therapeutic goal is to restore the physiological function of bile acids, thereby increasing bile flow and micelle formation (1-4). We discuss the use of bile acid therapy in both of these strategic modalities, focusing on the pharmacology and physiology of UDCA.

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PHARMACOLOGY OF URSODEOXYCHOLIC ACID (UDCA)

An ancient oriental folk medicine that consisted of a powder prepared from desiccated bear bile, known by the Chinese as Yutan, was used to treat “biliary disease” (5,6). Purified UDCA was packaged with a vitamin mixture and introduced in 1957 in Japan as a therapeutic agent for liver disease of any type (5,6). The recent resurgence of interest in this compound relates to the fact that UDCA has been shown to be effective in dissolution of radiolucent gallstones and in the management of patients with chronic cholestasis. UDCA (3α, 7β-dihydroxy-5β-cholan-24-oic acid) is a naturally occurring bile acid, which normally constitutes 1 to 2% of bile acids in human bile. It is formed by 7β-epimerization of the primary bile acid, chenodeoxycholic acid (CDCA), by intestinal bacteria (7). UDCA differs from CDCA only in the orientation of the hydroxyl group at position 7 (β instead of α); this difference accounts for the marked hydrophilicity of UDCA compared to CDCA (Fig. 1).

Fig. 1
Fig. 1
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The pharmacologic properties of UDCA have been extensively studied (7-10). UDCA is a relatively weak acid (pKa ≈ 5), and unconjugated (protonated) UDCA is poorly soluble in aqueous solutions. However, solubility increases directly with the pH of the solution. Because of the insolubility of the orally administered protonated acid (as available in capsules), UDCA must be solubilized in mixed micelles present in small intestinal content in order to achieve efficient absorption (3,9,10). Therefore, in the presence of cholestasis and a relative paucity of endogenous bile acid micelles in the duodenal lumen, UDCA bioavailability is limited, absorption being inversely related to the serum bilirubin concentration. Unconjugated UDCA is absorbed by passive (nonionic) diffusion in the proximal jejunum and in the ileum, and rapidly extracted from portal venous blood by the liver and biotransformed (conjugated with glycine or taurine). Conjugated UDCA is secreted into bile, ultimately to be reabsorbed by active transport in the terminal ileum and returned to the liver. UDCA is thus an “enterohepatic” drug since its distribution is limited to the enterohepatic circulation (targeted to the intestine, portal circulation, liver, and biliary tract) (11). During continuous oral administration, UDCA accumulates in the circulating bile acid pool, with a dose-dependent enrichment of UDCA in bile (3,9,12). Plasma levels are low due to efficient hepatic clearance, and thus the plasma UDCA concentration is not a reliable marker of bioavailability. There are practical considerations in the oral administration of UDCA: (a) Because the halflife of UDCA in the portal circulation is short, maximum steady-state concentrations in liver/bile are best achieved by dividing the dose equally over 24 h. (b) Cholestyramine can be administered to patients receiving UDCA as long as intake of the two is separated in time (>5 h) (13). (c) It is difficult to alter the bitter taste of the crushed powder; incorporation into apple sauce or various flavoring agents have been tried.

UDCA was documented to be safe by in vitro and in vivo studies in humans (3,7-9,12,14). When incubated with isolated hepatocytes, UDCA is much less cytotoxic than CDCA or other dihydroxy bile acids (3,7). In view of the proven efficacy and lack of side effects, UDCA has supplanted CDCA as the drug of choice for dissolution of cholesterol gallstones. The inherent toxicity of the latter is related to the fact that CDCA undergoes bacterial conversion (7α-dehydroxylation), giving rise to the secondary bile acid-lithocholic acid (LA). The 7β-hydroxy group of UDCA is more resistant to bacterial dehydroxylation. LA, a toxic monohydroxy bile acid, can accumulate in the enterohepatic circulation to varying degrees among different species (3,9,12,15,16). Humans are capable of effectively detoxifying LA via sulfation; this precludes reabsorption and leads to fecal excretion of LA (5,17,18).

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RATIONALE FOR BILE ACID THERAPY IN LIVER DISEASE

Elucidation of the potential cellular mechanisms of bile acid-induced liver injury has allowed the development of therapeutic strategies for the treatment of cholestasis (19-40,41-62) (Table 1). The rationale for the use of UDCA in liver disease is based on the hypothesis that intracellular accumulation of toxic, endogenous bile acids leads to hepatobiliary injury (12,63-65).

Table 1
Table 1
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Bile acids, which are potentially toxic endobiotics, are predominantly excreted in bile. In the presence of obstruction, these compounds are retained in the liver cell with harmful effects on hepatic structure or function (63). Based on the observed toxicity of whole bile and specific bile acid species, hepatocellular retention of bile acids is postulated to play an important role in the initiation or perpetuation of liver injury in humans (63-65). Cellular injury is presumed to result from direct membrane damage by a detergent-like effect of the bile acid steroidal moiety (Table 1). The degree of cytotoxicity of a given bile acid is influenced by the chemical structure and the degree of hydrophobicity (66-68). Endogenous dihydroxy (CDCA) or monohydroxy (LA) bile acids are cytotoxic and cholestatic when parenterally administered to rodents, delivered to isolated perfused livers, or incubated with isolated hepatocytes (19-21,69). During chronic administration to animals, bile acids can induce bile duct injury and ductular proliferation, as well as fibrosis and cirrhosis (15). Administration of CDCA has been associated with a documented rise in aminotransferase (ALT) levels in patients who receive the drug for gallstone dissolution (70,71).

Additional nondetergent mechanisms of bile acid toxicity are postulated (41,66,67) (Table 1). For example, induction of an increase in cytosolic free calcium (Ca++) or magnesium (Mg++) may, in part, be responsible for hepatocyte injury (72,73). Typically apoptosis (programmed cell dropout associated with acidophilic bodies) is more prominent than widespread liver cell necrosis in most forms of cholestasis (66,67). Hydrophobic bile acids induce apoptosis in hepatocytes, presumably through induction of Mg++ influx, which results in stimulation of Mg++-dependent endonucleases (66). Bile acid cytotoxicity is dose-dependent-high concentrations induce cell lysis/necrosis, lower concentrations result in apoptosis (66,67). Incubation of mitochondria with hydrophobic bile acids replicates the mitochondrial dysfunction seen in cholestasis (32,37,38,73) (Fig. 2). Intrahepatocytic retention of cytotoxic hydrophobic bile acids during cholestasis is postulated to lead to mitochondrial dysfunction (39), with impairment of oxidative phosphorylation, leading to adenosine diphosphate (ATP) depletion. This is analogous to lethal cell injury of anoxia (74), in which altered membrane permeability is followed by cell injury. UDCA interrupts this process (32), due, in part, to prevention of accumulation of toxic bile acids in mitochondrial membranes (37). Bile acids that accumulate intracellularly during cholestasis may also mediate cytotoxicity via free radical generation in the hepatocyte (42).

Fig. 2
Fig. 2
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Given these postulated injurious mechanisms, there are several potential explanations for the beneficial effects of UDCA in patients with cholestasis; (a) a direct cytoprotective effect of UDCA on hepatocytes (inhibition of bile acid-induced hepatocyte injury); (b) a choleretic effect, since UDCA increases bile flow and induces efflux of hydrophobic bile acids from hepatocytes; and (c) induction of alterations in the immune system (Table 1):

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Cytoprotective/Membrane-Stabilizing Effect

Since intracellular retention of hydrophobic bile acids is thought to lead to liver cell injury, replacement of these compounds with a nontoxic hydrophilic bile acid such as UDCA should ameliorate cholestasis (14,75). This hepatoprotective effect of UDCA has been well documented (22-32,76). Continuous administration of UDCA will alter the composition and distribution of the bile acid pool (77,78). While UDCA does not suppress the synthesis of the primary bile acids, CA and CDCA (79), the fractional turnover rate of both is increased by UDCA due to decreased intestinal absorption and increased hepatic clearance of CA and CDCA (9,80). UDCA also improves hepatic bile acid excretion and reduces bile acid transit time through the liver (50). The net effect is that UDCA (mostly glyco-UDCA), becomes the major component of the bile acid pool (14). There is a reciprocal decrease in the proportion of potentially toxic, endogenous dihydroxy bile acids (81), diminishing the concentration to which liver cells are exposed (82) and thereby reducing the risk of bile acid-induced damage to liver cell membranes (83,84).

The ability of UDCA to displace the endogenous bile acid pool has been shown in several studies (9,52,77,85,86). In analysis of biliary bile acids in adults with cholestasis before and after UDCA administration (≈8 mg/kg/day), the UDCA content rose from trace amounts to become the predominant biliary bile acid (33%) (77). Enrichment of the bile acid pool with UDCA is related to the ability of UDCA to compete with endogenous bile acids for intestinal absorption, thus promoting the fecal excretion of CA and CDCA (9,52,85,87). Batta et al. noted an increase in the mean percentage of UDCA in serum from 2 to 40% after UDCA therapy (86). There was a diminution in the CDCA and CA concentrations, with an overall decrease in serum bile acid levels.

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Choleretic Effect of UDCA

In experimental models, UDCA has an inherent, potent choleretic effect. This effect, which is much more pronounced than that due to primary bile acids such as CA, has been called hypercholeresis because it cannot be accounted for solely by UDCA secretion into bile (3,7,46,47,49). This is best explained by the cholehepatic shunt hypothesis (3,7) (Fig. 3). Hypercholeresis leads to a decrease in the viscosity of bile and a decrease in the amount of sludging of bile in the biliary tree (3,8). The degree of UDCA-induced hypercholeresis in rats in linearly related to the recovery of unconjugated UDCA in bile (46,47). However, choleresis induced by cholehepatic circulation of unconjugated UDCA is unlikely to be the major mechanism of action of UDCA in patients with cholestasis, since biliary levels of unconjugated UDCA do not increase markedly during UDCA administration (77,88). Other mechanisms for UDCA-induced choleresis have been postulated, such as direct stimulation of ductular secretion through opening of membrane Cl- channels (36) or enhanced basolateral liver plasma membrane Na+, H+ exchange activity (89). UDCA also exerts a choleretic effect via a direct influence on the enterohepatic circulation of bile acids, directly increasing the intrinsic ability of hepatocytes to excrete bile acids. UDCA increases the vectorial transport of bile acids out of the liver by facilitating intracellular or canalicular flux, thus leading to a decrease in their intrahepatic concentration and limiting their toxicity. When potentially toxic bile acids are simultaneously infused with UDCA in rats, not only is the cholestasis that results from the excess bile acid load prevented, but canalicular excretion of total bile acids is greater, thus preserving bile flow and hepatocellular viability (14,24,43,90,91).

Fig. 3
Fig. 3
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EFFECT OF UDCA IN PATIENTS WITH CHOLESTASIS

The initial suggestion that UDCA may be of benefit in patients with liver disease was based on the serendipitous observation that in patients with gallstones who had “co-existing liver disease” (chronic hepatitis), biochemical improvement was noted during UDCA therapy (92). Since this observation, there have been multiple reports of the successful utilization of UDCA to treat a variety of cholestatic diseases (Table 2), leading to an improvement in biochemical values and, most dramatically, an amelioration of clinical symptoms such as pruritus.

Table 2
Table 2
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It is unclear why patients with cholestasis experience pruritus (96). The most commonly cited mechanism is local irritation due to bile acid deposition in the skin (97). However, this has not been proven (98). Bile acids, perhaps through a detergent effect, may release endogenous pruritogens. Alternatively, endogenous opiates, which are retained in the presence of cholestasis, may mediate the sensation of itch through central mechanisms (96,99,100). The beneficial effect of UDCA in the treatment of pruritus may be related to (a) the relative changes in the bile acid profile; (b) stabilization of hepatocellular membranes; or (c) induction of choleresis with “flushing” of the pruritogen.

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Primary Biliary Cirrhosis

The effect of UDCA has been most extensively studied in patients with primary biliary cirrhosis (PBC), a chronic cholestatic disease characterized by portal inflammation and necrosis of biliary cells in the small and medium size ducts (101-109). In this disorder, UDCA reduces the degree of cholestasis and may alter the basic defect in immune regulation. In a multicenter, double-blind controlled trial of UDCA (13-15 mg/kg/day), immunologic features of PBC improved markedly, with fewer treatment failures (defined as an increase in bilirubin and onset of complications) in UDCA recipients versus placebo recipients (8 vs. 18%) (104). The improvement in liver biochemistries directly correlated with the degree of enrichment of biliary bile acids with UDCA (103). In a 2-year multicenter double-blind controlled trial in which 145 patients with PBC were randomly assigned to receive UDCA (15 mg/kg/day) or placebo, disease progression was significantly less frequent in the UDCA recipients (p < 0.002) (105). Lindor et al. have recently demonstrated a survival benefit in PBC patients treated with UDCA compared to a control group (110).

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Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC), a chronic inflammatory fibrosing disease of the intra and/or extrahepatic bile ducts, is another form of prolonged progressive cholestasis highlighted by pruritus and fatigue. The goals of UDCA therapy are to retard the progression and improve the quality of life. Initial studies of patients with PSC noted an improvement in clinical symptoms and reduction in enzyme levels, with worsening after withdrawal of UDCA therapy (111-114). Chazouilleres et al., in an uncontrolled trial of 15 PSC patients treated with UDCA (750-1,250 mg/day for 6 months), noted a decrease in the degree of pruritus and a lowering of alkaline phosphatase, ALT, and gamma-glutamyltransferase (GGT) levels (113). O'Brien et al., in a 30-month, open-label, pilot trial of 12 patients given UDCA (10 mg/kg/day), noted a decrease in the degree of fatigue and pruritus and a lowering of serum ALT and cholesterol (114). There was relapse with interruption of the drug in 2 patients and continued improvement after 2 years in 10 patients. While the use of UDCA in PSC appears promising, controlled trials are needed.

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Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy is characterized by intense generalized pruritus, usually beginning late in gestation and is associated with increased levels of serum bile acids (115,116). UDCA appears to have a beneficial effect (116,117). In an open-label trial of eight patients, Palma et al. demonstrated that UDCA therapy (1.0 g/day), begun after the 25th week of pregnancy, resulted in a significant improvement in pruritus and serum ALT levels (116). There were no adverse effects detected in the mother or their newborns.

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Graft versus Host Disease

Chronic cholestasis occurs in the majority of patients with chronic graft versus host disease (GVHD). There are biochemical, clinical, and histological similarities between GVHD and PBC. Therefore, the efficacy of UDCA was tested in the therapy of GVHD of the liver by Fried et al. in a short-term, open-label study of UDCA (10-15 mg/kg/day) for 6 weeks (118). ALT values improved, but the biochemical abnormalities returned after discontinuation of UDCA.

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Veno-occlusive Disease

Essell et al. explored the use of prophylactic UDCA to decrease the incidence and severity of veno-occlusive disease (VOD) of the liver after allogeneic bone marrow transplantation in 22 consecutive patients (119). Compared to a “historical control group,” there was a reduction in the incidence of VOD (9 vs. 64%; p < 0.001), in maximum bilirubin levels (2.4 vs. 5.1 mg/dl), and in percent mortality due to VOD (4.5 vs. 21.4%). Further studies are needed.

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Orthotopic Liver Transplantation (OLT)

UDCA has been used as adjuvant treatment after orthotopic liver transplantation (OLT) in hopes of decreasing the frequency and severity of rejection episodes (8,120-122), based on the cytoprotective and presumed immunomodulatory (123) effects of UDCA. Friman indicated that UDCA (10 mg/kg/day) begun during the first postoperative week, was associated with improved liver tests and fewer episodes of rejection (120). Other studies have not confirmed this salutary effect (122). A preliminary report suggested that early initiation of UDCA after hepatic artery thrombosis following OLT may prevent the hepatotoxic effect of bile acid retention (124); this must be confirmed.

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Chronic Hepatitis

UDCA has been used as an adjunct to standard therapy in patients with either autoimmune (125-130) or chronic viral hepatitis (131,132). In patients with chronic liver disease caused by hepatitis C virus infection, the addition of UDCA to interferon (IFN) therapy significantly prolonged the period for which serum ALT values remain within the normal range after discontinuation of IFN (131,132). Further studies must determine whether UDCA has any potential for long-term amelioration of the histological severity of either form of chronic hepatitis.

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Benign Recurrent Intrahepatic Cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by the abrupt onset of severe cholestasis, which spontaneously subsides after several weeks in otherwise healthy subjects. These recurrent attacks have been attributed to unknown factors impairing bile acid transport at the canalicular level in genetically susceptible subjects (133). UDCA apparently is not effective in preventing these acute episodes of cholestasis (134,135).

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UDCA IN PEDIATRIC HEPATOBILIARY DISEASE

Preliminary reports have indicated the potential for UDCA therapy in various forms of chronic cholestasis in children (1,2,95,136-156) (Table 3).

Table 3
Table 3
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Cystic Fibrosis

Attendant to the advanced age of survival of patients with cystic fibrosis (CF), hepatobiliary disease has become more prevalent and has become a limiting factor in long-term survival (157). At present, 5 to 10% of adolescents or young adults with CF will develop multilobular biliary cirrhosis. Hepatobiliary disease in patients with CF has been attributed to obstruction of small bile ductules with inspissated granular material presumably leading to ductular proliferation. A perpetuating effect may be the accumulation of potentially toxic endogenous bile acids.

In patients with CF, the administration of UDCA should decrease bile viscosity, improve biliary drainage, and displace cytotoxic bile acids (157). A series of uncontrolled studies have reported the positive effects of UDCA in patients with CF-associated liver disease; there is consistent and sustained improvement in biochemical indices related to cytolysis and cholestasis (136-142). Three controlled trials have confirmed the beneficial effects of UDCA; administration of this drug has been reported to reduce cholestasis and improve the nutritional status of patients with CF (143-145). One study showed scintigraphic documentation of an improvement in bile flow associated with UDCA therapy; this correlated well with the beneficial effect of UDCA on liver function and bile acid metabolism (141). During UDCA administration, bile enrichment was achieved; the mean UDCA percent composition increased from 6 to 36%. The optimal daily dose of UDCA is 20 to 30 mg/kg body weight, which is higher than that used in the treatment of adults with cholestatic disease; this is probably due to poor intestinal absorption of UDCA in CF patients (88,140). Despite the fact that UDCA is known to form micelles less efficiently than primary bile acids, the coefficient of fat absorption increased in some of the patients along with an improvement in growth rate (136,141,145). Absorption of vitamin E may also improve (158). This needs further evaluation, since improved nutritional status was not universal (159).

These data suggest that UDCA treatment is safe and effective in CF patients with mild to moderate liver disease; however, it may not be effective once cirrhosis is present (142). We believe that UDCA therapy should be instituted in all patients with documented CF-associated hepatobiliary disease. A long-term controlled trial is needed to establish whether UDCA therapy is of value of preventing CF-associated liver disease in patients at high risk or in forestalling the progression to cirrhosis.

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Inborn Errors of Bile Acid Biosynthesis

A novel category of metabolic disease, manifest as intrahepatic cholestasis and associated with specific enzymatic defects (Fig. 4) in the conversion of cholesterol to the primary bile acids, has been defined (160). Delineation of these disorders has been possible through application of recent technological advances, specifically fast-atom bombardment-mass spectrometry (FAB-MS), to screening of urine samples (160-163). Three distinct primary inborn errors in bile acid synthesis, each associated with varying degrees of cholestasis that may progress to end-stage liver disease, have been recognized: (a) Δ4-3-oxosteroid 5β reductase deficiency (162); (b) 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD) deficiency (163), and (c) 24,25-dihydroxy-cholanoic cleavage enzyme deficiency (94). In these inherited defects, primary bile acid synthesis is absent or markedly impaired. The bile acid profiles of the urine, serum, and bile from affected patients are characterized by the predominance of atypical bile acids retaining the structure of the steroid nucleus characteristic of the substrates for the inactive or deficient enzyme (160-162). In the presence of defective biosynthesis is contraction of the bile acid pool size, impaired bile flow, and intracellular accumulation of potentially hepatotoxic bile acids. Cholestasis and liver injury in affected patients is therefore speculated to be due to (a) failure to synthesize adequate amounts of the normal trophic or choleretic primary bile acids essential for the secretion of bile and/or (b) increased production of unusual, primitive bile acid metabolites (monohydroxy compounds) that have the potential to damage hepatocytes. In patients with inborn errors of bile acid biosynthesis, UDCA has been used to displace toxic bile acids and improve bile flow; primary bile acids have been co-administered as replacement therapy (160). Early detection is imperative.

Fig. 4
Fig. 4
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Δ4-3-Oxosteroid 5β-Reductase Deficiency

Δ4-3-Oxosteroid 5β-reductase deficiency was first discovered in male twins born with marked cholestasis and a severe coagulopathy; a previous male sibling with “neonatal hepatitis” died of liver failure at age 4 months (162). Initial screening using FAB-MS and detailed analysis of urine from both infants indicated the presence of elevated amounts of taurine conjugates of hydroxy-oxo-cholenoic and dihydroxy-oxo-cholenoic acids. Gallbladder bile contained only trace amounts (<2 μmol/L) of bile acids. Δ4-3-Oxo bile acids represented the major urinary bile acids. Urinary excretion was the major route for bile acid loss; estimates from daily calculated urinary output indicated markedly reduced total bile acid synthesis rates (<3 mg/day). These biochemical findings indicated a defect in bile acid synthesis affecting the conversion of the 3-oxo-Δ4 intermediates to the corresponding 3α-hydroxy-5β(H)-structures, a reaction catalyzed by an NADPH-dependent Δ4-3-oxosteroid-5β reductase. Cholestasis and liver injury were presumed to result from the lack of synthesis of adequate amounts of primary bile acids combined with accumulation of Δ4-3-oxo- and allobile acids. The latter compounds are not transported by canalicular transporters and are presumed to be hepatotoxic (164). In the face of severe hepatic dysfunction, we administered a combination of UDCA and CA (100 mg/day of each bile acid) orally in solution. Complete suppression of Δ4-3-oxo- and allobile acids occurred, and normalization of liver tests, hepatic histology, and bile canalicular morphology were noted during bile acid therapy (160,165). These infants and a similarly affected younger sibling, whose treatment was initiated at age 6 days, continue to grow and thrive at age 8 and 4 years, respectively.

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3β-Hydroxysteroid Dehydrogenase/Isomerase (3β-HSD) Deficiency

3β-Hydroxysteroid dehydrogenase/isomerase was first recognized in a Saudi Arabian infant who was the third child of five to have been affected by progressive liver disease (163). The lack of primary bile acid synthesis was due to the failure to convert 7α-hydroxy-cholesterol into 7α-hydroxy-4-cholesten-3-one, a reaction catalyzed by microsomal 3β-HSD. In patients with this enzyme defect, the levels of primary bile acids in serum, bile, and urine are low, and there are high concentrations of 3β, 7α-dihydroxy-5-cholenoic and 3β, 7α, 12α-trihydroxy-5-cholenoic acids in the urine and serum (160,161). The liver disease presumably results from the accumulation of these atypical bile acids, perhaps exacerbated by the lack of primary bile acids. The clinical presentation in the reported cases has been variable, ranging from familial cholestasis to a chronic hepatitis pattern (160,161,163). This disorder of bile acid synthesis should be strongly suspected when idiopathic cholestatic liver disease with clinical features akin to Byler disease is associated with a normal serum GGT level, a normal serum bile acid concentration measured by usual methods, and an absence of pruritus (151,160). In a series of 30 children with progressive intrahepatic cholestasis, 17% were found to have 3β-HSD deficiency, suggesting that the disorder may be more common than previously believed (151). In patients with 3β-HSD deficiency there is a return to normal liver function during UDCA therapy (151,160,161).

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Intrahepatic Cholestasis

In preliminary uncontrolled studies, the effect of UDCA in patients with chronic intrahepatic cholestasis was highly encouraging; UDCA therapy improved liver function tests, relieved otherwise refractory pruritus, and raised the quality of life (1,2). A beneficial response was not universal. In our experience, to achieve desired endpoints it was necessary to administer larger doses of UDCA (up to 45 mg/kg/day in divided doses). In addition, persistence with UDCA therapy may be required since early in the course of therapy many patients will experience exacerbated pruritus.

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Alagille Syndrome

In our pilot study of 31 patients with Alagille syndrome, 15 had a beneficial clinical response after 1 month of UDCA therapy (15-30 mg/kg/day), as documented by a decrease in the degree of pruritus (1,146,166). For the 16 nonresponsive patients, the UDCA dose was increased (up to 45 mg/kg/day), and pruritus was ameliorated in an additional 11. Five patients were nonresponsive to high-dose UDCA therapy; in 3 of these nonresponsive patients, partial external biliary diversion, combined with UDCA therapy, was effective in relieving the pruritus. In general, the responsive patients in each group were older (mean age 10.1 years) than the nonresponsive patients (mean age 3.5 years) (1,146,166). The hepatocytoprotective and choleretic effects were demonstrated by almost uniform decrease in serum ALT and bilirubin levels (1,2). UDCA was effective in significantly decreasing the markedly elevated serum cholesterol levels, from a baseline mean of >600 mg/dl to <390) (1,146,166). UDCA was well tolerated by most patients and readily accepted by parents in view of the relief of symptoms and the ability of the child to have restful nights. Levy et al. also noted a beneficial effect of UDCA in a patient with Alagille Syndrome: decrease in serum cholesterol, triglyceride, and phospholipid levels (149). Krawinkel et al. noted a decrease in the degree of pruritus, as well as the serum bilirubin, alkaline phosphatase, ALT, and serum cholesterol levels in a patient with Alagille Syndrome during UDCA administration (15 mg/kg/day). There was complete disappearance of cutaneous xanthomas; however, UDCA did not forestall the progression of the liver disease (150).

Controlled trials are needed to truly define the role in UDCA in Alagille Syndrome. However, in view of the beneficial effect noted in preliminary studies, we believe that UDCA should be the drug of choice for pruritus and hypercholesterolemia (1,146,166). No data applies to whether UDCA will prevent progression of the disease or affect other complications, such as poor growth. There is no data regarding the correlation of the successful achievement of these endpoints with the degree of enrichment of bile with UDCA.

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Progressive Familial Intrahepatic Cholestasis (PFIC) or Byler Disease

Patients with progressive familial intrahepatic cholestasis (PFIC) have a high rate of progression to cirrhosis and end-stage liver disease. Therapeutic efforts have been aimed at relieving symptoms and retarding the rate of decompensation. The rationale for UDCA therapy was based, in part, on data that suggested the existence of a defect in canalicular transport of bile acids in patients with PFIC. There is a distinct compartmentalization of individual bile acids in affected subjects; the biliary bile acid concentrations are low and CA predominates. However, CDCA predominates in serum, suggesting altered canalicular excretion (167,168). In addition, there is substantial phenotypic overlap with 3β-HSD deficiency, in which UDCA therapy is effective (151,152,160). In our pilot study of 27 patients with PFIC, 23 noted an improvement in the degree of pruritus after administration of UDCA at the initial dose of 15 mg/kg/day (1,146,166). For the four nonresponsive patients, the dose was increased or combined with partial external biliary diversion (1,2,166); this was effective in reducing the degree of pruritus in two of the refractory patients. There was a decline in biochemical indices of liver injury during UDCA therapy. Jacquemin et al. have recently confirmed these findings in a study of 39 children with PFIC treated with UDCA (20-30 mg/kg/day) (152). Controlled trials are needed to determine the long-term effects of UDCA on symptoms and disease progression.

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Biliary Atresia

Similar to PBC and PSC, biliary atresia is a common disorder of unknown etiology in which a persistent necroinflammatory process leads to fibro-obliteration of the extrahepatic bile ducts; intrahepatic bile ducts are also affected (169). There have been several uncontrolled studies of the utility of UDCA therapy in patients with biliary atresia. This drug was a logical choice to retard the rate of progression to endstage liver disease in view of the demonstrated value of the drug in analogous experimental situations: (a) UDCA limits the severity of liver disease after bile duct ligation in the rat (170,171) and (b) UDCA has been shown to exert immunosuppressive effects (60). Because immunologic mechanisms have been invoked in the perpetuation of progressive biliary tract disease in biliary atresia, UDCA could potentially reverse immune-mediated bile duct obliteration.

Ullrich et al. administered UDCA to two children with biliary atresia whose growth arrest had occurred despite maximization of calories with nasogastric feedings and supplementation with medium-chain triglycerides (153). UDCA therapy (17 mg/kg/day orally at bedtime) was associated with an increase in weight and in length; in one of the children there was a trend toward a decrease in the indices of hepatobiliary dysfunction. Nittono et al. administered UDCA (10-15 mg/kg/day) to six patients with biliary atresia; four had a decrease in serum bilirubin and bile acids and two did not respond (154).

In our prospective evaluation of patients with biliary atresia, UDCA was given promptly after the diagnosis was made and the hepatoportoenterostomy was completed (155). Biliary enrichment with UDCA, measured at 1 month, was significantly higher (p < 0.05) in the UDCA recipients (mean 16.4%; range 9.6 to 21.9%) compared to the placebo group (3.8%; range 0.9 to 4.9%) (1,2,146,155). There were significant reductions in the serum biochemical values in UDCA recipients compared to placebo recipients. There was a decrease in the degree of pruritus in the UDCA recipients, and an increase was noted in several patients after discontinuation. We also noted a decrease in the intensity of pruritus in several placebo recipients after transition to UDCA. Despite biochemical and clinical improvement, most of the patients exhibited progressive liver disease. There were no observed differences in survival or the need for liver transplantation between the two groups. However, the clinical condition at time of transplant was significantly different in UDCA recipients; the mean age and weight at transplantation for UDCA recipients was 14.3 months and 7.2 kg, compared to 11.1 months and 6.4 kg for placebo recipients (1,2,146,155).

Although UDCA therapy (in a dose range of 15-30 mg/kg/day) may be associated with improvement of biochemical and clinical parameters in patients with biliary atresia, it does not appear to alter the eventual outcome of the disease. The lack of effect of UDCA in patients with biliary atresia may be related to low levels of biliary UDCA enrichment and/or failure of the hepatoportoenterostomy to establish adequate bile flow. In our study, we were unable to halt disease progression in those patients with scanty bile output. In addition, cirrhosis was already established by age 4 months in many patients. The importance of these factors is suggested by the rapid rate of progression: 50% of the patients in each group (UDCA or placebo) required liver transplantation before the first year of life.

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TPN-Associated Cholestasis

The pathogenesis of total parenteral nutrition-associated cholestasis (TPN-AC) is not known. However, the clinical setting that places patients at greatest risk is well defined and includes low birth weight, absence of oral intake, and gut damage (166,172). UDCA might benefit patients at risk for TPN-AC; this compound could theoretically improve bile flow (7,172) and protect liver cells against toxic injury (22-26,173). UDCA might modify gut-derived endotoxemia, a postulated pathogenetic mechanism (174).

There have been no controlled trials of UDCA in the treatment of TPN-AC. Lindor and Burnes noted a biochemical and clinical improvement in an adult with TPN-AC following the initiation of UDCA (600 mg/day) (175). Beau et al. carried out a prospective study to determine the effects of short-term UDCA administration in nine adults treated with long-term TPN (176). UDCA (≈11 mg/kg/day) induced a significant reduction in GGT and ALT from baseline values, but with no significant change in alkaline phosphatase or bilirubin levels. There are two preliminary studies: (a) Kowalski et al. suggested that administration of UDCA significantly reduced biochemical markers of cholestasis in adult patients receiving long-term TPN (177); and (b) Cocjin et al. reported results regarding the use of UDCA in an attempt to alter the course of TPN-associated cholestasis in neonates (156). Further studies are needed. However, a major limitation to the use of oral UDCA in patients at risk for TPN-AC is the poor degree of biliary enrichment attained in low-birth-weight infants or in patients with reduced intestinal length (178). Parenteral administration of UDCA or enteral infusion of a solution of NaUDCA might seem to be logical solutions (178,179), but the safety and efficacy of these alternatives have not been determined.

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FUTURE

Since clinical responsiveness appears to correlate with the relative percent of UDCA in bile, methods to further enhance the degree of enrichment and bioavailability of the drug may be beneficial (180-182). This has been attempted via administration of UDCA in a solution of bicarbonate to raise the pH (1,146,155). Based on the inverse relationship between bile acid toxicity and hydrophilicity of the molecule, it is possible that bile acids which are even more hydrophilic than unconjugated UDCA (e.g., tauro-UDCA) will have greater therapeutic effects (183,184).

Since submission of this manuscript, two studies have addressed the role of UDCA in TPNAC. Duerksen, et al. (Gastroenterology 111:1111, 1996) have shown that intravenous UDCA improves bile flow and reduces serum bilirubin levels in the piglet with TPN-induced cholestasis. In a clinical study, Spagnuolo, et al. (Gastroenterology 111:716, 1996) reported that seven children undergoing long-term TPN because of intractable diarrhea syndrome developed cholestasis which was effectively treated with UDCA. In addition, Kardorff, et al. (Klin-padiat 208:118, 1996) reported the beneficial effects of UDCA in 20 children with a wide variety of cholestatic disorders.

Acknowledgment: This work was supported by FD-R-000357. For original studies, UDCA was supplied by the Falk Foundation, Freiburg, Germany. The author thanks the numerous clinicians and investigators who collaborated in these studies.

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REFERENCES

1. Balistreri WF, A-Kader HH, Setchell KDR and the Ursodeoxycholic Acid Study Group. Ursodeoxycholic acid therapy in pediatric patients with chronic cholestasis. In: Lentze M, Reichen J, eds. Paediatric cholestasis: novel approaches to treatment. Lancaster, England: Kluwer Academic Press, 1997:333-44.

2. Balistreri WF, A-Kader HH, Ryckman FC, Whitington PF, Heubi JE, Setchell KDR. Biochemical and clinical response to ursodeoxycholic acid administration in pediatric patients with chronic cholestasis. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids as therapeutic agents. Lancaster, England: Kluwer Academic Publishers, 1991:323-33.

3. Hofmann AF. Targeting drugs to the enterohepatic circulation: lessons from bile acids and other endobiotics. J Controlled Release 1985;2:3-11.

4. Balistreri WF. Fetal and neonatal bile acid synthesis and metabolism-clinical implications. J Inherit Metab Dis 1991;14:459-77.

5. Bachrach WH, Hofmann AF. Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Dig Dis Sci 1982;24:737-61; 833-56.

6. Ichida F. Clinical experience with ursodeoxycholic acid (S-urso) for chronic hepatitis. Diagn Treat 1961;36:388.

7. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol 1994;29 (suppl): S1-15.

8. Rubin RA, Kowalski TE, Khandelwal M, Malet PF. Ursodiol for hepatobiliary disorders. Ann Intern Med 1994;121:207-18.

9. Aldini R, Montagnani M, Roda A, Hrelia S, Biagi PL, Roda E. Intestinal absorption of bile acids in the rabbit: different transport rates in jejunum and ileum. Gastroenterology 1996;110:459-68.

10. Bouscarel B, Nussbaum R, Dubner H, Fromm H. The role of sodium in the uptake of ursodeoxycholic acid in isolated hamster hepatocytes. Hepatology 1995;21:145-54.

11. Parquet M, Metman EH, Raizman A, Rambaud JC, Berthaux N, Infante R. Bioavailability, gastrointestinal transit, solubilization and faecal excretion of ursodeoxycholic acid in man. Eur J Clin Invest 1985;15:171-8.

12. Tint GS, Salen G, Shefer S. Effect of ursodeoxycholic acid and chenodeoxycholic acid on cholesterol and bile acid metabolism. Gastroenterology 1986;91:1007-18.

13. Taha AS, Allison MC, Myara A, Trivin F, Duncan A, Russell RI. Does cholestyramine reduce the efficacy of ursodeoxycholic acid in primary biliary cirrhosis? Eur J Gastroenterol Hepatol 1994;6:535-8.

14. Schlomerich J, Becher MS, Schmidt K, et al. Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties-studies on isolated hepatocytes and lipid membrane vesicles. Hepatology 1984;4:661-6.

15. Palmer RH. Bile acids, liver injury, and liver disease. Arch Intern Med 1972;130:606-17.

16. Cohen BI, Hofmann AF, Mosbach EH, et al. Differing effects of nor-ursodeoxycholic or ursodeoxycholic acid on hepatic histology and bile acid metabolism in the rabbit. Gastroenterology 1986;91:189-97.

17. Cowen AC, Korman MG, Hofmann AF, Cass OW, Coffin SB. Metabolism of lithocholate in healthy man. Gastroenterology 1975;69:62-76.

18. Hirano S, Masuda N, Oda H. In vitro transformation of chenodeoxycholic acid and ursodeoxycholic acid by human intestinal flora, with particular reference to the natural conversion between the two bile acids. J Lipid Res 1981;22:735-43.

19. Heuman DM. Hepatoprotective properties of ursodeoxycholic acid [Editorial; Comment]. Gastroenterology 1993;104:1865-70.

20. Alvaro D, Benedetti A, Gigliozzi A, et al. Functional and ultrastructural features of ethanol/bile salts interaction in the isolated perfused rat liver. Hepatology 1995;21:1120-9.

21. Hertel M, Harvey RC, Swanson PE, et al. Evidence of preservation injury to bile ducts by bile salts in the pig and its prevention by infusions of hydrophilic bile salts. Hepatology 1995;21:1130-7.

22. Heuman DM, Bajaj R. Ursodeoxycholate conjugates protect against disruption of cholesterol-rich membranes by bile salts. Gastroenterology 1994;106:1333-41.

23. Guldutuna S, Zimmer G, Imhof M, Bhatti S, You T, Leuschner U. Molecular aspects of membrane stabilization by ursodeoxycholate. Gastroenterology 1993;104:1736-44.

24. Kitani K, Kanai S. Tauroursodeoxycholate prevents taurocholate induced cholestasis. Life Sci 1982;30:515-23.

25. Sagawa H, Tazuma S, Kajiyama G. Protection against hydrophobic bile salt-induced cell membrane damage by liposomes and hydrophilic bile salts. Am J Physiol 1993;264:G835-9.

26. Tsukahara K, Kanai S, Ohta M, Kitani K. Taurine conjugate of ursodeoxycholate plays a major role in the hepatoprotective effect against cholestasis induced by taurochenodeoxycholate in rats. Liver 1993;13:262-9.

27. Queneau PE, Montet JC. Hepatoprotection by hydrophilic bile salts. J Hepatol 1994;21:260-8.

28. Galle PR, Theilmann L, Radesch R, Otto G, Stiehl A. Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology 1990;12:486-91.

29. Heuman DM, Pandak WM, Hylemon PB, Vlahcevic ZR. Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts: in vitro studies in rat hepatocytes and human erythrocytes. Hepatology 1991;14:920-6.

30. Lim AG, Ahmed HA, Jazrawi RP, Northfield TC. The effect of ursodeoxycholic acid and chenodeoxycholic acid on human hepatocyte and erythrocyte membranes Gut 1993;34:45.

31. Arrese M, Pizarro, Solis N, Koenig C, Accatino L. Enhanced biliary excretion of canalicular membrane enzymes in ethynylestradiol-induced cholestasis-Effects of ursodeoxycholic acid administration. Biochem Pharmacol 1995;50:1223-32.

32. Botla R, Spivey JR, Aguilar H, Bronk SF, Gores FJ. Ursodeoxycholate inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection. J Pharmacol Exp Ther 1995;272:930-8.

33. Beuers U, Nathanson MH, Boyer JL. Effect of tauroursodeoxycholic acid on cytosolic Ca2 + signals in isolated rat hepatocytes. Gastroenterology 1993;104:604-12.

34. Beuers U, Nathanson MH, Isales CM, Boyle JL. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J Clin Invest 1993;92:2984-93.

35. Bouscarel B, Fromm H, Nussbaum R. Ursodeoxycholic acid mobilizes intracellular calcium and activates phosphorylase A in isolated hepatocytes. Am J Physiol 1993;264:G243-G51.

36. Shimokura GH, McGill JM, Schlenker T, Fitz JG. Ursodeoxycholate increases cytosolic calcium concentration and activates C1- currents in a biliary cell line. Gastroenterology 1995;109:965-72.

37. Krahenbuhl S, Fischer S, Talos C, Reichen J. Ursodeoxycholate protects oxidative mitochondrial metabolism from bile acid toxicity: dose-response study in isolated rat liver mitochondria. Hepatology 1994;20:1595-1601.

38. Krahenbuhl S, Talos C, Fischer S, Reichen J. Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 1994;19:471-9.

39. Krahenbuhl S, Talos C, Lauterburg BH, Reichen J. Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats. Hepatology 1995;22:607-12.

40. Sokol RJ, Devereaux M, Khandwala R, O'Brien K. Evidence for involvement of oxygen free radicals in bile acid toxicity to isolated rat hepatocytes. Hepatology 1993;17:869-81.

41. Sokol RJ, Devereaux M, Mierau GW, Hambidge KM, Shikes RH. Oxidant injury to hepatic mitochondrial lipids in rats with dictary copper overload. Gastroenterology 1990;99:1061-71.

42. Sokol RJ, Winklhofer-Roob BM, Devereaux MW, McKim JM Jr. Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids. Gastroenterology 1995;109:1249-56.

43. Kitani K, Kanai S. Interactions between different bile salts in the biliary excretion of the rat. Chem Path Pharm 1983;39:139-52.

44. Poupon R, Poupon RE. Mechanisms of action of ursodeoxycholic acid in cholestasis. In: van Berge Henegowen GP, van Hoek B, de Groote J, Matern S, Stockbrugger RW, eds. Cholestatic liver diseases: new strategies for prevention and treatment of hepatobiliary and cholestatic liver diseases (Falk Symposium 75). London: Kluwer Academic Press, 1994:211-17.

45. Bouscarel B, Gettys TW, Fromm H, Dubner H. Ursodeoxycholic acid inhibits glucagon-induced cAMP formation in hamster hepatocytes: a role for PKC. Am J Physiol 1995;268:G300-10.

46. Dumont M, Erlinger S, Uchman S. Hypercholeresis induced by ursodeoxycholic acid and ketolithocholic acid in the rat: possible role of bicarbonate transport. Gastroenterology 1980;79:82-9.

47. Yoon YB, Hagey LR, Hofmann AF, Gurantz D, Michelotti EL, Steinbach JH. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on billiary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology 1986;90:837-52.

48. Alvaro D, Mennone A, Boyer JL. Effect of ursodeoxycholic acid on intracellular pH regulation in isolated rat bile duct epithelial cells. Am J Physiol 1993;265:G783-G971.

49. Elsing C, Sagessar H, Reichen J. Ursodeoxycholate-induced hypercholeresis in cirrhotic rats: further evidence for cholehepatic shunting. Hepatology 1994;20:1048-54.

50. Jazrawi RP, De Caestecker JS, Goggin PM, et al. Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid. Gastroenterology 1994;106:134-42.

51. Verkade HJ, Vonk RJ, Kuipers F. New insights into the mechanism of bile acid-induced biliary lipid secretion. Hepatology 1995;21:1174-88.

52. Stiehl A, Radesch R, Rudolph G. Acute effects of ursodeoxycholic and chenodeoxycholic acid on the small intestinal absorption of bile acids. Gastroenterology 1990;98:424-8.

53. Ohiwa T, Katagiri K, Hoshino M, Hayakawa T, Nakai T. Tauroursodeoxycholate and tauro-β-muricholate exert cytoprotection by reducing intrahepatic taurochenodeoxycholate content. Hepatology 1993;17:470-6.

54. Haussinger D, Saha N, Hallbrucker C, Lang F, Gerok W. Involvement of microtubles in the swelling-induced stimulation of transcellular taurocholate transport in perfused rat liver. Biochem J 1993;291:355-60.

55. Thibault N, Maurice M, Maratrat M, Cordier A, Feldmann G, Ballet F. Effect of tauroursodeoxycholate on actin filament alteration induced by cholestatic agents. A study in isolated rat hepatocyte couples. J Hepatol 1993;19:367-76.

56. Marks DL, LaRusso NF, McNiven MA. Isolation of the microtuble-vesicle motor kinesin from rat liver: selective inhibition by cholestatic bile acids. Gastroenterology 1995;108:824-33.

57. Nakai T, Katagiri K, Hoshino M, Hayakawa T, Ohiwa T. Microtubule-independent choleresis and anti-cholestatic action of tauroursodeoxycholate in colchicine-treated rat liver. Biochemical J 1992;288:613-17.

58. Sakisaka S, Harada M, Gondo K, Yoshitake M, Tanikawa K. Tubulovesicular transport of horseradish peroxidase in isolated rat hepatocyte couplets: effects of low temperature, cytochalasin B and bile acids. Hepatology 1994;20:1015-23.

59. Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology 1990;11:12-15.

60. Calmus Y, Weill B, Osier Y, Chereau C, Houssin D, Poupon R. Immunosuppressive properties of chenodeoxycholic and ursodeoxycholic acids in the mouse. Gastroenterology 1992;103:617-21.

61. Poupon RE, Poupon R. Ursodeoxycholic acid for the treatment of cholestatic diseases. In: Boyer JL, Ockner RK, eds. Progress in liver disease. vol 10. Philadelphia: WB Saunders, 1992:219-38.

62. Lacaille F, Paradis K. The immunosuppressive effect of ursodeoxycholic acid: a comparative in vitro study on human peripheral blood mononuclear cells. Hepatology 1993;18:165-72.

63. Akashi Y, Miyazaki H, Yanagisawa J, Nakayama F. Bile acid metabolism in cirrhotic liver tissue-altered synthesis and impaired hepatic secretion. Clin Chim Acta 1987;168:199-206.

64. Greim H, Czygan P, Schaffner F, Popper H. Determination of bile acids in needle biopsies of human liver. Biochem Med 1973;8:280-6.

65. Greim H, Trulzsch D, Czygan P, et al. Mechanism of cholestasis V and VI. Bile acids in human livers with or without biliary obstruction. Gastroenterology 1972;63:837-45; 846-50.

66. Patel T, Bronk SF, Gores GJ. Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes. J Clin Invest 1994;94:2183-92.

67. Patel T, Gores GJ. Apoptosis and hepatobiliary disease. Hepatology 1995;21:1725-39.

68. Attili AF, Angelico M, Cantafora A, Alvaro D, Capocaccia L. Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses 1986;19:57-68.

69. Holsti P. Experimental cirrhosis of the liver in rabbits induced by gastric instillation of desiccated whole bile. Acta Pathol Microbiol Scand 1956;112:1-67.

70. Schoenfield LJ, Lachin JM Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallstone Study: a controlled trial of efficacy and safety. Ann Intern Med 1981;95:257-82.

71. La Russo NF, Szcepanik PA, Hofmann AF. Effect of deoxycholic acid ingestion on bile acid metabolism and biliary lipid secretion in normal subjects. Gastroenterology 1977;72:132-40.

72. Answer MS, Engelking LR, Nolan K, Sullivan D, Zimniak P, Lester P. Hepatotoxic bile acids increase cytosolic calcium activity of isolated rat hepatocytes. Hepatology 1991;8:887-91.

73. Rosser BG, Gores GJ. Liver cell necrosis: cellular mechanisms and clinical implications. Gastroenterology 1995;108:252-75.

74. Spivey JR, Bronk SF, Gores GJ. Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes: role of ATP depletion and cytosolic free calcium. J Clin Invest 1993;92:17-24.

75. Poupon RE, Chretien Y, Poupon R, Paumgartner G. Serum bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid therapy. Hepatology 1993;17:599-604.

76. Marschall HU, Griffiths WJ, Gotze U, et al. The major metabolites of ursodeoxycholic acid in human urine are conjugated with N-acetylglucosamine. Hepatology 1994;20:845-53.

77. Crosignani A, Podda M, Battezzati PM, et al. Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic-acid administration. Hepatology 1991;14:1000-7.

78. Stiehl A, Rudolph G, Raedsch R, et al. Ursodeoxycholic acid-induced changes of plasma and urinary bile acids in patients with primary biliary cirrhosis. Hepatology 1990;12:492-7.

79. Nilsell K, Angelin B, Leijd B, Einarsson K. Comparative effects of ursodeoxycholic acid and chenodeoxycholic acid on bile acid kinetics and biliary lipid secretion in humans. Evidence for different modes of action on bile acid synthesis. Gastroenterology 1983;85:1248-56.

80. Rudolph G, Endele R, Senn M, Stiehl A. Effect of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis. Hepatology 1993;17:1028-32.

81. Mazella G, Parini P, Bazzoli F, et al. Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis. Dig Dis Sci 1993;38:896-902.

82. Hillaire S, Ballet F, Franco D, Setchell KDR, Poupon R. Effects of ursodeoxycholic acid and chenodeoxycholic acid on human hepatocytes in primary culture. Hepatology 1995;22:82-7.

83. Batta AK, Salen G, Arora R, et al. Effect of ursodcoxycholic acid on bile acid metabolism in primary biliary cirrhosis. Hepatology 1989;10:414-19.

84. Ota S, Tsukahara H, Terano A, et al. Protective effect of tauroursodeoxycholate against chenodeoxycholate-induced damage to cultured rabbit gastric cells. Dig Dis Sci 1991;36:409-26.

85. Marteau P, Chazouilleres O, Myara A, Jian R, Rambaud JC, Poupon R. Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in man. Hepatology 1990;12:1206-8.

86. Batta AK, Arora R, Salen G, Tint GS, Eskreis D, Katz S. Characterization of serum and urinary bile acids in patients with primary biliary cirrhosis by gas-liquid chromatographymass spectrometry: effect of ursodeoxycholic acid treatment. J Lipid Res 1989;30:1953-62.

87. Eusafzai S, Ericsson S, Cederlund T, Einarsson K, Angelin B. Effect of ursodeoxycholic acid treatment on ileal absorption of bile acids in man as determined by the SeHCAT Test. GUT 1991;32:1044-8.

88. Nakagawa M, Colombo C, Setchell KDR. Comprehensive study of the biliary bile acid composition of patients with cystic fibrosis and associated liver disease before and after UDCA administration. Hepatology 1990;12:322-4.

89. Moseley RH, Ballatori N, Smith DJ, Boyer JL. Ursodeoxycholate stimulates Na+,H+ exchange in rat liver basolateral plasma membrane vesicles. J Clin Invest 1987;80:684-90.

90. Heuman DM, Mills AS, McCall J, Hylemon PB, Pandak WM, Vlahcevic ZR. Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. Gastroenterology 1991;100:203-11.

91. Schmucker DL, Ohta M, Kanai S, Sato Y, Kitani K. Hepatic injury induced by bile salts: correlation between biochemical and morphological events. Hepatology 1990;12:1216-21.

92. Leuschner U, Leuschner M, Sieratzki J, Kurtz W, Hubner K. Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci 1985;30:642-9.

93. Laurin JM, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464-6.
94. Clayton PT, Casteels M, Mieli-Vergani G, Lawson AM. Familial giant cell hepatitis with low bile acid concentrations and increased urinary excretion of specific bile alcohols: a new inborn error of bile acid synthesis? Pediatr Res 1995;37:424-31.

95. Bousvaros A, Werlin S, Tolia V, Raynaud S, Ferry G, Kirschner B. Effects of ursodeoxycholic acid on biochemical parameters in children with primary sclerosing cholangitis [Abstract]. J Pediatr Gastroenterol Nutr 1995;21:325.

96. Bergasa NV, Jones EJ. The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastroenterology 1995;108:1582-8.

97. Schoenfield LJ, Sjovall J, Penman E. Bile acids on the skin of patients with pruritic hepatobiliary disease. Nature 1967;213:93-4.

98. Ghent CN. Pruritus of cholestasis is related to the effects of bile salts on the liver, not the skin. Am J Gastroenterol 1987;82:117-8.

99. Jones EA, Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists. Hepatology 1990;11:884-7.

100. Bergasa NV, Thomas DA, Vergalla J, Turner ML, Jones EA. Plasma from patients with the pruritus of cholestasis induces opioid receptor-mediated scratching in monkeys. Life Sci 1993;53:1253-7.

101. Poupon R, Chretien Y, Poupon RE, Ballet F, Calmus Y, Darnis F. Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 1987;1:834-6.

102. Leuschner U, Fischer H, Kurtz W, et al. Ursodeoxycholic acid in primary biliary cirrhosis-results of a controlled double-blind trial. Gastroenterology 1989;97:1268-74.

103. Jorgensen RA, Dickson ER, Hofmann AF, Rossi SS, Lindor KD. Characterisation of patients with a complete biochemical response to ursodeoxycholic acid. Gut 1995;36:935-8.

104. Poupon RE, Balkau B, Eschwege E, Poupon R, and the UDCA-PBC Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1991;324:1548-54.

105. Poupon RE, Poupon R, Balkau B, and the UDCA-PBC Study Group. Ursodiol for the long-term treatment of primary biliary cirrhosis. N Engl J Med 1994;330:1342-7.

106. Poupon RE, Ouguerram K, Chretien Y, et al. Cholesterol-lowering effect of ursodeoxycholic acid in patients with primary biliary cirrhosis. Hepatology 1993;17:577-82.

107. Combes B, Carithers RL Jr, Maddrey WC, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1995;22:759-66.

108. Heathcote EJ, Cauch-Dudek K, Walker V, et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994;19:1149-56.

109. Lindor KD, Dickson ER, Baldus WP, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994;106:1284-90.

110. Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology 1996;110:1515-18.

111. Stiehl L, Rudolph G, Raedsch R, Stiehl A. Effects of ursodeoxycholic acid in patients with primary sclerosing cholangitis. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids as therapeutic agents: from basic science to clinical practice. London: Kluwer Academic Press, 1991:305-7.

112. Stiehl A. Ursodeoxycholic acid in the treatment of primary sclerosing cholangitis. Ann Med 1994;26:345-9.

113. Chazouilleres O, Poupon R, Capron J-P, et al. Ursodeoxycholic acid for primary sclerosing cholangitis. J Hepatol 1990;11:120-3.

114. O'Brien CB, Senior JR, Arora-Mirchandani R, Batta AK, Salen G. Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study. Hepatology 1991;14:838-47.

115. Mazzella G, Rizzo N, Salzetta A, Iampieri R, Bovicelli L, Roda E. Management of intrahepatic cholestasis in pregnancy. Lancet 1991;2:1594-5.

116. Palma J, Reyes H, Ribalta J, et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992;15:1043-7.

117. Floreani A, Paternoster D, Grella V, Sacco S, Gangemi M, Chiaramonte M. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 1994;101:64-5.

118. Fried RH, Murakami CS, Fisher LD, Willson RA, Sullivan KM, McDonald GB. Ursodeoxycholic acid treatment of refractory chronic graft-versus-host disease of the liver. Ann Intern Med 1992;116:624-9.

119. Essell JH, Thompson JM, Harman GS, et al. Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1992;10:367-72.

120. Friman S, Svanvik JK. A possible role of ursodeoxycholic acid in liver transplantation. Scand J Gastroenterol 1994;29(suppl):62-4.

121. Persson H, Friman S, Schersten T, Svanvik J, Karlberg I. Ursodeoxycholic acid for prevention of acute rejection in liver transplant recipients. Lancet 1990;2:52-3.

122. Sama C, Mazzioti A, Grigioni W, et al. Ursodeoxycholic acid administration does not prevent rejection after OLT. J Hepatol 1991;13:S2:68.

123. Friman S, Mjornstedt L, Persson H, Karlbert I, Olausson M. Ursodeoxycholic acid reduces acute rejection in heart allografted rats. Transplant Proc 1992;24:344-5.

124. Bilik R, Superina RA, Phillips J, Edwards V. Prevention of biliary cirrhosis following hepatic arterial thrombosis after liver transplantation in children by using ursodeoxycholic acid. J Pediatr Surg 1995;30:49-52.

125. Atilli AF, Rusticali A, Varriale M, Carli L, Repice AM, Callea F. The effect of ursodeoxycholic acid on serum enzymes and liver histology in patients with chronic active hepatitis; a 12 month double-blind, placebo-controlled trial. J Hepatol 1994;20:315-20.

126. Bellentani S, Podda M, Tiribelli C, et al. Ursodiol in the long-term treatment of chronic hepatitis: a double-blind multicenter clinical trial. J Hepatol 1993;19:459-64.

127. Crosignani A, Battezzati PM, Setchell KD, et al. Effects of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis: a dose-response study. Hepatology 1991;13:339-44.

128. Mima S, Sekiya C, Kanagawa H, Uchida T. Ursodeoxycholic acid therapy for autoimmune hepatitis. Int Hepatol Communications 1994;2:207-12.

129. Podda M, Ghezzi C, Battezzati PM, Crosignani A, Zuin M, Roda A. Effects of ursodeoxycholic acid on serum liver enzymes and bile acids in chronic hepatitis. Gastroenterology 1990;98:1044-50.

130. Simko V, Michael S, Prego V. Ursodeoxycholic therapy in chronic liver disease: a meta-analysis in primary biliary cirrhosis and in chronic hepatitis. Am J Gastroenterol 1994;89:392-8.

131. Boucher E, Jouanolle H, Andre P, et al. Interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral C hepatitis: results from a controlled randomized trial in 80 patients. Hepatology 1995;21:322-7.

132. Takano S, Ito Y, Yokusuka O, et al. A multicenter randomized controlled dose study of ursodeoxycholic acid for chronic hepatitis C. Hepatology 1994;20:558-64.

133. Bijleveld CM, Vonk RJ, Kuipers F, et al. Benign recurrent intrahepatic cholestasis: altered bile acid metabolism. Gastroenterology 1989;97:427-32.

134. Bijleveld CM, Vonk RJ, Kuipers F, Havinga R, Fernandes J. Benign recurrent intrahepatic cholestasis: a long-term follow-up study of two patients. Hepatology 1989;9:532-7.

135. Crosignani A, Podda M, Bertoloni E, Battezzati PM, Zuin M, Setchell KDR. Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism. Hepatology 1990;13:1076-83.

136. Colombo C, Setchell KDR, Podda M, et al. Effect of ursodeoxycholic acid on liver disease associated with cystic fibrosis. J Pediatr 1990;117:482-9.

137. Cotting J, Lentze MJ, Reichen J. Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and long-standing cholestasis. Gut 1990;31:918-21.

138. Galabert C, Montet JC, Leugrand D, et al. Effects of ursodeoxycholic acid treatment on liver in patients with cystic fibrosis and chronic cholestasis. J Pediatr 1992;121:138-41.

139. Feigelson J, Anagnostopoulos C, Poquet M, Pecau Y, Munck A, Navarro J. Liver cirrhosis in cystic fibrosis-therapeutic implications and long-term follow-up. Arch Dis Child 1993;68:653-7.

140. Colombo C, Crosignani A, Assaisso M, et al. Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose-response study. Hepatology 1992;16:924-30.

141. Colombo C, Castellani MR, Balistreri WF, Seregni E, Assaisso ML, Guinta A. Scintigraphic documentation of an improvement in bile flow in patients with cystic fibrosis and associated liver disease after treatment with ursodeoxycholic acid. Hepatology 1992;15:677-84.

142. Strandvik B, Lindblad A. Cystic fibrosis: is treatment with ursodeoxycholic acid of value? Scand J Gastroenterol 1994;29(suppl):65-7.

143. Bittner P, Posselt HG, Sailer T, et al. The effect of ursodeoxycholic acid in cystic fibrosis and hepatopathy: results of a placebo-controlled study. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids as therapeutic agents: from basic science to clinical practice. London: Kluwer Academic Press, 1991:345-8.

144. O'Brien S, Fitzgerald MX, Hegarty JE. A controlled trial of ursodeoxycholic acid treatment in cystic fibrosis-related liver disease. Eur J Gastroenterol Hepatol 1992;4:857-63.

145. Colombo C, Battezzati PM, Podda M, Bettinardi N, Giunta A. Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. Hepatology 1996;23:1484-90.

146. Balistreri WF, Setchell KDR, Ryckman FC, and the UDCA Study Group. Bile acid therapy in paediatric liver disease. In: Paumgartner G, Stiehl A, Gerok W, eds, Bile acids and the hepatobiliary system. London: Kluwer Academic Publishers, 1993:271-82.

147. Narkewicz MR, Sokol RJ, Smith D, Gregory C, Lear J. Ursodeoxycholic acid does not improve quantitative tests of hepatic function in children with intrahepatic cholestasis despite clinical improvement [Abstract]. Hepatology 1992;16:258.

148. Paradis K, El Arab N, Yousef I, et al. Use of ursodeoxycholic acid in children with cholestatic liver disease. Hepatology 1993;18:301.

149. Levy E, Benydayan M, Thibault L, Lambert M, Paradis K. Lipoprotein abnormalities in two children with minimal biliary excretion. J Pediatr Gastroenterol Nutr 1995;20:432-9.

150. Krawinkel MB, Santer R, Oldigs HD. Ursodeoxycholic acid: effect on xanthomas in Alagille-Watson syndrome. J Pediatr Gastroenterol Nutr 1994;19:476-7.

151. Jacquemin E, Setchell KDR, O'Connell NC, et al. A new cause of progressive intrahepatic cholestasis: 3β-hydroxy-C27-steroid dehydrogenase/isomerase deficiency. J Pediatr 1994;125:379-84.

152. Jacquemin E, Habes D, Debray D, Hadchouel M, Bernard O. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis [Abstract]. Hepatology 1995;22:318.

153. Ullrich D, Rating D, Schroter W, et al. Treatment with ursodeoxycholic acid renders children with biliary atresia suitable for liver transplantation. Lancet 1987;2:1234.

154. Nittono H, Tokita A, Hayashi M, et al. Ursodeoxycholic acid therapy in the treatment of biliary atresia. Biomed Pharmacother 1989;43:37-41.

155. A-Kader HH, Santangelo JD, Setchell KDR, Heubi JE, Ryckman FC, Balistreri WF. The effects of ursodeoxycholic acid therapy in biliary atresia: a double blind, randomized, placebo controlled trial. Pediatr Res 1993;33:97A.

156. Cocjin J, Vanderhal A, Sehgal S, Rosenthal P. Ursodeoxycholic acid therapy for total parenteral nutrition-associated cholestasis in the neonate. Gastroenterology 1993;104:A615.

157. Balistreri WF. The liver-the next frontier in the treatment of patients with cystic fibrosis. In: Reyee H, Leuschner V, Arias IM, eds. Pregnancy, sex hormones, and the liver. Proceedings of the Falk Symposium 89. London: Kluwer Academic Publishers, 1996:114-35.

158. Thomas PS, Bellamy M, Geddes D. Malabsorption of vitamin E in cystic fibrosis improved after ursodeoxycholic acid. Lancet 1995;346:1230-1.

159. Merli M, Bertasi S, Servi R, et al. Effect of a medium dose of ursodeoxycholic acid with or without taurine supplementation on the nutritional status of patients with cystic fibrosis: a randomized, placebo-controlled, crossover trial. J Pediatr Gastroenterol Nutr 1994;19:198-203.

160. Balistreri WF. Inborn errors of bile acid metabolism: clinical and therapeutic aspects. In Hofmann AF, Paumgartner G, Stiehl A, eds. Bile acids in gastroenterology: basic and clinical advances (proceedings of the 13th international Bile Acid Symposium). London: Kluwer Academic Publishers, 1995:333-53.

161. Setchell KDR, O'Connell NC. Inborn errors of bile acid biosynthesis: update on biochemical aspects. In: Hofmann AF, Paumgartner G, Stiehl A, eds. Bile acids in gastroenterology: basic and clinical advances. London: Kluwer Academic Publishers, 1995:129-36.

162. Setchell KDR, Suchy FJ, Welsh MB, Zimmer-Nechemias L, Heubi J, Balistreri WF. Δ4-3-Oxosteroid 5β-reductase deficiency described in identical twins with neonatal hepatitis-a new inborn error in bile acid synthesis. J Clin Invest 1988;82:2135-46.

163. Clayton PT, Leonard JV, Lawson AM, et al. Familial giant cell hepatitis associated with synthesis of 3β,7α-dihydroxy-and 3β,7α,12α-trihydroxy-5-cholenoic acids. J Clin Invest 1987;79:1031-8.

164. Stieger B, Zhang J, O'Neill B, Sjovall J, Meier PJ. Transport of taurine conjugates of 7α-hydroxy-3-oxo-4-cholenoic acid and 3β, 7α-dihydroxy-5-cholenoic acid in rat liver plasma membrane vesicles. In van Berge GP, van Hoek B, de Groote J, Matern S, Stockbrugger RW, eds. Cholestatic liver diseases: new strategies for prevention and treatment of hepatobiliary and cholestatic liver diseases. London: Kluwer Academic Publishers, 1994:82-7.

165. Daugherty CC, Setchell KDR, Heubi JE, Balistreri WF. Resolution of liver biopsy alterations in 3 siblings with bile acid treatment of an inborn error of bile acid metabolism (Δ4-3-oxosteroid 5β-reductase deficiency). Hepatology 1993;18:1096-1101.

166. Balistreri WF. Ursodeoxycholic acid in the treatment of pediatric liver disease. In Fromm H, Leuschner U, eds. Proceedings of the Falk Symposium 84; Advances in basic and clinical bile acid research. London: Kluwer Academic Publishers, 1995:327-42.

167. Jacquemin E, Dumont M, Bernard O, Erlinger S, Hadchouel M. Evidence for defective primary bile acid secretion in children with progressive familial intrahepatic cholestasis. Eur J Pediatr 1994;153:424-8.

168. Tazawa Y, Yamada M, Nakagawa M, Konno T, Tada K. Bile acid profiles in siblings with progressive intrahepatic cholestasis: absence of biliary chenodeoxycholic acid. J Pediatr Gastroenterol Nutr 1985;4:32-7.

169. Balistreri WF, Grand R, Hoofnagle JH, et al. Biliary atresia: current concepts and research directions, summary of a symposium. Hepatology 1996;23:1682-92.

170. Poo JL, Feldman G, Erlinger S, et al. Ursodeoxycholic acid acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat. Gastroenterology 1992;102:1752-9.

171. Frezza EE, Gerunda GE, Plebani M, et al. Effect of ursodeoxycholic acid administration on bile duct proliferation and cholestasis in bile duct ligated rat. Dig. Dis. Sci 1993;38:1291-6.

172. Balistreri WF, Bove K. Hepatobiliary consequences of parenteral nutrition: In: Progress in liver disease; vol 9. 1989:567-601.

173. Leuschner U, Guldutuna S, Bhatti S, Sipos P, You T, Zimmer G. Cytoprotection by ursodeoxycholic acid. In: van Berge Henegouwen GP, van Hoek B, de Groote J, Matern S, Stockbrugger RW, eds. Cholestatic liver diseases (Falk Symposium 75). London: Kluwer Academic Publishers, 1994:218-25.

174. Schwarzenberg SJ, Bundy M. Ursodeoxycholic acid modified gut-derived endotoxemia in neonatal rats. Pediatr Res 1994;35:214-17.

175. Lindor KD, Burnes J. Ursodeoxycholic acid for the treatment of home parenteral nutrition associated cholestasis-a case report. Gastroenterology 1991;101:250-3.

176. Beau P, Labat-Labourdette J, Ingrand P, Beauchant M. Is ursodeoxycholic acid an effective therapy for total parenteral nutrition related liver disease? J Hepatol 1994;20:240-4.

177. Kowalski TE, Bosse M, Mullen J, Holt PR, Tint G, Malet PF: Randomized double-blind trial of ursodeoxycholic acid versus placebo for the treatment of parenteral nutrition-associated cholestasis. Gastroenterology 1994;106:A615.

178. Hofmann AF. Defective biliary secretion during total parenteral nutrition: probable mechanisms and possible solutions. J Pediatr Gastroenterol Nutr 1995;20:376-90.

179. Duerksen D, Chan G, Thompson ABR, Van Aerde J. Intravenous ursodeoxycholic acid reduces severity of cholestasis in parenterally fed newborn piglets. Hepatology 1993;18:296A.

180. Roda A, Pellicciari R, Polimeni C, et al. Metabolism, pharmacokinetics, and activity of a new 6-fluoro analogue of ursodeoxycholic acid in rats and hamsters. Gastroenterology 1995;108:1204-14.

181. Roda A, Roda E, Marchi E, Simoni P, et al. Improved intestinal absorption of an enteric-coated sodium ursodeoxycholate formulation. Pharm Res 1994;11:642-7.

182. Higginbottom S, Mallinson CB, Burns SJ, Attwood D, Barnwell SG. Ursodeoxycholic acid: effects of formulation on in vitro dissolution. Int J Pharmaceutics 1994;109:173-80.

183. Rodrigues CMP, Kren BT, Steer CJ, Setchell KDR. Tauro-ursodeoxycholate increases rat liver ursodeoxycholate levels and limits lithocholate formation better than ursodeoxycholate. Gastroenterology 1995;109:564-72.

184. Baumgartner U, Schölmerich J, Sellinger M, Reinhardt M, Ruf G, Farthmann EH. Different protective effects of tauro-ursodeoxycholate, ursodeoxycholate, and 23-methyl-ursodeoxycholate against taurolithocholate-induced cholestasis. Dig Dis Sci 1996;41:250-5.

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