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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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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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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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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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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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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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