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

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. 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). 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). 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). 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 Bile acids that accumulate during cholestasis may cytotoxicity via free in the hepatocyte these postulated are potential for the effects of UDCA in patients with (a) a direct effect of UDCA on hepatocytes of bile acid-induced hepatocyte (b) a since UDCA increases bile flow and of hydrophobic bile acids from and (c) induction of in the (Table intracellular retention of hydrophobic bile acids is to lead to liver cell replacement of these compounds with a nontoxic bile acid as UDCA cholestasis This effect of UDCA has been well documented administration of UDCA will alter the composition and distribution of the bile acid pool UDCA not the of the primary bile acids, and CDCA the of both is by UDCA due to intestinal absorption and hepatic of and CDCA UDCA hepatic bile acid excretion and bile acid time through the liver The effect is that UDCA the major of the bile acid pool There is a decrease in the of potentially toxic, endogenous dihydroxy bile acids the concentration to which liver are and thereby the of bile acid-induced damage to liver cell membranes The of UDCA to displace the endogenous bile acid pool has been shown in studies In of biliary bile acids in with cholestasis and UDCA administration the UDCA content from to the biliary bile acid of the bile acid pool with UDCA is related to the of UDCA to with endogenous bile acids for intestinal thus the fecal excretion of and CDCA an increase in the of UDCA in serum from to UDCA therapy There was a in the CDCA and with an decrease in serum bile acid of UDCA In UDCA has an effect. This which is much more than that due to primary bile acids as has been be for by UDCA into bile This is best by the hypothesis leads to a decrease in the of bile and a decrease in the of of bile in the biliary The degree of in in related to the of unconjugated UDCA in bile However, by circulation of unconjugated UDCA is to be the major of of UDCA in patients with cholestasis, since biliary levels of unconjugated UDCA not increase during UDCA administration mechanisms for have been as direct stimulation of ductular through of membrane or liver plasma membrane UDCA a effect via a direct on the enterohepatic circulation of bile acids, directly increasing the of hepatocytes to bile UDCA increases the transport of bile acids of the liver by intracellular or thus leading to a decrease in their intrahepatic concentration and their When potentially toxic bile acids are with UDCA in not only is the cholestasis that results from the bile acid excretion of bile acids is thus bile flow and hepatocellular OF UDCA IN The that UDCA may be of benefit in patients with liver disease was based on the that in patients with gallstones who liver disease” biochemical was during UDCA therapy this have been of the of UDCA to treat a of cholestatic (Table leading to an in biochemical most an amelioration of clinical symptoms as pruritus. It is patients with cholestasis The most is due to bile acid in the However, this has not been proven Bile acids, through a may endogenous endogenous which are retained in the presence of cholestasis, may the of through mechanisms The effect of UDCA in the treatment of may be related to (a) the relative in the bile acid (b) of hepatocellular or (c) induction of with of the Primary The effect of UDCA has been most extensively studied in patients with primary biliary cirrhosis a chronic cholestatic disease by portal and necrosis of biliary in the small and In this UDCA the degree of cholestasis and may alter the in In a of UDCA of with treatment as an increase in bilirubin and of in UDCA The in liver directly with the degree of enrichment of biliary bile acids with UDCA In a in which patients with to receive UDCA or disease progression was less in the UDCA have a survival benefit in patients with UDCA compared to a group Primary Primary a chronic disease of the and/or bile is of progressive cholestasis by and The of UDCA therapy are to the progression and the quality of studies of patients with an in clinical symptoms and in with of UDCA therapy in an of patients with UDCA for a decrease in the degree of and a of and levels in a of patients given UDCA a decrease in the degree of and and a of serum and cholesterol There was with of the drug in patients and in the use of UDCA in are of cholestasis of is by in and is associated with levels of serum bile acids UDCA to have a effect In an of that UDCA therapy the of in a in and serum levels There no effects in the or their cholestasis in the of patients with chronic disease There are and and Therefore, the efficacy of UDCA was in the therapy of of the liver by in a of UDCA for the biochemical returned of UDCA. the use of UDCA to decrease the and of disease of the liver in patients to a was a in the of in maximum bilirubin levels and in due to studies are UDCA has been used as treatment liver in of the and of based on the and presumed effects of UDCA. that UDCA during the was associated with liver and of studies have not this effect A that initiation of UDCA hepatic may the effect of bile acid retention this must be UDCA has been used as an to therapy in patients with or chronic In patients with chronic liver disease by the of UDCA to therapy the for which serum the of studies must UDCA has any potential for long-term amelioration of the of of chronic intrahepatic cholestasis is by the of severe cholestasis, which in have been to bile acid transport at the in UDCA is not effective in these of cholestasis UDCA IN DISEASE have the potential for UDCA therapy in various forms of chronic cholestasis in children to the of survival of patients with cystic fibrosis hepatobiliary disease has more and has a in long-term survival to of or with will biliary disease in patients with has been to of small bile with presumably leading to ductular A effect may be the accumulation of potentially toxic endogenous bile In patients with the administration of UDCA decrease bile biliary and displace cytotoxic bile acids A of studies have the effects of UDCA in patients with liver is and in biochemical related to and cholestasis have the effects of administration of this drug has been to cholestasis and the of patients with of an in bile flow associated with UDCA this well with the effect of UDCA on liver function and bile acid During UDCA administration, bile enrichment was the UDCA composition from to The dose of UDCA is to which is than that used in the treatment of with cholestatic this is due to poor intestinal absorption of UDCA in patients the fact that UDCA is known to micelles less than primary bile acids, the of absorption in of the patients with an in of vitamin may This since was not that UDCA treatment is safe and effective in patients with to liver may not be effective cirrhosis is present We that UDCA therapy be in all patients with documented hepatobiliary disease. A long-term is to UDCA therapy is of of liver disease in patients at high or in the progression to of Bile A of as intrahepatic cholestasis and associated with specific (Fig. in the conversion of cholesterol to the primary bile acids, has been of these has been through of recent to of primary in bile acid associated with varying degrees of cholestasis that may to end-stage liver have been (a) (b) and (c) In these primary bile acid is or The bile acid of the and bile from affected patients are by the of bile acids the structure of the of the for the or In the presence of defective biosynthesis is of the bile acid pool bile and intracellular accumulation of potentially bile and liver injury in affected patients is to be due to (a) to of the or primary bile acids for the of bile and/or (b) of bile acid that have the potential to damage In patients with of bile acid UDCA has been used to displace toxic bile acids and bile primary bile acids have been as replacement therapy is was in with marked cholestasis and a severe a with “neonatal of liver at and of from both infants the presence of of of and bile only of bile bile acids the major bile excretion was the major for bile acid from bile acid biochemical a in bile acid the conversion of the to the a by an and liver injury presumed to result from the lack of of of primary bile acids with accumulation of and The latter compounds are not by and are presumed to be In the of severe hepatic administered a of UDCA and of bile acid) orally in solution. of and acids and of liver hepatic and bile during bile acid therapy infants and a affected treatment was at to and at and was in a who was the of to have been affected by progressive liver disease The lack of primary bile acid was due to the to into a by In patients with this the levels of primary bile acids in bile, and are and are high concentrations of and acids in the and serum The liver disease presumably results from the accumulation of these bile acids, by the lack of primary bile The clinical in the has been from cholestasis to a chronic This of bile acid be when cholestatic liver disease with clinical to disease is associated with a serum a serum bile acid concentration by and an of In a of children with progressive intrahepatic cholestasis, to have that the may be more than In patients with is a to liver function during UDCA therapy In the effect of UDCA in patients with chronic intrahepatic cholestasis was UDCA therapy liver function and the quality of life A was not In to achieve desired was to of UDCA to in In with UDCA therapy may be since in the of therapy patients will pruritus. In of patients with a clinical 1 of UDCA therapy as documented by a decrease in the degree of For the the UDCA dose was to and was in an patients to UDCA in of these biliary with UDCA was effective in the pruritus. In the patients in group than the patients The and effects by decrease in serum and bilirubin levels UDCA was effective in the serum cholesterol from a of to UDCA was well by most patients and by in view of the of symptoms and the of the to have a effect of UDCA in a with decrease in serum and levels a decrease in the degree of as well as the serum and serum cholesterol levels in a with during UDCA administration There was of UDCA not the progression of the liver disease are to the role in UDCA in However, in view of the effect in that UDCA be the drug of choice for and to UDCA will progression of the disease or other as poor There is no the of the of these with the degree of enrichment of bile with UDCA. or with progressive intrahepatic cholestasis have a high of progression to cirrhosis and end-stage liver disease. have been aimed at symptoms and the of The rationale for UDCA therapy was in part, on that the of a in transport of bile acids in patients with There is a of bile acids in affected the biliary bile acid concentrations are low and However, CDCA in altered excretion In is with in which UDCA therapy is effective In of patients with an in the degree of administration of UDCA at the dose of For the the dose was or with biliary this was effective in the degree of in two of the There was a in biochemical of liver injury during UDCA have these in a of children with with UDCA are to the long-term effects of UDCA on symptoms and disease to and biliary is a of in which a persistent process leads to of the bile intrahepatic bile are affected There have been studies of the of UDCA therapy in patients with biliary This drug was a choice to the of progression to liver disease in view of the of the drug in analogous (a) UDCA the of liver disease bile duct in the and (b) UDCA has been shown to effects Because mechanisms have been in the perpetuation of progressive biliary disease in biliary atresia, UDCA potentially bile duct administered UDCA to two children with biliary of with and with UDCA therapy orally at was associated with an increase in weight and in in of the children was a a decrease in the of hepatobiliary administered UDCA to patients with biliary a decrease in serum bilirubin and bile acids and two not In of patients with biliary atresia, UDCA was given the was and the was enrichment with at 1 was in the UDCA to compared to the group to There in the serum biochemical in UDCA compared to There was a decrease in the degree of in the UDCA and an increase was in patients We a decrease in the of in to UDCA. biochemical and clinical most of the patients progressive liver disease. There no observed in survival or the for liver the two However, the clinical at time of was different in UDCA the and weight at for UDCA was and compared to and for UDCA therapy a dose of may be associated with of biochemical and clinical in patients with biliary atresia, not to alter the of the disease. The lack of effect of UDCA in patients with biliary may be related to low levels of biliary UDCA enrichment and/or of the to bile In to halt disease progression in patients with bile In cirrhosis was by in The of these is by the of of the patients in group or liver the of The of cholestasis is not However, the clinical that patients at is well and low of oral and damage UDCA might benefit patients at for this compound bile flow and liver toxic injury UDCA might a postulated There have been no of UDCA in the treatment of and a biochemical and clinical in an with the initiation of UDCA a to the effects of UDCA administration in with long-term UDCA a in and from with no in or bilirubin There are two (a) that administration of UDCA biochemical of cholestasis in patients receiving long-term and (b) results the use of UDCA in an to alter the of cholestasis in studies are However, a major to the use of oral UDCA in patients at for is the poor degree of biliary enrichment in infants or in patients with intestinal administration of UDCA or of a solution of might to be the and efficacy of these have not been clinical to with the relative of UDCA in bile, to the degree of enrichment and bioavailability of the drug may be This has been via administration of UDCA in a solution of to the pH Based on the bile acid toxicity and hydrophilicity of the is that bile acids which are more than unconjugated UDCA will have therapeutic effects of this two studies have the role of UDCA in have shown that UDCA bile flow and serum bilirubin levels in the with cholestasis. In a clinical that children long-term of intractable cholestasis which was effectively with UDCA. In the effects of UDCA in children with a of cholestatic This was by For UDCA was by the The the and who in these biochemical of ursodeoxycholic acid and chenodeoxycholic acid The in the of the group accounts for the pharmacologic and these two compounds mechanisms of hepatocyte necrosis by toxic bile as the glycine of In cholestasis, toxic bile accumulate the The toxic bile mitochondrial leading to an of oxidative and formation of toxic species by the mitochondrial and adenosine (ATP) a increase in calcium (Ca++) concentration with stimulation of The of membranes and leads to cell by adenosine diphosphate to this as the unconjugated is into the bile and protonated in the biliary into ursodeoxycholic The bile acid is into the protonated by a by of acid formed via from The process that is secreted into bile. The protonated bile acid is soluble and absorbed by the biliary into the and to the which into bile, the of the absorbed bile acid bile flow in the for primary bile acid from cholesterol and their the in bile acid are