Hepatoprotection by hydrophilic bile salts

Copyright © Journal of Hepatology 1994

Journal o f Hepatology 1994; 21:260-268 Printed in Denmark. All rights reserved Munksgaard. Copenhagen

Journal of Hepatology ISSN 0168-8278

Review

Hepatoprotection by hydrophilic bile salts Pierre-Edouard Queneau and Jean-Claude Montet INSERM, Marseille, France

(Received 25 January 1993)

Cholestatic diseases, whatever their etiopathogenesis, can result in an accumulation of bile salts in the liver (1,2). Endogenous bile salts have been shown in vitro to act as a detergent for cell membranes (3-5). They could therefore aggravate cholestasis by injuring hepatocytes and biliary ductular cells. In contrast, ursodeoxycholate (UDC), a tertiary bile salt first used as a dissolvent of cholesterol lithiasis, is virtually devoid of toxicity at therapeutic doses (6) although it may contribute to occasional gallstone calcification (7,8). In addition, UDC has clearly demonstrated its efficacy in many cholestatic liver diseases. Since UDC is hydrophilic, whereas the major endogenous bile salts, chenodeoxycholate and deoxycholate, are hydrophobic, the toxic or beneficial effects are considered to depend on the hydrophilic - hydrophobic balance of the bile salt pool (9,10). However, the use of UDC as a treatment for various cholestatic disorders remains to be defined. The aim of this review is to attempt to clarify its role and place in the light of recent clinical and physico-chemical publications.

Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic disease predominantly affecting middle-aged women. No satisfactory explanation has ever been found for the intrahepatic bile duct injury which leads to inflammation and cholestasis. However, the role of an immunological factor is admitted. As opposed to normal subjects, where HLA expression is limited in the liver, PBC patients present an overexpression of HLA class I molecules on hepatocyte membranes and HLA class II molecules on bile duct cells (11). In addition, accumulation of endogenous bile salts probably participates in inflammation and bile duct destruction (12). Treat-

ments such as cyclosporine A, methotrexate, or colchicine have shown some efficacy but can have significant sideeffects (13,14). Treatment with UDC for primary biliary cirrhosis is now well documented and has shown its efficacy in both clinical (pruritus) and biological (transaminases, alkaline phosphatases, bilirubin) areas. The first positive results were reported in 1985 (15) and 1986 (16), followed by Poupon et al. in 1987 in a 2-year uncontrolled study (17), which was later supported by several controlled trials (18-21). Some of these studies also described histological amelioration (18,21). After this first encouraging phase, the question was asked whether UDC would be as efficient in the long term, and whether improvement was correlated with a longer life expectancy. For instance, Hadzyiannis et al. (22) described the deterioration of serum bilirubin levels at the end of a 2-year treatment in a controlled study despite the initial beneficial effects of UDC after 1 year. As in other uncontrolled studies (23-25), the authors also noticed a poor response in patients in late stages of the disease. All of the above studies differ in their methodological form and must be analyzed accordingly. The number of patients included was sometimes very small, except for multicenter studies (19,20,26), due to the relative rarity of PBC. The histological stage was not always specified (19,22) and the duration of UDC treatment varied from 3 months to 2 years. Of course, uncontrolled studies must be considered with care since in controlled studies, improvements in clinical and biological parameters under placebo have been described (26). Doses typically ranged between 8 and 15 mg/kg per day. Recently, several multicenter, double-blind, randomized, controlled studies have clarified the effect of UDC in the long term. In a 2-year controlled study with 146 patients, Poupon et al. (27) con-

Correspondence to: J. C. Montet, INSERM, 46 Boulevard de la Gaye, 13009 Marseille, France.

HEPATOPROTECTION BY HYDROPHIL1C BILE SALTS firmed the efficiency of a 13-15-mg/kg per day dose of UDC both clinically and biologically. Histological characteristics also improved, except for fibrosis, as well as immunological parameters such as IgM, thus strengthening the hypothesis of an action of UDC in that field. No information has been provided for severe-stage disease, because the number of patients has been insufficient. The positive effect on biological parameters has also been demonstrated in two 4-year and one 2-year multicenter, controlled studies (28-30). However, a beneficial effect on histological progression, symptoms and time of transplantation remains controversial.

Primary Sclerosing Cholangitis UDC has also been evaluated in primary sclerosing cholangitis, which is another characteristic, although rare, chronic cholestatic disease manifested as a succession of strictures and dilatations of the intra- and extrahepatic bile ducts. As in PBC, the pathogenesis of primary sclerosing cholangitis has yet to be completely defined. Bile duct cell inflammation is thought to result from an immunological conflict, which is supported by the frequently noted association of primary sclerosing cholangitis and ulcerative colitis. As in PBC, accumulated bile salts could help to aggravate cholestasis. No medical (steroids, methotrexate, D penicillamine etc.) or interventional therapy has ever clearly proved its efficacy, and liver transplantation is currently the only way to avoid a fatal evolution. All clinical trials with UDC have resulted in an improvement of symptoms (asthenia, pruritus), cholestasis and hepatolysis enzyme markers, and even in a reduction in the predicted mortality risk. Due to the limited number of patients, most of the studies have been uncontrolled (31,32). Two controlled studies with placebo, performed by Stiehl et al. (33) and Beuers et al. (34) for over I year, are confirmative. Doses were similar (10-15 mg/kg per day) and the number of patients never exceeded 15. O'Brien et al. (31) reported the persistence of beneficial effects, with relapse after withdrawal, in a 30-month study. Overall, UDC appears to be an effective treatment for primary sclerosing cholangitis, although the inevitably low number of patients still represents a great handicap for performing more informative clinical trials.

261 Since interest has arisen in UDC, its properties have been witnessed in well-documented drug-induced cholestasis. For instance, Koga (35) and Zhao & Montet (36) have demonstrated the protective effect of oral intake of UDC or tauroursodeoxycholate (TUDC), a conjugate of UDC, on ethinyl estradiol-induced cholestasis in rats. Moreover, a TUDC perfusion showed beneficial effects on acute estradiol-17~D-glucuronide-induced cholestasis in the perfused rat liver, while another hydrophilic bile salt, dehydrocholate, was ineffective (37). Cholestasis improvement was interestingly correlated with an increased elimination of the estradiol derivative in bile. Further studies in man are required for confirmation. Cyclosporine A-related cholestasis, in either long-term or acute administration, may also benefit from TUDC, as shown by recent studies in rats (38,39). A positive effect was associated with a facilitation of cyclosporine A transport and its elimination in bile. In man, one study has reported the disappearance of cholestasis under UDC in heart-transplanted patients taking cyclosporine A (40). However, no well-conducted trial has ever been performed to clearly assess a specific action of UDC on cyclosporine A-induced hepatotoxicity. Chlorpromazine is another widely used and potentially cholestatic drug on which UDC has also been successfully experimented in rats (41). As for estrogens and cyclosporine A, TUDC led to the enhancement of biliary elimination of chlorpromazine in bile. All these drugs partially express their cholestatic effect by disturbing the hepatocyte membrane structure (42-45). In addition, cyclosporine A and ethinylestradiol inhibit bile salt uptake on the sinusoidal side (46-50). This results in an accumulation of toxic bile salts as well as the drug itself, which may aggravate the cholestasis. At least in animals, UDC has been shown to be effective in this particular field. In man, only a few reports have tended to confirm animal experiments (40). It seems of great interest in clinical practice to definitely assess the efficiency of UDC in preventing drug-induced hepatotoxicity, especially for irreplaceable or widely-prescribed drugs. Furthermore, the association of hepatotoxic molecules is likely to occur under pathological conditions. In liver diseases, where the benefit appears especially relevant, this would represent another indication for preventive and/or curative treatment with UDC.

Drug-Induced Cholestasis The hepatobiliary tract is a key area for the metabolism, detoxification and elimination of drugs. Therefore, the liver is highly exposed to drug toxicity, especially in the case of previous hepatic disorders.

Cystic Fibrosis Together with recent therapeutic advances such as heart-lung transplantation and the subsequent improvement in cystic fibrosis survival, the incidence of hepatobil-

262 iary involvement has greatly increased. Inspissation of dehydrated bile in the biliary ductutes and the resulting inflammation is considered to lead progressively to cholestasis, then to focal and multilobular biliary cirrhosis. Clinically apparent cirrhosis affects up to 25% of adolescent and adult patients, while complications related to cholesterol gallstones tend to become worse. These features require an adapted therapeutic approach in clinical practice. Given the conclusive results in PBC, UDC has clearly emerged as a possible treatment of hepatobiliary impairment in cystic fibrosis, first for dissolving cholesterol gallstones and additionally as a protective agent against intrahepatic cholestasis. Two uncontrolled pilot studies in 1990 showed improvement in conventional liver tests after 6 months of treatment (51.52) and have been confirmed by a placebo-controlled study (53). Since then, uncontrolled studies have assessed the persistence of positive results after 1- and 2-year intake studies (54-56). Lastly, multicenter double-blind trials have recently been undertaken (57). Whenever measured, the UDC concentration in bile appears largely increased under treatment, at the expense of other endogenous bile salts. Cotting et al. (55) have also concentrated on the optimal dose of UDC: a 20-mg/kg dose permitted improvement of nutritional parameters while a lower one did not (52,53). This may be explained by a major cystic fibrosis-associated malabsorption resulting in considerable fecal loss of bile salts, consequently leading to diminution of lipid absorption. In this respect UDC therapy may also be clinically relevant by increasing the bioavailability of poorly absorbed liposoluble drugs, for example cyclosporine A in transplanted patients. Chronic Hepatitis Evidence of a positive effect of UDC on liver indices in chronic hepatitis was previously reported in man in the 1960's (58) but without international impact. Attention was again focused by Leuschner et al. (59,60), who studied a group of patients with chronic hepatitis receiving UDC for gallstone dissolution, and described a diminution in transaminase levels. Since then, uncontrolled studies (61-63) as well as double-blind controlled trials (64-66) have been performed and tend to confirm these results. Selected patients were usually B or non-A non-B (mostly C)-virus carriers, notwithstanding the severity of the disease. Interestingly, the efficacy of UDC was identical regardless of the duration of treatment (from 2 months to 6 months). No difference was found in a doseresponse study on transaminase decrease between a 250 rag/day dose or higher doses (500 mg/day and 750 rag/ day). However, UDC intake, though absolutely safe, did

P.E. QUENEAU and J. C. MONTET not consistently diminish symptoms and was never reported to improve histological parameters. The impact of UDC on the evolution of chronic hepatitis and its efficacy regarding the severity or the type of disease remain to be defined. Results of long-term controlled trials are awaited. Other Liver Diseases and Liver Transplantation The properties of UDC have been evaluated in several other cholestatic conditions. In pediatrics, clinical and biological improvements have been observed in patients with biliary atresia (67,68), Alagille syndrome and idiopathic intrahepatic cholestasis (69), thus allowing a better clinical state before liver transplantation. In adults, UDC is reported to be beneficial in parenteral nutrition-associated cholestasis (70), benign recurrent intrahepatic cholestasis (71), cholestasis of pregnancy (72) and in alcoholic cirrhosis (73). UDC has also been found to reverse cholestasis in a graft-versus-host liver disease in bone marrow transplant recipients (74). Accumulation of endogenous bile salts in the liver, as encountered in cholestasis, is supposed to generate immunological disorders (75,76). In contrast, UDC treatment has been shown to reduce aberrant HLA class I expression on hepatocytes (11) but also HLA class I+II expression on bile duct cells (77) where PBC is supposed to originate. UDC could act on HLA expression either directly or indirectly by improving cholestasis. In addition, Yoshikawa et al. (78) have also demonstrated the suppressive effect of UDC on cytokine production by lymphocytes in patients with PBC. These hypotheses have led to experiments in the liver transplantation where immunological disorders appear similar to those of PBC, UDC could have the following effects: improvement of bile flow and diminution of potential endogenous bile salt toxicity, modulation of HLA expression and diminution of drug-induced cholestasis with, for example, cyclosporine A. In 1990, a Swedish team first described the absence of acute rejection after UDC intake in a controlled study (against 75% in controls), together with improvement of liver tests (79). The number of patients was 11 and 8 for the treated and control groups respectively, and the mean evaluation period was 5 months. Concordant results have been published by the same team on 33 patients (vs the same 8 controls) (80) with 15% acute rejection after a 1month study. These encouraging reports, however, suffer from methodological problems. A long-term and multicenter, randomized, double-blind study versus placebo is under way (R. Poupon, personal communication), which may shed light on UDC's positive effect on rejection in liver transplantation.

HEPATOPROTECTION BY HYDROPHILIC BILE SALTS

Mechanisms of Action of Bile Acids

Bile acid-related toxicity is a constant feature of cholestatic liver diseases, but can also participate in certain cytolytic diseases such as chronic hepatitis (81). It is thought to depend largely on the proportion of hydrophobic versus hydrophilic bile salts in the bile acid pool (9,10). Hydrophobicity of individual bile salts can be defined using reversed phase high performance liquid chromatography (C18-HPLC) (82-84). Hydrophobicity decreases in the following order: Deoxycholate>Chenodeoxycholate>Cholate> Ursodeoxycholate>]3 Muricholate. Slightly different results are obtained with the octanolwater partition method (85), where UDC acid appears less hydrophilic than cholic acid. The HPLC methodology predominantly emphasizes the apolar interaction between the ]3 hydrophobic face of the bile acid molecule and the C18 stationary phase. Consequently, the hydrophobicity of bile salts, thus determined, seems particularly adapted to predict many biological properties such as solubilization of cholesterol and phospholipids (86-92) and disruption of membranes (93,94)~ Concerning hydrophobic bile salts such as chenodeoxycholate and deoxycholate, it has been shown that: h7 vitro, these bile salts self-associate at low concentrations (95), their capacity to solubilize lecithins and cholesterol in micellar aggregates is large (87,88), their own solubility in lipids is large (96) and they are surface active molecules (86). All of these characteristics demonstrate the high affinity of these bile salts for lipids. They are cytotoxic from bile salt concentrations of 0.1-1 mM, in a dose-dependent manner, for red blood cells (97,98), mast cells (99) and hepatocytes (3-5). Hydrophobic bile salts seem to be toxic as a consequence of their great interaction with cell membranes. In contrast, very hydrophilic bile salts such as UDC and ]3 muricholate are less surface active than hydrophobic ones, they self-associate at larger concentrations, their solubility in lipids is lower and they have a limited detergent capacity (86-92,100). These bile salts have little tendency to partition into membranes and to solubilize membrane lipids. Consequently, UDC has only a slight damaging effect upon biological membranes as confirmed by h7 vitro studies conducted on red blood cells (98), hepatocytes (4) and liposomes (101). Taurocholate, which is less hydrophilic than TUDC as determined by HPLC, is cytotoxic at high concentrations (94,102,103). Human bile contains large amounts of hydrophobic bile salts. Chenodeoxycholate and deoxycholate represent more than 50% of the total bile acid pool, whereas UDC never exceeds 3% (104). In some pathological situations

263 such as cholestasis which is accompanied by a partial loss of vectorial secretion of bile salts, an accumulation of the conjugates of chenodeoxycholate and deoxycholate occurs in the liver cell. Moreover, it is noteworthy that the distribution of bile salts in the liver cell is not homogeneous and that their partitioning into subcellular organelles is dependent on the bile salt species (105). The mean concentration of bile salts in the human hepatocyte is estimated to be 50 pM (104). Larger local concentrations could be found in the canalicular and mitochondrial regions, especially in a cholestatic situation. Taurochenodeoxycholate concentrations of 300-500 pM are able to induce a surface activity (100) large enough to cause membrane damage (99). These considerations are supported by the fact that chenodeoxycholate used for gallstone dissolution may lead to morphological abnormalities such as mitochondrial changes (106) and signs of liver cell necrosis (107). With UDC treatment, the critical surface pressure sufficient to cause membrane alternations could only be attained with intrahepatic UDC concentrations of 2 mM (100), which is highly improbable. Accordingly, UDC has never been reported to induce liver injuries in therapeutic doses. Membrane disturbances would occur with a fl muricholate intrahepatic concentration of 5 mM, since ]3 muricholate is less surface active than UDC (100). Recent findings indicate that UDC species may protect the cell membrane against disruption by more hydrophobic bile salts. In vitro experiments have shown that TUDC protected red blood cells (94,108) and hepatocytes (5,94) from chenodeoxycholate-induced cytolysis as determined by the decrease in enzyme release into the medium of cytosolic lactate dehydrogenase or hemoglobin. Using electron spin resonance spectroscopy, Giald~tuna et al. (109) found that UDC protected isolated basolateral liver plasma membranes against the damaging effect of chenodeoxycholate. Similarly, in vivo, UDC limited the severity of liver disease induced by bile duct ligation in hamsters (110) and rats (111) and TUDC improved the biliary secretion of taurocholate and taurochenodeoxycholatetreated rats (100,103,112,113). A similar improvement has been obtained with rats receiving ethinyl estradiol (36) or cyclosporine A (38,39). These molecules are both hydrophobic and thus may be incorporated and even accumulate between the hydrocarbon chains of membrane phospholipids. Drug administration leads to a decrease in bile flow secretion and to an increase in plasma bilirubin levels. UDC treatment stimulates the biliary elimination of estrogen (37) or cyclosporine A (38,39), improves the clearance of bilirubin and restores a quasi normal choleresis. Therefore, h7 vivo, UDC conjugates appear to protect

264 hepatocytes by facilitating the biliary elimination of potentially toxic molecules, thereby preventing their accumulation in the liver. To explain this protective effect, it may be assumed (100,113) that UDC conjugates, by linking to the membrane surface, would hamper the insertion of hydrophobic molecules into cell organelles where they have injurious effects. The hydrophilic interactions of UDC conjugates with the polar heads of membrane phospholipids could modify the headgroup repulsion in phospholipids and lead to a larger separation of the phospholipid molecules. UDC conjugates binding at the interfacial polar layer of biological membranes and the subsequent structural changes in these membranes may explain the poor incorporation of hydrophobic species into phospholipids. A recent study has confirmed that T U D C and glycoursodeoxycholate are bound to the interface of the membrane (114). If such mechanisms occurred, it would be useful to search for new hydrophilic bile salts, fl muricholate, which is more hydrophilic than UDC (89,90,100) due to an additional hydroxyl group at the 6fl position, would seem to be a good candidate. Experiments in animals (100,115) have confirmed that fl muricholate efficiently prevents the hepatic dysfunctions induced by hydrophobic molecules. Since fl muricholate is not metabolized by human intestinal flora (116), it could, in contrast to UDC, constitute a very large part of the bile acid pool. Thus, the enhanced hydrophilicity of bile resulting from the presence of a hydrophilic bile salt is a seductive attempt to explain the observed beneficial effects. In support of this, enhanced UDC levels in both bile and serum at the expense of other bile salts after chronic administration have been noted. A few clinical studies (63,117) found no correlation between the improvement in liver function tests and the percentage of UDC in bile. Whether or not enrichment of bile in UDC results mainly from a competitive inhibition with endogenous bile salts at the ileal active transport site is still debated (118,119). It is noteworthy that there is a hydrophilicity limit beyond which a bile salt loses its efficacy in cell detoxification. Thus, very polar molecules such as tauroursocholate or taurodehydrocholate cannot counteract the effects of hydrophobic steroids in rat liver (37,120). Modulation by UDC of abnormally expressed HLA antigens on hepatocytes and epithelial bile duct cells (11,77) has widened the field of the molecule's properties. It would be of interest to correlate this with the interaction of UDC with membranes and with the constantly underlying hydrophilic-hydrophobic balance since accumulated toxic bile salts are supposed to alter HLA expression (11). Lastly, UDC, which can produce a bicarbonate-rich

P.E. QUENEAU and J. C. MONTET hypercholeresis (121,122) possibly resulting from the cholehepatic recycling of protonated UDC (123), could facilitate the elimination of toxic bile components in cholestatic disease. However, UDC does not totally express its properties in the case of bile duct paucity, as experienced in late stage cholestatic diseases. Overall, one could suggest that if some of the various mechanisms of action of UDC are common in all cholestatic conditions, others could be specific to certain patterns. Thus diminution of endogenous bile salt-related injuries is probably a constant phenomenon. On the other hand, the immunological properties of UDC may be of particular concern in PBC, primary sclerosing cholangitis or even liver transplantation by acting on a more etiological side. Similarly, the protective effect on membranes and the enhancement of choleresis may represent the major impact of UDC on drug-induced hepatotoxicity. In addition, increased biliary secretion may be beneficial to the nutritional state, as described for cystic fibrosis, and to the oral availability of lipophilic treatments, as reported for cyclosporine-A-treated patients after liver transplantation (124,125).

Conclusion UDC is now considered an effective treatment of various cholestatic conditions, regardless of origin. Thanks to its hydrophilic properties, resulting in a modification of the hydrophilic-hydrophobic balance of the bile acid pool, UDC is thought to act mainly by preventing membrane deletion from accumulated endogenous bile salts. This is particularly reflected by the action on drug-induced cholestasis, as newly reported in this paper. Moreover, an additional immunological role of UDC is highly appealing and is the subject of several exciting trials which are evaluating the molecule's influence on acute rejection in liver transplantation. However, although short-term studies are all confirmative, long-term studies sometimes reveal discrepancies that question the clinical influence of UDC on life expectancy. Nevertheless, the difficulty of conducting long-term trials must be considered, especially with relatively rare diseases such as PBC and primary sclerosing cholangitis. Poor methodology may markedly alter the results. Nevertheless, it is encouraging that two well-conducted studies clearly assess the clinical benefit o f a UDC treatment in PBC. UDC's poor effect on late-stage disease is another possible reason for these contradictory results since patient populations differ largely from one study to another. Moreover, despite a possible role in immunological modulation, UDC appears to act mainly on self-induced cholestasis caused by toxic bile salt accumulation and not on the primary pro-

HEPATOPROTECTION BY HYDROPHILIC BILE SALTS

cesses. Thus, a l t h o u g h this substance m a y slow the evolution a n d i m p r o v e biological a n d clinical parameters, it m a y n o t significantly alter the course o f the disease. W h e t h e r increasing the doses could help, as d e m o n s t r a t e d by some a u t h o r s in cystic fibrosis, must be clarified. A t the m o m e n t , U D C therapy seems to be of clinical interest preferentially for chronic cholestatic liver diseases such as PBC, p r i m a r y sclerosing cholangitis a n d cystic fibrosis. T r e a t m e n t should be initiated early, with a starting dose of 15 mg/kg per day, increasing in case of u n r e s p o n siveness or a b s o r p t i o n disorders, such as in cystic fibrosis. U D C still offers i m p o r t a n t fields of investigations, which it is to be hoped, will increase its indications. Particularly interesting is the association of U D C with other effective b u t potentially toxic therapies of chronic liver diseases: cyclosporine A, methotrexate, D penicillamine, colchicine a n d others. Besides a n additive effect, U D C could facilitate their use either by allowing a reduction in their doses or by directly preventing side-effects on the liver. In addition, long-term a d m i n i s t r a t i o n o f U D C could be useful by slowing the e v o l u t i o n of the disease a n d thus creating better c o n d i t i o n s for liver t r a n s p l a n tation. In that respect, a positive action of U D C on the p r e v e n t i o n of acute rejection could be of great benefit. Recent well-conducted, multicenter studies have greatly helped to define U D C ' s place in clinical practice, a n d conclusions from new studies in other fields o f research are impatiently awaited. However, certain questions still rem a i n u n a n s w e r e d , which could benefit from new methodological tools such as meta analysis. Lastly, other hydrophilic bile salts such as fl muricholate, which could constitute a very large part of the bile acid pool, might be m o r e effective than U D C .

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