Treatment of Chronic Cholestasis: What We Know and What We Will Know?

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1 REVIEW Treatment of Chronic Cholestasis: What We Know and What We Will Know? James L. Boyer HISTORICAL PERSPECTIVES For many years, the treatment of cholestatic liver disease was limited to surgical relief of bile duct obstruction and therapies that focused on symptomatic relief from pruritus and other complications of these diseases. The mainstay for treatment of pruritus was and still is the administration of the anion exchange resin, cholestyramine. 1 Alternative therapies such as rifampin, a cytochrome p-450 Cyp3A microsomal enzyme inducer, were introduced 2 with some success. Less benefit came from third-line treatments that included opiate receptor antagonists (naltrexone and nalmefene) 3 and more heroic measures that included plasmapheresis, charcoal hemoperfusion, and more recently, MARS. 4 Treatment for complications of cholestasis focused on prevention/reduction in progression of osteoporosis with the use of bisphosphonates, risedronate and alendronate. Fat-soluble vitamin deficiencies brought on by the impaired excretion of bile acids (BAs) and the resulting steatorrhea called for supplementation with vitamin D to prevent osteomalacia, vitamin K for the coagulopathy brought about by malabsorption of vitamin K, and vitamin A for night blindness, mostly observed in pediatric causes of cholestasis. The demonstration by Poupon and associates 5 in 1997 that ursodeoxycholic acid seemed to prolong the course of patients with primary biliary cirrhosis (PBC) provided the first and only medication at that time for primary treatment of a cholestatic disease. Although the U.S. Abbreviations: A 2, anion; ABCC4, ATP-binding cassette subfamily C member 4; ABST, apical sodium-dependent bile salt transporter; AE2, anion exchange protein 2; BA, bile acid; BS 2, bile salts; BSEP, bile salt export pump; CYP, cytochrome p-450; FXR, farnesoid X receptor; FGF, fibroblast growth factor; GSH, glutathione; MARS, molecular adsorbents recirculation system; MDR3, multidrug resistance-associated protein 3; NTCP, sodium taurocholate cotransporting peptide; OA 2, organic anion; OATP, organic anion transporting polypeptide; OC 1, organic cation; PBC, primary biliary cirrhosis; PL, phospholipid; PPARa, peroxisome proliferator-activated receptor a; PSC, primary sclerosing cholangitis; SLC10A, solute carrier family 10A. From the Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. Potential conflict of interest: Nothing to report. Received 30 July 2016; accepted 25 September 2016 View this article online at wileyonlinelibrary.com VC 2016 by the American Association for the Study of Liver Diseases 140 CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

2 FIG 1 Molecular determinants of bile formation. Modified from New England Journal of Medicine. 7 Copyright 1998, Massachusetts Medical Society. Abbreviations: A 2, anion; AE2, anion exchange protein 2; BS 2, bile salts; GSH, glutathione; OA 2, organic anion; OATP, organic anion transporting polypeptide; OC 1, organic cation; PL, phospholipid. Food and Drug Administration approved the use of ursodeoxycholic acid for PBC in 2004, the drug has been widely used in other cholestatic disorders and was shown to improve liver tests in primary sclerosing cholangitis (PSC), cholestasis of pregnancy, and cystic fibrosis. It is also used in some cases of drug-induced cholestasis, graft versus host disease, and post-liver transplant cholestasis despite lack of clinical trial evidence of efficacy. 141 CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

3 FIG 2 Fibrates and cholestasis. Reproduced with permission from Hepatology. 10 Copyright 2015, American Association for the Study of Liver Diseases. Abbreviations: ABCB4, ATP binding cassette family B4; HNF4, hepatocyte nuclear factor 4; IL, interleukin; NF-kB, nuclear factor kappa beta; PC, phosphatidylcholine; TNF-a, tissue necrosis factor-a. Indeed, American Association for the Study of Liver Diseases guidelines do not recommend its use in PSC. Multiple studies have attempted to evaluate its mechanisms of action, which still remain controversial, but include increasing the hydrophilicity of the bile pool, increasing bile flow, thus facilitating the elimination of hydrophobic BAs, stimulating the hydroxylation of more hydrophobic BAs such as lithocholic acid, stimulating exocytosis, and blocking apoptosis. 6 The field of cholestasis was greatly stimulated by the molecular evolution in the mid-1990s, which resulted in elucidating the mechanisms of bile formation and cholestasis at the molecular level 7 (Fig. 1). The clinical relevance of these discoveries was brought home when mutations in canalicular BA and lipid transporters were found to account for the several primary familial intrahepatic cholestasis syndromes (types 1, 11, and 111) in infants, as well as some cases of benign recurrent cholestasis, intrahepatic cholestasis of pregnancy, low-phospholipid-associated cholelithiasis, and some forms of chronic idiopathic cholestatic liver diseases in adults. The next major event came from the nuclear receptor field with the discovery that BAs were the physiological ligands for the previously orphaned farnesoid X receptor (FXR). 8 FXR response elements were soon discovered in bile salt export pump (BSEP), multidrug resistance-associated protein 3 (MDR3), and SHP (an inhibitor of CYP7a, the rate-limiting enzyme in the conversion of cholesterol to BA and NTCP/SLC10A, the conjugated BA uptake transporter, sodium taurocholate cotransporting polypeptide). FXR response elements were also discovered in fibroblast growth factor (FGF) receptors 15 (mice) and 19 (humans) in the ileum. BA activation of these growth factors results in their increased synthesis and release into the portal circulation whereby they interact with the FGF receptor 4/betaklotho complex on the hepatocyte sinusoidal membrane. This interaction sets up a signal transduction pathway leading to the inhibition of CYP7A1 and resultant reduction in BA synthesis and the BA pool. Thus, FXR became recognized as a master regulator of the enterohepatic circulation and a prime therapeutic drug discovery target for cholestatic liver disease. 9 Recent U.S. Food and Drug Administration approval of Intercept Pharma s potent FXR agonist, obeticholic acid, as alternative therapy for PBC is the first clinical outcome of this sequence of discoveries. Another nuclear receptor, peroxisome proliferatoractivated receptor a (PPARa), has also emerged as a potential druggable target for cholestatic liver disease. Fibrates are ligands for the PPARs and a number of clinical studies, predominantly in patients with PBC, have demonstrated significant improvement in alkaline phosphatase after administration of bezafibrate, which activates all three isoforms (PPARa, d, andg). Fenofibrate, a PPARa agonist, also has demonstrated efficacy in patients with PBC. PPARa response elements are prominent in the canalicular membrane phospholipid export pump (MDR3/ABCC4), and the biliary excretion of phosphatidylcholine by this transporter may improve the buffering of BAs in the bile, thereby protecting the biliary tree from bile-acid-induced toxicity. PPARa also inhibits CYP7A1 and BA synthesis, as well as having beneficial anti-inflammatory responses 10 (see Fig. 2). Advances in therapy of patients with primary familial intrahepatic cholestasis syndrome type 2 also have been made where administration of sodium phenyl butyrate seems to act as a chaperone to facilitate targeting of mutant BSEP to the apical membrane in a few patients CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

4 FIG 3 Different drugs under development for cholestatic liver disease act at different sites. Abbreviation: PL, phosphatidylcholine. FUTURE DIRECTIONS Nevertheless, despite these considerable advances, much remains to be discovered. We still do not know the pathogenesis of either PBC or PSC. Genome-wide association studies in large populations of these patients have not generally led to better understanding of their cause or pathogenesis. An exception may be the FUC1 gene, which regulates intestinal mucous production and where mutations have been discovered in patients with PSC, pointing to possible gut-liver pathogenic mechanisms. Other roadblocks include the lack of good animal models for these diseases and the unlikely possibility that they may be forthcoming. Clinical trials with orphan diseases such as PBC and PSC are often underpowered, and these studies are traditionally lacking in the United States compared with Europe. International collaborations are only just beginning to be developed. What alternative treatments for cholestatic liver disease may emerge in the near future? With an increase in understanding of biliary pathophysiology, new therapeutic advances seem likely. For example, several novel agents are currently in the developmental stage including a variant of FGF-19 that lacks oncogenic activity. This agent inhibits CYP7A1 activity and reduces BA synthesis and is currently being assessed in a phase 2 multicenter trial in primary biliary cholangitis. Inhibitors of the ileal BA transporter modulate BA synthesis and decrease serum BAs. Apical sodium-dependent bile salt transporter (ABST) inhibitors are now in a phase 1 trial in healthy 143 CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

5 adults. Nor-ursodeoxycholic acid is in phase 2 trials in a multicenter study in patients with sclerosing cholangitis. WHAT ABOUT COMBINATION THERAPIES? Figure 3 illustrates several targets that are amenable to drug therapy but that act at different sites. A key target is CYP7A1 because it regulates the synthesis of BAs and its inhibition results in a diminution of the BA pool size. Drugs including obeticholic acid, FGF-19, and retinoic acid appear to act by this mechanism. Other targets at the level of the hepatocyte include the PPARs. Both bezafibrate and fenofibrate act as pan PPAR isoform and PPARa isoform agonists, respectively, and have been shown to improve liver function tests in PBC and in a few patients with PSC. Another site that regulates BA metabolism is located at the level of the ileum and kidney. Here inhibitors of the ABST in the ileum by A4250 result in increased fecal excretion of BAs, whereas inhibition of ABST in the proximal tubule of the kidney results in increases in urinary BA excretion. It remains to be determined whether combinations of these drugs with or without therapy with UDCA might enhance the anticholestatic properties of these drugs when administered as monotherapy. If we are to achieve answers to these important questions in these lowprevalence cholestatic diseases, a multicenter effort and partnerships with both federal and pharmaceutical sources will be required. ACKNOWLEDGMENT The author expresses his thanks to Carol Soroka, Ph.D., for her critical review of the manuscript and for preparation of Figure 3. CORRESPONDENCE James Boyer, Department of Internal Medicine, Yale University School of Medicine, P.O. Box , New Haven, CT james.boyer@yale.edu REFERENCES 1) Mela M, Mancuso A, Burroughs AK. Review article: pruritus in cholestatic and other liver diseases. Aliment Pharmacol Ther 2003;17: ) Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology 1988;94: ) Bergasa NV, Alling DW, Talbot TL, Wells MC, Jones EA. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol 1999;41: ) Campli CD, Gaspari R, Mignani V, Stifano G, Santoliquido A, Verme LZ, Proietti R, et al. Successful MARS treatment in severe cholestatic patients with acute on chronic liver failure. Artif Organs 2003;27: ) Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113: ) Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002;36: ) Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Eng J Med 1998;339: ) Karpen SJ. Bile acids go nuclear! Hepatology 1999;30: ) Cai SY, Boyer JL. FXR: a target for cholestatic syndromes? Expert Opin Ther Targets 2006;10: ) Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology 2015;62: ) Gonzalez E, Grosse B, Schuller B, Davit-Spraul A, Conti F, Gueltier C, Cassio D, Jaquemin E. Targeted pharmacotherapy in progressive familiar intrahepatic cholestasis type 2: Evidence for improvement of cholestasis with 4-phenylbutyrate. Hepatology 2015;62: CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD