Treatment of chronic cholestasis: What we know and what we will know?

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Abbreviations

A⁻

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⁻

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⁻

organic anion

OATP

organic anion transporting polypeptide

OC⁺

organic cation

PBC

primary biliary cirrhosis

PL

phospholipid

PPARα

peroxisome proliferator‐activated receptor α

PSC

primary sclerosing cholangitis

SLC10A

solute carrier family 10A

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 introduced2 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 associates5 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. 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. 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 level7 (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.

Figure 1.

Molecular determinants of bile formation. Modified from New England Journal of Medicine.7 Copyright 1998, Massachusetts Medical Society. Abbreviations: A⁻, anion; AE2, anion exchange protein 2; BS⁻, bile salts; GSH, glutathione; OA⁻, organic anion; OATP, organic anion transporting polypeptide; OC⁺, organic cation; PL, phospholipid.

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/beta‐klotho 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 proliferator‐activated receptor α (PPARα), 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 (PPARα, δ, and γ). Fenofibrate, a PPARα agonist, also has demonstrated efficacy in patients with PBC. PPARα 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. PPARα also inhibits CYP7A1 and BA synthesis, as well as having beneficial anti‐inflammatory responses10 (see Fig. 2).

Figure 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‐α, tissue necrosis factor‐α.

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.11

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 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 PPARα 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.

Figure 3.

Different drugs under development for cholestatic liver disease act at different sites. Abbreviation: PL, phosphatidylcholine.

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 low‐prevalence 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.