Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment

Abstract

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic cholangiopathy that can progress to cirrhosis, end-stage liver disease, hepatobiliary cancer, and/or colorectal cancer. The course of PSC is often complicated by portal hypertension, symptoms of cholestasis, and recurrent bacterial cholangitis, among other conditions, with a consequent decrease in survival (median, approximately 20 years) and quality of life. The etiopathogenesis of PSC remains poorly understood, and, as such, pharmacotherapy has yet to be definitively established. Despite its rarity, PSC is the fifth leading indication for liver transplantation (LT) in the United States. Although the only intervention known to extend survival of patients with PSC, LT is costly and invasive, and recurrent PSC affects approximately 30% of LT recipients. Over the past several years, owing in part to progress in the understanding of PSC, novel pharmacotherapeutics have been developed, some of which are currently in the PSC clinical trial pipeline. Here, in the first of a 2-part series, we provide a review and update of the epidemiology, etiopathogenesis, clinical features, and treatment of PSC. The second part of the series will focus on cancer risk, prevention, and surveillance of PSC.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by stricturing of the intra- and/or extrahepatic ducts. PSC represents an important cause of morbidity and mortality in Western societies, with many patients ultimately requiring liver transplantation (LT) due to end-stage liver disease or other complications.^1-4 Patients with PSC are also at significantly increased risk of hepatobiliary cancer and colorectal cancer (CRC), particularly in the 70% of patients who also have inflammatory bowel disease (IBD).^5-7

Currently, there is no known pharmacotherapy for PSC that halts disease progression. Numerous agents have been tested, although none have yielded convincingly promising results.^8-26 The rarity of PSC, its elusive etiopathogenesis, its long natural history, the challenges of retaining patients long enough in clinical trials to achieve sufficient endpoints, and the lack of validated surrogate biomarkers (eg, of treatment success) remain major barriers to developing effective and safe therapies for PSC.

Given the progressive nature of PSC and its associated morbidity and mortality, there is a large unmet need for effective medical therapies for this disease. Here, in the first of a 2-part series, we provide an overview and update of PSC, including its epidemiology, etiopathogenesis, clinical features, associated disorders, and potential therapies. The second part of the series will focus on cancer risk, prevention, and surveillance of PSC.

Clinical Epidemiology

PSC is most common in Northern European countries and North America, where the reported incidence and prevalence range from approximately 0.5 to 1.3 cases per 100,000 person-years and 3.85 to 16.2 cases per 100,000 person-years, respectively.^27-29 A recent British study reported an incidence of 0.68 per 100,000 person-years and a prevalence of 5.58 per 100,000 person-years³⁰; these figures represent the highest incidence and prevalence reported to date in the United Kingdom. PSC appears to be much less common in Southern Europe³¹ and Southeast Asia,³² although in many regions (eg, much of the Eastern Hemisphere), its incidence and prevalence have not been well studied. The prevalence of PSC appears to be considerably higher in Australia than in New Zealand, although both areas have a higher prevalence than Southern Europe and Southeast Asia.^33,34 Epidemiologic studies of PSC in pediatric patients are scarce; however, the incidence and prevalence of PSC appear to be lower in children than in adults.³⁵

As noted previously, approximately 70% of patients with PSC also have IBD, mainly ulcerative colitis,³⁶ whereas only 2% to 8.1% of patients with IBD have PSC,³⁷ although rates reach up to 14%.³⁸ The exact nature of the PSC-IBD relationship is not well understood. Notably, PSC and IBD can be diagnosed simultaneously, although in many patients, there is a dissociation in the time of diagnosis of PSC and IBD (with the diagnosis of IBD typically being made first). In addition, PSC can present after proctocolectomy for IBD, and IBD can present after LT for PSC.³⁹ The PSC-IBD phenotype is associated with milder colitis, rectal sparing, and backwash ileitis, and the extent and distribution of colitis are associated with the timing of the IBD diagnosis (ie, pre- vs post-PSC).⁴⁰ Pediatric PSC-IBD is generally more severe than adult-onset disease.^41,42

It should be highlighted that PSC has phenotypic variants (Table 1) in addition to overlap syndromes and various disease mimics, whether biochemical, cholangiographic, or other types (Table 2). Recognizing and distinguishing these variants and mimics is critical for ensuring appropriate management, particularly for conditions with readily available therapies.

Table 1.

Phenotypic Variants of PSC

Varianta	Cholangiographic Features	Liver Histology Features
Classic PSC	Multifocal intrahepatic and extrahepatic strictures and resultant upstream (ie, proximal) ductal dilation	Typical changes (ie, nonsuppurative paucicellular cholangitis, periductal fibrosis, ductular reaction, and ductopenia)
Intrahepatic PSC	Multifocal intrahepatic strictures and resultant upstream (ie, proximal) segmental ductal dilation	Typical changes
Extrahepatic PSC	Extrahepatic-only strictures and resultant upstream (ie, proximal) ductal dilation	Nondiagnostic or nonspecific features of cholestasis, particularly in early-stage disease
Small-duct PSC	Normal findings	Typical changes

^aAll of these variants will generally have a cholestatic serum biochemical profile, although a small minority of patients can have normal serum liver test results.

PSC, primary sclerosing cholangitis.

Table 2.

Causes of Secondary Sclerosing Cholangitis and Mimics of PSC

Infectious Causes	AIDS cholangiopathy (eg, Cryptosporidium parvum, cytomegalovirus)
	Helminthic infection (eg, Clonorchis, Opisthorchis, Ascaris)
	Recurrent pyogenic cholangitis (also referred to as oriental cholangio-hepatitis)
Intrinsic or Extrinsic Compressive Causes (Benign or Malignant)	Mirizzi syndrome
	Cholangiocarcinoma
	Diffuse intrahepatic malignancy
	Compressive lymphadenopathy
	Portal hypertensive biliopathy
	Postoperative strictures
	Chronic pancreatitis
Immunologic Causes	IgG4-associated cholangiopathy
	Eosinophilic cholangitis
	Mast cell cholangiopathy
	Histiocytosis X
	Systemic vasculitis
	Hepatic allograft rejection
	Primary biliary cholangitis
Ischemic Causes	Posttransplant nonanastomotic strictures
	Postintraarterial chemotherapy
	Postradiation therapy
Congenital and/or Idiopathic Causes	Choledochal cyst (eg, Caroli disease)
	Progressive familial intrahepatic cholestasis

IgG4, immunoglobulin G subclass 4; PSC, primary sclerosing cholangitis.

Etiopathogenesis

The etiopathogenesis of PSC remains uncertain, although PSC is increasingly thought to be a heterogeneous, complex disorder with environmental, immunobiologic, and genetic underpinnings (Figure). In addition, the epithelial cells lining the bile ducts (ie, cholangiocytes) are now thought to be not only a target of injury in PSC but also actively involved drivers in the course of disease.^3,43 Indeed, cholangiocytes are a morphologically, biochemically, and functionally dynamic population of cells. Various hypotheses regarding the etiopathogenesis of PSC have been proposed, and a prevailing theme is that predisposing genetic elements and (as of yet uncertain) environmental exposures intersect and together play a fundamental role (Figure).^1,2

Figure.

A conceptual model of the etiopathogenesis and natural history of PSC. Biliary epithelial cells (ie, cholangiocytes) exist in an environment with multiple potential etiologic mediators of hepatobiliary injury. Approximately 95% of bile acids are reabsorbed in the terminal ileum and, together with other intestinal molecules, are transported back to the liver via the enterohepatic circulation. Portal blood flows into hepatic sinusoids, wherein hepatocytes may take up and modify these molecules and secrete them into bile, which is synthesized by hepatocytes and delivered into canaliculi by means of specialized membrane transporters. Canalicular bile drains into the biliary tree and is modified by cholangiocytes as it percolates through the biliary tree. Cholangiocytes recognize (eg, through cell surface receptors) and react to various molecules and may release chemokines/cytokines, growth factors, and morphogens, initiating both autocrine and paracrine signaling cascades. With respect to the source of hepatobiliary injury, it remains uncertain whether there is (1) increased exposure to microbial molecules (eg, through the enterohepatic circulation, potentially facilitated by compromised intestinal barrier function), (2) alteration to the repertoire of microbial and other intestinal molecules (eg, due to microbial dysbiosis, xenobiotics), and/or (3) an aberrant or exaggerated cholangiocyte (or another hepatic cell) response to these molecules (eg, increased induction of cholangiocyte senescence and the senescence-associated secretory phenotype). In addition, host immunogenetics (4) likely modulate the development and/or impact of any of these variables and thus play a role in determining whether hepatobiliary injury resolves or if it persists and results in chronic disease (ie, PSC). These variables may also determine whether PSC progresses to its associated major clinical endpoints, including CCA and cirrhosis. Further investigation of the cellular, molecular, and microbial interactions and signaling represented in this figure is underway and expected to advance understanding of the etiopathogenesis of PSC.

CCA, cholangiocarcinoma; HLA, human leukocyte antigen; NOD, nucleotide-binding oligomerization domain receptor; PSC, primary sclerosing cholangitis; TLR, toll-like receptor.

Perhaps the most contemporary and substantiated hypothesis regarding the etiopathogenesis of PSC, although still a work in progress, is the PSC-microbiome hypothesis.^44,45 This hypothesis, which represents an expansion of the leaky gut hypothesis, is compatible with the aforementioned theme of environmental exposures and the notion that cholangiocytes play a central role in PSC, and is based on the association between PSC and IBD and the therapeutic benefits seen with specific antibiotics. The hypothesis posits that PSC may develop as a result of (1) increased enterohepatic circulation of microbial molecules (possibly facilitated by compromised intestinal barrier function), (2) alterations in microbial diversity and/or the repertoire of metabolites (eg, due to intestinal microbial dysbiosis), and/or (3) an aberrant or exaggerated cholangiocyte response (eg, induction of cholangiocyte senescence and senescence-associated secretory phenotype) to microbial molecules.^3,45,46 This is supported by various observations in vitro,^43,47,48 in animal models,^49-53 and in human PSC.^1,3,54-58

Recently, several studies have explored the potential etiopathogenetic role of the microbiome in PSC. Compared to healthy controls and patients with IBD alone, patients with PSC have decreased microbial diversity and overrepresentation of Escherichia, Fusobacterium, Enterococcus, Lactobacillus, Blautia, Veillonella, Barnesiellaceae, Lachnospiraceae, Megasphaera, Rothia, Ruminococcus, and Streptococcus.^59-65 Conversely, patients with PSC have decreased populations of Clostridium cluster II, Prevotella, Roseburia, Adlercreutzia, and Bacteroides compared to healthy individuals and patients with IBD alone.^60,64,66 Additionally, patients with PSC-IBD have a distinct bile-acid profile compared to patients with IBD alone; the serum bile-acid pool is increased, but the stool bile-acid pool is decreased in patients with PSC-IBD compared to patients with IBD alone.⁶⁵ The unique microbial signature in patients with PSC-IBD is thought to lead to changes in the stool bile-acid pool (or vice versa), which could ostensibly explain the increased risk for CRC in PSC-IBD; however, further studies are needed.

The role of genetics in the development and/or progression of PSC has long been suspected and is based on several lines of data. First, the risk of PSC is significantly increased in offspring and siblings of patients with PSC (hazard ratio, approximately 11).⁶⁷ Second, genome-wide association studies (GWASs) suggest that the human leukocyte antigen (HLA) gene family collectively represents the strongest risk locus associated with PSC⁶⁸; associations have been described with both class 1 and 2 HLAs, including B8, DR3, DR2, and A1,⁶⁹ and with select haplotypes.⁷⁰ Moreover, variations in MICA (major histocompatibility complex class I–related MIC gene family) are associated with PSC predisposition; for example, independent of other HLA haplotypes, the MICA 002 allele appears to be associated with a significantly reduced risk of developing PSC, whereas the MICA 008 allele is associated with an increased risk.⁷¹ Third, non-HLA PSC susceptibility and modifier genes have been identified, including (but not limited to) stromelysin-1 (ie, matrix metalloproteinase 3) and intracellular adhesion molecule 1.^72,73 In addition, recent GWASs have identified associations between PSC and (1) the fucosyltransferase 2 gene (found to influence the microbial community composition of the bile),⁷⁴ (2) the IL2RA gene (which regulates the number of FOXP3[+] regulatory T cells in peripheral blood),⁷⁵ (3) various other risk loci,^76,77 and (4) IBD at several new risk loci, including genetic variants associated with PSC progression.⁷⁸

It is worth mentioning that numerous animal models have been developed to study PSC. Given the uncertainties regarding the etiopathogenesis of PSC, it is not surprising that no single model has fully recapitulated its biochemical, cholangiographic, histologic, and premalignant features, as reviewed recently.⁷⁹ For example, the most widely studied model, the mdr2 (ABCB4) knockout mouse model, exhibits biochemical,⁸⁰ histologic,⁸¹ and cholangiographic features of PSC^79,82; however, there is no male predominance, disease severity appears to be greater in female mice (not corresponding to PSC), there is no association with IBD or cholangiocarcinoma (CCA), and the primary mechanism of injury is not representative of PSC. Thus, there is no consensus regarding the optimal model, which has hindered development of new therapies. Of note, other murine models include the experimental biliary obstruction murine model (C57BL/6J), chemically induced cholangitis models using agents such as lithocholic acid and 3,5-diethoxycarbonyl-1,4-dihydrocollidine, and models involving biliary epithelial and endothelial cellular injury.^79,83,84 Also of note, an in-vitro model of persistent cholangiocyte injury has recently been developed³ to facilitate the study of PSC and other cholangiopathies,⁴ and demonstrates various features seen in isolated primary PSC cholangiocytes as well as cholangiocytes in PSC liver sections.^3,43 However, although this represents a useful culture-based system, a better animal model is still needed.

Management

Pharmacotherapy

As previously mentioned, there are no approved pharmacotherapies for PSC. Ursodeoxycholic acid (UDCA) is the most extensively investigated agent in PSC, but its current use in this disease is controversial.⁸⁵ Preliminary studies of UDCA in PSC showed improvement in liver biochemistries.^86-88 However, the results of the 2 largest clinical trials of UDCA in PSC were disappointing^16,18; one trial used an intermediate dose of UDCA and showed only a trend toward statistically significant benefit, and the other trial used high-dose UDCA and was terminated early due to excess adverse events in the UDCA-treated group. Currently, some experts maintain that a trial of UDCA at intermediate doses (18-21 mg/kg body weight/day) should be considered.^1,2

Recent advances in understanding the pathobiologic pathways implicated in cholestatic liver diseases have led to the development of several new experimental agents targeting these pathways.⁸⁹ Tables 3 and 4 summarize clinical trials that have been completed and those currently underway in patients with PSC. Some of the prominent clinical trial findings are noted in the following paragraphs.

Table 3.

Completed Clinical Trials for the Treatment of PSC

Agent(s)	Sample Size, n	Study Design	Summary of Main Findings
Penicillamine14	39 vs 31 (drug vs placebo)	Double-blind, placebo-controlled	No significant effect on survival 21% stopped the drug due to side effects
Prednisone plus colchicine17	12	Open-label	Improved serum liver biochemistries No significant difference in histologic change
Methotrexate143	12 vs 12 (drug vs placebo)	Double-blind, placebo-controlled	Decrease in ALP No significant difference in histologic and cholangiographic progressions
Tacrolimus25	10	Open-label	Decrease in ALP, bilirubin, AST, and ALT 31% stopped the drug due to side effects
Colchicine19	44 vs 40 (drug vs placebo)	Double-blind, placebo-controlled	No significant improvement in symptoms, histologic progression, and survival
UDCA plus methotrexate15	19	Open-label	No effect on serum liver biochemistries 26% stopped methotrexate due to side effects
UDCA86,a	51 vs 51 (drug vs placebo)	Double-blind, placebo-controlled	Improved serum liver biochemistries No significant clinical benefit in time to death, histologic progression, doubling of bilirubin, and need for liver transplantation
UDCA16,18	76 vs 7416 (drug vs placebo) 91 vs 10118 (drug vs placebo)	Double-blind, placebo-controlled	No significant clinical benefit in primary endpoints (time to death or need for liver transplantation) in the Scandinavian trial Early termination of the US trial due to futility and significant advantage of placebo over UDCA with regard to primary endpoints (time to development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death)
Nicotine9	8	Open-label	No significant improvement in serum liver biochemistries 38% of patients reduced the dose due to adverse effects
Budesonide or prednisone plus UDCA24	6 vs 6 vs 6 (budesonide 9 mg vs prednisone 3 mg vs 10 mg)	Double-blind, randomized, pilot	Improvement in ALP and pruritus in patients treated with prednisone
Budesonide8	21	Open-label, pilot	Improvement in ALP, AST, and portal inflammation Increase in bilirubin Marked bone loss
Pentoxifylline11	20	Open-label, pilot	No significant improvement in serum liver biochemistries
Cladribine12	4	Open-label, pilot	No significant improvement in symptoms or serum liver biochemistries
Etanercept144	10	Open-label, pilot	Resolution of pruritus in 40% Increase in bilirubin No change in ALP
Mycophenolate mofetil plus UDCA145	12 vs 13 (drug vs placebo)	Double-blind, randomized	No significant improvement in serum liver biochemistries, liver histology, or cholangiographic findings
Metronidazole plus UDCA100	39 vs 41 (drug vs placebo)	Double-blind, randomized, placebo-controlled	Improvement in ALP and histology compared to UDCA monotherapy group
Mycophenolate mofetil22	30	Open-label, pilot	Improvement in ALP 23% stopped the drug due to side effects
Infliximab13	6 vs 4 (drug vs placebo)	Double-blind, placebo-controlled	No significant improvement in ALP or liver histology
Ecologic 641 (probiotic)26	7 vs 7 (drug vs placebo)	Double-blind, placebo-controlled	No significant improvement in serum liver biochemistries or symptoms
Vancomycin in pediatric patients95,96,99,146,147	19 (total of the 5 studies)	Open-label, pilot, and case series	Improvement in GGT, ALT, C-reactive protein, symptoms, and cholangiographic findings
Vancomycin or metronidazole in adults98	8 vs 9 vs 9 vs 9 (low-dose vs high-dose vancomycin vs low-dose vs high-dose metronidazole)	Randomized, double-blind	Improvement in ALP (primary endpoint) in the vancomycin groups Decrease in bilirubin in the low-dose metronidazole group and trend toward significant decrease in the low-dose vancomycin group (P=.06) Decrease in Mayo PSC risk score in the low-dose vancomycin group and low-dose metronidazole group
Vancomycin97	18 vs 11 (drug vs placebo)	Triple-blind, randomized, placebo-controlled	Improvement in ALP, GGT, and symptoms
Rifaximin21	16	Open-label, pilot	No significant improvement in serum liver biochemistries or symptoms
Minocycline20	16	Open-label, pilot	Improvement in ALP
Bezafibrate148	15	Open-label, pilot	Improvement in ALP, GGT, ALT, and AST
All-trans retinoic acid plus UDCA149	15	Open-label, pilot	Improvement in ALP and ALT
Obeticholic acid150	76 (total)b	Randomized, double-blind, placebo-controlled	Preliminary data presented at the 2017 AASLD meeting Improvement in ALP
Simtuzumab151	79 vs 77 vs 78 (drug 75 mg/day vs 125 mg/day vs placebo)	Randomized, double-blind, placebo-controlled	Preliminary data presented at the 2017 EASL meeting No significant change in ALP, hepatic collagen, and fibrosis stage
NorUDCA90	39 vs 41 vs 39 vs 40 (drug 500 mg/day vs 1000 mg/day vs 1500 mg/day vs placebo)	Double-blind, randomized, placebo-controlled	Improvement in ALP in all 3 arms Pruritus was the main side effect

^aNumerous other studies of UDCA alone have also been reported.^1,2

^b76 patients were randomized to placebo (n=25), drug 1.5 mg (n=25), and drug 5 mg (n=26) once daily for 12 weeks. Patients tolerating the drug were titrated from 1.5 mg to 3 mg (n=22) or from 5 mg to 10 mg (n=16).

AASLD, American Association for the Study of Liver Diseases; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; EASL, European Association for the Study of the Liver; GGT, gamma-glutamyl transpeptidase; norUDCA, 24-norursodeoxycholic acid; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid.

Table 4.

Clinical Trials in Progress for the Treatment of PSC

Therapeutic Agent	Study Characteristics and Outcome
Cenicriviroc (inhibitor of CCR2 and CCR5)	NCT02653625 (open-label, phase 2) Outcome: % change in ALP from baseline
BTT1023 (vascular adhesion protein-1 inhibitor)	NCT02239211 (open-label, phase 2) Outcome: % change in ALP from baseline
Curcumin (anti-inflammatory, antifibrotic, antisenescent)	NCT02978339 (open-label, phase 2) Outcome: % change in ALP from baseline
NGM282 (fibroblast growth factor 19 analog)	NCT02704364 (randomized, placebo-controlled, phase 2) Outcome: % change in ALP from baseline
GS-9674 (farnesoid X receptor agonist)	NCT02943460 (randomized, placebo-controlled, phase 2) Outcome: % change in ALP from baseline
UDCA in pediatric PSC	NCT01088607 (open-label, phase 1) Outcome: % change in GGT and ALT from baseline
Vancomycin in pediatric PSC	NCT01802073 (open-label, phase 3) Outcome: % change in ALT, GGT, MRCP findings, and biopsy findings from baseline
Mitomycin C (antineoplastic)	NCT01688024 (randomized, placebo-controlled, phase 2) Outcome: change in Mayo risk score from baseline
LUM001 (apical sodium-dependent bile-acid transporter inhibitor)	NCT02061540 (open-label, pilot, phase 2) Outcome: Safety change in fasting serum bile acid from baseline
Fecal microbiota transplantation	NCT02424175 (open-label, pilot, phase 1 and 2) Outcome: change in gut microbial profile, ALP, AST, ALT, and bilirubin from baseline

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CCR, C-C chemokine receptor; GGT, gamma-glutamyl transpeptidase; MRCP, magnetic resonance cholangiopancreatography; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid.

24-Norursodeoxycholic Acid 24-Norursodeoxycholic acid (norUDCA), a C(23) homolog of UDCA, has been found to exert anticholestatic, anti-inflammatory, and antifibrotic effects in murine models.^80,82 In a phase 2 clinical trial, 161 patients with PSC were randomized to 1 of 3 doses of norUDCA (500, 1000, or 1500 mg per day) or placebo for 12 weeks.⁹⁰ Compared to placebo, norUDCA reduced serum alkaline phosphatase (ALP) levels by 12.3%, 17.3%, and 26.0% in the 500-, 1000-, and 1500-mg arms, respectively. No difference was reported in the incidence of pruritus between the treatment and placebo groups. A phase 3 trial of norUDCA in PSC is underway.

Obeticholic Acid Obeticholic acid (OCA) is an analog of chenodeoxycholic acid and an endogenous ligand of the farnesoid X receptor (FXR). FXR plays a key role in bile-acid homeostasis; its activation leads to transcriptional repression of the CYP7A1 gene, which encodes cholesterol 7α hydroxylase (critical for bile-acid biosynthesis), through fibroblast growth factor 19 (FGF19) signaling and other pathways.⁹¹ OCA has recently been approved by the US Food and Drug Administration (FDA) as therapy for primary biliary cholangitis (PBC).⁹² Pruritus has been the most common and expected side effect in clinical trials, occurring in approximately 60% of patients treated with OCA in a dose-dependent manner, and 4% to 12% of patients discontinued OCA. Phase 3 clinical trial data are needed.

Simtuzumab Lysyl oxidase homolog 2 catalyzes the first step in the formation of cross-links in collagen and elastin and has been shown to contribute to hepatic fibrogenesis.⁹³ In a phase 2 clinical trial, 234 patients with PSC were randomized to weekly injections of simtuzumab (75 or 125 mg) or placebo for 96 weeks. Neither dose of simtuzumab led to significant reduction in ALP.⁹⁴ However, the role of simtuzumab in delaying the progression of fibrosis in PSC merits further study.

Alteration of the Microbiome Oral vancomycin is a nonsystemic, selective antibacterial drug; it has been found to be well tolerated and associated with significant improvement in ALP and other markers in both adult and pediatric patients with PSC,^95-98 and pediatric patients have additionally experienced IBD-related symptom resolution.^95,96,99 A phase 3 clinical trial of vancomycin in PSC has been completed, and the data are awaiting analyses. Metronidazole has been shown to decrease ALP and bilirubin in PSC^98,100; however, long-term safety is a concern, and longer-term clinical trials are lacking. Fecal microbiota transplantation has been investigated in 10 patients with PSC; 3 patients had at least a 50% reduction in ALP.¹⁰¹ With interventions aiming to treat PSC through alteration of the microbiome, it would be of interest to examine intestinal microbial and metabolic changes (eg, bile acids), as such data may reveal further mechanistic and therapeutic insights.

Interruption of the Enterohepatic Circulation of Bile Acids Bile acids are secreted into the small intestine and are reabsorbed by the liver via the enterohepatic circulation. At the level of the intestine, absorption of bile acids occurs through the apical sodium-dependent bile-acid transporter (ASBT). LUM001 (an ASBT inhibitor) and NGM282 (a FGF19 analog) are currently in phase 2 clinical trials for the treatment of PSC.

Other Agents BTT1023 (a human monoclonal antibody that binds vascular adhesion protein-1), mitomycin-C (an antineoplastic agent), curcumin (an anti-inflammatory, antifibrotic, and antisenescent agent), and cenicriviroc (a dual C-C chemokine receptor [CCR] 2 and CCR5 antagonist) are all undergoing evaluation for use in PSC.

Endoscopic Management

With the advent of magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiography (ERC) has largely become a therapeutic modality in PSC.¹⁰² Of the various potential applications of ERC in patients with PSC (eg, choledocholithiasis, acute cholangitis, palliative stenting of CCA), one of the most common and important indications is management of dominant strictures (DSs), which are loosely defined as stenoses with a diameter of no more than 1.5 mm in the common bile duct or no more than 1 mm in a hepatic duct. DSs develop in approximately 45% of patients with PSC and may present (although not always) with progressive jaundice, pruritus, right upper quadrant pain, and/or acute cholangitis. It is recommended that patients with clinical signs and symptoms attributable to a DS undergo evaluation; ERC with or without cholangioscopy is typically necessary in this scenario to further examine the biliary tree, obtain specimens (eg, intraductal brushings and/or biopsies), and perform therapeutic maneuvers (mainly balloon dilation). Short-term biliary stenting may also be performed, although the available data do not support this as a routine practice due to increased risk of treatment-related adverse events.¹⁰³

Satisfactory remediation of DSs may require multiple ERC sessions, following which a subset of patients will demonstrate biochemical and symptomatic improvements.^104,105 Therefore, it is thought that endoscopic therapy for DSs may offer long-term benefit (at least in some patients) in addition to short-term benefit. However, it remains unclear which patients with PSC are most likely to experience long-term benefit from endoscopic intervention.¹⁰⁶ Therefore, further research is needed.

Surgical Management

PSC is a common indication for LT globally and is the leading indication in Northern European countries. LT is the only potentially curative treatment currently available for PSC. Compared to PBC, for which the rate of LT has declined, the trend for LT for PSC has persisted. Specific indications for LT relatively unique to patients with PSC include recurrent acute cholangitis and refractory PSC-related symptoms (specifically fatigue and pruritus).¹⁰⁷ In select, highly specialized centers, patients with PSC complicated by CCA meeting specific criteria are also candidates for LT.¹⁰⁸

Recurrent PSC (rPSC) is an enduring clinical dilemma. It occurs in 1.8% to 36.8% of LT recipients and is associated with a greater need for repeat LT, a 4-fold increased risk of death, and decreased overall survival compared to patients who remain rPSC-free.¹⁰⁹ Potential risk factors include the presence of IBD, use of a living related donor, young age, sex, and colectomy prior to LT.^110-113

Associated Disorders and Complications

Symptoms

Data from referral centers have found that 45% to 55% of patients with PSC are symptomatic at the time of PSC diagnosis,¹¹⁴ and up to 22% of asymptomatic patients will develop symptoms of PSC, mainly fatigue and pruritus, within 5 years.¹¹⁴ Patients with PSC who have symptoms at the time of diagnosis have significantly worse survival and impaired health-related quality of life (HRQOL) than those who are asymptomatic at the time of PSC diagnosis.¹¹⁴ Significant reduction in HRQOL in terms of physical and social functioning, general and mental health, and bodily pain have been well described in PSC.¹¹⁵

Inflammatory Bowel Disease

The robust association between PSC and IBD has been known for decades, but the mechanism(s) by which these 2 diseases are related remains elusive. Several theories have been proposed, many of which involve crosstalk between the inflamed colon and the liver in susceptible individuals^116,117 or a connection to the enteric microbiome, as discussed earlier.^62-64,66

It is worth mentioning that even in the absence of concomitant PSC, abnormalities of serum liver biochemistries are frequently encountered in patients with IBD; 29% to 55% of patients with IBD have been reported to have concomitant serum liver test abnormalities.¹¹⁸ This is clinically important, as this subset of patients has a 4.8-fold higher risk of death compared to patients with IBD who have normal serum liver test results.¹¹⁸

Portal Hypertension

Portal hypertension is a frequent complication of PSC. For example, esophageal varices develop at a rate of 5% every year in patients with PSC, including parastomal varices in patients with ileostomy (or other stomas).^119,120 The management of portal hypertension and its related complications in patients with PSC is no different than in non-PSC patients, as outlined in societal guidelines.¹²¹

Hepatic Osteodystrophy

Bone loss is a common complication of PSC and other cholestatic liver diseases.¹²² Severe osteoporosis has been found to be 6.1 times more prevalent in patients with PSC than in matched healthy controls.¹²² Age at least 54 years, body mass index no more than 24, and presence and duration of IBD have all been found to correlate with the presence of osteoporosis in patients with PSC.¹²² Moreover, patients with PSC (especially middle-aged patients) have been found to have a high rate of nonvertebral fracture, which in turn has a negative impact on physical and mental aspects of HRQOL.^123,124 Patients with PSC should be screened at the time of diagnosis and then at regular intervals (every 1-5 years per the European Association for the Study of the Liver and every 2-3 years per the American Association for the Study of Liver Diseases [AASLD]).^125,126 Calcium and vitamin D supplements (for osteopenia) and bisphosphonates (for osteoporosis) are also recommended.

Cancer Risk

Compared to the general population, there is a 2-fold increased risk of any cancer and a 40-fold increase in the risk of liver cancer in patients with PSC.¹²⁷ Moreover, PSC confers a 400-fold increased risk of CCA, and nearly one-third of all-cause mortality in patients with PSC is from CCA.¹²⁸ The risk of CRC in PSC is nearly an order of magnitude higher compared to that of the general population and even higher (nearly 30-fold) in patients with PSC-IBD.¹²⁹

Surrogate Endpoints

Serum, imaging, and other biomarkers that could potentially be used in clinical trials as surrogate endpoints in PSC represent an area of need and active study. ALP has perhaps been the most commonly investigated biomarker and appears to be promising for prognostic purposes as well as a surrogate endpoint for therapeutic response in PSC.^130-134 A joint workshop (AASLD-FDA) in March 2016 recommended the use of a biliary-specific blood test (ALP) and measurement of hepatic stiffness and fibrosis by transient elastography or, ideally, histology when designing clinical trials in PSC.^134-137

Several prognostic models have been proposed for predicting major outcomes of PSC using parameters such as age, sex, hepatomegaly, splenomegaly, albumin, bilirubin, cholangiography, and histology.^114,138-141 More recently, a spleen length of more than 120 mm has been found to be predictive of adverse outcomes (hepatic decompensation, liver-related death, and need for LT).¹⁴²

Summary

PSC is an important global cause of morbidity and mortality. Currently, there is no effective pharmacotherapy for PSC that prevents major adverse outcomes (eg, progression to cirrhosis, carcinogenesis, or need for LT). The rarity of PSC, limited understanding of its etiopathogenesis, paucity of validated surrogate markers, and long natural history are barriers to developing effective medical therapies. LT, the only treatment shown to extend the survival of patients with PSC, is reserved for highly select patients, and even then, rPSC can be problematic. There are several experimental agents in the pharmacologic pipeline, some of which have demonstrated encouraging results and are currently being evaluated in phase 2 (or higher) trials. Overall, there continues to be progress in the understanding and management of this disease, with potential on the horizon.