Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronicity and progressive inflammation, fibrosis and destruction of intrahepatic and extrahepatic bile ducts, which inevitably leads to end-stage liver disease Citation[1]. PSC is often diagnosed by the fifth decade of life and is commonly observed with a concurrence of inflammatory bowel disease (IBD), where the prevalence of IBD in PSC is estimated at 60–80% Citation[2]. Patients with a combined diagnosis of PSC and IBD are at an amplified risk of colorectal neoplasia when compared with patients with only IBD Citation[3]. The global trend of PSC incidence is limited due to a lack of epidemiological data from developing countries. However, a meta-analysis comprising eight studies estimates the incidence of PSC in North America and Europe at 0.77 (range: 0.45–1.09) per 100,000 person years, which is increasing with time Citation[4].
PSC remains a challenging disease to manage, and ongoing explorations of various therapeutic options are taking place. It is worth asking, what are the clinical goals of managing patients with PSC? In a chronic disease like PSC, the aims are mainly centered on slowing histological progression and reducing the risk of serious adverse events such as the development of cancer or end-stage liver disease. With a great deal to be clarified regarding the pathogenesis of PSC, effective modification of pathogenesis through medical intervention is not yet available. Currently, no curative treatment has been established and no drug has been shown to slow progression. Liver transplantation remains the only intervention with proven survival benefit in eligible patients with end-stage liver disease.
It is important to note that when investigating new therapeutic options for patients with PSC, trial design is of crucial importance. Conducting studies with flaws in design may lead to efficacious agents being regarded as nonefficacious, or to safety issues being overlooked. Moreover, as PSC is currently regarded as an ‘umbrella’ term encompassing several subtypes (IgG4 sclerosing cholangitis, small duct PSC and classic PSC) stratifying patients according to the subtype of PSC and histological stage of disease is also important. Limitations of histological sampling in PSC, along with the presence of various disease subtypes, makes trial design challenging. In primary biliary cirrhosis, stratification of patients receiving ursodeoxycholic acid (UDCA) as responders and nonresponders is fundamental in determining how patients are managed, whereas in PSC this difference is less important but may be applicable when studying combination therapies where a novel agent is added to UDCA. Some agents may be less versatile for usage in PSC due to the occurrence of side effects that lead to decreased patient compliance or withdrawal from the study. This is particularly the case with dose-escalation trials, where higher doses of the medication are more likely to induce adverse side effects.
Patients with PSC show a biochemical profile representative of cholestasis, with a predominant elevation of alkaline phosphatase in most patients and a possible fluctuation of liver biochemistries taking place during the course of the disease.
Other findings include moderately elevated aminotransferases and decreased albumin levels, especially in PSC patients with IBD. Finally, altered prothrombin times and albumin levels in the patient’s serum may reflect progression of PSC Citation[5]. Although several medications have been shown to improve serum biochemistries in PSC patients, a reflective reduction in disease progression was not achieved.
Bile acids have been intensively studied for the management patients with PSC.
UDCA, one of the commonly used bile acids in PSC patients, acts through several mechanisms; these include reducing the toxicity of bile and hence protecting the biliary epithelium, stimulating hepatobiliary secretion by upregulating transporters and inhibiting apoptosis. Long-term treatment with 13–15 mg/kg/day of UDCA in patients with primary biliary cirrhosis improves biochemical liver tests, delays histological progression and prolongs survival without liver transplantation. Conversely, PSC patients receiving the same dose of UDCA (13–15 mg/kg/day) showed no survival benefit or delay in histological progression. Higher doses (28–30 mg/kg/day) improved biochemical tests but were unsafe due to the increased occurrence of adverse events (death, liver transplantation, cirrhosis, esophageal varices or cholangiocarcinoma) in patients receiving UDCA when compared with placebo Citation[6]. Counterintuitively, these adverse events occurred more frequently in patients with early-stage disease and normal liver biochemistries receiving high-dose UDCA Citation[7]. This helps to emphasize the fact that when therapeutic options are sought, safety is a major concern that should be approached with great caution. The adverse outcomes, as seen in the high-dose UDCA study, were unexpected and surprising. It has been suggested that accumulation of lithocholic acid, a by-product of UDCA metabolism in the liver, may lead to bile duct inflammation and eventual hepatotoxicity at high doses.
Manipulation of the UDCA molecule through shortening its side chain by a single carbon atom has led to the production of compounds such as nor-ursodeoxycholic acid, a c23 analog of UDCA which causes less inflammation in the portal tracts and bile duct proliferation; its metabolite, nor-lithocholate, did not accumulate in the hepatocytes and hence produced no hepatotoxicity in animal models Citation[8]. This advantage may place nor-UDCA as a potential option for PSC patients without the complications witnessed with UDCA.
Genetics may play a vital role in the development of PSC, where the disease prevalence in first-degree relatives and specifically siblings may reach several fold that of the general population Citation[9]. Furthermore, the presence of autoantibodies in PSC patients and the association of PSC with human leukocyte antigen (HLA) and non-HLA haplotypes suggests a central role for an autoimmune immune-modulated mechanism in disease development and progression, which was strongly supported by the recent genome-wide association study Citation[10]. Trials of immunosuppressants such as oral tacrolimus showed significant improvements in alkaline phosphatase and AST levels after 1 year of therapy, but treatment was poorly tolerated, with more than 30% of patients withdrawing from the study Citation[11]. However, although mycophenolate mofetil shows excellent tolerability, it does not appear to have any clinically beneficial effects on PSC patients Citation[12].
Patients with PSC may show cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, which leads to decreased docosahexaenoic acid levels. Administration of oral docosahexaenoic acid in a small pilot study was associated with some decline in alkaline phosphatase levels in PSC patients Citation[13]. Furthermore, antibiotics such as vancomycin, minocycline and metronidazole also showed biochemical improvement in small trials. Vancomycin’s effect on liver biochemistries was exhibited by the pediatric PSC population Citation[14,15]. Minocycline, with its anti-inflammatory and antiapoptotic properties, was well tolerated and is potentially effective, as seen by the reduction of alkaline phosphatase levels and Mayo risk scores in adult patients with PSC Citation[16].
Combination therapies, where UDCA is combined with another medication, may prove a successful option; when combining metronidazole with UDCA in PSC patients, improved serum alkaline phosphatase and Mayo risk scores were noted Citation[17]. Conversely, adding drugs such as oral budesonide to UDCA showed no benefit, increased the Mayo risk scores and caused significant bone loss from the lumbar spine Citation[18]. Moreover, as a single therapeutic agent, oral budesonide (9 mg/day for 1 year) was found to have minimal benefit and worsened osteoporosis in 21 patients with PSC Citation[19].
When studying histological disease progression, it appears that modulation of fibrosis, essentially the precirrhotic stage on histology, may be a promising pathway for slowing the progression of disease in patients with PSC, thus forestalling the inevitable development of end-stage liver disease and cirrhosis. Intrabiliary rapamycin has been reported to inhibit hepatic fibrosis in animal models, and human studies may help determine if this effect is similar in patients Citation[20]. Rapamycin displays antiproliferative and immunosuppressive effects by blocking cell cycle progression through inhibiting the activation of B and T cells by cytokines and hence may provide an option for reducing liver fibrosis in patients with PSC.
In summary, several mechanisms may be involved in the pathogenesis of PSC and can serve as vital targets for slowing disease progression and deterioration.
In the next few years, as novel agents are investigated, it will be of massive importance to ensure successful clinical trial design that will help establish statistical significance, clinical efficacy and safety of the investigated regimen. The appropriate selection of end points and usage of strict criteria for inclusion and exclusion of patients along with strong collaborations between chief medical centers will help produce powerful clinical trials with informative results, which will substantially aid in the management of this chronic debilitating disease.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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References
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