Although the understanding of primary sclerosing cholangitis (PSC) and comorbid conditions such as inflammatory bowel disease (IBD) has improved, little is unknown about the pathogenesis of this uncommon heterogeneous hepatobiliary disease, which was first described in the mid-1850s. Frequent concomitant IBD suggests that these two conditions share common but little understood factors underlying gut and bile-duct inflammation.
While PSC is thought to have autoimmune characteristics, it does not respond strongly to immunosuppressants and is likely complex and multifactorial in nature, involving genetic, microbial, immune, and environmental drivers that account for its unpredictable course.
Concurrent inflammatory bowel disease (IBD) is important for diagnosing PSC since 60% to 80% of PSC patients also have IBD. By subtype, in western countries an estimated 2.4% to 7.5% of ulcerative colitis patients will have PSC, and 3.4%, Crohn’s disease.
In a 2012 report, Dutch researchers studying 597 PSC patients found that 380 (66%) had coexistent IBD, mainly ulcerative colitis (75%).
IBD in PSC patients presents as a clinically distinct phenotype, with an earlier onset than non-PSC-IBD and frequent quiescence, with mild or no symptoms for long periods. Other hallmarks of PSC-IBD are an increased incidence of pancolitis and malignancy, infrequent rectal bleeding, right-sided colitis, and backwash ileitis. Doubly affected patients may be more likely to develop pouchitis after ileoanal anastomosis.
In the Dutch study, 207 PSC-ulcerative colitis patients (83%) had pancolitis, 32 (13%) had left-sided colitis, and nine (4%) had proctitis alone. Of PSC-Crohn’s disease patients, 70 (95%) had an ileocolitis and four (5%) had ileitis only.
“Rarely are there strictures or fistula in PSC-IBD patients, but there is a much greater risk of colon cancer in PSC patients with IBD compared with IBD patients without PSC,” Christopher L. Bowlus, MD, division chief of Gastroenterology and Hepatology at the University of California, Davis in Sacramento, told MedPage Today. “In addition, the presence of Crohn’s disease has been associated with a less severe course of PSC. The absence of IBD does not appear to significantly impact the course of PSC.”
In other associations, progressive PSC requiring transplantation appears related to ulcerative colitis that is more quiescent and less likely to require colectomy. In contrast, patients without progressive PSC more often require colectomy and have more severe histologic inflammation and the noted heightened risk of colorectal malignancy. “These observations may indirectly support a model of PSC and IBD pathogenesis that involves aberrant lymphocyte homing,” according to a 2013 overview by John Eaton, MD, and colleagues.
Timing of Diagnosis
In terms of the timing of diagnosis, those researchers said, PSC can be diagnosed after colectomy just as IBD can develop after liver transplantation, and the chronological order of diagnosis may be changing: In a 2003-2007 cohort, most patients were diagnosed with PSC first, while in a 1993-1997 cohort, most patients were diagnosed with IBD first. Colonoscopy/biopsy every 5 years after PSC diagnosis is recommended to address the potential for IBD and malignancy, said Eaton et al.
The significance of the IBD-PSC association remains elusive, according to research by James Tabibian, MD, and Keith Lindord, MD, writing in a 2014 article in Expert Review of Gastroenterology & Hepatology. Growing evidence points to the enteric microbiome and the circulation of microbiota-derived molecules within the liver as possible mechanistic links between PSC and IBD, Tabibian and Lindord said. Microbial metabolites may be potential targets for effective new pharmacotherapies.
“A general concept is that the gut and liver are directly connected by the portal vein,” Bowlus said in an interview for this article. “IBD leads to a leaky gut with increased exposure to bacterial or food antigens or other factors in the liver, which initiates the inflammation and recruitment of the intestinal lymphocytes that normally circulated between the intestine and the liver.” He cited studies by David Adams at the University of Birmingham in the United Kingdom as demonstrating the presence of intestinal lymphocytes in PSC livers.
Other researchers have compared the intestinal microbiomes of IBD patients with and without PSC. For example, João Sabino and colleagues studied microbiota in the stools of PSC patients and found intestinal dysbiosis independent of IBD signatures, with decreased microbiota diversity and overrepresentation of Enterococcus, Fusobacterium, and Lactobacillus.
“While there does appear to be some difference in the dysbiosis observed, study findings have not been consistent in terms of specific microbes,” Bowlus said, noting that a study of local microbial transfer is now under way by Jessica Allegretti, MD, and colleagues at Massachusetts General Hospital in Boston.
On the genetic front, only 23 gene regions have been associated with PSC, versus more than 160 with IBD, and 14 of the 23 loci are also associated with ulcerative colitis (UC), Crohn’s disease (CD), or both, Bowlus explained. In four of these loci, the variant in PSC was different from that in IBD, while in six loci, the same mutation was associated with PSC, UC, and CD. The overall genetic correlation between these three diseases, he noted, is as follows: UC:CD>>UC:PSC>CD:PSC. Hence, UC and CD are much more genetically similar than either UC or CD is to PSC.
Despite decades of clinical trials, pharmacotherapies from ursodeoxycholic acid (“urso”) to immunosuppressives, safe and effective medical treatment for PSC remains unestablished, a lack of success that supports PSC’s multifactorial nature. “It is likely that this complexity and clinical heterogeneity are responsible for the negative results of clinical trials, but novel insights about and approaches to PSC may shift this trend,” Tabibian and colleagues wrote.
Currently, researchers are analyzing the effectiveness of vedolizumab and anti-tumor necrosis factor therapy in PSC.
Many basic questions about the mechanisms behind PSC remain: “Genetic studies have pointed to some clues to understanding the initiating events, but these may not be important factors once the disease is established, and targeting these pathways may not lead to effective therapies,” Bowlus explained. “The microbiome may offer some insights and therapeutic opportunities, but we are in the very early stages, and the results of trials in IBD so far do not make me optimist about this approach.”
Several novel PSC therapies — notably nor-urso and obeticholic acid — are in the early stages of testing. “A key challenge to drug development is the validation of surrogate markers of clinical outcomes, which will be robust and reflect a change in the natural history of the disease. Until this is achieved, drug development will remain a major challenge.”
In the meantime, researchers are counting on animal studies and genomic analyses to expand the understanding of PSC-IBD pathophysiology and eventually lead to therapeutic strategies.