Ursodeoxycholic acid in primary sclerosing cholangitis: If withdrawal is bad, then administration is good (right?)
Authors: James H. Tabibian, Keith D. Lindor
Journal: Hepatology (2014)

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, cholestatic liver disease characterized by biliary inflammation and periductal fibrosis.1, 2 Unlike most other cholestatic liver diseases, PSC affects individuals of essentially all ages and racial backgrounds, remains etiopathogenically perplexing, and lacks established medical therapy despite extensive laboratory-based investigation, translational research, and clinical trials.1, 3 It is on this basis that PSC has, regrettably, come to be regarded as the "black box" of liver disease. Although the molecular underpinnings and management of PSC remain uncertain, it is clear, consequent to these uncertainties and the progressive nature of PSC, that both its public health and patient-level burden are substantial; indeed, PSC represents a major risk factor for cholangiocarcinoma (CCA),4 carries a median liver transplantation (LT)-free survival of 15 years,5 and is a leading indication for LT in countries worldwide, despite its rarity.6 Although LT can be curative for PSC and PSC-associated CCA, it is only performed in highly selected patients and institutions, and even suitable candidates can experience recurrent disease (≈3%-4% per year).7 Last, quality of life (QOL) is also significantly impaired in patients with PSC, both pre- and post-LT, and is related to debilitating symptoms, such as pruritus and fatigue, as well as worries related to the unpredictable disease course (personal clinical observations).8, 9 Prevailing hypotheses, based on both clinical and animal model data as well as the remarkable association with inflammatory bowel disease (IBD), suggest that a disruption of gut-liver axis signaling plays a fundamental etiopathogenic role in PSC. These hypotheses can be broadly categorized into (1) aberrant enterohepatic circulation of microbial signaling molecules and (2) bile acid (BA) pathophysiology. Whereas the former has only recently gained favor (in part because of methodological, e.g., high-throughput sequencing and "meta"-omics, limitations), the latter has been a subject of ongoing investigation for decades. Within this latter category, and representing the most widely studied pharmacotherapy in PSC, is ursodeoxycholic acid (UDCA). First isolated over a century ago from Thalarcos maritimus (now known as Ursus maritimus), that is, the Polar bear, UDCA is a 3,7-dihydroxy, hydrophilic BA. In most vertebrates, including Homo sapiens, UDCA is a secondary BA and only a minor component (<1%-5%) of the BA pool; the major known exception is the Ursidae family, wherein UDCA can be a primary BA and in fact a major component (>30%) of the BA pool.10 The potentially therapeutic effects of UDCA in cholestasis include augmentation of epithelial membrane stability, BA excretion, and bicarbonate-rich choleresis.10, 11 Prospective clinical studies of UDCA in PSC first began in the late 1980s12 and, albeit uncontrolled, demonstrated both symptomatic and objective improvements.13 These studies soon led to the first randomized, controlled trial (RCT) of UDCA (13-15 mg/kg/day), which, as reported in HEPATOLOGY in 1992, demonstrated significant improvements in multiple biochemical endpoints as well as liver histology.14 Since then, seven other RCTs have been conducted, initially with low- (10-15 mg/kg/day), then intermediate- (17-23 mg/kg/day), and most recently high-dose (28-30 mg/kg/day) UDCA. In brief, whereas low-dose UDCA was associated with significant biochemical improvements, but no differences in "hard endpoints," such as death, LT, or CCA, high-dose UDCA was associated with an approximately 2-fold increase in serious adverse events.15 Perhaps the most intriguing RCT data come from intermediate-dose UDCA: Mitchell et al.16 reported significant improvements in serum liver biochemistries, hepatic fibrosis stage, and cholangiographic progression. Subsequently, Olsson et al.,17 in the largest trial to date, reported a 34% relative reduction in progression to LT, 31% relative reduction in death, and 22% relative reduction in CCA; however, ostensibly as a result of the low incidence of these endpoints and failure to enroll the planned number of patients, the results did not reach statistical significance, but have been regarded as showing a trend toward such. Therefore, because of the lack of consistently perceived benefits (possibly related to the heterogeneity of PSC and long time to/low incidence of hard endpoints), in their respective practice guidelines, the American Association for the Study of Liver Diseases18 recommended against, and the European Association for the Study of the Liver19 offered no specific recommendation regarding, the use of UDCA for PSC. In this issue of HEPATOLOGY, Wunsch et al. provide timely insight regarding the role of UDCA in the treatment of PSC.20 The investigators prospectively evaluated the effects of 3 months of UDCA withdrawal on serum biochemical tests as well as QOL and symptoms among 26 patients with PSC. The median sample age was 34 years, 62% were male, 69% had IBD, 19% had cirrhosis, and the baseline UDCA dose was 10-15 mg/kg/day. At study entry, 18 patients (69%) had an abnormal ALK and 54% had serum alkaline phosphatase (ALK) >1.5× the upper limit of normal (ULN). At the end of UDCA withdrawal, there was significant worsening of ALK level (76% increase) as well as alanine aminotransferase, aspartate aminotransferase, bilirubin, and Mayo PSC risk score. With respect to BAs, not surprisingly, UDCA and its conjugates decreased significantly from 50% to <2% of the total peripheral blood BA pool; other changes in BAs were also noted, but were comparatively small in magnitude. Serum fibroblast growth factor 19 (FGF-19), a negative feedback regulator of CYP7A1 (encoding cholesterol 7α-hydroxylase, the first and rate-limiting enzyme in BA biosynthesis) transcribed in response to BA binding to farnesoid X receptor, did not change significantly. Changes in QOL were variable across parameters as well as within individual patients, and the majority did not change significantly; of note, however, there was a near doubling in numerical pruritus rating (trend toward statistical significance), which coincided with worsened fatigue in 42% and deterioration in overall general health (a domain of the short form-36 QOL instrument) in 60% of patients. One patient dropped out of the study (i.e., resumed UDCA) as a result of severe pruritus. This study represents the largest prospective evaluation of UDCA withdrawal in PSC. The significant worsening of serum liver tests is conceivably the main finding and consistent with what would be expected based on earlier reports in PSC and other liver diseases.12 Unfortunately, several limitations mitigate the overall impact of the study. First, there was a paucity of information regarding the characteristics of the sample: For example, it is unknown whether the sample consisted of those who demonstrated an initial therapeutic response to (and thus remained on) UDCA, which could introduce selection bias. In addition, disease features (e.g., years with PSC and stage) were not well reported, and it is unclear why low-dose UDCA was used at baseline. Second, some results are difficult to interpret: For example, it is unspecified whether UDCA withdrawal affected patients with cirrhosis differently than those with earlier-stage disease. Also, one might wonder whether 3-month UDCA withdrawal is sufficient to rule out a transient rebound effect (e.g., in biochemical tests). Moreover, the significance of FGF-19 in this study and how it relates to BA pathophysiology is largely speculative and not biologically intuitive, particularly when considering (1) FGF-19 is secreted into portal, and not peripheral, venous blood and is only one of several regulators of BA biosynthesis and (2) the likely varied stages of PSC and small number of patients in the sample. Last, the unblinded nature of UDCA withdrawal may have inadvertently biased self-reporting of pruritus and QOL. Therefore, the findings of the current study should be considered in the context of its limitations. The question thus arises as to "what now?" Given the unmet clinicopharmacotherapeutic needs in PSC, it might be helpful to seek direction by analogy. In primary biliary cirrhosis, for example, although it is well described that >20% of patients are nonresponders to UDCA, UDCA is still widely recommended as primary therapy. Even in nonresponders, there are no recommendations to stop UDCA, with the hope being that some benefit might still be gained. In IBD, there have been no RCTs demonstrating reduction in death or colorectal cancer, and even the most effective therapies (e.g., infliximab) induce remission in less than 50% of patients at 1 year and are associated with serious potential infectious and neoplastic complications; nevertheless, societal practice guidelines recommend their use. Parenthetically, mucosal healing, which has become a major endpoint in IBD, might be of similar value in the biliary tree and could represent an area of future investigation in PSC in the advent of cholangioscopy and continued improvements in other imaging modalities. Last, in osteoarthritis, there is little reservation in recommending nonsteroidal anti-inflammatory drug use, despite the risk of hepatonephrotoxicity (among others) and trivial impact on the natural history of arthropathy; instead, symptomatic relief is felt to be meritorious in its own right. Therefore, until safer, more effective pharmacotherapies and more robust biomarkers become available for PSC, and based on the available literature, the present study, and patient preferences, we believe that the stringency toward the use of UDCA in PSC might be reconsidered. With that in mind, there may still be a role for judicious use of UDCA in patients with well-compensated disease. We propose a practical, yet unproven, algorithmic approach (Fig. 1), which would (1) offer patients with PSC the opportunity to experience the potential therapeutic benefits of UDCA, including, but not limited to, ALK normalization (which has recently been associated with adverse endpoint-free survival13) and symptomatic relief and (2) lend itself to collecting information that could be used to plan a prospective study and may help expedite evidence-based treatment recommendations regarding UDCA. Efforts to identify novel pharmacotherapies are currently in clinical trials, such as norUDCA, and the preclinical data suggest that it may, in fact, be more effective in combination with UDCA. Although many questions remain unanswered, we believe the field is better positioned now than ever to develop and rigorously test emerging therapies. With continued innovation, collaboration, and dedication, it is only a matter of (hopefully little) time before a more broadly therapeutic impact can be offered for those who suffer from this disorder. James H. Tabibian, M.D.1,2 Keith D. Lindor, M.D.3 1Division of Gastroenterology and Hepatology 2Center for Clinical and Translational Sciences Mayo Clinic Rochester, MN 3College of Health Solutions Arizona State University Phoenix, AZ