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Cited by 42Liver Diseases and ImmunityPediatric Hepatobiliary Diseases and TreatmentsInflammatory Bowel Disease

Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal is bad, then administration is good (right?)

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Tabibian, James H., Lindor, Keith D.·2014·Hepatology
DOI 10.1002/hep.27180
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Abstract

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

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  • Serum ALP activity <1.5x ULN has been associated with a favourable long-term prognosis in PSC.

    “Serum ALP activity <1.5x ULN has been associated with a favourable long-term prognosis in PSC.109”

    From EASL Clinical Practice Guidelines on sclerosing cholangitis (2022) · cites this paper as [109]

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  1. Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, Larusso NF. Chol- angiocyte senescence via N-Ras activation is a characteristic of primary sclerosing cholangitis. HEPATOLOGY 2014;59:2263-2275.

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Authors
Tabibian, J. H., & Lindor, K. D.
Affiliations
  • Mayo Clinic (US)
  • Arizona State University (US)
Corresponding author
Lindor, Keith D.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-09
Volume
60
Issue
3
Pages
785-788
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.27180
OpenAlex
W2169274431
Cited by
42
References
20
Citations by year
2026: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 10 · 2016: 5 · 2015: 4 · 2014: 1
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 365 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Mayo Clinic (UL1-TR000135)
  • National Institutes of Health (UL1TR000135)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007198)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
Keywords
primary sclerosing cholangitis, ursodeoxycholic acid, bile acid therapy, cholestatic liver disease, gut-liver axis, inflammatory bowel disease, cholangiocarcinoma, liver transplantation, pruritus, quality of life, enterohepatic circulation, cholestasis, fatigue, liver fibrosis
MeSH terms
Contraindications, Bile Acids and Salts, Cholagogues and Choleretics, Female, Humans, Male, Ursodeoxycholic Acid, Cholangitis, Sclerosing

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