The ascending pathophysiology of cholestatic liver disease
Open accessAbstract
In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in “downstream” bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)–mediated toxic injury of the “upstream” liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom‐poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%‐60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more “tailored” use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium‐dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis–suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti‐inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor‐ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end‐stage disease. These are arguments to consider a step‐wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage–defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (H epatology 2017;65:722‐738).
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- Findingown data
After intravenous CLF in bile duct-ligated mice at day 3, the compound accumulates in individual sporadic hepatocytes.
“Overview picture of cholestatic liver (BDL, day 3) after intravenous injection of CLF showing accumulation in individual sporadic hepatocytes (arrowheads).”
Quote in the paperNot a substantial claim - Findingown data
In healthy mice, bile canaliculi clear CLF within about two hours after injection.
“The bile canaliculi were evacuated from CLF within approximately 2 hours after injection.”
Quote in the paperSubstantial claim - Premisecitation
Ursodeoxycholic acid produces beneficial effects in roughly 60% of patients with primary biliary cholangitis.
“while UDCA has proven beneficial effects in about 60% of PBC patients, it is less effective in PSC.(69)(70)(71)”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
The liver's adaptation to cholestasis may explain the variable symptom-poor interval often observed.
“The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Because disease stages are unevenly distributed over time, a one-drug-fits-all approach may produce suboptimal responses.
“In view of an unequal distribution of time-related disease stages, application of the principle of “one-drug-fits-all” may lead to suboptimal responses.”
Quote in the paperNot a substantial claim
- Interpretationnone given
In primary sclerosing cholangitis, the primary injury sites are the larger intrahepatic and extrahepatic bile ducts.
“while larger intrahepatic and extrahepatic bile ducts represent sites of primary injury in PSC.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Bile escaping from canaliculi, ductuli, and ducti seems required for bile salt-mediated toxicity to matter in cholestatic liver disease.
“Thus, leakage of bile from canaliculi, ductuli, and ducti seems a prerequisite for BS-mediated toxicity to play a role in cholestatic liver disease.”
Quote in the paperSubstantial claim - Interpretationreasoning
The variation in drug response may result from differences in the architecture of the two diseases.
“These differences in drug effects may be due to different architectures of the diseases.”
Quote in the paperSubstantial claim - Premisecitation
In a controlled trial, primary sclerosing cholangitis patients given high-dose UDCA had more portal hypertension-related complications than those given placebo.
“In a controlled trial PSC patients received high-dose UDCA or placebo.Patients allocated to the UDCA group developed more complications related to portal hypertension than placebo-treated patients.(71)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [71] source
Not checked in the free run.
- Interpretationreasoning
Bile salt synthesis-suppressing drugs such as FXR agonists are most effective before optimal adaptation is established.
“The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established.”
Quote in the paperNot a substantial claim - Interpretationnone given
In primary biliary cholangitis, the lesions occur in interlobular ducts and ductules.
“In PBC these lesions are in the interlobular ducts and ductules”
Quote in the paperNot a substantial claim - Interpretationreasoning
Even at the stage of early bile duct damage, local bile-salt-mediated injury probably contributes.
“although manifest cholestasis with jaundice occurs at a later stage, local BS-mediated bile duct injury likely plays a role already at the time of early bile duct injury.”
Quote in the paperSubstantial claim - Interpretationnone given
Other compartments, including hepatocytes, do not reach bile salt levels sufficient for toxicity.
“BS concentrations in other compartments (e.g., hepatocytes) are simply not high enough.”
Quote in the paperNot a substantial claim - Premisecitation
A prior trial of obeticholic acid found that alkaline phosphatase fell by 40% in one fifth of patients.
“An earlier study with this compound showed a 40% reduction of alkaline phosphatase in 20% of patients.(73)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [73] source
Not checked in the free run.
- Interpretationreasoning
Because portal veins lie close to the biliary tree, especially the ductular mesh around them, UDCA may worsen portal hypertension in some patients.
“Because the portal veins are in close proximity to the biliary tree, in particular the ductular network that forms a mesh around the portal veins, UDCA may augment portal hypertension in selected patients.”
Quote in the paperSubstantial claim- Rests on an assumption: Portal veins are located close to the biliary tree, particularly the ductular network that surrounds them.
- Interpretationreasoning
Cholestasis causes bile-salt-mediated toxic injury to the upstream liver parenchyma.
“This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the “upstream” liver parenchyma.”
Quote in the paperNot a substantial claim - Interpretationnone given
The likely primary trigger in cholestatic liver disease is immune-mediated necroinflammatory damage to the biliary tree in people with genetic susceptibility.
“Immune-mediated necroinflammatory damage of the biliary tree in genetically susceptible individuals is probably the main initiating event in cholestatic liver disease.”
Quote in the paperNot a substantial claim - Interpretationreasoning
PBC and PSC progress over time in an ascending pattern from downstream bile ducts to upstream canaliculi and liver parenchyma.
“cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process.”
Quote in the paperNot a substantial claim - Interpretationnone given
Bile salt levels in the canalicular and ductular network are sufficiently high to cause toxicity upon leakage into adjacent cells.
“The canalicular and ductular network contain BS concentrations high enough to be toxic when they leak into cells in close proximity.”
Quote in the paperNot a substantial claim - Interpretationnone given
The earliest lesions in cholestatic liver diseases occur in downstream bile ducts.
“The first and early lesions are in “downstream” bile ducts.”
Quote in the paperNot a substantial claim - Premisecitation
Ursodeoxycholic acid is less effective in primary sclerosing cholangitis than in primary biliary cholangitis.
“while UDCA has proven beneficial effects in about 60% of PBC patients, it is less effective in PSC.(69)(70)(71)”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Bile leakage from the canalicular network and bile ducts is likely an important driver of toxicity.
“Leakage of bile from this network and ducts could be an important driver of toxicity.”
Quote in the paperNot a substantial claim
- May combine two claims. 12
- Classified as probably not a substantial claim. 1
May combine two claims.
Findingown dataIn mice at day 3 after bile duct ligation, CLF remains in sinusoids, shows weak hepatocyte enrichment, and produces weak bile canaliculi signals that persist for the entire 165-minute imaging period.
“Liver of a mouse (day 3 after BDL) showing prolonged presence of CLF in the sinusoids, only weak enrichment in hepatocytes, and weak CLF signals in the bile canaliculi, which persist over the entire time of imaging (165 minutes).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn bile duct-ligated mice at day 3, bile canaliculi are extremely widened compared with controls, although some canaliculi remain near normal in diameter.
“The liver of a BDL mouse (day 3) shows extremely widened bile canaliculi (arrow) compared to the control.However, the diameter of some bile canaliculi remains close to normal (asterisk).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn ex vivo liver stained for dipeptidyl peptidase 4, there are spine-like protrusions into hepatocyte cytoplasm and some canaliculi are only moderately widened, perhaps because of postmortem shrinkage.
“In contrast, ex vivo dipeptidyl peptidase 4-stained liver shows spine-like protrusions into the hepatocyte cytoplasm and only a moderately widened diameter of some canaliculi, possibly due to postmortem shrinkage.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe second hit likely has a toxic origin and could involve bile salts present at high local concentrations.
“The “second hit” is probably toxic in origin and may be mediated by BS in locally high concentrations.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNecroinflammatory injury of bile ducts underlies both PBC and PSC, with interlobular ducts affected in PBC and large intrahepatic/extrahepatic ducts in PSC.
“PBC and PSC result from necroinflammatory injury of the bile ducts: the interlobular bile ducts and their branches in PBC and the intrahepatic and extrahepatic large bile ducts in PSC”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2]
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningA step-wise pathophysiology with therapy adjusted to disease stage should be considered.
“These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningInjury to bile ducts causes leakage of bile and local toxic damage.
“Bile duct injury leads to bile leakage and local toxic injury.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn a randomized trial of primary biliary cholangitis patients without cirrhosis or jaundice who had an inadequate response to UDCA, obeticholic acid reduced serum alkaline phosphatase in 50%-60% of patients, with a 10% placebo effect.
“The drug was given to PBC patients who did not have cirrhosis or jaundice but had an inadequate response to UDCA.Obeticholic acid was effective at lowering serum alkaline phosphatase in 50%-60% of patients with a 10% placebo effect.(72)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [72] source
Not checked in the free run.
May combine two claims.
InterpretationreasoningTreating downstream targets may reduce or prevent cholestasis, which would lower toxicity at upstream sites.
“By addressing downstream targets, cholestasis may be reduced or prevented, and this will reduce toxicity at the site of upstream targets.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationnone givenIncreased biliary pressure may contribute in primary sclerosing cholangitis and extrahepatic cholestasis, while adhesion molecule and junctional complex mechanisms may be more important in other cholestatic diseases.
“Increased biliary pressure may play a role in PSC and extrahepatic cholestasis, but mechanisms that affect adhesion molecules and junctional complexes may be more important in other cholestatic liver diseases.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIn primary biliary cholangitis, the increased bile flow from UDCA is not problematic, but in primary sclerosing cholangitis, where biliary outflow resistance is elevated, UDCA may raise intrabiliary pressure.
“This hypersecretion is not a problem in PBC, but in PSC, where resistance to biliary outflow is increased, UDCA may increase intrabiliary pressure.”
Quote in the paperSubstantial claim- Rests on an assumption: UDCA causes choleresis through water efflux after its own secretion and through bicarbonate stimulation, and it lowers bile viscosity.
- Rests on an assumption: In primary sclerosing cholangitis, resistance to biliary outflow is increased.
May combine two claims.
Interpretationnone givenEarly disease is dominated by inflammation, while toxic injury becomes more prominent later.
“Inflammation prevails in the early phase and toxic injury in the later phase.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Drugs targeting bile salt toxicity are effective in only about 50%-60% of PBC patients, and no effective therapy exists for PSC.
“Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC.”
The paper relies on this without support.
Disease stage-defining biomarkers are lacking.
“An obstacle in such an approach is that disease stage-defining biomarkers are still lacking.”
The paper relies on this without support.
ASBT inhibitors reduce intestinal bile salt absorption and lower bile salt load.
“Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients.”
The paper relies on this without support.
UDCA causes choleresis through water efflux after its own secretion and through bicarbonate stimulation, and it lowers bile viscosity.
“Both by water efflux following its own secretion and by stimulation of bicarbonate secretion, UDCA causes some degree of choleresis in addition to reducing the viscosity of bile.”
The paper relies on this without support.
In primary sclerosing cholangitis, resistance to biliary outflow is increased.
“in PSC, where resistance to biliary outflow is increased”
The paper relies on this without support.
Portal veins are located close to the biliary tree, particularly the ductular network that surrounds them.
“Because the portal veins are in close proximity to the biliary tree, in particular the ductular network that forms a mesh around the portal veins”
The authors state this as an assumption.
The pathophysiology of primary biliary cholangitis and primary sclerosing cholangitis ascends from the biliary tree to upstream liver tissue.
“Because we postulate the concept of an ascending pathophysiology of PBC and PSC”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cholestasis may be considered an efflux problem resulting in accumulation of potentially cytotoxic and proinflammatory bile acids and other cholephiles.
“while cholestasis may be considered an efflux problem resulting in accumulation of potentially cytotoxic and proinflammatory BAs and other cholephiles.13 14”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [14]
Bile acid-induced cell stress may occur both at the level of hepatocytes and cholangiocytes.
“BA-induced cell stress may occur both at the level of hepatocytes (eg, via BA retention) and cholangiocytes (eg, via toxic bile composition and/or biliary stasis).5 14”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [14]
Bile acids are potentially cytotoxic and proinflammatory at higher pathophysiological concentrations, so it is important to maintain their homeostasis by controlling BA transport and metabolism.
“Since BAs are potentially cytotoxic and proinflammatory at higher pathophysiological concentrations14 it is important to maintain their homoeostasis by controlling BA transport and metabolism (figure 2).13”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [14]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
One parameter is assigned two different meanings
MinorThe equation legend defines the same symbol as both the maximum intensity gained and the total intensity lost. Those are distinct quantities, so the notation does not identify which one the symbol represents.
“I max a represents maximum intensity acquired by accretion of CLF”
“I max a represents total intensity lost by depletion of CLF”
The citation lists haven’t been fetched yet
References 105 · Cited by 301
Research works printed but not linked: 7
- 2011, Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis, Am J Pathol, 178, 175, 10.1016/j.ajpath.2010.11.026 · DOI · Paper page
- 1960, Changes in bile canaliculi produced by norethandrolone: electron microscopic study of human and rat liver, J Lab Clin Med, 56, 623
- 2016, Metabolic preconditioning protects BSEP/ABCB11–/– mice against cholestatic liver injury, J Hepatol, 66, 95
- 2011, In vivo, imaging of bile accumulation and biliary infarction after common bile duct ligation in rats. Eur Surg Res, 47, 240
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- Authors
- Jansen, P. L. M., Ghallab, A., Vartak, N., Reif, R., Schaap, F. G., Hampe, J., & Hengstler, J. G.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- South Valley University (EG)
- TU Dortmund University (DE)
- Maastricht University (NL)
- Technische Universität Dresden (DE)
- Corresponding author
- Jansen, Peter L.M.
- Venue
- Hepatology
- Published
- 2017-01-23
- Volume
- 65
- Issue
- 2
- Pages
- 722-738
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W2565416332
- Cited by
- 301
- References
- 105
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 28 · 2023: 27 · 2022: 41 · 2021: 31 · 2020: 31 · 2019: 42 · 2018: 35 · 2017: 16
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- European Commission
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Keywords
- cholestatic liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, bile salt toxicity, bile salt transporters, farnesoid X receptor agonist, ursodeoxycholic acid, disease stage, biomarkers, endoscopic stenting, cholestasis
- MeSH terms
- Adaptation, Physiological, Animals, Anti-Inflammatory Agents, Anti-Bacterial Agents, Bile Acids and Salts, Bile Ducts, Cholestasis, Humans, Liver Diseases, Prognosis, Cholangitis, Sclerosing, Biomarkers, Disease Progression, Mice
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