CD14 is associated with biliary stricture formation

Friedrich, Kilian; Smit, Mark; Brune, Maik; Giese, Thomas; Rupp, Christian; Wannhoff, Andreas; Kloeters, Petra; Leopold, Yvonne; Denk, Gerald; Weiss, Karl Heinz; Stremmel, Wolfgang; Sauer, Peter; Hohenester, Simon; Schirmacher, Peter; Schemmer, Peter; Gotthardt, Daniel

doi:10.1002/hep.28543

Cited by 16 publications

(12 citation statements)

References 43 publications

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“…Other possible confounders are genetic determinants of sCD14 expression. In a previous study in PSC patients, genetic variation in the rs2569190 single‐nucleotide polymorphism in the CD14 gene correlated with sCD14 concentration . However, when using genotype data of rs2569190 available from 72 of the included PSC patients from a previous study, there was no relationship between rs2569190 genotype and circulating sCD14 concentration in the present cohort, irrespective of genetic model (genotype or dominant/recessive, data not shown).…”

Section: Resultscontrasting

confidence: 58%

“…Only limited data and non‐conclusive studies are available about some of these markers in PSC . Based on the observations described above, we hypothesized that circulating markers of gut barrier function are elevated in PSC compared with controls and that high levels of the same markers are associated with reduced liver transplantation–free survival.…”

Section: Introductionmentioning

confidence: 99%

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Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis

Dhillon

Kummen

Trøseid

et al. 2018

Liver International

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Background & Aims One important hypothesis in primary sclerosing cholangitis pathophysiology suggests that bacterial products from an inflamed leaky gut lead to biliary inflammation. We aimed to investigate whether circulating markers of bacterial translocation were associated with survival in a Norwegian primary sclerosing cholangitis cohort. Methods Serum levels of zonulin, intestinal fatty acid binding protein, soluble CD14, lipopolysaccharide and lipopolysaccharide‐binding protein were measured in 166 primary sclerosing cholangitis patients and 100 healthy controls. Results Lipopolysaccharide‐binding protein and soluble CD14 were elevated in primary sclerosing cholangitis compared with healthy controls (median 13 662 vs 12 339 ng/mL, P = 0.010 and 1657 vs 1196 ng/mL, P < 0.001, respectively). High soluble CD14 and lipopolysaccharide‐binding protein (values >optimal cut‐off using receiver operating characteristics) were associated with reduced liver transplantation–free survival (P < 0.001 and P = 0.005, respectively). The concentration of soluble CD14 was higher in patients with hepatobiliary cancer compared to other primary sclerosing cholangitis patients and healthy controls. Zonulin was lower in primary sclerosing cholangitis than controls, but when excluding primary sclerosing cholangitis patients with increased prothrombin time zonulin concentrations were similar in primary sclerosing cholangitis and healthy controls. Concomitant inflammatory bowel disease did not influence the results, while inflammatory bowel disease patients without primary sclerosing cholangitis (n = 40) had lower concentration of soluble CD14. In multivariable Cox regression, high soluble CD14 and high lipopolysaccharide‐binding protein were associated with transplantation‐free survival, independent from Mayo risk score (HR: 2.26 [95% CI: 1.15‐4.43], P = 0.018 and HR: 2.00 [95% CI: 1.17‐3.43], P = 0.011, respectively). Conclusions Primary sclerosing cholangitis patients show increased levels of circulating markers of bacterial translocation. High levels are associated with poor prognosis measured by transplantation‐free survival, indicating that ongoing gut leakage could have clinical impact in primary sclerosing cholangitis.

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Section: Resultscontrasting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis

Dhillon

Kummen

Trøseid

et al. 2018

Liver International

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“…In PSC, interleukin‐8 levels in serum and bile are elevated . Serum of PSC patients with biliary strictures showed elevated interleukin 8 when exposed to lipopolysaccharide in vitro . Thus, interleukin 8 might be a candidate biomarker for PSC, but whether it is sensitive enough to be useful in stratification of the disease needs to be explored.…”

Section: Stage‐dependent Biomarkersmentioning

confidence: 99%

The ascending pathophysiology of cholestatic liver disease

Ghallab²,

et al. 2017

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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. (Hepatology 2017;65:722‐738).

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“…The variant CD14-260C>T polymorphism was associated with the development of DS and an increased risk of cholangitis. It appears from this data that the innate immune response may be important during biliary stricture formation [18]. …”

Section: Dominant Strictures In Pscmentioning

confidence: 99%

Are Dominant Strictures in Primary Sclerosing Cholangitis a Risk Factor for Cholangiocarcinoma?

Chapman

Williamson

2017

Curr Hepatology Rep

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Purpose of ReviewCholangiocarcinoma is a devastating, unpredictable complication of large duct primary sclerosing cholangitis (PSC), which occurs in 5–15% of patients. The aim of this review is to discuss whether dominant strictures (DS) occurring in the larger bile ducts in PSC are a risk factor for the development of cholangiocarcinoma.Recent FindingsThe development of DS is related to specific genetic polymorphisms affecting the innate immune system and the microbiome. In a recent study, the mean survival of PSC patients with DS was much worse (13.7 years) than for those without a DS (23 years). Survival difference was related to a 26% risk of cholangiocarcinoma, which developed only in those with DS. Half of the patients with cholangiocarcinoma presented within 4 months of the diagnosis of PSC. In another study, the risk of developing cholangiocarcinoma was directly related to the presence of underlying IBD, although this remains controversial. Efforts are being made towards surveying for cholangiocarcinoma including magnetic resonance imaging, endoscopic surveillance and serum tumour markers, but so far, an effective surveillance strategy has not been identified. DS should be treated endoscopically in the setting of symptoms, and there is limited evidence to suggest this may impact protectively on progression to cholangiocarcinoma.SummaryIt is established that the presence of symptomatic DS occurring in the larger bile ducts in PSC can be the first presentation of cholangiocarcinoma. There is an increasing body of evidence that even when proven to be benign, dominant biliary strictures predispose to the future development of cholangiocarcinoma. Regular surveillance should be targeted at this selected high-risk group of PSC patients.

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CD14 is associated with biliary stricture formation

Cited by 16 publications

References 43 publications

Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis

Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis

The ascending pathophysiology of cholestatic liver disease

Are Dominant Strictures in Primary Sclerosing Cholangitis a Risk Factor for Cholangiocarcinoma?

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