Review: Pathogenesis of cholestatic liver diseases

Yokoda, Raquel T; Rodríguez, Eduardo A.

doi:10.4254/wjh.v12.i8.423

Cited by 44 publications

(52 citation statements)

References 79 publications

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“…norUDCA, a derivate of UDCA, and obeticholic acid, a FXR ligand, are currently under investigation for treatment of PSC and showed improvement of alkaline phosphatase levels [ 336 , 337 ]. Further therapeutic strategies being explored are cilofexor, a nonsteroidal FXR agonist; NGM282, an FGF-19 analog, and all- trans -retinoic acid (ATRA) which activates FXR [ 4 , 338 , 339 , 340 , 341 ] as well as TGR5 agonists, and inhibitors of the ileal apical sodium bile acid transporter [ 342 ].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

The Gut-Liver Axis in Cholestatic Liver Diseases

Blesl

Stadlbauer

2021

Nutrients

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The gut-liver axis describes the physiological interplay between the gut and the liver and has important implications for the maintenance of health. Disruptions of this equilibrium are an important factor in the evolution and progression of many liver diseases. The composition of the gut microbiome, the gut barrier, bacterial translocation, and bile acid metabolism are the key features of this cycle. Chronic cholestatic liver diseases include primary sclerosing cholangitis, the generic term secondary sclerosing cholangitis implying the disease secondary sclerosing cholangitis in critically ill patients and primary biliary cirrhosis. Pathophysiology of these diseases is not fully understood but seems to be multifactorial. Knowledge about the alterations of the gut-liver axis influencing the pathogenesis and the outcome of these diseases has considerably increased. Therefore, this review aims to describe the function of the healthy gut-liver axis and to sum up the pathological changes in these cholestatic liver diseases. The review compromises the actual level of knowledge about the gut microbiome (including the mycobiome and the virome), the gut barrier and the consequences of increased gut permeability, the effects of bacterial translocation, and the influence of bile acid composition and pool size in chronic cholestatic liver diseases. Furthermore, therapeutic implications and future scientific objectives are outlined.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

The Gut-Liver Axis in Cholestatic Liver Diseases

Blesl

Stadlbauer

2021

Nutrients

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“…Intrahepatic cholestasis results from obstruction of bile flow. Some causes of intrahepatic cholestasis include progressive familial intrahepatic cholestasis, primary biliary cholangitis, hepatitis, metastatic disease, certain medications, and intrahepatic cholestasis of pregnancy (ICP) [ 1 ]. ICP is the most common gestational disorder of the liver, with an occurrence that varies by ethnicity and geographic region (0.1-15.6%) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Intrahepatic Cholestasis of Pregnancy: Role of Baby’s Sex on Itch Severity and Bile Acid Levels

Bartolone¹,

Mayrovitz²

2021

Cureus

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Background Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy. It occurs when bile flow from the liver is obstructed, causing bile acid to accumulate. ICP usually presents with itching that lasts for the remainder of pregnancy. Untreated ICP has been shown to increase the incidence of adverse outcomes for the baby, including respiratory distress, meconium aspiration, neonatal intensive care unit hospitalization, and stillbirth. The probability of these events increases when bile acid levels are greater than 40 mmol/L. The current standard of care for ICP patients is a combination of ursodeoxycholic acid by mouth and early delivery, as the risk of stillbirth due to ICP increases in the last weeks of pregnancy. ICP has been linked to preeclampsia and gestational diabetes; studies have shown that the occurrence of both diseases is greater when the baby is male. The purpose of this study was to investigate if the occurrence, timing of diagnosis, peak bile acid levels, or severity of itching is dependent on the baby's sex in mothers who had ICP. Methods An online question-set (survey) was offered to women who had had ICP and were members of three different online support groups. Results A total of 1,502 women responded for a total of 2,289 documented ICP pregnancies, in which there were 1,059 female babies and 1,230 male babies. Based on chi-square analysis of differences in frequencies, no difference was found between pregnancies with male versus female babies regarding the occurrence, timing of diagnosis, peak bile acid levels, or severity of itching in the evaluated population. However, surprisingly, the findings revealed that first-trimester diagnosis of ICP was made in 5.6% of the pregnancies, and there were 30 (1.8%) cases of ICP diagnosed in the absence of itching. Conclusions The findings suggest that the baby's sex does not impact the occurrence, timing of diagnosis, peak bile acid levels, or itch severity in ICP. The findings that 5.6% of the ICP pregnancies in the present study were diagnosed in the first trimester and 1.8% were diagnosed without the presence of itching reinforce the need to investigate these less common presentations. More studies are needed to determine if these findings are consistent across other populations.

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“…Sterile inflammation is also evident in other cholestatic conditions [38]. Increasing evidence supports a role of bile acids herein through multiple potential pathways.…”

Section: Bile Acids In Cholestatic Liver Diseasesmentioning

confidence: 98%

“…This, in combination with disturbed hepatic bile acid synthesis [37], results in an altered bile acid composition and localization and hence to disturbed bile acid signaling during cholestasis. Evidently, bile acids influence the immune system during cholestasis and thereby affect disease progression through various complex pathways [38,39]. This paragraph will elaborate on bile acid actions on immunity during cholestasis and on potential treatment options that target bile acid metabolism.…”

Section: Bile Acids In Cholestatic Liver Diseasesmentioning

confidence: 99%

Role of bile acids in inflammatory liver diseases

et al. 2021

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Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

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Review: Pathogenesis of cholestatic liver diseases

Cited by 44 publications

References 79 publications

The Gut-Liver Axis in Cholestatic Liver Diseases

The Gut-Liver Axis in Cholestatic Liver Diseases

Intrahepatic Cholestasis of Pregnancy: Role of Baby’s Sex on Itch Severity and Bile Acid Levels

Role of bile acids in inflammatory liver diseases

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