Primary biliary cholangitis as a roadmap for the development of novel treatments for cholestatic liver diseases†

Nevens, Frederik; Trauner, Michael; Manns, Michael P.

doi:10.1016/j.jhep.2022.10.007

Cited by 29 publications

(17 citation statements)

References 155 publications

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“…Since 2021, the IBAT inhibitor odevixibat is approved in Europe for PFIC patients, who are 6 months or older, but not for patients with milder forms of hereditary intrahepatic cholestasis so far [26]. Moreover, norUDCA can improve cholestasis and liver damage in mice deficient for Abcb4, which are often used as PSC models and clinical development has progressed to a phase III trial for PSC (NCT03872921) [43][44][45]. Despite the improvement of clinical findings, symptom relief by targeting pruritus or fatigue with potential therapeutic options is important to improve the patients' impaired quality of life.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic workup of suspected hereditary cholestasis in adults: a case report

et al. 2023

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Hereditary cholestasis comprises a broad spectrum of clinical phenotypes of varying severity. Severe forms such as progressive familial intrahepatic cholestasis (PFIC) mostly affect children with disease onset within their first years. Nevertheless, late-onset PFIC forms are increasingly diagnosed. Most adults present with less severe forms of hereditary cholestasis, often suffering from pruritus, gallstone disease, jaundice, or elevated liver enzymes. To identify the underlying genetic background and to rule out potential differential diagnoses, a broad genetic analysis like whole exome sequencing (WES) is recommended. Knowledge of the affected gene may have an impact not only on patient surveillance due to risk for disease progression or tumor development but also on potential therapeutic strategies. This case of the adult patient illustrates the importance of broad genetic analysis, which brought up the potentially relevant rare multidrug resistance protein 3 (MDR3) missense variant p.(Asn489Tyr) underlying the patient’s clinical phenotype of low phospholipid-associated cholelithiasis (LPAC). Patients with MDR3 disease may have an increased risk for cholangiocarcinoma (CCA) development and therefore need an individualized surveillance strategy. Most MDR3-affected patients benefit from life-long therapy with ursodeoxycholic acid (UDCA), which is well tolerated. Bezafibrate treatment can reduce pruritus, one of the main symptoms affecting the quality of life. Whether the administration of ileal bile acid transporter (IBAT) inhibitors is beneficial in adult patients with MDR3 disease is so far unknown.

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Section: Discussionmentioning

confidence: 99%

Diagnostic workup of suspected hereditary cholestasis in adults: a case report

et al. 2023

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“…Several published studies have shown that semisynthetic and nonsteroidal agonists of FXR are able to reduce liver inflammation and fibrosis in animal models of cholestasis [ 93 – 95 ]. The synthetic BA derivative obeticholic acid (OCA) is a potent and selective FXR agonist with anti-cholestatic effects [ 96 , 97 ]. In human clinical studies (Table 1 ), OCA significantly reduced ALP and GGT, compared with placebo, in PBC patients who had inadequate responses to UDCA [ 98 ].…”

Section: Bas In Cholestatic Liver Diseasesmentioning

confidence: 99%

Bile acid-mediated signaling in cholestatic liver diseases

Zeng¹,

Fan²,

Zhou³

2023

Cell Biosci

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Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.

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“…As a strong farnesoid X nuclear receptor agonist that downregulates the intestinal bile acid transporter, obeticholic acid is currently the only approved second-line therapy for UDCA nonresponders or intolerance to UDCA; however, only half of these patients respond to obeticholic acid. Patients who do not respond to treatment with UDCA and/or obeticholic acid have an increased risk of progression to biliary cirrhosis, end-stage liver disease and death or liver transplantation[ 96 , 97 ]. Oral vancomycin has been reported to improve liver biochemical tests (ALT and γGTP) and symptoms in children with primary sclerosing cholangitis due to its minimal oral absorption, high concentration in the gut and inhibition of cytokine release from T cells[ 98 ].…”

Section: Challenges In Treatmentmentioning

confidence: 99%

Challenges in pediatric inherited/metabolic liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders

Zou¹,

Wang²,

Li³

et al. 2023

World J Gastroenterol

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The clinical scenario of pediatric liver disease is becoming more intricate due to changes in the disease spectrum, in which an increasing number of inherited/ metabolic liver diseases are reported, while infectious diseases show a decreasing trend. The similar clinical manifestations caused by inherited/metabolic diseases might be under-recognized or misdiagnosed due to nonspecific characteristics. A delayed visit to a doctor due to a lack of symptoms or mild symptoms at an early stage will result in late diagnosis and treatment. Moreover, limited diagnostic approaches, especially liver biopsy, are not easily accepted by pediatric patients, leading to challenges in etiological diagnosis. Liver dysfunction due to inherited/metabolic diseases is often caused by a variety of metabolites, so precision treatment is difficult; symptomatic treatment is a compelling option for inherited disorders.

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Primary biliary cholangitis as a roadmap for the development of novel treatments for cholestatic liver diseases†

Cited by 29 publications

References 155 publications

Diagnostic workup of suspected hereditary cholestasis in adults: a case report

Diagnostic workup of suspected hereditary cholestasis in adults: a case report

Bile acid-mediated signaling in cholestatic liver diseases

Challenges in pediatric inherited/metabolic liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders

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