Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies

Gerussi, Alessio; D’Amato, Daphne; Cristoferi, Laura; O’Donnell, Sarah; Carbone, Marco; Invernizzi, Pietro

doi:10.1016/j.aohep.2019.09.009

Cited by 15 publications

(13 citation statements)

References 135 publications

(162 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After four weeks, interim analysis showed a dose-dependent reduction in GGT, ALP, and hepatocellular damage (ALT). Therefore, this study indicates the potential benefit of Tropifexor in PBC, and further studies are warranted [45].…”

Section: Non-bile Acids Fxr Agonistsmentioning

confidence: 72%

“…Finally, at the end of 2018, the ENHANCE trial started. It was a 52-week, double-blind, placebo-controlled, randomized phase 3 study that included subjects with PBC and an inadequate response to UDCA or intolerance to UDCA ("ENHANCE: Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)", NCT03602560) [45]. Unfortunately, the open-label extension phase of this study was suspended after the onset of a similar trial evaluating the role of Seladelpar in NASH that found the occurrence of interface hepatitis in histological specimens.…”

Section: Ppar Agonistsmentioning

confidence: 99%

“…The efficacy of Baricitinib (LY3009104), a reversible inhibitor of Janus kinase 1 (JAK1) and JAK2 currently used in rheumatoid arthritis, is currently being evaluated in an ongoing, placebo controlled phase 2 trial (NCT03742973) [45].…”

Section: Immunomodulatory Strategiesmentioning

confidence: 99%

“…Up to now, no pharmacological treatment is universally approved for PSC. The lack of a clear pathogenesis and the absence of consistent endpoints have contributed to the difficulties in unravelling novel molecular targets and in designing effective clinical trials for PSC treatment [45]. The principal promising treatments and ongoing trials will be summarized in this section.…”

Section: Primary Sclerosing Cholangitismentioning

confidence: 99%

See 3 more Smart Citations

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

Mazzetti

Marconi

Mancinelli

et al. 2021

JCM

View full text Add to dashboard Cite

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.

show abstract

Section: Non-bile Acids Fxr Agonistsmentioning

confidence: 72%

Section: Ppar Agonistsmentioning

confidence: 99%

Section: Immunomodulatory Strategiesmentioning

confidence: 99%

Section: Primary Sclerosing Cholangitismentioning

confidence: 99%

See 2 more Smart Citations

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

Mazzetti

Marconi

Mancinelli

et al. 2021

JCM

View full text Add to dashboard Cite

show abstract

“…To date, only a few pharmacological therapies have been proven to be effective and only in limited pathology conditions (urosodeoxycholic acid, obeticholic acid, and bezafibrate in primary biliary cholangitis), while the vast majority of cholangiopathies are still orphan. Liver transplantation remains the only option when the disease is advanced (8)(9)(10). Major efforts for developing effective therapeutic strategies in cholangiopathies should be devoted to halt biliary fibrogenesis (4,11).…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of Macrophages in Chronic Cholangiopathies Featuring Biliary Fibrosis: An Attractive Therapeutic Target for Orphan Diseases

et al. 2020

View full text Add to dashboard Cite

Cholangiopathies are a heterogeneous group of chronic liver diseases caused by different types of injury targeting the biliary epithelium, such as genetic defects and immune-mediated attacks. Notably, most cholangiopathies are orphan, thereby representing one of the major gaps in knowledge of the modern hepatology. A typical hallmark of disease progression in cholangiopathies is portal scarring, and thus development of effective therapeutic approaches would aim to hinder cellular and molecular mechanisms underpinning biliary fibrogenesis. Recent lines of evidence indicate that macrophages, rather than more conventional cell effectors of liver fibrosis such as hepatic stellate cells and portal fibroblasts, are actively involved in the earliest stages of biliary fibrogenesis by exchanging a multitude of cues with cholangiocytes, which promote their recruitment from the circulating compartment owing to a senescent or an immature epithelial phenotype. Two cholangiopathies, namely primary sclerosing cholangitis and congenital hepatic fibrosis, are paradigmatic of this mechanism. This review summarizes current understandings of the cytokine and extracellular vesicles-mediated communications between cholangiocytes and macrophages typically occurring in the two cholangiopathies to unveil potential novel targets for the treatment of biliary fibrosis.

show abstract

Measurement of Gamma Glutamyl Transferase to Determine Risk of Liver Transplantation or Death in Patients With Primary Biliary Cholangitis

Gerussi

Bernasconi

O’Donnell

et al. 2021

Clinical Gastroenterology and Hepatology

Self Cite

View full text Add to dashboard Cite

In patients with urinary magnesium wasting, oral and intravenous supplementation often fail to adequately improve serum magnesium levels. Glucose intolerance and diabetes mellitus frequently accompany hypomagnesemia. Clinical trials examining inhibitors of the type 2 sodium glucose cotransporter (SGLT2) show small but significant increases in serum magnesium levels in diabetic patients. This report describes dramatic improvement in serum magnesium levels and associated symptoms after initiating SGLT2 inhibitor therapy in 3 patients with refractory hypomagnesemia and diabetes. Each patient received a different SGLT2 inhibitor: canagliflozin, empagliflozin, or dapagliflozin. One patient discontinued daily intravenous magnesium supplements and exhibited higher serum magnesium levels than had been achieved by magnesium infusion. 2 of the 3 patients exhibited reduced urinary fractional excretion of magnesium, suggesting enhanced tubular reabsorption of magnesium. These observations demonstrate that SGLT2 inhibitors can improve the management of patients with otherwise intractable hypomagnesemia, representing a new tool in this challenging clinical disorder.

show abstract

Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies

Cited by 15 publications

References 135 publications

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

The Emerging Role of Macrophages in Chronic Cholangiopathies Featuring Biliary Fibrosis: An Attractive Therapeutic Target for Orphan Diseases

Measurement of Gamma Glutamyl Transferase to Determine Risk of Liver Transplantation or Death in Patients With Primary Biliary Cholangitis

Contact Info

Product

Resources

About