2024-03-18 03:02:59
In efforts to optimize the treatment of primary biliary cholangitis, chronic liver disease affecting the bile ducts, new studies have emerged led by researchers Kris V. Kowdley and Gideon M. Hirschfield of the Liver Institute Northwest from Seattle USA and Toronto Centre for Liver Disease in Canada, respectively. These support the use of elafibranor y seladelparagonists of peroxisome proliferator-activated receptors (PPARfor its acronym in English), as an alternative therapy.
This is an autoimmune disease characterized by inflammation in the portal tracts and death of the biliary epithelial cells (cholangiocytes) in the small bile ducts. It is caused by genetic, epigenetic and environmental factors (figure 1). During its progression, the number of bile ducts decreases, causing cholestasisa key factor for the development of fibrosis y cirrhosis. Most patients are between 40 and 60 years old and the incidence is higher in women. Clinical features include fatigue, pruritus, and progressive jaundice.
Given its slow progress and low prevalence, it is a challenge to design statistically supported trials and evaluate clinical events. Biochemical serum markers are currently used as endpoints. The levels of alkaline phosphatase y bilirubin can predict the results: Liver transplant Or death.
He ursodeoxycholic acid It is the first line therapy, it slows down biochemical processes and progression. However, between 30-40% of patients do not respond, therefore, the availability of second-line therapies is important. He obeticholic acid, a bile acid analogue, has been approved as an alternative treatment. However, its use is not permitted in people with decompensated cirrhosis and itching is known to be a possible side effect.
PPARs are members of the nuclear receptor family of ligand-activated transcription factors and include PPAR-α, PPAR-δ, and PPAR-γ. Upon ligand binding, they form heterodimers with the retinoid X receptor and induce the transcription of genes involved in inflammation and fatty acid and glucose metabolism. They can also suppress the transcription of inflammatory genes (Figure 1). PPAR-α is mainly expressed in the hepatocytes, while PPAR-δ has ubiquitous expression, including hepatocytes, macrophages (Kupffer cells), stellate cells and cholangiocytes. PPAR agonists have emerged as potential therapies for primary biliary cholangitis and other cholestatic liver disorders.
Figure 1: Pathogenesis of primary biliary cholangitis and targets of peroxisome proliferator-activated receptor (PPAR) agonists.
Elafibranor is a dual agonist of PPAR-α and PPAR-δ, and seladelpar is a selective agonist of PPAR-δ (Figure 1). A key mechanism for both is suppression of bile acid synthesis. PPAR-α agonism is known to reduce bile acid toxicity and bile acid absorption by hepatocytes (Figure 1). These notable anticholestatic characteristics are critical to the effectiveness of these medications. Trials with elafibranor and seladelpar resulted in improved lipid profiles, which might be mediated by their known induction of fibroblast growth factor 21 (FGF21). Although PPAR-α agonism reduced the liver fibrosis In preclinical models, only seladelpar decreased liver stiffness and fibrosis in patients with chronic disease.
Although primary biliary cholangitis is autoimmune, immunomodulatory medications have not shown clinical benefits. PPAR-α and PPAR-δ agonists have anti-inflammatory properties and affect both innate and adaptive immunity by switching macrophages from an inflammatory to an anti-inflammatory phenotype and by suppressing type 1 helper T cell polarization. PPAR-agonism α induces regulatory T cell differentiation, while PPAR-δ agonism suppresses type 17 helper T cell polarization (Figure 1). It is unknown to what extent these anti-inflammatory properties contribute to the beneficial effect of each drug, although both reduced the levels of total IgM and IgG (markers of immune activation), and seladelpar decreased the levels of high-sensitivity C-reactive protein. A crucial aspect for patients is that seladelpar effectively relieved pruritus, with a molecular mechanism still unknown.
Although ursodeoxycholic acid will continue to be the first-line therapy, medication options are increasing for patients who have no effect. Those at high risk of disease progression might benefit from early combination therapy. Furthermore, people with pre-existing liver fibrosis face a high risk of an inadequate response, even with a combined regimen. In such cases, the introduction of a antifibrotic drug It can not only delay the progression of the pathology but also potentially reverse existing fibrosis.
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