Role of the Gut-Liver Axis in the Pathobiology of Cholangiopathies: Basic and Clinical Evidence.

The "Gut-Liver Axis" refers to the physiological bidirectional interplay between the gut and its microbiota and the liver which, in health, occurs thanks to a condition of immune tolerance. In recent years, several studies have shown that, in case of a change in gut bacterial homeostasis or impairment of intestinal barrier functions, cholangiocytes, which are the epithelial cells lining the bile ducts, activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Intestinal dysbiosis or impaired intestinal barrier functions cause cholangiocytes to be exposed to an increasing amount of microorganisms that can reactivate inflammatory responses, thus inducing the onset of liver fibrosis. The present review focuses on the role of the gut-liver axis in the pathogenesis of cholangiopathies.

Final Results from the First European Real-World Experience on Lusutrombopag Treatment in Cirrhotic Patients with Severe Thrombocytopenia: Insights from the REAl-World Lusutrombopag Treatment in ITalY Study.

Background and aims: Management of severe thrombocytopenia poses significant challenges in patients with chronic liver disease. Here, we aimed to evaluate the first real-world European post-marketing cohort of cirrhotic patients treated with lusutrombopag, a thrombopoietin receptor agonist, verifying the efficacy and safety of the drug. Methods: In the REAl-world Lusutrombopag treatment in ITalY (REALITY) study, we collected data from consecutive cirrhotic patients treated with lusutrombopag in 19 Italian hepatology centers, mostly joined to the "Club Epatologi Ospedalieri" (CLEO). Primary and secondary efficacy endpoints were the ability of lusutrombopag to avoid platelet transfusions and to raise the platelet count to ≥50,000/µL, respectively. Treatment-associated adverse events were also collected. Results: A total of 66 patients and 73 cycles of treatment were included in the study, since 5 patients received multiple doses of lusutrombopag over time for different invasive procedures. Fourteen patients (19%) had a history of portal vein thrombosis (PVT). Lusutrombopag determined a significant increase in platelet count [from 37,000 (33,000-44,000/µL) to 58,000 (49,000-82,000), p < 0.001]. The primary endpoint was met in 84% of patients and the secondary endpoint in 74% of patients. Baseline platelet count was the only independent factor associated with response in multivariate logistic regression analysis (OR for any 1000 uL of 1.13, CI95% 1.04-1.26, p 0.01), with a good discrimination power (AUROC: 0.78). Notably, a baseline platelet count ≤ 29,000/µL was identified as the threshold for identifying patients unlikely to respond to the drug (sensitivity of 91%). Finally, de novo PVT was observed in four patients (5%), none of whom had undergone repeated treatment, and no other safety or hemorrhagic events were recorded in the entire population analyzed. Conclusions: In this first European real-world series, lusutrombopag demonstrated efficacy and safety consistent with the results of registrational studies. According to our results, patients with baseline platelet counts ≤29,000/µL are unlikely to respond to the drug.

Hemodynamic Evaluation of the Right Heart-Pulmonary Circulation Unit in Patients Candidate to Transjugular Intrahepatic Portosystemic Shunt.

In Europe, liver cirrhosis represents the fourth-most common cause of death, being responsible for 170,000 deaths and 5500 liver transplantations per year. The main driver of its decompensation is portal hypertension, whose progression radically changes the prognosis of affected patients. Transjugular intrahepatic portosystemic shunt (TIPS) is one of the main therapeutic strategies for these patients as it reverts portal hypertension, thus improving survival. However, the coexistence of portal hypertension and pulmonary hypertension or heart failure is considered a contraindication to TIPS. Nevertheless, in the latest guidelines, the definition of heart failure has not been specified. It is unclear whether the contraindication concerns the presence of clinical signs and symptoms of heart failure or hemodynamic changes in the right heart-pulmonary circulation. Moreover, data about induced right heart volume overload after TIPS and the potential development of heart failure and pulmonary hypertension is currently scanty and controversial. In this article we revise this issue in finding predictors of cardiac performance after TIPS procedure. Performing a fluid challenge during right heart catheterization might be a promising expedient to test the adaptation of the right ventricle to a sudden increase in preload in the first few months after TIPS. This test may unmask a potential cardiac inability to sustain the hemodynamic load after TIPS, allowing for a clearer definition of heart failure and, consequently, a more robust indication to TIPS.

Emerging Therapies for Advanced Cholangiocarcinoma: An Updated Literature Review.

Cholangiocarcinoma is a group of malignancies with poor prognosis. Treatments for the management of advanced-stage cholangiocarcinoma are limited, and the 5-year survival rate is estimated to be approximately 5-15%, considering all tumor stages. There is a significant unmet need for effective new treatment approaches. The present review is provided with the aim of summarizing the current evidence and future perspectives concerning new therapeutic strategies for cholangiocarcinoma. The role of targeted therapies and immunotherapies is currently investigational in cholangiocarcinoma. These therapeutic options might improve survival outcomes, as shown by the promising results of several clinical trials illustrated in the present review. The co-presence of driver mutations and markers of susceptibility to immunotherapy may lead to rational combination strategies and clinical trial development. A better understanding of immunologically based therapeutic weapons is needed, which will lead to a form of a precision medicine strategy capable of alleviating the clinical aggressiveness and to improve the prognosis of cholangiocarcinoma.