Therapeutic success in primary biliary cholangitis and gut microbiota: a safe highway?

Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease, characterized by destruction of bile ducts. PBC predominantly affects women between 40 and 60 years of age. The presence of antimitochondrial antibodies (AMA) is a serological feature of PBC. These highly specific antibodies are found in about 95% of patients with the disease. The family of enzymes located in the inner membrane of the mitochondria, called the 2-oxo-acid dehydrogenase complex represents the target of the AMA. Ursodeoxycholic acid (UDCA) is a synthetic bile acid capable of protecting cholangiocytes from cholestatic damage caused by the accumulation of bile acids with a mechanism of action not yet well clarified. UDCA represents the gold standard therapy for PBC patients with recommended dose of 13-15 mg/kg/day. However, not every patient responds to therapy. On the other hand, the gut microbiota plays a key role in the onset of PBC through still unclear biochemical pathways. Less is known about its role as a potential biomarker after drug treatment. Actually, few studies analyzed the changes in gut microbiota composition before and after UDCA treatment. For this reason, this review represents an examination of the studies carried out on changes in gut microbiota composition in patients affected by PBC before and after treatment.

Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol-associated liver disease.

BACKGROUND & AIMS: Alcohol use disorder (AUD) represents the most common cause of liver disease. The gut microbiota plays a critical role in the progression of alcohol-related liver damage. Aim of this study was to characterize the gut microbial composition and function in AUD patients with alcohol-associated liver disease (AALD). METHODS: This study included 36 AUD patients (14 with cirrhosis) who were active drinkers and an equal number of matched controls. Stool microbial composition, serum levels of lipopolysaccharide, cytokines/chemokines and gut microbiota functional profile were assessed. RESULTS: AUD patients had a decreased microbial alpha diversity as compared to controls (0.092 vs 0.130, P = .047) and a specific gut microbial signature. The reduction of Akkermansia and the increase in Bacteroides were able to identify AUD patients with an accuracy of 93.4%. Serum levels of lipopolysaccharide (4.91 vs 2.43, P = .009) and pro-inflammatory mediators (tumour necrosis factor alpha 60.85 vs 15.08, P = .001; interleukin [IL] 1beta 4.43 vs 1.72, P = .0001; monocyte chemoattractant protein 1 225.22 vs 16.43, P = .006; IL6 1.87 vs 1.23, P = .008) were significantly increased in AUD patients compared to controls and in cirrhotic patients compared to non-cirrhotic ones (IL6 3.74 vs 1.39, P = .019; IL8 57.60 vs 6.53, P = .004). The AUD-associated gut microbiota showed an increased expression of gamma-aminobutyric acid (GABA) metabolic pathways and energy metabolism. CONCLUSIONS: AUD patients present a specific gut microbial fingerprint, associated with increased endotoxaemia, systemic inflammatory status and functional alterations that may be involved in the progression of the AALD and in the pathogenesis of AUD.

Regorafenib: a promising treatment for hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors with 854,000 new cases per year and represents the second most frequent cause of cancer-death. Despite surveillance, the number of patients that are diagnosed at a stage in which they are eligible for curative treatments ranges from 30% to 60%. Advanced HCC (BCLC-C) is characterized by a median survival of 6 months. Sorafenib, the first systemic drug proven to be effective in prolonging survival of unresectable HCC, was approved by the FDA in 2007 but no second-line treatment was available for a decade for patients progressing on sorafenib. Finally, in 2016, the RESORCE trial demonstrated regorafenib as an effective second-line treatment. Areas covered: In this manuscript, the authors review the principal preclinical and clinical trials on regorafenib used in the treatment of unresectable HCC patients progressing on sorafenib and highlight both the advantages and the limitations of this drug. Expert opinion: Regorafenib is the only second-line treatment available for patients progressing on sorafenib. Despite its promising clinical application, many doubts still remain, necessitating further investigation to explore the tolerability of this drug in Child-Pugh B and sorafenib-intolerant patients, while its scarce cost-effectiveness must also be improved.

Thrombosis after liver transplantation for hepatocellular carcinoma.

The influence of thrombosis on the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT) and the role of the commonest inherited thrombophilia abnormalities factor V Leiden and prothrombin G20210A in the development of thrombosis are unknown. We investigated a cohort of patients who underwent LT for HCC with the aim to estimate the incidence rate (IR) of thrombosis, its influence on mortality and re-transplantation rates and, in the frame of a nested case-control study, the role of thrombophilia in donors and recipients for the development of thrombosis. Four-hundred and thirty patients underwent LT and were followed for a median of 7.2 years. Twenty-six recipients (6%) developed thrombosis (IR 1.06 [95%CI: 0.71-1.53] per 100 pts-yr). Mortality rate after LT was 3.95 (95%CI: 3.22-4.79) per 100 pts-yr and was not influenced by thrombosis. Re-transplantation was planned for 33 patients and was more common in patients with thrombosis than in those without (HR 2.50 [95%CI: 0.87-7.17]). The risk of thrombosis was 4 times higher in recipients with thrombophilia than in those without (OR 4.23 [95%CI: 0.99-18.04]) and 6 times higher when the analysis was restricted to venous thrombosis (OR 6.26 [95%CI: 1.19-32.85]). The presence of inherited thrombophilia in the donors did not increase the risk of thrombosis of the recipient. In conclusion, thrombosis is a complication of 6% of patients transplanted for HCC and increases the risk of re-transplantation but not of mortality. The risk of thrombosis, particularly venous, is increased in the presence of thrombophilia abnormalities in the recipients.

HepPar1-Positive Circulating Microparticles Are Increased in Subjects with Hepatocellular Carcinoma and Predict Early Recurrence after Liver Resection.

Circulating microparticles (MPs) are novel potential biomarkers in cancer patients. Their role in hepatocellular carcinoma (HCC) is under intensive investigation. In this study, we tested the hypothesis that MPs expressing the antigen HepPar1 are increased in the blood of subjects with HCC and may serve as markers of early recurrence after liver resection (LR). We studied 15 patients affected by HCC undergoing LR, and used flow cytometry to assess the number of circulating HepPar1+ MPs. Ten subjects without HCC (five with liver cirrhosis and five with healthy livers) were used as controls. After LR, HCC patients underwent a follow-up to check for early recurrence, which occurred in seven cases. The number of circulating HepPar1+ MPs was significantly higher in subjects affected by HCC, compared to individuals without cancer (p < 0.01). We also found that, among HCC patients, the number of circulating HepPar1+ MPs, measured before LR, was significantly higher in those who displayed early recurrence compared to those without recurrence (p = 0.02). Of note, other types of circulating MPs, such as those derived from endothelial cells (CD144+) or those produced by the activated endothelium (CD144+/CD62+), were not associated with HCC, nor could they predict HCC recurrence. HepPar1+ MPs deserve further investigation as novel biomarkers of disease and prognosis in HCC patients.

How to modulate gut microbiota: diet, preprobiotics or antibiotics?

The gut microbiota is involved in the maintenance of humans' health and its alterations have been associated to several intestinal and extra intestinal disorders. For this reason, there is increasing interest on gut microbiota modulation as both a preventive strategy or as a therapeutic option in different gastrointestinal, hepatic and systemic diseases. Many studies have tried to find out the impact of diet, prebiotic, probiotic and antibiotics on gut microbiota composition and function, obtaining very heterogeneous and sometimes conflicting results, especially as regards the effect on clinical outcomes. However, these preliminary data represent a promising premise for further studies that will provide a more comprehensive knowledge about the role of gut microbiota as a therapeutic target.

Treatment of hepatitis C recurrence is less successful in female than in male liver transplant recipients.

It has been recently suggested that the risk of graft loss after liver transplantation (LT) may increase in female HCV patients. The aim of the study was to examine gender differences in HCV therapy tolerance and outcome in LT patients treated for HCV recurrence. A retrospective study was conducted on liver recipients with HCV recurrence, who were given antiviral therapy from 2001 to 2009 in 12 transplant centers in Italy. Sustained virological response (SVR), adherence-to-therapy, and side effects were evaluated. A multivariate logistic regression model was used after adjusting for possible confounders. The data regarding 342 treated patients were analyzed. SVR was reported in 38.8% of patients. At baseline, male and female did not differ in HCV viral load, histology, or rate of diabetes. SVR was lower in females than in males (29.5% vs. 42.1%; P=0.03). Adherence-to-therapy was also lower in females than in males 43.4% vs. 23.8%; P=0.001); anemia was the main reason for lower adherence. In a multivariate analysis in patients Genotype1, female gender (P<0.04), early virological response (P<0.0001), and adherence to therapy (P<0.0001) were independent predictors for SVR. In conclusion, female gender represents an independent negative prognostic factor for the outcome of HCV antiviral therapy after LT.

Portal vein thrombosis: insight into physiopathology, diagnosis, and treatment.

Portal vein thrombosis (PVT) is a relatively common complication in patients with liver cirrhosis, but might also occur in absence of an overt liver disease. Several causes, either local or systemic, might play an important role in PVT pathogenesis. Frequently, more than one risk factor could be identified; however, occasionally no single factor is discernable. Clinical examination, laboratory investigations, and imaging are helpful to provide a quick diagnosis, as prompt treatment might greatly affect a patient's outcome. In this review, we analyze the physiopathological mechanisms of PVT development, together with the hemodynamic and functional alterations related to this condition. Moreover, we describe the principal factors most frequently involved in PVT development and the recent knowledge concerning diagnostic and therapeutic procedures. Finally, we analyze the implications of PVT in the setting of liver transplantation and its possible influence on patients' future prognoses.