Research lines

• Interplay between HBV, HDV and host factors: impact on liver disease progression

  Hepatitis delta is caused by infection with the hepatitis D virus (HDV) and is considered to be the most severe form of human viral hepatitis. Chronic HDV infection has an accelerated progression to fibrosis and increased risk of hepatocellular carcinoma, hepatic decompensation and liver-related mortality. Hepatitis B virus (HBV) plays an essential role as a helper virus for HDV because HDV is a defective RNA virus which requires the envelope proteins of HBV (HBsAg) for its propagation. Little is known about the interactions between HBV and HDV and the infected hepatocytes. This is in part because of the limited experimental models to study HBV and HDV infection and the lack of studies using liver tissue samples from HBV/HDV infected patients. Therefore, the main objective of this research line is to define viral and host factors contributing to rapid disease progression in HBV/HDV coinfected patients as compared to HBV monoinfected patients.

• Novel biomarkers and clinical relevance of the persistence of cccDNA in chronic HBV infection

  There is no curative treatment for HBV infection. This is mainly due to the persistence of cccDNA (covalently closed circular DNA) in the nucleus of hepatocytes, an intermediate of HBV replication that is refractory to nucleos(t)ide analog therapy, and to a profound alteration of the immune response against HBV. Therefore, it is essential to study biomarkers of viral replication and, in particular, to monitor the cccDNA reservoir during the different phases of chronic hepatitis B and the development of novel therapeutic strategies.

• Natural history of chronic HBV infection in different clinical situations

  There are very few data on the role of the immune response (and especially of the specific or adaptive) in the viral events that characterize the natural history of HBV infection (anti-HBe seroconversion, anti-HBs seroconversion, reactivation of infection). We hypothesize that each disease phase, characterized by a defined serological pattern, is reflecting profound changes in the adaptive immune response. Dissecting the mechanisms underlying the different phases of the disease is particularly relevant for the development of new therapies aiming at achieving higher rates of functional cure in patients with chronic hepatitis B.

• Clinical, virological and immunological predictors of response after antiviral treatment interruption in chronic hepatitis B

  Despite the existence of an efficient hepatitis B vaccine for more than 30 years, hepatitis B virus (HBV) infection is still a global health problem. Antiviral therapy can be discontinued in some patients with chronic hepatitis B (CHB) without cirrhosis (EASL guidelines 2017). We have recently shown that decreased cccDNA transcription and low HBsAg levels are associated with functional cure (HBsAg loss) upon antiviral therapy discontinuation in patients with HBeAg-negative CHB. The strength of HBV-specific immune responses, particularly within the liver, may contribute to successful viral control after treatment withdrawal. Our comprehensive study aims to provide in-depth data on virological and immunological factors that can help guide individualized therapy in CHB patients.

• Characterization of humoral and intrahepatic HBV immune responses and the effect of antiviral therapy

  Although most studies have focused on the analysis of T cell responses in chronic hepatitis B, humoral / B cell responses are important for prevention and for ongoing control of HBV infection. Using fluorochrome-labelled surface (HBsAg) and core (HBcAg) antigen baits that allow the detection of HBV-specific B cells, we want to study the phenotype and effector capacity of the target cell population using flow cytometry. In patients initiating antiviral treatment, this study will be also carried out in the intrahepatic compartment before and after therapy in order to evaluate the changes induced by viral replication inhibition. If antiviral therapy is associated with a restoration of B cell responses, this would have an impact on the design of clinical trials that evaluate the association of immunotherapy or new therapeutic vaccination approaches.

• Strategies of hepatitis C microelimination in our geographical area, focused in PWID and psychiatric populations

  Significant scale-up of treatment among people who inject drugs (PWID) is crucial to achieve WHO hepatitis C virus (HCV) elimination targets. We have established on-site HCV diagnosis and treatment on PWID in an externalized Hepatology clinic at the biggest harm reduction center (HRC) in Barcelona, attending a marginalized PWID population with ongoing high-risk practices. We have shown that HCV treatment can be successfully delivered to active PWID with high-risk practices and has a significant benefit beyond HCV elimination.

  In addition, we have explored the prevalence of viral hepatitis in the population of patients with acute and chronic psychiatric diseases. After one year of universal screening, the increased prevalence of viral hepatitis has been shown to be associated with patients with dual pathology only. This recent update might be helpful for the design of microelimination programs and health strategies in our territory.

• Long-term impact of Hepatitis C cure in patients with advanced liver disease

  Portal hypertension (PH) is the key driver of hepatic decompensation in patients with advanced chronic liver disease. Accordingly, interventions that ameliorate portal hypertension have been shown to prevent hepatic decompensation in patients who are at risk, i.e., those with clinically significant portal hypertension (CSPH), which is defined by a hepatic venous pressure gradient (HVPG) ≥10mmHg. However, hemodynamic evaluation is invasive and non-available in all centers. Non-invasive tests (NITs) for diagnosis of CSPH are relevant in this setting, but have predominantly been studied in patients with active HCV-infection. We are actively working on evaluating if NITs can estimate the probability of CSPH after HCV-cure and predict clinical outcomes. This will improve the management of patients with HCV- advanced chronic liver disease that have achieved sustained virological response after antiviral therapy.

• Understanding the immunopathogenesis of autoimmune hepatitis (AIH) to develop risk stratification tools at presentation

  The incidence of AIH has been steadily increasing within the last decades.  However, standard treatment of the disease, which consists of corticosteroids (CS) and azathrioprine (AZA), has not been changed within the last 40 years. Intolerance, insufficient response or contraindication to CS and AZA, indicate that there is an urgent need for a fully understanding of the immunopathogenesis of AIH. To this end, we are trying to comprehensively describe the clinical and histological characteristics of the AIH patients at presentation, and we are seeking to unravel their transcriptomic and immunological characteristics, in order to create risk stratification tools at presentation. This line of research, which implements for the first time cutting edge technologies (scRNAsec of fine needle aspirates and spectral cytometry analyses), in combination with robust in-depth analysis tools (i.e. next generation sequencing of liver biopsies) will shed light into the pathogenesis of AIH, which is needed not only in understanding the insufficient response to current treatment but also in developing more effective regimens.

• Evolution of AIH in special populations (pregnancy, compensated and decompensated cirrhosis)

  Approximately 30% of patients with AIH have cirrhosis at the time of diagnosis, and 20-30% of the remaining patients will develop cirrhosis during the follow-up. The management of immunosuppression in patients with decompensated cirrhosis could be cumbersome due to the risk of adverse events (further decompensation, cytopenias and infections). There is little information regarding the management of AIH patients with cirrhosis, especially those with decompensated cirrhosis. Therefore, we are working in the identification of predictive biological markers of treatment response and re-compensation.

• Identification of biomarkers of success of immunosuppression withdrawal and treatment response in AIH

  We have performed a prospective clinical trial to identify biomarkers able to predict the success of immunosuppression withdrawal in patients with AIH. Here we found that the immunological, histological, and biochemical characteristics are very similar between groups. However, we want to extend the analysis of these patients to use modern techniques to compare liver biopsies and peripheral lymphocytes subpopulations. Subsequently, we will move to validation phase.

• Natural history of modern primary biliary cholangitis (PBC) and predictive factors of portal hypertension in patients in non-cirrhotic patients with PBC

  PBC is chronic liver disease affecting small bile ducts. If left untreated, patients will develop ductopenia and cirrhosis with all its complications. However, in recent years, the disease is diagnosed at early stages and tends to control better with the prescribed treatment. Here we seek to analyze the natural history of the disease diagnosed in recent years and compared that with patients diagnosed before in order to determine that changes in disease progression and treatment response.

  In addition, it is well known that patients with PBC can develop signs of portal hypertension at early stages, before the development of cirrhosis. Therefore, the criteria currently used in clinical practice to select patients who are candidates for an upper endoscopy to rule-out the presence of varices are not useful in this situation. We want to characterize non-cirrhotic portal hypertension in patients with PBC to find predictive factors of this phenomenon.

• Impact of exercise programs in the treatment PBC-associated fatigue

  Up to 50% of patients with PBC experience clinically significant fatigue, and it is more common in younger patients. Fatigue diminishes quality of life and interferes with many activities of daily living. Intriguingly, it is not related to the severity of the underlying liver disease and currently there is no treatment for fatigue in PBC. Fatigue is described as a combination of 2 elements: a sense of brain fog and muscular weakness. We aim to study the physiopathology of fatigue, evaluating the cognitive impairment with a complete neuropsychometric assessment and using brain magnetic resonance imaging together with the assessment of the muscular functional capacity. After that, in patients with severe fatigue, we seek to perform a prehabilitation program including personalized body exercises and mindfulness to improve the quality of life and the fatigue in those patients.

• Clinical and biological characterization of patients with Wilson’s disease

  Wilson's Disease is a rare genetic condition characterized by copper deposition mainly in the liver and other tissues afterwards. Clinical presentation is highly heterogeneous. Diagnosis of patients with chronic liver disease is a big challenge, as WD may mimic many other prevalent liver diseases. The development of a new serum biomarker representing the toxic fraction of copper overload (exchangeable copper) has been shown to be useful in clinical practice. We have implemented this biomarker, and we have been able to show its accuracy at diagnosis and follow-up of our patients. We are currently working on the assessment of exchangeable copper in different clinical scenarios, in which this biomarker has not been evaluated to date (acute presentations, dynamic long-term follow up). We additionally aim to explore the usefulness of liver ultrasound in this disease, as some differential characteristics can be defined, increasing clinical suspicion. In addition, we want to explore the value of transient elastography (liver fibrosis and steatosis) and their correlation with liver biopsies at different time-points. The evaluation of novel histological biomarkers in liver tissue (such as metallothionine immunohistochemistry), constitutes another objective of this line.

• Epidemiology of drug-induced liver disease

  The real incidence of drug-induced liver injury is difficult, but it seems clear that it is increasing due to the growth of prescriptions. Epidemiological studies of DILI are still limited and more importantly, data from old studies may not reflect the current spectrum of the disease. In addition, there is very limited information on the relevance of hepatotoxicity due to herbal and dietary supplements. Thus, one of the goals of our group is to determine the real relevance of DILI, both at the hospital level and in the community.