Interview: An overview of liver diseases

esanum: What does a hepatology specialist take home from the 2024 edition of the congress organised by EASL - European Association for the Study of the Liver?

Prof. Umberto Vespasiani-Gentilucci: When we come to the EASL congress, we expect to acquire the latest in diagnostics and therapy of the various liver diseases. At this particular time, very important news is coming in the field of both cholestatic diseases and metabolic diseases, in particular MASLD (metabolic dysfunction-associated steatotic liver disease). There is also a lot of interesting research in the field of hepatocarcinoma. Participating in these congresses allows one to get the latest results of many ongoing studies and thus to read the present with an eye to the short-term future.

Prof. Umberto Vespasiani-Gentilucci: My lecture during the seminar on PBC (primary biliary cholangitis)¹ focused on identifying biochemical parameters that can help us find out which patients are having better or worse results during specific treatments.

PBC is a rare disease. The available therapies, in particular ursodeoxycholic acid (UDCA) and the only second-line treatment approved to date, obeticholic acid (OCA), make it possible to reduce some of these biochemical parameters and in particular alkaline phosphatase and to stabilise or reduce bilirubin levels. In rare diseases, it is difficult to demonstrate that these effects on relevant biochemical parameters translate in the long term into a reduction of disease-related complications (liver-related events: onset of cirrhosis, disease decompensation, onset of liver cancer). Therefore, since the disease is rare and the timeframe for demonstrating an impact on liver-related events is long, we try to obtain additional data from real-life studies. We are no longer in the context of clinical trials, but in the ‘real world setting’. We can go and observe, first and foremost, the efficacy of a drug and whether its adverse event profile is in line with those observed in registered trials. In addition, by having a longer observation time, we can check whether the effect on biochemical parameters translates into a reduction in liver-related effects compared with what was observed in some historical short control trials not treated with the drug.

Studies have shown that ursodeoxycholic acid (UDCA) is effective in reducing alkaline phosphatase and bilirubin levels in patients with PBC. As early as 1999, it was observed that patients treated with UDCA had significantly improved survival compared to untreated patients. These results were confirmed in a study published in 2008, where UDCA treatment was shown to provide a clear survival benefit even in patients who did not fully respond to the drug according to predefined biochemical criteria. Several studies have shown that OCA has a robust impact on biochemical parameters, reducing alkaline phosphatase levels by 40% in the first year of treatment. Bilirubin and ALT levels also show significant improvements, suggesting a reduction in overall liver inflammation.

The importance of real-world data became clear in the Italian RECAPITULATE study², which analysed patients treated with OCA from numerous centres throughout Italy. The Italian PBC Registry was at the heart of this project and supported its organisational structure, but a key role in its creation and in the numerical extension of the group of patients evaluated was also played by the CLEO (Club Epatologi Ospedalieri), which collected a substantial case history from non-academic centres. Unity made strength and determined the national and international success of the study. One part of the RECAPITULATE project set out to compare the results obtained with those of an untreated control cohort with OCA derived from the Global PBC study, which collects the largest cohort of PBC patients from around the world. This analysis showed that treatment with OCA is associated with a 60% improvement in liver transplant-free survival and reduction in liver-related events.

A further sub-analysis of the RECAPITULATE study showed that those who respond to treatment with OCA according to predefined criteria (POISE) have a significant reduction in liver stiffness over time, a key indicator of fibrotic disease progression. These data are essential to understand how biochemical improvements translate into objective clinical benefits.

Real-world data play a crucial role in confirming these benefits, providing a more complete view of the efficacy of treatments in daily clinical practice. These results underline the importance of targeting not only the reduction of biochemical parameters but also the complete normalisation and evaluation of non-invasive tools to monitor liver disease progression.

esanum: Talking about PBC and OCA, you participated in a recently published study³ with the aim of creating a score to predict drug response. Please tell us what this is all about?

Prof. Umberto Vespasiani-Gentilucci: Patients with PBC who benefit most from obeticholic acid therapy respond to treatment according to certain characteristic criteria. But we did not have a tool to know, before starting OCA therapy, who was more or less likely to respond positively to therapy. This study, which used data from a large series of patients in the “real world” context, aimed to identify a score, based on biochemical and clinical variables, to see who will or will not respond to this treatment. This new score (https://ocaresponsescore.github.io/calculator/) has good accuracy. In the future, when we will have new molecules available, this score, together with other scores, will probably help the doctor choose the right drug for the right patient.

esanum: Chronic liver disease is considered an epidemiological emergency, both locally and globally. What is being done to improve healthcare for these patients, in Italy and in the rest of the world?

Prof. Umberto Vespasiani-Gentilucci: In the field of liver disease there are two aspects to consider when talking about chronic disease: advanced liver disease, with its complications, and metabolic disease.

When we are dealing with advanced liver disease and its complications, care must be given to the patient and caregivers must be supported. Careful monitoring is needed out of hospital, so that organ failures are reduced or, if they occur, that effective action can be taken. In Italy, but not only in Italy, the lacking part concerns care out of hospital. We need doctors and nurses who, at this stage of the disease, can periodically check the patient at home in order to anticipate interventions and prevent organ failure events.

With regard to metabolic liver disease (MASLD), the most emerging one, linked to obesity, diabetes, sedentary lifestyle, there is much to be done in the integration of different specialists (diabetes, cardiology, hepatology, nephrology, ...). In fact, usually, the same patient has a number of combined problems. Therefore, integrating the various disciplines by creating multidisciplinary working groups is certainly a line of development on which there is little experience at the moment. In Italy there is little, probably in other countries, especially the United States, something more effective is being done in this field.

Artificial intelligence and new technologies: Strong impact on hepatology

esanum: What are new technologies bringing to the clinical practice in hepatology?

Prof. Umberto Vespasiani-Gentilucci: New technologies provide us with new ways of working every day. For those dealing with liver disease, there have been major innovations in recent years from an instrumental point of view. The ability to noninvasively measure liver stiffness, for example, has revolutionised clinical practice. Through this simple physical principle, namely that the harder the liver is the more fibrotic it becomes, we have reduced the need for liver biopsy. Radiologically, the development of MRI analysis techniques is enabling innovative tools to noninvasively assess the amount of fat within the liver, the level of inflammation and fibrosis.

On the prevention side, the use of artificial intelligence in the risk stratification of patients, for example, will bring about a real revolution. This will be useful both in specialist medicine and in primary care, where the family doctor, using these new tools, will be able to recognise risk profiles and refer the patient to the specialist in good time.

These are just a few examples of how new technologies are changing the way we do hepatology.

esanum: Will improvements in the treatment of liver disease decrease the incidence of hepatocarcinoma, one of the leading causes of death from cancer in the world today?

Prof. Umberto Vespasiani-Gentilucci: Yes, in the next future we expect to have the possibility to reduce the occurrence of liver cancer by controlling various liver diseases.

The possibility of eradicating the infection in the vast majority of patients with hepatitis C, for example, is a major step in terms of the disease and thus also the risk of cancer associated with this disease. Even when it comes to hepatitis B, treatments that control viral replication have lowered the risk of hepatitis B-related cancer.

In MASLD, certainly drugs that can act on metabolism – make people lose weight, better control diabetes, in the future drugs that target liver fat – will hopefully also reduce the risk of cancer linked to this disease aetiology.

Prof. Umberto Vespasiani-Gentilucci: The main aspect concerning liver transplantation today is the reduction in viral-based causes and the proportional increase in metabolic, alcoholic and biliary-based causes.

Talking about the latter cause, PBC, thanks to effective therapies, is decreasing to be a cause of liver transplantation. Primary sclerosing cholangitis (PSC), on the other hand, although a rare disease, is still a rather stable cause of needing a transplant because we have no treatment.

Strengthening liver health through regular exercise

Prof. Umberto Vespasiani-Gentilucci: The ‘Run for liver’ is an event that has been organised for several years by our hepatology unit at the Fondazione Policlinico Universitario Campus Bio-Medico in Rome.

Usually, when people talk about running, in general about physical activity, they think about cardiovascular disease or diabetes, obesity. Physical activity is hardly ever associated with liver wellbeing. Instead, saying ‘run for your liver’, ‘go for a run because it is good for your liver’, puts the emphasis on an emerging problem, MASLD, which is becoming the leading cause of liver cirrhosis, liver cancer, and the need for transplantation in the western world. This disease is treated first of all by hygiene practices, then by an optimal diet – low in refined carbohydrates and animal-derived fats, ultra-processed meats – and by physical activity. Physical activity is a cornerstone of treatment, perhaps more important than diet. A diet can be very effective in the short to medium term, but if one does not add physical activity, one usually loses the results in the long term. Only a radical change in lifestyle that also relies on physical activity can hold over time.

It is therefore necessary to stimulate the patient with metabolic disorders to start a diet and to start moving. Movement means, indicatively, doing one hour of physical activity at least 3 times a week. Physical activity is exertion, breathlessness, sweat, to be achieved gradually and after cardiological clearance. A walk through the city centre streets window-shopping is not enough.

esanum: It is therefore no coincidence that, in 2016, you obtained a master's degree in Dietetics and Nutrition... In this field today, many patients, especially younger ones, rely on the advice of the Internet, especially social media influencers. What do you think about this?

Prof. Umberto Vespasiani-Gentilucci: We, as physicians, have to learn more and more, to avoid giving generic answers. We must try to be able to go deeper into certain topics, such as nutrition. If the doctor shows that he lacks competence, if the patient receives incomplete answers from the doctor, he/she is likely to look elsewhere. It is important for doctors, at this time in history, to acquire a higher level of knowledge and to make this perceived by those who ask us questions.

We have to spend time on these questions, we have to be good at not considering them the least important part of the visit, compared to the therapeutic drug prescription. We have to make the patient perceive that diet and physical activity are important elements of therapy.

In the near future, in the field of metabolic diseases, we will see a real therapeutic revolution. We will have increasingly effective drugs against obesity, diabetes, but these drugs then very often work if they are accompanied by a change in awareness, a change in eating habits, a change in attitude to life.

We must also not underestimate the motivational aspect, the investment we put into these aspects. Influencers often win because of the charismatic aspect. We are all looking for someone who is a leader, who acts as a point of reference, who can guide us, who can push us to make sacrifices and change course. We doctors must therefore commit ourselves to believing a lot in what we say, even when we talk about diet and physical activity. We need to be real leaders in promoting good health, not just generic 2-minute recommendations at the end of the visit-who can really pay attention to us otherwise?

Prof. Umberto Vespasiani-Gentilucci: We live in a world where change is really the order of the day. I have the impression that we are raising the bar at all levels. In medicine, as in other fields.

Maybe I'm trite, but I think the biggest revolution will come from artificial intelligence: in the approach to diagnostics, in the risk stratification of patients, in the identification of phenotypes of patients who may benefit more or less from a treatment, and so on. In the study we talked about earlier, we came up with a score using our heads. The scores that will be generated by AI will probably be easier and faster to obtain. Maybe better.

What I expect in 2034 is that we will be back to discussing not so much how much our brilliant minds will have been able to process from a diagnostic-therapeutic point of view, but how much our brilliant minds will have been able to use the tools derived from artificial intelligence in the most correct way to better direct diagnoses and therapies.

Certainly the human mind is the foundation of everything, and so our skill as physicians and scientists will be to use these new tools in the most effective and ethically and scientifically sound manner.

Berenguer M, Vespasiani-Gentilucci U. AdvanzPharma: Shifting Paradigms in PBC Management. EASL 2024. Friday, 7 Jun, 10:00 - 10:30 CEST
F. Terracciani et al. Long-term results from the Italian real-world experience on obeticholic acid treatment in primary biliary cholangitis: The RECAPITULATE study. Digestive and Liver Disease, Volume 55, Supplement 1, 2023, Pages S44-S45, ISSN 1590-8658, https://doi.org/10.1016/j.dld.2023.01.088.
De Vincentis A. et al. Development and validation of a scoring system to predict response to obeticholic acid in primary biliary cholangitis. Clin Gastroenterol Hepatol. 2024 May 21:S1542-3565(24)00482-8. doi: 10.1016/j.cgh.2024.05.008. Epub ahead of print. PMID: 38782175.

Interview: An overview of liver diseases

Liver diseases expert Prof. Umberto Vespasiani-Gentilucci addresses important innovations in disease management with a focus on PBC and ‘real world’ data use.

PBC patients: Blood test helps to find a suitable treatment

Artificial intelligence and new technologies: Strong impact on hepatology

Strengthening liver health through regular exercise