Thank you so much. Thank you to the organiser for inviting me. It is really a pleasure and a honour for me to be here today. All right. My task is to talk about the rationale for surveillance in HCC for patients with NASH and metabolic syndrome. These are my disclosures. The premise for surveillance is that, of course, patients at high risk of developing HCC should be entered into surveillance programmes. However, the utility and applicability of surveillance is influenced by a number of factors. First, the incidence of HCC in the target population. Secondly, the availability of efficient diagnostic tests at acceptable costs. And third, availability and effectiveness of treatment. Now, this is the journey from NAFLD to HCC. The peculiarity of NAFLD is that it is so widespread in the general population, 25% in the general population. And among this large group, approximately 15% of these patients can develop NASH. But they can also reverse back to NAFLD, to simple fatty liver. However, once they get NASH, particularly when they get NASH with fibrosis, the reversal is much less likely to be compared to the progression towards NASH with severe fibrosis, cirrhosis and hepatocellular carcinoma. Of course, there are several factors that can influence this transition pathway. Strength of lifestyle, high caloric intake, obesity, insulin resistance, type 2 diabetes, genetic modifier. In the end, one of the most worrisome complications, of course, it is HCC. So, the annual incidence rate of HCC in people with NASH and cirrhosis is supposed to be between 2.4 and 12.8%, which is considered lower compared to hepatitis C or other kinds of chronic hepatitis. However, as Dr. S. Ragh was showing you in the first talk, this has to wait it out with the much larger spread in the general population and also with increasing number of people at risk. Now, who can have an increased risk of HCC in NAFLD? If we look at the profile coming from different studies, we know that patients with NAFLD and HCC are mainly white, male, obese, significantly older than patients with HCC of other origins and, of course, with an increased prevalence of diabetes and cardiovascular mortality, which is more or less overlapping with the features of those patients with NAFLD that are more at risk of having NASH. However, we shouldn't stop at a first glance, because the problem is that HCC in NAFLD arises from multiple risk factors, not just NAFLD itself or NAFLD cirrhosis, but also the independent risk brought by the metabolic syndrome, in particular by type 2 diabetes, and probably by insulin resistance itself, which is the underlying risk factor in all the components of the metabolic syndrome. And then, Jessica and Dr. S. Ragh also showed you that there are several genetic risk factors, and maybe there is some role for the hepatocellular adenoma. Now, you have already heard about the relative risk of the components of the metabolic syndrome, in particular obesity and type 2 diabetes, independent of the risk of liver disease and their possible synergic effect. Now, the problem is that obesity and also type 2 diabetes are time-dependent factors. So if obesity arises early during lifetime, for example during childhood, the risk of developing HCC is going to increase. This is a very nice study made in a cohort of almost 300,000 Copenhagen schoolchildren aged between 7 to 13, who were prospectively followed for 30 years. Well, the presence of obesity at the age of 7, between 7 and 13, was associated with an increased risk of developing HCC during adulthood. And this risk was increasing by each unit increase of BMI Z. So, for example, for a boy of 13 years, the hazard ratio of having a hepatocellular carcinoma for each one BMI increase was 1.39. And this increase has been also validated, confirmed in another study, that is obesity in early adults in the age between the mid-20s to the mid-40s, associated with an increased risk of developing HCC at a younger age and in the absence of major HCC risk factor. And again, each unit increase in BMI in early adults was associated with a 4-month decrease in age of HCC diagnosis, although it did not affect the outcome of the patient with HCC. And then, again, PMPF3, the famous PMPF3GG variant, which has been repeatedly associated with a 2.26-odd ratio of developing HCC independent of age, presence of cirrhosis, type 2 diabetes, and obesity. And the risk carried by this variant is more or less similar to the one carried by type 2 diabetes. And as Jessica was shown, there is a synergic addictive effect of the number of PMPF3, TM6SF2, and BOAT7 risk variant and the likelihood that you might have a hepatocellular carcinoma. So if you look at HCC frequency with one risk allele, you see that the risk is still, the percentage of hepatocellular carcinoma is still low, 10% in this cohort of 700 patients. But if you increase the number of risk alleles to 2, 3, 4, and 5, of course, this risk is going to greatly increase. Now, hepatocellular adenoma. Hepatocellular adenoma has already been mentioned. In particular, the inflammatory variant is associated with obesity and metabolic syndrome. And one of the first studies that was the study from Valérie Paradis that was associating metabolic syndrome with the risk of HCC found that in one-third of the patients that were diagnosed with HCC, there was a pre-existing hepatocellular adenoma. We still don't know if this is really a risk factor, the mechanism beyond this risk factor, but I think it is something that should be further evaluated. So in summary, I would say that the progression from AFL-D to HCC during a lifetime is probably slow. However, if you start very early in your lifetime to have obesity, or you have genetic variants, or you have the combination of childhood obesity and genetic variants, the increased risk of HCC, of course, is greater. And during your lifetime, you might also have some superimposites such, for example, some alcohol use or abuse, viral infector, adenoma, that may hasten the progression to HCC in an unpredictable way. Now, how to screen high-risk population for HCC in AFL-D? Of course, the high-risk population is people with NASH and advanced fibrosis. And this is a primary care referral pathway called the Camden-Arlington pathway that has been tested in a population of the UK. Now, general prediction had to screen patients with raised ALT in the absence of alcohol consumption or other causes of chronic liver disease and in the presence of fatty liver ultrasound by a two-step combination. The first non-invasive algorithm was FIP4, which is an algorithm that you can calculate from the web, and it's composed by ST, ALT, age, and platelets. And if patients were below the lower threshold, there were a low risk of developing advanced fibrosis. If they were higher compared to the high threshold, there were higher high risk and referred to a pathologist. But then there was an area, a gray area of uncertainties, and these patients were further rescued by dosing the ALF test. And again, subdivided the patient according to the lower or the higher risk for NASH with advanced fibrosis. And indeed, this primary care referral was effective because compared with standard care, which is refer everyone, refer no one, or refer by chance, you see that the percentage of patients referred unnecessary, which is the red, 92% of the patients were referred unnecessary, fell to 70%. And on the contrary, the percentage of patients with advanced fibrosis grow from 8% to 30%. And more importantly, the percentage of patients referred with cirrhosis increases from 8% to 14% by this referral. The problem with non-invasive tests is quite, I mean, clear in, to stratify the risk for NASH and advanced fibrosis in the NAPFLD population. We do have some tests with a high negative predictive value, but the positive predictive value, this blue portion of the bar is very low, and most importantly, there is a wide gray area of uncertainty. So this is the reason why each first level screening test, like FIB4, should be also followed by a second line screening test with a higher negative predictive value, higher positive predictive value, and possibly a lower uncertainty area, such as, for example, liver fibroscan. And to add more on the uncertainties, there is the problem with the detection of nodule into abdominal obesity, because of the thickness of the wall, but also because of the fatty liver itself, which is a foggy liver, where there is heterogeneity in the ecostructure, because the fats infiltration can be spread throughout the liver, or can be confined to certain area, or there might be escape lesion, and this leads to high rates of under-recognition or misinterpretation of small nodules. So in the end, it looks like looking for HCC in NASH is more something physician thing, magician thing, rather than physician thing. And if I have to talk about HCC surveillance in NAFLD in 2019, I would say that poor surveillance is a constant problem for NAFLD patient, because just 23% of patient with NAFLD have their HCC detected by surveillance, and so NAFLD HCC are diagnosed as a more advanced stage compared to viral or alcohol-related HCC. Three out of the five guidelines on the management of NAFLD support the practice of oncologic follow-up on an individual basis, particularly for patients with obesity and type 2 diabetes, and the guidelines of the Asia-Pacific region suggest extensional screening to those cancers whose incidence is increased by the metabolic syndrome. If we look at European clinical practice guidelines for the management of NAFLD, they say that a large number of NAFLD cases at risk of HCC make systematic surveillance largely impractical. Of course, the genetic variants of PMPLA3 may be an effective tool, but it is not yet considered cost-effective. So the conclusion is that although NAFLD is a risk factor for HCC, which may also develop in the prostherotic stage, and the risk is further increased by the present OGG variant or the PMPLA3 polymorphism, no recommendation can be currently made on the timing of surveillance and its cost-effectiveness. And here, just to remind you that HCC can arise also in non-sterotic NASH, and there are many studies that have demonstrated this. However, the true incidence and prevalence rate are still unknown. And these are the American practice guidelines for the management of hepatocellular carcinoma. So surveillance is deemed cost-effective if the expected HCC risk exceeded 1.5% per year. And this is true for hepatitis B, for hepatitis C, but for genetic hemochromatosis and so on. But you cannot see NAFLD listed in this table because it is within other cirrhosis where the incidence of HCC is unknown. And what about non-sterotic NAFLD? Surveillance is not deemed cost-effective because, again, the incidence of HCC is unknown and is believed to be below the threshold. And if we look at the same table in the ASLD-HCC guidance published last year, there is not much change. Actually, NAFLD is again not listed in this table. It is included in other cirrhosis. And again, NAFLD without cirrhosis has no clue with regards to surveillance. Similarly, the European guidelines for the management of hepatocellular carcinoma recommend surveillance in specific target populations, in particular for cirrhotic patients, non-sterotic HBV patients, intermediate or high risk of HCC, non-sterotic F3 patients based on individual risk assessment. But they say the role of surveillance for patients with NAFLD without cirrhosis is unclear. And of course, this translates into a lower survival of this patient with HCC. These are data from the SIR database. Among almost 6,000 HCC cases, NAFLD accounts for one quarter of these. And factors associated with one-year mortality is older age, lower income, unstaged tumor, and NAFLD. And as you can see here, the NAFLD survival, which is the black line, is definitely lower compared to viral hepatitis B and viral hepatitis C. Now this is a study that was comparing clinical presentation treatment and outcomes of HCC due to hepatitis C and NAFLD. NAFLD patients, again, presented with larger tumors that were less likely to be amenable to curative therapy as compared to HCV patients. However, those patients who were amenable of treatment had a similar overall survival compared to patients with HCV. This is because of the increased number of patients with a preserved liver function among NAFLD patients, including patients with no cirrhosis compared to those with a hepatitis C. But the true problem is the possibility to have a liver transplant because here, liver transplantation over 14 years was 29% in hepatitis C and only 9.9% in patients with HCC in NAFLD. So the best that we can do so far is try to prevent the development of HCC in NAFLD. How? First of all, lifestyle intervention. So in an HCC case control data set from Italy and Greece, the Mediterranean diet was associated with a reduction in HCC incidence. In the NIH RP diet and health study, approximately 500,000 men and women were included in this study. Red meat and saturated fat were associated with increased risk of HCC, while white meat was protected. In the EPIC study, physical activity reduced the risk of HCC by about 45%. And the decrease in waist circumference explained about 40% in decrease in BMI, 30% of the overall association of total physical activity with improvement in HCC. However, there are no randomized controlled trials investigating the effects of lifestyle intervention on HCC. So we should follow the recommendation of the American Cancer Society guidelines to achieve and maintain a healthy weight, to increase plant-based food, decrease salt, decrease red meat and processed meat, and to make moderate to vigorous exercise 30 minutes at least five days a week. And then, as Dr. El-Sarag was reminding you, while we are waiting for an effective treatment of NASH that probably will decrease the burden of HCC related to NASH, there are still some old drugs that might be useful, such as metformin. Metformin has proven to be effective in diabetic patients. They reduce by 50% the likelihood of developing HCC compared with an increased risk with sulfonylurea or insulin and a risk unchanged with glitazone. And statins. Statins are very important. All these patients have an increased cardiovascular risk. All these patients should be considered for studying treatments. Again, in the meta-analysis, the use of statins was associated with a 37% reduction in HCC incidence after adjusting for confounders. There is, of course, no current evidence to suggest their use, but it is highly, how can I say, safe to keep this drug in these patients. So in conclusion, hepatocellular carcinoma associated with NAFLD is rising markedly, but robust epidemiological data about prevalence of incidence are still unavailable. The burden of potential candidates for systemic surveillance in the absence of reliable invasive tool and molecular signature to stratify the risk of HCC are important limitations to surveillance. So we need clear epidemiological data to define the population risk, early and reliable non-invasive test formation for HCC. Future curative treatment of NASH, of course, will impact on the risk of the development of HCC, but while waiting for those, promotional lifestyle change might prevent or delay progression to HCC and NAFLD, and in particular, prevention of obesity from childhood should be a priority on the agenda of educational programs. And I thank you so much for your attention. Thank you very much, Elisabetta. Your presentation is open for questions. So I will ask the first question. Do you have some hypothesis to understand why obesity in the young age of the patients increase so much the risk of epithelial casinoma? Because it is an increased exposure to a clear risk factor. So if you are obese for the last five years, probably it is not impacting so much on the development of HCC. But if you have been obese for the last 30 years, this is definitely a much higher risk. Very interesting talk. I was wondering about the same thing, but in a little bit different context. There is a lot of experimental mouse data that obesity during pregnancy programs animals for disease later, including NASH and HCC. Has something like that been observed in humans already? Or is that something on the radar for people like you to track these things? Not so far. Not that I am aware there are not studies in pregnancy. But we know, for example, that small for gestational weight and large for gestational weight children are at risk of developing NASH early during the life. So probably there is also an association with HCC, but this association has never been explored so far.

surveillance in hepatocellular carcinoma

NASH

metabolic syndrome

high-risk patients

diagnostic tests

treatment availability