A summary of the current situation regarding non-alcoholic fatty liver disease (NAFLD), followed by an interview with Prof. Dr Sven Francque, a worldwide leading researcher in the field.
Current Situation
The liver is a fascinating and complex organ. It is the largest solid internal organ and has more than 500 vital functions, such as breaking down toxic substances and waste products, storing energy and vitamins, producing and regulating hormones. The liver can also regenerate itself if at least 25% of the healthy liver remains. Unfortunately, liver health in the western population is going through a dark period. Indeed, WHO data show that liver disease is one of the leading causes of years of working life lost in Europe. In fact, on average, two-thirds of all potential years of life lost due to mortality from liver diseases are years of working life. The most widespread chronic liver disease worldwide is Non-alcoholic fatty liver disease (NAFLD). The global prevalence of NAFLD has drastically increased to about 25% over the last few years and keeps rising rapidly. The highest prevalence was found in South America (30.45%) and the Middle East (31.79%), whereas the lowest prevalence was reported in Africa. In Europe NAFLD is becoming a leading cause of liver-related mortality and it is predicted to become the leading cause of end-stage stage liver disease. Data projections reveal that the burden of advanced liver disease due to NAFLD will more than double during 2016–30. The annual pr,edicted economic burden of NAFLD in Europe is estimated to be more than €35 billion in direct costs and a further €200 billion in societal costs.
NAFLD has two main phenotypes: non-alcoholic fatty liver (NAFL), i.e., simple steatosis characterized by the presence of lipids in ≥ 5% of the hepatocytes, and nonalcoholic steatohepatitis(NASH) characterized by the presence of inflammation and hepatocellular damage. In certain cases, NAFL eventually progresses to NASH, which may subsequently advance to more severe liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), which is the fifth most often diagnosed cancer worldwide.
Figure 1. Graphical summary of NAFLD
Risk Factors
There are multiple risk factors associated with the development and progression of NAFLD, such as obesity, diabetes, insulin resistance, dyslipidemia, metabolic syndrome, and exposure to xenobiotics and environmental toxicants such as endocrine and/or metabolism-disrupting chemicals. A recent analysis reported by the Lancet Commission on liver disease in the UK and epidemiological studies led by the European Association for the Study of the Liver (EASL) displays that the prevalence of NAFLD is very high in people with obesity (75–92%) or severe obesity (>90%), and the prevalence of biopsy-proven NASH among people with type 2 diabetes was 37.3%, of whom 17% had significant fibrosis.
Modern research considers NAFLD as a hepatic manifestation of metabolic diseases. Several stressors, including environmental factors, genetics, epigenetics, and microbiota, can further increase susceptibility. Hence, a group of international experts together with EASL has recently proposed to change the name from NAFLD to MAFLD, which stands for Metabolic Associated Fatty Liver Disease, to accurately reflect the current knowledge of fatty liver diseases associated with metabolic dysfunction.
Childhood obesity and NAFLD represent a second wave of metabolic liver disease that will hit Europe over the coming decades. Present day middle-aged adults with NAFLD belong to a generation that was mostly normal weight in childhood, whereas many children nowadays risk spending the majority of their lives overweight. A survey from the Health Behaviour in School-aged Children (WHO collaborative cross-national study) reported that one in five adolescents (21%) had a Body Mass Index (BMI) equal to or great than 25, which classifies overweight or obese in adults. The data comes from more than 220 000 young people in 45 countries and regions in Europe and Canada. Of note, the prevalence of overweight and obesity increased in up to a third of the countries or regions between 2014 and 2018. Not surprisingly, socioeconomic inequalities seem to play a major role difference in the prevalence of obesity, where wealthy boys or girls were less likely to have a BMI over 25. In general, there is a wide variation in children’s diets across Europe, with a high prevalence of unhealthy dietary patterns, including lower daily fruit and vegetable intake and higher added sugar intake among the least wealthy than among high-affluence socioeconomic groups. Moreover, only 19% of adolescents achieved the recommended 60 min of moderate-to-vigorous daily physical activity. Also in this case, it seems clear that participation in physical activity was lower among adolescents from low-affluence families than among those from high-affluence families.
Alcohol is another big factor contributing to liver diseases, particularly in Europe. Indeed, Europe has the highest levels of alcohol consumption per person, the highest prevalence of heavy episodic drinking, and the lowest rates of abstention from alcohol in the world. For most countries in the WHO European region, there is a strong correlation between liver-related mortality rates and population-level alcohol consumption, as is clearly illustrated in the latest report of the EASL. The evidence linking liver-related mortality and population-level alcohol consumption sends a crucial message for disease prevention: the most effective and cost-effective (not to mention obvious) means to reduce mortality rates from alcohol-related liver disease are interventions from the affected countries to educate their population to reduce individual alcohol consumption.
Diagnosis
Currently, most diagnoses of NAFLD and liver diseases are made at a late stage, often when complications or end-stage liver disease have already developed and the scope for intervention is narrow, e.g., cirrhosis, which is the result of progressive fibrosis over many years or decades. The process can be silent with no early signs or symptoms, in fact, according to the latest reports more than two-thirds of hospitalised patients had not previously been referred to a liver clinic.
The first step of investigation of potential liver disease is commonly based on serum liver enzyme levels (such as alanine aminotransferase). These generic liver blood panels have an important role in the detection of inflammatory liver diseases such as viral and autoimmune hepatitis. However, interpreted in isolation they are not good indicators or predictors of advanced liver fibrosis or cirrhosis: over 60% to 90% of people with undetected cirrhosis who participated in a recent study had alanine aminotransferase concentrations within the normal range. Experts in this field urged that “Europe should rise to this challenge to increase the widescale rollout of a standardised liver blood test with an implicit assessment of liver fibrosis, coupled with automated, laboratory reflex testing (also known as automated responsive testing) and clinical follow-up”.
The strong correlation between high serum levels of γ-glutamyl transferase and excessive alcohol consumption makes the former an attractive marker for liver diseases. In fact, the European Association for the Study of the Liver (EASL) is already considering making it the new standard for the prediction of a future liver event (provided that appropriate cutoff values are identified and codified), and the insurance industry already uses it as a cost-effective parameter for the exclusion of clients at high risk for liver-related morbidity and mortality.
Prevention
In patients diagnosed with NAFLD, the American Association for the Study of Liver Diseases (AASLD), EASL and Asia-Pacific Working Party on NAFLD practice guidelines recommend a combination of a hypocaloric diet and moderate-intensity exercise to sustain weight loss. Such lifestyle modifications are fundamental to reduce the risk of diabetes, obesity and subsequent HCC, however no specific weight loss programs are mentioned. In a Cuban study on 293 patients, a target weight loss of 10% or more showed efficacy in the amelioration of NASH and regression of fibrosis in up to 90% of patients. However, other studies revealed that most patients with NAFLD are unable to sufficiently modify their lifestyle to lose weight, despite intensive dietary counselling and encouragement to perform physical exercise.
A recent EASL article aimed at healthcare providers and public health policymakers states that “a fundamental shift must occur, in which health promotion, prevention, proactive case-finding, early identification of progressive liver fibrosis, and early treatment of liver diseases replace the current emphasis on the management of end-stage liver disease complications”.
Treatment (standard of care)
With no Food and drug administration (FDA) approved drugs, current first-line treatments rely on dietary management, lifestyle modification, and physical exercise, whereas second-line treatment includes bariatric surgery. Various pharmacological approaches using existing drugs have also been considered in the management of NAFLD and NASH. These attempts mainly focus on antidiabetics, anti-obesity drugs, antioxidants and cytoprotective agents, including insulin sensitizers (e.g., metformin), thiazolidinediones (e.g., pioglitazone), glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide), a natural dihydroxy bile acid (e.g., ursodeoxycholic acid) or antioxidants (vitamin E). However, evidence-based practice guidelines and practice guidance issued by a committee of hepatology experts recommend only pioglitazone and vitamin E for clinical use only in selected NASH patients.
At the same time, due to the lack of human trials, chemoprevention (prescription of a drug to prevent a particular pathology) cannot be routinely recommended for complications of NAFLD at this point, but three compounds could have a role in the future: metformin, statins and possibly aspirin. Given the observational nature of the studies presented up to now and their limited number, more research is required to confirm these findings and identify which subgroups of patients with NAFLD would benefit most from chemoprevention use.
Several drug candidates are being tested for NAFLD and NASH over 50 phase I to III trials. They can be broadly classified into five categories: i) metabolic targeted therapies, ii) oxidative stress targeted therapies, iii) inflammation targeted therapies, iv) apoptosis targeted therapies, and v) fibrosis targeted therapies.
At the University of Antwerp the medicinal chemistry research group of Prof. Pieter Van der Veken in collaboration with the physio pharmacology group of Prof. Wim Martinet have ongoing research projects to develop new autophagy inducers as possible drug candidates for NAFLD. Currently, Dr Lorenzo Cianni (yes, that's me) and the PhD student Sergei Grintsevich, are developing new liver-targeting autophagy modulators by using medicinal chemistry as an innovative therapeutic strategy for metabolic disorders (more info here).
We wanted to write a paragraph about the main molecular targets currently investigated for the therapy of NAFLD, but even a cursory look at the argument is sufficient to realize how vast and complex it really is. Even just considering therapies in phases I-III we already find agonists of nuclear receptors FXR and PPAR, analogues of GLP-1 and FGF21, thyroid hormone receptor-ß agonists, and SGLT2 inhibitors. We decided it would be more interesting and informative to talk directly with an expert in the field, and we didn’t have to look much farther: on our same campus, less than two km away from us, the University Hospital of Antwerp is the office of Prof. Dr Sven Francque, one of the leading researchers worldwide in the field of NAFLD and NASH. He is currently leading the clinical trials of Inventiva Pharma’s Lanifibranor, a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH.
Prof. Dr Sven Francque is chairman of the Department of Gastroenterology and Hepatology of the University Hospital Antwerp and senior full professor of medicine at the Faculty of Medicine and Health Sciences of the University of Antwerp. His research unit continues to study the pathophysiological mechanisms of NASH. He is also conducting clinical research and his unit is a partner in several research consortia supported by the European Commission and the Innovative Medicines Initiative with a focus on NASH pathophysiology, biomarker research and hepatocellular carcinoma. His clinical trial unit participates from the early days of clinical trials in NASH in many clinical trials in the field. Prof. Francque is a scientific committee member involved in the design of several phase 2 and current phase 3 trials in NAFLD and is the national and international lead PI of several of these trials. He is the author/co-author of over 180 papers in peer-reviewed journals and authored several book chapters on NAFLD.
Click here to read the full interview with Prof. Dr Sven Francque
Useful links for those who want to dig in the topic:
Open-access review: the authors present the current understanding of NAFLD pathogenesis, potential molecular targets, and emerging therapeutics with intended mechanisms of action (MOA). A highlight on recent regulatory perspectives for NAFLD-NASH drug development and approval process is also discussed.
Seminar: the authors describe the current picture of liver diseases in the world.
Open-access review: the authors classify and summarize the potential roles of therapeutic targets in the treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.
Open-access article: the authors (EASL–Lancet Liver Commission) fully depict the current situation of liver diseases in Europe and present ten actionable recommendations, half of which are oriented towards healthcare providers and half of which focus primarily on health policy.
Open-access review: the authors delineate the risk factors for NAFLD-related HCC and propose preventive strategies to tackle this growing problem.
Lorenzo Cianni and Nicolò Filippi (PhD colleague at the University of Antwerp and creator of the blog's name)