STELLA project protocol
Principal Investigators:
– Luis Antonio Diaz, M.D. Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
– Marco Arrese, M.D. Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
– Juan Pablo Arab, M.D. Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada.
Collaborating centers:
Multicenter study with collaborators from Latin America and the Caribbean.
Alcohol-associated liver disease and non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD), also known as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is one of the leading causes of chronic liver disease worldwide (1,2). Notably, this entity has been increasing during the last decades worldwide, with a consequent rise in the burden of cirrhosis and hepatocellular carcinoma (HCC) by 61% and 157%, respectively (2,3). In addition, alcohol-associated liver disease (ALD) is currently the leading cause of liver disease, especially in Western countries. These temporal trends are probably due to several factors, including the decrease in hepatitis C and B incidence, the sustained levels of alcohol use in the overall population, and the increasing prevalence of obesity and type 2 diabetes mellitus (T2DM)(4–6). In particular, the global prevalence of NAFLD is estimated at 25% and is notably higher in South America (31%)(5). NAFLD is extremely frequent in metabolic diseases, reaching 65% in overweight patients, 90% in obese patients, and up to 70% in T2DM patients (7,8). For example, the Chilean National Health Survey 2016-2017 showed that 87% of inhabitants have a sedentary lifestyle, 39.8% are overweight, 34.4% are obese, and 12.3% have T2DM (9). Thus, NAFLD is closely related to obesity and overweight, as well as to the presence of metabolic dysfunction (10). Alcohol use and metabolic dysfunction can overlap since they share multiple damage pathways. Also, both conditions encompass a broad spectrum of clinical phenotypes ranging from isolated steatosis, and different degrees of inflammation and fibrosis, to cirrhosis and its complications (10). In the case of NAFLD, these features have also been described in the absence of known factors that promote fat accumulation, including alcohol misuse (more than 30 grams per day in men and 20 grams in women), chronic viral hepatitis, and hereditary metabolic disease, which should be excluded to make NAFLD diagnosis (10). Thus, NAFLD is usually diagnosed in patients with obesity, insulin resistance (IR), T2DM, dyslipidemia, and metabolic syndrome in the absence of significant alcohol consumption (11). Although these alcohol use thresholds have been widely used in clinical guidelines, there is no strong evidence supporting these thresholds, which could be excessive for some individuals. For example, a man could drink up to 14 beers per week and be considered as NAFLD.
Several genes have been involved in the development of ALD and NAFLD. Particularly, Patatin-like phospholipase domain-containing protein (PNPLA3) nonsynonymous gene variant (rs738409 c.444 C>G p.I148M) is robustly associated with steatosis, steatohepatitis, and fibrosis in patients with NAFLD (12). Interestingly, in Latin America, an allelic frequency of the high-risk allele G has been reported in around 60% of the general population (13). In both conditions, genetic factors are also associated with the onset and progression of the disease. For example, genetic polymorphisms among Amerindian populations in Mexico would increase the predisposition and severity of liver disease (14,15), similar to what was observed in the United States of America in the Hispanic ancestry population (16,17). The PNPLA3 polymorphisms, which are highly prevalent in the general Latin American population, would also play a vital role; however, there is no information on subjects with Mapuche ancestry or other ethnicities. Subjects carrying PNPLA3 have an increased risk of ALD or NAFLD, and progression to cirrhosis and HCC (18,19). A higher risk has been observed in subjects with the GG genotype than in the CC genotype (which had a four-fold risk of having ALD)(20). Also, the Transmembrane 6 superfamily member 2 (TM6SF2) and Membrane-Bound O-acyltransferase Domain Containing 7 (MBOAT7) genes, related to lipid metabolic processes, confer risk for severe NAFLD (21,22). The TM6SF2, like PNPLA3, would have a role in the modulation of hepatic fat accumulation, fibrosis, and HCC development (23). On the other hand, the MBOAT7 polymorphism is mainly associated with the generation of fibrosis (24). These important differences in polymorphisms among populations could partially explain the contradictory data observed in different populations regarding liver injury due to concurrent alcohol consumption in patients with NAFLD. Thus, it is crucial to have regional data on the burden of disease and the natural history of ALD and NAFLD in Latin America and the Caribbean.
PRIMARY OBJECTIVE
The primary objective of this study is to develop a large multinational de-identified clinical database (both retrospective and prospective) in steatotic liver disease, including individuals with alcohol-associated liver disease (ALD) and metabolic-dysfunction-associated steatotic liver disease (MASLD).
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