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Grant number: 18/17333-6
Support Opportunities:Regular Research Grants
Duration: February 01, 2019 - March 31, 2021
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Daniel Ferraz de Campos Mazo
Grantee:Daniel Ferraz de Campos Mazo
Host Institution: Hospital de Clínicas (HC). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated researchers:Maria Cândida Ribeiro Parisi ; Maria Lucia Cardillo Corrêa Giannella ; Mauy Frujuello Mana


Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease in the world. It encompasses a broad spectrum of liver changes, ranging from isolated accumulation of fat in the liver (steatosis), to situations where lobular inflammatory infiltrate and ballooning (steatohepatitis, NASH) are added, with potential for progressive fibrosis, cirrhosis and complications. It is considered one of the manifestations of the metabolic syndrome and is associated with other clinical conditions such as obesity, cardiovascular disease and type 2 diabetes mellitus (DM2). Among the clinical predictors of NASH, the presence of obesity and diabetes are also associated with the presence of hepatic fibrosis, a strong predictor of morbidity and mortality. NAFLD has a complex and multifactorial pathophysiology, which includes genetic factors of the host and environmental factors that interact to produce the phenotype of the disease and determine its progression. Recent studies have identified variants in the Patatin-like Phospholipase Domain Containing 3 gene (PNPLA3) associated with steatosis and progression of NAFLD, but national data on diabetics are scarce. Studies with variants in the fibroblast growth factor gene 21 (FGF-21) have also been associated with NAFLD in normoglycemic Chinese, but their role in Brazilian diabetics is unknown. In recent years, non-invasive markers of steatosis and fibrosis have been developed, as well as serum biomarkers such as cytokeratin-18 and FGF-21, which may aid in the detection of NAFLD and its severity, but studies using these tools are rare or absent. Thus, the diagnosis of this hepatic disease can help in the management of diabetic patients, with potential consequences in clinical outcomes, making important the evaluation of the prevalence of NAFLD, its severity and correlation with complications of diabetes.Objectives: 1- To evaluate the prevalence of NAFLD in a cohort of ambulatory diabetic patients and its association with demographic, clinical and laboratory variables; 2 - To stage liver fibrosis in patients with NAFLD through non-invasive markers and correlate with the above variables; 3- To evaluate serum levels of the biomarkers cytokeratin 18 (CK-18) and fibroblast growth factor 21 (FGF-21) and its associations with presence of NAFLD, liver fibrosis, demographic, clinical and laboratory variables; 4- To evaluate in this population the association of chronic complications of diabetes (micro and macrovascular) with the presence of NAFLD and advanced liver fibrosis; 5- To evaluate the polymorphisms in the PNPLA3 and FGF-21 gene in these patients and their association with the presence of NAFLD and with demographic, clinical and laboratory variables.Methods: A prospective observational study to be performed in the Diabetes Outpatient Clinic of the Discipline of Endocrinology and at Gastrocentro Unicamp in patients with type 2 diabetes mellitus. Demographic, anthropometric, clinical and laboratory characteristics will be evaluated. Hepatic steatosis will be assessed by abdominal ultrasonography and application of liver fat score (FLI) and hepatic steatosis index (HSI). The non-invasive evaluation of fibrosis will be calculated by the clinical-biochemical scores APRI, FIB4 and NAFLD Fibrosis Score and also by transient liver elastography by Fibroscan®. Serum levels of the biomarkers CK-18 and FGF-21 will be evaluated. Polymorphisms of PNPLA3 (rs738409 c.444 C> G) will be obtained by real-time PCR. Inclusion criteria: 1-Adults between 18 and 75 years; 2- Diagnosis of DM2 in outpatient follow-up. Exclusion criteria: 1- Other chronic liver diseases not NAFLD; 2- Significant consumption of alcohol; 3- Presence of concomitant medications or diseases associated with liver steatosis; 3- Other types of diabetes; 4- Patients who did not sign an informed consent form (EHIC). This study was approved by the research ethics committee of Unicamp. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MANA, MAUY FRUJUELLO; PARISI, MARIA CANDIDA R.; CORREA-GIANNELLA, MARIA LUCIA; NETO, ARNALDO MOURA; YAMANAKA, ADEMAR; CUNHA-SILVA, MARLONE; CAVALEIRO, ANA MERCEDES; DOS SANTOS, CRISTINA RODRIGUES; PAVAN, CELIA REGINA; SEVA-PEREIRA, TIAGO; et al. Non-Alcoholic Fatty Liver Disease in Long-Term Type 2 Diabetes: Role of rs738409 PNPLA3 and rs499765 FGF21 Polymorphisms and Serum Biomarkers. Molecules, v. 27, n. 10, p. 14-pg., . (18/17333-6)

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