Early Diagnosis of NAFLD
At the current stage, we can provide the clinical research community with a non-invasive research tool to identify and monitor patients with NAFL-NASH in early, subclinical phases addressing current bottlenecks in NASH diagnosis.
Non-Alcoholic Fatty Liver Disease (NAFLD) is defined by the presence of a determined hepatic steatosis, which corresponds to an accumulation of triglycerides in hepatocytes representing more than 5% of the total weight of the liver, in the absence of significant alcohol consumption, of the use of steatogenic drugs (tamoxifen or amiodarone) and of another liver pathology (viral or autoimmune hepatitis, hemochromatosis, Wilson's disease, …) (Chalasani et al. 2012; Neuschwander-Tetri 2003). NAFLD distinguishes liver steatosis (non-alcoholic fatty liver, NAFL) from non-alcoholic steatohepatitis (NASH) (Chalasani et al. 2012). NAFL, which corresponds to the first stage of NAFLD and is considered to be a benign, asymptomatic and reversible condition, is defined by the presence of hepatic steatosis (≥ 5%) without evidence of hepatocytes ballooning (Chalasani et al. 2012; Neuschwander-Tetri 2003; Spengler and Loomba 2015). In some patients, NAFL may progress to a serious and irreversible pathological condition, non-alcoholic steatohepatitis (NASH), which is characterized by the presence of hepatic steatosis associated with inflammation and hepatocytes ballooning that causes their dysfunction and death. This condition, which may or may not be accompanied by the presence of fibrosis, may progress to cirrhosis, liver failure and, in rare cases, to liver cancer (Chalasani et al. 2012; Spengler and Loomba 2015).
Based on an epidemiological study that identified NAFLD cases in published scientific studies, the overall prevalence of NAFLD is 25% (Younossi et al. 2016). In a worrying way, this prevalence increased sharply, from 15 to 25% between 2005 and 2010 (Younossi et al. 2016). While NAFL remains considered as a benign and poorly symptomatic condition, its progression to NASH and the onset of co-morbidities, such as atherosclerosis or type 2 diabetes mellitus (T2DM), are major health problems. Among the leading causes of death in NAFLD patients, cardiometabolic complications are extremely common, including coronary heart disease and T2DM (Rafiq et al. 2009).
The ever-increasing pandemic of Obesity fuels NAFLD prevalence and, as such, NASH has become one of the most common liver disorders. NASH is a critical public health concern with high unmet medical needs and remains widely untreated. Despite major efforts by the industry, no approved therapies are marketed.
Early Diagnosis of NAFL-NASH
Nowadays, the standard method for diagnosing and assessing the severity of NAFLD remains liver biopsy, where hepatic steatosis, lobular inflammation, hepatocytes ballooning, and fibrosis are semi-quantitatively scored (Jennison et al. 2019; Lee 2017). However, this invasive procedure is associated with potential complications (such as bleeding), and the small sample volume could be responsible for sampling error, especially for mild steatosis (Jennison et al. 2019; Lee 2017). In addition, a poor reproducibility among different pathologists has been observed (Lee 2017). For these reasons, liver biopsy is not suitable for large scale diagnosis of NAFLD, but also for patient follow-up and analysis of the efficacy of a treatment. As a result, many studies have sought to develop new non-invasive methods for the reliable diagnosis of NAFLD. Many imaging methods have been developed (Jennison et al. 2019; Lee 2017). Computed tomography scan (CT-scan), although less dangerous than liver biopsy, is associated with radiation exposure, and is not adapted for mild steatosis (Jennison et al. 2019; Lee 2017). If ultrasonography is free of radiations and widely available, the sensitivity and specificity for detecting mild steatosis are poor and there is substantial intra- and inter-pathologist variability (Jennison et al. 2019; Lee 2017). Transient elastography demonstrates a better sensitivity and specificity for mild, moderate and severe steatosis than ultrasonography, but failure of examination has been observed in about 7 % of cases, particularly in obese individuals (because of larger skin capsular distance) (Jennison et al. 2019; Lee 2017). Magnetic resonance spectroscopy and imagery demonstrate an excellent diagnostic performance to detect and grade steatosis and are free of radiation, but the limited availability and the high cost of examination limit the utilization of these technics for large scale screening of subjects at risk to develop NAFLD (Jennison et al. 2019; Lee 2017). Based on blood samples, the Fatty Liver Index (that includes BMI, waist circumference, gamma-glutamyltransferase, and triglycerides) and the NAFLD Liver Fat Score (that includes the presence of MetS, T2DM, fasting serum insulin, aspartate aminotransferase, and the aspartate aminotransferase/alanine aminotransferase ratio) have been developed, but these scores have not been validated against liver histology (Jennison et al. 2019).
- Currently, no method for the early and subclinical detection of NAFL-NASH is validated.
- The availability of such a test will address the current under-diagnosis of NAFL-NASH.
- Non-invasive blood-based diagnostics will enable a large-scale approach to patient identification.
- In parallel, it will improve the clinical management of patients suffering from NAFL-NASH.
CellMade’s approach towards development of an IVD test for the early, subclinical diagnosis of NAFL-NASH
As part of our innovation road map and strategy to address the unmet needs in NAFLD, we are rapidly advancing a diagnostic program based on the discovery that lipid mediators are expressed at different levels in patients with NAFL-NASH. This discovery resulted in the development of what we target to become a validated diagnostic test allowing identification of patients suffering from NAFL-NASH in early and subclinical stages when the disease is possibly still reversible. These patients are the appropriate candidates for preventive treatment.
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