Nonalcoholic fatty liver disease, ... (Non-alcoholic fatty liver disease) - Genes PNPLA3, APOC3, GCKR, MBOAT7, TM6SF2 and TRIB1  

Disease Nonalcoholic fatty liver disease (NAFLD) is an accumulation of excess fat in the liver that can cause liver damage like damage caused by alcohol abuse, but occurs in people who do not drink alcohol excessively. It is considered that an individual has a fatty liver (hepatic steatosis) if the liver contains more than 5 to 10 percent fat.

Usually the fat deposits in the liver associated with NAFLD do not cause symptoms, but can result in an increase in liver enzymes. Some affected individuals have abdominal pain or fatigue. Between 7 and 30 percent of people with NAFLD develop liver inflammation (nonalcoholic steatohepatitis -NASH-), which causes liver damage. The body can repair minor liver damage; however, severe long - term damage can lead to cirrhosis. Signs and symptoms of cirrhosis, which worsen as the fibrosis affects the liver, include fatigue, weakness, loss of appetite, weight loss, nausea, edema and jaundice. Scarring of the portal vein may cause portal hypertension, leading to varicose veins inside the digestive system. The rupture of these varices can lead to bleeding that threaten life.

It is believed that NAFLD and NASH account for many cases of cryptogenic cirrhosis. It is estimated that at least one third of people with NASH develop cirrhosis. People with NAFLD, NASH and cirrhosis are also at increased risk of developing hepatocellular cancer. NAFLD develops most often in middle - aged or older, although young people, including children, are also affected. Often, NAFLD is considered part of the metabolic syndrome; Besides NAFLD, metabolic syndrome includes obesity, insulin resistance, high concentrations of lipids such as cholesterol and triglycerides, and hypertension. However, a person with NAFLD may not have all or any of the characteristics associated with metabolic syndrome, and people with some or all of these clinical manifestations may not have NAFLD.

Specific causes of NAFLD are unclear. Genetic variations and environmental factors contribute to its development. When dietary fat exceeds the body 's needs and the ability to decompose and remove part of the fat is stored in the liver. It has been suggested that excessive consumption of certain nutrients such as iron, cholesterol and refined sugars used in processed foods, can increase the likelihood of developing NAFLD. It is also unclear what causes non - alcoholic steatohepatitis (NASH) and cirrhosis developed in some people with NAFLD. Some possible reasons include inflammation due to an immune system reaction to excess fatty tissue in the liver, inflammatory toxic chemicals (cytokines) released by liver cells or fat cells, apoptosis of liver cells and oxidative stress . The effects of intestinal microbiota on decomposition and nutrient absorption are also an active area of research.

Studies have identified many genetic changes that may be associated with the development of NAFLD and NASH. Among them is a particular gene variation in PNPLA3 (patatin like phospholipase domain containing 3), located on the long arm of chromosome 22 (22q13.31). This gene encodes synthesis adiponutrin a protein found in adipocytes and hepatocytes. Although the function of this protein is not fully understood, it is believed to help regulate lipogenesis and lipolysis, and the development of adipocytes. Studies indicate that expression of PNPLA3 gene decreases during periods of fasting and increases after food intake, suggesting that the amount of adiponutrin encoded protein is regulated as necessary to help process and store fat from the diet. PNPLA3 genetic variation associated with NAFLD replaces the amino acid isoleucine with the amino acid methionine at position 148 of the protein (or I148M Ile148Met). It is believed that genetic variation associated with NAFLD PNPLA3 results in increased production and decreased the breakdown of fats in the liver.

Besides the gene identified in PNPLA3 variation, other genes have been described whose variations may be involved in the development of the disease. These genes include:

  • The APOC3 gene (apolipoprotein C3), located on the long arm of chromosome 11 (11q23.3), which encodes the apolipoprotein C-III, a constituent of very low-density lipoprotein triglyceride - rich lipoproteins (VLDL) and high density lipoproteins (HDL) plasma. It plays a multifaceted role in the homeostasis of triglycerides. Intracellularly, it promotes hepatic uptake and secretion of very low-density lipoprotein 1 (VLDL1); Extracellularly, attenuates the hydrolysis and removal of triglyceride - rich lipoproteins (TRL).
  • The GCKR (glucokinase regulator) gene, located on the short arm of chromosome 2 (2p23.3), which encodes a protein belonging to the subfamily GCKR protein family SIS. The gene product is a regulatory protein that inhibits glucokinase in the liver cells.
  • The MBOAT7 gene (membrane bound O-acyltransferase domain containing 7), located on the long arm of chromosome 19 (19q13.42), encoding a member of the family of membrane bound proteins integral O-acyltransferase acyltransferase activity having . The encoded protein is an acyltransferase lysophosphatidylinositol having specificity for arachidonoyl-CoA acyl facilitator. This protein is involved in the reactivation of phospholipids as part of the route remodeling of phospholipids known as Earth cycle.
  • The gene TM6SF2 (Transmembrane 6 superfamily member 2), located on the short arm of chromosome 19 (19p13.11), which encodes a regulatory protein fat metabolism influencing liver triglyceride secretion and content of droplets liver.
  • And TRIB1 gene (tribbles pseudokinase 1), located on the long arm of chromosome 8 (8q24.13), encoding a protein that interacts with and regulates MAPK kinases MAP kinase activation.

It can transmit a higher risk of developing NAFLD in families through generations, but the pattern of inheritance is unknown. Variations in certain genes, as well as lifestyle and environmental factors contribute to the risk of developing this complex process.

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with disease nonalcoholic fatty liver disease (NAFLD), by complete PCR amplification of the exons of PNPLA3, APOC3, GCKR, MBOAT7, TM6SF2 and TRIB1 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).