Polygenic score
Influential genes: PNPLA3,GCKR
Several studies have shown an association between the PNPLA3 gene and NAFLD.
GCKR regulates glucose metabolism, and its polymorphisms are associated with changes in serum triglyceride and glucose levels, which are risk factors for NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is an excessive fat build-up in the liver that can lead to irreversible liver tissue destruction. Worldwide, it’s the most common cause of liver enzyme elevation diagnosed in patients without heavy alcohol abuse (defined as a daily income of over 20g of clear alcohol). Fat presence in the liver is physiological up to an amount of 5%, anything over is described as liver steatosis. NAFLD progresses from the above-mentioned liver steatosis (“only” fat present in the liver) to an inflammatory state (also known as non-alcoholic steatohepatitis – NASH) that can potentially lead to a replacement of normal liver tissue with scar tissue (fibrosis), which results in irreversible liver damage (cirrhosis). Cirrhosis drastically increases the risk for the development of hepatocellular carcinoma.
NAFLD is rapidly becoming the most common cause of chronic liver disease in western countries due to a continuous rise in the prevalence of obesity. The modern lifestyle brings a lot of challenges with it, especially when it comes to making time for a regular and balanced diet, physical activity, and lowering the stress levels in our body. The world obesity rate is quickly rising and with it, its complications – including non-alcoholic fatty liver disease. The risk also increases for people with already persisting medical conditions, such as high blood pressure, metabolic syndrome, or diabetes mellitus type 2. The prevalence differs around the globe, depending on the regional lifestyles and access to resources. The Highest prevalence was reported in American countries at 30%, whereas studies from Africa (although only limited resources are available) report a prevalence of 13%. Globally, we’re facing a prevalence of 25% in the world’s population, although it varies significantly based on your geographical location.[1]
Non-alcoholic fatty liver disease (NAFLD) is a complex and multifactorial disease influenced by both genetics and environment. Due to its nature, not all people at risk will develop the disease, and the severity can also vary.
The genetic background of NAFLD has been the focus of research in the past 10 years, specifically the impact of single nucleotide polymorphisms (SNPs). Multiple approaches were included, e.g. candidate gene association studies, genome-wide association studies (GWAS), and exome-wide association studies (EWAS).
According to the results, the heritability component is estimated to be between 20 and 70%. Of course, it depends on the design of the study, the ethnicity, or the technologies used.
The rs738409 variant, the G allele in the PNPLA3 gene, is strongly associated with higher levels of liver fat across all ethnicities. In carriers of the homozygous GG genotype, liver fat levels are 73% higher compared to the CC genotype. The severity and progression of NAFLD is also higher in carriers of the GG genotype.
Genes affecting inflammation and immune responses are known to play a role in susceptibility to NAFLD. Furthermore, many research groups have focused on identifying other susceptibility genes throughout the genome and this has led to the description of several candidate genes such as FDFT1, PPP1R3B, ERLIN1, TM6SF2, SAMM50, APCO3[2-4].
Genetic testing allows us to detect whether you have the predisposition to develop this disease and therefore directs us to take steps toward prevention, monitoring, and possible treatment options. In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.
NAFLD stays silent for a very long time and the first symptoms are often exhibited in the later stages of the disease. Sometimes, even in the earlier stages, patients report abdominal pain or fatigue, and it may be possible to detect increased liver enzymes in routine blood tests. When the body can't control the inflammatory processes anymore and worse states of damage develop, patients can experience fatigue, weakness, loss of appetite, weight loss, or yellowing of the skin and eyes - jaundice. Bruising and excessive bleeding (e.g., nose bleeding – epistaxis) can appear as the damage progresses, as well as abdominal distention or varices. It’s necessary to realize that the liver is an important organ that produces many irreplaceable proteins and enzymes for whole-body functioning and metabolism and can cause a broad scheme of symptoms.
Since NAFLD doesn’t usually cause symptoms, or the symptoms are very mild, the disease is often diagnosed unexpectedly, based on abnormal blood liver enzyme levels or an unusual ultrasound. It’s important to rule out any other possible cause of liver damage first, such as viral hepatitis. Blood tests, including liver enzyme levels (ALT, AST, ALP) and other liver function indicators (albumin, bilirubin), combined with an ultrasound scan are key methods for the right diagnosis. A liver biopsy (tissue sample removal) can be recommended in case of inconclusive results.
So far, there have unfortunately been no pharmacological treatment agents approved for the treatment of NAFLD or NASH. Lifestyle modifications remain the only essential therapy for NAFLD and correspond to the ones used to prevent the disease in the first place. It’s also necessary to manage any other risk factors such as high blood pressure or high blood sugar. In case of progressed liver cirrhosis, a liver transplant may be indicated.
As already mentioned above, the development of the disease is hugely based on one’s lifestyle. Introducing diet changes can be highly beneficial, especially when combined with regular exercise. Implementing at least basic diet principles, such as regular eating or avoiding saturated and trans fats, processed food, and foods high in sugars, can prevent a broad spectrum of metabolic diseases.
The early stage of NAFLD does not cause any harm and the patient’s health isn’t severely endangered, but it’s important to not underestimate the disease in its primary stage. Fat buildup in the liver can increase the risk of other serious health conditions, such as diabetes, high blood pressure, or kidney disease, including all their complications. Between 7 to 30 percent of patients with the non-alcoholic fatty liver disease eventually develop inflammation of the liver (non-alcoholic steatohepatitis), followed by the main complication, liver cirrhosis[5]. That can eventually lead to end-stage liver failure or liver cancer which are highly endangering patient’s life.
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