Original ArticleNon-alcoholic fatty liver disease, metabolic syndrome and patatin-like phospholipase domain-containing protein3 gene variants
Introduction
Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging liver disease in Western countries [1], [2]. Fatty liver includes a wide spectrum of histologic alterations ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation and fibrosis. Moreover, NAFLD has been traditionally interpreted as a condition, which may eventually progress to liver related complications such as cirrhosis, liver cancer and liver mortality [3], [4], [5].
However, the pathogenesis of NAFLD is multifactorial and many mechanisms that cause fatty liver infiltration, inflammation, oxidative stress and fibrosis have been proposed.
The association of liver steatosis with a number of common metabolic conditions and cardiovascular risk factors has been extensively reported. Notably, increased mortality of NAFLD patients is primarily a result of cardiovascular diseases and, to a lesser extent, to liver-related diseases [6], [7], [8], [9], [10], [11], [12]. It has been suggested that fatty liver can be considered as the hepatic consequence of the metabolic syndrome (MetS), a cluster of metabolic disorders including central obesity, hyperglycemia, arterial hypertension, hypertriglyceridemia and low HDL-cholesterol. Thus, a strong bidirectional association between NAFLD and MetS has been proposed. Insulin resistance, the key feature of MetS, is considered to play a central role in the first stages of fatty liver infiltration [13], [14], [15]. However, whether insulin resistance and hyperinsulinemia are components of MetS promoting fatty liver or whether NAFLD itself induces chronic hyperinsulinemia by impaired insulin degradation is still under debate. In addition, not all subjects with MetS will develop NAFLD and not all subjects with NAFLD will develop MetS.
Several lines of evidence clearly indicated that also genetic factors may predispose to NAFLD and among the others a variant (I148M) located at the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene appears to show the strongest effect. Based on the presence of I148M genotype, two different clinical presentations of NAFLD have been recently proposed [16], [17], [18], [19], [20], [21], [22], [23]. The first one is associated to the presence of common I148I allele and characterized by a high prevalence of obesity and possibly high cardiovascular risk, whereas the other one is associated to the I148M allele presenting an higher susceptibility to more severe liver histology and liver disease progression.
The aim of the study was to evaluate whether PNPLA3 gene variants may predict different clinical phenotypes in a large series of Italian patients with NAFLD.
Section snippets
Study patients
The study was performed in 211 consecutive patients referred to our metabolic outpatient clinic who had evidence of fatty liver disease at a liver ultrasonographic scanning (US) performed as part of routine clinical examination.
To be eligible for the study, patients had to have fulfilled the following inclusion criteria: no history of current or past excessive alcohol drinking as defined by an average daily consumption of alcohol > 20 g; negative tests for the presence of hepatitis B surface
Results
Mean age was 54.5 + 11.9 years. Among the 211 subjects with fatty liver, US examination revealed mild steatosis in 40, moderate steatosis in 90 and severe steatosis in 81. Clinical and laboratory characteristics of subjects (mean age 54.5 ± 11.9 years) with different severity of fatty liver according to Hamaguchi's classification of steatosis are reported in Table 1. A progressive, statistically significant increase in the mean values of the indexes of central obesity (BMI, waist and hip
Discussion
Our results show for the first time that PNPLA3-I148M gene variant is associated with a lower prevalence of MetS and reduced cardiometabolic risk in a large series of individuals with NAFLD. In fact, univariate and multivariate analyses suggest that individuals carrying the PNPLA3 MM genotype have a lower probability of having MetS.
Recently, the widely accepted assumption that NAFLD should be always considered the hepatic manifestation of MetS has been disputed and the study of PNPLA3-I148M
Conclusions
We suggest that NAFLD may not always represent the hepatic manifestation of MetS. In fact, in our study, patients with NAFLD carrying PNPLA3-I148M gene had a lower prevalence of MetS and lower cardiometabolic risk. Further studies are needed to confirm the possible role of PNPLA3 polymorphisms to differentiate clinical phenotypes of NAFLD and to discriminate NAFLD with possible metabolic and cardiovascular consequences from fatty liver at risk for liver related complications.
Conflict of interests
All authors declare that they have no conflicts of interest.
Authors' contribution
MDB wrote the manuscript and researched data. LP, DP, FB and LD contributed to data collection, analysis and interpretation; LL and PP reviewed the manuscript; MB and AD contributed to data collection; MA contributed to study design and reviewed the manuscript; FV reviewed and edited the manuscript. FA designed the study and wrote the manuscript; he is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and
Learning points
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NAFLD does not always represent the hepatic manifestation of MetS.
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PNPLA3 I148M gene variant is associated with a lower prevalence of metabolic syndrome and lower cardiometabolic risk.
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