Non-alcoholic fatty liver disease (NAFLD) is characterized by fat infiltration of the liver in the absence of significant alcohol intake, viral hepatitis, medications that may cause fatty liver, or other obvious causes [
1]. According to a meta-analysis, the annual incidence rate of NAFLD in Asia was 50.9 cases per 1,000 person-years [
2], while its prevalence in Asia was 29.6%.2 The reported global prevalence of NAFLD is 30%, and it is rapidly increasing with a predicted rate of 50% of the population by 2040 [
3,
4]. The overbearing burden of the disease requires an increased understanding of the disease.
In this issue of
Clinical and Molecular Hepatology, Konyn et al. [
5] have presented the results of an extensive review of the current literature, focusing on the causes and risk profiles of mortality in patients with NAFLD. Based on their findings, the authors have concluded that 1) NAFLD
per se may not independently increase the risk of all-cause mortality; 2) the most common causes of death in patients with NAFLD include cardiovascular disease, extra-hepatic cancer, liver disease, and diabetes; 3) risk factors for increased mortality in NAFLD are mutation in the patatin like phospholipase domain containing 3 (PNPLA3) gene, low thyroid function, and sarcopenia; and 4) dietary modification and physical activity leading to weight loss have a significant effect on decreasing the mortality.
In the aforementioned review, the notion that the risk of NAFLD independently increases all-cause mortality was negated by a study by Kim et al. [
6], wherein metabolic-associated fatty liver disease (MAFLD), but not NAFLD, was associated with increased all-cause mortality after adjusting for metabolic risk factors. Another review by Ng et al. [
7] stated that all-cause mortality and cardiovascular mortality may be higher in MAFLD when compared with NAFLD. However, a recent study by Younossi et al. [
8] reported that all-cause mortality and cause-specific mortality in patients with NAFLD and MAFLD were not significantly different. de Avila et al. [
9] stated that NAFLD was independently associated with increased all-cause mortality. Another recent meta-analysis by Fu et al. [
10] reported that NAFLD was associated with an increased risk of all-cause mortality but not with liver-related mortality. The authors attributed this finding to a low rate of fibrosis in the community. These differences in the results may be due to the broad range of accepted definitions of NAFLD, since the individual studies used ultrasonography, transient elastography, or fatty liver index for diagnosis. Further studies are required to determine whether NAFLD is an independent risk factor for increased all-cause mortality.
Generally, cause-specific mortality associated with NAFLD is attributed to cardiovascular disease, extrahepatic cancer, and liver disease. In the review by Konyn et al. [
5], an emphasis on the impact of diabetes on NAFLD is noteworthy, since mortality among patients with diabetes and chronic liver disease is increasing, while age-standardized mortality due to diabetes is declining. According to the authors’ recommendations, clinicians should be cognizant of the bidirectional impact of NAFLD and diabetes.
Konyn et al. [
5] stated that the risk factors for increased mortality in patients with NAFLD include mutation in the PNPLA3 gene, low thyroid function, and sarcopenia. Another recent review regarding risk factors for the development and progression of NAFLD included not only mutations in the PNPLA3 gene and sarcopenia but also obesity, diet, type 2 diabetes mellitus, obstructive sleep apnea, and gut microbiome [
11]. The proposed factors contributing to the progression of the disease warrant further studies discussing the impact of mortality in patients with NAFLD.
The degree of fibrosis is a well-established risk factor predicting the mortality of NAFLD patients. Recent advances in stratification of fibrosis incorporating artificial intelligence, machine learning, and deep learning to the gold diagnostic standard of liver biopsy is reported to have increased the prediction of mortality. The diagnostic power of noninvasive tests including blood test panels (fibrosis-4 [FIB-4] index or NAFLD fibrosis score), transient elastography, and magnetic resonance elastography (MRE) have been studied and compared to liver biopsy. The use of more than 2 noninvasive tests (MEFIB [MRE plus FIB-4] or FAST [FibroScan-AST] for detecting significant fibrosis.) to increase the yield of the diagnostic power for fibrosis have recently been reported [
12]. Further studies in predicting the mortality of NAFLD incorporating newly developed methods in diagnosing and stratifying fibrosis is warranted.
Lifestyle modifications, including physical activity and dietary modifications, are the cornerstones of therapy in patients with NAFLD to achieve a weight loss of ≥5% of total body weight for improvement in NAFLD, ≥7% for resolution of non-alcoholic steatohepatitis, and ≥10% for regression/stability of fibrosis [
1,
13,
14]. Diets including a high volume of whole and unprocessed foods, fiber, and unsaturated fats are recommended, with restrained consumption of red and processed meats, refined carbohydrates, and saturated fat [
15].
The disease burden of NAFLD is growing in all-cause mortality and liver-related mortality. The importance of risk factors on mortality in NAFLD cannot be stressed enough. With the recent advances in genetics and diagnostic tools, the better prediction on the prognosis of NAFLD can be possible. Additionally, we may expect the reduction of mortality in NAFLD if new therapeutics is established beyond life style modification and currently available drugs in the near future.
FOOTNOTES
-
Authors’ contributions
All authors contributed in conception of the work and drafting of the article. WS contributed in critical revision of the article. All authors provided final approval of the version to be published.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
non-alcoholic fatty liver disease
metabolic-associated fatty liver disease
magnetic resonance elastography
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