Non-alcoholic fatty liver disease (NAFLD) is the condition in which hepatic fat accumulation is present after all other causes of hepatic steatosis are excluded; these include liver disease caused by other factors, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. The clinical spectrum of NAFLD is wide-ranging and spans NAFL to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD is the most common liver disease in the world, and NASH may soon become the most common indication for liver transplantation ¹ . The incidence and prevalence of NAFLD is rising globally owing to increasing rates of obesity and diabetes ^{2, 3} . The development of liver cancer in patients with NAFLD, even without the presence of cirrhosis, was observed recently in a number of studies. These outcomes contribute substantially to the burden of disease to the individual and also to society. It is therefore a public health priority to develop effective measures for the identification and treatment of this condition. The recent advances in understanding and managing NAFLD are reviewed below.

The true worldwide incidence rate of NAFLD/NASH is not known. It was found through a few studies that the incidence rates were widely variable owing to multiple factors which include the different characteristics of study populations, exclusion criteria, study methodology, and approach for diagnosis. The variable presentations of the disease as well as the unavailability of sensitive diagnostic studies besides the liver biopsy, which remains the gold standard to date, probably contribute to the underreported incidence and prevalence of NAFLD ⁴ . Analysis of liver ultrasound data collected between 1988 and 1994 from the Third National Health and Nutrition Examination Survey (NHANES III) reported that 19% of adults have NAFLD, while a meta‐analysis of studies from 2006–2014 estimated a NAFLD prevalence of 24% (20–29%) in the general population. The Dionysos ⁵ study in Italy first reported that the global prevalence of NAFLD is 24–25% of the general population; this is the most accurate estimated figure to date, and it was confirmed recently by Younossi ^{6, 7} , who described some regional differences with the highest rates reported in South America and the Middle East, followed by Asia, the USA, and Europe. The increasing prevalence of NAFLD/NASH is in parallel to the pandemic spread of obesity, diabetes mellitus (DM), and metabolic syndrome. One-third of American adults are thought to have NAFLD ⁸ . The prevalence of NAFLD in Europe and the Middle East ranges from 20–30%. The highest prevalence of NAFLD was reported in South America and the Middle East, whereas the lowest was reported in Africa. Although the global burden of NAFLD is unknown, on the basis of the above studies, we estimate that ~one billion individuals have NAFLD at the current time. Liver biopsy is the gold-standard diagnostic test. There are also some non-invasive diagnostic modalities including hepatic ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). The discrepancy in prevalence data for NAFLD could be attributed to the difference in sensitivity of these diagnostic tests. Younossi et al. reported that the pooled regional NAFLD prevalence estimates among patients diagnosed by blood test were 13.00% (95% confidence interval [CI]: 4.44–32.47) for Europe, 12.89% (95% CI: 8.32–19.44) for North America, and 9.26% (95% CI: 7.07–12.05) for Asia ⁹ . Estes et al. reported that by 2030, the NAFLD population was projected to increase by 21% to 100.9 million cases. Prevalence in 2030 is estimated at 33.5% (aged ≥15 years) and 28.4% (all ages). The NAFLD population is estimated to have a median age of 50 (2015), which increases to 55 by 2030. During 2015–2030, there would be 1.2 prevalent NAFLD cases among male individuals for every 1.0 among female individuals ¹⁰ . Because of the small number of studies that contained NAFLD incidence results, Younossi et al.’s meta-analysis results were obtained only for Asia (only available for China and Japan) and Israel. In Asia, the pooled regional NAFLD incidence rate was estimated to be 52.34 per 1,000 person-years (95% CI: 28.31–96.77), and in Israel it was estimated to be 28.01 per 1,000 person-years (95% CI: 19.34–40.57) ⁹ . According to Estes et al., the fastest growth in obesity prevalence occurred during 2000–2002. In comparison, the fastest growth in DM prevalence occurred during 2012–2014. The number of NAFLD cases increased following obesity, resulting in a peak NAFLD incidence in 2008 with an estimated 4.17 million new cases. Since then, a slowing rate of increase in NAFLD was forecasted, and new cases were estimated to decline to 3.62 million annually. Thus, the total number of NAFLD cases is still increasing but at a lower rate compared to the 2005–2008 period. However, given the rising prevalence of type 2 diabetes, the proportion of individuals with NASH is predicted to increase, and with prolonged disease exposure the number of individuals with end-stage liver disease is likely to triple by 2030. It has been estimated that, in the USA, NAFLD is responsible for $292 billion in annual medical and societal costs ¹⁰ . The projected cost of caring for patients is expected to increase by 18% from 2000 to 2035, and the health-related quality of life of NAFLD patients is described as declining ^{11, 12} .

A substantial body of literature has accumulated and provides a framework to understand the pathogenesis of NAFLD. With increasing caloric intake and changes in dietary composition, excess calories are stored as fat within adipose tissue and also induce changes in the microbiome. This triggers changes in intestinal permeability and increased systemic exposure to intestinal microbial products, triggering activation of the innate immune system and adipose tissue inflammation. The metabolic consequence is the development of an insulin-resistant state. The insulin-resistant state which drives increased lipolysis along with the consumption of excess calories deliver an increased load of lipotoxic lipids including free fatty acids to the liver along with excess carbohydrates. This is further compounded by increased de novo lipogenesis, which is driven by hyperinsulinemia and retained sensitivity to the lipogenic effects of insulin in an otherwise insulin-resistant state. The liver attempts to react by increasing lipid oxidation and export of lipids; when lipid influx and synthesis exceed its metabolism and export, the excess lipids accumulate in lipid droplets, creating a fatty liver. Recently, it has been shown that the PNPLA3 protein accumulates on the surface of lipid droplets ¹³ . Under conditions of lipotoxic stress, proteasomal impairment drives such accumulation where, in those with mutant PNPLA3, impaired lipolysis leads to further accumulation of fat. However, this does not explain how the mutation drives the development of steatohepatitis and cirrhosis. Cell stress including oxidative stress and unfolded protein response can trigger apoptosis, cell death, and inflammation. Apoptosis can also trigger cell regenerative activity. While much is known about how lipotoxicity drives cell death and inflammation, there is still a paucity of information on the biological mechanisms driving tissue adaptation and regeneration. Prolonged inflammation drives fibrogenic remodeling of the liver. Recently, considerable advances in the development of in vivo and in vitro models of NASH have been made ^{14– 16} . The criteria for the validation of such models as models of human NASH are clearer ¹⁷ . In reviewing data from such models for understanding human disease, it is important to ascertain if such validations have been performed in the model. These criteria include whether gene manipulations that are not reflective of the human state are used, if the macronutrient composition reflects human diet, if features commonly seen in humans such as obesity, systemic inflammation, dyslipidemia, insulin resistance, steatohepatitis, and fibrosis are present, and if there is concordance of cell signaling and transcriptome to human disease.

Most of the data on the natural history of NAFLD are based on indirect evidence and have come from a selected population. Despite NAFLD’s high prevalence, only a minority of NAFLD patients progress to significant fibrosis or experience associated morbidity ¹⁸ . The reason for this variability is, partly, subtle individual genetic differences that change one’s response to environmental factors and lifestyle, thus determining disease phenotype ^{19– 21} . Recent data from a population study in Olmsted County reported a significantly higher mortality in NAFLD patients compared with the general population; however, overall mortality and liver-related death were lower than previously reported from referral centers. Mortality in these patients was associated with older age, glucose intolerance/diabetes, and the presence of cirrhosis. The top three leading causes of death in patients with NAFLD in descending order are cardiovascular disease, cancer, and liver disease ²² . A patient’s chance of progressing to advanced liver disease, including hepatic decompensation and HCC, is higher if they suffer from NASH than if they suffer from NAFLD. Recent studies have suggested that NAFLD can evolve to NASH with advanced fibrosis, which would imply that it may not be an entirely benign condition ^{23, 24} . A recent study found that 44% of patients with NAFLD at the index liver biopsy progressed to NASH and 37% progressed to fibrosis, including 22% to advanced degree ²⁵ . Managing NAFLD requires markedly increased healthcare resources as fibrosis worsens, especially after the development of cirrhosis. Although there are no exact models to estimate the incidence and the disease burden of NAFLD in the next few years, the changing trends of obesity and DM suggest that this problem is increasing worldwide and might place a growing strain on healthcare systems.

NAFLD remains asymptomatic in a significant proportion of patients, and the diagnosis is often suspected when liver functions are found to be abnormal on biochemical testing or hepatic imaging (ultrasonography, CT, or MRI of liver) suggests fatty liver when performed for some other reason. Liver biopsy remains the gold standard for diagnostic evaluation of NAFLD. In the past, the NASH Clinical Research Network histological scoring system was the most widely used, representing a validated scoring system that generates a NAFLD activity score (NAS). A NAS of 5 or more is sometimes considered NASH and less than 3 is considered not NASH ²⁶ . However, NAS cannot be used as a surrogate for discrimination between NASH and NAFLD, although it is useful for the histological diagnosis ^{27, 28} . Given that the prevalence of NAFLD is high, using liver biopsy to detect fibrosis-cirrhosis is unfeasible. The accuracy of liver biopsy to assess fibrosis has also been questioned owing to sampling errors and intra- and inter-observer variability that may lead to over- or under-staging. Cost, procedure-related complications, and intra- and inter-observer variations in reporting the histology are the major drawbacks of liver biopsy, and, therefore, it is usually not recommended in clinical practice, except in circumstances where other differential diagnoses are to be excluded. Over the past decade, there has been a growing interest in alternative novel strategies for the non-invasive evaluation of fibrosis. These techniques require two distinct but complementary approaches: the measurement of serum biomarkers or the estimation of liver stiffness using ultrasound-based elastography with transient elastography (TE) as the forerunner ²⁹ . In NAFLD patients, TE, the fibrosis index (FIB-4), and NAFLD fibrosis scores are the best validated non-invasive tests ^{30, 31} . For instance, in a recent meta-analysis ³² based on 64 studies including a total of 13,046 NAFLD patients, the summary AUROC values of TE, FIB-4, and the NAFLD fibrosis score for diagnosing severe fibrosis-cirrhosis were 0.88, 0.84, and 0.84, respectively. When all three were compared head to head, TE was the most accurate in the diagnosis of cirrhosis ³³ . Lastly, recent evidence shows that non-invasive tests, including FIB-4 and NAFLD fibrosis score as well as TE-derived liver stiffness measurements, accurately identify the subgroup of patients with NAFLD at a higher risk of developing liver-related complications and death or liver transplantation ³⁴ . Liver enzymes can often be normal in a number of patients with NAFLD. Although several biochemical markers, such as TNF-a, IL-6, CRP, pentraxin, ferritin, serum prolidase enzyme activity, soluble receptor for advanced glycation end product, and cytokeratin-18, have been proposed as useful in predicting the severity of NAFLD/NASH in the past, none of these markers have shown sufficient sensitivity or specificity for routine clinical application for diagnosis ³⁵ . Ultrasonography, CT, and MRI of the liver are the standard imaging modalities used in clinical practice for the diagnosis of NAFLD. In general, about 30% of liver steatosis cases should be present for sonography to detect NAFLD. TE is an ultrasound-based imaging technique to detect the degree of fibrosis in patients with NAFLD and NASH. The sensitivity and specificity of TE to diagnose various stages of fibrosis have been reported to be 79–92% and 75–92%, respectively ³⁶ . Recent evidence also suggests that the ultrasound-based controlled attenuation parameter value used in the TE technique can predict the degree of steatosis in patients with NAFLD ³⁷ . The gold standard for the non-invasive assessment of hepatic steatosis is the use of MRI protein density fat fraction. Newer MRI techniques, such as MR elastography, can stage the degree of fibrosis non-invasively to diagnose and assess the prognosis of patients with NAFLD ³⁸ .

Lifestyle modification, consisting of diet and exercise, is the cornerstone of therapy for NAFLD and has been shown by many studies to improve liver histology ^{39, 40} . However, lifestyle modification is difficult to achieve and to sustain ⁴¹ . The remarkable progress that has been made in previous years in understanding disease pathogenesis has led to an explosion of medical therapies targeting various aspects of the fat accumulation and injury pathways. These therapies can be classified according to their intended targets into four general groups ( Figure 1).

NAFLD is the most common cause of chronic liver disease in the Western world today. With rising levels of obesity and type 2 DM, its prevalence will increase in the future and cause considerable morbidity and mortality. The field of NAFLD continues to evolve rapidly. Advances in the understanding of classical steatosis and disease progression are also reviewed with a view toward providing translational insights into how this knowledge can be used to prevent or treat the disease in the future. Despite considerable research and multiple clinical trials, at present no single pharmacologic agent has achieved a clinically meaningful benefit/risk profile to warrant regulatory approval for marketing. There are currently a number of drugs undergoing pivotal trials as potential therapy for NASH. It is anticipated that the first drugs to be approved for NASH will likely become available by 2020. The ideal treatment will lead, in the short term, to a reduction in liver inflammation and fibrosis as well as an improvement in insulin sensitivity and metabolic complications but, in the long term, will need to reduce cardiovascular and liver outcomes.