The globalization of nonalcoholic fatty liver disease: Prevalence and impact on world health

Potential conflict of interest: Dr. Charlton consults and received grants from Gilead. He consults for Intercept and received grants from GenFit. See Article on Page 73 As far as the scientific community can tell, the first prokaryotic cells emerged on an inhospitable Earth ∼3.8 billion years ago. The first mammalian fossils date to ∼200 million years ago and those of Homo sapiens to a mere 200,000 years ago. The human transition from existence exclusively as hunter‐gatherers to agriculture‐based civilizations began less than 12,000 years ago. Until a blink of an eye ago in biological terms, the ability to find enough food to survive was inconsistent and unpredictable. For several decades we have been producing enough calories at low enough cost for mass overnutrition to occur. Inexpensive grains, especially corn, have translated into inexpensive sugars and, simultaneously, inexpensive animal meat and fat. The US Department of Agriculture's Economic Research Service estimates that caloric intake per capita in the United States is 2700 calories/day, 800 calories/day above that consumed in 1950 (http://www.ers.usda.gov/data‐products/food‐availability‐(per‐capita)‐data‐system/.aspx). The excess of calorie production and consumption is a global phenomenon (Fig. 1). The increase in daily caloric consumption is more than enough to explain the global epidemic of obesity. The most recent analysis by the World Health Organization reports that worldwide obesity has more than doubled since 1980.1 Globally, about 2 billion (39%) adults are overweight and over 600 million (13%) are obese.1 Most of the world's population lives in countries where the consequences of excess nutrition kill more people than undernutrition. The burden of obesity is uneven in geographic terms, with more than half of the world's obese living in just 10 countries.1 In the United States, the most recent National Health and Nutrition Education Survey reports that two‐thirds of adults are overweight or obese and over 1 million individuals have a body mass index >60 kg/m2.2Figure 1: Geographic variation in the daily energy availability per capita (kilocalories) and in the prevalence of NAFLD is shown.In this issue of hepatology Younossi et al.3 present the results of a remarkable study that estimates the global prevalence, incidence, progression, and outcomes of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), bringing together more than 700 individual reports from around the world published between 1989 and 2015. The work has resulted in a new and clearer picture of the worldwide burden of NAFLD and NASH. The results should shape our thinking and approach to fatty liver disease. In a world beset by a litany of critical health challenges, concern about one of the consequences of overnutrition may seem quaint and, probably, transient. The study by Younossi et al. points to a different reality and merits detailed consideration of its three primary conclusions. The global burden of NASH is high, affecting one in four adults, with substantial geographic variation in prevalence. The analysis by Younossi et al. included a sample size of 8,515,431 from 22 countries. The main finding is that the global prevalence of NAFLD is 25.24% (range 22.10%‐28.65%), with the highest prevalence in the Middle East and South America and the lowest in Africa (Fig. 1). Ascertainment and sampling biases may have resulted in this being an overestimate of the prevalence of NAFLD but probably not by much given that the prevalence reported here is consistent with that generated in population studies. An interesting aspect of the report by Younossi et al. is the weak predictivity of the prevalence of obesity and daily caloric excess for the prevalence of NAFLD and NASH, a finding that hints at the importance of factors other than body mass index in the pathophysiology of NAFLD. Genetic susceptibility is an undoubted contributing factor, e.g., to the high prevalence of NASH in Central and South America, where the rs738409 G allele of the PNPLA3 gene is highly prevalent,4 despite much lower daily caloric intake than in North America and western Europe (Fig. 1). Cultural phenomena, such as dietary composition and the prevalence of daily exercise, a strong predictor of NAFLD,5 are also likely to contribute to variation in the geographic prevalence of NASH. With the obvious exception of genetics, almost all of the susceptibility factors for NASH are theoretically modifiable, highlighting the potential impact of education and policy in attenuating the burden of NASH. Fibrosis progression in NAFLD, to the point of liver‐related clinical outcomes, is slow and unusual, with non‐liver‐related mortality being >50‐fold more common than liver‐related mortality for patients with NAFLD. The second compelling observation is that, based on longitudinal analyses, the mean annual rate of progression in NASH is 0.09 fibrosis stages per year (range 0.06‐0.12). With mean ages of patients at diagnosis typically between 40 and 50 years, progression to cirrhosis would occur well beyond the life expectancy of the great majority of patients with NASH. Malaria will remain a more pressing public health concern than NASH in Africa and Asia for some time. If the results of the study by Younossi et al. are combined with those of a recently published large, multicenter, multicontinental longitudinal analysis6 and a large longitudinal cohort study,7 a natural history of NAFLD can be quilted together (Fig. 2). Out of every 100 patients with NAFLD, only one to two will die a liver‐related death. The incidence of development of hepatocellular carcinoma, a common source of liver‐related mortality, is also low among NAFLD patients, occurring at a frequency of 0.44/1000 person‐years (range 0.29‐0.66). This is much (>90%) lower than the incidence of hepatocellular carcinoma among patients with hepatitis C and hepatitis B infection. However, the population‐attributable fraction of the burden of hepatocellular carcinoma in NAFLD is substantial, given its high prevalence. The liver transplant rate among patients with NAFLD in North America is 1:420.6 Despite the low frequency of liver‐related mortality, the staggering denominator of over 1 billion adults with NAFLD coupled with a lifetime risk of ∼2% for liver‐related mortality will eventually translate into ∼20,000,000 liver‐related deaths among patients currently alive with NAFLD. NAFLD thus may already exceed hepatitis C viral infection, which causes 350,000 liver‐related deaths a year globally, as a cause of liver‐related death. If it does not, it soon will. The same is true for hepatitis B infection. And that brings us to the third conclusion that should be drawn from the report by Younossi et al. Although liver‐related events are a relatively minor cause of mortality among patients with NAFLD, NAFLD or more specifically NASH is on the threshold of becoming, or has already become, the most common cause of liver disease and liver‐related death globally. Liver‐related outcomes occur nearly exclusively in patients with NASH, who comprise approximately 25% of those with NAFLD. Liver‐specific mortality among patients with NASH was estimated to be 15.44/1000 person‐years (11.72‐20.34). The impact of NASH as a cause of liver‐related mortality may increase several‐fold as the age at onset of disease retreats not just to childhood but to the in utero state,8 potentially increasing the duration and progression of liver disease. Figure 2: The natural history of NAFLD is depicted, with the lifetime frequency of clinically relevant progression of fibrosis and development of liver‐related and non‐liver‐related deaths.Perspective is important. All of the mass extinctions in the history of life on Earth are thought to have been mediated by loss of food through climate change, including the greatest of them all—the meteor impact at Chicxulub in Yucatán that saw off the dinosaurs over 60 million years ago. While NASH itself will not cause a Chicxulub‐like event, the emergence of global overnutrition as a major cause of morbidity and mortality is an irony that has been 60 million years in the making. As Homo sapiens warms the Earth in a fog of greed and denial, the age of diseases of excess and the epidemic of NAFLD may be short‐lived.