Changing epidemiology of chronic liver disease among ethnic groups in the United States
Authors: Stuart McPherson, Quentin M. Anstee
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. See Article on page 1969 Aspects of this work have been supported by the facilities of the Newcastle NIHR Biomedical Research Centre Chronic liver disease (CLD) is a major cause of morbidity and mortality in the United States and other countries worldwide. In the United States, there are approximately 66,000 deaths from liver disease each year, with the major underlying causes being alcohol‐related liver disease (ARLD), hepatitis C virus (HCV), and nonalcoholic fatty liver disease (NAFLD).1 Data from the National Health and Nutrition Examination Surveys (NHANES) conducted between 1988 and 2008 has shown that the overall prevalence of CLD in the community rose from 12% to 15%, a change attributable to increases in rates of NAFLD.2 Rates of hepatitis B virus (HBV), HCV, and ARLD remained stable over this period. Now, estimates suggest that in excess of one third of the U.S. population have radiological evidence of steatosis.3 Although many patients with NAFLD have mild liver disease and do not progress to cirrhosis,4 the prevalence of end‐stage liver disease attributed to NAFLD is increasing, with the number of new liver transplant waiting list registrations in the United States for NAFLD increasing by 170% between 2004 and 2013, which was much higher than for ARLD (45%) and HCV (14%).5 Despite the known high prevalence of NAFLD and other liver diseases in the population, few studies have attempted to address the burden of disease across a broad spectrum of ethnicity, preferring to focus on whites, Latinos, and African Americans. In their seminal population‐based study, Browning et al. demonstrated the prevalence of hepatic steatosis (HS), assessed by magnetic resonance spectroscopy, was higher in Latinos (45%) than whites (33%) and African Americans (24%).3 Differences in lifestyle and diet, insulin resistance (IR), pattern of adiposity, and genetic variants all contribute to these differences. There are also known differences in the prevalence of other liver diseases between ethnic groups, particularly viral hepatitis, with higher rates in African Americans, Latinos, and Asian Americans than whites. Mortality from liver disease is also significantly different between ethnic groups, with American Indians and Alaska Natives having double the rate of liver‐related deaths per population compared to whites and African Americans,1 although these statistics may, at least in part, reflect a range of socioeconomic factors. In this issue of Hepatology, Setiawan et al. aimed to define the prevalence of CLD and cirrhosis, by etiology, in the large, racially diverse, Multiethnic Cohort.6 This cohort enrolled 215,000 individuals, aged 45‐75 years, between 1993 and 1996, to study the effect of diet on cancer among ethnic minority groups living in California and Hawaii. Through extensive longitudinal data collection, the researchers were able to assess the prevalence of CLD and cirrhosis among 106,458 individuals using fee‐for‐service Medicare claim data between 1999 and 2012, defining the underlying etiology of liver disease from International Classification of Diseases, Ninth Revision codes. Importantly, the cohort included individuals from two ethnic groups that have not previously been well studied (Japanese Americans and Native Hawaiians) as well as African American, Latino, and white subjects. Overall, a total of 5,783 (5.4%) cases of noncirrhotic CLD or cirrhosis were identified. When assessed separately, Japanese Americans had the highest prevalence of CLD or cirrhosis (6.7%), followed by Latinos (6.7%), whites (4.1%), African Americans (3.9%), and Native Hawaiians (3.9%). In keeping with other reports,2 NAFLD was the most common etiology of CLD and cirrhosis in the whole cohort, accounting for 51.7% of cases, followed by ARLD (20.7%), HCV (8.6%), HBV (3.1%), and HCV/HBV (2.9%). Whereas NAFLD was the most common etiology of CLD across all the ethnic groups studied, striking variations in the etiological spectrum were noted among the ethnic groups (Fig. 1). In particular, Japanese Americans and Native Hawaiians were significantly more likely to have NAFLD attributed as the cause of CLD than whites. Moreover, Japanese Americans were less likely to have ARLD and HCV than whites. By contrast, in comparison with whites, African Americans were significantly less likely to have NAFLD, but more likely to have HCV. When individuals with cirrhosis (n = 2,208) were assessed in the different ethnic groups, NAFLD was the most common etiology for Native Hawaiians, Japanese Americans, and Latinos. However, in whites and in African Americans, ARLD and HCV were the predominant causes, respectively.Figure 1: Breakdown of the causes of chronic liver disease and cirrhosis for each of the ethnic groups in the study by Setiawan et al.6An important and novel finding was that Japanese Americans had the highest prevalence of CLD or cirrhosis (6.9%; predominantly NAFLD) of all the ethnic groups studied and was similar to the prevalence in Latinos (6.7%), who are known to be at high risk of NAFLD.3 This finding has significant implications, given that Japanese Americans were not previously considered a high‐risk group for liver disease. The prevalence of NAFLD has been increasing in Japan, with the one study from 2005 showing a population prevalence of 29% for HS,7 although this was diagnosed using a relatively insensitive modality (ultrasound). It is therefore possible that rates of NAFLD are even higher than suspected. The potential biological reason for the high rate of NAFLD in those of Japanese origin requires further study. However, in comparison to whites, it has been reported that subjects of Japanese ethnicity have a greater propensity to develop visceral adipose tissue, rather than subcutaneous fat, with weight gain, and central obesity is primarily associated with the development of IR and NAFLD.8 Genetic factors, such as carriage of PNPLA3 genetic variants that confer susceptibility to the development of HS, could also be a contributing factor given that they have been shown to explain a proportion of the ethnic differences in steatosis between African Americans, Hispanics, and whites.9 This study does, however, have a number of methodological limitations; the use of Medicare claims data may have introduced selection bias based on cohort age and socioeconomic status, which has not been addressed in the current study. Furthermore, the effect of genetic variants that may reduce alcohol consumption in some ethnic groups were not considered in the analysis. The ALDH2*2 variant is common in Asia, where frequencies of up 30%‐50% have been reported in Japanese populations.10 Given that Setiawan et al. used a binary classification between NAFLD and ARLD, this important omission implies that patients with "dual etiology" fatty liver disease (obesity/metabolic syndrome plus alcohol consumption above the defined thresholds) will be classified as ARLD, and that such cases will not be evenly distributed across ethnicities, potentially introducing an artefactual difference in the apparent relative prevalence of NAFLD between Japanese and non‐Japanese ethnicities. Finally, it is known that cirrhosis, particularly attributed to NAFLD, is under‐recognized by clinicians, and so disease burden may be significantly underestimated in the community. Data from the NHANES study, where participants had blood tests looking for liver disease, showed a much higher prevalence of CLD than in this study (∼15% vs. 5.4%).2 It is also important to note in the current study that there was a significant change in the predominant etiology of liver disease between 1999 and 2012, with rates of NAFLD increasing between these time points in all the ethnic groups studied. In contrast, rates of ARLD fell in all groups, whereas HCV rates fell in all groups except Native Hawaiians. With increased access to the new, highly efficacious direct acting antivirals for HCV and effective HBV vaccination strategies in place, it is likely that rates of viral hepatitis will decline in the future and NAFLD will continue to dominate as the major liver disease in the community. Overall, the current study by Setiawan et al. adds to the body of literature showing that the prevalence of NAFLD and NAFLD‐related cirrhosis is dramatically increasing in all ethnic groups in the United States. The findings related to interethnic differences in NAFLD prevalence are intriguing, but, for the moment at least, should be interpreted with caution pending further validation that controls for potentially important confounding factors. Notwithstanding this, NAFLD is clearly a major risk to public health, and efforts to control obesity at a population levels are urgently needed. In addition, there is an urgent need for effective treatments for NAFLD to reduce the proportion of patients progressing to advanced liver disease.