Metabolic and Pharmacodynamic Specialist, Celerion, 2420 W. Baseline Rd, Tempe, Arizona, United States
Received date: October 07, 2016; Accepted date: December 03, 2016; Published date: December 07, 2016
Citation: Sharon H Jaycox. A Fatty World: Exploring Racial Disparity in NAFLD/NASH. J Hep. 2016, 2:2.
Background: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic
steatohepatitis (NASH) are metabolic disorders that affect the liver. A world crisis
is unfolding as the number of people with NAFLD/NASH is substantially increasing.
Chronic liver disease is now estimated to be the leading cause for liver transplant.
Studies have shown that NAFLD/NASH is often more pronounced in certain ethnic
populations, particularly Asian and Hispanic communities. An explanation for this
increased incidence may be associated with intrinsic ethnic factors and/or genetic
polymorphism (variants in a particular DNA sequence). Further, the etiology of
NAFLD/NASH is also linked to obesity, diabetes, and other risk factors which are
highly pronounced in racial communities. Unfortunately, there currently is no
NAFLD/NASH-specific medication on the market to treat these diseases. New drug
development and ongoing research is necessary to treat and cure NAFLD/NASH,
with particular attention given to engage high risk populations. Importantly,
the discovery of new treatments may be beneficial with ongoing support and
collaboration between the research community and ethnic groups.
Conclusion: For NAFLD/NASH clinical studies, participation of Asians and Hispanics is vital and may be important in drug development programs for successful and targeted treatment.
NAFLD; NASH; Polymorphism; Variants; Ethnic; Metabolic
BMI: Body Mass Index; GWA: Genome-Wide Associated; GCKR: Glucokinase Regulatory Protein; JASSO: Japanese Society for the Study of Obesity; NHANES: National Health and Nutrition Examination Survey; NCAN: Neurocran; NAFLD: Nonalcoholic Fatty Liver Disease; NASH: Nonalcoholic Steatohepatitis; PNPLA3: Patatin-like phospholipase 3; TM6SF2: Transmembrane 6 Superfamily Member 2; WHO: World Health Organization.
Several metabolic diseases as well as their associated underlying risk factors have been found to be more pronounced in selective ethnic communities. For example, in the United States (US) type 2 diabetes is more prevalent in African and Native Americans than Caucasians . In addition, obesity is highly widespread among both African American and Hispanic groups. This point was emphasized in a recent publication that described nearly half of African Americans (48%) and Hispanics (43%) in the US are categorized as obese . Many of these race-related differences are derived from intrinsic ethnic factors and/or genetic polymorphism (variants in a particular DNA sequence). A similar trend has arisen for liver metabolic disorders such as nonalcoholic fatty liver disease (NAFLD). This overview will highlight the prevalence of NAFLD and the associated risk factors within ethnic populations from a national and global perspective.
NAFLD is a metabolic disease with a broad spectrum of liver manifestations that is histologically subdivided into simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. NASH is characterized by steatosis, liver inflammation and injury with or without fibrosis. While steatosis in itself is generally considered to have a benign hepatological prognosis, NASH a detrimental form of the disease, often progresses to cirrhosis and hepatocellular carcinoma, and is estimated to become the leading cause of liver transplantation in the US by 2020 . Although still unknown, the etiology of this fatty liver pathology is strongly associated with obesity, insulin resistance and dyslipidemia. NAFLD is also often predicted by an increased body mass index (BMI), waist circumference, and waist-to-hip ratio . Additional risk factors may include a family history of diabetes, cardiovascular diseases, metabolic syndrome, and high blood pressure .
An Upward Trend
NAFLD has emerged as a major public health issue and is the most common cause of liver disease in Western countries, affecting up to 20 to 35% of the general population . The National Health and Nutrition Examination Survey (NHANES), a large and representative survey of the US population reported the prevalence of fatty liver disease in adults (aged 20-74 years) increased from 18% in 1988-1991, to 29% in 1999-2000, and to 31% in 2011-2012 . Along with the growing occurrence of obesity, type 2 diabetes, and metabolic syndrome, these data reflects how the incidence of NAFLD has increased steadily over the last few decades. Currently, there is an estimated 1 billion people worldwide affected by NAFLD . In this respect, NAFLD is no longer considered a disease exclusive to developed Western countries, as the frequency of this metabolic disorder is also increased in developing countries; with an estimated prevalence of nearly 10% in developing nations . Additionally, the prevalence of NAFLD is expected to increase by 50% by 2030 . Furthermore, NAFLD is now widely recognized as the next big global epidemic. Moreover, these numbers are largely influenced by a booming incidence within certain ethnic classes.
NAFLD and Ethnicity
Although NAFLD reaches every corner of the world due to increased rates of obesity and insulin resistance, two ethnic groups especially stand out for their high risk of fatty liver disease, mainly those of Asian and Hispanic descent. In China and Japan, the prevalence of NAFLD has reached epidemic proportions  and is rising in many other Asian-Pacific communities as well . NAFLD prevalence in the Asian population may be secondary to the rising rate of obesity. Importantly, according to the World Health Organization (WHO) and the Japanese Society for the Study of Obesity (JASSO), waist circumference and BMI cutoff values associated with increased metabolic risk are adjusted for race (Table 1). A critical consideration since Asian populations demonstrate greater risk for fat-related disorders such as NAFLD, heart disease and diabetes when comparing Asians and Caucasians of the same anthropometric measurements (weight and height) . In a 2009 article, Fan and Farrell, reported the prevalence of fatty liver in the general population of East and South China (two densely populated regions) were 17% and 15%, respectively ; of which, nearly 90% of the fatty liver cases appeared to be related to metabolic factors such as NAFLD. Furthermore, the rate of NAFLD in Central China has doubled in the past 7-10 years; it has increased from 13% to 25% . Alarmingly, in a Korean study in which liver biopsies were performed on 589 consecutive potential liver transplant donors, NAFLD prevalence was exhibited in 51% of the donors . Altogether, the data reflects the severity of NALFD within the Asian populations.
|Asian||>28 kg/m2||>35 (90 cm) >31 (80 cm)|
|Non-Asian||>30 kg/m2||>40 (102 cm) >35 (88 cm)|
|Japanese||>25 kg/m2||> 33 (85 cm) >35 (90 cm)|
The disparity in NAFLD prevalence in diverse ethnic groups may be explained by the different rates of metabolic syndrome in those ethnicities; in the US 22% of African Americans, 24% of non-Hispanic Whites and, 32% of Mexican Americans develop metabolic syndrome [14-16]. Similar trends have been reported for the incidence of NAFLD in the same ethnic groups whereas it is: 13.5% for African Americans, 18% for non-Hispanic Whites and, 24% for Hispanics .
One theory suggests that these differences in NAFLD by race may be attributed to the distribution of adipose tissue or serum triglyceride levels. This stems from observational studies showing that despite increased insulin resistance in African Americans, there is a relatively lower risk of developing NAFLD/NASH, due to less visceral adipose tissue and lower triglycerides than Hispanics, a phenomena coined the ‘insulin resistance paradox’ . On the other hand, a number of studies have found that NAFLD prevalence in the Hispanics population is secondary to the high consumption of carbohydrates, which impact liver metabolism . Histologic and serologic properties of NAFLD in different ethnic groups were reflected in a retrospective analysis of liver biopsies which revealed that Hispanics displayed greater liver damage . In addition, the analysis also revealed more pronounced hepatocyte damage and more advanced fibrosis than non-Hispanic Whites or African Americans . Moreover, a more prominent inflammatory status is also considered a contributing factor for Hispanics with NAFLD due to higher levels of liver function enzymes such as aminotransferases . Taken altogether the causative factors noted above have led to both Hispanic men and women exhibiting a chronic liver disease rate that is twice that of the Caucasian population  (Table 2).
Table 1 Obesity standards for BMI and Waist Circumference.
|PNPLA3||G||rs738409||NHW||Hepatic Steatosis with high ALT level|||
|Increased ALT and AST level|||
|(PNPLA3)||S453I||rs6006460||AA||Lower Hepatic Fat|||
|NCAN||T||P92S||rs2228603||NHW||Hepatic Steatosis with high ALT level|||
NHW: Non-Hispanic white, NHB: Non-Hispanics Black, MA: Mexican America, African Americans (AA), TM6SF2 Transmembrane 6 superfamily member2, GCKR: Glucokinase regulatory protein, PPP1R3B: Protein phosphatase 1 regulatory subunit 3b, NCAN: Neurocran
Table 2 Single nucleotide polymorphism (SNP) associated with NAFLD/NASH.
Genetic Factors Associated with NAFLD/NASH
With a growing focus on epigenetic and genome-wide associated (GWA) studies, researchers have established that ethnic variations in NAFLD prevalence may arise from a genetic susceptibility. In particular, a polymorphism in the patatin-like phospholipase 3 (PNPLA3) gene, which encodes the enzyme adiponutrin, a regulator of hepatic fat content and lipid secretion, has been implicated in the development of NAFLD/NASH . Specifically, the PNPLA3 I148M rs738409 variant has been suggested to be a major determinant of race-related differences in hepatic fat accumulation, independent of insulin resistance and serum lipid concentrations across multiple ethnicities [3,20,21]. Similar to NAFLD/NASH incidence rates, Hispanics (49%) demonstrated the highest frequency of the I148M polymorphism, followed by non- Hispanic Whites (23%), and African Americans (17%) [18,20]. In addition, several studies have also established that the I148M variant contributes to fibrogenesis in the development of NASH and cirrhosis . Moreover, polymorphisms within PNPLA3 have also been associated with the advancement of NAFLD/NASH in Chinese , Japanese , and Asian Indian  cohorts. Other genes of interest with racial significance associated with NAFLD/NASH are GCKR, TM6SF2, and SAMM50 [17,26,27]. Taken altogether, intrinsic genetic factors such as body habitus and genetic variants with gene expression within the Asian and Hispanic cohorts have identified these two ethnic groups as high risk populations for the development of NAFLD/NASH.
Ethnicity and NAFLD/NASH therapy
There currently are no NAFLD-specific therapeutic agents available on the market; however, a number of insulin sensitizers, antioxidants and new investigational products are being developed for the treatment of NAFLD/NASH. Two landmark studies in this domain have shown promising results, the FLINT and PIVENS studies. Obeticholic acid, a farnesoid × nuclear receptor was investigated in NASH subjects in the multicenter, FLINT study with the primary outcome to improve histological liver features. This randomized placebo-controlled study of 283 participants constituted mainly of a White demographic with only 6% Asians, and 15% reported as being of Hispanic ethnic origin . These values of self-reported ethnicity are also similar for the PIVENS study, a phase 3, multicenter study which examined the effect of pioglitazone versus vitamin E compared to placebo in NASH subjects . The lack of drugs to treat NAFLD/NASH and the increasing world crises necessitates ongoing research, specifically in the high risk groups; unfortunately, participation of ethnic groups in clinical research has always been historically low . In part, this may be related to several social and cultural impediments that have limited inclusion of disparate groups within clinical studies . Nonetheless, the potential contribution of a subject’s genetic makeup with respect to drug development and metabolism must be taken into consideration, a statement that was echoed by the National Pharmaceutical Council and National Medical Association . Moreover, pharmaceutical and biotech companies are increasingly cognizant of the diversity, as they work to find treatments. Importantly, as NAFLD/NASH therapies are developed it may be in the best interest of all stakeholders to conduct those clinical studies on disparate groups of subjects, particularly those identified as Hispanic and Asian. Furthermore, minority inclusivity was emphasized by the Food and Drug Administration when they published the Demographic Rule in 1998, a regulatory guidance for pharmaceutical companies to report and tabulate clinical study data by race and ethnicity .
NAFLD and NASH are a spectrum of liver disease recognized as a growing phenomenon, slated to become the leading cause for liver transplant by 2020 . Metabolic diseases which include diabetes, as well as NAFLD and NASH are prevalent in select disparate communities. African and Native American communities are at greater risk for diabetes and NAFLD/NASH has predominance in the Asian and Hispanic ethnicities. The incidence of NAFLD/ NASH in minority groups can be linked to genetic-predisposition, metabolic risk factors, environmental factors, and culture. As NAFLD/NASH becomes increasingly recognized as a global health issue, therapies will need to be developed. During the drug discovery process ethnicity should be taken in account with both pharmacogenomics and pharmacological consideration given to the populations identified as high risk. Unfortunately historical distrust for the medical system has led to a lack of minority participation in clinical studies. It will therefore be imperative for research organizations to identify ways to gain the trust and participation from high risk populations so that they are involved in this critical drug discovery process. Perhaps, a solution to this may be collaborations between pharma and culturally specific groups, agencies, and/or organizations. These alliances may prove advantageous while developing NAFLD/NASH drugs and treatments as, these relationships foster partnerships and trust.
SHJ is an employee of Celerion Inc.
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