The large NASH CRN cohort of patients with well-characterized, biopsy-proven disease allowed for a detailed analysis of the associations of ethnicity and race with clinical and histological features of NAFLD. We found that, among individuals with NASH histology, Latinos were younger, consumed more carbohydrate calories and engaged in less physical activity, compared to Non-Latino Whites. Additionally, Latinos with NASH had lower income and lower prevalence of hypertension compared to Non-Latino Whites, which may be a reflection of similar ethnic trends in the general U.S. adult population with respect to these two characteristics.(21
) With respect to specific histological features seen on liver biopsy between Latinos and Non-Latino Whites with NAFLD, Latinos had significantly greater inflammation, but significantly less advanced fibrosis. Although it is conceivable that Latino individuals may have less risk for fibrosis as an ethnic group, it is likely that the lower frequency of advanced fibrosis may be explained, at least in part, by the overall younger age of the Latino population in this study. A notable finding of this study is the differential effect of HOMA-IR on risk of NASH (versus Non-NASH histology), such that HOMA-IR conferred an increased risk of NASH in Non-Latino Whites, but not in Latinos. We did not find differential effect of HOMA-IR on the risk of advanced fibrosis.
Several studies have described racial and ethnic variations in NAFLD, primarily with respect to differences in frequency of the disorder, with consistent reporting of increased frequency in Latino populations and decreased frequency among African Americans.(3
) Although the NASH CRN was not designed to be a population-based study, within our group of study participants with NAFLD we found an increased frequency of NASH histology among Latinos (63%) compared to Non-Latino Blacks (52%), which is in keeping with previously published trends.
Although many studies of racial and ethnic variation in NAFLD have focused primarily on the prevalence (or frequency) of the disorder, a few studies have delved further into metabolic associations of NAFLD in different racial and ethnic groups. A recently published study by Lomonaco et al. compared Hispanic and Caucasian individuals with biopsy-proven NASH with respect to several metabolic features, including measures of adipose and hepatic insulin resistance. The investigators found no significant difference between Hispanic and Caucasian individuals with respect to NASH severity, but their data suggested that in Hispanic diabetic patients there may be a trend towards increased risk for fibrosis progression, warranting further investigation.(24
) In two separate investigations from the population-based Dallas Heart Study, Browning et al. and Guerrero et al., investigated the well-described dissociation between NAFLD and stereotypical metabolic risk factors, such as insulin resistance and obesity, among different racial and ethnic groups.(3
) Using magnetic resonance spectroscopy (MRS) to detect hepatic steatosis in a multi-ethnic population-based sample, Browning et al. reported the highest prevalence of hepatic steatosis among Latinos (45%) and lowest prevalence of steatosis among African Americans (24%), with Whites having an intermediate prevalence of 33%. They also speculated that the increased prevalence of hepatic steatosis among Latinos might be attributable to the high prevalence of obesity and insulin resistance in this ethnic group. However, similar rationale did not apply to the African American population, given that the prevalence of obesity and insulin resistance are actually highest in this segment of the U.S. population.(25
) The authors reasonably speculated that the racial and ethnic differences they described in the prevalence of hepatic steatosis were likely a reflection of differences in metabolic responses to obesity and insulin resistance occurring among racial and ethnic groups. Further data supporting the hypothesis that there may be differences in metabolic responses related to NAFLD in different racial and ethnic groups was provided by Guerrero et al. in another investigation from the Dallas Heart Study. They demonstrated that, although intraperitoneal adipose content was linked to the degree of hepatic steatosis regardless of race or ethnicity, there was a difference in the metabolic response in African Americans to the presence of obesity and insulin resistance, such that African Americans appeared to be more resistant to the development of hepatic steatosis and abdominal adiposity, despite having insulin resistance and obesity.(9
) Similar to the dissociations between metabolic risk factors and NAFLD that were described in African Americans in the Dallas Heart Study using MRS assessment of hepatic steatosis, we report a differential association between HOMA-IR and the risk of NASH histology among Latinos and Non-Latino Whites, with HOMA-IR being a significant risk factor for NASH among Non-Latino Whites, but not among Latinos. This differential effect of HOMA-IR is intriguing and warrants confirmation in larger studies and further investigation.
Our data suggest that pathogenic differences may exist between Latinos and Non-Latino Whites with respect to the development of NASH. Indeed, this hypothesis is supported by recent data demonstrating a significant association between hepatic steatosis detected with MRS and the PNPLA3 polymorphism (rs738409), an association that was most pronounced among Latinos in the study.(10
) The authors found that individuals who were heterozygous for the PNPLA3 polymorphism had higher hepatic triglyceride levels compared to individuals with the wild-type, and that individuals who possessed two copies of the variant allele had a multiplicative effect with respect to hepatic triglycerides. Additional investigations of PNPLA3 suggest that it may play a role, in association with other stressors, in hepatic inflammation and cirrhosis.(26
The limitations of our study should also be acknowledged. As the NASH CRN was not designed to be a population-based study, we cannot draw strong conclusions regarding the frequency of NAFLD histological sub-types (i.e., NASH versus Non-NASH) with respect to race and ethnicity. The participant population consists of consenting individuals with a potential self-selection that is inherent to many large-scale, prospectively enrolled studies. Additionally, it should be noted that the NASH CRN also included a clinical trial (PIVENS), which specifically selected for patients with NASH histology.(14
) Despite this, the demographics of our participant population and frequency of metabolic risk factors within the population were entirely consistent with the characteristics of patient populations that have been described in other studies of NAFLD. Additionally, the current study was designed to assess risk factors for NASH histology compared to Non-NASH histology rather than compared to normal liver histology, as the NASH CRN does not currently include a population of individuals without NAFLD. Finally, although the NASH CRN is the largest cohort of NAFLD patients that has been assembled to date with rigorous collection of extensive clinical, laboratory and histological data, we were limited in our ability to reliably assess risk factors for histological severity among other racial groups due to small numbers of individuals self-reporting as African American and Asian.
In summary, the findings of the present study demonstrate differences in metabolic and socio-demographic factors associated with NASH histology between Latino and Non-Latino White adults. HOMA-IR, as a marker of insulin resistance, was not a significant risk factor for NASH among Latinos, but was a significant risk factor among Non-Latino Whites. These findings suggest that there may be pathophysiological variation between the two ethnic groups with respect to the development of NASH and additional investigations are warranted to define this further.