NAFLD in Lean Asians

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Abbreviations

BMI

body mass index

FXR

farnesoid X receptor

¹H‐MRS

proton magnetic resonance spectroscopy

NAFLD

nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) affects about 20% to 30% of the global population and increases the risk for hepatic and extrahepatic complications, including cardiovascular disease, diabetes, and some types of cancer.1 Although NAFLD is strongly associated with obesity, not all obese subjects will experience development of disease; conversely, a significant proportion of patients will have a normal body mass index (BMI) and are commonly referred to as having “lean NAFLD,” or NAFLD in a lean person.

Definition

Lean NAFLD is defined as disease that develops in subjects with a normal BMI based on ethnic‐specific cutoffs of 25 kg/m² in Caucasian patients and 23 kg/m² in Asian patients. A limitation of this definition is that it relies solely on BMI, an imperfect index of body fat topography, and fails to identify body fatness in nearly half of adults. Notably, visceral adiposity is more strongly implicated in the predisposition to NAFLD development irrespective of BMI. Similarly, there is a lack of incorporation of concepts surrounding metabolic health in the current definition, with nearly a third of lean individuals likely being metabolically unhealthy (Fig. 1).

Figure 1.

Relationship between BMI and metabolic health status. Subjects who are obese by BMI criteria can be metabolically healthy, whereas a proportion of those who have a normal BMI are metabolically unhealthy. The term metabolic health refers to the metabolic health status of an individual and is a composite of a number of metabolic indicators. A metabolically healthy individual has a low risk for impending cardiometabolic disease. Metabolic health is related to, but not the same as, the absence of metabolic syndrome. Currently there are different subsets of variables that define metabolic health, with no universal consensus.15

Prevalence

Lean NAFLD prevalence rates range from 5% to 26%, but 5% to 45% in Asians and 5% to 20% in European populations1 (Fig. 2). In China, of 6905 subjects with a BMI < 25 kg/m², 7.27% had ultrasonographic evidence of hepatic steatosis, whereas in another study of 2000 Chinese subjects with BMI < 24 kg/m², 18% had NAFLD. In Hong Kong, the prevalence rate of NAFLD based on proton magnetic resonance spectroscopy (¹H‐MRS) spectroscopy was 19% in subjects with a BMI < 25 kg/m². Other countries in Asia demonstrate a similar prevalence of BMI‐based lean NAFLD (Japan: 15.2% in 3271 nonobese subjects; India [urban West Bengal]: 5% in those with BMI < 25 kg/m² based on ultrasonography and subsequent computed tomographic validation; Korea: 12.6% in 29,994 health check nonobese participants). In western populations, the Dallas Heart Study revealed a prevalence rate of hepatic steatosis by ¹H‐MRS that ranged from 11% in African Americans to 20% in Caucasians and 26% in Hispanics with a BMI < 30 kg/m². Similarly, a large study including subjects from Australia and Italy suggested that the prevalence rate of NAFLD was 20% in those of Caucasian descent with a BMI < 25 kg/m².2 Data on the true population prevalence and ethnicity‐based variations in lean NAFLD prevalence are still limited.

Figure 2.

Prevalence of NAFLD in lean patients in the published literature. In these studies, BMI <25 kg/m² was used as a cutoff for definition of leanness in most of the studies.

Clinical and Histological Characteristics and Outcome of Lean NAFLD

By definition, patients with lean NAFLD have a lower BMI, but they also have a lower waist circumference and a more favorable metabolic profile with lower levels of dyslipidemia, diabetes, hypertension, glycemia, and homeostasis model assessment insulin resistance index compared with their obese counterparts. In cross‐sectional studies, lean patients also have less hepatic inflammation and fibrosis. Despite the favorable phenotype, however,2, 3 lean patients with NAFLD may have a worse outcome and accelerated disease progression,4, 5 although one study in Chinese patients with shorter follow‐up (4 years) suggested that nonobese patients may have a better prognosis, although this was not significant.3 As would be expected from the underlying metabolic abnormalities, lean NAFLD is associated with an increased risk for incident diabetes and cardiovascular disease compared with those without NAFLD.6

Pathophysiology

The pathophysiological pathways underlying the development and progression of NAFLD in lean subjects are not entirely clear. However, emerging evidence indicates that lean NAFLD is a distinct entity shaped by the dynamic interaction of genetic predisposition, metabolic dysregulation, the gut microbiota, and the enterohepatic circulation. Comparing lean and nonlean patients with NAFLD, the prevalence of the PNPLA3 (G) allele was reported to be higher in lean individuals in some but not all reports.7, 8 An increased prevalence of the TM6SF2 (T)² and IFNL3/IFNL4 (C) allele among lean patients has also been demonstrated.9, 10

Lean patients with NAFLD tend to have a distinct metabolic and gut microbiota profile with higher concentrations of lysine that is implicated in visceral fat accumulation.7 In another study, patients were reported to have increased bile acids and farnesoid X receptor (FXR) activity (measured by fibroblast growth factors 15/19), implying that they have better metabolic adaptation and are perhaps relatively obese resistant. Notably, this adaptation attenuates with progression of disease2 (Fig. 3). Intriguingly, pilot data suggest that patients with lean NAFLD may have a distinct gut microbiota profile with enrichment of species implicated in the generation of liver fat.2

Figure 3.

Metabolic adaptation in patients with NAFLD. Conceptually, the evolution of NAFLD in lean patients can be divided into three stages: (1) subjects at high risk for NAFLD have increased susceptibility likely from genetic factors, the fetal microenvironment, dietary intake including its composition, changes in the epigenetic code during the intrauterine period and early life, as well as changes in gut microbiota; (2) in lean patients with NAFLD, there is a phase of adaptation through increasing bile acids, FXR activity, and potentially other mechanisms; and (3) with advancement of disease, individuals with lean NAFLD have a failure of metabolic adaptation brought about by the interaction of various and complex systemic processes.

Approach to Management

No specific guidelines exist for the management of lean as opposed to nonlean NAFLD. The current recommendations of the American Association for the Study of Liver Disease and the European Association for the Study of the Liver are weight loss alone or accompanied by increased physical activity for all patients with NAFLD. Although weight loss might intuitively appear to be less beneficial in lean patients, there are demonstrable effects of lifestyle intervention even in this subgroup.11 High fructose and cholesterol intake has been reported in patients with lean NAFLD, and it would seem appropriate to recommend reducing intake of these nutrients, while encouraging adoption of a Mediterranean‐type diet. The latter also has beneficial effects on cardiovascular disease and visceral fat accumulation.12 Similarly, emerging evidence indicates that exercise can reduce liver fat independent of weight loss.13

Lean patients with NAFLD are underrepresented in ongoing clinical trials; thus, the impact of current investigational agents on lean disease is unclear. Of interest, inhibition of ileal bile acid uptake led to resolution of steatohepatitis in a mouse model, ² whereas liraglutide, a glucagon‐like peptide‐1 analogue, improved liver histology in lean patients.14

Conclusion

A significant proportion of patients with NAFLD are lean; however, this entity remains poorly characterized and understood. Although these patients demonstrate distinct pathophysiological mechanisms culminating in similar liver histology to obese patients, individuals with lean NAFLD remain at risk for development of hepatic and extrahepatic complications. Targeted studies are required to further clarify lean NAFLD pathogenesis and to develop appropriate management approaches.