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Nonalcoholic Fatty Liver Disease in Lean/Nonobese and Obese Individuals: A Comprehensive Review on Prevalence, Pathogenesis, Clinical Outcomes, and Treatment

  • Ankoor H. Patel1,2 ,
  • Dhiraj Peddu1,2,
  • Sahil Amin1,2,
  • Mohamed I. Elsaid3,4 ,
  • Carlos D. Minacapelli1,2 ,
  • Toni-Marie Chandler1,2,
  • Carolyn Catalano1,2 and
  • Vinod K. Rustgi1,2,* 
Journal of Clinical and Translational Hepatology   2023;11(2):502-515

doi: 10.14218/JCTH.2022.00204

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Revised:

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Published online:

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Citation: Patel AH, Peddu D, Amin S, Elsaid MI, Minacapelli CD, Chandler TM, et al. Nonalcoholic Fatty Liver Disease in Lean/Nonobese and Obese Individuals: A Comprehensive Review on Prevalence, Pathogenesis, Clinical Outcomes, and Treatment. J Clin Transl Hepatol. 2023;11(2):502-515. doi: 10.14218/JCTH.2022.00204.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with an estimated prevalence of 25% globally. NAFLD is closely associated with metabolic syndrome, which are both becoming increasingly more common with increasing rates of insulin resistance, dyslipidemia, and hypertension. Although NAFLD is strongly associated with obesity, lean or nonobese NAFLD is a relatively new phenotype and occurs in patients without increased waist circumference and with or without visceral fat. Currently, there is limited literature comparing and illustrating the differences between lean/nonobese and obese NAFLD patients with regard to risk factors, pathophysiology, and clinical outcomes. In this review, we aim to define and further delineate different phenotypes of NAFLD and present a comprehensive review on the prevalence, incidence, risk factors, genetic predisposition, and pathophysiology. Furthermore, we discuss and compare the clinical outcomes, such as insulin resistance, dyslipidemia, hypertension, coronary artery disease, mortality, and progression to nonalcoholic steatohepatitis, among lean/nonobese and obese NAFLD patients. Finally, we summarize the most up to date current management of NAFLD, including lifestyle interventions, pharmacologic therapies, and surgical options.

Keywords

NAFLD, Lean or nonobese nonalcoholic fatty liver disease, Obese nonalcoholic fatty liver disease, Clinical outcomes, Treatment, Incidence, Prevalence, Risk factors

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with an estimated prevalence of 25% globally.1,2 NAFLD encompasses a disease spectrum that ranges in severity from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis.2,3 While NAFLD is usually asymptomatic, an estimated 25% of NASH patients may develop cirrhosis, and 10% will develop decompensated liver disease.3,4 Patients with NAFLD do not typically require medical therapy and should, instead, pursue lifestyle modifications; however, NASH, especially NASH-fibrosis, are targets for liver-directed medical therapy and innovative interventions, such as clinical trials.5,6 Although liver-related death is currently the third leading cause of death in NAFLD patients,7–9 NASH related fibrosis is the most rapidly rising cause of liver transplantation and is projected to be the leading cause in the coming years.10 Furthermore, fibrosis in NAFLD/NASH is expected to become the leading risk factor for liver-related mortality.10

NAFLD is the hepatic manifestation of MetS due to its association with obesity-induced insulin resistance, dyslipidemia, and hypertension.11,12 Although NAFLD is strongly associated with obesity, NAFLD occurs in clinically obese and nonobese (lean) patients.13,14 Lean/nonobese NAFLD patients can be further subdivided into two categories, (1) overweight with or without excess visceral fat or normal weight with excess visceral fat and (2) lean with no excess visceral fat mass.13 Risk factors for lean/nonobese NAFLD include central obesity, physical inactivity, weight gain, genetic predisposition, high fructose intake, protein malnutrition, and steatogenic drug usage (amiodarone, tamoxifen, methotrexate, prednisolone).11,14 A Mediterranean diet has been demonstrated to help alleviate hepatic insulin sensitivity and reduce hepatic fat accumulation, while a diet consisting of high fructose and saturated fats is correlated with NAFLD development and progression.15,16

The definition of lean/nonobese NAFLD and body mass index (BMI) categorization are not standardized globally and have made literature interpretation difficult. Studies have shown that Asians have a higher proportion of body fat and elevated type 2 diabetes mellitus (T2DM), hyperlipidemia, and hypertension prevalence at a lower BMI than Europeans.17,18 An estimated 8–19% of Asians with a body mass index <25 kg/m2 have NAFLD.18 As a result, definitions of overweight and obesity are generally more stringent than those in Western populations. Asian NAFLD patients with BMI <23 kg/m2 and <25 kg/m2 for non-Asians are considered lean/nonobese NAFLD patients. The BMI cutoffs for nonobese NAFLD are <25 kg/m2 for Asian populations, and <30 kg/m2 for non-Asian populations.17,19,20 There is currently limited literature comparing outcomes in lean/nonobese NAFLD and obese NAFLD patients. To address this knowledge gap, we aimed to conduct a comprehensive review to explore the differences between the subgroups of NAFLD patients.

Clinical definition

NAFLD is defined as the presence of hepatic steatosis, by imaging or histology, in the absence of a secondary cause such as hepatic viral infection(s), drug-induced hepatotoxicity, excessive alcohol consumption, or hereditary disorders.11,21,22 NAFLD encompasses a spectrum of histological states ranging in severity from simple intrahepatic fat accumulations, nonalcoholic fatty liver (NAFL), to necrotic inflammation in the presence of ballooned hepatocytes, NASH. NAFL is defined as steatosis in greater than five percent of hepatocytes without additional hepatocellular damage (i.e. ballooning of hepatocytes or cirrhosis).11,22,23 NASH encompasses more advanced hepatic damage steatosis in greater than five percent of hepatocytes, inflammation, and hepatocyte injury with or without fibrosis. Patients with NASH can further develop NASH-cirrhosis, which is recognized by the presence of regenerative nodules enclosed by fibrous bands that results in portal hypertension and end-stage liver disease.24

Epidemiology

Disease prevalence

The prevalence of NAFLD has shown an upward trend over the past few decades. In a systematic review, the global prevalence of lean and nonobese NAFLD among the general population was 5.1% and 12.1%, respectively.25 The prevalence of NAFLD among the lean patients was 10.6% and 18.3% in nonobese individuals, both lower than the 25% prevalence estimate in the general population.25 The variability in prevalence rates between studies may be attributed to several factors, including patient selection, diagnostic criteria, BMI cutoff values, and lifestyle differences in the investigated population.

Studies have also shown regional differences in NAFLD prevalence. Those differences might be attributed to industrialization, lifestyle, diet, and genetic predisposition.26–28 In a systematic review and meta-analysis by Lu et al.,29 the prevalence of lean NAFLD was highest in Asia (4.8%), followed by Oceania (3.5%), North America (3.1%), and the lowest in Europe (2.2%). In an estimate of prevalence by country, the USA had the lowest prevalence of lean NAFLD (3.1%), whereas China had the highest prevalence (5.5%).

In a study conducted in the US using data from the National Health and Nutrition Examination Survey III (NHANES III), 18.8% had NAFLD and 3.7% had lean NAFLD. The overall prevalence of NAFLD in lean subjects was 9.67%.30 In a more recent study from the USA, 29.7% and 13.6% of NAFLD subjects were nonobese and lean, respectively.31 The overall NAFLD prevalence in Korea is estimated to be 20.1%, with NAFLD prevalence ranging from 12.6 to 27.4% in nonobese individuals.32,33 Furthermore, the prevalence of lean NAFLD in Korea is estimated to be 11%.34 In a study of 1,779 Chinese individuals with a BMI <24 kg/m2, 7.5% of individuals had ultrasound-detected liver steatosis.35 Additionally, in a Chinese population study, NAFLD prevalence was 7.3% in nonobese subjects.36 In a study from Hong Kong, the prevalence of NAFLD detected via proton-MRI spectroscopy was 14.8% in nonobese individuals.37 A study from Japan showed the prevalence of nonobese NAFLD to be 12.6%.38 In a study from rural India, the overall prevalence of NAFLD and prevalence among lean (BMI <23 kg/m2) patients was 8.7% and 5.1%, respectively. In a study from northern Italy, the prevalence of NAFLD in a lean, non-drinking population was 16.4%. The variability in the data suggests that further studies with standardized criteria and accurate diagnostic tools are needed to provide a more accurate prevalence of lean NAFLD/NASH worldwide.

Disease incidence

Limited data on NAFLD incidence have been reported in the literature.11,39–41 A 5 year follow-up study found the NAFLD incidence on ultrasound to be 12%.11 Another study conducted in Israel reported a NAFLD incidence rate of 28 per 1,000 person-years.11,41 A Japanese study of 11,500 adults reported a 5 year cumulative NAFLD incidence of 10%.42 A study conducted in England estimated the incidence rate of NAFLD to be 29 per 1,000 person-years. The pooled regional NAFLD incidence rate was quantified to be 52.3 per 1,000 person-years (95% CI: 28.3–96.8) and 28.00 per 1,000 person-years (95% CI: 19.3–40.6) in Asia and Western countries, respectively.11,41 In a meta-analysis of five studies, the NAFLD incidence in lean patients was (23.2 [95% CI: 7.3–48.0] per 1,000 person-years.25 Similarly, the study found NAFLD incidence in nonobese individuals to be 24·6 (95% CI: 13.4–39.2) per 1,000 person-years. In contrast, NAFLD incidence in the obese population was 77.5 (95% CI: 28.3–150.6) per 1,000 person-years.

Diagnostic procedures in NAFLD

The diagnostic workup of NAFLD combines both invasive and noninvasive procedures. Liver biopsy is the gold standard for prognostication and diagnosis, confirming the pattern of injury, distribution and grade of steatosis, and fibrosis stage. However, this procedure is limited by its invasiveness and intra- and interobserver variability in pathological interpretations. With the rising global incidence of NAFLD, routine liver biopsy is not a feasible first-line tool in diagnosing and staging NAFLD. As a result, noninvasive diagnostic tools such as serum biomarkers/panels, elastography-based tests, and MRI-based imaging have been commonly used to detect NAFLD.43

Clinical prediction rules such as fibrosis-4 (FIB-4) and fatty liver index (FLI) provide viable information for risk stratification. FIB-4 is a noninvasive scoring estimate of liver scarring using age, aspartate transaminase (AST), alanine transaminase (ALT), and platelet count that is well validated, but is more useful in excluding fibrosis than identifying it.44 The FLI uses BMI, waist circumference, gamma-glutamyl transferase (GGT), and triglyceride in its scoring estimate and has been well validated in the lean NAFLD population, with Hsu et al.45 identifying FLI ≥15 as a cutoff for screening for lean NAFLD.44,45 Serum biomarkers and blood-based panels, including NAFLD liver fat score and the SteatoTest, are noninvasive diagnostic tools used to predict and identify presence of hepatic steatosis. NAFLD liver fat score uses presence of MetS, T2DM, insulin level, AST, and ALT/AST ratio. Although it has been shown to adequately identify hepatic steatosis with an area under the curve of 0.87, the use of insulin level, which is not routinely measured, limits its use.46 SteatoTest is a panel which combines six FibroTest elements (α2-macroglobulin, haptoglobin, apolipoprotein A1, GGT, total bilirubin and ALT) as well as BMI, TGs, cholesterol, and serum glucose. It is adjusted for sex and age, has shown to have good accuracy in predicting hepatic steatosis confirmed by hepatic biopsy (area under the curve =0.80).47 However, the test is expensive and unable to determine the degree of steatosis. Other serum biomarkers (e.g., proteomics, metabolomics, lipidomics) are currently being investigated to elucidate specific molecules that may be useful in predicting NAFLD.

Noninvasive diagnostics further include abdominal ultrasound (US), elastography-based tests such as vibration-controlled transient elastography (TE), or magnetic resonance-based imaging (MRI). According to a meta-analysis comparing ultrasound findings to histopathologic findings, abdominal ultrasound had a sensitivity of 85% and a specificity of 94% for moderate to severe fatty liver diagnosis.48 However, pitfalls of ultrasound include dependence on the ultrasound technician and decreased accuracy in patients with morbid obesity or hepatic steatosis of less than 20%.48

TE is a more sensitive method than ultrasound alone for detecting liver steatosis with low-fat content. The controlled attenuation parameter (CAP) measurement by TE allows for the quantification of liver fat via evaluation of ultrasound attenuation in the liver. As a result, this method is more sensitive than ultrasound alone and can detect histopathological grade 1 steatosis (5–33% fat content in the liver) with a sensitivity of 69% and a specificity of 82%.48 MRI-based diagnostic tools for quantifying liver steatosis include MRI Elastography (MRE), MRI proton density fat fraction (MRI-PDFF), and proton magnetic spectroscopy (MRS). MRE has been shown to demonstrate a higher diagnostic accuracy compared to TE for the detection of individual stages of fibrosis.49,50 However, other studies have found MRE to be superior to TE in specific degrees of fibrosis.51,52 Therefore, these modalities need further statistical validation and are less commonly used due to expensive equipment.48

Pathophysiology

In previous years, the prevailing dogma regarding NAFLD pathogenesis revolved around a two hit hypothesis in which insulin resistance (IR) serves as the first hit by inducing lipid accumulation in hepatocytes and thereby increasing the vulnerability of the liver to a second hit that can cause hepatic injury, inflammation, and fibrosis.53,54 Recent evidence suggests that NAFLD is a multifactorial disease resulting from a complex interaction of multiple risk factors such as insulin resistance, fat distribution/metabolic dysfunction, gut microbiota dysbiosis, dietary factors, physical inactivity, sarcopenia, and genetic predisposition (Fig. 1).55,56 While lean NAFLD shares several pathophysiological mechanisms with obese NAFLD, multiple studies have proposed unique roles of the aforementioned risk factors in lean NAFLD pathogenesis.57,58

Schematic representation of the pathogenesis of NAFLD and progression from NAFLD to NASH, cirrhosis, and HCC.
Fig. 1  Schematic representation of the pathogenesis of NAFLD and progression from NAFLD to NASH, cirrhosis, and HCC.

NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; HCC, Hepatocellular carcinoma.

IR

IR plays a major role in the development of obese NAFLD, but recent evidence shows that it also plays a major role in developing lean NAFLD.59–61 Studies in lean individuals highlighted that IR is more commonly observed in NAFLD patients than in healthy subjects and revealed that higher intrahepatic triglyceride content is associated with increased IR in skeletal muscles, hepatocytes, and adipose tissue regardless of BMI.57,59–61 IR contributes to hepatic steatosis by accumulating excess free fatty acids (FFAs) in the liver via enhanced de novo lipogenesis, decreased oxidation, and increased uptake.61–63 Studies have shown that a significant proportion of lean NAFLD patients have insulin resistance in the absence of other metabolic risk factors.59,61 However, other studies have revealed a far lower degree of insulin resistance in the lean NAFLD population.30,64 The discordance between the presence or absence of insulin resistance in this population may be explained by other factors, such as genetic predisposition, that may confer susceptibility to NAFLD without insulin resistance. Gastaldelli et al.65 showed severe insulin resistance in adipose tissue in patients with NASH independent of the degree of obesity. Additionally, another study found lean patients with NAFLD to have insulin resistance and dysfunctional adipose tissue.57 Further studies are warranted to better understand insulin resistance in this population and how the underlying mechanisms may be different compared to obese NAFLD patients.

Fat distribution and metabolic dysfunction

Abdominal fat distribution is a critical factor implicated in metabolic dysfunction. A higher visceral-to subcutaneous fat ratio is associated with an increased risk of NAFLD development and progression to fibrosis.56 The findings are supported by a recent biopsy-based study of 250 lean living liver donors that found that the severity of NAFLD was positively correlated with visceral fat accumulation.66 The specific inflammatory pathways implicated in lean NAFLD pathophysiology have yet to be elucidated, with multiple studies debating the role of key cytokines in the progression of the disease.57,67,68 Similar to obesity-related NAFLD, one study found that lean individuals with NAFLD present decreased adiponectin levels, an anti-inflammatory hormone with an insulin-sensitizing effect.57,69 Additionally, animal models provide preliminary evidence implicating interleukin 6 (IL6) overexpression in the pathogenesis of NAFLD regardless of weight.68 However, other studies have found that alterations in tumor necrosis factor alpha (TNF- α), IL6, and leptin levels are not significantly different between nonobese NAFLD subjects and healthy controls.57 Further research is needed to elucidate the true impacts of cytokines in lean NAFLD pathophysiology.

Gut microbiota dysbiosis

The gut microbiome and bile acids contribute significantly to metabolic homeostasis, and emerging evidence implicates the dysfunction of these entities in NAFLD pathogenesis. A change in the microbial environment marks gut microbial dysbiosis through an increase in pathogenic bacteria and a decrease in the number of beneficial bacteria.70 This dysbiosis is hypothesized to contribute to NAFLD through multiple mechanisms, including increased gut permeability, endotoxemia, endogenous ethanol production, increased energy harvest from food, and alterations in choline and bile acid metabolism, all resulting in liver inflammation and steatosis.70 Recent studies highlight that lean NAFLD subjects have a distinct gut microbiota profile from obese ones.56 In a study conducted in a Chinese population, lean NAFLD subjects demonstrated a reduced population of Firmicutes, including Lachnospiraceae, Ruminococcaceae, Lactobacillaceae, and an increase in lipopolysaccharide-producing Gram-negative bacteria.71 Chen et al.72 similarly reported a distinct microbiome profile in a Caucasian population of lean NAFLD patients who were found to have an increased population of Ruminococcaceae compared to obese NAFLD patients and an increased population of Dorea and decreased populations of Marvinbryantia and Christensellenaceae compared with healthy controls. Furthermore, compared to their non-lean counterparts, the lean NAFLD subjects included in this study displayed an obesity-resistant phenotype partially mediated by higher total bile acid and fibroblast growth factor 19 (FGF19) levels.72 Gut microbiome and bile acid alterations may predispose individuals to develop NAFLD at a lower BMI, and further research into microbiome modulation is required to better understand its role as both a potential biomarker and a therapeutic option in NAFLD patients.73

Dietary factors

High fructose and cholesterol diets play an essential role in developing NAFLD. In the body, fructose has both lipogenic and proinflammatory effects as fructose is rapidly phosphorylated inside cells, depleting intracellular ATP stores. High uric acid production induces mitochondrial oxidative stress triggering both lipogenesis and impaired fatty acid oxidation.74 Intake of fructose, primarily in soft drinks containing high fructose corn syrup, is strongly associated with NAFLD development and progression. A study found soft drink consumption to be significantly associated with hepatic steatosis independent of metabolic factors.75 Expanding further, a systematic review discovered a dose-dependent relationship between the amount of sugar-sweetened beverages per week and NAFLD, with a relative risk of 1.56 for seven cups per week and a relative risk of 1.10 for one cup per week.76 Fructose has a role in the development of lean/nonobese NAFLD. Nonobese NAFLD subjects have been found to consume higher amounts of added sugar, such as soft drinks and juices, compared to healthy controls.77 This connection is supported by a study on nonobese NAFLD cases with no underlying metabolic risk factors, which revealed that 80% of the NAFLD patient consume more than 50 g of added sugar per day versus 20% in the healthy control group.77

Consumption of a high-cholesterol diet may lead to NAFLD in lean subjects despite modest total caloric intake. Multiple studies found that cholesterol intake was significantly higher in nonobese NAFLD patients than in their obese NAFLD counterparts.78,79 cholesterol may promote apoptosis of hepatocytes and macrophages, formation of reactive oxygen species, and lipid peroxidation.80,81 Cholesterol metabolites, such as oxysterols, serve as endogenous ligands for the liver X receptor alpha (LXRa), which ultimately increases de novo lipogenesis and hepatic steatosis.82 Increased expression of LXRa has been found in patients with nonobese NAFLD, compared with obese patients.83,84

Physical inactivity

Physical inactivity or sedentary lifestyle is associated with both lean/nonobese and obese NAFLD. Physical exercise plays an important role in a variety of molecular pathways regulating metabolic homeostasis, such as AMP-activated protein kinase, glucose transporter 4. Some studies have pointed to specific genetic polymorphisms (e.g., PNPLA3 alleles) that are more likely to benefit from lifestyle modifications such as physical activity.85 Although physical inactivity or sedentary lifestyle is closely linked to sarcopenia, MetS, obesity, cardiovascular diseases, etc., which are all predispositions to NAFLD, increased physical activity has shown beneficial effects on NAFLD independent of weight loss.86 Another study showed an inverse relationship between physical activity and the prevalence of NAFLD in a dose-dependent manner, which was independent of visceral adiposity and insulin resistance.87 One study showed that prolonged sitting time, which is usually related with high caloric intake and unhealthy dietary practices, and decreased physical activity are independent risk factors for NAFLD.88 Further research is needed to assess the role of physical activity and sedentary lifestyles in NAFLD pathophysiology and the impact of their interplay with other closely associated risk factors.

Sarcopenia

Sarcopenia is marked by low skeletal muscle mass with reduced function and is thought to contribute to the pathogenesis of lean/nonobese NAFLD, with multiple studies identifying lower skeletal muscle mass in lean individuals with NAFLD as compared to patients with obesity.89,90 The relationship between NAFLD and sarcopenia is explained by crosstalk between the liver and muscle, where insulin resistance and sarcopenia have been found to create a vicious cycle that harms both organs. insulin resistance contributes to the loss of lean body mass by activating the ubiquitin-proteasome proteolytic pathway (UPP) in skeletal muscle. Initially, insulin resistance reduces the activity of PI3K, which then reduces the levels of phosphorylated Akt.58 The decreased level of phosphorylated Akt induces the expression of E3 ubiquitin-conjugating enzymes, activating the UPP and decreasing skeletal muscle mass.58 Because muscle has a primary role in insulin-mediated glucose disposal, the decrease in muscle mass causes reduced glucose uptake and metabolism.91

Sarcopenia is further propagated by chronic inflammation caused by abnormal cytokine production in NAFLD. Chronic exposure to IL-6 and C-reactive protein levels (CRP) leads to increased muscle catabolism and atrophy, and elevated levels of TNF-α induce ceramide accumulation that has been observed to contribute to muscle cell atrophy.92–94 In addition, visceral adipose tissue and sarcopenia act together in NAFLD pathogenesis, where NAFLD patients with a decreased muscle mass and increased visceral adipose tissue are found to have worsened steatosis and increased progression of liver fibrosis.95 Moreover, several studies have reported the association of sarcopenia with NAFLD pathogenesis and progression independent of obesity.96,97 A study from Korea investigating a large cohort of obese and nonobese subjects elucidated a strong inverse relationship between skeletal muscle index and NAFLD, where the prevalence of NAFLD in sarcopenic subjects was higher compared to non-sarcopenic subjects, irrespective of the presence of obesity or the MetS.97

Genetic predisposition

As discussed, genetic predisposition to nonobese NAFLD has been identified as a component of NAFLD development and progression. Several genes have been identified as known NAFLD variants. The rs738409 single nucleotide polymorphism in patanin-like phospholipase domain-containing protein 3 (PNPLA3) has been linked with NAFLD development and progression.57PNPLA3 encodes a protein expressed in both adipocytes and hepatocytes. The protein is found in the endoplasmic reticulum and surface of lipid. It has acyl hydrolase activity, which plays a role in the hydrolysis of major glycolipids, including mono, diacylglycerol, and triacylglycerol. Mutation in the rs738409 polymorphism, known as the G allele, has been shown to decrease the enzymatic activity, resulting in increased hepatic fat contents and increased hepatic inflammation and thus increasing the severity of NAFLD.60,98–100 A recent meta-analysis has shown that this polymorphism is more prevalent in nonobese and lean NAFLD patients than in both obese NAFLD and nonobese controls.101 Interestingly, the prevalence of the rs738409 [G] allele in PNPLA3 varies among ethnicities. Romeo et al.98 found that the rs738409 [G] allele frequency was directly associated with the prevalence of NAFLD in different ethnic groups. In a population of Hispanic, African American, and European American individuals, the G allele was most common in Hispanics, followed by European-Americans, and lowest among African Americans. Another allele of PNPLA3, or rs6006460 [T], was associated with lower hepatic fat content and was most common in African Americans, the group at lowest risk of NAFLD. Studies in the Asian population have shown a higher prevalence of the PNPLA3 risk allele than European and African subjects.102

Another gene variant identified is the rs58542926 encoding a Glu157Lys substitution in the transmembrane 6 superfamily 2 (TM6SF2) gene. The substitution has been shown to be associated with increased hepatic triglyceride content and NAFLD disease severity; however, the finding does not show as strong an association as the PNPLA3 mutation.103 Sterol regulatory element-binding factor 2 (SREBF-2) is another genetic marker that has been identified as a potential contributor to the pathogenesis of NAFLD. Studies have shown that the rs133291 polymorphism in the SREBF-2 gene impacts lipid and glucose metabolism, as the nuclear transcription factor is responsible for regulating genes involved in cholesterol metabolism.104 Studies by Musso et al.104,105 demonstrated that the SREBF-2 gene polymorphism might be used to predict the 7-year incidence of NAFLD in nonobese or non-diabetic patients without MetS. In their study, SREBF was able to predict the 7-year incidence of NAFLD in the former group, and it conferred an increased risk of NASH in the biopsy-proven NAFLD group. Although the SREBF-1c polymorphism is associated with impaired glucose and lipoprotein metabolism, further evidence is needed to elucidate this association to better understand how it may aid in NAFLD prognostication. Cholesteryl transfer protein, apolipoprotein C3, glucokinase regulatory gene (GCKR), and membrane-bound O-acyl transferase domain-containing 7 (MBOAT7) genes are additional genes identified in the literature that may lead to NAFLD predisposition.100,106

Clinical outcomes in lean vs. obese NAFLD/NASH

Regardless of lean or obese status, patients with NAFLD experience poor outcomes, metabolic irregularities, and liver disease progression. In this section, we have reviewed the literature and compared and contrasted NAFLD/NASH in lean/nonobese patients and patients with obesity (Figs. 2 and 3).

Comparison of clinical, laboratory, and histology in lean/nonobese NAFLD and obese NAFLD.
Fig. 2  Comparison of clinical, laboratory, and histology in lean/nonobese NAFLD and obese NAFLD.

NAFLD, nonalcoholic fatty liver disease; ALT, alanine transaminase; AST, aspartate transaminase; HDL, High-density lipoprotein.

Comparison of phenotypes and clinical outcomes between lean/nonobese and obese NAFLD.
Fig. 3  Comparison of phenotypes and clinical outcomes between lean/nonobese and obese NAFLD.

**Significant differences. NAFLD, nonalcoholic fatty liver disease.

MetS

NAFLD is strongly associated with metabolic syndrome (MetS) features, which represent at least three of the following conditions: elevated triglycerides, blood pressure, glucose, waist, or low high-density lipoprotein (HDL) cholesterol. MetS conditions confer a higher risk for cardiovascular disease, dyslipidemia, insulin resistance, and T2DM. A higher MetS severity score, which is a validated tool that combines and describes the extent of all 5 metabolic abnormalities, has shown to be linked to higher risk of mortality from all causes, heart disease, diabetes, and hypertension.107 A study in the US concluded that lean (BMI <25 kg/M2) NAFLD patients compared with lean, healthy subjects, had a higher prevalence of the following MetS conditions: IR, T2DM, hypercholesterolemia, and hypertension.30 Several studies have reported that lean subjects with NAFLD have a higher risk of T2DM, dyslipidemia, hypertension, and cardiovascular outcomes than obese subjects with NAFLD.108–113

A study from South Korea showed a higher prevalence of MetS conditions in nonobese (BMI <25 kg/m2) NAFLD patients compared with obese NAFLD patients after adjusting for confounders.33 Similarly, Lee et al.114 reported a higher prevalence of MetS components in nonobese (BMI <25 kg/m2) NAFLD patients than obese NAFLD patients. On the other hand, a study conducted on NAFLD patients in Italy showed that lean (BMI <25 kg/M2) NAFLD patients had a lower prevalence of hypertension, T2DM, and MetS compared to overweight (25 kg/m2≤BMI<30 kg/m2) and obese (BMI ≥30 kg/m2) NAFLD patients.115 Obese (BMI >25 kg/m2) patients with NAFLD had a higher prevalence of MetS than their nonobese counterparts in 2 studies conducted in China.116,117 Additionally, Akyuz et al.118 reported a lower prevalence of MetS in lean (BMI <25 kg/m2) NAFLD compared to overweight NAFLD patients in a prospective study in Turkey. Several studies have suggested that lean/nonobese NAFLD represents a metabolic phenotype somewhere in the spectrum between healthy individuals and NAFLD patients with obesity.119,120 We will attempt to further delineate and summarize the data by metabolic condition.

Dyslipidemia

Obese and lean/nonobese NAFLD patients often have dyslipidemia and other characteristics of MetS, which contributes to the high risk of mortality because of cardiovascular disease and further hepatic dysfunction in both populations. In both the lean/nonobese and overweight/obese populations, NAFLD was found to be associated with higher levels of triglycerides, low-density lipoprotein (LDL), and total cholesterol compared to their non-NAFLD controls.35 Li et al.121 showed that obese (BMI >25 kg/M2) patients had a higher prevalence of elevated serum triglyceride levels compared to nonobese with NAFLD in a Chinese population. Similarly, serum triglycerides were higher in obese (BMI >25 kg/m2) and overweight (BMI 25–29 kg/m2) NAFLD patients compared with lean patients in Japan and Spain.122,123 Shao et al.124 and Alam et al.125 reported lower serum total cholesterol and triglycerides in nonobese (BMI <25 kg/m2) patients compared to obese (BMI >25 kg/m2) patients with NAFLD. Several studies have shown that obese or overweight NAFLD is associated with lower serum high-density cholesterol (HDL-C) compared to lean NAFLD patients.57,123,125,126

IR

Although insulin resistance is associated with both lean/nonobese and obese NAFLD, the degree of glycemic abnormalities among the two populations differs. Fasting plasma glucose (FPG), insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) have been used to assess the degree of insulin resistance in patients with NAFLD. Li et al.121 reported a higher proportion of Chinese patients with elevated FPG in obese (BMI >25 kg/m2) compared with nonobese NAFLD patients. Similarly, Wang et al.127 showed a higher FPG in obese women (BMI >28 kg/m2) with NAFLD compared to nonobese/lean women with NAFLD in a study conducted in China. Shao et al.124 reported lower FPG in nonobese (BMI <25 kg/m2) Chinese NAFLD patients compared to obese NAFLD patients. Yoshitaka et al.126 reported lower FPG levels in lean (BMI <23 kg/m2) compared with overweight Japanese NAFLD patients. In studies conducted in Japan,122 Bangladesh,125 and Austria,57 obese (BMI >25 kg/m2) NAFLD patients had higher FPG, insulin, and HOMA-IR index compared with nonobese NAFLD patients. Nonobese/lean (BMI <23 kg/m2) NAFLD patients in India had lower serum insulin, HOMA-IR index, and prevalence of T2DM compared with obese (BMI >25 kg/m2) patients with NAFLD.64 In a study conducted in Spain, overweight (BMI: 25–29 kg/m2) NAFLD patients had a higher HOMA-IR compared with lean NAFLD patients.123 The aforementioned studies are in agreement with the cross-sectional NHANES III study in which lean (BMI <25 kg/m2) NAFLD patients had lower FPG and HOMA-IR and less frequently had T2DM compared with overweight/obese NAFLD patients.30

Cardiovascular disease

Hypertension

Hypertension is a common comorbidity in patients with NAFLD, regardless of lean or overweight/obese classification. The prevalence of hypertension is significantly higher in lean NAFLD patients than lean patients without NAFLD.30 The presence of NASH further increases the prevalence of hypertension.128 In a hospital-based study, Lee et al.114 reported that nonobese (BMI <25 kg/m2) NAFLD patients had a higher prevalence of MetS and hypertension compared to obese NAFLD. On the other hand, multiple studies conducted in Italy115 and China116,117 reported a lower prevalence of hypertension in lean/nonobese (BMI <25 kg/m2) compared with overweight or obese NAFLD patients. In a case-control study conducted in Sri Lanka99 and a study conducted in Japan,126 lean (BMI <23 kg/m2) NAFLD patients had a lower prevalence of hypertension compared to non-lean NAFLD patients. A meta-analysis of 45 studies reported a lower prevalence of hypertension in lean/nonobese NAFLD population as compared with non-lean/obese patients with NAFLD.26

Coronary artery disease

NAFLD is associated with cardiovascular disease, including hypertension, coronary artery disease, cardiomyopathy, cardiac arrhythmias, and patients are at increased risk of cardiovascular mortality. A meta-analysis of 16 observational studies including 24,043 patients with a median seven-year follow-up showed that patients with NAFLD had a 64% higher risk of developing fatal or non-fatal cardiovascular events compared with non-NAFLD patients.129 Yoshitaka et al.126 reported a higher risk (hazard ratio 10.4) of cardiovascular events in lean (BMI <23 kg/m2) NAFLD patients compared with lean non-NAFLD patients, independent of potential confounders. In an analysis of the NHANES III survey, lean NAFLD patients had a higher risk of cardiovascular-related mortality (hazard ratio 2.38) compared with lean non-NAFLD patients after adjusting for potential confounding variables.112 Patients with NAFLD are at an increased risk of developing atherosclerotic disease. A meta-analysis including 25,837 patients demonstrated a higher risk of clinical coronary artery disease compared with non-NAFLD patients.130 NASH was found to be an independent predictor of high-risk coronary plaques, which may explain the higher risk of coronary events in this population.131 In a retrospective study, lean NAFLD patients, reported higher atherosclerotic cardiovascular disease (ASCVD) scores (defined as ASCVD >10%), 51.6% compared with 39.8% in obese NAFLD and 25.5% in patients without NAFLD.66 On the other hand, Fracanzani et al.115 reported that lean NAFLD patients had significantly thinner carotid intima-media, which is indicative of a decreased atherosclerotic burden, compared to obese NAFLD. Data regarding cardiovascular mortality and atherosclerotic burden among lean/nonobese vs. obese NAFLD patients are scarce and more longitudinal data comparing the NAFLD cohorts are needed.

Risk of mortality

There is still a debate whether patients with NAFLD are at an increased risk of mortality compared to those without. A recent meta-analysis including 498,501 patients showed that patients with NAFLD had an elevated risk of all-cause mortality (hazard ratio 1.34) compared with patients without NAFLD.132 There are fewer studies that have studied the differences in mortality among obese/non-lean vs. nonobese/lean NAFLD patients. Compared with lean non-NAFLD patients, lean (BMI <25 kg/m2) NAFLD had a 50% increase in all-cause mortality (hazard ratio 1.54) after adjustment for potential confounding variables.112 A cohort study of 646 patients with biopsy-proven NAFLD showed patients with lean (BMI <25) had no increased risk of mortality compared with patients who were overweight (BMI 25.0–29.9 kg/m2) or obese (BMI >30 kg/m2).133 On the other hand, a meta-analysis conducted in the US showed lean/nonobese NAFLD individuals had a higher 15-year cumulative all-cause mortality (51.7%) compared with obese NAFLD (27.2%) and non-NAFLD (20.7%) patients.31 Another study in the US that included 483 patients with biopsy-confirmed NAFLD, reported a higher all-cause mortality in lean (BMI <25 kg/m2) compared to non-lean patients during a follow-up of 133 months. Another study reported a higher risk of mortality in lean (BMI <25 kg/m2) compared with obese NAFLD patients. Lean NAFLD was an independent risk factor (hazard ratio 11.8) for higher all-cause mortality after adjustment for potential confounders.134

Progression of NAFLD to NASH

NAFLD, which can initially present as simple steatosis, can progress to NASH, cirrhosis, and hepatocellular carcinoma (HCC). Several studies have reported outcomes regarding the degree of injury and fibrosis and the risk of developing NASH, cirrhosis, and HCC in NAFLD patients. One study from Bangladesh found no significant histologic difference between lean and obese NAFLD patients.125 Kumar et al.64 reported a lower NAFLD activity score in lean NAFLD patients compared to obese NAFLD. The proportion of patients with hepatic fibrosis was lower in the lean population than in the obese NAFLD population. However, the prevalence of NASH was statistically similar in lean (28%) and obese (38%) NAFLD patients. In a prospective cohort study from China involving 307 NAFLD patients, lean/nonobese (BMI <25 kg/m2) had a lower NAFLD activity score (3.3±1.3 vs. 3.8±1.2; p=0.019) and lower fibrosis stage (1.3±1.5 vs. 1.7±1.4; p=0.004). Interestingly, during 49 months of follow-up, death, HCC, and liver failure only occurred in the obese population.117 Studies from Japan,122 Belgium,135 and Turkey118 have shown lower histological severity in lean NAFLD patients compared with obese NAFLD patients. In a study with patients with a similar liver fat content as measured by 1H-MRS, lean NAFLD patients had a lower liver stiffness compared to obese NAFLD patients.37 In a retrospective cohort study including 646 biopsy-proven NAFLD patients in Sweden, lean (BMI <25 kg/m2) NAFLD patients had a lower fibrosis stage and lower prevalence of NASH but had a higher risk of cirrhosis, decompensated cirrhosis, and HCC compared to the overweight (25 kg/m2≤BMI<30 kg/m2) patients. Similar to the previous study, obese NAFLD had the highest mortality.133

In a meta-analysis including eight studies64,115,117–119,122,125,136 and 2,702 patients (493 lean NAFLD patients vs. 2,209 overweight/obese NAFLD patients), lean NAFLD patients had a significantly lower NAFLD activity score and fibrosis score compared with overweight/obese NAFLD patients.137 Interestingly, in a meta-analysis of five studies including 1,886 patients, lean NAFLD patients had significantly lower steatosis scores compared to overweight/obese NAFLD. Data from six studies (n=1,679 participants) reported a lower prevalence of NASH in lean NAFLD patients compared to their overweight/obese counterparts.137 On the other hand, a biopsy-based study of a Greek population showed that the prevalence of NASH and degree of inflammation and fibrosis were statistically similar between patients with normal and increased BMI.136 A biopsy-based study in Austria demonstrated a higher rate of NASH in lean patients compared with overweight but similar to obese NAFLD patients. The rate of cirrhosis was higher in lean patients compared to overweight and obese NAFLD patients. Weight loss due to cirrhosis may be present and may obscure whether lean NAFLD is a risk factor for cirrhosis.138 Further studies are warranted to elucidate the mechanism and pathways that lead to liver disease progression in both lean and obese NAFLD populations.

Treatment of lean/nonobese vs. obese NAFLD

Lifestyle modification

Weight loss

Lifestyle interventions, including exercise and dietary modifications, have been an important and effective component in the treatment of NAFLD and remain the first-line therapy for NAFLD. The American Association for the Study of Liver Disease (AASLD) reports that a 3–5% reduction in body weight via calorie restriction and, or increased physical activity could reduce NAFLD in patients with obesity.11 A prospective study showed that the degree of histological improvement was correlated with weight loss. A weight reduction of 3–5% effectively improved steatosis, while a decrease of 5–7% showed improvement in hepatic inflammation. Weight reductions of >7% and >10% showed improvement in histopathologic features of NASH including hepatic steatosis, ballooning, and lobular inflammation, and improvement in fibrosis and portal inflammation.139

Weight loss is effective in both lean and obese NAFLD populations. Studies from Korea140 and Turkey141 showed that a 5% reduction in body weight led to a significant decrease in steatosis in lean NAFLD patients. In a study involving 333 patients with NAFLD with a mean follow-up of 28.7 months, weight change was an independent predictor of disease progression or resolution. In the population who experienced disease progression, lean patients had a more significant weight gain compared to patients with obesity. However, in patients who experienced NAFLD resolution, lean patients showed a smaller degree of weight loss compared with obese NAFLD patients.142 Weight loss has shown to be effective in the improvement of NAFLD and NASH in lean and obese populations and is the foundation of treatment for patients with NAFLD regardless of BMI.

Dietary modification

Although several diets have been studied in patients with NAFLD/NASH, the Mediterranean diet has been the most studied, and adherence to the diet has shown a reduction in the risk and progression of NAFLD via antioxidant and anti-inflammatory mechanisms linked to the consumption of monounsaturated and omega-3-fatty acids, and phytosterols found in the diet.143,144 The Mediterranean diet consists of fresh vegetables, legumes, fruit, minimally processed whole grains, fish, and foods rich in omega-3-fatty acids, such as olive oil, nuts, and seeds. It includes minimal to low consumption of dairy and red or processed meats.145 The EASL-EASD-EASO clinical practice guidelines recommend the Mediterranean diet for NAFLD patients.146 In patients with NAFLD, the Mediterranean diet has been shown to reduce hepatic steatosis and insulin resistance without weight loss compared to a low-fat, high carbohydrate diet.147 Interestingly, an increase in the Mediterranean diet score, which is a measure of Mediterranean diet consumption, was shown to be associated with a reduction in liver fat accumulation and severity. Each standard deviation increase in the score reduced the odds for incident fatty liver by 26%.148

Other dietary changes, such as coffee consumption, sugar, and calorie-deficits, have been studied in patients with NAFLD/NASH. As mentioned previously, weight loss has been shown to improve hepatic steatosis and lead to a dose-dependent improvement of NAFLD in lean/nonobese and overweight/obese patients. A hypocaloric diet should be considered in patients with NAFLD to achieve the aforementioned results associated with a total body weight loss. NAFLD/NASH and certain MetS conditions, such as insulin resistance, are associated with an increased intake of fructose and high fructose corn syrup products.149 In patients with NAFLD, higher amounts of fructose intake via sugar-sweetened beverages are associated with increased hepatic fibrosis, inflammation, and hepatocellular ballooning.150 On the other hand, fructose found in fruits was not associated with NAFLD. Therefore, patients with NAFLD should restrict fructose intake via artificial sweeteners or high fructose corn syrup but do not need to limit fruit consumption. In several studies, coffee consumption has been shown to play a protective role in NAFLD.151,152 However, it requires further investigation in lean NAFLD patients.

Physical activity

As mentioned previously, weight loss is linked to NAFLD improvement and remission. Physical activity likely accentuates the therapeutic benefits of weight loss. Still, it has been shown to improve NAFLD independently of weight loss via a reduction in hepatic steatosis, insulin resistance, hepatic lipogenesis, adipocyte lipolysis, and fatty acid delivery to the liver.153 The EASL–EASD–EASO guidelines recommend 150 to 200 min/week of moderate-intensity aerobic exercise in three to five sessions.146 The AGA recommends a goal of 150 to 300 min of moderate-intensity or 75 to 150 min of vigorous-intensity aerobic exercise per week with resistance training as a complement to the aerobic exercises.154 Li et al.86 found that the benefits of physical activity were dose-dependent and that moderate and vigorous levels of intensity in physical activity had beneficial effects on NAFLD, regardless of energy intake and sedentary time. A meta-analysis reported both resistance and aerobic exercise was able to show a reduction in hepatic steatosis in NAFLD patients with a similar period of exercise, duration, and frequency.155 These results suggest that patients in poor cardiorespiratory shape or those unable to tolerate or participate in aerobic exercises should opt for resistance exercises, especially if it will lead to continued adherence.

Surgical intervention

Bariatric surgery is an effective method for weight loss. Research behind its therapeutic benefits in NAFLD/NASH is limited to the obese population. Bariatric surgery is currently recommended in patients with a BMI ≥40 kg/m2 and no comorbidities or a BMI of 35–39.9 kg/m2 with comorbidities such as diabetes, hypertension, or NAFLD/NASH.156 It has been shown to improve obesity-related diseases such as T2DM, dyslipidemia, obstructive sleep apnea, hypertension, and reduce the risk of cardiovascular diseases. Interestingly, bariatric surgery in NAFLD patients with severe obesity was associated with a significant reduction in the risks of any cancer and obesity-related cancers.157

Roux-en-Y gastric bypass (RYGB) and laparoscopic gastrectomy (LSG) are most commonly performed among the available surgical methods. In a meta-analysis including 15 studies with 766 paired liver biopsies, the pooled proportion of patients with improvement or resolution in steatosis was 91.6% [95% confidence interval (CI), 82.4–97.6%)], in steatohepatitis was 81.3% (95% CI, 61.9–94.9%), in fibrosis was 65.5% (95% CI, 38.2–88.1%), and for complete resolution of nonalcoholic steatohepatitis was 69.5 (95% CI, 42.4–90.8%) after undergoing bariatric surgery.158 In a review of 12 studies including 496 patients with paired liver biopsies who underwent RYGB or LSG, the average NASH resolution rate was 87.4% (LRYGB: 91.9%, LSG: 80%) in a mean follow-up period of 14.5 months. Furthermore, both surgical techniques led to significant improvement or resolution of liver fibrosis.159 Lassaily et al.160 reported resolution of NAFLD/NASH in most patients and significant regression of liver fibrosis. Cazzo et al.161 reported a significant reduction in mean NAFLD fibrosis score and a resolution rate of 55% of severe fibrosis in a 12 month observation in patients who underwent RYGB. Several studies have shown significant improvement in NAFLD activity score, steatosis, inflammation, and liver ballooning in a 1-year observation period following RYGB.162,163 In patients with morbid obesity who had undergone LSG, Cabre et al.164 showed that patients’ histology and liver function significantly improved via mechanisms that reduced oxidative stress and inflammation. In a study from Egypt that included 81 patients who underwent LSG, a significant reduction in steatosis, liver fibrosis, lobular inflammation, and hepatocyte ballooning was observed in the postoperative biopsies (p<0.001 each). An 18-month observation showed significant improvement in postoperative liver function tests (AST, ALT, GGTP).165 In a Swedish study, bariatric surgery was associated with lower serum AST and ALT at 2- and 10-year follow-up with a reduction in ALT levels proportional to the degree of weight loss.166

Endoscopic bariatric and metabolic treatment (EBMT), such as intragastric balloon and endoscopic sleeve gastroplasty, is safer and less invasive compared to bariatric surgery. In a meta-analysis including 18 studies and 863 patients, EBMT was shown to significantly reduce liver fibrosis, hepatic steatosis, and histologic NAFLD activity score. EBMT was shown to significantly improve other metabolic parameters, including insulin resistance, waist circumference, and weight reduction.167 Although results are promising, further studies are warranted.

Pharmacologic intervention

Although lifestyle modifications are effective and should be considered the first line in managing patients with NAFLD/NASH, pharmacological treatments should be considered. Several factors may help optimize medical therapy, including lean vs. obese status, stage of disease/fibrosis, etc. Thiazedinediones, such as pioglitazone, are PPAR-γ agonists and exhibit anti-inflammatory properties, improving insulin sensitivity and hepatic fatty acid oxidation. In a randomized controlled trial, pioglitazone improved hepatic steatosis, ballooning, and inflammation in patients with NASH.168 Vitamin E is an antioxidant able to inhibit lipid peroxidation and improve lipid metabolism. In the PIVENS trial (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis), vitamin E resulted in significant improvement in ALT levels, liver steatosis, and inflammation but did not significantly improve fibrosis. Patients in this study were overweight or obese, and therefore, the results cannot be applied to lean/nonobese individuals.169 Liraglutide, a GLP-1 agonist, has been studied in obese and diabetic NAFLD patients, leading to improvement and less fibrosis progression.170 However, the effects of the drug have not been studied in lean NAFLD patients. Several agents are currently in phases II and III, and further investigation is necessary to delineate further which population of NAFLD patients may benefit from specific pharmacologic interventions.

Other interventions

Poor quality of sleep and short sleep duration have been associated with an increased incidence of NAFLD.171,172 A significant proportion of lean NAFLD patients have been linked to poor sleep quality.173 Patients with NAFLD should receive recommendations for more rest and other measures that may improve sleep quality.

Conclusions

NAFLD has predominantly been a disease associated with obesity and other metabolic conditions. However, the prevalence of NAFLD in lean/nonobese subjects is growing worldwide, heightening the importance of understanding the differences between lean and obese patients. A standardized definition delineating obese and lean NAFLD is necessary to understand the pathophysiology and disease outcomes more precisely. Patients with NAFLD, regardless of BMI, are associated with a genetic predisposition, increased visceral adiposity, insulin resistance, sarcopenia, gut dysbiosis, and poor diet/exercise habits. Lean NAFLD patients displayed MetS conditions compared to lean non-NAFLD patients. Among patients with NAFLD, patients with obesity were typically found to have a higher prevalence and degree of MetS conditions, such as dyslipidemia, insulin resistance, and hypertension, compared to lean subjects. Patients with NAFLD have a higher overall cardiovascular mortality risk compared to non-NAFLD patients. However, the differences among obese and lean NAFLD patients were inconclusive, and further research is required. Obese NAFLD patients are typically associated with a greater degree of hepatic steatosis, inflammation, and fibrosis than lean patients. Still, data on advanced liver diseases, such as cirrhosis and HCC are relatively mixed. Lifestyle modifications remain the first line of treatment in NAFLD, regardless of BMI or body weight. Future therapies include PPAR-γ, such as pioglitazone, GLP-1, vitamin E, and many other options currently in clinical trials are being studied. Further understanding of the mechanisms and pathways of NAFLD in both lean and obese cohorts is necessary to optimize our current clinical practice and decision-making in this patient population.

Abbreviations

ALT: 

alanine transaminase

AST: 

aspartate transaminase

BMI: 

body mass index

CAP: 

controlled attenuation parameter

CRP: 

C-reactive protein

FFA: 

free fatty acid

FGF 19: 

fibroblast growth factor 19

FIB-4: 

fibrosis-4

FLI: 

fatty liver index

GGT: 

gamma-glutamyl transferase

IL-6: 

interleukin 6

IR: 

insulin resistance

LXRa: 

liver X receptor alpha

MRI: 

magnetic resonance imaging

MRI-PDFF: 

MRI proton density fat fraction

MRS: 

proton magnetic resonance spectroscopy

NAFL: 

nonalcoholic fatty liver

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

NHANES III: 

National Health and Nutrition Examination Survey III

PNPLA3: 

patanin-like phospholipase domain-containing protein 3

T2DM: 

type 2 diabetes mellitus

TE: 

transient elastography

TM6SF2: 

transmembrane 6 superfamily 2

TNF-α: 

tumor necrosis factor alpha

UPP: 

ubiquitin-proteasome proteolytic pathway

US: 

ultrasound

Declarations

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

All authors worked in all 4 aspects of authorship as per ICMJE guidelines.

References

  1. Chrysavgis L, Ztriva E, Protopapas A, Tziomalos K, Cholongitas E. Nonalcoholic fatty liver disease in lean subjects: Prognosis, outcomes and management. World J Gastroenterol 2020;26(42):6514-6528 View Article PubMed/NCBI
  2. Papatheodoridi AM, Chrysavgis L, Koutsilieris M, Chatzigeorgiou A. The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis. Hepatology 2020;71(1):363-374 View Article PubMed/NCBI
  3. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol 2019;71(4):793-801 View Article PubMed/NCBI
  4. Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010;59(7):969-974 View Article PubMed/NCBI
  5. Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018;68(1):361-371 View Article PubMed/NCBI
  6. Gawrieh S, Chalasani N. Emerging Treatments for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clin Liver Dis 2018;22(1):189-199 View Article PubMed/NCBI
  7. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129(1):113-121 View Article PubMed/NCBI
  8. Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44(4):865-873 View Article PubMed/NCBI
  9. Söderberg C, Stål P, Askling J, Glaumann H, Lindberg G, Marmur J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51(2):595-602 View Article PubMed/NCBI
  10. Bertolotti M, Lonardo A, Mussi C, Baldelli E, Pellegrini E, Ballestri S, et al. Nonalcoholic fatty liver disease and aging: epidemiology to management. World J Gastroenterol 2014;20(39):14185-14204 View Article PubMed/NCBI
  11. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328-357 View Article PubMed/NCBI
  12. Kanwar P, Kowdley KV. The Metabolic Syndrome and Its Influence on Nonalcoholic Steatohepatitis. Clin Liver Dis 2016;20(2):225-243 View Article PubMed/NCBI
  13. Wang AY, Dhaliwal J, Mouzaki M. Lean non-alcoholic fatty liver disease. Clin Nutr 2019;38(3):975-981 View Article PubMed/NCBI
  14. Albhaisi S, Chowdhury A, Sanyal AJ. Non-alcoholic fatty liver disease in lean individuals. JHEP Rep 2019;1(4):329-341 View Article PubMed/NCBI
  15. Zelber-Sagi S, Salomone F, Mlynarsky L. The Mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: Evidence and plausible mechanisms. Liver Int 2017;37(7):936-949 View Article PubMed/NCBI
  16. Trovato FM, Martines GF, Brischetto D, Trovato G, Catalano D. Neglected features of lifestyle: Their relevance in non-alcoholic fatty liver disease. World J Hepatol 2016;8(33):1459-1465 View Article PubMed/NCBI
  17. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363(9403):157-163 View Article PubMed/NCBI
  18. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol 2017;67(4):862-873 View Article PubMed/NCBI
  19. Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet 2005;366(9491):1059-1062 View Article PubMed/NCBI
  20. Kim D, Kim WR. Nonobese Fatty Liver Disease. Clin Gastroenterol Hepatol 2017;15(4):474-485 View Article PubMed/NCBI
  21. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55(7):434-438 View Article PubMed/NCBI
  22. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142(7):1592-1609 View Article PubMed/NCBI
  23. Patel V, Sanyal AJ, Sterling R. Clinical Presentation and Patient Evaluation in Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2016;20(2):277-292 View Article PubMed/NCBI
  24. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371(9615):838-851 View Article PubMed/NCBI
  25. Ye Q, Zou B, Yeo YH, Li J, Huang DQ, Wu Y, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2020;5(8):739-752 View Article PubMed/NCBI
  26. Shi Y, Wang Q, Sun Y, Zhao X, Kong Y, Ou X, et al. The Prevalence of Lean/Nonobese Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2020;54(4):378-387 View Article PubMed/NCBI
  27. Zou ZY, Wong VW, Fan JG. Epidemiology of nonalcoholic fatty liver disease in non-obese populations: Meta-analytic assessment of its prevalence, genetic, metabolic, and histological profiles. J Dig Dis 2020;21(7):372-384 View Article PubMed/NCBI
  28. Younes R, Bugianesi E. NASH in Lean Individuals. Semin Liver Dis 2019;39(1):86-95 View Article PubMed/NCBI
  29. Lu FB, Zheng KI, Rios RS, Targher G, Byrne CD, Zheng MH. Global epidemiology of lean non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2020;35(12):2041-2050 View Article PubMed/NCBI
  30. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore) 2012;91(6):319-327 View Article PubMed/NCBI
  31. Zou B, Yeo YH, Nguyen VH, Cheung R, Ingelsson E, Nguyen MH. Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999-2016. J Intern Med 2020;288(1):139-151 View Article PubMed/NCBI
  32. Sinn DH, Gwak GY, Park HN, Kim JE, Min YW, Kim KM, et al. Ultrasonographically detected non-alcoholic fatty liver disease is an independent predictor for identifying patients with insulin resistance in non-obese, non-diabetic middle-aged Asian adults. Am J Gastroenterol 2012;107(4):561-567 View Article PubMed/NCBI
  33. Kwon YM, Oh SW, Hwang SS, Lee C, Kwon H, Chung GE. Association of nonalcoholic fatty liver disease with components of metabolic syndrome according to body mass index in Korean adults. Am J Gastroenterol 2012;107(12):1852-1858 View Article PubMed/NCBI
  34. Kim Y, Han E, Lee JS, Lee HW, Kim BK, Kim MK, et al. Cardiovascular Risk Is Elevated in Lean Subjects with Nonalcoholic Fatty Liver Disease. Gut Liver 2022;16(2):290-299 View Article PubMed/NCBI
  35. Feng RN, Du SS, Wang C, Li YC, Liu LY, Guo FC, et al. Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. World J Gastroenterol 2014;20(47):17932-17940 View Article PubMed/NCBI
  36. Xu C, Yu C, Ma H, Xu L, Miao M, Li Y. Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study. Am J Gastroenterol 2013;108(8):1299-1304 View Article PubMed/NCBI
  37. Wei JL, Leung JC, Loong TC, Wong GL, Yeung DK, Chan RS, et al. Prevalence and Severity of Nonalcoholic Fatty Liver Disease in Non-Obese Patients: A Population Study Using Proton-Magnetic Resonance Spectroscopy. Am J Gastroenterol 2015;110(9):1306-1314 View Article PubMed/NCBI
  38. Nishioji K, Sumida Y, Kamaguchi M, Mochizuki N, Kobayashi M, Nishimura T, et al. Prevalence of and risk factors for non-alcoholic fatty liver disease in a non-obese Japanese population, 2011-2012. J Gastroenterol 2015;50(1):95-108 View Article PubMed/NCBI
  39. Gaglio PJ. Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2016;20(2):xiii-xxiv View Article PubMed/NCBI
  40. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34(3):274-285 View Article PubMed/NCBI
  41. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64(1):73-84 View Article PubMed/NCBI
  42. Sung KC, Wild SH, Byrne CD. Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension. J Hepatol 2014;60(5):1040-1045 View Article PubMed/NCBI
  43. Vilarinho S, Ajmera V, Zheng M, Loomba R. Emerging Role of Genomic Analysis in Clinical Evaluation of Lean Individuals With NAFLD. Hepatology 2021;74(4):2241-2250 View Article PubMed/NCBI
  44. Maier S, Wieland A, Cree-Green M, Nadeau K, Sullivan S, Lanaspa MA, et al. Lean NAFLD: an underrecognized and challenging disorder in medicine. Rev Endocr Metab Disord 2021;22(2):351-366 View Article PubMed/NCBI
  45. Hsu CL, Wu FZ, Lin KH, Chen YH, Wu PC, Chen YH, et al. Role of Fatty Liver Index and Metabolic Factors in the Prediction of Nonalcoholic Fatty Liver Disease in a Lean Population Receiving Health Checkup. Clin Transl Gastroenterol 2019;10(5):1-8 View Article PubMed/NCBI
  46. Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 2009;137(3):865-872 View Article PubMed/NCBI
  47. Poynard T, Ratziu V, Naveau S, Thabut D, Charlotte F, Messous D, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol 2005;4:10 View Article PubMed/NCBI
  48. Nakatsuka T, Tateishi R, Koike K. Changing clinical management of NAFLD in Asia. Liver Int 2022;42(9):1955-1968 View Article PubMed/NCBI
  49. Hsu C, Caussy C, Imajo K, Chen J, Singh S, Kaulback K, et al. Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants. Clin Gastroenterol Hepatol 2019;17(4):630-637.e8 View Article PubMed/NCBI
  50. Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, et al. Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease. Gastroenterology 2017;152(3):598-607.e2 View Article PubMed/NCBI
  51. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, et al. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology 2016;150(3):626-637.e7 View Article PubMed/NCBI
  52. Chen J, Yin M, Talwalkar JA, Oudry J, Glaser KJ, Smyrk TC, et al. Diagnostic Performance of MR Elastography and Vibration-controlled Transient Elastography in the Detection of Hepatic Fibrosis in Patients with Severe to Morbid Obesity. Radiology 2017;283(2):418-428 View Article PubMed/NCBI
  53. Day CP, James OF. Steatohepatitis: a tale of two “hits”?. Gastroenterology 1998;114(4):842-845 View Article PubMed/NCBI
  54. Day CP, Saksena S. Non-alcoholic steatohepatitis: definitions and pathogenesis. J Gastroenterol Hepatol 2002;17(Suppl 3):S377-S384 View Article PubMed/NCBI
  55. Caligiuri A, Gentilini A, Marra F. Molecular Pathogenesis of NASH. Int J Mol Sci 2016;17(9):E1575 View Article PubMed/NCBI
  56. Kuchay MS, Martínez-Montoro JI, Choudhary NS, Fernández-García JC, Ramos-Molina B. Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges. Biomedicines 2021;9(10):1346 View Article PubMed/NCBI
  57. Feldman A, Eder SK, Felder TK, Kedenko L, Paulweber B, Stadlmayr A, et al. Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver. Am J Gastroenterol 2017;112(1):102-110 View Article PubMed/NCBI
  58. Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology 2006;147(9):4160-4168 View Article PubMed/NCBI
  59. Kim HJ, Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 2004;164(19):2169-2175 View Article PubMed/NCBI
  60. Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 2008;134(5):1369-1375 View Article PubMed/NCBI
  61. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005;48(4):634-642 View Article PubMed/NCBI
  62. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115(5):1343-1351 View Article PubMed/NCBI
  63. García-Monzón C, Lo Iacono O, Mayoral R, González-Rodríguez A, Miquilena-Colina ME, Lozano-Rodríguez T, et al. Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C. J Hepatol 2011;54(1):142-152 View Article PubMed/NCBI
  64. Kumar R, Rastogi A, Sharma MK, Bhatia V, Garg H, Bihari C, et al. Clinicopathological characteristics and metabolic profiles of non-alcoholic fatty liver disease in Indian patients with normal body mass index: Do they differ from obese or overweight non-alcoholic fatty liver disease?. Indian J Endocrinol Metab 2013;17(4):665-671 View Article PubMed/NCBI
  65. Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 2009;50(4):1087-1093 View Article PubMed/NCBI
  66. Lee S, Kim KW, Lee J, Park T, Khang S, Jeong H, et al. Visceral adiposity as a risk factor for lean non-alcoholic fatty liver disease in potential living liver donors. J Gastroenterol Hepatol 2021;36(11):3212-3218 View Article PubMed/NCBI
  67. Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi LE. Nonalcoholic fatty liver disease: Evolving paradigms. World J Gastroenterol 2017;23(36):6571-6592 View Article PubMed/NCBI
  68. Singh MK, Jayarajan R, Varshney S, Upadrasta S, Singh A, Yadav R, et al. Chronic systemic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver. Biochim Biophys Acta Mol Cell Biol Lipids 2021;1866(5):158905 View Article PubMed/NCBI
  69. Woodward L, Akoumianakis I, Antoniades C. Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease. Br J Pharmacol 2017;174(22):4007-4020 View Article PubMed/NCBI
  70. Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci 2019;76(8):1541-1558 View Article PubMed/NCBI
  71. Wang B, Jiang X, Cao M, Ge J, Bao Q, Tang L, et al. Altered Fecal Microbiota Correlates with Liver Biochemistry in Nonobese Patients with Non-alcoholic Fatty Liver Disease. Sci Rep 2016;6:32002 View Article PubMed/NCBI
  72. Chen F, Esmaili S, Rogers GB, Bugianesi E, Petta S, Marchesini G, et al. Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation. Hepatology 2020;71(4):1213-1227 View Article PubMed/NCBI
  73. Phipps M, Wattacheril J. Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals. Frontline Gastroenterol 2020;11(6):478-483 View Article PubMed/NCBI
  74. Basaranoglu M, Basaranoglu G, Bugianesi E. Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction. Hepatobiliary Surg Nutr 2015;4(2):109-116 View Article PubMed/NCBI
  75. Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 2009;51(5):918-924 View Article PubMed/NCBI
  76. Chen H, Wang J, Li Z, Lam CWK, Xiao Y, Wu Q, et al. Consumption of Sugar-Sweetened Beverages Has a Dose-Dependent Effect on the Risk of Non-Alcoholic Fatty Liver Disease: An Updated Systematic Review and Dose-Response Meta-Analysis. Int J Environ Res Public Health 2019;16(12):E2192 View Article PubMed/NCBI
  77. Assy N, Nasser G, Kamayse I, Nseir W, Beniashvili Z, Djibre A, et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol 2008;22(10):811-816 View Article PubMed/NCBI
  78. Yasutake K, Nakamuta M, Shima Y, Ohyama A, Masuda K, Haruta N, et al. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand J Gastroenterol 2009;44(4):471-477 View Article PubMed/NCBI
  79. Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003;37(4):909-916 View Article PubMed/NCBI
  80. Yao PM, Tabas I. Free cholesterol loading of macrophages induces apoptosis involving the fas pathway. J Biol Chem 2000;275(31):23807-23813 View Article PubMed/NCBI
  81. Marí M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 2006;4(3):185-198 View Article PubMed/NCBI
  82. Nakamuta M, Fujino T, Yada R, Yada M, Yasutake K, Yoshimoto T, et al. Impact of cholesterol metabolism and the LXRalpha-SREBP-1c pathway on nonalcoholic fatty liver disease. Int J Mol Med 2009;23(5):603-608 View Article PubMed/NCBI
  83. Enjoji M, Yasutake K, Kohjima M, Nakamuta M. Nutrition and nonalcoholic Fatty liver disease: the significance of cholesterol. Int J Hepatol 2012;2012:925807 View Article PubMed/NCBI
  84. Nakamuta M, Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, et al. The significance of differences in fatty acid metabolism between obese and non-obese patients with non-alcoholic fatty liver disease. Int J Mol Med 2008;22(5):663-667 View Article PubMed/NCBI
  85. Shen J, Wong GL, Chan HL, Chan RS, Chan HY, Chu WC, et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2015;30(1):139-146 View Article PubMed/NCBI
  86. Li Y, He F, He Y, Pan X, Wu Y, Hu Z, et al. Dose-response association between physical activity and non-alcoholic fatty liver disease: a case-control study in a Chinese population. BMJ Open 2019;9(3):e026854 View Article PubMed/NCBI
  87. Kwak MS, Kim D, Chung GE, Kim W, Kim YJ, Yoon JH. Role of physical activity in nonalcoholic fatty liver disease in terms of visceral obesity and insulin resistance. Liver Int 2015;35(3):944-952 View Article PubMed/NCBI
  88. Ryu S, Chang Y, Jung HS, Yun KE, Kwon MJ, Choi Y, et al. Relationship of sitting time and physical activity with non-alcoholic fatty liver disease. J Hepatol 2015;63(5):1229-1237 View Article PubMed/NCBI
  89. Shida T, Oshida N, Suzuki H, Okada K, Watahiki T, Oh S, et al. Clinical and anthropometric characteristics of non-obese non-alcoholic fatty liver disease subjects in Japan. Hepatol Res 2020;50(9):1032-1046 View Article PubMed/NCBI
  90. Tobari M, Hashimoto E, Taniai M, Ikarashi Y, Kodama K, Kogiso T, et al. Characteristics of non-alcoholic steatohepatitis among lean patients in Japan: Not uncommon and not always benign. J Gastroenterol Hepatol 2019;34(8):1404-1410 View Article PubMed/NCBI
  91. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58(4):773-795 View Article PubMed/NCBI
  92. Haddad F, Zaldivar F, Cooper DM, Adams GR. IL-6-induced skeletal muscle atrophy. J Appl Physiol (1985) 2005;98(3):911-917 View Article PubMed/NCBI
  93. De Larichaudy J, Zufferli A, Serra F, Isidori AM, Naro F, Dessalle K, et al. TNF-α- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism. Skelet Muscle 2012;2(1):2 View Article PubMed/NCBI
  94. Alemán H, Esparza J, Ramirez FA, Astiazaran H, Payette H. Longitudinal evidence on the association between interleukin-6 and C-reactive protein with the loss of total appendicular skeletal muscle in free-living older men and women. Age Ageing 2011;40(4):469-475 View Article PubMed/NCBI
  95. Shida T, Oshida N, Oh S, Okada K, Shoda J. Progressive reduction in skeletal muscle mass to visceral fat area ratio is associated with a worsening of the hepatic conditions of non-alcoholic fatty liver disease. Diabetes Metab Syndr Obes 2019;12:495-503 View Article PubMed/NCBI
  96. Kim HY, Baik SJ, Lee HA, Lee BK, Lee HS, Kim TH, et al. Relative fat mass at baseline and its early change may be a predictor of incident nonalcoholic fatty liver disease. Sci Rep 2020;10(1):17491 View Article PubMed/NCBI
  97. Lee YH, Jung KS, Kim SU, Yoon HJ, Yun YJ, Lee BW, et al. Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES 2008-2011). J Hepatol 2015;63(2):486-493 View Article PubMed/NCBI
  98. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40(12):1461-1465 View Article PubMed/NCBI
  99. Niriella MA, Kasturiratne A, Pathmeswaran A, De Silva ST, Perera KR, Subasinghe SKCE, et al. Lean non-alcoholic fatty liver disease (lean NAFLD): characteristics, metabolic outcomes and risk factors from a 7-year prospective, community cohort study from Sri Lanka. Hepatol Int 2019;13(3):314-322 View Article PubMed/NCBI
  100. Oniki K, Saruwatari J, Izuka T, Kajiwara A, Morita K, Sakata M, et al. Influence of the PNPLA3 rs738409 Polymorphism on Non-Alcoholic Fatty Liver Disease and Renal Function among Normal Weight Subjects. PLoS One 2015;10(7):e0132640 View Article PubMed/NCBI
  101. Yuan X, Waterworth D, Perry JR, Lim N, Song K, Chambers JC, et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 2008;83(4):520-528 View Article PubMed/NCBI
  102. Lin YC, Chang PF, Hu FC, Yang WS, Chang MH, Ni YH. A common variant in the PNPLA3 gene is a risk factor for non-alcoholic fatty liver disease in obese Taiwanese children. J Pediatr 2011;158(5):740-744 View Article PubMed/NCBI
  103. Sookoian S, Castaño GO, Scian R, Mallardi P, Fernández Gianotti T, Burgueño AL, et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 2015;61(2):515-525 View Article PubMed/NCBI
  104. Musso G, Cassader M, Bo S, De Michieli F, Gambino R. Sterol regulatory element-binding factor 2 (SREBF-2) predicts 7-year NAFLD incidence and severity of liver disease and lipoprotein and glucose dysmetabolism. Diabetes 2013;62(4):1109-1120 View Article PubMed/NCBI
  105. Musso G, Bo S, Cassader M, De Michieli F, Gambino R. Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism. Am J Clin Nutr 2013;98(4):895-906 View Article PubMed/NCBI
  106. Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 2010;139(5):1567-1576.e1-e6 View Article PubMed/NCBI
  107. Elsaid MI, Bridges JFP, Li N, Rustgi VK. Metabolic Syndrome Severity Predicts Mortality in Nonalcoholic Fatty Liver Disease. Gastro Hep Advances 2022;1(3):445-456 View Article PubMed/NCBI
  108. Semmler G, Wernly S, Bachmayer S, Wernly B, Schwenoha L, Huber-Schönauer U, et al. Nonalcoholic Fatty Liver Disease in Lean Subjects: Associations With Metabolic Dysregulation and Cardiovascular Risk-A Single-Center Cross-Sectional Study. Clin Transl Gastroenterol 2021;12(4):e00326 View Article PubMed/NCBI
  109. Feng R, Luo C, Li C, Du S, Okekunle AP, Li Y, et al. Free fatty acids profile among lean, overweight and obese non-alcoholic fatty liver disease patients: a case - control study. Lipids Health Dis 2017;16(1):165 View Article PubMed/NCBI
  110. Sinn DH, Kang D, Cho SJ, Paik SW, Guallar E, Cho J, et al. Lean non-alcoholic fatty liver disease and development of diabetes: a cohort study. Eur J Endocrinol 2019;181(2):185-192 View Article PubMed/NCBI
  111. Fukuda T, Hamaguchi M, Kojima T, Hashimoto Y, Ohbora A, Kato T, et al. The impact of non-alcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals. Liver Int 2016;36(2):275-283 View Article PubMed/NCBI
  112. Golabi P, Paik J, Fukui N, Locklear CT, de Avilla L, Younossi ZM. Patients With Lean Nonalcoholic Fatty Liver Disease Are Metabolically Abnormal and Have a Higher Risk for Mortality. Clin Diabetes 2019;37(1):65-72 View Article PubMed/NCBI
  113. Ahmed OT, Gidener T, Mara KC, Larson JJ, Therneau TM, Allen AM. Natural History of Nonalcoholic Fatty Liver Disease With Normal Body Mass Index: A Population-Based Study. Clin Gastroenterol Hepatol 2022;20(6):1374-1381.e6 View Article PubMed/NCBI
  114. Lee SW, Lee TY, Yang SS, Tung CF, Yeh HZ, Chang CS. Risk factors and metabolic abnormality of patients with non-alcoholic fatty liver disease: Either non-obese or obese Chinese population. Hepatobiliary Pancreat Dis Int 2018;17(1):45-48 View Article PubMed/NCBI
  115. Fracanzani AL, Petta S, Lombardi R, Pisano G, Russello M, Consonni D, et al. Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity. Clin Gastroenterol Hepatol 2017;15(10):1604-1611.e1 View Article PubMed/NCBI
  116. Zeng J, Yang RX, Sun C, Pan Q, Zhang RN, Chen GY, et al. Prevalence, clinical characteristics, risk factors, and indicators for lean Chinese adults with nonalcoholic fatty liver disease. World J Gastroenterol 2020;26(15):1792-1804 View Article PubMed/NCBI
  117. Leung JC, Loong TC, Wei JL, Wong GL, Chan AW, Choi PC, et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology 2017;65(1):54-64 View Article PubMed/NCBI
  118. Akyuz U, Yesil A, Yilmaz Y. Characterization of lean patients with nonalcoholic fatty liver disease: potential role of high hemoglobin levels. Scand J Gastroenterol 2015;50(3):341-346 View Article PubMed/NCBI
  119. Sookoian S, Pirola CJ. Systematic review with meta-analysis: risk factors for non-alcoholic fatty liver disease suggest a shared altered metabolic and cardiovascular profile between lean and obese patients. Aliment Pharmacol Ther 2017;46(2):85-95 View Article PubMed/NCBI
  120. Young S, Tariq R, Provenza J, Satapathy SK, Faisal K, Choudhry A, et al. Prevalence and Profile of Nonalcoholic Fatty Liver Disease in Lean Adults: Systematic Review and Meta-Analysis. Hepatol Commun 2020;4(7):953-972 View Article PubMed/NCBI
  121. Li H, Chen Y, Tian X, Hong Y, Chen C, Sharokh NK, et al. Comparison of clinical characteristics between lean and obese nonalcoholic fatty liver disease in the northeast Chinese population. Arch Med Sci Atheroscler Dis 2019;4:e191-e195 View Article PubMed/NCBI
  122. Honda Y, Yoneda M, Kessoku T, Ogawa Y, Tomeno W, Imajo K, et al. Characteristics of non-obese non-alcoholic fatty liver disease: Effect of genetic and environmental factors. Hepatol Res 2016;46(10):1011-1018 View Article PubMed/NCBI
  123. Gonzalez-Cantero J, Martin-Rodriguez JL, Gonzalez-Cantero A, Arrebola JP, Gonzalez-Calvin JL. Insulin resistance in lean and overweight non-diabetic Caucasian adults: Study of its relationship with liver triglyceride content, waist circumference and BMI. PLoS One 2018;13(2):e0192663 View Article PubMed/NCBI
  124. Shao C, Ye J, Li F, Lin Y, Wu T, Wang W, et al. Early Predictors of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease: Non-obese Versus Obese Patients. Dig Dis Sci 2020;65(6):1850-1860 View Article PubMed/NCBI
  125. Alam S, Gupta UD, Alam M, Kabir J, Chowdhury ZR, Alam AK. Clinical, anthropometric, biochemical, and histological characteristics of nonobese nonalcoholic fatty liver disease patients of Bangladesh. Indian J Gastroenterol 2014;33(5):452-457 View Article PubMed/NCBI
  126. Yoshitaka H, Hamaguchi M, Kojima T, Fukuda T, Ohbora A, Fukui M. Nonoverweight nonalcoholic fatty liver disease and incident cardiovascular disease: A post hoc analysis of a cohort study. Medicine (Baltimore) 2017;96(18):e6712 View Article PubMed/NCBI
  127. Wang Z, Xu M, Hu Z, Shrestha UK. Prevalence of nonalcoholic fatty liver disease and its metabolic risk factors in women of different ages and body mass index. Menopause 2015;22(6):667-673 View Article PubMed/NCBI
  128. Sung KC, Ryan MC, Wilson AM. The severity of nonalcoholic fatty liver disease is associated with increased cardiovascular risk in a large cohort of non-obese Asian subjects. Atherosclerosis 2009;203(2):581-586 View Article PubMed/NCBI
  129. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol 2016;65(3):589-600 View Article PubMed/NCBI
  130. Mahfood Haddad T, Hamdeh S, Kanmanthareddy A, Alla VM. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: A systematic review and meta-analysis. Diabetes Metab Syndr 2017;11(Suppl 1):S209-S216 View Article PubMed/NCBI
  131. Osawa K, Miyoshi T, Yamauchi K, Koyama Y, Nakamura K, Sato S, et al. Nonalcoholic Hepatic Steatosis Is a Strong Predictor of High-Risk Coronary-Artery Plaques as Determined by Multidetector CT. PLoS One 2015;10(6):e0131138 View Article PubMed/NCBI
  132. Liu Y, Zhong GC, Tan HY, Hao FB, Hu JJ. Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis. Sci Rep 2019;9(1):11124 View Article PubMed/NCBI
  133. Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study. Hepatol Commun 2018;2(1):48-57 View Article PubMed/NCBI
  134. Cruz ACD, Bugianesi E, George J, Day CP, Liaquat H, Charatcharoenwitthaya P, et al. 379 Characteristics and Long-Term Prognosis of Lean Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2014;146(5):S-909 View Article PubMed/NCBI
  135. Vos B, Moreno C, Nagy N, Féry F, Cnop M, Vereerstraeten P, et al. Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease. Acta Gastroenterol Belg 2011;74(3):389-394 View Article PubMed/NCBI
  136. Margariti A, Deutsch M, Manolakopoulos S, Tiniakos D, Papatheodoridis GV. The severity of histologic liver lesions is independent of body mass index in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol 2013;47(3):280-286 View Article PubMed/NCBI
  137. Sookoian S, Pirola CJ. Systematic review with meta-analysis: the significance of histological disease severity in lean patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2018;47(1):16-25 View Article PubMed/NCBI
  138. Denkmayr L, Feldman A, Stechemesser L, Eder SK, Zandanell S, Schranz M, et al. Lean Patients with Non-Alcoholic Fatty Liver Disease Have a Severe Histological Phenotype Similar to Obese Patients. J Clin Med 2018;7(12):E562 View Article PubMed/NCBI
  139. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 2015;149(2):367-78.e5 View Article PubMed/NCBI
  140. Jin YJ, Kim KM, Hwang S, Lee SG, Ha TY, Song GW, et al. Exercise and diet modification in non-obese non-alcoholic fatty liver disease: analysis of biopsies of living liver donors. J Gastroenterol Hepatol 2012;27(8):1341-1347 View Article PubMed/NCBI
  141. Hamurcu Varol P, Kaya E, Alphan E, Yilmaz Y. Role of intensive dietary and lifestyle interventions in the treatment of lean nonalcoholic fatty liver disease patients. Eur J Gastroenterol Hepatol 2020;32(10):1352-1357 View Article PubMed/NCBI
  142. Kim NH, Kim JH, Kim YJ, Yoo HJ, Kim HY, Seo JA, et al. Clinical and metabolic factors associated with development and regression of nonalcoholic fatty liver disease in nonobese subjects. Liver Int 2014;34(4):604-611 View Article PubMed/NCBI
  143. Saeed N, Nadeau B, Shannon C, Tincopa M. Evaluation of Dietary Approaches for the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review. Nutrients 2019;11(12):E3064 View Article PubMed/NCBI
  144. Di Daniele N, Noce A, Vidiri MF, Moriconi E, Marrone G, Annicchiarico-Petruzzelli M, et al. Impact of Mediterranean diet on metabolic syndrome, cancer and longevity. Oncotarget 2017;8(5):8947-8979 View Article PubMed/NCBI
  145. Tosti V, Bertozzi B, Fontana L. Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms. J Gerontol A Biol Sci Med Sci 2018;73(3):318-326 View Article PubMed/NCBI
  146. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402 View Article PubMed/NCBI
  147. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013;59(1):138-143 View Article PubMed/NCBI
  148. Ma J, Hennein R, Liu C, Long MT, Hoffmann U, Jacques PF, et al. Improved Diet Quality Associates With Reduction in Liver Fat, Particularly in Individuals With High Genetic Risk Scores for Nonalcoholic Fatty Liver Disease. Gastroenterology 2018;155(1):107-117 View Article PubMed/NCBI
  149. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 2008;48(6):993-999 View Article PubMed/NCBI
  150. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010;51(6):1961-1971 View Article PubMed/NCBI
  151. Wijarnpreecha K, Thongprayoon C, Ungprasert P. Coffee consumption and risk of nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017;29(2):e8-e12 View Article PubMed/NCBI
  152. Chen YP, Lu FB, Hu YB, Xu LM, Zheng MH, Hu ED. A systematic review and a dose-response meta-analysis of coffee dose and nonalcoholic fatty liver disease. Clin Nutr 2019;38(6):2552-2557 View Article PubMed/NCBI
  153. Keating SE, Hackett DA, George J, Johnson NA. Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012;57(1):157-166 View Article PubMed/NCBI
  154. Younossi ZM, Corey KE, Lim JK. AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology 2021;160(3):912-918 View Article PubMed/NCBI
  155. Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H, Nago T, et al. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review. J Hepatol 2017;66(1):142-152 View Article PubMed/NCBI
  156. Stahl JM, Malhotra S. Obesity Surgery Indications And Contraindications. Treasure Island (FL): StatPearls Publishing; 2022 View Article PubMed/NCBI
  157. Rustgi VK, Li Y, Gupta K, Minacapelli CD, Bhurwal A, Catalano C, et al. Bariatric Surgery Reduces Cancer Risk in Adults With Nonalcoholic Fatty Liver Disease and Severe Obesity. Gastroenterology 2021;161(1):171-184.e10 View Article PubMed/NCBI
  158. Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008;6(12):1396-1402 View Article PubMed/NCBI
  159. Mazzini GS, Augustin T, Noria S, Romero-Marrero C, Li N, Hameed B, et al. ASMBS Position Statement on the Impact of Metabolic and Bariatric Surgery on Nonalcoholic Steatohepatitis. Surg Obes Relat Dis 2022;18(3):314-325 View Article PubMed/NCBI
  160. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology 2015;149(2):379-388 View Article PubMed/NCBI
  161. Cazzo E, Jimenez LS, Pareja JC, Chaim EA. Effect of Roux-en-Y gastric bypass on nonalcoholic fatty liver disease evaluated through NAFLD fibrosis score: a prospective study. Obes Surg 2015;25(6):982-985 View Article PubMed/NCBI
  162. Pedersen JS, Rygg MO, Serizawa RR, Kristiansen VB, Albrechtsen NJW, Gluud LL, et al. Effects of Roux-en-Y Gastric Bypass and Sleeve Gastrectomy on Non-Alcoholic Fatty Liver Disease: A 12-Month Follow-Up Study with Paired Liver Biopsies. J Clin Med 2021;10(17):3783 View Article PubMed/NCBI
  163. Clark JM, Alkhuraishi AR, Solga SF, Alli P, Diehl AM, Magnuson TH. Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res 2005;13(7):1180-1186 View Article PubMed/NCBI
  164. Cabré N, Luciano-Mateo F, Fernández-Arroyo S, Baiges-Gayà G, Hernández-Aguilera A, Fibla M, et al. Laparoscopic sleeve gastrectomy reverses non-alcoholic fatty liver disease modulating oxidative stress and inflammation. Metabolism 2019;99:81-89 View Article PubMed/NCBI
  165. Salman AA, Sultan AAEA, Abdallah A, Abdelsalam A, Mikhail HMS, Tourky M, et al. Effect of weight loss induced by laparoscopic sleeve gastrectomy on liver histology and serum adipokine levels. J Gastroenterol Hepatol 2020;35(10):1769-1773 View Article PubMed/NCBI
  166. Burza MA, Romeo S, Kotronen A, Svensson PA, Sjöholm K, Torgerson JS, et al. Long-term effect of bariatric surgery on liver enzymes in the Swedish Obese Subjects (SOS) study. PLoS One 2013;8(3):e60495 View Article PubMed/NCBI
  167. Jirapinyo P, McCarty TR, Dolan RD, Shah R, Thompson CC. Effect of Endoscopic Bariatric and Metabolic Therapies on Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2022;20(3):511-524.e1 View Article PubMed/NCBI
  168. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135(4):1176-1184 View Article PubMed/NCBI
  169. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-1685 View Article PubMed/NCBI
  170. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690 View Article PubMed/NCBI
  171. Wang H, Gu Y, Zheng L, Liu L, Meng G, Wu H, et al. Association between bedtime and the prevalence of newly diagnosed non-alcoholic fatty liver disease in adults. Liver Int 2018;38(12):2277-2286 View Article PubMed/NCBI
  172. Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Ungprasert P. Short sleep duration and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2016;31(11):1802-1807 View Article PubMed/NCBI
  173. Li C, Guo P, Okekunle AP, Ji X, Huang M, Qi J, et al. Lean non-alcoholic fatty liver disease patients had comparable total caloric, carbohydrate, protein, fat, iron, sleep duration and overtime work as obese non-alcoholic fatty liver disease patients. J Gastroenterol Hepatol 2019;34(1):256-262 View Article PubMed/NCBI

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