Editorial Open Access
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2020; 26(42): 6514-6528
Published online Nov 14, 2020. doi: 10.3748/wjg.v26.i42.6514
Nonalcoholic fatty liver disease in lean subjects: Prognosis, outcomes and management
Lampros Chrysavgis, Eleftheria Ztriva, Adonis Protopapas, Konstantinos Tziomalos, Evangelos Cholongitas
Lampros Chrysavgis, Evangelos Cholongitas, First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens 11527, Greece
Eleftheria Ztriva, Adonis Protopapas, Konstantinos Tziomalos, First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
ORCID number: Lampros Chrysavgis (0000-0003-2632-0742); Eleftheria Ztriva (0000-0002-4013-2767); Adonis Protopapas (0000-0002-7117-0547); Konstantinos Tziomalos (0000-0002-3172-1594); Evangelos Cholongitas (0000-0002-3645-582X).
Author contributions: Chrysavgis L, Ztriva E, Protopapas A, Tziomalos K and Cholongitas E contributed to this paper; Chrysavgis L, Ztriva E, Protopapas A and Tziomalos K wrote the paper; Cholongitas E made critical revisions to the manuscript and final approved the version of the article to be published.
Conflict-of-interest statement: All the authors have no conflict of interest to disclose with respect to this review.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Evangelos Cholongitas, MD, Associate Professor, First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Agiou Thoma 17, Athens 11527, Greece. cholongitas@yahoo.gr
Received: August 30, 2020
Peer-review started: August 30, 2020
First decision: September 12, 2020
Revised: September 24, 2020
Accepted: October 20, 2020
Article in press: October 20, 2020
Published online: November 14, 2020

Abstract

Nonalcoholic fatty liver disease (NAFLD) accounts for most cases of chronic liver disease worldwide, with an estimated global prevalence of approximately 25% and ranges from simple steatosis to nonalcoholic steatohepatitis and cirrhosis. NAFLD is strongly connected to metabolic syndrome, and for many years, fatty liver was considered to be an exclusive feature of obese patients. However, recent studies have highlighted the presence of NAFLD in non-obese subjects, with or without increased visceral fat or even in lean subjects without increased waist circumference. “Lean NAFLD” is a relatively new concept and there is significant scientific interest in understanding the differences in pathophysiology, prognosis and management compared with NAFLD in overweight/obese patients. In the present editorial, we discuss the clinical and metabolic profiles and outcomes of lean NAFLD compared with both obese NAFLD and lean healthy individuals from Asian and Western countries. Moreover, we shed light to the challenging topic of management of NAFLD in lean subjects since there are no specific guidelines for this population. Finally, we discuss open questions and issues to be addressed in the future in order to categorize NAFLD patients into lean and non-lean cohorts.

Key Words: Lean nonalcoholic fatty liver disease, Non-obese nonalcoholic fatty liver disease, Clinical outcomes, Metabolic outcomes, Disease management, Lifestyle interventions

Core Tip: Affecting approximately one fourth of the global population, non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease and for many years it was considered as a disease affecting only obese people. However, a significant proportion of non-obese or even lean individuals develop NAFLD. Therefore, it is of great interest to discuss the differences in prognosis, metabolic profiles and outcomes as well as the current management of lean NAFLD patients as compared with both obese NAFLD patients and lean healthy controls.



INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) has been recognized as the predominant cause of chronic liver disease in the industrialized world[1]. It encompasses a wide spectrum of clinical and histological entities, ranging from simple steatosis, defined as triglyceride (TG) accumulation > 5% within the hepatic parenchyma, to nonalcoholic steatohepatitis (NASH), which is characterized by inflammation and fibrosis and can lead to cirrhosis and even hepatocellular carcinoma (HCC)[2,3]. The prevalence of NAFLD is increased in patients with type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS) and obesity[4]. Although the latter is not only a risk factor for NAFLD but is also associated with more severe forms of the disease, a significant proportion of subjects develop NAFLD despite having a relatively normal body mass index (BMI), a condition referred to as non-obese or lean NAFLD[5]. Non-obese/lean NAFLD is divided into 2 major categories[5]: The first and more prevalent includes non-obese patients who may be overweight (BMI between the 85th-95th percentile for age) with or without increased waist circumference and adipose tissue, while the second category includes lean subjects with no excess visceral fat mass[5]. In the latter category, several secondary causes have been implicated, such as high fructose intake, protein malnutrition (Kwashiorkor) as well as administration of steatogenic drugs (amiodarone, tamoxifen, methotrexate, prednisolone, etc.) and genetic predisposition[5,6]. Regarding the latter, Romeo et al[7] have emphasized the involvement of the rs738409 single nucleotide polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA 3) gene in NAFLD onset and progression. Yet, a plethora of other gene variants have been also associated with increased susceptibility to NAFLD/NASH and progression to liver fibrosis and even HCC, such as the transmembrane 6 superfamily member 2 (TM6SF2)[8-10], glucokinase regulatory gene (GCKR)[11,12] and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes[13]. In addition, a variant of interferon-λ3 (IFN-λ3) gene has been related with increased liver inflammation and fibrosis among NAFLD patients[14], while the rs72613567 polymorphism in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene was recently shown to reduce the risk of liver fibrosis, NASH and HCC[15,16]. Of note, both dietary composition and socioeconomic factors have been correlated with NAFLD development. Adherence to Mediterranean diet has been demonstrated to ameliorate hepatic insulin sensitivity and reduce hepatic fat accumulation while the Western dietary pattern, which mainly consists of high fructose and saturated fats intake, has been involved in NAFLD development[17,18]. Moreover, prolonged sitting time, usually related with high calorie intake and unhealthy dietary composition, and decreased physical activity are independent risk factors for NAFLD, even in lean subjects[19].

Current data on the prevalence of non-obese/lean NAFLD worldwide is characterized by wide variability. In a recent systematic review including 84 studies with 10530308 individuals, Ye et al[20] demonstrated that among the general population, the prevalence of lean and non-obese NAFLD was 5.1% and 12.1%, respectively. In addition, the overall prevalence of NAFLD among the lean general population was 10.6%, while the prevalence of NAFLD in the non-obese population was 18.3%. Interestingly, the prevalence of non-obese NAFLD among the total NAFLD population was highest in Europe (51.3%) and lowest in eastern Asia (37.8%)[20]. Of note, NAFLD patients were categorized according to the World Health Organization (WHO) and Asian Pacific recommendations as overweight and lean when their BMI was 25 to 30 kg/m2 and < 25 kg/m2, respectively, in non-Asian populations and 23 kg/m2 to 27.5 kg/m2 and < 23 kg/m2, respectively, in Asian populations[21-23]. However, it is well-established that individuals with similar BMI may have different degrees of visceral obesity, which is closely associated with the development of NAFLD[24-26]. Waist circumference is considered a more accurate marker of visceral obesity than BMI, but is not available in the majority of the relevant studies[27]. The present editorial will discuss the metabolic profile, prognosis and related clinical outcomes, as well as the management of non-obese or lean patients suffering from NAFLD.

CLINICAL IMPACT OF NON-OBESE/LEAN NAFLD
Literature search

PubMed database was systematically searched from the date of inception of this editorial until April 2020, to identify studies focusing on non-obese/lean NAFLD. The terms used were “Lean non-alcoholic fatty liver disease” OR “Lean nonalcoholic fatty liver disease” OR “Lean NAFLD” OR “Non-obese non-alcoholic fatty liver disease” OR “Non-obese nonalcoholic fatty liver disease” OR “Non-obese NAFLD” OR “Non-overweight fatty liver disease” OR “Non-overweight NAFLD”. Since we aimed to emphasize the metabolic, hepatic and cardiovascular outcomes in obese vs non-obese/lean NAFLD patients as well as non-obese/lean individuals with or without NAFLD, studies evaluating the histological aspects of NAFLD were excluded.

Non obese/lean NAFLD vs controls: Metabolic and clinical outcomes (Table 1)
Table 1 Main findings and outcomes of lean (or non-obese) non-alcoholic fatty liver disease patients’ vs lean (or non-obese) healthy individuals.
Ref./Year/CountryPopulation (lean/non-obese NAFLD population)Metabolic profile lean/non-obese NAFLD vs healthy controlsLiver function tests findings, lean/non-obese NAFLD vs healthy controlsHistological outcomes, lean/non-obese NAFLD vs healthy controlsSurvival-related outcomes, lean/non-obese NAFLD vs healthy controls
Younossi et al[28]/2012/United States11613 study population; 4457 lean subjects (431)↑ Prevalence of insulin resistance, T2DM, hypercholesterolemia and hypertensionNANA
Golabi et al[29]/2019/United States5375 lean subjects (581)↑ Prevalence of metabolic comorbiditiesNANA↑ Hazard for all-cause and cardiovascular-related mortality
Zou et al[30]/2020/United States9654 controls (1528)↑ BP, HOMA-IR, glucose, insulin, TC, LDL-C, TG, ↓ HDL-C↑ ALT, AST, γ-GTNA↑ 15-yr overall, cardiovascular, cancer and other causes-related mortality (not confirmed in Cox model)
Yoshitaka et al[31]/2017/Japan1647 individuals; 984 non-overweight subjects (69)↑ BP, glucose, TG, UA, ↓ HDL-C↑ AST, ALT, γ-GTNA↑ HR of CVD incident
Fukuda et al[32]/2016/Japan4629 participants (2989) in the non-overweight group (139)↑ Adjusted HR for T2DM, ↑ BP, TC, TG, ↓ HDL-C↑ ALT, AST, γ-GTNANA
Nishioji et al[33]/2015/Japan3271 enrolled individuals; 2606 non-obese (511)↑ BP, TC, TG, HbA1c, glucose↑ ALT, AST, γ-GTNANA
Kim et al[34]/2018/South Korea2920 participants; 2119 in non-obese group (420)↑ HR for T2DM, ↑ TG, TC, LDL-C, ↓ HDL-C↑ ALT, AST, γ-GTNANA
Sinn et al[35]/2019/South Korea51463 total population; 21984 lean subjects (2262)↑ HR for T2DM onset, ↑ glucose, HbA1c, TG, TC and LDL-C, ↓ HDL-C↑ ALT and ASTNANA
Sung et al[36]/2009/South Korea30172 all non-obese; (7101)↑ Prevalence of hypertension, T2DM, MetS in elevated ALT, steatosis and NASH groupsNANAIn men: ↑ Cardiovascular risk for group with elevated ALT serum levels and for steatosis and NASH groups. In women: ↑ Cardiovascular risk for steatosis and NASH groups
Kim et al[37]/2013/South Korea759 individuals (98 in NAFLD group)↑ Glucose, TG, UA, HOMA-IR, ↓ HDL-C↑ ALT, AST, γ-GTNANA
Kwon et al[38]/2012/South Korea29994 study population; 24008 non-obese (3014)↑ BP, glucose, insulin, HOMA-IR, ↓ HDL-C↑ AST, ALT, γ-GTNANA
Feng et al[39]/2014/China1779; 731 in the lean group (134)↑ OR for hypertension, T2DM, central obesity and MetS, UA, TC, LDL-C, TG, glucose, insulin, HOMA-IR ↓ HDL-C↑ ALT, AST, γ-GTNANA
Lee et al[40]/2018/China2008 enrolled subjects; 953 non-obese (208)↑ TC, TG, glucose↑ ALTNANA
Zeng et al[41]/2020/China2715 enrolled participants (1100 NAFLD patients)↑ Prevalence of hypertension and MetS, TG, LDL-C, ↓ HDL-CNANANA
Yu et al[42]/2014/China1296 non-obese subjects of whom 246 were NAFLD patients↑ Arterial stiffness, assessed by the higher brachial-ankle pulse wave velocity, TC, LDL-C, TG, glucose, insulin, UA, HOMA-IR↑ ALT, ASTNANA
Wang et al[43]/2015/China9360 women population (1194 were NAFLD patients)↑ TG, TC, LDL-C, glucose↑ AST, ALTNANA
Kumar et al[44]/2013/India205 NAFLD patients (27 lean) plus 131 lean healthy subjects↑ Prevalence of MetS, dyslipidemiaNANA
Oral et al[45]/2019/Turkey367 non-obese individuals (225 in NAFLD group and 142 in the control group)↑ TG, TC, UA, creatinine, HOMA-IR↑ AST, ALTNANA
Erkan et al[46]/2014/Turkey219 non-obese non diabetic individuals of whom 143 NAFLD patients↑ Prevalence of hypertension, MetS, hyperglycemia, hypertriglyceridemia and insulin resistance, insulin, HOMA-IR↑ AST, ALT, γ-GTNANA
Feldman et al[47]/2017/Austria187 subjects (116 suffering from NAFLD of whom 55 were lean)↑ Prevalence of T2DM, glucose, ↓ adiponectin↑ ALT, γ-GTNANA
Gonzalez-Cantero et al[48]/2018/Spain113 non-obese enrolled individuals (55 NAFLD patients)↑ HOMA-IR, TG, insulin, ↓ HDL-C, adiponectin↑ ALT, AST, γ-GTNANA

Younossi et al[28] in a study performed in the United States reported that lean (BMI < 25 kg/m2) NAFLD patients compared to lean healthy subjects had higher prevalence of insulin resistance (IR), T2DM, hypercholesterolemia and hypertension, i.e., the components of MetS. In the cross-sectional NHANES III study, Golabi et al[29] reported that lean (BMI < 25 kg/m2) NAFLD patients, had higher risk of all-cause [Hazard Ratio (HR): 1.54] and cardiovascular-related mortality (HR: 2.38) than lean non-NAFLD subjects after adjustment for potential confounding variables[29]. Interestingly, in another study from the United States, Zou et al[30] showed that in a non-obese population (BMI < 30 kg/m2 for non-Asians and < 27 kg/m2 for Asians), patients with NAFLD had higher blood pressure, fasting plasma glucose (FPG), insulin, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and TG levels and higher Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), a marker of IR, than subjects without NAFLD. In addition, the former group had increased overall, cardiovascular and cancer-related mortality during a 15-year follow-up, but these findings were not confirmed in multivariate analysis[30].

In a post hoc analysis in Japanese subjects, Yoshitaka et al[31] reported that lean (BMI < 23 kg/m2) NAFLD patients had higher blood pressure, increased FPG and TG serum levels, as well as greater risk (HR: 10.4) for cardiovascular events than to lean non-NAFLD individuals, independently of potential confounders. In a retrospective cohort study of 4629 lean Japanese participants (BMI < 23 kg/m2) who were enrolled in a regular health checkup program, Fukuda et al[32] showed that patients with NAFLD had more than 3 times higher incidence of T2DM than subjects without NAFLD. Regarding non-obese subjects, Nishioji et al[33] found that non-obese (BMI < 25 kg/m2) Japanese NAFLD patients had a higher prevalence of MetS components compared with healthy individuals. Both retrospective and prospective studies from South Korea also showed that non-obese NAFLD patients have an increased risk for T2DM than non-NAFLD, non-obese individuals, independently of other risk factors[34,35]. Moreover, Sung et al[36] in a large cohort of non-obese (BMI < 27 kg/m2) South Korean individuals, reported that non-obese NAFLD patients have higher estimated cardiovascular risk based on the Framingham risk score than healthy controls, whereas in another South Korean cross-sectional study, non-obese (BMI < 25 kg/m2) subjects without NAFLD had better metabolic profile than non-obese patients with NAFLD[37]. Accordingly, Kwon et al[38], in another retrospective study from South Korea, showed that non-obese (BMI < 25 kg/m2) NAFLD patients had higher prevalence of MetS components than non-obese controls and had.

In lean (BMI < 23 kg/m2) Chinese individuals, the presence of NAFLD was associated with increased odds for T2DM and MetS, independently of demographic and lifestyle parameters[39]. Regarding non-obese populations, 2 independent studies in China confirmed that non-obese (BMI < 25 kg/m2) patients with NAFLD suffered more frequently from hypertension and MetS than healthy non-obese subjects[40,41], whereas a cross-sectional study in China reported that non-obese (BMI < 27.5 kg/m2), normotensive and non-diabetic NAFLD patients had increased arterial stiffness, higher serum levels of FPG, TC, LDL-C, TG and greater HOMA-IR than non-obese, healthy subjects[42]. Similar findings were observed in Chinese women[43]. Moreover, a cohort study in India also showed that NAFLD patients are at higher risk for metabolic disorders irrespectively of the presence of obesity[44].

In accordance to the aforementioned studies, Oral et al[45] reported that non-obese (BMI < 30 kg/m2) NAFLD patients from Turkey were more frequently glucose intolerant and had higher TG and TC levels than non-obese controls. Similar findings were also reported in another Turkish study, where lean (BMI < 25 kg/m2) NAFLD patients had higher prevalence of hypertension and MetS as well as higher HOMA-IR[46]. Finally, in Europe, Feldman et al[47] reported that Austrian lean (BMI < 25 kg/m2) healthy subjects were more frequently glucose tolerant and had lower prevalence of T2DM than lean NAFLD patients and these findings were confirmed by Gonzalez-Cantero et al[48] in a non-obese (BMI < 30 kg/m2) Spanish cohort.

Obese vs non-obese/lean NAFLD (Table 2)
Table 2 Main findings and outcomes of lean (or non-obese) non-alcoholic fatty liver disease patients’ vs obese ones.
Ref./Year/CountryPopulation (lean/non-obese NAFLD patients)Metabolic profile, lean/non-obese NAFLD vs non-lean/obese NAFLDLiver function tests findings, lean/non-obese NAFLD vs non-lean/obese NAFLDHistological outcomes, lean/non-obese NAFLD vs non-lean/obese NAFLDSurvival-related outcomes, lean/non-obese NAFLD vs non-lean/obese NAFLD
Younossi et al[28]/2012/United States11613 study population; 2491 NAFLD patients (431 lean)↓ Prevalence of insulin resistance, T2DM, hypocholesteremia, hypertension, HOMA score↓ AST, ALTNANA
Zou et al[30]/2020/ United States4711 patients with NAFLD (1528 non-obese)Similar prevalence of T2DM and MetS, Metabolic comorbidities: More commonNA↑ Prevalence of advanced liver fibrosis↑ 15-yr overall, cardiovascular, cancer and other causes related mortality (not significant in a Cox model)
Yoshitaka et al[31]/2017/Japan1647 individuals; 312 NAFLD patients (69 non-overweight)↓ BP, glucose, ↑ HDL-C↓ AST, ALT, and γ-GTNANA
Kwon et al[38]/2012/South Korea29994 study population; 6039 NAFLD patients (3014 non-obese)↑ Prevalence ratios for high BP, glucose intolerance, and ↑ TG, ↓ HDL-C especially among women populationNANANA
Feng et al[39]/2014/China1779 study population; 898 NAFLD patients (134 lean)↓ Insulin, TC, UA, HOMA-IR, ↑ HDL-C↓ ALT and γ-GTNANA
Lee et al[40]/2018/China2008 enrolled subjects; 493 NAFLD patients (208 non-obese)↑ Prevalence of MetS and hypertension, ↓HDL-CNANANA
Zeng et al[41]/2020/China2715 enrolled participants; 1100 NAFLD patients (142 lean)↑ Prevalence of MetSNALess severe hepatic steatosis, evaluated by ameliorated values of CAP and FLINA
Wang et al[43]/2015/China9360 women population; 1194 were NAFLD patients (514 non-obese)↑ UA, glucose↓ ALT, AST but ↑ AST/ALT ratioNANA
Kumar et al[44]/2013/India205 NAFLD patients (27 lean)↓ Hyperinsulinemia, HOMA-IR, ↓ prevalence of T2DM, MetS↓ Mean NAS and ↓ proportion of patients with liver fibrosisNA
Feldman et al[47]/2017/Austria187 subjects; 116 NAFLD patients (55 lean)↓ Glucose, insulin, HOMA-IR, ↑ HDL-C, adiponectin↓ ALTNANA
Fracanzani et al[49]/2017/Italy669 NAFLD patients (143 lean)↓ Prevalence of hypertension, T2DM, MetS, NASH, carotid plaques and significant thinner carotid intima-mediaNA↓ Prevalence of NAFLD and ↓ median NASNA
Shao et al[50]/2020/China534 NAFLD patients (240 non-obese)No ↑ risk of cardiovascular damage and ↑ TC, FFA, TG, BP, insulin resistance↓ ALT and ASTNANA
Li et al[51]/2019/China496 NAFLD patients (101 lean)↑ Proportion of patients with ↑ TG, glucose↓ Proportion of patients with ↑ ALTNANA
Leung et al[52]/2017/Hong-Kong307 NAFLD patients (72 non-obese)↓ Prevalence of MetS, hypertensionNA↓ NAS, ↓ fibrosis stage, serum cytokeratine-18 fragments and liver stiffness measurementSevere clinical outcomes (6 deaths, 2 HCC,1 liver failure) were observed only in the obese group
Niriella et al[53]/2018/Sri Lanka2985 initial cohort; 936 NAFLD patients (120 lean)↓ Prevalence of hypertension and central obesity, no significant difference in prevalence of other metabolic comorbidities at baseline. No remarkable alterations of new onset of metabolic comorbidities at the completion of follow-upNANANA
Honda et al[54]/2016/Japan1562 enrolled subjects; 540 NAFLD patients (134 non-obese)↑ HOMA-IR, glucose, insulin, TG, ↓ genotype prevalence of (PNPLA3) GG↓ ALT and AST↓ Lobular inflammation, steatosis grade, hepatocyte ballooning and NASNA
Wei et al[55]/2015/Hong-Kong262 patients with NAFLD (135 non-obese)↓ Insulin resistance, BP and cytokeratin-18 fragments and ↓ prevalence of MS, ↑ genotype (PNPLA3) GG prevalenceNALess non-obese NAFLD patients with ↑ NAFLD fibrosis scoreNA
Alam et al[56]/2014/Bangladesh465 NAFLD patients (119 non-obese)Similar prevalence of T2DM and hypertension and ↓ TC, glucose, HOMA-IR, ↑ HDL-C↓ ALT, AST, γ-GTNo significant difference in histological findingsNA
Akyuz et al[57]/2015/Turkey483 NAFLD patients (37 lean)↓ BP, ↓ prevalence of MetS, less severe hepatic steatosis, ↑ hemoglobin levelsNALess severe hepatic fibrosisNA
Cruz et al[58]/2014/United States1090 NAFLD patients (125 lean)↓ Insulin resistance, ↓ prevalence of low HDL-C, hypertriglyceridemia and hypertension↓ ALT↓ Steatosis degree and less advanced fibrosis↓ Cumulative survival
Hagström et al[59]/2018/Sweden646 NAFLD patients (123 lean, 335 overweight, 188 obese)↓ TG, glucose↓ ALT, AST compared to both overweight and obese counterparts↓ Prevalence of NASH and ↓ mean fibrosis stage compared to both overweight/obese patients↓ Risk for overall mortality, ↑ risk for severe hepatic disease development as compared to overweight patients

Studies with metabolic outcomes: Regarding metabolic outcomes in NAFLD obese and NAFLD non-obese/lean patients, in a retrospective study of 669 NAFLD patients in Italy, lean (BMI < 25 kg/m2) NAFLD patients had lower prevalence of hypertension, T2DM and MetS than overweight (25 kg/m2 ≤ BMI < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) NAFLD patients[49]. Notably, the former group had significantly thinner carotid intima-media, indicating less atherosclerotic burden[49]. Although this result was not confirmed in a study by Shao et al[50] in obese (BMI > 25 kg/m2) and non-obese Chinese NAFLD patients, the authors showed that the latter group had lower FPG and serum TC and TG levels as well as a lower prevalence of hypertension. Moreover, Li et al[51] demonstrated that the proportion of Chinese patients with elevated FPG and serum TG levels was higher among obese (BMI > 25 kg/m2) compared with non-obese NAFLD patients, while another cross-sectional study from China confirmed that obese NAFLD women (BMI > 28 kg/m2) had higher FPG than non-obese women[43]. In addition, 2 studies from China showed a higher prevalence of MetS and hypertension in obese (BMI > 25 kg/m2) compared to non-obese patients with NAFLD[41,52]. In the Indian population, Kumar et al[44] reported that among NAFLD patients, lean (BMI < 23 kg/m2) patients had had lower serum insulin levels and HOMA-IR, as well as lower prevalence of T2DM and MetS than obese (BMI > 25 kg/m2) patients. In a case control study from Sri Lanka, Niriella et al[53] reported a higher prevalence of hypertension in non-lean (BMI > 23 kg/m2) patients with NAFLD compared with lean NAFLD patients. In studies performed in Japan, Yoshitaka et al[31] reported lower blood pressure and FPG and higher serum high density cholesterol (HDL-C) levels in lean (BMI < 23 kg/m2) than in overweight NAFLD patients[44], while Honda et al[54] reported that FPG, insulin, TG and HOMA-IR were increased among Japanese obese (BMI > 25 kg/m2) NAFLD patients compared with non-obese NAFLD patients. In a study form Hong-Kong, Wei et al[55] reported that non-obese (BMI < 25 kg/m2) NAFLD patients had lower IR than obese NAFLD patients. Moreover, the prevalence of MetS and hypertension was increased in obese patients. A study performed in Bangladesh also showed that non-obese (BMI < 25 kg/m2) NAFLD patients had lower TC, FPG, HOMA-IR and higher HDL-C levels than obese NAFLD patients[56].

Similar findings were observed in the cross-sectional NHANES III study, in which lean (BMI < 25 kg/m2) NAFLD patients had less frequently hypertension, T2DM and hypercholesteremia as well as lower levels of FPG and HOMA-IR than overweight /obese NAFLD patients[28]. In a prospective study from Turkey, Akyuz et al[57] reported that lean (BMI < 25 kg/m2) NAFLD patients had a less prevalence of MetS and hypertension than overweight NAFLD patients, while in a study from Spain, Gonzalez-Cantero et al[48] also confirmed that overweight (BMI: 25-29 kg/m2) patients with NAFLD had higher HOMA-IR and TG and lower HDL-C serum levels than lean NAFLD patients. In a study from Austria, Feldman et al[47] also reported that lean (BMI < 25 kg/m2) NAFLD patients had lower FPG, insulin and HOMA-IR and higher HDL-C levels than obese NAFLD patients.

In contrast to these findings, a retrospective study from South Korea reported a higher prevalence of MetS components in non-obese (BMI < 25 kg/m2) NAFLD patients compared with obese NALFD patients, even after adjusting for confounders[38]. It is possible that unrecorded differences in dietary patterns, physical activity and smoking status between the 2 groups might explain this paradoxical might[38]. Lee et al[40] also reported that non-obese (BMI < 25 kg/m2) NAFLD patients had higher prevalence of MetS and hypertension as well as lower serum HDL-C levels than obese NAFLD patients. However, this study was hospital- and not community-based suggesting the presence of selection bias as an explanation for these unexpected findings[40].

Studies with both metabolic and clinical outcomes: In a prospective cohort study in 307 NAFLD patients from Hong-Kong, Leung et al[52] reported that non-obese patients (23.5% patients of the total cohort) had lower prevalence of MetS and hypertension as well as lower NAFLD activity score, serum cytokeratin-18 fragments and decreased liver stiffness based on transient elastography than obese patients. Of note, deaths, HCC and liver failure occurred only in obese patients during a follow-up period of 49 mo[52].

In contrast, a United States study in 483 biopsy-confirmed NAFLD patients showed that lean (BMI < 25 kg/m2) patients had higher all-cause mortality than non-lean patients during a follow-up of 133 mo, although they had lower prevalence of T2DM, MetS, hypertriglyceridemia and hypertension, and less advanced fibrosis. Notably, even after adjustment for potential confounders, lean NAFLD was an independent risk factor (HR: 11.8) for higher all-cause mortality[58]. In the NHANES study, Zou et al[30] also reported that non-obese NAFLD (BMI < 30 kg/m2 for non-Asians and < 27 kg/m2 for Asians) patients had a higher prevalence of metabolic comorbidities, more advanced fibrosis and higher mortality due to cardiovascular disease and cancer and higher all-cause mortality than obese NALFD. However, these findings were not confirmed in a multivariate analysis, where only T2DM and fibrosis stage were independent risk factors for mortality[30]. Finally, in a retrospective cohort study in 646 NAFLD patients in Sweden, Hagström et al[59] reported that lean (BMI < 25 kg/m2) NAFLD patients had higher risk for cirrhosis, decompensated cirrhosis and HCC than overweight (25 kg/m2 ≤ BMI < 30 kg/m2) patients, independently of confounders; all-cause mortality did not differ between the 2 groups. Of note, lean patients had lower serum TG and FPG levels as well as lower prevalence of NASH and lower fibrosis stage[59].

It may seem paradoxical that most studies[30,58,59], although not all[52], reported a worse prognosis in non-obese/lean patients with NAFLD compared with obese NAFLD patients. Zou et al[30] attributed the worse outcome of non-obese NAFLD patients to the advanced fibrosis stage and the higher frequency of metabolic comorbidities in this group. Hagström et al[59] speculated that genetic predisposition and unhealthy lifestyle were associated with the worse liver-related outcomes of lean NAFLD patients. Another explanation could be that in all studies, BMI was used as a surrogate marker to define the thresholds for leanness or obesity. However, BMI is not a specific marker of abdominal obesity; waist circumference reflects more accurately the visceral adiposity fat fraction[60]. Nonetheless, even waist circumference cannot distinguish visceral from subcutaneous fat and cannot allow quantification of adipose tissue parts. Accordingly, more accurate markers of abdominal obesity, such as magnetic resonance imaging (MRI), might be useful in distinguishing between obese and lean patients with NAFLD. Indeed, MRI is considered a more accurate and quantitative tool for evaluation of visceral adipose tissue[61]. Thus, both the definition of lean/non-obese NAFLD and the categorization of patients into lean/non-obese or obese should be based in the near future on MRI to overcome the limitation of current, BMI-based definitions.

MANAGEMENT OF NON-OBESE/LEAN NAFLD

Management of NAFLD in lean patients is particularly challenging, since the cornerstone of NAFLD treatment is weight loss, which might not apply in these patients. In addition, there are no specific guidelines for the management of NAFLD in lean subjects. However, accumulating data suggest that several interventions might be useful in this population. A summary of the key elements of management of lean NAFLD is given in Table 3.

Table 3 Key elements of management of lean non-alcoholic fatty liver disease.
Evaluation of severity of liverLiver fibrosis (serological markers, elastography, biopsy)
Presence of NASH (biopsy or serological evidence of inflammation)
Weight reduction5% of body weight reduction can be effective in reducing steatosis
Physical activityPositive effect regardless of weight reduction
Dietary Intervention↓ Fat intake, ↑ protein intake
CommorbiditiesStrict control of:
Diabetes mellitus (consider pioglitazone)
Hypertriglyceridemia (baseline triglyceride count was independently correlated with NAFLD resolution)
Hypercholesterolemia (reduction of total cholesterol was independently correlated with steatosis reduction)
Hypertension
Sleep patternsEmphasize the significance of adequate sleep duration and quality
Pharmacological therapyPioglitazone and vitamin E as the only accepted therapies, but proposed only on an individual basis
Possible role of probiotics
Small number of trials for lean patients
According to the results of trials focusing on non-lean patients
Initial workup and assessment of disease severity

To select the most appropriate management, a thorough diagnostic workup should be performed. The initial workup of a lean patient with suspected NAFLD may include a variety of modalities. Usually, ultrasound is the screening imaging method of choice and can provide information regarding the presence and severity of steatosis and the presence of cirrhosis. The Fibrosis-4 (FIB-4) and NAFLD fibrosis score can be useful for assessing the severity of liver fibrosis in patients with NAFLD[62,63]. In patients with inconclusive findings, elastography (transient, shear wave, or magnetic resonance) is the most widely used method to assess the severity of hepatic fibrosis, otherwise liver biopsy is recommended[64,65].

Management of NAFLD in lean subjects

Weight reduction: Similar with obese patients with NAFLD, weight reduction appears effective in lean subjects with NAFLD. In a study in 333 patients with NAFLD, weight change was an independent predictor of disease progression or resolution after a mean follow-up of 28.7 mo. Interestingly, among patients who also experienced NAFLD progression, non-obese subjects had greater weight gain than obese patients whereas among patients who experienced NAFLD resolution, non-obese patients showed smaller weight loss than obese subjects[66]. Moreover, 2 studies showed that 5% of body weight reduction led to significant decrease in steatosis in lean patients with NAFLD[67,68]. In the first study (n = 120 patients with NAFLD), a 10-wk program including diet modification and exercise resulted in improvement in steatosis in the repeated liver biopsy[67], while in the second one (n = 14 Lean NAFLD patients), an 8-wk intervention consisting of intensive dietary and lifestyle measures induced a decrease in both steatosis and stiffness assessed with transient elastography[68].

Dietary modifications and physical activity: Diet appears to improve NAFLD in lean patients independently of weight loss. It has been reported that lean patients with NAFLD have comparable total caloric intake with obese patients with NAFLD[69,70]. However, the former have higher intake of cholesterol and lower intake of polyunsaturated fatty acids (PUFAs)[70]. In a study in 120 patients with NAFLD who followed a 10-wk program including diet modification and exercise, most patients achieved a reduction of steatosis without weight reduction; instead, a reduction in fat intake and in overall body fat was observed and might have contributed to the improvement in steatosis[67]. Therefore, low-fat diet appears more appropriate for lean patients with NAFLD.

There are also reports highlighting physical exercise as a contributing factor to NAFLD amelioration irrespectively of its effect on body weight. In a large retrospective study (n = 3718), lack of physical activity was independently associated with the presence of NAFLD, after adjusting for visceral adiposity and IR. These results might be particularly relevant for lean patients with NAFLD, who have lower prevalence of IR and visceral adiposity compared with obese patients[28,58].

Management of comorbidities: As already mentioned, lean patients with NAFLD appear to have higher incidence of T2DM compared with overweight patients without NAFLD[32]. Given that T2DM is a major risk factor for NAFLD progression[71-73], these findings highlight the importance of T2DM prevention in this population. Furthermore, it has been reported that elevated TG levels are independently associated with development or resolution of NAFLD, especially in non-obese patients[66]. In another study, a ≥ 10% reduction in TC levels was independently associated with ≥ 20% reduction of steatosis in biopsy after a 10-wk exercise and diet modification program[67]. Given the increased cardiovascular risk of lean NAFLD patients, screening for and management of cardiometabolic comorbidities are essential to reduce cardiovascular morbidity in this population.

Sleep patterns: Short duration and poor quality of sleep have been associated with increased incidence of NAFLD[74-77]. Considering that a substantial proportion of lean patients with NAFLD have disturbed sleep[69], recommendations for more rest and efforts to improve sleep quality should be considered in this population.

Pharmacological interventions

Treatment options for NAFLD include pioglitazone and vitamin E but are limited to non-diabetic patients with biopsy-proven NASH. However, in both European and American guidelines, these agents are recommended to be used with caution and in carefully selected patients[4,64]. In addition, only ezetimibe has been evaluated in lean patients with NAFLD. In a pilot study (n = 8 non-obese patients), treatment with ezetimibe for 12 mo resulted in a decrease in aminotransferase levels but had no effect on hepatic steatosis assessed with ultrasound[78]. Interestingly, BMI did not change during the study. A larger, placebo-controlled, randomized study evaluated a symbiotic supplement consisting of seven bacterial strains in 50 lean NAFLD patients who also received lifestyle recommendations[79]. The supplement resulted in a greater reduction in liver stiffness and steatosis, in serum TG and TC levels and in inflammatory markers including high-sensitivity C-reactive protein and nuclear factor-κB activity than placebo. This study supports the findings of a previous report in obese patients with NAFLD[80] and suggests a role of gut microbiota manipulation in the management of NAFLD.

CONCLUSION

Even though NAFLD is strongly associated with obesity and related comorbidities, a substantial proportion of lean subjects can also develop NAFLD. Visceral obesity as opposed to general obesity, genetic predisposition, unhealthy dietary pattern consisting of high cholesterol and fructose intake may be associated with lean NAFLD. Although lean patients appear to have a worse prognosis but a healthier metabolic profile than obese patients with NAFLD, we should bear in mind that the current categorization into lean or obese cohorts was mostly based on BMI and not on visceral fat mass evaluation. Thus, the use of MRI as a reliable and quantitative diagnostic tool for evaluating the presence and severity of abdominal obesity in NAFLD patients might be useful. Currently, lifestyle interventions including weight loss, physical activity and a healthier dietary pattern seem to have beneficial impact on lean NAFLD. Beyond that, sleep interventions and pharmacotherapy along with strict management of comorbidities should also be incorporated in the management of this disease. Without a doubt, lean NAFLD raises many challenges since the pathophysiology and the natural history of the disease has not been widely studied and physicians should have high clinical suspicion in order to identify individuals at risk of lean NAFLD who lack the common, easily recognizable phenotype of obesity.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: Greece

Peer-review report’s scientific quality classification

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Grade C (Good): C, C

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P-Reviewer: Enomoto H, Tomizawa M S-Editor: Huang P L-Editor: A P-Editor: Ma YJ

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