v
Search
Advanced Search

Publications > Journals > Journal of Translational Gastroenterology > Article Full Text

  • Review Article
  • OPEN ACCESS

Obesity and Metabolic Dysfunction-associated Fatty Liver Disease: Understanding the Intricate Link

  • Jayavardhan Vulchi1,
  • Varun Suryadevara1,
  • Pazhanivel Mohan2,* ,
  • Sadishkumar Kamalanathan1,
  • Jayaprakash Sahoo1,
  • Dukhabandhu Naik1 and
  • Sandhiya Selvarajan3,* 
 Author information
Journal of Translational Gastroenterology   2023;1(2):74-86

doi: 10.14218/JTG.2023.00043

Abstract

Obesity is a complex disease resulting from excessive adipose tissue in the body, leading to various metabolic, mechanical, and psychological complications. The prevalence of obesity has increased exponentially in the past few decades to reach an epidemic proportion. Obesity can predispose to or aggravate the fatty liver. Metabolic dysfunction-associated fatty liver disease (MAFLD) represents fatty liver in individuals who are either overweight/obese, or have type 2 diabetes, or have normal weight with at least two metabolic risk factors. MAFLD pathogenesis is multifactorial and involves an interplay of genetics, lifestyle-related factors, gut dysbiosis, lipotoxicity, and oxidative stress. Besides hepatic complications, MAFLD also has systemic implications in the form of increased risk for various metabolic diseases, cardiovascular diseases, malignancies, and infectious diseases. If left untreated, MAFLD can progress to liver cirrhosis and end-stage liver disease. Many noninvasive strategies like serum-based markers and imaging help diagnose MAFLD at an early stage. Timely detection and appropriate intervention are crucial for preventing its progression to advanced liver disease and hepatocellular carcinoma. Though lifestyle modification remains the main pillar of management, with advances in the treatment of obesity, newer agents are being tried for patients with MAFLD. The current therapeutic strategies are limited, and future research is needed to identify the subset of patients with MAFLD who are at a higher risk of hepatic and systemic complications and to develop more effective and personalized therapies.

Keywords

Obesity, MAFLD, Metabolic syndrome

Introduction

Obesity represents a persistent metabolic state characterized by the abnormal accumulation of body fat, which can potentially jeopardize one’s health. Between 1975 and 2016, the number of obese people has tripled worldwide. As per the World Health Organization report in 2016, more than 650 million people aged 18 years and older (13%) were obese; of this, 11% were men and 15% women.1 The COVID-19 pandemic increased the prevalence of overweight and obesity, primarily linked to quarantine measures, lockdowns, self-isolation, and decreased physical activity.

The fundamental principle underlying obesity is an imbalance between energy intake and expenditure. The hypothalamus plays a central role in the regulation of appetite and energy balance. However, the regulation of food intake is complex and involves a combination of physiological, psychological, and environmental factors (such as calorie-dense and easily accessible foods). Food marketing, larger portions, and the prevalence of high-calorie, low-nutrient options contribute to overeating. Obesity is associated with various metabolic, mechanical, and psychological complications including social stigma and unemployment. Obesity affects cardiovascular health and significantly increases the risk of conditions like gastrointestinal (GI) diseases, diabetes, and cancer, ultimately reducing life expectancy. The relationship between obesity and GI diseases involves complex mechanisms, including mechanical stress on the GI tract, promoting a cancer-friendly environment, low-grade inflammation, and influence of dietary constituents.2Table 1 provides a comprehensive compilation of GI complications linked to obesity.

Table 1

Obesity-related gastrointestinal complications

SiteLesion
EsophagusGastroesophageal reflux disease; Erosive esophagitis; Barrett’s esophagus; Esophageal adenocarcinoma
StomachErosive gastritis; Gastric cancer
Small intestine and colonDiarrhea; Colonic diverticular disease; Polyps; Cancer; Clostridium difficile infection; Dyssynergic defecation
LiverMetabolic dysfunction-associated fatty liver disease; Cirrhosis; Hepatocellular carcinoma
GallbladderGallstones; Gallbladder carcinoma
PancreasAcute pancreatitis; Pancreatic cancer

Metabolic dysfunction-associated fatty liver disease (MAFLD) is of paramount concern among the various GI complications associated with obesity, increasing the risk of liver as well as systemic complications. Due to the significant increase in obesity and type 2 diabetes mellitus (T2DM) prevalence, and advancements in viral hepatitis care, MAFLD is swiftly emerging as the most prevalent liver disease in numerous regions worldwide.3 According to studies conducted among the general population, body mass index (BMI), and the prevalence of MAFLD have a positive association and suggest shared pathogenic mechanisms. As per estimates, the prevalence of MAFLD among adults in general ranges from 25 to 30%, while the occurrence of underlying nonalcoholic steatohepatitis (NASH) is estimated to be between 3% and 6%.4 This review narrates the association between obesity and MAFLD and their clinical implications on comorbidities, diagnosis, and treatment.

Genesis of MAFLD

Ludwig et al.5 first adopted the term “nonalcoholic fatty liver disease” (NAFLD) in 1980 to refer to fatty liver disease without a history of heavy alcohol consumption. A prerequisite for the diagnosis of NAFLD is the absence of any secondary causes of hepatic steatosis, such as alcohol consumption, autoimmune liver disease, use of steatogenic medications, and drug misuse.6 However, understanding the disease pathophysiology has significantly improved, blurring the border between alcoholic liver disease and NAFLD.7 In 2020, a group of international experts introduced a novel term MAFLD. This can be diagnosed in people with fatty liver who are either overweight/obese or have type 2 diabetes, or have normal weight with at least two metabolic risk factors, as shown in Figure 1.8

Comparison of NAFLD and MAFLD diagnostic criteria.
Fig. 1  Comparison of NAFLD and MAFLD diagnostic criteria.

AASLD, American Association for the Study of Liver Diseases; BP, blood pressure; CRP, C-reactive protein; EASL, European Association for the Study of the Liver; FBS, fasting blood sugar; HDL, high-density lipoprotein; MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, nonalcoholic fatty liver disease; PPBS, postprandial blood sugar; TG, serum triglycerides.

Natural history of MAFLD

MAFLD encompasses a range of conditions, from fatty liver to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (Fig. 2). Traditionally, steatohepatitis has been regarded as the advanced stage of fatty liver disease. However, current evidence suggests a dynamic course between the two conditions, especially in the early stages. However, fibrosis progression may be faster in individuals with steatohepatitis. Although both fatty liver and steatohepatitis can progress to fibrosis, the rate of progression is slower in fatty liver (nearly 14 years to advance one fibrosis stage) compared to steatohepatitis (7 years).9 While the majority experience slow fibrosis progression, around 20–30% may exhibit rapid fibrosis progression.10

Pathogenesis and spectrum of MAFLD.
Fig. 2  Pathogenesis and spectrum of MAFLD.

Hepatic steatosis is promoted by factors such as obesity, insulin resistance, de novo lipogenesis, high-calorie diets, genetic factors, and gut microbiome dysbiosis. In contrast, VLDL export, and increased fatty acid oxidation in the initial stages clear the excessively accumulated fat from hepatocytes. However, ongoing hepatic steatosis that exceeds the capacity of the liver to oxidize intracellular lipids in the mitochondria activates alternate oxidation pathways and generates reactive oxygen species, resulting in steatohepatitis. Both fatty liver stage and steatohepatitis can progress to cirrhosis and subsequent hepatocellular carcinoma unless the risk factors are modified. MAFLD, metabolic dysfunction-associated fatty liver disease; VLDL, very low-density lipoproteins. (Image created with BioRender.com)

Pathophysiology

Hepatic steatosis in obesity results from disruption of the delicate equilibrium between hepatic fat synthesis, fat oxidation, and fat export. Various mechanisms that lead to increased hepatic fat synthesis include enhanced transport of free fatty acids (FFAs) to the liver due to insulin resistance (IR), activation of hepatic de novo lipogenesis (DNL) and consumption of a high-calorie diet. Adipose tissue lipolysis contributes to about 59% of stored hepatic fatty acids, while DNL and dietary intake contribute 26% and 15%, respectively.11 Liver compensation for ongoing fat accumulation involves increased export of fats and enhanced oxidation of accumulated fatty acids.

IR

In the healthy state, insulin regulates glucose metabolism and inhibits adipose tissue lipolysis and hepatic production of very low-density lipoprotein (VLDL). As a result, fewer FFAs and energy substrates from adipose tissue are delivered to the liver.12 However, there is increased peripheral lipolysis and release of FFAs from adipose tissue, along with enhanced hepatic uptake of FFAs in people with IR.13 As a result, FFAs accumulate in the liver and are converted into hepatic triglycerides, which results in hepatic steatosis.14 It is noteworthy that lean individuals with MAFLD may have coexisting IR and hepatic steatosis. This finding suggests that hepatic steatosis may be the initiating event leading to IR in lean individuals.15

DNL

DNL is the synthesis of fatty acids from two-carbon precursors that are derived from glucose, fructose, and amino acids. Sterol regulatory element binding protein 1c (SREBP1c) and carbohydrate regulatory element binding protein (ChREBP) are two essential transcription factors that play critical roles in regulating lipogenesis in the liver.16,17 Insulin and the liver X receptor activate SREBP1c, whereas products of glucose metabolism activate ChREBP.18 In MAFLD patients, SREBP1c expression is elevated, leading to increased patatin-like phospholipase domain-containing protein 3 (PLNPLA3) gene transcription and lipogenesis.19 The expression of genes associated with lipogenesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), is promoted by ChREBP activation, which is induced by high blood glucose levels.20

High-calorie diets

Overconsumption of sugar-sweetened beverages containing sucrose or high-fructose corn syrup is associated with increased visceral fat, fatty liver, and steatohepatitis.21 Dietary sugars, especially simple sugars, strongly promote fatty acid synthesis. A high-calorie Western diet also reduces gut microbe diversity, as processed nutrients are quickly absorbed in the small intestine thus depriving the colonic microbiota of essential nutrients.22 The microbiota resort to the gut mucosal barrier during dietary fiber deficiency to obtain nutrients. This reduces the mucus layer and exposes the epithelial cells to luminal pathogens resulting in leaky gut and inflammation promoting steatohepatitis.23

Altered export of fat

The triglyceride export plays a vital role in regulating the amount of fat stored in the liver. This process involves two critical components: apolipoprotein B100 (apoB100) and microsomal triglyceride transfer protein (MTTP).24 ApoB100 secretion is stimulated by moderate exposure to fatty acids. However, high levels of fatty acids induce Endoplasmic reticulum stress, inhibiting the secretion of apoB100 and contributing to the development of steatosis.25 Genetic defects in MTTP impact the export of triglycerides from the liver and can result in MAFLD.26

Defective fatty acid oxidation and hepatic lipotoxicity

Previous studies have shown that the hepatic mitochondrial capacity is initially stimulated by the greater availability of lipids in the liver of obese people with MAFLD. However, this stimulation eventually leads to excessive oxidative stress and a decline in mitochondrial functionality, promoting the progression from fatty liver to steatohepatitis.27 Furthermore, compromised mitochondrial beta-oxidation leads to alternative peroxisomal and cytochrome oxidation pathways for fatty acids, producing excess free radicals. These reactive oxygen and nitrogen species contribute to lipid peroxidation and hepatic stellate cells’ activation, thus accelerating the development of fibrosis.28 The increased influx of FFAs into the liver also triggers inflammatory responses and damage. These processes can stimulate hepatic stellate cells and promote liver fibrosis.

Role of genetics

Several studies have identified candidate genes associated with risk of MAFLD and progression to steatohepatitis. These genes encode proteins involved in hepatic and/or extra-hepatic lipid metabolism. Mutations in genes such as PNPLA3 or adiponutrin (involved in remodeling of hepatic fatty acids),29 transmembrane 6 superfamily member 2 (TM6SF2) (involved in lipidation of VLDL in a pre-Golgi compartment of liver),30 membrane-bound O-acyl transferase domain-containing protein 7 (involved in phospholipid remodeling),31 and glucokinase regulatory protein (regulator of hepatic DNL)32 increase the risk of developing MAFLD. Conversely, mutations in the mitochondrial amidoxime-reducing component 1 and the hydroxysteroid 17-beta dehydrogenase 13 genes are linked to a lower chance of progression to steatohepatitis.33,34

Role of gut microbiome

The gut microbiome has a pivotal role in preserving the integrity of the mucosal barrier function, facilitating nutrient absorption, and regulating energy balance. Intestinal dysbiosis in obesity is characterized by reduced bacterial diversity and richness, along with a shift toward a higher Firmicutes to Bacteroidetes ratio. This dysbiosis, coupled with compromised gut permeability, results in elevated levels of gut-derived toxins entering the bloodstream. This, in turn, contributes to the chronic low-grade inflammation observed in obesity and MAFLD.35

A prominent endotoxin produced by Gram-negative bacilli (lipopolysaccharide) can trigger a signaling cascade, ultimately increasing intestinal permeability by modulating the distribution of tight junction proteins.36 Some bacterial species rely on choline for phosphatidylcholine production, reducing the choline available to the host liver. Choline deficiency can lead to hepatic steatosis as it is essential for formation of lipoproteins and lipid transfer in liver.37 The gut microbiota produces short-chain fatty acids (SCFAs) from indigestible starch and dietary fiber. SCFAs are the primary source for colonic epithelial cells. In addition, SCFAs can be transported to liver for citric acid cycle, gluconeogenesis, or lipogenesis. Thus, any alteration in levels of SCFA production can potentially affect the energy delivery to the liver.22

The gut microbiota also impacts bile acid metabolism and composition through enzymatic actions like bile salt hydrolase (BSH). Unconjugated primary and secondary bile acids have a higher affinity for farnesoid X receptor (FXR), a key regulator found in the liver and intestines.38 FXR modulates bile acid synthesis, reduces uptake, and aids their secretion into bile. In the liver, FXR activation dampens DNL by repressing SREBP1 and suppresses the lipogenic genes such as FAS, ACC, stearoyl-Co A desaturase-1. It also influences lipid transport, promotes fatty acid oxidation [via peroxisome proliferator-activated receptor (PPAR)-α activation], and boosts triglyceride hydrolysis through carboxylesterase 1, supporting mitochondrial fatty acid oxidation.39 A gut microbiome with reduced BSH activity leads to increased conjugated bile acids with less affinity for FXR. Reduced FXR activation increases DNL and the synthesis of FFAs in the liver.40

Role of gut hormones and other small molecules

Ghrelin, a gut hormone, is involved in appetite regulation and adiposity control. Certain gene variations in the ghrelin gene are associated with obesity, type 2 diabetes, metabolic syndrome, MAFLD, and hepatocellular carcinoma.41 Sirtuins are a class of enzymes involved in cellular processes like metabolism and inflammation. They are potential therapeutic targets in MAFLD due to their impact on cellular metabolism, oxidative stress, and inflammation.42

Adipokines

Obesity also affects the liver through adipokines. The substances released from adipose tissue, including hormones, cytokines, extracellular matrix proteins, and angiogenic proteins are collectively referred to as adipokines. Adipose tissue expansion results in imbalance between adipokines [decreased adiponectin, obestatin, elevated leptin, resistin, retinol-binding protein 4 (RBP-4) and increased proinflammatory cytokines and innate immune cells IL-1, IL-6, TNF-α, macrophages, B lymphocytes, T lymphocytes and neutrophils] promoting hepatic steatosis and steatohepatitis by adipose tissue-liver cross talk.43 Elevated RBP4 levels are associated with IR and may contribute to liver fat accumulation and inflammation in MAFLD.44

Hepatokines

Obesity is associated with enhanced release of hepatokines from the liver. Hepatokines predominantly function as liver-derived pro-inflammatory mediators, exerting a pivotal role in the promotion of liver steatosis and steatohepatitis through their influence on lipid metabolism, reactive oxygen species generation, and the inflammatory response. Notable hepatokines include hepassocin, angiopoietin-like protein 8, fetuin-A, and fetuin-B, as well as fibroblast growth factors (FGFs) 19 and 21.45 Among these, FGF21 stands out for its positive impact on adipose tissue, insulin sensitivity, lipogenesis, and mitochondrial function. Exogenous administration of FGF21 has shown promise as a potential therapeutic approach for MAFLD in preclinical models.46

Role of inflammation

Obesity is characterized by a low-grade chronic inflammation resulting from inflammatory adipokines and intestinal inflammation due to dysbiosis. Lipotoxicity of hepatocytes activates innate and adaptive immunity. Recruitment of the immune cells to the liver is an important step in the pathogenesis of NASH. Inflammation triggers hepatic stellate cell activation and fibrogenic transformation, culminating in liver fibrosis and cirrhosis.47

GATA binding protein 3 and MAFLD

Macrophages are the source of low-grade inflammation referred to as meta-inflammation in obesity. GATA binding protein 3 is the transcription factor responsible for regulation of macrophage polarization and infiltration and is proposed as an important determinant of inflammation.48 The people with obesity were also found to have increased expression of hepatic dendritic cells which may be contributing to the inflammation.49

Role of GH-IGF1 axis

Obesity reduces the secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF1) from the liver. Recent studies in pediatric subjects with obesity indicate that GH/IGF1 axis anomalies are linked to higher rates of steatosis, rapid progression to steatohepatitis, cirrhosis, and liver disease. GH and IGF1 play pivotal roles in glucose and lipid metabolism, with GH increasing blood sugar levels and promoting lipolysis, while IGF1 lowers blood sugar and encourages lipogenesis. GH and IGF1 deficiencies in the liver contribute to MAFLD development, increasing hepatic triglyceride accumulation and IR.50

Systemic effects of MAFLD

Apart from the hepatic complications, MAFLD has been linked to diverse systemic comorbidities. Individuals with MAFLD have a higher risk of acquiring cardiovascular disease [congestive heart failure, valvular heart disease, ischemic stroke, atrial fibrillation, and ventricular arrhythmias] than the general population, and cardiovascular disease is the most common cause of mortality in patients with MAFLD.51 Likewise, chronic kidney disease and sleep apnea are more prevalent among patients with MAFLD. It is associated with many malignancies such as colon, gastric, breast, and uterine cancer. Endocrine conditions associated with MAFLD include polycystic ovarian syndrome, hypothyroidism, and GH deficiency.52 Limited research on MAFLD’s impact on infectious diseases shows higher infection rates, longer/complicated courses, and increased fatality from infections like Helicobacter pylori, Clostridium difficile, COVID-19, bacterial pneumonia, periodontitis, urinary tract infection, and HIV.53

Diagnosis

Several techniques have been suggested for a minimally invasive evaluation of hepatic fat, inflammation, and fibrosis. These techniques encompass various imaging modalities and multiple biomarkers. However, no commonly used, accurate methods exist that can noninvasively distinguish between steatosis and NASH other than liver biopsy.

Assessment of steatosis

Liver enzymes alone are not precise predictors of MAFLD. Although patients with MAFLD are expected to have abnormal liver enzymes, up to 80%, have normal liver functions in clinical practice.54 So, many steatosis indicators have been explored to increase diagnostic accuracy.55 These include the fatty liver index, NAFLD liver fat score, NAFLD ridge score, hepatic steatosis index, steatotest, visceral adiposity index,56 triglycerides and glucose index,57 lipid accumulation product.58Table 2 shows a list of blood-based biomarkers.

Table 2

Blood-based biomarkers or scores for steatosis and fibrosis in MAFLD

Blood marker of steatosisComponent or formulaCutoffAUROCSensitivity, %Specificity, %
Hepatic steatosis indexALT, AST, BMI, type 2 DM, female sexRule out cutoff <30; Rule in cutoff >360.8292.592.4
Fatty liver indexTG, BMI, GGT, WCRule out cutoff <30; Rule in cutoff ≥600.848786
NAFLD liver fat scoreMetabolic syndrome, type 2 DM, insulin, AST, ALT>0.160.806587
SteatoTestALT, α2-macroglobulin, apolipoprotein A1, haptoglobin, total bilirubin, GGT, total cholesterol, TG, glucose, age, sex, BMIRule out cutoff <0.3; Rule in cutoff >0.70.72–0.869189
NAFLD ridge scoreALT, HbA1c, HDL, Hypertension, leucocyte count, TGDual cutoffs of 0.24 and 0.440.87–0.889290
Visceral adiposity indexWC, BMI, TG, HDL>1.250.927992
Triglyceride/glucose indexTG, glucose<60.817574

ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operating characteristic curve; BMI, body mass index; DM, diabetes mellitus; ELF, enhanced liver fibrosis; FIB-4, fibrosis-4 score; F2, significant fibrosis; F3, advanced fibrosis; GGT, gamma glutamyl transferase; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; HbA1c glycated hemoglobin; IFG, impaired fasting glycemia; NFS, nonalcoholic fatty liver disease fibrosis score; TG, triglycerides; WC, waist circumference.

Conventional ultrasonography

B-mode ultrasonography (USG) is frequently employed as the first imaging technique to diagnose hepatic steatosis due to its ease of use and low cost. The diagnosis of steatosis on USG is based on comparing the hepatic acoustic properties with that of surrounding structures, attenuation of the deep beam, parenchymal and vessel wall brightness, gallbladder wall definition, etc. However, USG has limited sensitivity for the detection of mild steatosis.59 Additional constraints of USG involve its inability to objectively quantify liver fat and its dependency on the skills and judgment of the examiner, resulting in limited reproducibility among different observers.60

Controlled attenuation parameter (CAP)

Novel USG-based methods, like CAP, provide a superior evaluation of liver fat compared to conventional USG. In a meta-analysis involving 2,375 patients from 19 studies, the sensitivity of CAP in comparison with histologically graded steatosis ranged from 82–89% based on the CAP cutoff (248 dB/m to 280 dB/m) to identify increasing severity of steatosis (>11–66% steatosis).61 Compared with magnetic resonance imaging-proton density fat fraction (MRI-PDFF), the CAP thresholds of 288 dB/m and 306 dB/m correlate with ≥5% and ≥10% steatosis respectively.62 These thresholds were higher than the CAP thresholds noticed in liver diseases of other etiologies. It is important to note that obesity can influence the CAP value. An obesity-specific XL probe has been developed to address this issue.63 Therefore, the optimal steatosis detection thresholds using various probes still need further clarification.

Magnetic resonance-based studies

Among noninvasive methods, proton magnetic resonance spectroscopy (1H-MRS) stands out as the most accurate technique for measuring hepatic triglyceride content (HTGC).64 It employs resonance frequencies to identify triglyceride-associated protons and calculates the fat fraction as the ratio of fat signal to the sum of water and fat signals. 1H-MRS shows excellent correlation with total lipid quantification in liver tissue specimens and can potentially replace liver biopsy for assessing liver fat content.65 However, its availability and clinical application are limited. In contrast, MRI-PDFF has shown strong correlations with histological assessment of fat content.66 MRI-PDFF reflects the concentration of triglycerides within liver tissue by measuring the ratio of mobile proton density from triglycerides to the combined mobile proton density originating from both triglycerides and water. MRI-PDFF demonstrates high diagnostic accuracy for detecting steatosis and can reliably detect small changes in HTGC.67 MRI/MRS-based techniques can utilize a 3% or lower cutoff to identify patients with hepatic steatosis. Studies indicate that the conventional cutoff of 5% for normal HTGC might be too high, given that metabolic changes can occur even at lower levels.68

Steatohepatitis scoring systems

Fatty liver, inflammation, and hepatocellular damage with or without fibrosis constitute steatohepatitis. Although serum alanine aminotransferase (ALT) is the commonly used biomarker for identifying and tracking chronic liver disease, it is not accurate enough to diagnose NASH. According to recent systematic reviews and meta-analyses, new biomarkers for detecting histologic steatohepatitis without fibrosis have been studied, but none have shown enough reliability for current clinical use.69 These include the CA index (type4 Collagen 7S and AST), NAFIC score (Non-Alcoholic steatohepatitis (NASH), serum Ferritin, serum Insulin and type IV Collagen 7S), NASH diagnostics panel, G-NASH model, and ClinLipMet score. Elastography (MRI or Fibro Scan based) is not a reliable predictor of steatohepatitis, and therefore, not currently recommended for the detection of steatohepatitis.70

Fibrosis assessment

The standard method for assessing fibrosis using routine serological tests may not precisely reflect extracellular matrix turnover and fibrogenic cell changes. Direct serum markers have been developed to improve accuracy by detecting specific changes associated with different fibrosis stages. These include the fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, BARD score (BMI, AST/ALT ratio, Diabetes), NAFLD fibrosis score, Hepamet fibrosis score, enhanced liver fibrosis test, FibroMax,56 and FibroMeter.71

Vibration-controlled transient elastography (VCTE)

This technique uses pulse-echo ultrasonography to quantify the results in kilopascals as a marker of hepatic fibrosis by measuring the velocity of shear waves across the liver to obtain a liver stiffness measurement (LSM). The VCTE result is derived as the median of a minimum of ten measurements, evaluating a liver tissue region approximately 1 cm in diameter and 4 cm in length.72 LSM values below 8 kPa serve to rule out advanced fibrosis, while values between 8 and 12 kPa have been suggested to identify advanced fibrosis, showing sensitivities ranging from 81 to 87% and specificities from 85 to 88%.73 Conventional ultrasonography devices incorporate shear wave elastography and acoustic radiation force impulse techniques for LSM. Although both methods demonstrate comparable performance characteristics, they are susceptible to a considerable rate of failures.74

Magnetic resonance elastography (MRE)

MRE involves application of low-frequency vibrations to the abdominal wall to generate hepatic shear waves that are tracked and processed to create elastograms reflecting liver stiffness. In various studies, MRE has demonstrated high diagnostic accuracy in detecting advanced fibrosis in MAFLD, with cutoff values ranging from 3.35 to 6.70 kPa and an area under the receiver operating characteristic curve of ≥0.90.75 Fasting for 2 h before MRE is essential, as postprandial blood flow can temporarily increase liver stiffness and overestimate fibrosis. Patient body factors do not affect it and show an excellent interobserver agreement.76 However, MRE is constrained by the need for specialized MRI facilities, cost, and time-consuming nature.

Liver biopsy

Liver biopsy is the gold standard method for differentiating MAFLD from steatohepatitis. MAFLD is diagnosed based on the presence of hepatic steatosis in 5% or more of hepatocytes. On the other hand, steatohepatitis is identified through histological examination using a semiquantitative grading system that considers factors such as lobular and portal inflammation and hepatocyte ballooning in addition to steatosis. Histology shows inflammation predominantly in zone 3 in contrast to other etiologies. The NAFLD activity score and the score for steatosis, activity, and fibrosis (commonly known as the SAF score) algorithm are commonly used in histologic assessment clinical trials.77 The classification of fibrosis from stage F0 to stage F4 is based on a five-point scale developed by Brunt et al.78 and updated by Kleiner et al.79 Although liver biopsy is considered as the gold standard, its acceptance rate is relatively low due to various limitations.

Future developments for serum-based markers of MAFLD

Advancements in omics have resulted in more noninvasive markers for MAFLD. Changes in bile acids and glutathione levels, lipidomic-based markers the oxNASH panel, which includes parameters like linoleic acid and 13-hydroxy octadecadienoic acid,80 hyaluronic acid, serum procollagen III amino-terminal peptide, Pro-C3,81 and tissue inhibitor of metalloprotease-1 (commonly known as TIMP1)82 are being studied. Cytokeratin-18, alone or in combination with FGF21, shows promise as a biomarker for hepatic apoptosis and NASH.83 Circular RNAs, microRNAs, long-noncoding RNAs, and noncoding messenger RNAs all have potential as new biomarkers for NAFLD and NASH.84 Although these approaches show promise, they still need more validation for clinical use.

Treatment of MAFLD

The USA Food and Drug Administration has not approved any medications specifically for treating MAFLD. Treatment in patients with MAFLD is focused on weight loss and medications with proven benefits in MAFLD. In addition, evaluation and management of various nonhepatic complications of obesity and MAFLD is also important. Weight loss is effective in lean and obese MAFLD patients and is the first-line approach for MAFLD regardless of BMI. A direct relationship exists between the extent of weight loss and the improvement observed in MAFLD. Specifically, different levels of weight loss are associated with varying degrees of histological improvement in MAFLD. For instance, weight loss of 3–5% leads to an improvement in steatosis, ≥7% is associated with amelioration of steatohepatitis, and ≥10% is linked to an improvement in fibrosis.85

Dietary modification

Numerous diets have been investigated in patients with MAFLD. The Mediterranean diet has undergone the most extensive research and has been shown to decrease the risk and progression of MAFLD.86 The Mediterranean diet comprises fresh vegetables, legumes, fruits, minimally processed whole grains, and foods abundant in omega-3 fatty acids, such as olive oil, nuts, seeds, and fish. It advocates for minimal to low consumption of red meat and processed meats.

Physical activity

Physical activity enhances weight loss benefits. The European Association for the Study of Liver (commonly referred to as the EASL) recommends moderate aerobic exercise of 150–200 m/week.87 The American Gastroenterological Association advises combining resistance training with 150–300 m of moderate aerobic activity or 75–150 m of vigorous aerobic activity.88 Resistance exercises are suitable for patients unable to do aerobic exercises. Exercise improves IR and hepatic steatosis, even without weight loss, benefiting lean MAFLD patients.89

Pharmacologic intervention

The pharmacological treatment of MAFLD is a continuously evolving field, with only a limited number of drugs currently recommended by different societies. Many other drugs are still in the early phases of clinical trials. As per the EASL guidelines,87 pharmacological therapy should be reserved for specific conditions, including progressive NASH with bridging fibrosis and cirrhosis, early-stage NASH at high risk for disease progression (such as individuals over 50 years of age, those with metabolic syndrome, diabetes mellitus, or elevated ALT levels), and active NASH with high necrosis and inflammatory activity on histology.90 The American Association for the Study of Liver Diseases and Asia-Pacific guidelines recommend pharmacological intervention only for patients with NASH and fibrosis.6 The National Institute for Health and Care Excellence guidelines suggest pharmacological treatment for patients with advanced liver fibrosis [as measured by an enhanced liver fibrosis score (ELF) test score of >10.51].91 Meanwhile, an Italian Association for the Study of the Liver position paper recommends drug therapy for patients at high risk for disease progression.92 Currently, insulin sensitizers, incretins, SGLT2 inhibitors and antioxidants are used.

Insulin sensitizers

Pioglitazone is a PPAR-γ agonist and promotes the redistribution of fat from ectopic tissues to adipose tissue through an increase in adiponectin synthesis. This leads to improved fatty acid β-oxidation in the liver and muscles.93 In addition, the upregulation of GLUT-4 and adenosine monophosphate-activated protein kinase (AMPK) reduces IR.94 Pioglitazone is incorporated into many treatment guidelines for NASH.

Metformin reduces endogenous glucose synthesis by activating AMPK and inhibiting the mitochondrial glycerophosphate dehydrogenase shuttle. Although metformin shows modest improvement in body weight, it failed to show any histological improvement in NASH patients.95

Incretin-based medications

Glucagon-like peptide-1 receptor agonists (GLP1-Ras) can decrease body weight, enhance IR, improve liver enzyme levels, and reduce liver fat content in patients with T2DM.96 Furthermore, the use of dual agonists in NASH treatment has been explored, combining GLP-1 with glucose-dependent insulinotropic polypeptide (GIP) agonism (tirzepatide) or GLP-1 with glucagon agonism (cotadutide).97–99 Tirzepatide has been found to have greater efficacy than GLP1ra in terms of weight loss. Triple receptor agonist (GLP-1, GIP, and glucagon; retatrutide) and a combination of long acting amylin analog and GLP1R agonist (cagrilintide-semaglutide) are under phase 3 trials. Other gut peptide based agents like dual amylin and calcitonin receptor agonists, neuropeptide Y2R agonists, Peptide YY analogues are in the early stages of drug development.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i)

SGLT2 is effectively lower blood glucose levels by inhibiting glucose reabsorption in the kidneys. A retrospective analysis revealed that SGLT2i may positively impact steatosis and fibrosis in patients with T2DM. This suggests that SGLT2 inhibitors may offer potential benefits for individuals with MAFLD.100 Animal models have shown promising results regarding the improving liver enzymes, steatosis, hepatocyte damage, and fibrosis. However, clinical efficacy is currently lacking when it comes to randomized controlled trials.101

Antioxidants

Vitamin E protects against oxidative damage caused by free radicals. It prevents mitochondrial toxicity, suppresses intrinsic apoptotic pathways, and shields against liver damage. In addition, it can control gene expression, cell signaling, and NF-kB-dependent inflammatory pathways. Numerous studies have consistently demonstrated that vitamin E decreases liver enzymes and improves histology in adult and pediatric steatohepatitis patients. This improvement encompasses aspects such as steatosis, inflammation, and ballooning. However, vitamin E has not shown significant effects on fibrosis in these patients.102,103

Emerging therapeutics of MAFLD

Multiple drugs targeting different aspects of MAFLD have been developed in the past 15 years, aiming to reduce fatty acid accumulation, inflammation, and fibrosis. However, many of these drugs are still in development or have failed to show improvement. The USA Food and Drug Administration and European Medicines Agency define NASH resolution as minimal steatosis, no ballooning, minimal lobular inflammation, and stable or improved fibrosis stage. Promising drug categories include: cholesterol-lowering drugs (e.g., aramchol),104 FXR agonists (e.g., obeticholic acid,105 tropifexor),106 PPAR agonists [e.g., elafibranor (PPAR α/δ),107 saroglitazar (PPAR α/γ),108 pemafibrate (PPARα)109], Thyroid hormone receptor β agonists (e.g., resmetirom),110 and FGF21 analog (e.g., pegbelfermin).46 Other potential drugs include (e.g., TVB2640,111 namodenoson,112 HM15211,113 BMS-986263114).

End-points of pharmacological treatment

Limited data exist on the role of noninvasive tests in assessing treatment response in NASH. Based on findings from the FLINT trial, it has been observed that a reduction in serum ALT by 17 U/L at 24 weeks is associated with histological improvement and NASH resolution. However, specific ALT decline thresholds for fibrosis improvement require further investigation.115 According to the REGENERATE trial analysis, increases in ALT and markers, including FIB-4, FAST, ELF, and VCTE are correlated with a decrease in histological fibrosis, suggesting noninvasive tests can track histological response.116 Multiple studies have consistently demonstrated that a reduction of ≥30% in MRI-PDFF was linked to improved NASH resolution.117 Nevertheless, the thresholds for liver stiffness measures in treatment-induced fibrosis improvement are not well established. Further studies are necessary to comprehensively understand the long-term effects on liver fat, histological response, and clinical outcomes.

Surgical intervention

Bariatric surgery is effective for weight loss in obese individuals. It is advisable for patients with a BMI ≥ 35 kg/m2 or a BMI of 30–34.9 kg/m2 with comorbidities.118 It has been shown to improve comorbidities like T2DM, dyslipidemia, sleep apnea, and hypertension and reduce cardiovascular risk. Roux-en-Y gastric bypass and laparoscopic gastrectomy are widely used surgical procedures for weight loss. However, for patients who do not meet the BMI criteria or are deemed unsuitable for surgery, endoscopic bariatric and metabolic treatment (referred to as EBMT) provides an alternative approach. This includes techniques such as the intragastric balloon and endoscopic sleeve gastroplasty.119 Nonetheless, as of now, bariatric surgery and EBMT are not recommended as primary treatments for MAFLD owing to limited research and associated risks.120 However, these interventions may be considered in cases of obesity or comorbidities, as they could aid in the resolving steatohepatitis and regression of fibrosis in noncirrhotic individuals.121

Limitations

Although we have provided a comprehensive overview regarding the links between obesity and MAFLD, the manuscript has an inherent limitation of being a narrative review and prone to selection bias.

Conclusions

Obesity is associated with many systemic consequences. In this narrative review, we discuss GI complications of MAFLD and their association with obesity as the prime focus of interest. Although obesity is not a prerequisite, it is seen in most patients with MAFLD. The pathogenesis of MAFLD is multifactorial, with obesity, IR, genetic predisposition, and gut microbiome dysbiosis having significant roles. Obesity and MAFLD interact, leading to a vicious cycle with one leading to another. A better understanding of the pathophysiology is necessary for better phenotyping of MAFLD patients and development of diagnostic noninvasive markers and novel therapeutic agents. The increasing rate of MAFLD will result in increased hepatic and nonhepatic complications. Various noninvasive biomarkers can predict the subset of patients who may progress to fibrosis and develop extrahepatic complications. A liver biopsy is considered the gold standard for diagnosis. The current therapeutic landscape of the treatment of MAFLD is focused on lifestyle changes and weight loss. Incretin-based medications and bariatric surgery cause significant weight loss and improve MAFLD. However, no medications are USA Food and Drug Administration-approved as of now. Novel therapeutic agents that halt fibrosis are the need of the hour for patients with MAFLD.

Abbreviations

1H-MRS: 

proton magnetic resonance spectroscopy

ACC: 

acetyl-CoA carboxylase

ALT: 

alanine aminotransferase

AMPK: 

adenosine monophosphate-activated protein kinase

apoB100: 

apolipoprotein B100

AST: 

aspartate aminotransferase

AUROC: 

area under receiver operator characteristic

BARD score: 

BMI, AST/ALT ratio, Diabetes

BMI: 

body mass index

BSH: 

bile salt hydrolase

CAP: 

controlled attenuation parameter

ChREBP: 

carbohydrate regulatory element binding protein

DNL: 

de novo lipogenesis

EASL: 

European Association for the Study of Liver

EBMT: 

endoscopic bariatric and metabolic treatment

ELF: 

enhanced liver fibrosis score

FAS: 

fatty acid synthase

FFA: 

free fatty acid

FGF: 

fibroblast growth factor

FXR: 

farnesoid x receptor

GH: 

growth hormone

GI: 

gastrointestinal

GIP: 

glucose-dependent insulinotropic polypeptide

GLP1: 

glucagon like peptide 1

GLP1-Ras: 

glucagon-like peptide-1 receptor agonist

GLUT4: 

glucose transporter 4

HDL: 

high-density lipoprotein

HTGC: 

hepatic triglyceride content

IGF1: 

insulin-like growth factor-1

IR: 

insulin resistance

LSM: 

liver stiffness measurement

MAFLD: 

metabolic dysfunction-associated fatty liver disease

MRE: 

magnetic resonance elastography

MRI-PDFF: 

magnetic resonance imaging-proton density fat fraction

MTTP: 

microsomal triglyceride transfer protein

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

NF-κB: 

nuclear factor kappa B

PLNPLA3: 

patatin-like phospholipase domain-containing protein 3

PPAR: 

peroxisome proliferator-activated receptor

RBP4: 

retinol-binding protein 4

ROS: 

reactive oxygen species

SAF: 

steatosis, activity, and fibrosis

SCFA: 

short-chain fatty acid

SGLT2i: 

sodium-glucose cotransporter 2 inhibitor

SREBP1c: 

sterol regulatory element binding protein 1c

T2DM: 

type 2 diabetes mellitus

TIMP1: 

tissue inhibitor of metalloprotease-1

TM6SF2: 

transmembrane 6 superfamily member 2

USG: 

B-mode ultrasonography

VCTE: 

vibration-controlled transient elastography

VLDL: 

very low-density lipoprotein

Declarations

Acknowledgement

None.

Funding

None.

Conflict of interest

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

Authors’ contributions

Study concept and design (SS, SK), acquisition of data (JV, VS), analysis and interpretation of data (JV, VS, SS, SK), drafting of the manuscript (JV, VS), critical revision of the manuscript for important intellectual content (SS, SK, JS, PM, DN), and study supervision (SS, SK, JS, PM, DN). All authors contributed significantly to this work and have approved the final manuscript.

References

  1. Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 2019;15(5):288-298 View Article PubMed/NCBI
  2. Emerenziani S, Guarino MPL, Trillo Asensio LM, Altomare A, Ribolsi M, Balestrieri P, et al. Role of Overweight and Obesity in Gastrointestinal Disease. Nutrients 2019;12(1):111 View Article PubMed/NCBI
  3. Paik JM, Golabi P, Younossi Y, Mishra A, Younossi ZM. Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD. Hepatology 2020;72(5):1605-1616 View Article PubMed/NCBI
  4. 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
  5. 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 PubMed/NCBI
  6. 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
  7. Åberg F, Helenius-Hietala J, Puukka P, Färkkilä M, Jula A. Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. Hepatology 2018;67(6):2141-2149 View Article PubMed/NCBI
  8. Eslam M, Sanyal AJ, George J, International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020;158(7):1999-2014.e1 View Article PubMed/NCBI
  9. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015;13(4):643-54.e1-9 View Article PubMed/NCBI
  10. De A, Duseja A. Natural History of Simple Steatosis or Nonalcoholic Fatty Liver. J Clin Exp Hepatol 2020;10(3):255-262 View Article PubMed/NCBI
  11. 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
  12. Tanase DM, Gosav EM, Costea CF, Ciocoiu M, Lacatusu CM, Maranduca MA, et al. The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). J Diabetes Res 2020;2020:3920196 View Article PubMed/NCBI
  13. Londos C, Honnor RC, Dhillon GS. cAMP-dependent protein kinase and lipolysis in rat adipocytes. III. Multiple modes of insulin regulation of lipolysis and regulation of insulin responses by adenylate cyclase regulators. J Biol Chem 1985;260(28):15139-15145 PubMed/NCBI
  14. Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 2014;59(1):154-169 View Article PubMed/NCBI
  15. Eslam M, El-Serag HB, Francque S, Sarin SK, Wei L, Bugianesi E, et al. Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight. Nat Rev Gastroenterol Hepatol 2022;19(10):638-651 View Article PubMed/NCBI
  16. Moon YA. The SCAP/SREBP Pathway: A Mediator of Hepatic Steatosis. Endocrinol Metab (Seoul) 2017;32(1):6-10 View Article PubMed/NCBI
  17. Benhamed F, Denechaud PD, Lemoine M, Robichon C, Moldes M, Bertrand-Michel J, et al. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J Clin Invest 2012;122(6):2176-2194 View Article PubMed/NCBI
  18. Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med 2008;21(4):507-511 PubMed/NCBI
  19. Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A 2010;107(17):7892-7897 View Article PubMed/NCBI
  20. Amemiya-Kudo M, Shimano H, Yoshikawa T, Yahagi N, Hasty AH, Okazaki H, et al. Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J Biol Chem 2000;275(40):31078-31085 View Article PubMed/NCBI
  21. 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
  22. Kang GG, Trevaskis NL, Murphy AJ, Febbraio MA. Diet-induced gut dysbiosis and inflammation: Key drivers of obesity-driven NASH. iScience 2023;26(1):105905 View Article PubMed/NCBI
  23. De Munck TJI, Xu P, Verwijs HJA, Masclee AAM, Jonkers D, Verbeek J, et al. Intestinal permeability in human nonalcoholic fatty liver disease: A systematic review and meta-analysis. Liver Int 2020;40(12):2906-2916 View Article PubMed/NCBI
  24. Fabbrini E, Magkos F. Hepatic Steatosis as a Marker of Metabolic Dysfunction. Nutrients 2015;7(6):4995-5019 View Article PubMed/NCBI
  25. Ota T, Gayet C, Ginsberg HN. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 2008;118(1):316-332 View Article PubMed/NCBI
  26. Peng XE, Wu YL, Lu QQ, Hu ZJ, Lin X. MTTP polymorphisms and susceptibility to non-alcoholic fatty liver disease in a Han Chinese population. Liver Int 2014;34(1):118-128 View Article PubMed/NCBI
  27. Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 2015;21(5):739-746 View Article PubMed/NCBI
  28. Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 2006;6(1):1-28 View Article PubMed/NCBI
  29. 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
  30. Luo F, Smagris E, Martin SA, Vale G, McDonald JG, Fletcher JA, et al. Hepatic TM6SF2 Is Required for Lipidation of VLDL in a Pre-Golgi Compartment in Mice and Rats. Cell Mol Gastroenterol Hepatol 2022;13(3):879-899 View Article PubMed/NCBI
  31. Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology 2016;150(5):1219-1230.e6 View Article PubMed/NCBI
  32. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011;7(3):e1001324 View Article PubMed/NCBI
  33. Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, et al. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. N Engl J Med 2018;378(12):1096-1106 View Article PubMed/NCBI
  34. Emdin CA, Haas ME, Khera AV, Aragam K, Chaffin M, Klarin D, et al. Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. PLoS Genet 2021;17(4):e1009503 View Article PubMed/NCBI
  35. Guo L, Yang K, Zhou P, Yong W. Gut microbiota in obesity and nonalcoholic fatty liver disease. Surg Pract Sci 2021;5:100030 View Article
  36. Nighot M, Al-Sadi R, Guo S, Rawat M, Nighot P, Watterson MD, et al. Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. Am J Pathol 2017;187(12):2698-2710 View Article PubMed/NCBI
  37. Arias N, Arboleya S, Allison J, Kaliszewska A, Higarza SG, Gueimonde M, et al. The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases. Nutrients 2020;12(8):2340 View Article PubMed/NCBI
  38. Li M, Rajani C, Zheng X, Jia W. The microbial metabolome in metabolic-associated fatty liver disease. J Gastroenterol Hepatol 2022;37(1):15-23 View Article PubMed/NCBI
  39. Jiao TY, Ma YD, Guo XZ, Ye YF, Xie C. Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease. Acta Pharmacol Sin 2022;43(5):1103-1119 View Article PubMed/NCBI
  40. Jiao Y, Lu Y, Li XY. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin 2015;36(1):44-50 View Article PubMed/NCBI
  41. Estep M, Abawi M, Jarrar M, Wang L, Stepanova M, Elariny H, et al. Association of obestatin, ghrelin, and inflammatory cytokines in obese patients with non-alcoholic fatty liver disease. Obes Surg 2011;21(11):1750-1757 View Article PubMed/NCBI
  42. Hajighasem A, Farzanegi P, Mazaheri Z, Naghizadeh M, Salehi G. Effects of resveratrol, exercises and their combination on Farnesoid X receptor, Liver X receptor and Sirtuin 1 gene expression and apoptosis in the liver of elderly rats with nonalcoholic fatty liver. PeerJ 2018;6:e5522 View Article PubMed/NCBI
  43. Francisco V, Sanz MJ, Real JT, Marques P, Capuozzo M, Ait Eldjoudi D, et al. Adipokines in Non-Alcoholic Fatty Liver Disease: Are We on the Road toward New Biomarkers and Therapeutic Targets?. Biology (Basel) 2022;11(8):1237 View Article PubMed/NCBI
  44. Hu R, Yang X, He X, Song G. The relationship between NAFLD and retinol-binding protein 4 - an updated systematic review and meta-analysis. Lipids Health Dis 2023;22(1):8 View Article PubMed/NCBI
  45. Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 2017;13(9):509-520 View Article PubMed/NCBI
  46. Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 2019;392(10165):2705-2717 View Article PubMed/NCBI
  47. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010;52(5):1836-1846 View Article PubMed/NCBI
  48. El-Arabey AA, Abdalla M. GATA3 as an immunomodulator in obesity-related metabolic dysfunction associated with fatty liver disease, insulin resistance, and type 2 diabetes. Chem Biol Interact 2022;366:110141 View Article PubMed/NCBI
  49. Barranco-Fragoso B, Pal SC, Díaz-Orozco LE, Dorantes-Heredia R, Qi X, Méndez-Sánchez N. Identification of Hepatic Dendritic Cells in Liver Biopsies Showing Steatosis in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Associated with Obesity. Med Sci Monit 2022;28:e937528 View Article PubMed/NCBI
  50. Mosca A, Della Volpe L, Alisi A, Panera N, Maggiore G, Vania A. The Role of the GH/IGF1 Axis on the Development of MAFLD in Pediatric Patients with Obesity. Metabolites 2022;12(12):1221 View Article PubMed/NCBI
  51. 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
  52. Manikat R, Nguyen MH. Nonalcoholic fatty liver disease and non-liver comorbidities. Clin Mol Hepatol 2023;29(Suppl):s86-s102 View Article PubMed/NCBI
  53. Krznarić J, Vince A. The Role of Non-Alcoholic Fatty Liver Disease in Infections. Life (Basel) 2022;12(12):2052 View Article PubMed/NCBI
  54. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40(6):1387-1395 View Article PubMed/NCBI
  55. Fedchuk L, Nascimbeni F, Pais R, Charlotte F, Housset C, Ratziu V, et al. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2014;40(10):1209-1222 View Article PubMed/NCBI
  56. Chandra Kumar CV, Skantha R, Chan WK. Non-invasive assessment of metabolic dysfunction-associated fatty liver disease. Ther Adv Endocrinol Metab 2022;13:20420188221139614 View Article PubMed/NCBI
  57. Wang J, Yan S, Cui Y, Chen F, Piao M, Cui W. The Diagnostic and Prognostic Value of the Triglyceride-Glucose Index in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD): A Systematic Review and Meta-Analysis. Nutrients 2022;14(23):4969 View Article PubMed/NCBI
  58. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006;6:33 View Article PubMed/NCBI
  59. Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011;54(3):1082-1090 View Article PubMed/NCBI
  60. Strauss S, Gavish E, Gottlieb P, Katsnelson L. Interobserver and intraobserver variability in the sonographic assessment of fatty liver. AJR Am J Roentgenol 2007;189(6):W320-W323 View Article PubMed/NCBI
  61. Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Lédinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol 2017;66(5):1022-1030 View Article PubMed/NCBI
  62. Caussy C, Alquiraish MH, Nguyen P, Hernandez C, Cepin S, Fortney LE, et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology 2018;67(4):1348-1359 View Article PubMed/NCBI
  63. Caussy C, Brissot J, Singh S, Bassirian S, Hernandez C, Bettencourt R, et al. Prospective, Same-Day, Direct Comparison of Controlled Attenuation Parameter With the M vs the XL Probe in Patients With Nonalcoholic Fatty Liver Disease, Using Magnetic Resonance Imaging-Proton Density Fat Fraction as the Standard. Clin Gastroenterol Hepatol 2020;18(8):1842-1850.e6 View Article PubMed/NCBI
  64. Charatcharoenwitthaya P, Lindor KD. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin Liver Dis 2007;11(1):37-54 View Article PubMed/NCBI
  65. Roldan-Valadez E, Favila R, Martínez-López M, Uribe M, Ríos C, Méndez-Sánchez N. In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver disease: Correlation with biochemical method and morphometry. J Hepatol 2010;53(4):732-737 View Article PubMed/NCBI
  66. Noureddin M, Lam J, Peterson MR, Middleton M, Hamilton G, Le TA, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 2013;58(6):1930-1940 View Article PubMed/NCBI
  67. Gu J, Liu S, Du S, Zhang Q, Xiao J, Dong Q, et al. Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis. Eur Radiol 2019;29(7):3564-3573 View Article PubMed/NCBI
  68. Nasr P, Forsgren MF, Ignatova S, Dahlström N, Cedersund G, Leinhard OD, et al. Using a 3% Proton Density Fat Fraction as a Cut-Off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results From Histopathology Analysis. Gastroenterology 2017;153(1):53-55.e7 View Article PubMed/NCBI
  69. Verhaegh P, Bavalia R, Winkens B, Masclee A, Jonkers D, Koek G. Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018;16(6):837-861 View Article PubMed/NCBI
  70. 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
  71. Van Dijk AM, Vali Y, Mak AL, Lee J, Tushuizen ME, Zafarmand MH, et al. Systematic Review with Meta-Analyses: Diagnostic Accuracy of FibroMeter Tests in Patients with Non-Alcoholic Fatty Liver Disease. J Clin Med 2021;10(13):2910 View Article PubMed/NCBI
  72. Ozturk A, Grajo JR, Dhyani M, Anthony BW, Samir AE. Principles of ultrasound elastography. Abdom Radiol (NY) 2018;43(4):773-785 View Article PubMed/NCBI
  73. Mózes FE, Lee JA, Selvaraj EA, Jayaswal ANA, Trauner M, Boursier J, et al. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis. Gut 2022;71(5):1006-1019 View Article PubMed/NCBI
  74. Cassinotto C, Boursier J, de Lédinghen V, Lebigot J, Lapuyade B, Cales P, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 2016;63(6):1817-1827 View Article PubMed/NCBI
  75. Selvaraj EA, Mózes FE, Jayaswal ANA, Zafarmand MH, Vali Y, Lee JA, et al. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis. J Hepatol 2021;75(4):770-785 View Article PubMed/NCBI
  76. Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging 2013;37(3):544-555 View Article PubMed/NCBI
  77. Bedossa P, FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology 2014;60(2):565-575 View Article PubMed/NCBI
  78. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94(9):2467-74 View Article PubMed/NCBI
  79. Kleiner DE, Makhlouf HR. Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children. Clin Liver Dis 2016;20(2):293-312 View Article PubMed/NCBI
  80. Ferslew BC, Xie G, Johnston CK, Su M, Stewart PW, Jia W, et al. Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis. Dig Dis Sci 2015;60(11):3318-3328 View Article PubMed/NCBI
  81. Boyle M, Tiniakos D, Schattenberg JM, Ratziu V, Bugianessi E, Petta S, et al. Performance of the PRO-C3 collagen neo-epitope biomarker in non-alcoholic fatty liver disease. JHEP Rep 2019;1(3):188-198 View Article PubMed/NCBI
  82. Abdelaziz R, Elbasel M, Esmat S, Essam K, Abdelaaty S. Tissue Inhibitors of Metalloproteinase-1 and 2 and Obesity Related Non-Alcoholic Fatty Liver Disease: Is There a Relationship. Digestion 2015;92(3):130-137 View Article PubMed/NCBI
  83. Shen J, Chan HL, Wong GL, Choi PC, Chan AW, Chan HY, et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J Hepatol 2012;56(6):1363-1370 View Article PubMed/NCBI
  84. Di Mauro S, Scamporrino A, Filippello A, Di Pino A, Scicali R, Malaguarnera R, et al. Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD. Int J Mol Sci 2021;22(21):11905 View Article PubMed/NCBI
  85. Glass LM, Dickson RC, Anderson JC, Suriawinata AA, Putra J, Berk BS, et al. Total body weight loss of ≥10% is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis. Dig Dis Sci 2015;60(4):1024-1030 View Article PubMed/NCBI
  86. 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
  87. 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 nonalcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402 View Article PubMed/NCBI
  88. 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
  89. 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
  90. Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L, American Association for the Study of Liver Diseases, United States Food and Drug Administration. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 2015;61(4):1392-1405 View Article PubMed/NCBI
  91. Glen J, Floros L, Day C, Pryke R, Guideline Development Group. Non-alcoholic fatty liver disease (NAFLD): summary of NICE guidance. BMJ 2016;354:i4428 View Article PubMed/NCBI
  92. Italian Association for the Study of the Liver (AISF). AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig Liver Dis 2017;49(5):471-483 View Article PubMed/NCBI
  93. Raza S, Rajak S, Upadhyay A, Tewari A, Anthony Sinha R. Current treatment paradigms and emerging therapies for NAFLD/NASH. Front Biosci (Landmark Ed) 2021;26(2):206-237 View Article PubMed/NCBI
  94. Leclercq IA, Sempoux C, Stärkel P, Horsmans Y. Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats. Gut 2006;55(7):1020-1029 View Article PubMed/NCBI
  95. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomed Rep 2013;1(1):57-64 View Article PubMed/NCBI
  96. Petit JM, Vergès B. GLP-1 receptor agonists in NAFLD. Diabetes Metab 2017;43(Suppl 1):2S28-2S33 View Article PubMed/NCBI
  97. Ghosal S, Datta D, Sinha B. A meta-analysis of the effects of glucagon-like-peptide 1 receptor agonist (GLP1-RA) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D). Sci Rep 2021;11(1):22063 View Article PubMed/NCBI
  98. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018;392(10160):2180-2193 View Article PubMed/NCBI
  99. Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 2018;391(10140):2607-2618 View Article PubMed/NCBI
  100. Raj H, Durgia H, Palui R, Kamalanathan S, Selvarajan S, Kar SS, et al. SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review. World J Diabetes 2019;10(2):114-132 View Article PubMed/NCBI
  101. Gaborit B, Ancel P, Abdullah AE, Maurice F, Abdesselam I, Calen A, et al. Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study. Cardiovasc Diabetol 2021;20(1):57 View Article PubMed/NCBI
  102. Usman M, Bakhtawar N. Vitamin E as an Adjuvant Treatment for Non-alcoholic Fatty Liver Disease in Adults: A Systematic Review of Randomized Controlled Trials. Cureus 2020;12(7):e9018 View Article PubMed/NCBI
  103. Lin M, Zeng H, Deng G, Lei J, Li J. Vitamin E in paediatric non-alcoholic fatty liver disease: a meta-analysis. Clin Res Hepatol Gastroenterol 2021;45(3):101530 View Article PubMed/NCBI
  104. Iruarrizaga-Lejarreta M, Varela-Rey M, Fernández-Ramos D, Martínez-Arranz I, Delgado TC, Simon J, et al. Role of Aramchol in steatohepatitis and fibrosis in mice. Hepatol Commun 2017;1(9):911-927 View Article PubMed/NCBI
  105. Kulkarni AV, Tevethia HV, Arab JP, Candia R, Premkumar M, Kumar P, et al. Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2021;45(3):101675 View Article PubMed/NCBI
  106. Pedrosa M, Seyedkazemi S, Francque S, Sanyal A, Rinella M, Charlton M, et al. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial. Contemp Clin Trials 2020;88:105889 View Article PubMed/NCBI
  107. Malik A, Nadeem M, Malik MI. Efficacy of elafibranor in patients with liver abnormalities especially non-alcoholic steatohepatitis: a systematic review and meta-analysis. Clin J Gastroenterol 2021;14(6):1579-1586 View Article PubMed/NCBI
  108. Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology 2021;74(4):1809-1824 View Article PubMed/NCBI
  109. Shinozaki S, Tahara T, Lefor AK, Ogura M. Pemafibrate decreases markers of hepatic inflammation in patients with non-alcoholic fatty liver disease. Clin Exp Hepatol 2020;6(3):270-274 View Article PubMed/NCBI
  110. Younossi ZM, Stepanova M, Taub RA, Barbone JM, Harrison SA. Hepatic Fat Reduction Due to Resmetirom in Patients With Nonalcoholic Steatohepatitis Is Associated With Improvement of Quality of Life. Clin Gastroenterol Hepatol 2022;20(6):1354-1361.e7 View Article PubMed/NCBI
  111. Loomba R, Mohseni R, Lucas KJ, Gutierrez JA, Perry RG, Trotter JF, et al. TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial. Gastroenterology 2021;161(5):1475-1486 View Article PubMed/NCBI
  112. Safadi R, Braun M, Francis A, Milgrom Y, Massarwa M, Hakimian D, et al. Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis. Aliment Pharmacol Ther 2021;54(11-12):1405-1415 View Article PubMed/NCBI
  113. Abdelmalek MF, Suzuki A, Sanchez W, Lawitz E, Filozof C, Cho H, et al. A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis - Study design and rationale of HM-TRIA-201 study. Contemp Clin Trials 2023;130:107176 View Article PubMed/NCBI
  114. Lawitz EJ, Shevell DE, Tirucherai GS, Du S, Chen W, Kavita U, et al. BMS-986263 in patients with advanced hepatic fibrosis: 36-week results from a randomized, placebo-controlled phase 2 trial. Hepatology 2022;75(4):912-923 View Article PubMed/NCBI
  115. Loomba R, Sanyal AJ, Kowdley KV, Terrault N, Chalasani NP, Abdelmalek MF, et al. Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. Gastroenterology 2019;156(1):88-95.e5 View Article PubMed/NCBI
  116. Rinella ME, Dufour JF, Anstee QM, Goodman Z, Younossi Z, Harrison SA, et al. Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study. J Hepatol 2022;76(3):536-548 View Article PubMed/NCBI
  117. Stine JG, Munaganuru N, Barnard A, Wang JL, Kaulback K, Argo CK, et al. Change in MRI-PDFF and Histologic Response in Patients With Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2021;19(11):2274-2283.e5 View Article PubMed/NCBI
  118. Eisenberg D, Shikora SA, Aarts E, Aminian A, Angrisani L, Cohen RV, et al. 2022 American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) Indications for Metabolic and Bariatric Surgery. Obes Surg 2023;33(1):3-14 View Article PubMed/NCBI
  119. 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
  120. Khajeh E, Aminizadeh E, Eslami P, Ramouz A, Kulu Y, Billeter AT, et al. Outcomes of bariatric surgery in patients with obesity and compensated liver cirrhosis. Surg Obes Relat Dis 2022;18(6):727-737 View Article PubMed/NCBI
  121. Zhou H, Luo P, Li P, Wang G, Yi X, Fu Z, et al. Bariatric Surgery Improves Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Obes Surg 2022;32(6):1872-1883 View Article PubMed/NCBI
Copyright © 2023 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Translational Gastroenterology
  • eISSN 2994-8754

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2025976
  • Visits today : 150
Back to Top

Obesity and Metabolic Dysfunction-associated Fatty Liver Disease: Understanding the Intricate Link

Jayavardhan Vulchi, Varun Suryadevara, Pazhanivel Mohan, Sadishkumar Kamalanathan, Jayaprakash Sahoo, Dukhabandhu Naik, Sandhiya Selvarajan
  • Reset Zoom
  • Download TIFF