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 1Obesity-related gastrointestinal complications
| Site | Lesion |
|---|
| Esophagus | Gastroesophageal reflux disease; Erosive esophagitis; Barrett’s esophagus; Esophageal adenocarcinoma |
| Stomach | Erosive gastritis; Gastric cancer |
| Small intestine and colon | Diarrhea; Colonic diverticular disease; Polyps; Cancer; Clostridium difficile infection; Dyssynergic defecation |
| Liver | Metabolic dysfunction-associated fatty liver disease; Cirrhosis; Hepatocellular carcinoma |
| Gallbladder | Gallstones; Gallbladder carcinoma |
| Pancreas | Acute 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
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
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 2Blood-based biomarkers or scores for steatosis and fibrosis in MAFLD
| Blood marker of steatosis | Component or formula | Cutoff | AUROC | Sensitivity, % | Specificity, % |
|---|
| Hepatic steatosis index | ALT, AST, BMI, type 2 DM, female sex | Rule out cutoff <30; Rule in cutoff >36 | 0.82 | 92.5 | 92.4 |
| Fatty liver index | TG, BMI, GGT, WC | Rule out cutoff <30; Rule in cutoff ≥60 | 0.84 | 87 | 86 |
| NAFLD liver fat score | Metabolic syndrome, type 2 DM, insulin, AST, ALT | >0.16 | 0.80 | 65 | 87 |
| SteatoTest | ALT, α2-macroglobulin, apolipoprotein A1, haptoglobin, total bilirubin, GGT, total cholesterol, TG, glucose, age, sex, BMI | Rule out cutoff <0.3; Rule in cutoff >0.7 | 0.72–0.86 | 91 | 89 |
| NAFLD ridge score | ALT, HbA1c, HDL, Hypertension, leucocyte count, TG | Dual cutoffs of 0.24 and 0.44 | 0.87–0.88 | 92 | 90 |
| Visceral adiposity index | WC, BMI, TG, HDL | >1.25 | 0.92 | 79 | 92 |
| Triglyceride/glucose index | TG, glucose | <6 | 0.81 | 75 | 74 |
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
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.