Non-Alcoholic Fatty Liver Disease, Awareness of a Diagnostic Challenge—A Clinician’s Perspective

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease globally. NAFLD is a complex pathology, considered to be the hepatic expression of metabolic syndrome (MetS). It is supposed to become the main indication for liver transplantation in the coming years and is estimated to affect 57.5–74.0% of obese people, 22.5% of children and 52.8% of obese children, with 50% of individuals with type 2 diabetes being diagnosed with NAFLD. Recent research has proved that an increase in adipose tissue insulin resistance index is an important marker of liver injury in patients with NAFLD. Despite being the main underlying cause of incidental liver damage and a growing worldwide health problem, NAFLD is mostly under-appreciated. Currently, NAFLD is considered a multifactorial disease, with various factors contributing to its pathogenesis, associated with insulin resistance and diabetes mellitus, but also with cardiovascular, kidney and endocrine disorders (polycystic ovary syndrome, hypothyroidism, growth hormone deficiency). Hepatitis B and hepatitis C, sleep apnea, inflammatory bowel diseases, cystic fibrosis, viral infections, autoimmune liver diseases and malnutrition are some other conditions in which NAFLD can be found. The aim of this review is to emphasize that, from the clinician’s perspective, NAFLD is an actual and valuable key diagnosis factor for multiple conditions; thus, efforts need to be made in order to increase recognition of the disease and its consequences. Although there is no global consensus, physicians should consider screening people who are at risk of NAFLD. A large dissemination of current concepts on NAFLD and an extensive collaboration between physicians, such as gastroenterologists, internists, cardiologists, diabetologists, nutritionists and endocrinologists, is equally needed to ensure we have the knowledge and resources to address this public health challenge.

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting approximately 25% of the general population worldwide and thus representing an important burden on the health system [1,2].

NAFLD is characterized by a deposit of fat in at least 5% of hepatocytes, in the absence of secondary causes of chronic liver disease and without notable alcohol consumption (<20 g/day in women and <30 g/day in men) [3,4]. NAFLD is a heterogeneous condition, initially developing as simple steatosis and progressing to non-alcoholic steatohepatitis (NASH). Currently, it is estimated that up to 25% of patients with NAFLD will develop NASH, histologically expressed by inflammation, hepatocellular ballooning and different stages of fibrosis [5]. Without adequate treatment, NASH can lead to liver cirrhosis, followed by liver failure and then hepatocellular carcinoma (HCC). Notably, some patients with NAFLD may develop HCC without underlying fibrosis or cirrhosis [6]. Patients with NAFLD present a higher risk not only of liver complications but also of increased incidence of cardiovascular mortality [7,8].

According to European guidelines, imaging investigations, such as ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI), are the first-line tests in NAFLD diagnosis. Abdominal ultrasound is preferred due to its greater accessibility and lower costs, although it has limited sensitivity in detecting steatosis when it is below 20% or in people with a high body mass index (BMI) (>40 kg/m²) [3]. The first elastographic method used to quantify the degree of fibrosis was one-dimensional transient elastography (TE), followed by the emergence of elastographic methods integrated into conventional ultrasound devices, such as point shear wave elastography (pSWE) or two-dimensional elastography (2D-SWE). TE and MRI elastography can provide additional information in subjects with NAFLD, allowing the quantification, in addition to fibrosis, of steatosis by using the controlled attenuation parameter for TE, also known as CAP [9], as well as fat-proton density by using the proton density fat fraction (PDFF) mode for MRI elastography [10]. MRI-PDFF is able to detect any degree of steatosis with a high accuracy [11]. MRI-PDFF is the most accurate method but appears to be more suitable for the evaluation and selected follow-up of patients in clinical trials, while conventional ultrasound and CAP could be used as triage in large, unselected populations [12].

The gold standard for assessing the severity of liver disease is liver biopsy, an invasive and expensive method; for this reason, non-invasive methods of assessing liver fibrosis in NAFLD have been developed over time, namely scores based on clinical and laboratory parameters. According to current clinical guidelines, scores such as NAFLD fibrosis score (NFS) and FIB-4 (Table 1) are considered accessible tools for an initial assessment of fibrosis in NAFLD patients. When such scores cannot exclude an advanced fibrosis, an elastography-based method is adopted in the risk stratification algorithm, FibroScan being the most validated and widely available tool. In the decision to use one test or another in clinical practice, the availability, accessibility and cost must be carefully considered, and, given their rapid development, noninvasive methods have almost completely replaced invasive tests in practice. Therefore, only when noninvasive methods cannot rule out significant fibrosis should liver biopsy be considered [3,13].

Table 1. Examples of evaluation scores in predicting NAFLD severity.

	Steatosis Evaluation Scores		Fibrosis Evaluation Scores
Scores	Fatty Liver Index	NAFLD Liver Fat Score	NAFLD Fibrosis Score	Fibrosis-4
Parameters	Body mass index Waist circumference Triglycerides GGT	Metabolic syndrome Type 2 Diabetes Insulin AST ALT	Age Body mass index Impaired fasting Glucose AST ALT Platelet count Albumin	Age AST ALT Platelet count

ALT—Alanine aminotransferase; AST—Aspartate aminotransferase; GGT—Gamma-glutamyl transpeptidase.

2. New Considerations in Terminology

NAFLD is a bidirectional link to metabolic diseases, from the perspective of both pathogenesis and epidemiologically. Currently, NAFLD is considered a multifactorial disease, with many factors contributing to its pathogenesis, such as genetic predisposition (PNPLA3, TM6SF2 and MBOAT7 genes), diet (intake of saturated fatty acids and fructose), sedentary lifestyle, obesity, insulin resistance and changes in the intestinal microbiome [14,15]. Therefore, NAFLD has a high prevalence among populations with obesity (50–90%), type 2 diabetes (T2DM) (43–72%) or dyslipidemia (20–80%) compared to the general population (25%) [16].

Similarly, NAFLD patients have a high prevalence of metabolic conditions, such as obesity, dyslipidemia, insulin resistance (IR) and T2DM. In this context, NAFLD is frequently recognized as the hepatic expression of metabolic syndrome (MetS), a perspective that led, in 2020, to the modification of the nomenclature and diagnostic criteria. The definition of NAFLD, proposed in 2020, was metabolic dysfunction-associated fatty liver disease (MAFLD) [17].

Thus, MAFLD describes a condition characterized by hepatic steatosis (diagnosed by imaging techniques, blood biomarkers or histological examination) and one of the following metabolic criteria: overweight/obesity, T2DM or a metabolic disorder, defined by the presence of a minimum of two metabolic anomalies, including an increased abdominal circumference, arterial hypertension, dyslipidemia, prediabetes, increased values of homeostasis model assessment-insulin resistance (HOMA-IR) and elevated serum levels of C-reactive protein (CRP) (Table 2) [18].

Table 2. Metabolic dysregulation criteria in MAFLD diagnosis.

Metabolic Dysregulation Criteria in MAFLD Diagnosis
At least two of seven criteria
WC ≥ 102 cm (M) 88 cm (F)
HbA1c 5.7–6.4% or fasting plasma glucose of 5.6–6.9 mmol/L or 2 h post-load glucose levels of 7.8–11.0 mmol/L
Blood pressure ≥ 130/85 mmHg or under antihypertension therapy
Plasma HDL < 1.0 mmol/L (M) and < 1.3 mmol/L (F)
Plasma triglycerides ≥ 1.70 mmol/L or specific drug treatment
HOMA-IR score ≥ 2.5
hs-CRP level > 2 mg/L

WC—Waist circumference; M—Male; F—Female; HDL—High-density lipoprotein; HOMA-IR—Homeostasis model assessment-insulin resistance; hs-CRP—Hypersensitive C-reactive protein.

However, the term MAFLD was not universally accepted in the medical scientific community. Although several studies used its definition and highlighted its accuracy, there were opinions that this definition could be improved upon; for instance, nutritionists considered it not useful to include in the diagnostic criteria both abdominal circumference and BMI and disputed the specificity of BMI in evaluating overweight/obesity. Furthermore, it has been pointed out that MAFLD could not exclude other etiologies of liver injury such as alcohol, viruses or drugs [19].

All these controversies determined that, in June 2023, hepatic steatosis was given a new name. The new nomenclature aimed to eliminate the terms “non-alcoholic” and “fatty”; therefore, “MASLD” replaced the term NAFLD. Its diagnosis implies the presence of a minimum of one of the five cardiometabolic risk factors presented in Table 3. The term MetALD was also defined to describe patients with MASLD who consumed higher amounts of alcohol (140 g/week to 350 g/week for female and 210 g/week to 420 g/week for male) [20].

Table 3. Cardiometabolic criteria diagnosis of MASLD.

Cardiometabolic Risk Factors in MAFLD Diagnosiss
	At least one of five criteria
BMI subgroup	BMI ≥ 24 kg/m2 or WC > 90 cm (M) 80 cm (F)
DM subgroup	Fasting serum glucose ≥ 5.6 mmol/L or 2 h post-load glucose levels ≥ 7.8 mmol/L or HbA1c ≥ 5.7% or diagnosis of DM or treatment for DM
HT subgroup	Blood pressure ≥ 130/85 mmHg or specific antihypertensive treatment
TG subgroup	Plasma triglycerides ≥ 1.70 mmol/L or lipid-lowering treatment
HDL subgroup	Plasma HDL ≤ 1.0 (M) and ≤ 1.3 mmol/L (F) or lipid-lowering treatment

BMI—Body Mass Index; WC—Waist circumference; M—Male; F—Female; DM—Diabetes mellitus; HT—Hypertension; TG—Triglycerides; HDL—High-density lipoprotein.

Steatotic liver disease (SLD) encompasses certain types of steatosis other than MASLD and MetALD, namely, alcohol-associated liver disease (ALD), SLD with specific etiology—drug-induced liver damage (DILI), monogenic diseases (lysosomal acid lipase deficiency, hypobeta-lipoproteinemia, inborn errors of metabolism, Wilson’s disease) and others (hepatitis C virus, malnutrition, celiac disease) [20], as well as cryptogenetic SLD, defined in patients without cardiometabolic risk factors or any other known steatosis etiology [21]. In accordance with the current global consensus, going forward, we will use the new universally accepted terminology in our paper.

3. MASLD, a Common Link Through Various Pathologies

3.1. T2DM, Consequence of MASLD?

Complex interactions between the hepatic fat deposit, perivisceral adiposity [22] and IR make it challenging to assess the mechanisms whereby MASLD increases the risk of T2DM [5].

In MASLD, IR occurs in skeletal muscle, liver and adipose tissue. Therefore, the hepatic glucose synthesis and the lipolysis of adipose tissue will be barely suppressed by insulin, consequently with an increased basal glucose and plasma-free fatty acid (FFA) concentration. IR also affects glucose tolerance; therefore, pancreatic β cells are overstimulated, leading to T2DM appearance [23].

Endogenous hepatic glucose synthesis is regulated by insulin and glucagon, which maintain glycemic values in an optimal range. In MASLD patients, postprandial glucose synthesis by gluconeogenesis is increased, despite a high level of insulin, causing a permanent hyperglycemic status [23].

Patients with both MASLD and T2DM have hepatic IR (Figure 1). The excessive gluconeogenetic substrate is used in novo glycerol synthesis, through glyceroneogenesis, part of triglyceride synthesis. De novo lipogenesis is characterized by the synthesis of fatty acids from acetyl-CoA units derived mainly from dietary carbohydrates. A diet rich in carbohydrates, together with hyperinsulinemia, stimulates liver lipogenesis, FFA synthesis and very low-density lipoproteins (VLDL) synthesis. The lipotoxicity of saturated fatty acids exerts both on liver cells, pancreatic β cells, endothelial cells, skeletal muscle and cardiomyocytes [24]. Therefore, the accumulation of ectopic adipose tissue in patients with MASLD occurs not only in the liver and skeletal muscles but also intrapancreatically, which causes β-cell dysfunction. A study conducted by Gastaldelli A et al. proved that reducing liver and pancreatic adipose tissue improves both glycemic control and β-cell function in T2DM patients [25].

Figure 1. Relationship between MASLD, obesity, insulin resistance and diabetes mellitus.

Excess adipose tissue is a key to inflammation, releasing the pro-inflammatory cytokines involved in IR and T2DM. Given that the liver is the main organ where ectopic accumulation of adipose tissue occurs, hepatic FFA will exacerbate IR, with lysosomal instability and increased pro-inflammatory cytokine release. Compensatory, hepatocytes increase the beta-oxidation of fatty acids, and lipid overload will alter mitochondrial antioxidant capacity [25].

These processes lead to oxidative stress and intensify IR. Thus, the interaction between hepatic lipid tissue accumulation and IR creates a vicious cycle that develops and maintains both MASLD and T2DM.

3.2. MASLD, Consequence of T2DM?

T2DM plays a significant role in the evolution of simple steatosis to NASH, liver cirrhosis and HCC. T2DM is a major factor in disease progression. Younossi ZM et al. showed, in a study conducted in 20 countries, an alarming prevalence (55%) of MASLD among T2DM individuals [26]. Accordingly, an increased incidence of MASLD and liver fibrosis was described in patients with T2DM based on eight studies from 2020 and 2021, conducted by Stefan N Cusi et al., using TE and/or MRI-based techniques as screening diagnostics for MASLD, NASH and liver fibrosis [27]. Current data estimates that 20 to 30% of patients with MASLD develop NASH, a condition that precedes advanced fibrosis. Kabarra K et al. showed that T2DM increases the risk of disease progression by two to three times [28].

A strong connection between steatohepatitis and T2DM does not prove causality, but it does demonstrate the impact of diabetes on the liver [25]. Patrick Wainwright and Christopher D Byrne highlighted, in a study published in 2019, that IR increases the release of fatty acids from adipose tissue, which are subsequently transported to hepatocytes. Initially, the hepatic accumulation of lipids represents an adaptive mechanism to metabolic stress. Later, however, the continuous flow of FFA in the liver activates pro-inflammatory pathways, leading to an intracellular increase of triglycerides [29].

Targher G and Byrne CD proved that lipotoxicity is associated with peripheral IR, hepatic glucose synthesis and gluconeogenesis, all these mechanisms leading to hyperglycemia, pancreatic cell dysfunction and altered insulin secretion [30,31]. The excess of intracellular fatty acids promotes mitochondrial dysfunction and oxidative stress, which are trigger factors for cellular apoptosis. Moreover, in diabetic patients, the release of pro-inflammatory mediators from the adipose tissue, as well as the presence of intestinal microbiota endotoxins resulted by bacterial translocation, activate Kupffer liver cells and interleukin secretion (IL-1b, IL-6 and αTNF). Secondary hepatocellular injury leads to the activation of stellate cells and the development of collagen deposits [31].

Recent and comprehensive meta-analyses have aimed to assess the bidirectional connection between MASLD and T2DM (Table 4).

Table 4. A summary of the most recent systematic reviews and meta-analyses aimed at evaluating the relationship between T2DM and MASLD.

Authors	Publication Year	Systematic Review/Meta-Analysis	Population Study	Objectives	Results	Reference
Cao et al.	2024	Systematic review and meta-analysis	395 studies with 6,878,568 participants	To assess the epidemiological feature of T2DM in patients with NAFLD/MAFLD	The global prevalence of T2DM among patients with NAFLD/MAFLD was 28.1% (95% CI 25.1–31.3%)	[32]
Younossi et al.	2019	Systematic review and meta-analysis	80 studies with 49,419 participants	To estimate the prevalence of NAFLD, NASH and advanced fibrosis among patients with T2DM	The global prevalence of NAFLD among patients with T2DM was 55.5% (95% CI 47.3–63.7)	[26]
En Li Cho et al.	2023	Systematic review and meta-analysis	156 studies with 1,832,125 participants	To quantify the prevalence of NAFLD and advanced fibrosis in people with T2DM	The prevalence rates of NAFLD/NASH in T2DM was 65.04% (95% CI 61.79–68.15) and 31.55% (95% CI 17.12–50.70), respectively. 35.54% (95% CI 19.56–55.56) of individuals with T2DM with NAFLD presented significant fibrosis; 14.95% (95% CI 11.03–19.95) with advanced fibrosis	[33]
Younossi et al.	2016	Meta-analysis	86 studies with 8,515,431 participants	To evaluate the incidence of comorbidities in NAFLD	Incidence of T2DM (22.51%; 95% CI 17.92–27.89)	[2]
Mantovani et al.	2018	Meta-analysis	19 studies with 296,439 participants	To assess the magnitude of the association between NAFLD and risk of T2DM.	Patients with NAFLD had a higher risk of T2DM than patients without NAFLD (random-effects HR 2.22, 95% CI 1.84–2.60)	[34]
Morrison et al.	2019	Meta-analysis	20 studies including 240,251 participants	To establish a causal association of NAFLD with CVD and T2DM	Associations of NAFLD with T2DM were reported in 20 studies. Comparing patients with NAFLD to patients without, the pooled RR was 2.17 (1.77, 2.65) for T2DM.	[35]
Mantovani et al.	2021	Meta-analysis	33 studies with 501,022 participants	To assess the magnitude of the association between NAFLD and risk of T2DM.	Patients with NAFLD had an increased risk of incident diabetes than patients without NAFLD (26 studies; random-effects HR 2.19, 95% CI 1.93–2.48)	[36]
Ballestri et al.	2016	Systematic review and meta-analysis	20 studies including 117,020 participants	Evaluating the magnitude of the risk of incident T2DM and MetS among patients with NAFLD	NAFLD was associated with an increased risk of incident T2DM; pooled RR of 1.97 (95% CI 1.80–2.15)	[37]
Alenezi et al.	2023	Systematic review and meta-analysis	8 studies with 4045 participants	Estimating NAFLD in association with an increased prevalence of diabetes mellitus and obesity.	The pooled prevalence of NAFLD among all adult populations in KSA was 16.8% (11.1–22.5). Among those with type 2 diabetes, the prevalence was 58.0% (45.0–70.9).	[38]
Jarvis et al.	2020	Systematic review and meta-analysis	12 studies with 22.8 million participants	Estimating metabolic risk factors and their potential to predict liver disease outcomes in patients with NAFLD.	T2DM was associated with an increased risk of incident severe liver disease events (adjusted HR 2.25, 95% CI 1.83–2.76).	[39]

NAFLD—Non-alcoholic fatty liver disease; MAFLD—Metabolic-associated fatty liver disease; T2DM—Type 2 diabetes mellitus; CI—Confidence interval; CVD—Cardiovascular disease; RR—Relative risk; HR—Hazard ratio; MetS—Metabolic syndrome; KSA—Kingdom of Saudi Arabia.

3.3. MASLD, a Link to Obesity

Obesity is reflected as a major risk factor in MASLD development; therefore, body mass index (BMI) and waist circumference are intensely correlated with both MASLD and the disease [40]. MASLD patients over 40 years of age are most likely to be obese. In fact, every range of obesity is correlated with MASLD, from overweight to moderate and severe obesity [41], and more than 95% of patients with severe obesity undergoing bariatric surgery may develop MASLD [42], thus highlighting the close pathogenic link between the two conditions [43].

Lipotoxicity and glucotoxicity are key factors in the initiation of simple steatosis and progression to NASH. Fatty liver deposition promoted by a high-fat, high-carbohydrate diet occurs through various mechanisms, as mentioned, such as mitochondrial and endoplasmic reticulum defects and oxidative stress [44]. Polyzos et al. focused, in their study, on the activation of immune liver cells and the release of cytokines with further inflammation promotion, also contributing to fibrosis [45]. Erica Vetrano et al. highlighted the relationship between obesity and MASLD/HCC, noting that obesity causes liver synthesis of adipokines and hormones, which may contribute to the progression of MASLD to NASH, cirrhosis and HCC [46], adipocytes being particularly secretory active substances. The most studied adipokines are adiponectin, leptin, resistin, visfatin, omentin and adipsin, the latter also having an immunological role in the alternative mechanism of complement activation, as highlighted by Margarete Milek et al. in 2022 [47].

Visfatin has metabolic actions similar to insulin, stimulating the uptake of glucose by adipose and muscle cells, at the same time inhibiting the release of glucose from hepatocytes. The role of visfatin and omentin in obesity-induced IR has been described in a recent study published in 2022 by Mona Mohamed et al. [48].

Resistin is an adipokine secreted by both adipocytes and macrophages. Adriana Nieva Vazquez et al. highlighted, in a study in 2014, the pro-inflammatory role of resistin in promoting IR in sepsis, mainly due to hepatic-releasing glucose [49].

Milan Obradovic et al. studied, in 2021, the role of leptin, a protein encoded by the obesity gene and secreted by adipocytes, which inhibits appetite and also contributes to metabolism. Leptin activity is mediated by specific receptors of target cells [50]. Obesity is characterized by an increased concentration of leptin, though hyperleptinemia in obesity and T2DM is rather associated with leptin resistance, as revealed by Lahlou et al. in a study on leptin resistance [50], similar to insulin resistance [51].

Liping Luo’s study showed that adiponectin is secreted almost exclusively by adipocytes, which circulate in high concentrations in the blood and promote insulin sensitivity [52]. Also, adiponectin accelerates the metabolism of fatty acids and reduces the expression of endothelial adhesion molecules (ICAM-1 and VCAM-1), improving endothelial function. This effect occurs due to the inhibition of nuclear factor κB (nuclear factors κB-NFκB), consequently decreasing the production of IL-6 synthesis. Sheetal Parida et al., as well as Nikolaos Perakakis, in their studies concluded that a low concentration of adiponectin was correlated with an increased risk of IR, T2DM and hypertension, as well as coronary heart disease [53,54].

Many researchers have focused on these interacting conditions, as shown in Table 5.

Table 5. A summary of the most recent systematic reviews and meta-analyses aimed at evaluating the relationship between obesity and MASLD.

Authors	Publication Year	Systematic Review/Meta-Analysis	Population Study	Objectives	Results	Reference
Quek et al.	2023	Systematic review and meta-analysis	151 studies with 101,028 participants	To report the prevalence of NAFLD, NAFL and NASH in overweight and obese populations	The prevalence of NAFLD in the overweight population was 69·99% (95% CI 65.40–74.21) Similar prevalence was reported in obese individuals for NAFLD (75.27%, 95% CI 70.90–79.18)	[55]
Younossi et al.	2016	Meta-analysis	86 studies with 8,515,431 participants	To evaluate the incidence of comorbidities in NAFLD	Incidence of obesity (51.34%, 95% CI 41.38–61.20)	[2]
Le et al.	2023	Systematic review and meta-analysis	63 studies with 1,201,807 participants	Assessing the prevalence of NAFLD and the association with obesity/overweight	NAFLD incidence rate was 4.612.8 (95% CI 3.931.5–5.294.2) per 100.000 person-years. Both the obese (vs. non-obese) and the overweight/obese groups (vs. normal weight) were about threefold more probable to develop NAFLD (8.669.6 vs. 2.963.9 and 8.416.6 vs. 3.358.2, respectively).	[56]
Ismaiel et al.	2023	Systematic review and meta-analysis	27 studies with 93,536 participants	Evaluating WHtR, a simple obesity metric in NAFLD patients	WHtR was significantly higher in NAFLD patients compared to controls, with an MD of 0.073 (95% CI 0.058–0.088).	[57]
Jarvis et al.	2020	Systematic review and meta-analysis	14 studies with 19.3 million participants	Assessing metabolic risk factors and incident advanced liver disease in NAFLD	Obesity was associated with an increase in risk of incident liver disease outcomes (adjusted HR 1.20, 95% CI 1.12–1.28).	[39]

NAFLD—Non-alcoholic fatty liver disease; NAFL—Non-alcoholic fatty liver; NASH—Non-alcoholic steatohepatitis; CI—Confidence interval; WHtR—Waist-to-height ratio; MD—Mean deviation; HR—Hazard ratio.

3.4. MASLD, a Link to Cardiovascular Disease (CVD)

Many epidemiological studies support the hypothesis that MASLD patients have an increased risk of cardiovascular events. However, the real prevalence of cardiovascular events in patients with MASLD is not completely accomplished and is assumed to be even underestimated, since MASLD diagnosis is often missed, as many patients with this condition have normal liver enzymes and the usual imaging methods of MASLD screening (abdominal ultrasound) do not detect steatosis when fat liver infiltration is below 30%. Generally, people with MASLD have increased cardio-metabolic risk, even in the absence of MetS components [58].

A 2015 report of the Framingham Heart Study showed that hepatic steatosis was strongly correlated with subclinical CVD events, independent of other metabolic risk factors [59]. A meta-analysis carried out by Morrison et al. in 2019 concluded that MASLD is accompanied by a thickening of the vascular intima, with endothelial and cardiac dysfunction [35].

A comprehensive meta-analysis of 10,576,383 people from 24 countries, regarding non-obese MASLD individuals and aiming to eliminate obesity as a main risk factor, highlighted an increased incidence of new-onset CVD in lean MASLD patients [60]. Another study published in 2020 showed that additional cardiac complications, such as cardiomyopathy, heart valve regurgitations and cardiac arrhythmias, were also more common in people with MASLD [61].

Many studies associate MASLD with an increased incidence of coronary atherosclerosis, favored by increased lipolysis and VLDL secretion, increased fibrinogen and CRP [62].

Recent meta-analyses focused on MASLD as an independent risk factor for developing CVD after excluding other risk factors, with related nonfatal and fatal CV events; moreover, this risk increases with MASLD progression to NASH [36,63].

Christopher D Byrne et al. concluded, in their study, that IR-associated MASLD and the resulting hyperglycemic status induce a series of vascular changes that include endothelial dysfunction, cell proliferation and changes in the LDL-cholesterol receptor of the extracellular matrix, with a decrease in LDL clearance. Its fraction, sdLDL, has increased affinity for the proteoglycans of the vascular intima, which causes the penetration of more LDL particles into the vascular wall [64]. Therefore, MASLD is commonly associated with dyslipidemia (high triglycerides level, low HDL level, increased VLDL) and elevated levels of proinflammatory cytokines that promote the development of CVD [65]. Yoo HJ highlighted, in a study published in 2015, that hepatokines (fibroblast growth factor 21, fetuin-A and selenoprotein P) may have a role in CVD development [66]. Sheila Gato et al. concluded, in a recent study, that a potential link mechanism between MASLD and CVD may have its origin in the expansion and inflammation of visceral adipose tissue [67]. CRP accelerates atherosclerosis by the increased expression of plasminogen activator inhibitor 1 (I1Pl) and adhesion receptors on endothelial cells and inhibits the formation of nitric oxide, increasing the uptake of LDL cholesterol by macrophages [67].

The liver has a dual role: it is the target of systemic inflammatory changes and, at the same time, the source of proatherogenic factors. MASLD and NASH contribute to CVD through inflammatory cytokines produced in the liver, but released systemically, and oxidative stress mediators incriminated in the NASH pathogenesis. Jingjing Cai et al. noted, in their study, the contribution of MASLD to the onset of CV-associated events driven by IR and dyslipidemia [67].

Increased cardiovascular morbidity and mortality [68] is probably the most important clinical feature associated with MASLD. To date, growing evidence has shown that CVD represents an important mortality risk factor in patients with MASLD, as highlighted by Giovanni Targher et al. [61].

Although large population studies are still needed for confirmation, this hypothesis draws attention to the possibility that MASLD, especially in its severe form (NASH), may be considered not only as a marker of cardiovascular disease but also the first site of the atherosclerosis process [61,69,70].

The association between CVD and MASLD is highlighted in various systematic reviews and meta-analysis, as illustrated in Table 6.

Table 6. A summary of the most recent systematic reviews and meta-analyses aimed at evaluating the relationship between CVD and MASLD.

Authors	Publication Year	Systematic Review/Meta-Analysis	Population Study	Objectives	Results	Reference
Zhou et al.	2023	Systematic review and meta-analysis	12 studies with 14,213,289 participants	Study of the association between AF and NAFLD or MAFLD	The meta-analysis concludes there is a significant correlation between NAFLD and risk of incident AF (HR = 1.18, 95% CI 1.12–1.23)	[71]
Younossi et al.	2016	Meta-analysis	86 studies with 8,515,431 participants	Evaluating the incidence of comorbidities in NAFLD	Incidence of hypertension (39.34%, 95% CI 33.15–45.88), incidence of MetS (42.54%, 95% CI 30.06–56.05)	[2]
Morrison et al.	2019	Meta-analysis	13 studies with 258,743 participants	Establishing a causal association of NAFLD with CVD and T2DM	Comparing patients with NAFLD to patients without; pooled RR was 1.48 (95% CI 0.96–2.29) for CVD.	[35]
Mantovani et al.	2021	Systematic review and meta-analysis	36 studies with 5,802,226 participants	Quantifying the magnitude of the association between NAFLD and risk of CVD events	NAFLD was associated with a moderately increased risk of fatal or non-fatal CVD events (pooled random-effects HR 1.45, 95% CI 1.31–1.61)	[72]
Targher et al.	2016	Meta-analysis	16 studies with 34,043 participants	Assessing the correlation between NAFLD (and NASH) and the risk of CVD events	Patients with NAFLD had a higher risk of CVD events than patients without NAFLD (random effect OR 1.64, 95% CI 1.26–2.13)	[73]
Bisaccia et al.	2023	Systematic review and meta-analysis	33 studies with 10,592,851 participants	Assessing the CV morbidity and mortality associated with NAFLD in the general population	NAFLD was strongly associated with an increased risk of MI (OR 1.6, 95% CI 1.5–1.7), stroke (OR: 1.6, 95% CI 1.2–2.1), atrial fibrillation (OR: 1.7, 95% CI 1.2–2.3). NAFLD is associated with excessive risk of non-fatal CV events.	[74]
Jaiswal et al.	2023	Meta-analysis	12 studies with 18,055,072 participants	Evaluating the association between the NAFLD and the risk of CVD events-atrial fibrillation, heart failure, stroke, CVM	The risk of AF (RR 1.42, 95% CI 1.19–1.68), HF (RR 1.43, 95% CI 1.03–2.00), risk of stroke (RR 1.26, 95% CI 1.16–1.36), revascularization (RR 4.06, 95% CI 1.44–11.46), risk of CVM (RR 3.10, 95% CI 1.43–6.73) was significantly higher in NAFLD patients compared to non-NAFLD patients	[75]
Mantovani et al.	2019	Meta-analysis	9 studies with 364,919 participants	Assessing the association between NAFLD and risk of CVD events	NAFLD was associated with a higher risk of AF (random-effects OR 2.07, 95% CI 1.38–3.10)	[76]
Haddad et al.	2017	Systematic review and meta-analysis	6 studies with 25,837 participants	Assessing the association between NAFLD and clinical CVE	Patients with NAFLD had a significantly higher risk of CVE compared to control groups (RR 1.77, 95% CI 1.26–2.48). The risk of coronary artery disease (RR 2.26, 95% CI 1.04–4.92) and ischemic stroke (RR 2.09, 95% CI 1.46–2.98). The risk of CVM was higher in the NAFLD group (RR 1.46, 95% CI 1.31–1.64).	[77]
Jamalinia et al.	2024	Systematic review and meta-analysis	19 studies with 147,411 participants	Evaluating MASLD as a prevalent and independent risk factor for CVD	The pooled OR for subclinical atherosclerosis was 1.27 (95% CI 1.13–1.41) in mild steatosis and significantly higher—1.68 (95% CI 1.41–2.00) in moderate to severe steatosis.	[78]

AF—Atrial fibrillation; NAFLD—Non-alcoholic fatty liver disease; MAFLD—Metabolic-associated fatty liver disease; HR—Hazard ratio; CI—Confidence interval; MetS—Metabolic syndrome; T2DM—Type 2 diabetes mellitus; RR—Relative risk; OR—Odds ratio; CV—Cardiovascular; MI—Myocardial infarction; HF—Heart failure; CVM—Cardiovascular mortality; CVE—Cardiovascular events; CVD—Cardiovascular disease.

3.5. The Relationship Between MASLD and Cancer

Consequently, due to a higher prevalence of obesity and T2DM, the prevalence of HCC-related MASLD is increasing. Thus, MASLD is estimated to become the main cause of HCC globally, exceeding hepatitis B and C virus infection. The risk of HCC is amplified by genetic predisposition, such as PNPLA3 or transmembrane superfamily member 2 -6, in the presence of obesity or T2DM [79].

There is growing evidence for the correlation between MASLD and HCC, which provides the pathophysiologic hypothesis that T2DM is associated with a two-fold increased risk of HCC [80,81], but with a lower association with extrahepatic cancers, especially colorectal cancer [82,83,84]. Therefore, even if extrahepatic cancer incidence is not alarming, the growing incidence of MASLD-HCC requires the need to improve strategies for cancer screening in these individuals [85].

A nationwide cohort study focused on the correlation between the risk of young-onset digestive tract cancers and MASLD, recently published by Joo-Hyun Park, showed that MASLD was associated with an increased risk of overall digestive tract cancers, such as stomach, colorectal, liver, pancreatic, biliary tract and gallbladder, suggesting that MASLD may be an independent, modifiable risk factor for an increasing incidence of young-onset digestive tract cancers [86]. Additionally, MASLD increases the development and recurrence of colorectal cancer liver metastasis [87,88].

3.6. MASLD, a Link to Endocrine Disorders

Endocrine disruptors (EDCs) are currently considered an important health and environmental concept. Growing evidence indicates that in utero exposure to bisphenol A is associated with hepatic steatosis in adults, with EDCs altering β-oxidation hepatic capacity, most probably by epigenetic mechanisms [89,90].

EDCs (dioxins, phthalates, bisphenol A, as well as organic pollutants) can lead to IR by inducing oxidative stress or by modifying gene transcription [91]. Further studies are needed to specify the role of EDCs in MASLD pathogenesis [92].

Obesity, IR and T2DM seem to be the underlying key factors associated with MASLD in several endocrine disorders, justifying active screening for MASLD in this population; conditions such as polycystic ovary syndrome (PCOS), hypothyroidism, growth hormone (GH) deficiency, primary hyperaldosteronism (PA) and hypogonadism are the most studied.

3.6.1. MASLD and Polycystic Ovary Syndrome

Women diagnosed with PCOS have a higher risk of developing T2DM and MASLD [93]. The mechanisms underlying the development of MASLD in PCOS are multifactorial; however, Falzarano C. Lofton et al. support the role of IR as a key factor in MASLD occurrence [93]. Moreover, women with PCOS and hyperandrogenism have a much higher risk of MASLD, strongly associated with severe IR [94]. Wu J Yao et al. showed, in a meta-analysis, that normo-androgenic women with PCOS do not appear to have an increased prevalence of MASLD compared to control groups [95]. The relation hyperandrogenism—MASLD can be explained by the down-regulation of LDL receptors, the elongation of VLDL and LDL half-life, the induction of fat accumulation in the hepatocytes and finally the development of MASLD [96]. For these reasons, screening for MASLD in women with PCOS and associated MetS or IR is vital [97,98]. Recent studies have focused on the link between PCOS and MASLD prevalence, as shown in Table 7.

Table 7. A summary of the most recent systematic reviews and meta-analyses aimed at evaluating the relationship between PCOS and MASLD.

Authors	Publication Year	Systematic Review/Meta-Analysis	Population Study	Objectives	Results	Reference
Manzano-Nunez et al.	2023	Systematic review, meta-analysis and meta-regression	36 studies with 7374 participants	Assessing NAFLD’s prevalence and risk factors in patients with PCOS.	NAFLD prevalence 43% (95% CI 35–52)	[99]
Rocha et al.	2017	Systematic review and meta-analysis	17 studies with 2734 participants	Evaluating NAFLD in women with PCOS	PCOS women have an increased NAFLD prevalence (OR 2.54, 95% CI 2.19–2.95).	[100]
Shengir et al.	2021	Systematic review and meta-analysis	23 studies with 7148 participants	Investigating the correlation between NAFLD and PCOS in premenopausal PCOS women.	Women with PCOS had a 2.5-fold increased risk of NAFLD compared to control groups (pooled OR 2.49, 95% CI 2.20–2.82)	[101]
Yao et al.	2023	Meta-analysis	32 studies with 145,131 participants	Assessing the association between PCOS and the risk of NAFLD	The study showed that PCOS was significantly associated with a higher risk of NAFLD (OR 2.93, 95% CI 2.38–3.62).	[102]

NAFLD—Non-alcoholic fatty liver disease; PCOS—Polycystic ovary syndrome; CI—Confidence interval; OR—Odds ratio.

3.6.2. MASLD and Hypothyroidism

Hypothyroidism appears to be associated with hepatic steatosis in various studies [103,104]. Mantovani et al. published a meta-analysis in 2018, which included a total of 15 studies with 44,140 participants, that suggested that hypothyroidism is strongly associated with both the presence and the severity of MASLD [105].

The most significant characteristics of patients with untreated hypothyroidism are the appearance of lipid metabolism disorders, such as increased serum cholesterol and triglycerides, and the accumulation of fat in the hepatocytes [106,107]. Moslehi A et al. highlighted, in a study published in 2018, the role of transcription factors in lipid synthesis, including the sterol regulatory element binding protein (SREBP) and the liver X receptor (LXR) [108]. SREBP controls lipid synthesis, notably influenced by thyroid hormone levels. The effect of thyroid hormones on SREBP-2, an isoform of SREBP, namely, decreasing LDL receptor expression, leads to an increase in serum cholesterol levels. The influence of thyroid hormones on lipid metabolism and liver function, together with the control molecular mechanisms, have been extensively studied [109].

Therefore, the interconnection between MASLD and hypothyroidism has been a topic for multiple studies, sometimes having contradictory results [110,111]. Liu et al. showed a positive association between free triiodothyronine (FT3), thyroid-stimulating hormone (TSH) levels and the incidence of MASLD in euthyroid people [112]. In a recently published meta-analysis, Guo et al. highlighted that TSH levels are positively correlated with MASLD, increasing with MASLD progression [113], an association also noted by Borges-Canha et al. in patients with morbid obesity [114]. Jaruvongvanich, V. et al. disproved these associations [115]. Therefore, it is reasonable to recognize the existence of non-thyroid etiologies of MASLD in patients with hypothyroidism [116]. However, Bano et al. highlighted the relationship between hypothyroidism and MASLD, independent of the presence of other metabolic risk factors [117]. A series of meta-analysis suggest the correlation between MASLD and hypothyroidism, as illustrated in Table 8.

Table 8. A summary of the most recent systematic reviews and meta-analyses aimed at evaluating the relationship between hypothyroidism and MASLD.

Authors	Publication Year	Systematic Review/Meta-Analysis	Population Study	Objectives	Results	Reference
Mantovani et al.	2018	Systematic review and meta-analysis	15 studies with 44,140 participants	Quantifying the magnitude of association between primary hypothyroidism and risk of NAFLD.	Hypothyroidism was associated with an increased prevalence of NAFLD (random-effects OR 1.42, 95% CI 1.15–1.77)	[105]
He et al.	2017	Systematic review and meta-analysis	13 studies with 42,143 participants	Evaluation of the relationship between hypothyroidism and NAFLD	The study showed a significant correlation between hypothyroidism and NAFLD (OR  =  1.52, 95% CI 1.24–1.87)	[110]
Mantovani et al.	2024	Meta-analysis	28 studies with 76.5 million participants	Quantifying the magnitude of the association between primary hypothyroidism and the risk of MASLD.	Primary hypothyroidism was positively associated with an increased risk of MASLD (random-effects OR 1.43, 95% CI 1.23–1.66)	[118]
Guo et al.	2018	Systematic review and meta-analysis	26 studies with 61,548 participants	Evaluating the effect of hypothyroidism on NAFLD/NASH development	NAFLD/NASH patients had increased TSH levels compared to controls in adults (NAFLD versus health: WMD = 0.105, 95% CI 0.012–0.197	[113]
Jaruvongvanich et al.	2017	Systematic review and meta-analysis	14 studies with 37,194 participants	Investigating the association between NAFLD and thyroid dysfunction	NAFLD was not positive associated with subclinical hypothyroidism (pooled OR 0.63, 95% CI 0.18–2.20), overt hypothyroidism (pooled OR = 1.37, 95% CI 0.78–2.41) or overall hypothyroidism (pooled OR = 1.21, 95% CI 0.91–1.61) compared with non-NAFLD controls	[115]
Zeng et al.	2021	Systematic review and meta-analysis	17 studies with 51,407 participants	Assessing the relationship between NAFLD and hypothyroidism	The study indicated an increased risk of NAFLD in hypothyroid individuals, with increased TSH levels (OR 1.23, 1.07–1.39)	[119]

NAFLD—Non-alcoholic fatty liver disease; OR—Odds ratio; CI—Confidence interval; MASLD—Metabolic-associated steatotic liver disease; NASH—Non-alcoholic steatohepatitis; TSH—Thyroid stimulating hormone; WMD—Weighted mean difference.

3.6.3. MASLD and GH Deficiency

Due to the extensive effects of GH on glucose metabolism, GH deficiency was commonly associated with MASLD [120]. MASLD usually develops shortly after the diagnosis of adult GH deficiency (GHDA) and can rapidly progress to NASH and/or advanced fibrosis [121]. Huang Z et al. highlighted that GH deficiency is defined by an imbalance between low levels of GH and elevated insulin levels [122], and Meienberg F et al. similarly concluded that MASLD was increasingly accepted as part of the metabolic complications associated with GHDA [123]. Furthermore, small studies using liver biopsy for diagnosis have shown a higher incidence of NASH in patients with GHDA [124], liver fibrosis and cirrhosis, even claiming liver transplantation as the cause. Furthermore, in patients with biopsy-diagnosed MASLD, a reduced GH has been correlated with advanced steatosis, while low IGF-1 and IGF-1/IGFBP-3 levels have been associated with liver fibrosis and/or NASH [125].

GH effects are mainly mediated by IGF-1, synthesized in hepatocytes. IGF-1 circulates are associated mainly with IGFBP-3 (secreted by Kupffer cells). Clemmons DR et al. noted, in a study, that IGFBP increases IGF-1 half-life, directing it to distinct tissues, whereas IGF-1 promotes cell growth and affects carbohydrate, protein and lipid metabolism [126]. The main effect of GH on adipose tissue is lipolysis, with increased serum levels of FFA and glycerol [127]. Sharma R et al. highlighted, in a recent study, that although increased circulating FFA is correlated with a higher risk of MASLD, this does not occur under physiological circumstances because GH induces FFA uptake by increasing lipoprotein lipase activity in skeletal muscle [127], and JAK2-STAT (Janus kinase (JAK)2 activator transcription) signaling suppresses lipid uptake and de novo lipogenesis in the liver [104,105].

However, data on the efficacy of GH therapy in patients with MASLD are limited and controversial [123,128,129]. Treatment initiation, impact on glucose metabolism and T2DM incidence, as well as the long-term effects of GH therapy and risk of HCC, particularly in patients with NASH and advanced fibrosis, should also be carefully evaluated [130,131,132].

3.6.4. MASLD and Acromegaly

Excessive GH and IGF-1 characterize acromegaly, the most common cause of GH-secreting pituitary adenoma. Petrossians, P et al. showed, in their study, that increased GH levels are correlated with an increased lipolysis and a proper body composition, with increased lean body mass and decreased adipose tissue, both visceral and subcutaneous [133]. It is known that acromegaly promotes IR, and consequently hyperglycemia, increased insulin and triglyceride levels, and an increased risk of T2DM [134].

While Winhofer, Y et al., in their study, showed that intrahepatic lipids, measured by magnetic resonance spectroscopy, are rather low in patients with active acromegaly compared to healthy subjects [135], Koutsou-Tassopoulou, A et al. concluded that hepatic steatosis is commonly found in acromegaly, suggesting that lipotoxicity and IR may overcome the direct effects of GH on liver cells [136].

3.6.5. MASLD and Panhypopituitarism

Panhypopituitarism, characterized by concomitant pituitary deficiencies, has also been associated with MASLD [137]. Ritter et al. noted the association between hypothyroidism and MASLD, due to the multiple consequences of thyroid hormones on hepatic lipid metabolism [104], and Sarkar et al. associated low free testosterone in men with a notably higher incidence of biopsy-diagnosed NASH and advanced liver fibrosis [138]. Zhang et al. concluded that a low prolactin level is a risk factor for MASLD occurrence, directly correlated with steatosis severity [139]. Additionally, MASLD is a common finding in hypogonadism, independent of gender and etiology [140].

3.6.6. MASLD and Estrogen Deficiency

Over time, numerous studies have been published attesting that conditions associated with estrogen deficiency, both physiologically in postmenopausal women and in women with hypogonadism, are associated with an increased prevalence of MASLD, NASH and advanced fibrosis [141].

Based on a consistent line of evidence, postmenopausal status is considered an independent risk factor for MASLD development and progression [142]. Klair et al. reported, in a study, that premature menopause is associated with a higher risk of advanced liver fibrosis [141]. Although adiposity disposal (subcutaneous adiposity and visceral adiposity) is closely linked with sex hormones [142], it has been proven that hypogonadism, in both men and women, is strongly associated with MASLD, by affecting glucose tolerance, IR and by the association of arterial hypertension and atherogenic dyslipidemia [143].

3.6.7. MASLD and Primary Hyperaldosteronism

PA is the most frequent endocrine cause of secondary hypertension, responsible for almost 10% of all cases. [144]. PA can cause not only hypertension but also IR and dyslipidemia [145]. Srinivasa S et al. reported that activation of the mineralocorticoid receptor by aldosterone leads to the impairment of insulin sensitivity in skeletal muscles and adipocytes by stimulating the pathogenic proinflammatory pathways and the metabolic pathways of oxidative stress, endothelial dysfunction, cell proliferation and inflammation, increasing the risk of MetS and MASLD [146,147].

3.6.8. MASLD and Hyperprolactinemia

Prolactin is a hormone derived from the pituitary gland and is involved in reproduction and lactation. Because the prolactin receptor is also present in the liver, it can play an important role in hepatic metabolic regulation [146]. A negative correlation between plasma prolactin levels and BMI, IR and MASLD development has been observed in recent observational studies [139,147].

Despite the favorable impact of prolactin on metabolic homeostasis, Serri O et al. reported that a significant increase in prolactin levels was commonly correlated with metabolic disorders, such as overweight, obesity and hyperinsulinemia, all of which are proposed crucial factors in MASLD pathogenesis [148]. Although prolactin is thought to reduce hepatic fat content, Zhang P et al. concluded that it is probable that a chronically increased prolactin level is involved in MASLD occurrence and progression [139].

3.7. MASLD and Vitamin D Deficiency

Vitamin D is currently recognized for its role in phospho-calcium metabolism. However, its receptors are ubiquitously present; thus, vitamin D exerts multiple effects in different organs and systems [149].

Recent studies associate vitamin D deficiency with several metabolic disorders, including MASLD [150,151]. Abramovitch S et al. showed, in their study, vitamin D’s effects in the liver, with an anti-inflammatory and anti-fibrotic result [152]. This protective effect may be due to the capacity of stellate cells to inhibit fibrogenesis [153]; meanwhile, several epidemiological studies point to an association between decreased vitamin D levels and MASLD, although no causal connection has been found [154,155]. A recent study by Borges-Canha et al. showed that vitamin D deficiency was associated with an increased risk of hepatic steatosis in morbidly obese patients [156]. In contrast, Wang et al. did not find a causal correlation between MASLD vitamin D deficiency in a Chinese population of over 9000 participants [157], and Barchetta et al., in a randomized trial, concluded that 24 weeks of high-dose oral vitamin D supplementation did not improve hepatic steatosis in patients with MASLD and T2DM [158]. For these reasons, future extensive studies are needed to focus on the role of vitamin D and its supplementation in MASLD.

Figure 2 summarizes the bidirectional connection between MASLD and the most commonly associated conditions.

Figure 2. MASLD and the most commonly associated conditions—a bidirectional connection.

4. MASLD Management—Actual and Future Perspectives

The ideal goal of the treatment is the resolution of histological lesions, to diminish the risk of evolution towards liver cirrhosis, with the objectives of the treatment therefore being the improvement of biochemical and histological liver parameters, as well as the control of all features of the metabolic syndrome associated with hepatic steatosis: weight, glycemic and lipid metabolism or blood pressure control. The treatment methods include lifestyle optimization, obesity pharmacotherapy and hypoglycemic therapy.

EASL recommends an energy restriction of 500–1000 kcal per week, with a target weight loss of 7–10% for obese/overweight patients, a low-fat, moderate-to-high-carbohydrate diet or a low-carb or high-protein ketogenic diet, such as the Mediterranean diet [159]. Alcohol is an aggravating factor, and AASLD recommends that people with MASLD or NASH should avoid alcohol. EASL allows alcohol consumption below 30 g/day for men and 20g/day for women. The role of coffee consumption for the treatment of MASLD is unclear, although some studies indicate that regular coffee consumption may have protective effects.

Pharmacological treatment is indicated for patients with fibrosis stage ≥ 2, and those with stages 0 or 1 have a high risk for the progression of fibrosis (elderly, diabetes, metabolic syndrome, elevated ALT and high necroinflammatory activity) [159].

4.1. Antioxidants

Vitamin E reduces reactive oxygen species level and prevents oxidative damage to cells by different mechanisms, alleviating senescence and cell apoptosis. These properties can slow the progression of liver damage and even facilitate the reversibility of liver fibrosis. The PIVENS (Pioglitazone, Vitamin E, or Placebo for Non-alcoholic Steatohepatitis) trial demonstrated an improvement in steatosis and a significant decrease in hepatocyte ballooning and inflammation [160]. Although vitamin D deficiency is common in MASLD/NASH, data on the efficacy of vitamin D supplementation have not been conclusive. Some studies have suggested that vitamin D may induce antifibrotic effects by suppressing the proliferation of stellate cells [161,162]. Other antioxidants, such as S-adenosyl methionine. (SAM) and betaine, are supplements with cytoprotective, antiapoptotic and antisteatotic effects and can also decrease IR [163]. N-acetyl cysteine (NAC), a glutathione precursor, increases glutathione levels in the hepatocyte and diminishes reactive oxygen species that cause hepatocyte damage; therefore, NAC supplementation can protect cellular structures against oxidative stress [164]. A pilot study showed that the administration of 300 mg/day glutathione for 4 months can decrease ALT and improves steatosis in patients without severe fibrosis [165].

4.2. Antidiabetic Drugs

Given that IR is one of the causes of non-alcoholic fatty liver disease, it is self-evident that the use of antidiabetic drugs in liver disease is an interesting issue. Drugs such as metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (iDPP-4), glucagon-like peptide-1 (GLP-1) agonists or sodium-glucose cotransporter 2 inhibitors (iSGLT2) have been shown to improve liver function in addition to lowering blood glucose.

GLP1 agonists are the most promising class, reducing hepatic steatosis and elevated liver enzymes in patients with diabetes and MASLD, but further studies are needed to assess their effect on progression to liver cirrhosis [166,167].

A therapeutic combination of a dual analogue of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) tirzepatide seems to have a favorable evolution on MASLD [168].

The promising results in improving the metabolic parameters of these new therapies led to the investigation of other more advanced molecules, such as triple analogs of GLP-1/GIP/glucagon. Retatrutide is one such triple analog used in clinical trials that appears promising in the management of MASLD, improving mitochondrial oxidative stress, with consequently possible antifibrotic effects [169].

Pioglitazone—a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist—contributes to a decrease in lipotoxicity, increasing hepatic lipogenesis and insulin sensitivity, adiponectin accumulation and improving necroinflammation, therefore delaying fibrosis progression [170]. The dual PPAR-α/γ agonist saroglitazar reduces steatosis, decreases inflammation and improves IR by increasing fatty acid oxidation and decreasing lipolysis [171]. The dual PPAR-α/δ agonist Elafibranor improves steatosis and reduces inflammation and fibrosis [172]. Pan-PPAR agonists, antifibrotics that activate all three types of PPAR receptors—alpha, gamma and delta—appear to improve insulin sensitivity and macrophage activation, reducing liver fibrosis and inflammation [173].

Analysis of the clinical trials on SGLT-2 inhibitors (canagliflozin and luseogliflozin) showed a decrease in alanine aminotransferase (ALT) and consequently a resolution of steatosis, inflammation and ballooning of hepatocytes [174].

DDP-4 inhibitors are often prescribed to diabetic MASLD patients due to their beneficial effects in decreasing ALT and AST, as well as glycated hemoglobin (HbA1c) [175].

Metformin decreases insulin resistance by reducing hepatic gluconeogenesis and fatty acid oxidation, increases peripheral and hepatic sensitivity to insulin and decreases intestinal glucose absorption and serum lipid concentration. Metformin has no significant effects on liver enzymes and histology in NASH/MASLD but is associated with reduced incidence of hepatocellular carcinoma [176].

4.3. Other Therapies

Hypolipemiant therapy has an important role in the therapeutic scheme of diabetic patients with MASLD because it decreases the cardiovascular risk. Statins administration is associated with the inhibition of liver inflammation, improving liver fibrosis and reduction carcinogenesis risk. Furthermore, the cholesterol absorption inhibitor ezetimibe may decrease liver enzymes and improve steatosis, but histological efficacy remains uncertain [177].

Angiotensin II receptor blockers reduce fibroblast activity and liver fibrosis by inhibiting the activation of stellate cells that express angiotensin receptors [178,179].

Farnesoid X receptor ligand obeticholic acid (AOC) represents the synthetic version of natural chenodeoxycholic bile acid, with a role in reducing hepatic gluconeogenesis, lipogenesis and steatosis [180].

Resmetirom, thyroid hormone receptor β, is the predominant hepatic receptor for thyroxine, which increases cholesterol metabolism and mediates its secretion through bile. The molecule is a highly selective agonist and was developed to address dyslipidemia but has been observed to also reduce hepatic steatosis [181].

Qualitative and quantitative changes in gut microbiome composition and disturbances in the gut–liver axis favoring the translocation of endotoxins into the bloodstream appears to be independently associated with the development of MASLD and the progression to NASH and HCC. In MASLD patients, a significantly increased Firmicutes/Bacteroidetes ratio has been revealed in recent studies, as well as reduced levels of Akkermansia and L. murinus [182,183]. Recent studies have suggested that the ingestion of L. acidophilus, L. fermentum, L. paracasei and L. plantarum significantly decreases serum triglyceride and total cholesterol levels and improves MASLD disease progression. Anaerobutyricum soehngenii (Eubacterium hallii) seems to improve insulin resistance and glycemic profiles in subjects with metabolic syndrome, representing a therapeutic potential in MASLD [184].

Concerning all these features, we emphasize that only through a concerted effort by the medical community can MASLD be successfully managed. Through education and awareness, early diagnosis, lifestyle change and appropriate therapeutic management, steatosis can regress and progressive forms of the disease to cirrhosis and HCC can be avoided, leading to an improved quality of life.

5. Conclusions

The exponential increase in the prevalence of metabolic diseases and obesity, primarily diabetes and cardiovascular diseases, justifies an active screening for MASLD in this context, given the strong correlation and common etiopathogenesis of these conditions.

MASLD is a highly heterogeneous metabolic disorder; therefore, recognizing clinical pathologic associations is crucial to implementing an individualized, personalized approach to our patients.

Based on its definition and pathophysiology, the monitoring of patients with MASLD must be multidisciplinary. The contribution of gastroenterologists, diabetologists, endocrinologists, nutritionists, internists and cardiologists must be managed within an integrated assessment, ideally requiring a multidisciplinary team. A large dissemination of current knowledge on MASLD and an extensive collaboration between physicians is equally needed to ensure we have the ability and resources to address this public health challenge.