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Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) has attained epidemic proportions in recent years, affecting nearly one-third of the general population and two-thirds of patients with type 2 diabetes (T2DM). It encompasses a wide spectrum of pathophysiological entities, ranging from simple steatosis to steatohepatitis to fibrosis and cirrhosis, with both hepatic and extrahepatic implications, including cardiovascular disease. The possibility of MASLD should be considered in high-risk groups such as T2DM, obesity, metabolic syndrome, polycystic ovarian syndrome (PCOS), etc., with/ without evidence of hepatic steatosis on imaging or persistently raised liver enzymes. Initial assessment should include a comprehensive evaluation of comorbidities, exclusion of secondary causes of steatosis, and fibrosis risk stratification. The presence of NASH and fibrosis is the most important predictor of adverse clinical outcomes, and non-invasive risk assessment has been an area of intense research in recent decades. FIB-4 can be used as a primary tool to effectively rule out significant fibrosis, followed by vibration-controlled transient elastography (VCTE) or enhanced liver fibrosis (ELF) tests as secondary tools if the FIB-4 score is indeterminate or high. The management of MASLD patients has shifted from a hepatocentric to a multicentric approach, with a focus on lifestyle interventions, disease-modifying pharmacotherapy in selected patients, and optimized management of comorbidities and complications.

Keywords

Cirrhosis diagnosis fatty liver fibrosis management MASLD NAFLD NASH steatohepatitis type 2 diabetes

Introduction

Metabolic dysfunction–associated steatotic liver disease (MASLD), earlier known as non-alcoholic fatty liver disease (NAFLD), is a chronic condition that has attained epidemic proportions in the current health landscape. It is characterized by the presence of macrovesicular steatosis in ≥5% of hepatocytes and encompasses a broad range of pathophysiological entities, ranging from steatosis to steatohepatitis to fibrosis and cirrhosis.¹ Non-alcoholic steatohepatitis (NASH), accounting for about 20% of NAFLD, represents a more aggressive form of NAFLD characterized by hepatic inflammation and fibrosis, with a higher propensity to progress to cirrhosis and hepatocellular carcinoma (HCC).

MASLD is the second most common cause of liver transplantation after hepatitis C and is one of the most common causes of hepatocellular carcinoma (HCC).^2-4 It has far-reaching implications beyond the liver, including an elevated risk of cardiovascular disease (CVD), obstructive sleep apnea, osteoporosis, chronic kidney disease, and extrahepatic malignancies such as carcinomas of the colon, stomach, pancreas, uterus, and breast.⁵ CVD is the principal cause of death, affecting approximately 40% of patients, while malignant and nonmalignant liver diseases account for deaths in less than 10% of patients.⁶

MASLD affects nearly 30% of the general population, with significant regional variations.⁷ Shalimar et al. conducted a meta-analysis to report a higher disease burden in India, with a pooled prevalence of 38.6% in Indian adults.⁸ On the other hand, NASH affects up to 12–14% of the general population.⁹ There has also been a secular trend towards an increasing prevalence of NAFLD over the decades, with an estimated yearly increase of 0.7%.^10,11 Patients with diabetes comprise a particularly high-risk group, with reported prevalence of NAFLD and NASH being as high as 55–70% and 30–40%, respectively. On the other hand, nearly half of NAFLD patients are diabetic, highlighting the bidirectional relationship between the two conditions.¹⁰

The majority of high-risk patients present to general practitioners, physicians, and endocrinologists, which necessitates adequate knowledge of the entity to enable early identification and initiate appropriate management and timely referrals. The landscape of MASLD has been in a constant flux, with the emergence of new research on simplified non-invasive identification of at-risk groups, research on newer disease-modifying drugs, and a shift from a hepato-centric approach to holistic multidisciplinary care. Our article aims to provide a brief overview of the recent developments, diagnosis, and management of MASLD.

What’s in a Name?

The term “non-alcoholic steatohepatitis” (NASH) was first used by Jurgen Ludwig in 1980 to describe hepatic steatosis and injury mimicking alcoholic hepatitis in overweight and obese individuals.¹² This subsequently became a part of the umbrella term “non-alcoholic fatty liver disease” (NAFLD), and this nomenclature has since served as the framework for use in clinical practice and research alike.

However, the nomenclature has been revisited in recent years in the search of a terminology that accurately describes the pathophysiology, acknowledges the overlapping disease mechanisms, and is inclusive and non-stigmatizing. The “non-alcoholic” part of the nomenclature does not acknowledge the etiopathogenesis of the condition and the potential overlap with alcohol-related liver disease. Additionally, the use of the word “fatty” can be stigmatizing and deter people from seeking medical attention. Hence, the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL), along with relevant stakeholders, published a consensus for revised nomenclature, the salient features of which have been summarized in Table 1.¹³

Table 1.

Revised Nomenclature of MASLD and Related Entities.¹³

Revised Nomenclature	Definition
Steatotic liver disease (SLD)	Umbrella term to describe steatosis, diagnosed histopathologically or by imaging, due to different causes
Metabolic dysfunction–associated steatotic liver disease (MASLD)	Steatotic liver disease with the presence of one or more adult or pediatric-specific cardiometabolic risk factors and the exclusion of other causes of hepatic steatosis
MASLD and increased alcohol intake (MetALD) or combination etiology	SLD with one or more cardiometabolic risk factors with the coexistence of other conditions like increased alcohol intake (average daily intake of >20–50 and >30–60 g in females and males, respectively) or other causes of steatosis (drugs, Wilson’s disease, inborn errors of metabolism, etc.)

The cardiometabolic criteria used for the diagnosis of MASLD in adults and pediatric age groups are represented in Table 2.

Table 2.

Cardiometabolic Criteria Used for the Diagnosis of MASLD in the Adult and Pediatric Populations.

Adult Population	Pediatric Population
• BMI ≥ 25 kg m⁻² (>23 in Asians) or WC > 90 cm (males), >80 cm (females) or ethnicity-adjusted • Fasting serum glucose ≥ 100 mg dl⁻¹ or 2-hour post-load glucose ≥ 140 mg dl⁻¹ or HbA1c ≥ 5.7% or type 2 diabetes or treatment for type 2 diabetes • Blood pressure ≥ 130/85 mmHg or specific anti-hypertensive drug treatment • Plasma triglycerides ≥ 150 mg dl⁻¹ or lipid-lowering treatment • Plasma HDL-cholesterol < 40 mg dl⁻¹ (males), <50 mg dl⁻¹ (females) or lipid-lowering treatment	• BMI ≥ 85th centile for age/sex (BMI Z-score > +1) ORWC > 95th centile or ethnicity-adjusted • Fasting serum glucose ≥ 100 mg dl⁻¹ or serum glucose ≥ 200 mg dl⁻¹ or 2-hour post-load glucose ≥ 140 mg dl⁻¹ or HbA1c ≥ 5.7% or type 2 diabetes or treatment for type 2 diabetes • Blood pressure age < 13 years with BP ≥ 95th centile or ≥ 130/80 mmHg (whichever is lower) Blood pressure age > 13 years, BP ≥ 130/85 mmHg or specific antihypertensive drug treatment • Plasma triglycerides ≥ 100 mg dl⁻¹ in age < 10 years, ≥ 150 mg dl⁻¹ in age ≥ 10 years or lipid-lowering treatment • Plasma HDL-cholesterol < 40 mg dl⁻¹ or lipid-lowering treatment

Adult Population

Pediatric Population

• BMI ≥ 25 kg m⁻² (>23 in Asians) or WC > 90 cm (males), >80 cm (females) or ethnicity-adjusted
• Fasting serum glucose ≥ 100 mg dl⁻¹ or 2-hour post-load glucose ≥ 140 mg dl⁻¹ or HbA1c ≥ 5.7% or type 2 diabetes or treatment for type 2 diabetes
• Blood pressure ≥ 130/85 mmHg or specific anti-hypertensive drug treatment
• Plasma triglycerides ≥ 150 mg dl⁻¹ or lipid-lowering treatment
• Plasma HDL-cholesterol < 40 mg dl⁻¹ (males), <50 mg dl⁻¹ (females) or lipid-lowering treatment

• BMI ≥ 85th centile for age/sex (BMI Z-score > +1) ORWC > 95th centile or ethnicity-adjusted
• Fasting serum glucose ≥ 100 mg dl⁻¹ or serum glucose ≥ 200 mg dl⁻¹ or 2-hour post-load glucose ≥ 140 mg dl⁻¹ or HbA1c ≥ 5.7% or type 2 diabetes or treatment for type 2 diabetes
• Blood pressure age < 13 years with BP ≥ 95th centile or ≥ 130/80 mmHg (whichever is lower) Blood pressure age > 13 years, BP ≥ 130/85 mmHg or specific antihypertensive drug treatment
• Plasma triglycerides ≥ 100 mg dl⁻¹ in age < 10 years, ≥ 150 mg dl⁻¹ in age ≥ 10 years or lipid-lowering treatment
• Plasma HDL-cholesterol < 40 mg dl⁻¹ or lipid-lowering treatment

Note: The presence of one or more criteria in an individual with steatotic liver disease can be considered diagnostic of MASLD after exclusion of other causes of steatosis.¹³ BMI: body mass index; WC: waist circumference.

We will be using the term MASLD interchangeably with NAFLD in the article, as the vast majority of scientific literature has been described with the older terminologies.

Diagnosis of MASLD

The diagnosis of MASLD is based on the presence of hepatic steatosis in addition to a lack of significant alcohol intake and the exclusion of other liver diseases, as outlined above. Abdominal ultrasound is not required to diagnose steatosis in patients at a high risk of MASLD, and clinicians can directly proceed to the initial evaluation and risk stratification for fibrosis after excluding secondary causes of steatosis, irrespective of transaminase levels.¹⁴ Targeted screening for MASLD and advanced fibrosis is recommended in the following high-risk groups:^14,15

Obesity and/or features of metabolic syndrome

Type 2 DM (T2DM), prediabetes

PCOD

NAFLD with moderate alcohol use

First-degree relative of a patient with cirrhosis due to NAFLD/NASH

Hepatic steatosis in any imaging study

Persistently elevated transaminases over six months

The most common clinical scenario remains that of a patient presenting with incidentally detected steatosis on abdominal imaging or raised transminases. It should be noted that alanine transferase (ALT) levels should be interpreted as per the normal range of 29–33 and 19–25 U L⁻¹ in males and females, respectively, which is lower than the usual ranges reported by laboratories.¹⁶ General population-based screening for NAFLD is not recommended.

The approach to a patient with suspected/confirmed NAFLD should be two-pronged:

Comprehensive evaluation of associated comorbidities and complications

Assessment of the risk of fibrosis

Initial Approach in MASLD Patients

The initial workup in patients with suspected/confirmed MASLD should include a comprehensive evaluation for attendant comorbidities and complications, as outlined in Table 3.

Table 3.

Initial Evaluation in Patients with Suspected/Confirmed MASLD.

History	• Comorbidities: diabetes, hypertension, overweight/obesity, OSA, cardiovascular disease • Liver-specific history: evidence of decompensation, portal hypertension • Medication intake • Details of alcohol use, if any Approximately 30 ml of whisky = 100 ml of wine = 240 ml of beer = 10 g of alcohol.
Examination	• Anthropometry: weight, BMI, waist and hip circumference, android vs. gynoid body fat distribution, any lipodystrophy • Blood pressure measurement • Features of insulin resistance: acanthosis nigricans, skin tags, dorsocervical fat pad • Features of chronic liver disease: jaundice, ascites, splenomegaly, prominent abdominal veins, gynecomastia, palmar erythema, spider veins, etc.
Laboratory	• Liver function test • Complete hemogram with platelets • OGTT, HbA1c • Fasting lipid profile • Creatinine • Urine albumin creatinine ratio • Hepatitis C • Investigations for other causes of steatohepatitis if clinical suspicion is present • Age-appropriate screening for malignancies

OGTT: oral glucose tolerance test; OSA: obstructive sleep apnea.

Imaging Modalities for Assessment of Hepatic Steatosis

The most common presentation is an incidental finding of hepatic steatosis on an abdominal ultrasound. Table 4 summarizes the imaging modalities that can be used to detect hepatic steatosis.

Table 4.

Imaging Modalities for Assessment of Hepatic Steatosis.

Imaging Modality for Assessment of Hepatic Steatosis	Remarks
Abdominal ultrasound	• Most commonly available, practical, and inexpensive • Accurate if >30% steatosis • Grading is possible • Sensitivity and specificity of 85% and 94%, respectively, as compared to liver histology¹⁷ • Operator-dependent, suboptimal at a liver fat content below 12.5% and in individuals with obesity¹⁸
Vibration-controlled transient elastography (VCTE)	• Sensitivity of >90% at controlled attenuation parameter (CAP) cutoff > 274 dB m⁻¹.^19,20 • Can detect milder steatosis (>10%) • Additionally, provides liver stiffness measurement (LSM) as an index of fibrosis. • Limited accuracy for grading the severity of steatosis • Operator dependent, unreliable in severe obesity²¹
Computed tomography (CT)	• Liver attenuation index (LAI): difference in attenuation of liver and spleen on non-contrast CT • LAI < −10 HU: specific for moderate to severe macrovesicular steatosis LAI > +5 HU: absence of significant steatosis • Radiation risk, cost²²
Magnetic resonance-proton density fat fraction (MR-PDFF)	• Most accurate²³ • Cost, limited availability • Predominant use in research settings currently

Non-invasive Assessment of Hepatic Inflammation and Fibrosis

Serum transaminases, often used in clinical practice for assessment of hepatic inflammation, have been found to have a poor correlation with hepatic inflammation in patients with MASLD.²⁴ Other non-invasive biomarkers for hepatic inflammation include cytokeratin-18 (CK18), integrated scores like Fibroscan-AST (FAST score), and MEFIB score (combination of MR elastography and fibrosis-4 score).^25-27 As steatohepatitis is a major driver of fibrosis progression, clinical algorithms have instead incorporated non-invasive biomarkers to accurately detect clinically significant fibrosis (≥F2) in lieu of those that detect active inflammation.

Hepatic fibrosis remains the most important factor for prognosis, treatment, and outcomes in NAFLD.⁶ While liver biopsy remains the gold standard for diagnosis of fibrosis and cirrhosis, several non-invasive serum-based markers (indirect and direct) as well as imaging-based biomarkers have been demonstrated to reliably predict clinically significant (≥F2), advanced (F3–F4) fibrosis, and cirrhosis (F4 fibrosis), and a few of them have been integrated into clinical practice algorithms. The available non-invasive biomarkers have been summarized in Table 5.^5,14,15,19

Table 5.

Non-invasive Serum and Imaging Biomarkers for Fibrosis Risk Stratification.

Non-invasive Tests for the Detection of Clinically Significant Fibrosis	Methodology	Remarks
FIB-4	Age (years) × AST (U L⁻¹)/ platelets (10⁹ L⁻¹) × √ALT (U L⁻¹)	• Indirect serum fibrosis biomarker • Most validated, simple, no added cost • AUROC: 0.78–0.8, excellent NPV: 88–95%, low PPV (40%) • Recommended by most guidelines as a primary tool for fibrosis risk assessment • Rule out test, not accurate in age <35 and >65 years • FIB-4 < 1.3: Low risk FIB-4 1.3–2.67: Indeterminate FIB-4 > 2.67: High risk • Can predict changes over time; useful for monitoring^28,30
AST platelet ratio index (APRI)	[AST (U L⁻¹)/upper limit of normal AST range × 100]/platelet count (10⁹ L⁻¹)	• Indirect serum fibrosis biomarker³¹ • < 0.5: Rule out 0.5-2: Gray zone >2: Rule in
NAFLD fibrosis score (NFS)	Uses age, BMI, presence of IFG/ diabetes, AST, ALT, platelet count, and albumin	• Indirect serum fibrosis biomarker • No added cost • AUROC: 0.72–0.75 • Not accurate in age < 35 years and in patients with diabetes and severe obesity^30,32 • NFS: < −1.455: Rule out NFS: −1.455–0.675: Gray zone NFS: ≥0.676: Rule in
Enhanced liver fibrosis (ELF)	Measures blood levels of tissue inhibitor of metalloproteinases 1(TIMP1), an amino-terminal propeptide of type III procollagen, and hyaluronic acid	• Direct serum biomarker of fibrosis • AUROC: 0.83 (95% CI: 0.71–0.9) with a threshold of 7.7 • High NPV • High cost, limited availability • Currently recommended as a second-line test if FIB-4 is indeterminate/high risk • <7.7: Rule in >9.8: Rule out^14,33
FibroSpect	Hyaluronic acid, TIMP1, and α2 macroglobulin	• Direct serum biomarker of fibrosis • Limited availability • Lower NPV³⁴
Vibration-controlled transient elastography (VCTE)	Liver stiffness measurement (LSM) using low-frequency ultrasound in kPa	• AUROC: 0.8 for advanced fibrosis and 0.9 for cirrhosis • Used as a second step in risk assessment algorithms • Can be used for risk stratification, including the prediction of portal hypertension • Wide availability, low cost, no radiation risk • Operator dependent • Falsely high LSM with recent alcohol/food intake, hepatic congestion, active hepatitis (ALT > 100 IU ml⁻¹), BMI ≥ 35 kg m⁻² • LSM < 8 kPa: Rule out LSM > 12 kPa: Rule in LSM ≥ 20 kPa: portal hypertension^35-37
Magnetic resonance elastography (MRE)	kPa	• More comprehensive assessment of liver • AUROC of 0.92 • Higher accuracy in clinical conditions with falsely high LSM on VCTE • < 2.5 kPa: Rule out > 3.6 kPa: Rule in^38,39

Note: ALT: alanine transferase; AUROC: area under the receiver operator characteristic curve; IFG: impaired fasting glucose; NPV: negative predictive value, PPV: positive predictive value.

Role of Liver Biopsy in MASLD

The gold standard for the diagnosis of steatosis, steatohepatitis, fibrosis, and cirrhosis is the histopathology of liver biopsy. However, liver biopsy remains an invasive procedure, with attendant risks like post-procedural pain in up to 50% of cases and potentially life-threatening complications such as hemorrhage in 0.6–1% of cases.³⁰ Additionally, it requires specialized equipment, trained staff, cost, and other logistical challenges. Hence, its utility is currently limited to patients with competing etiologies for hepatic steatosis, discordant results on non-invasive tests, and as an endpoint in clinical trials.⁵

Several staging systems have been proposed, of which the non-alcoholic fatty liver disease activity score (NAS) is the most commonly used and validated score. Salient features have been described in Table 6.

Table 6.

NASH and Fibrosis Staging.

Feature	Definition	Score or Code
Steatosis grade	Low- to medium-power evaluation of parenchymal involvement by steatosis	<5%: 0 5%–33%: 1 (mild) 33%–66%: 2 (moderate) >66%: 3 (severe)
Lobular inflammation	Overall assessment of all inflammatory foci per ×200 field	No foci: 0 <2 foci per 200 field: 1 2–4 foci per 200 field: 2 >4 foci per 200 field: 3
Ballooning		None: 0 Few (or borderline) balloon cells: 1 Many cells/prominent ballooning: 2
Non-alcoholic fatty liver disease activity score (NAS)	Sum of steatosis + lobular inflammation + ballooning scores	0–8
Fibrosis staging		None: 0 Mild: perisinusoidal or periportal (stage 1) Moderate: perisinusoidal and portal/periportal (stage 2) Severe: bridging fibrosis (stage 3) Cirrhosis: stage 4

Source: Reproduced from Cusi et al.¹⁴

Diagnostic Approach in MASLD

All patients with hepatic steatosis or clinical suspicion of MASLD based on the presence of metabolic risk factors should have a detailed initial assessment as detailed in Table 3 and fibrosis risk stratification as outlined in Figure 1.

Figure 1.

Source: Adapted from Cusi et al.¹⁴

Primary risk assessment for fibrosis can be easily done in primary care settings with FIB-4. FIB-4 < 1.3 effectively excludes significant fibrosis, and patients can be followed up periodically in the primary care setting. Patients with an indeterminate (1.3–2.67) or increased (>2.67) FIB-4 index can be followed up with a secondary risk assessment with vibration-controlled transient elastography (VCTE) or enhanced liver fibrosis (ELF) panel. The diagnostic algorithm and recommendations have been outlined in Figure 2.

Figure 2.

Source: Adapted from Cusi et al.¹⁴

Management of MASLD

The role of the clinician caring for patients with NAFLD is to reduce the morbidity and mortality associated with the condition, so management has to move beyond a “hepato-centric” approach to a multidisciplinary holistic approach that includes the following:

Lifestyle education and intervention

Liver-directed therapies for MASLD

Assessment and optimization of T2DM and other cardio-metabolic risk factors

Lifestyle Interventions for MASLD

One of the first-line recommendations for NAFLD management is caloric restriction and exercise to induce a net weight loss. The histological improvement in MASLD has a dose–response relationship with the degree of weight reduction. Overweight or obese patients with MASLD should be encouraged to lose at least 7–10% of their body weight; even modest weight loss of 3–5% results in improvement in steatosis, but greater weight loss (>10%) is required to improve NASH and fibrosis.^40,41

Sustained weight loss improves insulin sensitivity and adipose tissue stress. Only about one-third of overweight or obese adults with NAFLD receiving usual care achieve >5% weight reduction over 2 years of follow-up, and weight regain is common.⁴²

Dietary Interventions

Weight loss can be achieved by a calorie deficit of 500–1,000 kcal day⁻¹ while ensuring adequate protein intake (1.5 g kg⁻¹ body weight). The benefits are sustained irrespective of whether the calorie deficit is achieved by acute, very low-calorie diets (VLCD) or more modest reductions in calorie intake over an extended period.^5,15,43 Caloric restriction is of prime importance versus the type of diet per se. Dietary composition should be modified to minimize the intake of saturated fats, refined carbohydrates, fructose, and sugar-sweetened beverages.

Exercise

Studies have shown that aerobic exercise—30 to 60 minutes of moderate- to high-intensity exercise performed 2–5 days per week—results in a significant reduction in liver fat content despite minimal or no weight loss, which is particularly relevant in patients with lean NAFLD.⁴⁴ Overall, there is clear evidence demonstrating that exercise, be it aerobic, resistance, or modified high-intensity interval training (HIIT) training, has the ability to lower liver fat content to a similar degree.^14,45

Alcohol Use

Alcohol use can act synergistically with insulin resistance to accelerate fibrosis progression, especially with moderate to heavy alcohol use (>20 and >30 g day⁻¹ in women and men, respectively). Hence, alcohol intake should be assessed at regular intervals in all MASLD patients, and alcohol abstinence should be recommended in these patients, especially with clinically significant fibrosis (≥F2).¹⁵

Pharmacotherapy in MASLD

The therapeutic landscape in NAFLD is rapidly evolving and can be conceptualized into two broad mechanisms of action:

Restoration of normal adipose tissue biology, with fat redistribution from hepatic and visceral fat to subcutaneous fat (e.g., PPAR agonists) or

Weight loss agents, where reduction of excess adipose tissue also restores adipose tissue biology/function and responsiveness to insulin (e.g., glucagon-like peptide-1 receptor agonists [GLP-1RAs] and new dual agonists)

Although several agents have undergone clinical trials, there is currently no FDA-approved medication for management of NAFLD.

Anti-diabetic Agents in MASLD

T2DM occurs in nearly half of patients with MASLD. On the other hand, clinically significant liver fibrosis may be present in up to one-fourth of T2DM patients.^46,47 Due to the close bidirectional relationship, it is important to understand the interactions of various antidiabetic agents on the natural course of MASLD and choose appropriate agents that can serve the dual purpose of addressing hyperglycemia as well as MASLD.

Pioglitazone, a PPARγ agonist, has demonstrated beneficial effects on liver transaminases, hepatic steatosis, and inflammation in several RCTs, with improvement in fibrosis noted in fewer studies and a recent meta-analysis.^48-50 GLP-1 receptor agonists have changed the landscape of diabetes and obesity, and there is a growing interest in their role in the management of NASH. A recent meta-analysis of Liraglutide at doses used in diabetic patients reported efficacy in lowering plasma aminotransferases and liver fat content and improving liver histology in patients with MASLD.^51,52 Semaglutide, at daily doses of 0.1, 0.2, or 0.4 mg, was reported to improve NASH resolution, without worsening of fibrosis, to a similar degree in people with or without type 2 diabetes.⁵³ Tirzepatide, a novel dual agonist at GLP-1 and GIP receptors, has demonstrated impressive results in the SURPASS series of trials with respect to weight loss and control of diabetes. In a substudy of SURPASS-3 in which tirzepatide was administered subcutaneously once weekly at doses of 5, 10, and 15 mg, it demonstrated a significant reduction in liver fat content versus insulin degludec in T2DM patients as evaluated by MRI-PDFF, with a treatment difference of −4.71% (95% CI −6.72 to −2.7, p < .0001).⁵⁴

Sodium glucose cotransporter-2 inhibitors (SGLT2i) comprise another class of agents that offer significant cardio-renal benefits in addition to the management of hyperglycemia. They decrease the severity of hepatic steatosis in individuals with T2DM and NAFLD by approximately 10–39%. It was also noted that the reduction in hepatic steatosis was more than expected with the modest weight loss seen with SGLT2i, suggestive of mechanisms beyond weight loss for their hepatic effects.^55-58 A meta-analysis by Sinha et al. confirmed a reduction in liver enzymes and liver fat content with SGLT2i, suggestive of a salutary effect of SGLT-2i on NAFLD in T2DM, probably driven by an improvement of glycemia and body weight, which in turn attenuates hepatic inflammation and hepatic fat accumulation.⁵⁹

The impact of various anti-diabetic agents on MASLD has been summarized in Table 7.

Table 7.

Anti-diabetic Agents in MASLD.^5,14,15

Anti-diabetic Agents	Mechanism of Action	Impact on Non-invasive Assessment of NAFLD	Impact on Liver Histology	Remarks
Metformin	AMPKinase activation	No significant benefit	No significant benefit	No significant benefit
Pioglitazone	PPARγ agonist	Improvement in liver chemistry and reduction in hepatic steatosis	Decreased steatosis and inflammation, with resolution of NASH Debatable effect on fibrosis	Use recommended in NASH and fibrosis (diagnosed by biopsy/non-invasive tests) with/without T2DM Concerns: weight gain, bone fracture risk, and fluid retention
Liraglutide Semaglutide	GLP-1 analogues Indirectly act via: acute mechanisms: satiety, splanchnic vagal effects, insulin secretion Chronic effects: weight loss, improved glycemic control	Improved liver chemistry and decreased hepatic steatosis	Decreased steatosis, inflammation and resolution of NASH, inconsistent effect on fibrosis	Recommended Concerns: gastrointestinal, gallstones
Tirzepatide	Dual agonist (GLP-1/GIP)	Decreased steatosis		Encouraging results; further studies needed
Gliptins	DPP4 inhibitors	Inconsistent results	Inconsistent results	No significant benefit
SGLT-2 inhibitors	SGLT-2 inhibitors	Improvements in liver chemistry and decreased hepatic triglyceride content	Improvement in steatosis, inconsistent effects on NAS, and fibrosis	May be considered Concerns: genitourinary infections, volume depletion, bone loss

Non-diabetic Medications in MASLD

Vitamin E

Vitamin E is a potent antioxidant that has shown a reduction in transaminases, steatosis, inflammation, and cellular ballooning on biopsy in non-diabetic patients with NASH in doses of 800 IU day⁻¹, with no impact on fibrosis.⁵⁰ There is some evidence to suggest an increased risk of hemorrhagic stroke and all-cause mortality, although the data on the relationship to prostate cancer risk is less clear.⁶⁰

Saroglitazar (Dual PPAR α/γ agonist)

Saroglitazar is a dual potent PPAR-α/γ agonist. The synergistic effect of improved lipid oxidation and improved insulin resistance by PPAR-α and PPAR-γ, respectively, makes its use in NASH/NAFLD rational. Real-world data from India showed Saroglitazar 4 mg day⁻¹ is effective and safe for improving biochemical parameters, LSM, and CAP values, irrespective of weight reduction, with a debatable effect on fibrosis. It may be used in compensated cirrhotics with close monitoring for side effects.⁶¹ The Drug Controller General of India (DCGI) has approved its use in NASH with F1–F3 fibrosis and in NAFLD with comorbidities (obesity, T2DM, metabolic syndrome, dyslipidemia).

Upcoming disease-modifying drugs

Newer drugs that modify the disease pathogenesis are in the pipeline for phase 3 trials in patients with NASH. Salient features have been summarized in Table 8.

Table 8.

Newer Agents Undergoing Phase 3 Trials in MASLD.

Drug	Class	Key Results in Phase 2 Trials	Side Effects and Precautions
Obeticholic acid	Farnesoid X receptor agonist	NASH resolution without worsening of fibrosis: 12% (25 mg daily) vs. 8% (placebo) Fibrosis improvement without worsening of NASH: 23% (25 mg daily) vs. 12% (placebo) (72 weeks; phase 3 data)⁶²	Pruritus, atherogenic dyslipidemia
Lanifibranor	Pan-PPAR agonist	NASH resolution without worsening of fibrosis: 49% (1,200 mg daily) vs. 22% (placebo) Fibrosis improvement without worsening of NASH: 48% (1,200 mg daily) vs. 29% (placebo) (24 weeks)⁶³	Diarrhea, weight gain, fluid retention, anemia; PPAR-γ agonists may increase bone loss and bladder cancer
Aramchol	Partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1)	NASH resolution without worsening of fibrosis: 17% (600 mg daily) vs. 5% (placebo) Fibrosis improvement without worsening of NASH: 30% (600 mg daily) vs. 18% (placebo) (52 weeks)⁶⁴	Urinary tract infection and pruritus numerically more common
Resmetirom	Thyroid hormone receptor-beta agonist	Relative change in MRI-PDFF: −32.9% (Resmetirom) vs. −10.4% (placebo) (12 weeks) NASH resolution: 27% (Resmetirom) vs. 6% (placebo) (36 weeks)⁶⁵	Diarrhea, nausea
Aldafermin	FGF-19 analogue	No significant improvement in fibrosis (primary end point), improvement in steatosis and biochemistry⁶⁶	Injection site reactions, diarrhea
Pegbelfermin	FGF-21 analogue	Reduction in absolute MR-hepatic fat fraction with Pegbelfermin 10 mg day⁻¹ (−6.8%) versus -0.3% (placebo)⁶⁷	Diarrhea, nausea

Bariatric Surgery

Metabolic surgery, including bariatric surgery, is an effective therapy for obesity and T2DM. A recent systematic review and meta-analysis showed that, in addition to weight loss, bariatric surgery significantly reduces the risk of progression to cirrhosis in obese patients as compared to matched controls.⁶⁸ Bariatric surgery more reliably and predictably achieves a >10% loss in total body weight, which is associated with NASH resolution and fibrosis improvement, than lifestyle and pharmacological treatments of obesity.⁶⁹ A meta-analysis by Lee et al. confirmed a significantly improved liver histology, including steatosis, ballooning degeneration, inflammation, and fibrosis, after bariatric surgery. However, bariatric surgery is associated with new or worsening features of NAFLD, like fibrosis, in 12% of the patients.⁷⁰ Caution has to be exercised in patients with advanced fibrosis and cirrhosis, as these patients are at a higher risk of hepatic decompensation and mortality.¹⁴

Hence, bariatric surgery should be considered as an option to treat MASLD and improve cardiometabolic health in MASLD patients with a BMI ≥ 35 kg m⁻² (≥32.5 kg m⁻² in the Asian population), especially with coexisting T2DM. Additionally, it can also be considered in individuals with a BMI of ≥30–34.9 kg m⁻² (≥27.5–32.4 kg m⁻² in Asian population).¹⁴

Optimization of Management of Comorbidities and Complications

The management of dyslipidemia should be optimized for cardiovascular risk reduction. Statins are safe for CVD risk reduction across the spectrum of NAFLD, except in decompensated cirrhosis. Hypertriglyceridemia can be managed by lifestyle changes, omega-3 fatty acids, icosapent ethyl, or fibrates.

Hypertension can be managed as per prevailing guidelines, with ACE inhibitors/ARBs as first-line agents; their use has to be avoided in decompensated cirrhosis. Calcium channel blockers, beta blockers, diuretics, and other classes of antihypertensive agents can be added as per clinical requirements.

Last but not least, liver cirrhosis can be associated with complications such as portal hypertension, gastroesophageal varices, hepatocellular carcinoma, and osteoporosis, all of which would need specific management under the care of a gastroenterology team. Hence, the management of MASLD requires a collaborative approach from primary as well as specialized care for holistic management of this truly multisystem disease.

Conclusion

The awareness of MASLD remains low among patients and clinicians, and there is an increasing need to develop simplified clinical algorithms for early diagnosis of these individuals and appropriate management of these patients. MASLD should be considered in high-risk groups such as T2DM/ prediabetes, obesity, metabolic syndrome, etc., followed by appropriate workup. Recommendations from major societies have also highlighted the need for a shift in the management strategy to holistic personalized care, involving primary care physicians, endocrinologists, nutritionists, and gastroenterologists.

Weight loss and exercise are central to any successful cardio-metabolic management strategy. The risk of hepatic and extra-hepatic complications associated with NASH should prompt considering the use of agents with therapeutic benefits backed by evidence. The presence of MASLD in diabetic patients should prompt a tailored management strategy, much akin to the establishment of treatment pathways in diabetic patients with cardiovascular disease, heart failure, and renal disease. Diabetic patients with NASH can benefit from the use of GLP-1 receptor agonists and pioglitazone, while vitamin E can be used in non-diabetic patients with NASH. We anticipate that novel pharmacological agents will become available soon and transform the current NASH management landscape, in which a combination of current “dual diabetes-NASH pharmacological agents” such as pioglitazone, GLP-1RAs, and SGLT2 inhibitors plus novel NASH pharmacological agents will create the framework for a more comprehensive treatment strategy.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Diagnosis and Management of MASLD: An Metabolic Perspective of a Multisystem Disease

Abstract

Keywords

Introduction

What’s in a Name?

Diagnosis of MASLD

Initial Approach in MASLD Patients

Imaging Modalities for Assessment of Hepatic Steatosis

Non-invasive Assessment of Hepatic Inflammation and Fibrosis

Role of Liver Biopsy in MASLD

Diagnostic Approach in MASLD

Management of MASLD

Lifestyle Interventions for MASLD

Dietary Interventions

Exercise

Alcohol Use

Pharmacotherapy in MASLD

Anti-diabetic Agents in MASLD

Non-diabetic Medications in MASLD

Bariatric Surgery

Optimization of Management of Comorbidities and Complications

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References