Metabolic dysfunction associated steatotic liver disease (MASLD), is characterised by deposition of fat in liver which can be associated with necroinflammation and fibrogenesis, which may progress to liver cirrhosis or hepatocellular carcinoma (HCC). This review intends to highlight the increasing prevalence, increasing data on genetic predisposition, gut microbiome and pathophysiological processes involved in the complex interplay for development of MASLD. The complex pathways also highlight the association of MASLD with cardiometabolic disorders like diabetes, atherosclerotic heart disease and dyslipidaemia particularly for hypertriglyceridemia.  It also reviews briefly the diagnostic tools available in assessing the disease as well as lays outlay for the management of MASLD by various means including lifestyle interventions, pharmacotherapy and surgical options. Endoscopic and surgical weight management therapies have also been shown to be effective in MASLD. However, access and acceptability remain poor for these weight reduction methods. The developments in the integrated management of MASLD have been fairly encouraging with many programs encompassing lifestyle modifications and pharmacological interventions together. Further well-designed long-term prospective studies should be undertaken to generate evidence with definitive results.

Keywords: MASLD, fibrosis, lifestyle modifications, weight loss, endobariatrics, pharmacotherapy, GLP-1-GIP co-agonist, FGF analogs, THR-ß agonist, few PPAR-α/δ agonists, FXR agonist, and DGAT2i/ACCi

Metabolic dysfunction associated steatotic liver disease (MASLD) or more appropriately termed Metabolic (dysfunction) associated fatty liver disease or ‘MAFLD’ is a disease which encompasses multiple pathophysiological processes in a genetically susceptible individual leading the changes that trigger significant inflammation and fibrosis in the liver. It was previously named as Non-alcoholic fatty liver disease or NAFLD and is still popular with that name. It is now the most common chronic liver disease (CLD) with an estimated worldwide prevalence of approximately 30%.^1-5 MASLD usually leads to or can be associated with necroinflammation in the liver which is called Metabolic dysfunction associated steatohepatitis (MASH) which may lead to cirrhosis and hepatocellular carcinoma (HCC).^6,7 Hepatic steatosis  >5% of hepatocytes in the absence of alcohol abuse or any other hepatic disease associated with ballooning and inflammation in the liver biopsy confirms MASH.^4,5 It may lead to advanced hepatic fibrosis. MASH associated cirrhosis is currently the second indication for liver transplantation and is likely to become the leading one by the next decade, both globally and in India.^8,9 MASLD and MASH is also a marker of metabolic syndrome, and is associated with higher overall mortality with chronic kidney disease and poorer cardiovascular outcomes.^10,11 MASLD has a high all-cause-mortality (25.56 per 1000 person-years).¹² However, though MASH is now considered to be a  serious condition associated with severe morbidity and mortality, robust and viable diagnostic tools and treatment for cure are still evolving. The role of the current review is to elaborate rising prevalence, touching upon genetic predisposition, and elaborating on lifestyle interventions in management of MASLD. It also delves into emerging therapy targets and drug classes, investigating their efficacy in the treatment of patients with MASH.

MASLD and MASH Burden: Global and India

Getting a true prevalence of MASLD and MASH is difficult because of lack of a single screening test. Liver biopsies being the gold standard are difficult to acquire and there may be limitations to differentiate MASLD and MASH based on non-invasive parameters alone. 

The estimated overall global prevalence of MASLD in adults is ~32%. Various studies from the USA, Europe, and Asia have reported a prevalence of approximately 22%, 37%, and 31%, respectively in the general population.3 The prevalence of MASLD shows wide variation across India ranging from 9% to 53%.^13-15 This wide variation is possibly due to urban-rural divide but this may also be challenged in near future.^13,16 40-68% of MASLD patients will have progressed to definite biopsy-confirmed MASH. In Indian patients, biopsy-proven MASH has been found in >60% of patients and advanced fibrosis (≥F3) in 29-35% of patients usually at the time of diagnosis as most of the patients are picked up when liver function tests are deranged.^17-19 This may also reflect a referral bias as biopsy is usually done in patients with more advanced stage of disease.

There are age and gender differences as far as prevalence is concerned. It is higher in men as compared to women (~39% vs ~25%). Post Menopause, this difference tends to get abolished possibly due to hormonal protective effects prior to that.²⁰ The progression of MASH is also considered to be faster in elderly women.²¹ Diabetics have one of the highest prevalence of MASLD.²² People with obesity also have a higher prevalence of MASLD (90%) and MASH (30%) compared to non-obese (25-30%%).^23-25 Indian obese patients also have a high prevalence of MASLD, almost more than 80%.¹³ MASH was diagnosed in ~60% of those with both diabetes and obesity. MASH (non-viral factor) contributes almost equally as viral etiological factor for HCC [MASH >17% of patients, Hepatitis B (HBV) >20% and Hepatitis C (HCV ~17%)].²⁶ A systematic analysis of the Global Burden of Disease Study has shown that the age-standardized prevalence of compensated cirrhosis has doubled (33%) and decompensated cirrhosis tripled (55%) due to MASH compared to all other causes.²⁷ MASH-associated HCC and decompensated cirrhosis are now one of the leading indications for liver transplantation in India.¹³

Different phases of MASLD: Progress from healthy to cirrhosis MASLD

As explained above, MASLD is a complex disease which involves various pathophysiological mechanisms occurring leading to development of fibrosis and subsequent HCC.²⁸ It usually begins with simple steatosis leading to development of inflammation and fibrosis (Figure 1).²⁸

Figure 1Phases of MASLD (FFA-free fatty acids, IL-interleukin, HSC-hematopoietic stem cell, NKT-, ER-Endoplasmic reticulum, DNA-deoxyribonucleic acid, HCC-hepatocellular carcinoma, liver sinusoidal endothelial cells, NKT, natural killer; T, cells; y, years).

Role of Microbiome in MASH

Humans have a wide spectrum of commensal microbiota.^29-31 It has been well established that human microbiome plays an important role in various metabolic pathways in diseased states.  Though inconsistently reported dysbiosis has also been reported in pathways of MASLD and MASH, both in its inception as well as progression (Figure 2).³³

Figure 2 Composition of intestinal microbiota in MASH patients.

Studies done in patients with diabetics show a various interplay of dysbiosis and alterations in metabolic pathways leading to hepatic inflammation and fibrosis.³¹ There is marked prominence of bacteroids and elevated fecal short chain fatty acids in obese patients.

Mechanisms by which the gut microbiota impact the progression to MASH are being explored and a few have been described using experimental data (Table 1).³⁵ The compositional changes and mechanisms currently in pathogenesis of MASH and MASLD are inconsistent and not validated outside of research. Priobiotics, prebiotics and synbiotics all have been investigated in MASLD as well as Fecal microbiota transplantation.^36-47 These methods have shown to alter endotoxemia as well as intestinal permeability which leads to improvement in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, hepatic inflammation, increase the copiousness of Faecal bacterium prausnitzii and Bifidobacterium all of which were beneficial in MASH therapy. Various studies have also looked into role of FMT in modulation of inflammation in MASLD and MASH with limited success, currently at best as an experimental data.

Role of genetics

There is genetic heterogeneity in predisposition as well as progression of MASLD in various individuals.  Various studies have shown that steatosis and fibrosis can occur in families occur with a heritability value of ~ 0.5 in age-, gender- and ethnicity-adjusted analysis.⁴⁸ The risk of accelerated progression in fibrosis scale and cirrhosis is much faster in relatives of patients with MASLD or MASH.⁴⁹ Genome-wide association have identified various candidate genes which may increase predisposition and progression in MASH namely patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing 7 gene (MBOAT7), glucokinase regulator (GCKR), hydroxysteroid 17-beta dehydrogenase-13 (HSD17B13).^50,51 PNPLA3 gene has been the commonest in this group, found in 15% of the general population, in which a mutation at position 148 is linked to 2.5-fold greater odds of the development of severe steatohepatitis, excessive, inflammation, injury, and scarring; consequently, bearing higher risks of MASH, progression to cirrhosis and HCC.⁵² Other genes like  TM6SF2, GCKR, and MBOAT7 also increase the odds of promoting MASH progression by 1.18- to 1.55-fold but are rarer compared to PNPLA3.^53-55 Another variant is HSD17B13 although rare is a protective variant neutralizing some of the deleterious effects of the PNPLA3 gene in people with both gene variants. The risk of MASH was reduced by 14% in presence of the HSD17B13 variant.⁵⁶ It must be highlighted that MASLD and MASH are essentially a polygenic disease with multiple mutations may happen and lead to a fibrotic progression. It is possible that a polygenic score helps to quantitatively determine the composite risk of disease progression based on the proportion of deleterious and protective genes. Though the evidence is currently limited, it has been theorized that genetic factors also determine the response to MASH therapy e.g. decreased effect of PUFA or fish oil in patients with fatty liver with PNPLA3 variant.⁵⁷

The practical implications of genetics of MASLD are to be considered keeping in mind the environmental and lifestyle factors. The genetic propensity has been the same in a community pool but it is the environmental factors added to lifestyle features that change within communities leading to development of advanced stages of fibrosis and subsequently cirrhosis. 

Lean MASH

First reported in Asia, lean MASH is now an accepted diagnosis worldwide. Individuals with normal BMI (25 kg/m² in Caucasians and 23 kg/m² in Asian subjects) manifesting inflammation and fibrosis are considered as Lean MASLD or MASH. Insulin resistance is one of the important pathophysiological processes that leads to development of Lean MASLD. Though Lean MASLD is similar, but not identical to MASLD, current evidence suggests that MASH develops at a faster rate in these patients as compared to obese MASH.⁵⁸

Incidence

Asian populations tends to develop MASLD and MASH at much lower BMIs as compared to western population (Table 2).^59-66 These patients too exhibit the whole spectrum of the histopathological characteristics of MASH. 

The lean individuals with MASLD were phenotypically distinct: excess subcutaneous fat elevated fasting plasma glucose (FPG) and triglycerides (TGs).⁶⁵ Metabolic factors such as WC and TGs are predictors of lean MASLD. Apart from these, weight gain in early adulthood is significantly associated with MASLD in lean subjects. There seem to be a different genetic risk factors associated with lean MASLD and MASH.

Outcomes in LEAN MASLD/MASH

Given the different phenotype in Lean MASH, a study in Indian subjects (BMI <23 kg/m2) found the prevalence of biopsy-proven MASH to be ~8%.⁶⁵ Amongst these subgroups of patients, cirrhosis was found in approximately 2% of patients. The largest and longest series of patients with biopsy-proven MASLD with a mean follow-up time of >19 years found a high rate (19%) of MASLD in lean subjects.⁵⁹ Though there was no increased mortality in lean compared to overweight subjects, they were at higher risk, for the development of severe liver disease (decompensated liver disease, liver failure, HCC, or cirrhosis).⁶⁸ Patients who develop more severe disease in lean MASLD group were usually older, had more severe portal inflammation and higher fibrosis staging.⁶⁰

A study from US made a similar comparison found that lean patients developed significantly more severe lobular inflammation than the non-lean MASLD group.⁶¹ The age-adjusted cumulative survival is  significantly shorter in patients with lean MASLD as compared to those with non-lean MASLD.⁷¹ A European population study showed that lean patients had significantly less severe histological disease; and less advanced fibrosis. There were no significant differences in the prevalence of the PNPLA3 variant. Further follow-up for ~8 years, found no significant difference in hepatic events or survival.⁶² From UNOS database, A comparison of survival after liver transplant in lean and obese individuals after adjusting for confounders found that all obesity cohorts with MASH had significantly reduced risk of graft and patient loss at 10 years of follow-up compared with the lean BMI cohort.⁶³ 

Hence, the clinical evidence regarding survival and histological disease severity is not clear in lean MASH vs non lean MASH. We certainly need more data to. Nevertheless, these data do highlight the implication of a genetic link in absence of an excess adiposity in MASLD/MASH pathogenesis and serious negative clinical outcomes.

Risk factors for MASH

The susceptibility and progression of MASH are linked to the interaction between environmental and genetic risk factors. Obesity, older age, female sex, non-African American race/ethnicity, diabetes mellitus, and hypertension are the risk factors that increase the probability of MASH (Table 3).

There is a concept of metabolic inflexibility which leads to deranged of metabolic control in the body which leads to development of MASLD and MASH. The liver is incapable to shift back and forth between prandial and fasting states compliantly because of exacerbated insulin resistance which is an indication of MASLD/MASH.⁶⁴ Metabolic inflexibility is associated with hyperinsulinemia and systemic lipotoxic cell stress resulting in inflammation and fibrogenesis, and ultimately MASH.  Metabolic inflexibility tends to be higher in patients with diabetes mellitus and obesity.

Insulin resistance has been reported with patients with Lean MASH associated with metabolic syndrome. In a North Indian study, out of 117 patients with insulin resistance, twenty-three (15.3%) patients were lean NAFLD with BMI 21.6±1.5, WC 82.9±4.7 (BMI < 23, WC < 90 cm in men and < 80 cm in women) 80% of these 23 (18/23) had insulin resistance with mean HOMA-IR of 3.4±.1.9. Only 4 (17%) did not have any component of metabolic syndrome

Diagnostic challenges & unmet needs of MASH

MASH needs to be differentiated from simple steatosis as it has prognostic importance. Liver function tests like measuring plasma liver aminotransferase levels are unreliable and do not confidently predict significant hepatic fibrosis.  Figure 1  with the increasing need for liver transplantation, it is critical to accurately recognize and diagnose MASH in those with MASLD and its risk factors, as these patients are more prone to develop accelerated progression.^6-9 Imaging techniques and biomarker panels have been evolving for the diagnosis of MASH/MASLD. The features and challenges of these methods are depicted in Table 4-6.

Multiple biomarkers which incorporate clinical, biochemical and imaging markers can help to identify significant fibrosis (Table 6). Panels for the diagnosis of fibrosis have good specificity and negative predictive value (NPV) that allow the clinician to rule out advanced fibrosis, but they lack adequate sensitivity and positive predictive value (PPV) to establish the presence of advanced fibrosis. Therefore, several individuals fall in the “indeterminate-risk” group who need to be further evaluated with ELF test. All the clinical panels work better as patients with advanced disease have better prediction with marker panels.

The gold standard for diagnosis of MASH is Liver biopsy which is traditionally done via percutaneous route using ultrasonographic guidance. Endoscopic ultrasound (EUS) guided liver biopsy is now an established procedure that offers an alternative to conventional percutaneous and transjugular liver biopsy. EUS guided liver biopsy is seemingly is equally safe and better pain scores post biopsy. The safety and efficacy of EUS liver biopsy and confirming histopathological diagnosis has been evaluated in various studies.^65,66  Biopsy however. It is invasive and associated with potential adverse effects, such as pain, bleeding, and infection and has poor acceptability. It requires significant expertise, has intra-observer and interobserver variability, and possibility of sampling variability. Considering these factors along with the fact that it least impacts the choice of treatment alternatives in clinical practice settings, biopsy either by traditional or endoscopic method are impractical to use in large populations. At best, it may help in identifying patients with autoimmune hepatitis when the diagnosis is in doubt. It is primarily limited to research for assessment of clinical endpoints in pharmacological studies. Alternatively, though not validated, non-invasive tests both blood tests and imaging studies are used for the diagnosis of MASH and serve the purpose for choice of appropriate management.⁶⁷

Another important factor leading to deviation from guideline-practice is lack of health insurance coverage. Lack of health insurance coverage and inadequate coverage are important reasons for high out-of-pocket health expenditures. It typically forces people to delay or postpone medical care. The doctor’s reluctance to advise the patients to  undergo  various  diagnostic  tests  due  to out-of-pocket expenditure. Thus, resource constraints result in avoidance of recommended tests and frequency of follow up tests to control the expenditure. This is specifically an important factor in countries like India where out-of-pocket expenses accounts for about 62.6% of total health expenditure - one of the highest in the world as per a recent study.⁶⁸ 

Cardio-metabolic associations of MASLD and MASH

It has been clear over the years of the close association between metabolic syndrome and MASLD/MASH with various meta-analysis showing that almost 70% of patients with MASH had metabolic syndromes. Having MASLD is now considered as an independent risk factor for development of a coronary event. The accumulation of visceral adipose tissue (VAT) that usually accompanies MASLD has been theorized to be responsible, in part to the extra hepatic co-morbid conditions, with the increased release of free fatty acids (FFA) in the circulation leading to development of hepatic insulin resistance and hepatosteatosis. This along with alterations in the hepatic lipid metabolism leads to development of atherogenic dyslipidemia, especially elevated plasma triglyceride concentrations and small dense LDL particles which develop atherosclerotic plaques. Elevated levels of Triglyceride rich lipoproteins (TRLs), particularly ones containing apolipoprotein B (ApoB) are hallmark of MASLD and represent a biochemical markers for elevated CVD risk. Furthermore, altered glucose metabolism and insulin resistance, exacerbate cardiovascular metabolic risk in these patients. Recently, Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been linked to severity of hepatic steatosis and its gain of function mutation is associated with hypercholesteremia. This leads higher morbidity and mortality associated with cardiovascular diseases in patients suffering with MASLD or MASH. There are also some unanswered questions, the most important one being whether the association is due to shared risk factors or there is a role of hepatic steatosis in overall development of atherosclerosis. In addition, it still remains difficult to identify patients in this cohort, as which patients with MASLD will develop severe CVD complications or severe liver complications.

Non-pharmacological, Pharmacological, and Surgical Alternatives for the Treatment of MASH

Interventions for Weight Loss

Non-pharmacological

1. Diet and lifestyle Modifications

Weight loss is one of the strongest pillars for management of MASH patients, which improves histology along with the cardio-metabolic profile and glucose homeostasis.^69,70 Significant data suggests tells us that  5-10% weight loss results in an improvement in steatohepatitis in 58-90% patients with MASH.⁷¹ Significant improvement (40%) have also been reported in Asian patient population with 3–5% weight reduction.^72,73 In patients with obesity and MASH, ≥ 10% weight loss has also shown significant regression of hepatic fibrosis.⁷⁴ Not only obese but lean patients with MASH can also benefit from similar dietary and weight management strategies. A 12-month study comparing lean and non-lean patients found that any amount of weight reduction was associated with significantly improved steatosis, ballooning, and NAS scores in both groups.⁷⁵ These data support the notion that weight loss in terms of loss of adiposity improves histology in patients with MASH regardless of baseline BMI.⁷⁶

2. Exercise

Exercise has demonstrated benefits beyond weight loss in patients with MASH with its duration being proportional to improvement of hepatic steatosis.⁷⁷ There is a growing evidence which shows advantage of one type of exercise(aerobic, resistance, high intensity, or low-intensity exercise) over others but it is currently inconsistent in various studies. Recommended frequency for exercise is more than 30 minutes in a day for 5 days a week.⁷⁸

3. Combination of diet and exercise

A comparison of low calorie diet and aerobic exercise with low calorie diet alone in a short term study showed that  significant improvement in blood pressure, FPG, TG, homeostasis model assessment-estimated insulin resistance, US grading of steatosis, and Quality of life only in patients with MASH who followed aerobic exercise.⁷⁹ Maintenance of the weight loss is challenging due to its association with changes in dietary habits, and lifestyle.¹⁰² This necessitates a diet plan and exercise type based on patients’ preferences to ensure long-term adherence.

Thus it is clear from the above data, that combination of a dedicated exercise regimen and calorie restricted diet has synergistic effect which leads to improvement in hepatic steatosis and inflammation^103-104 (Figure 3).

Figure 3 Management of MASH.

Pharmacological and surgical interventions

Diet and exercise alone are usually helpful in initial weight loss but have been found limited in maintenance of weight loss.¹⁰⁵ Weight loss and its maintenance are challenging consequently a larger patient pool may need alternate methods to restrict excessive calories.⁸⁰ These include patients unable to achieve >5% loss of total body weight with lifestyle interventions or unable to sustain, or who have a BMI ≥27 kg/m² along with ≥1 metabolic comorbidity, or those with a BMI >30 kg/m² with comorbidities.  Over the years, several pharmacological agents which can achieve weight loss through different mechanisms have been tried in these patient groups.^106,107 However, among the plethora of approved medications only one glucagon-like peptide-1 (GLP-1) agonist, has been found to improve liver histology in MASH patients in a phase II study.⁸¹ Sodium-glucose cotransporter-2 (SGLT2) inhibitors have also been shown to be effective for weight loss and reduced hepatic fat content and may thus be beneficial in MASH.⁸² However, the need for chronic use, monitoring, and associated adverse events and sparse clinical evidence for improvement of MASH parameters limit the utility of these medications. Therefore, preference should be given to lifestyle interventions.

Bariatric surgery has also been studied for weight loss and benefits extrapolated in patients with MASH.^108,109,110 The largest prospective study done initially demonstrated a likely deterioration of fibrosis, with an increase in the severity of fibrosis in ~20% of patients during a one-year follow-up period, possibly due to rapidity of weight loss.⁸³ However, a study in severely obese patients with biopsy-proven MASH found improvement of MASH in 84% of patients with progressive and sustained reduction of fibrosis that began during the first year and was sustained through 5 years.⁸⁴ The intended benefits of the bariatric surgery should be seen along with the risks of weight loss surgery particularly when indication is just for MASLD and MASH⁸⁵ Further up to 20% of patients have normal BMI, in these patients for less severe obesity and related complications, including T2DM, endoscopic bariatric metabolic therapies⁸⁶ (EBMT) are rapidly emerging as less invasive  therapies  These include intragastric balloons (IGB), endoscopic sleeve gastroplasty (ESG), and duodenal mucosal resurfacing (DMR).^{111, 112} IGBs and ESG has shown to achieve adequate and sustained weight loss required for MASH improvement without significant adverse events.⁸⁷ These EBMTs can bridge the gap between lifestyle interventions having high safety but limited efficacy, while bariatric surgery has high efficacy with poor safety profile.⁸⁸ The last resort is Liver Transplantation indicated by practice guidelines for patients with MASH and ESLD or HCC only.^113,114 But a study has shown that within a month of LT, 40% of patients with MASH were identified to be at risk of developing renal dysfunction implying serious safety issues in this patient population. An alternative investigated in patients predominantly suffering from MASH (>50% MASH Cirrhosis) includes sleeve gastrectomy during LT which maintained greater weight loss and had fewer components of the metabolic syndrome.⁸⁹  Thus, a reduction in risk factors for post-LT metabolic syndrome may confer a significant survival benefit.

Current drug therapies targeting downstream and upstream pathways

Pioglitazone demonstrated improved hepatic steatosis, ballooning necrosis, inflammation, and fibrosis in steatohepatitis patients with or without prediabetes or T2DM.^90-93 However, these beneficial effects of pioglitazone are effected by an increased risk of weight gain, significant  edema, rare possibility of development of bladder cancer, and a decrease in bone mineral density.^115-119 Some clinical trials did demonstrate significant reductions in steatosis, lobular inflammation and fibrosis in patients treated with vitamin E (400 IU).^95-97 However, it was associated with an increased risk of all-cause mortality linked to hemorrhagic stroke and prostate cancer.^98,120

In a recent Phase 3, randomized, controlled trial, Harrison et al showed that a newer oral, liver directed, thyroid hormone receptor beta selective agonist, Resmetirom was studied in 966 patients with MASH and different stages of fibrosis. The oral drug improved the MASLD activity score by 2 points with no worsening of fibrosis. There was also improvement in fibrosis by one stage with no worsening of activity scores. This lead to its approval for patients with fibrosis due to MASH by FDA. This is the first drug to be approved for this indication.

With better understanding of the MASH pathophysiological pathways and identification of newer target pathways, various drug classes are being evaluated for their efficacy. Majorly the drug classes target either metabolic pathways, fibrosis or oxidative stress. The drug classes acting on the metabolic pathways have demonstrated some clinical benefit due to inhibition of de novo lipogenesis, improved insulin sensitivity, rectification of the link between de novo lipogenesis and bile acid metabolism, increased β-oxidation of fatty acids in the mitochondria and modulation of the uptake of fatty acids in the liver via thyroid hormone receptors.^99-101 The drugs are currently in phase IIb and phase III trials and their detailed description has been depicted in Table 7.¹⁰² The clinical outcomes of most of the remaining investigational drug classes have been disappointing.

Being one of the commonest diseases effecting the metabolic organ of the body, MASLD and MASH require a thorough management and newer insights into its pathogenesis.  Though liver biopsy is the possibly the only validated method of confirmation of diagnosis there has been progress in development of alternative biomarkers and imaging modalities. These methods seem to have provided improved understanding of the pathological changes in structure and function of the liver in recent years. Weight loss through lifestyle intervention remains the cornerstone of MASH therapy, the adherence to which is truly challenging and subjective. Though bariatric surgery shows significant advantages in terms of decline of fibrosis, patients with advanced disease are not appropriate candidates for it. Lean MASH patients have shown to develop more severe disease than obese patients, for whom pharmacotherapy is the only alternative. Few existing treatment alternatives include use of therapies like SGLT2i or antioxidants, vitamin E which have shown some benefits in patients with MASH. But there is a need for larger randomized trials with these drugs specifically in patients with MASH demonstrating histological benefits, attenuating progression to fibrosis and HCC. Newer drug classes targeting different sites are being investigated. Most agents are in phase 2 or 3 of their developmental phase. Currently, though results with certain classes like CCR2/CCR5 inhibitor, SCD1 inhibitor, ASK1 inhibitor III and Caspase inhibitor have been disappointing few have shown encouraging results. These include GLP-1-GIP co-agonist, FGF analogues, THR-ß agonist, few PPAR-α/δ agonist, FXR agonist and DGAT2i/ACCi. These agents have shown reduction in hepatic fat content, attenuation of fibrosis and a good tolerability profile in phase II studies. The results of larger phase 3 studies with these agents will end the long wait for an effective and well-tolerated universally approved drug class for the treatment of MASH.

MASLD and MASH are driven by the obesity and diabetes epidemic, poor lifestyle, compounded by dysbiosis and influenced by genetic factors in others. These aspects should become a new priority given the poor outcomes with associated hepatic and extrahepatic events. Though not completely successful, the developments in the management of MASH have been fairly encouraging. Further well-designed long-term prospective studies should be undertaken to generate evidence with definitive results.

1. Singal AG, Manjunath H, Yopp AC, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta–analysis. Am J Gastroenterol. 2014;109(3):325–334.
2. Loomba R, Lim JK, Patton H, et al. AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review. Gastroenterol. 2020;158(6):1822–1830.
3. Dufour JF, Scherer R, Balp MM, et al. The global epidemiology of nonalcoholic steatohepatitis (NASH) and associated risk factors–A targeted literature review. Endocrine and Metabolic Science. 2021;3:100089.
4. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease–meta–analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.
5. Younossi ZM, Loomba R, Anstee QM, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology. 2018;68(1):349–360.
6. Huang DQ, ElSerag HB, Loomba R. Global epidemiology of nafld–related hcc: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021;18(4):223–238.
7. Ajmera V, Loomba R. Imaging biomarkers of nafld, nash, and fibrosis. Mol Metab. 2021; 50:101167.
8. Perumpail BJ, Khan MA, Yoo ER, et al. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 2017;23(47):8263–8276.
9. Golabi P, Sayiner M, Fazel Y, et al. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis. Expert Rev Gastroenterol Hepatol. 2016;10(1):63–71.
10. Kasper P, Martin A, Lang S, et al. NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol. 2021;110(7):921–937.
11. Adams LA, Anstee QM, Tilg H, et al. Non–Alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138–1153.
12. Sheka AC, Adeyi O, Thompson J, et al. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323(12):1175–1183.
13. Duseja A, Singh SP, Saraswat VA, et al. Non–alcoholic fatty liver disease and metabolic syndrome–position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology. J Clin Exp Hepatol. 2015;5(1):51–68.
14. Duseja A, Najmy S, Sachdev S, et al. High prevalence of non–alcoholic fatty liver disease among healthy male blood donors of urban India. JGH Open. 2019;3(2):133–139.
15. De A, Duseja A. Nonalcoholic fatty liver disease: Indian perspective. Clin Liver Dis (Hoboken). 2021;18(3):158–163.
16. Mahajan R, Duseja A, Kumar R, et al. A community–based study to determine the prevalence of nonalcoholic fatty liver disease (NAFLD) and its metabolic risk factors in urban and rural communities of north India. J Gastroenterol Hepatol. 2019;34(suppl 3):310.
17. Duseja A, Singh SP, Saraswat VA, et al. Non–alcoholic fatty liver disease and metabolic syndrome–position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology. J Clin Exp Hepatol. 2015;5(1):51–68.
18. Rastogi A, Shasthry SM, Agarwal A, et al. Non–alcoholic fatty liver disease – histological scoring systems: a large cohort single–center, evaluation study. APMIS. 2017;125(11):962–973.
19. Duseja A, Singh SP, Mehta M, et al. Clinicopathological profile and outcome of a large cohort of patients with nonalcoholic fatty liver disease from South Asia: Interim Results of the Indian Consortium on Nonalcoholic Fatty Liver Disease. Metab Syndr Relat Disord. 2022;20(3):166–173.
20. DiStefano JK. NAFLD and NASH in postmenopausal women: implications for diagnosis and treatment. Endocrinology. 2020;161(10):134.
21. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol. 2011;46(1):63–69.
22. Golabi P, Paik, J, Deavila L, et al. The worldwide prevalence of non–alcoholic steatohepatitis (NASH) in patients with type 2 Diabetes Mellitus (DM). J. Hepatol. 2018;68:841.
23. Mehta R, Jeiran K, Koenig AB, et al. The role of mitochondrial genomics in patients with non–alcoholic steatohep– atitis (NASH). BMC Medical Genetics. 2016;17:63.
24. Rich NE, Oji S, Mufti AR, et al. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the united states: a systematic review and meta–analysis. Clin Gastroenterol Hepatol. 2018;16(2):198–210.
25. Anty R, Iannelli A, Patouraux S, et al. A new composite model including metabolic syndrome, alanine aminotrans– ferase and cytokeratin–18 for the diagnosis of non–alcoholic steatohepatitis in mor– bidly obese patients. Aliment Pharmacol Ther. 2010;32(11–12):1315–1322.
26. Tohra S, Duseja A, Taneja S, et al. Experience with changing etiology and nontransplant curative treatment modalities for hepatocellular carcinoma in a real–life setting–a retrospective descriptive analysis. J Clin Exp Hepatol. 2021;11(6):682–690.
27. GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3):245–266.
28. Aguilera–Méndez A. Esteatosis hepática no alcohólica: una enfermedad silente [Nonalcoholic hepatic steatosis: a silent disease]. Rev Med Inst Mex Seguro Soc. 2019;56(6):544–549.
29. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164(3):337–340.
30. Bäckhed F, Ley RE, Sonnenburg JL, et al. Host–Bacterial mutualism in the human intestine. Science. 2005;307(5717):1915–1920.
31. Bhute SS, Suryavanshi MV, Joshi SM, et al. Gut microbial diversity assessment of indian type–2–diabetics reveals alterations in eubacteria, archaea, and eukaryotes. Front Microbiol. 2017;8:214.
32. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19(1):55–71.
33. Chen J, Vitetta L. Gut microbiota metabolites in nafld pathogenesis and therapeutic implications. Int J Mol Sci. 2020;21(15):5214.
34. Patil DP, Dhotre DP, Chavan SG, et al. Molecular analysis of gut microbiota in obesity among Indian individuals. J Biosci. 2012;37(4):647–657.
35. Xiang H, Sun D, Liu X, et al. The role of the intestinal microbiota in nonalcoholic steatohepatitis. Front Endocrinol (Lausanne). 2022;13:812610.
36. Jena PK, Sheng L, Li Y, et al. Probiotics VSL#3 are effective in reversing non–alcoholic steatohepatitis in a mouse model. Hepatobiliary Surg Nutr. 2020;9(2):170–182.
37. Zhao Z, Chen L, Zhao Y, et al. Lactobacillus plantarum NA136 ameliorates nonalcoholic fatty liver disease by modulating gut microbiota, improving intestinal barrier integrity, and attenuating inflammation. Appl Microbiol Biotechnol. 2020;104(12):5273–5282.
38. Zhao Z, Wang C, Zhang L, et al. Lactobacillus plantarum na136 improves the non–alcoholic fatty liver disease by modulating the ampk/nrf2 pathway. Appl Microbiol Biotechnol. 2019;103(14):5843–5850.
39. Sawada Y, Kawaratani H, Kubo T, et al. Combining probiotics and an angiotensin–ii type 1 receptor blocker has beneficial effects on hepatic fibrogenesis in a rat model of non–alcoholic steatohepatitis. Hepatol Res. 2019;49(3):284–295.
40. Matsumoto K, Ichimura M, Tsuneyama K, et al. Fructo–Oligosaccharides and intestinal barrier function in amethionine–choline–deficientmousemodel of nonalcoholic steatohepatitis. PLoS One. 2017; 12(6):e0175406.
41.  singh dp, khare p, zhu j, et al. A novel cobiotic–based preventive approach against high–fat diet–induced adiposity, nonalcoholic fatty liver and gut derangement in mice. Int J Obes (Lond). 2016;40(3):487–496.
42. Takai A, Kikuchi K, Ichimura M, et al. Fructo–Oligosaccharides ameliorate steatohepatitis, visceral adiposity, and associated chronic inflammation via increased production of short–chain fatty acids in a mouse model of non–alcoholic steatohepatitis. BMC Gastroenterol. 2020;20(1):46.
43. Raso GM, Simeoli R, Iacono A, et al. Effects of a lactobacillus paracasei b21060 based synbiotic on steatosis, insulin signaling and toll–like receptor expression in rats fed a high–fat diet. J Nutr Biochem. 2014;25(1):81–90.
44. Cortez–Pinto H, Borralho P, Machado J, et al. Microbiota modulation with synbiotic decreases liver fibrosis in a high fat choline deficient dietmicemodel of non–alcoholic steatohepatitis (nash). GE Port J Gastroenterol. 2016;23(3):132–141.
45. Jena PK, Sheng L, Nagar N, et al. Synbiotics bifidobacterium infantis and milk oligosaccharides are effective in reversing cancer–prone nonalcoholic steatohepatitis using western diet–fed fxr knockout mouse models. J Nutr Biochem. 2018;57:246–254.
46. Zhou D, Pan Q, Shen F, et al. Total fecal microbiota transplantation alleviates high–fat diet–induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep. 2017;7(1):1529.
47. Houron C, Ciocan D, Trainel N, et al. Gut microbiota reshaped by pectin treatment improves liver steatosis in obese mice. Nutrients. 2021;13(11):3725.
48. Loomba R, Schork N, Chen C–H, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149(7):1784–1793.
49. Caussy C, Soni M, Cui J, et al. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J Clin Invest. 2017;127(7):2697–2704.
50. Sookoian S, Pirola CJ. Genetics of nonalcoholic fatty liver disease: from pathogenesis to therapeutics. Semin Liver Dis. 2019;39(2):124–140.
51. Valenti LVC, Baselli GA. Genetics of nonalcoholic fatty liver disease: a 2018 update. Curr Pharm Des. 2018;24(38):4566–4573.
52. Salameh H, Hanayneh MA, Masadeh M, et al. PNPLA3 as a genetic determinant of risk for and severity of non–alcoholic fatty liver disease spectrum. J Clin Transl Hepatol. 2016;4(3):175–191.
53. Chen X, Zhou P, De L, et al. The roles of transmembrane 6 superfamily member 2 rs58542926 polymorphism in chronic liver disease: a meta–analysis of 24,147 subjects Molecular Genetics & Genomic Medicine. 2019;7(8):824.
54. Tan H–L, Zain SM, Mohamed R, et al. Association of glucokinase regulatory gene polymorphisms with risk and severity of non–alcoholic fatty liver disease: an interaction study with adiponutrin gene. J Gastroenterol. 2014;49(6):1056–1064.
55. Mancina RM, Dongiovanni P, Petta S, et al. The MBOAT7–TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150(5):1219–1230.
56. Abul–Husn NS, Cheng X, Li AH, et al. A protein–truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378(12):1096–1106.
57. Sanyal A. Genetics of Nonalcoholic Steatohepatitis. Gastroenterol Hepatol. 2020;16:651–653.
58. Chen F, Esmaili S, Rogers GB, et al. Lean NAFLD: A distinct entity shaped by differential metabolic adaptation. Hepatology. 2020;71(4):1213–1227.
59. Xu C, Yu C, Ma H, et al. Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study. Am J Gastroenterol. 2013;108(08):1299–1304.
60. Feng RN, Du SS, Wang C, et al. Lean–non–alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. World J Gastroenterol. 2014;20(47):17932–17940.
61. Kwon YM, Oh SW, Hwang SS, et al. Association of nonalcoholic fatty liver disease with components of metabolic syndrome according to body mass index in Korean adults. Am J Gastroenterol. 2012;107(12):1852–1858.
62. Kim NH, Kim JH, Kim YJ, et al. Clinical and metabolic factors associatedwith development and regression of nonalcoholic fatty liver disease in nonobese subjects. Liver Int. 2014;34(04):604–611.
63. Nishioji K, Sumida Y, Kamaguchi M, et al. Prevalence of and risk factors for non–alcoholic fatty liver disease in a non–obese Japanese population, 2011–2012. J Gastroenterol. 2015;50(01):95–108.
64. Wei JL, Leung JC, Loong TC, et al. Prevalence and severity of nonalcoholic fatty liver disease in non–obese patients: a population study using proton–magnetic resonance spectroscopy. Am J Gastroenterol. 2015;110(09):1306–1314.
65. Das K, Das K, Mukherjee PS, et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology. 2010;51(05):1593–1602.
66. Bhat G, Baba CS, Pandey A, et al. Insulin resistance and metabolic syndrome in nonobese Indian patients with non–alcoholic fatty liver disease. Trop Gastroenterol. 2013;34(1):18–24.
67. Hagström H, Nasr P, Ekstedt M, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long–term follow–up study. Hepatol Commun. 2017;2(1):48–57.
68. VanWagner LB, Armstrong MJ. Lean NAFLD: A not so benign condition? Hepatol Commun. 201816;2(1):5–8.
69. Dela Cruz, Anna Christina. 379 Characteristics and Long–Term Prognosis of Lean Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2014;146:S–909.
70. Younes R, Govaere O, Petta S, et al. Caucasian lean subjects with non–alcoholic fatty liver disease share long–term prognosis of non–lean: time for reappraisal of BMI–driven approach? Gut. 2022;71(2):382–390.
71. Satapathy SK, Jiang Y, Agbim U, et al. Posttransplant Outcome of Lean Compared With Obese Nonalcoholic Steatohepatitis in the United States: The Obesity Paradox. Liver Transpl. 2020;26(1):68–79.
72. Albhaisi S, Sanyal AJ. Gene–Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis. Front Endocrinol (Lausanne). 2021;12:665987.
73. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non–alcoholic fatty liver disease. J Hepatol. 2008;48(6):993–999.
74. Jensen T, Abdelmalek MF, Sullivan S, et al. Fructose and sugar: A major mediator of non–alcoholic fatty liver disease. J Hepatol. 2018;68(5):1063–1075.
75. Maersk M, Belza A, Stodkilde–Jorgensen H, et al. Sucrose–sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6–mo randomized intervention study. Am J Clin Nutr. 2012;95(2):283–289.
76. Schwarz JM, Noworolski SM, Erkin–Cakmak A, et al. Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity. Gastroenterology. 2017;153(3):743–752.
77. Fatty Liver Disease: NASH and Related Disorders Edited by Geoffrey C. Farrell, Jacob George, Pauline de la M. Hall, Arthur J. McCullough Copyright © 2005 Blackwell Publishing Ltd.
78. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta–analysis. J Hepatol. 2019;71:793–801.
79. Ma C, Yan K, Wang Z, et al. The association between hypertension and nonalcoholic fatty liver disease (NAFLD): literature evidence and systems biology analysis. Bioengineered. 2021;12(1):2187–2202.
80. Li G, Peng Y, Chen Z, et al. Bidirectional Association between Hypertension and NAFLD: A Systematic Review and Meta–Analysis of Observational Studies. Int J Endocrinol. 2022;2022:8463640.
81. Ilan Y. Analogy between non–alcoholic steatohepatitis (NASH) and hypertension: a stepwise patient–tailored approach for NASH treatment. Ann Gastroenterol. 2018;31(3):296–304.
82. Sarkar M, Terrault N, Chan W, et al. Polycystic ovary syndrome (PCOS) is associated with NASH severity and advanced fibrosis. Liver Int. 2020;40(2):355–359.
83. Asfari MM, Niyazi F, Lopez R, et al. The association of nonalcoholic steatohepatitis and obstructive sleep apnea. Eur J Gastroenterol Hepatol. 2017;29(12):1380–1384.
84. Koo BK, Kim D, Joo SK, et al. Sarcopenia is an Independent Risk Factor for non–Alcoholic Steatohepatitis and Significant Fibrosis. J Hepatol. 2017;66:123–131.
85. Altajar S, Baffy G. Skeletal Muscle Dysfunction in the Development and Progression of Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol. 2020;8:414–423.
86. Wang L, Athinarayanan S, Jiang G, et al. Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition. Hepatology. 2015;61(1):119–128.
87. Araya J, Rodrigo R, Pettinelli P, et al. Decreased liver fatty acid delta–6 and delta–5 desaturase activity in obese patients. Obesity (Silver Spring). 2010;18(7):1460–1463.
88. Rossi E, Adams LA, Ching HL, et al. High biological variation of serum hyaluronic acid and Hepascore, a biochemical marker model for the prediction of liver fibrosis. Clin Chem Lab Med. 2013;51:1107–1114.
89. Kamada Y, Akita M, Takeda Y, et al. Serum Fucosylated Haptoglobin as a Novel Diagnostic Biomarker for Predicting Hepatocyte Ballooning and Nonalcoholic Steatohepatitis. PLoS One. 2013;8(6):e66328.
90. Nieto J, Dawod E, Deshmukh A, et al. EUS–guided fine–needle core liver biopsy with a modified one–pass, one–actuation wet suction technique comparing two types of EUS core needles. Endosc Int Open. 2020;8(7):E938–E943.
91. Nieto J, Khaleel H, Challita Y, et al. EUS–guided fine–needle core liver biopsy sampling using a novel 19–gauge needle with modified 1–pass, 1 actuation wet suction technique. Gastrointest Endosc. 2018;87(2):469–475.
92. EASL–EASD–EASO Clinical Practice Guidelines for the management of non–alcoholic fatty liver disease. J Hepatol. 2016;64:1388–1402.
93. Sriram S, Khan MM. Effect of health insurance program for the poor on out–of–pocket inpatient care cost in India: evidence from a nationally representative cross–sectional survey. BMC Health Serv Res. 2020;20: 839.
94. Muthiah MD, Sanyal AJ. Current management of non–alcoholic steatohepatitis. Liver Int. 2020;40(Suppl 1):89–95.
95. Wands JR, Fava J, Wing RR. Randomized Controlled Trial Testing the Effects of Weight Loss on Nonalcoholic Steatohepatitis (NASH). Hepatology. 2011;51:121–129.
96. Vilar–Gomez E, Martinez–Perez Y, Calzadilla–Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(367–378):e365.
97. Wong VW S, Chan RS M, Wong GL H, et al. Community–based lifestyle modification programme for non–alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2013;59:536–542.
98. Jin YJ, Kim KM, Hwang S, et al. Exercise and diet modification in non–obese non–alcoholic fatty liver disease: Analysis of biopsies of living liver donors. J Gastroenterol Hepatol. 2012;27:1341–1347.
99. Romero–gómez M, Zelber–sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67:829–846.
100. Alam S, Jahid Hasan M, Khan MAS, et al. Effect of Weight Reduction on Histological Activity and Fibrosis of Lean Nonalcoholic Steatohepatitis Patient. J Transl Int Med. 2019;7(3):106–114.
101. Kim NH, Kim JH, Kim YJ, et al. Clinical and metabolic factors associated with development and regression of nonalcoholic fatty liver disease in nonobese subjects. Liver Int. 2014;34:604–611.
102. Oh S, Shida T, Yamagishi K, et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology. 2015;61:1205–1215.
103. Eslam M, Sarin SK, Wong VW, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int. 2020;14(6):889–919.
104. Sima HR, Nikroo H, Nematy M, et al. Sa1042 effect of aerobic exercise added to calorie–restricted diet on non–alcoholic steatohepatitis, a randomized clinical trial. Gastroenterology. 2014;146:945.
105. Bray GA, Fruhbeck G, Ryan DH, et al. Management of obesity. Lancet. 2016;387(10031):1947–1956.
106. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non–alcoholic steatohepatitis (LEAN): a multicentre, double–blind, randomised, placebo–controlled phase 2 study. Lancet. 2016;387(10019):679–690.
107. Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E–LIFT Trial). Diabetes Care. 2018;41:1801–1808.
108. Mathurin P, Hollebecque A, Arnalsteen L, et al. Prospective study of the long–term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137(2):532–540.
109. Lassailly G, Caiazzo R, Ntandja–Wandji LC, et al. Bariatric Surgery Provides Long–term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology. 2020;159(4):1290–1301.
110. Xanthakos SA. Pharmacological, Endoscopic, Metabolic, and Surgical Procedures for Nonalcoholic Fatty Liver Disease. Clin Liver Dis (Hoboken). 2021;17(3):209–214.
111. Salomone F, Sharaiha RZ, Boškoski I. Endoscopic bariatric and metabolic therapies for non‐alcoholic fatty liver disease: evidence and perspectives. Liver Int. 2020;40:1262–1268.
112. Lee SY, Lai H, Chua YJ, et al. Endoscopic Bariatric and Metabolic Therapies and Their Effects on Metabolic Syndrome and Non–alcoholic Fatty Liver Disease – A Systematic Review and Meta–Analysis. Front Med (Lausanne). 2022;9:880749.
113. Giruzzi N. Plenity (Oral Superabsorbent Hydrogel). Clin Diabetes. 2020;38(3):313–314.
114. Zamora–Valdes D, Watt KD, Kellogg TA, et al. Long–term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy. Hepatology. 2018;68(2):485–495.
115. Belfort R, Harrison SA, Brown K, et al. A placebo–controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307.
116. Cusi K, Orsak B, Bril F, et al. Long–term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165:305–315.
117. Boettcher E, Csako G, Pucino F, et al. Meta analysis: pioglitazone improves liver histology and fibrosis in patients with non–alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35:66–75.
118. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo–controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–1184.
119. Tolman KG, Freston JW, Kupfer S, et al. Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3–year, randomized, comparator–controlled study in the US. Drug Saf. 2009;32:787–800.
120. Issa D, Wattacheril J, Sanyal AJ. Treatment options for nonalcoholic steatohepatitis –a safety evaluation. Expert Opin Drug Saf. 2017;16(8):903–913.
121. Townsend SA, Newsome PN. Non–alcoholic fatty liver disease in 2016. Br Med Bull. 2016;119(1):143–156.
122. Sato K, Gosho M, Yamamoto T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta–analysis of randomized controlled trials. Nutrition. 2015;31(7):923–930.
123. Povsic M, Oliver L, Jiandani NR, et al. A structured literature review of interventions used in the management of nonalcoholic steatohepatitis (NASH). Pharmacol Res Perspect. 2019;7(3):e00485.
124. Albhaisi SAM, Sanyal AJ. New drugs for NASH. Liver Int. 2021;41 Suppl 1:112–118.
125. Sharma M, Premkumar M, Kulkarni AV, et al. Drugs for Non–alcoholic Steatohepatitis (NASH): Quest for the Holy Grail. J Clin Transl Hepatol. 2021;9(1):40–50.
126. Kulkarni AV, Tevethia HV, Arab JP, et al. Efficacy and safety of obeticholic acid in liver disease–A systematic review and meta–analysis. Clin Res Hepatol Gastroenterol. 2021;45(3):101675.
127. Newsome PN, Buchholtz K, Cusi K, et al. A Placebo–Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021;384(12):1113–1124.