Impact of metabolic endoscopy on fibrosis regression in steatotic liver disease

Abstract

Metabolic endoscopy represents a promising alternative in the management of steatotic liver disease, particularly metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD). With the rising global prevalence of MASLD—affecting over one-third of the adult population—and its close association with obesity, insulin resistance, and metabolic syndrome, there is an urgent need for innovative, minimally invasive therapies that can reverse liver fibrosis and prevent progression to cirrhosis and hepatocellular carcinoma. Traditional management of MASLD relies on lifestyle modifications and bariatric surgery, yet these approaches are hampered by issues of adherence, invasiveness, and accessibility. This review examines endoscopic bariatric metabolic therapies including endoscopic sleeve gastroplasty (ESG), intragastric balloons (IGB), duodenal mucosal resurfacing (DMR), and duodeno-jejunal bypass liners (DJBL), as well as revisional procedures like endoscopic revisional gastroplasty (ERG) and transoral outlet reduction (TORe). Clinical studies and meta-analyses indicate that metabolic endoscopy is safe and effective for liver fibrosis in MASH. ESG appears to offer the greatest fibrosis reduction, while IGB and DJBL yield modest improvements, and DMR shows no significant effect. Among revisional therapies, ERG has demonstrated fibrosis reduction, although the benefits of TORe remain to be fully evaluated.

Key Words: Steatotic liver disease; Metabolic dysfunction associated steatohepatitis; Endoscopic bariatric metabolic therapies; Liver fibrosis regression; Endoscopic sleeve gastroplasty; Revisional metabolic endoscopy procedures

Core Tip: This review highlights the promise of metabolic endoscopy as a minimally invasive strategy for reversing liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis. It evaluates endoscopic bariatric metabolic therapies including endoscopic sleeve gastroplasty (ESG), intragastric balloon, duodenal mucosal resurfacing (DMR), and duodeno-jejunal bypass liners, along with revisional procedures such as endoscopic revisional gastroplasty (ERG) and transoral outlet reduction (TORe). Evidence indicates that ESG yields the greatest fibrosis reduction, while DMR shows minimal benefit and is not recommended. Among revisional metabolic endoscopic procedures, ERG is effective for fibrosis reduction, whereas TORe requires further evaluation.

INTRODUCTION

Steatotic liver disease per recent terminology includes metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis, which is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD)[1]. It is a growing health concern worldwide due to its association with obesity, insulin resistance, and metabolic syndrome[1,2].

MASLD affects approximately 38% of the global adult population and around 31.3% of adults in the United States[3] Among individuals with MASLD, 20% have type 2 diabetes mellitus, nearly 70% have hyperlipidemia (including atherogenic dyslipidemia), and about 40% have hypertension or metabolic syndrome[3]. While less common, MASH remains significant, affecting an estimated 12%–14% of the global population and 3%–6% in the United States[3,4]

MASH can lead to liver fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma[4]. Despite the rising prevalence, there is currently only one FDA-approved pharmacological treatment for MASH advanced-stage fibrosis (i.e. resmetirom), and as such, weight loss through lifestyle interventions remains the cornerstone of management[1]. However, achieving and sustaining significant weight loss through lifestyle interventions and medical management is challenging.

Bariatric surgery has demonstrated efficacy in improving MASH, but its invasive nature and limited access or insurance coverage limit its accessibility[3]. To address this limitation, non-surgical endoscopic bariatric metabolic procedures have emerged as a less invasive alternative. However, limited data is available on the effectiveness of non-surgical bariatric metabolic endoscopic procedures in improving MASH or reducing adverse outcomes. This review examines the outcomes of various endoscopic bariatric and metabolic therapies (EBMTs), including intragastric balloons (IGB), endoscopic sleeve gastroplasty (ESG), duodenal mucosal resurfacing (DMR), and other emerging techniques.

MECHANISMS OF MASH REGRESSION AFTER BARIATRIC SURGERY

Metabolic endoscopy and surgery, including ESG and Roux-en-Y gastric bypass (RYGB) among others, plays a pivotal role in reducing hepatic inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, all of which are key drivers of MASH[5,6]. This reduction in hepatic inflammation is partially mediated by post-surgical changes in ghrelin isoforms, particularly an increase in the acylated/desacyl ghrelin ratio, which has been shown to mitigate liver inflammation and enhance mitochondrial function (Figure 1)[6,7]. The improved mitochondrial function decreases oxidative stress and prevents hepatocyte injury, contributing to the histologic regression of MASH. Alongside these benefits, a significant reduction in hepatic ER stress allows for improved protein folding and reduced accumulation of misfolded proteins, further alleviating hepatocyte dysfunction and enhancing liver health[7,8].

Figure 1 Mechanisms associated with fibrosis regression in metabolic dysfunction-associated steatohepatitis after bariatric surgery and procedures. ESG: Endoscopic sleeve gastroplasty; MASH: Metabolic dysfunction-associated steatohepatitis; GLP-1: Glucagon-like peptide-1; PYY: Peptide tyrosine tyrosine.

Beyond its effects on inflammation, bariatric surgery induces profound lipid metabolic reprogramming that contributes to MASH regression[9]. A key factor in this process is the increased circulating levels of neuregulin 4, which activates ErbB4 signaling and enhances fatty acid oxidation within hepatocytes[9]. This shift in lipid metabolism leads to decreased intracellular lipid accumulation and a marked reduction in hepatic steatosis. Additionally, bariatric surgery enhances bile acid metabolism, promoting pathways that favor lipid clearance and decrease lipotoxicity (Figure 1)[9,10].

Hormonal changes also play a crucial role in this metabolic shift, as post-surgical increases in insulin-sensitizing hormones such as glucagon-like peptide-1 (GLP-1) and peptide peptide tyrosine tyrosine enhance glucose homeostasis and insulin action, further reducing hepatic fat deposition[11]. These metabolic and hormonal adaptations collectively create an environment that fosters the resolution of hepatic steatosis and fibrosis (Figure 1).

Bariatric surgery significantly reshapes the gut microbiome, impacting systemic metabolism and liver health. Beneficial bacteria such as Akkermansia and Bifidobacterium proliferate post-surgery, promoting anti-inflammatory pathways and strengthening the gut barrier, thereby reducing the influx of gut-derived endotoxins that contribute to hepatic inflammation and insulin resistance[10,11]. Simultaneously, harmful bacteria such as Bacteroides, which are associated with increased inflammatory cytokine production, are diminished[11,12]. This shift in microbiota composition is accompanied by enhanced production of short-chain fatty acids, which improve insulin sensitivity through modulation of gut hormone secretion, particularly by increasing GLP-1 Levels[9,11]. The interplay between gut microbiota, inflammation, and metabolic health highlights the multifactorial benefits of bariatric surgery in reversing the pathophysiology of MASH.

METABOLIC ENDOSCOPY PROCEDURES DEMONSTRATING LIVER FIBROSIS REGRESSION

EBMTs have emerged as promising minimally invasive interventions to indirectly manage MASLD and MASH, potentially slowing progression to cirrhosis. Key EBMTs include ESG, IGB, DMR, and duodeno-jejunal bypass liners (DJBL). These procedures promote weight loss and metabolic improvements while reducing liver fibrosis.

ESG

ESG is a non-surgical endoscopic procedure whereby introducing an endoscope through the mouth of the patients, the gastric lumen is invaginated luminally and suture using full-thickness endoscopic suturing to tubularize the stomach akin to a surgical sleeve gastrectomy[10]. ESG also delays gastric emptying[13], and impact gut hormones in the pathophysiology of obesity as demonstrated by Lopez-Nava et al[14]. ESG is safe and highly effective in reducing fibrosis markers in MASH[10,11]. Abad et al[12] reported that, ESG combined with lifestyle modification led to significantly greater total body weight loss (TBWL) (9.47% vs 3.91%) and a greater reduction in liver stiffness (−5.63 kPa vs −0.2 kPa; P < 0.05) compared to the sham group (P < 0.05)[10]. Hajifathalian et al[15] found that among 118 patients with obesity and MASLD or MASH undergoing ESG, 20% improved their fibrosis risk (shifting from F3–F4/indeterminate to F0–F2) over 72 weeks[15].

In a prospective study, Nixdorf et al[16] observed that 93 patients with obesity and MASLD/MASH achieved a significant reduction in the NAFLD fibrosis score (NFS) from –0.97 to –1.74 and improved liver stiffness, via vibration-controlled transient elastography (VCTE), within 3 months[16]. Furthermore, Jirapinyo et al[17] demonstrated that combining endoscopic gastric remodeling (a subtype of ESG) in combination with GLP-1 receptor agonists resulted in a 54% reduction in liver stiffness compared to 14% with GLP = 1 receptor agonists monotherapy, along with marked decreases in NFS (P = 0.004)[17].

IGB

IGBs function as both space-occupying and anti-motility devices to induce satiety, delay gastric emptying, and promote weight loss, remaining in place for up to 6 months. IGB therapy has also shown promising results for fibrosis regression in MASH[18]. Salomone et al[18] reported that 6-month IGB placement in 26 patients with obesity and MASH (liver stiffness ≥ 9.7 kPa) led to a significant decrease in fibrosis-4 index (FIB-4) score (from 3.2 ± 0.7 to 2.7 ± 0.8) and a reduction in liver stiffness from 13.3 ± 3.2 to 11.3 ± 2.8 kPa via VCTE (P < 0.001)[18].

Interestingly, the mentioned study showed a significant improvement in degree of steatosis. As the controlled attenuation parameter (CAP) score reduced from 355 (298–400) to 296 (255–352) dB/m (all P < 0.01)[18]. This suggests that the fibrosis improvement may be associated to the reduction in hepatic fat content.

DMR

DMR is a novel technique whereby the metabolically-active duodenal mucosa is ablated via different endoscopic methods (i.e. thermal, electro-pulse, or radiofrequency, steam-therapy), resulting in improvement in metabolic parameters such as hemoglobin A1c, albeit with less effect on body weight compared to other EBMTs[5]. As such, DMR has exhibited only modest effects on hepatic fibrosis. Chuang et al[19] in a meta-analysis of two studies (n = 67) observed a non-significant trend toward liver fat reduction [magnetic resonance imaging proton density fat fraction (MRI-PDFF) decreased by –2.22, 95%CI: –12.79-8.34] at 12 weeks[19]. Similarly, Mingrone et al[20] in the REVITA-2 trial demonstrated that DMR in T2D patients reduced liver fat by –5.4% (P = 0.035) at 12 weeks[20]. To date, there is no study proving MASH fibrosis regression with the use of DMR, however more research is needed to fully characterize this technique.

DJBL

Unlike DMR, which physically alters the absorptive and metabolically-active small intestinal mucosa, DJBL are synthetic barriers that are endoscopically placed in the proximal small bowel[5]. This procedure aims to simulate the temporary effects of a gastric bypass anatomy. This prevents both absorption of nutrients as well as biochemical triggering of endocrine and exocrine cascades caused by the interaction of nutrients with small bowel mucosa[5,21]. Roehlen et al[21] reported that DJBL implantation for 9–12 months (with a 6-month follow-up) significantly reduced the NFS (from 0.19 to –0.83, P < 0.001) and AST to platelet ratio index (APRI) (from 0.36 to 0.26, P < 0.0001)[21]. In a randomized trial by Karlas et al[22], 48-week DJBL therapy reduced the FAST score by 0.21 (95%CI: –0.28 to –0.13, P < 0.001), although changes in liver stiffness in VCTE, NFS, and enhanced liver fibrosis were minimal[22]. These findings suggest that DJBL may offer protective effects against fibrosis progression, though its impact appears less pronounced than that of ESG and IGB.

We focused on the most common, well-established endoscopic metabolic techniques and their effects on liver stiffness in MASH. We acknowledge that experimental therapies have shown potential to reverse MASH or remain untested[23-25]; however, due to their experimental nature, they were not included in this review. All the studies had a follow-up between 6 months and 2 years.

REVISIONAL ENDOSCOPIC BARIATRIC PROCEDURES DEMONSTRATING FIBROSIS REDUCTION

For patients experiencing weight regain or insufficient weight loss after initial EBMTs (e.g., IGB, ESG, or DJBL) and bariatric surgery, several revisional procedures can promote weight loss and potentially reduce liver fibrosis.

One popular approach is endoscopic revisional gastroplasty (ERG), which uses endoscopic suturing to reduce the size of the gastric pouch or stoma (mainly post-LSG), thereby enhancing weight loss and metabolic outcomes[26].

Another widely used, safe and effective procedure, transoral outlet reduction (TORe), decreases the size of a dilated and incompetent gastrojejunal anastomosis[21,23]. Although various revisional options exist, this review focuses on the two most used and well-established techniques: ERG and TORe.

Recent studies show that revisional procedures can also reduce hepatic fibrosis. In one retrospective study, endoscopic gastric plication significantly improved non-invasive fibrosis markers—NFS decreased from 0.48 to –1.18, FIB-4 declined from 1.4 to 1.2, and liver stiffness reduced from 13.9 to 8.9 kPa (all P < 0.001), with 63% of patients achieving ≥ 10% total weight loss[27].

Similarly, TORe in post RYGB patients with weight regain and MASLD led to significant improvements in FIB-4, with a trend toward reduced liver stiffness[26]. It also produced an average TBWL of 8.8% at 12 months, along with enhanced glycemic control[28-30]. For TORe, however, there are no dedicated studies that has focused on liver stiffness reduction after procedure (Table 1).

Table 1 Fibrosis reduction in patients with fatty liver disease undergoing metabolic bariatric procedures¹.

Ref.	Study design	Population	Intervention	Key findings
Abad et al[12], 2024	Multicenter, randomized, clinical trial	40 patients with MASH	ESG with lifestyle modification vs sham endoscopy with lifestyle intervention	The ESG group achieved significantly greater total body weight loss (9.47% vs 3.91%) and a greater reduction in liver stiffness (5.63 vs 0.2 kPa, both P < 0.05)
Hajifathalian et al[15], 2021	Prospective, single-arm interventional study	118 patients with obesity and MASLD or MASH	ESG	ESG reduced hepatic fibrosis risk in 20% of patients, shifting VCTE elastography readings from F3–F4 to F0–F2, while only 1% worsened (P = 0.02)
Nunes et al[28], 2023	Systematic review and meta-analysis	175 patients with obesity and MASLD	Four studies: ESG	Sgnificantly reduced hepatic steatosis index (–4.85, 95%CI –6.02 to –3.67), NFS (–0.5, 95%CI –0.80 to –0.19), TWL (–17.28%, 95%CI –18.24 to –16.31)
Jirapinyo et al[29], 2022	Systematic review and meta-analysis	Study sample sizes ranged from 21 to 29 patients with obesity and MASLD	One study ESG; One study IGB	EBMTs significantly reduced liver fibrosis (SMD 0.7, 95%CI: 0.1–1.3, P = 0.02), hepatic steatosis (SMD –1.0, 95%CI: –1.2 to –0.8, P < 0.0001) and NAS (–2.50, 95%CI: –3.5 to –1.5, P < 0.0001)
Salomone et al[18], 2021	Retrospective study	26 patients with obesity and MASH (liver stiffness ≥ 9.7 kPa at baseline)	IGB	FIB-4 decreased from 3.2 ± 0.7 to 2.7 ± 0.8, liver stiffness from 13.3 ± 3.2 to 11.3 ± 2.8 kPa, and CAP from 355 (298–400) to 296 (255–352) dB/m (all P < 0.01); no severe adverse events
Ren et al[30], 2022	Systematic review and meta-analysis	Study sample sizes ranged from 21 to 91 patients with obesity and MASLD or MASH	Two studies: IGB; One study DJBL	NFS decreased by –0.58 (95%CI –0.97 to –0.20), APRI lowered by 0.73 (P = 0.005) and MRE stiffness by 0.3 kPa (P = 0.03); VCTE elastography (–6.39 kPa) and FIB-4 (–0.28) changes were non-significant
Roehlen et al[21], 2022	Prospective interventional study	71 patients with T2DM, obesity and MASLD	DJBL	Significantly reduced fatty liver index (from 98.22 to 93.38, P < 0.001), NFS (from 0.19 to –0.83, P < 0.001), and APRI (from 0.36 to 0.26, P < 0.0001)
Karlas et al[22], 2022	Retrospective study	32 T2D patients with obesity undergoing DJBL	DJBL	Reduced FAST score by 0.21 (95%CI: –0.28 to –0.13, P < 0.001); fibrosis markers (LSM, NFS, ELF) were unchanged, with slight FIB4 improvement; device-related complications were noted
Chuang et al[19], 2023	Systematic review and meta-analysis	67 patients with obesity and MASLD or MASH (biopsy-proven or MRI-PDFF > 5%)	Two studies: DMR	Trend toward reduced liver fat (MRI-PDFF decreased by –2.22, 95%), though results were not statistically significant (P > 0.05)
Jirapinyo et al[17], 2024	Retrospective study from a prospectively collected registry	30 patients with obesity and MASLD	12 patients received EGR monotherapy, 18 patients received EGR+GLP-1RA	Combination therapy led to significantly greater fibrosis improvement: NFS decreased by 181% ± 182% vs 30% ± 83% (P = 0.04), and liver stiffness reduced by 54% ± 12% vs 14% ± 45% (P = 0.05)

¹All the studies had a follow-up between 6 months and 2 years.

APRI: Aspartate aminotransferase to platelet ratio index; CAP: Controlled attenuation parameter; DJBL: Duodenal-jejunal bypass liner; DMR: Duodenal mucosal resurfacing; EBMTs: Endoscopic bariatric and metabolic therapies; ERG: Endoscopic revisional gastroplasty; FIB-4: Fibrosis-4 index; FAST: Fibroscan- aspartate aminotransferase score; GLP-1RA: Glucagon-like peptide-1 receptor agonist; IGB: Intragastric balloon; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; MRI-PDFF: Magnetic resonance imaging proton density fat fraction; NAS: Non-alcoholic fatty liver disease activity score; T2D: Type 2 diabetes; TBWL: Total body weight loss; VCTE: Vibration-controlled transient elastography.

CONCLUSION

Take-home message

Our review details commonly used endoscopic bariatric metabolic procedures (ESG, IGB, DJBL, and DMR) and revisional therapies (ERG and TORe) using non-invasive tests (VCTE, FIB-4, CAP score, and MRI-PDFF) to assess liver fibrosis and fat deposition in MASLD/MASH.

Among primary interventions, ESG provides the greatest reduction in liver fibrosis, while IGB and DJBL yield improvements to a lesser extent. DMR shows no significant effect.

Among revisional therapies, ERG is the only intervention that has demonstrated fibrosis reduction, as evidenced by improvements in VCTE and FIB-4 scores. However, the potential benefits of TORe in reducing liver fibrosis still need further evaluation.

Although individual studies suggest ESG may be superior, no direct comparative studies exist; thus, causal causality cannot be drawn from this review. Further research is needed to define the roles of both primary and revisional endoscopic metabolic therapies (with particular attention to TORe) in reducing liver fibrosis and preventing cirrhosis.

Limitations and study heterogeneity

Despite the promising results outlined above, several limitations and sources of heterogeneity must be acknowledged. First, sample sizes varied widely across studies, from as few as 26 participants in certain IGB trials[18] to over 118 in some ESG cohorts[15], limiting the statistical power and generalizability of individual findings. Second, follow-up durations ranged from as short as 3 months (e.g., VCTE reassessment after ESG[16]) to up to 2 years in select meta-analyses[28], making it difficult to compare the durability of fibrosis regression or steatosis improvement across interventions. Third, endpoint definitions were inconsistent: Some studies used VCTE stiffness thresholds (e.g., shifting from F3–F4 to F0–F2[15]), while others relied on noninvasive scores such as FIB-4, NFS, or MRI-PDFF to quantify steatosis and fibrosis changes[18,19,21]. Differences in cutoff values and measurement modalities introduce variability in reported effect sizes. Fourth, patient selection criteria differed: Cohorts ranged from individuals with biopsy-proven MASH to those defined by elastography or serum biomarkers alone, thereby encompassing a spectrum of disease severity and comorbidities (e.g., type 2 diabetes, hypertension, or morbid obesity). Finally, procedural heterogeneity, such as variations in ESG suture patterns, types of IGB, or duration of DJBL implantation, complicates direct comparisons.