Duodenal mucosal resurfacing for nonalcoholic fatty liver disease

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BACKGROUND

Nonalcoholic fatty liver disease (NAFLD) results from fat accumulation within the liver and ranges from simple steatosis to steatohepatitis progressing to cirrhosis. NAFLD has become the most common cause of liver disease in the United States and Europe because of an aging population and increased prevalence of metabolic syndrome characterized by hypertension, hyperlipidemia, type 2 diabetes (T2DM), and central obesity. ¹ NAFLD is strongly associated with obesity and T2DM, where the prevalence of NAFLD in patients undergoing bariatric surgery exceeds 90% compared with an estimated prevalence of 25% in the general population. ² In patients with NAFLD, the estimated prevalence rates of obesity and T2DM are estimated at 51.3% and 22.5%, respectively, compared with 39.8% and 14.0% in the general US population. ² Currently, there are no US Food and Drug Administration (FDA)‐approved interventions to treat NAFLD; therefore, lifestyle modifications and weight loss are the mainstay of therapy, where 3%–5% total body weight loss improves steatosis and 7%–10% can improve fibrosis. ³ Bariatric surgery can successfully induce weight loss and has been shown to have favorable outcomes in those with NAFLD. ⁴ However, there is evidence that the effect of bariatric surgery on metabolic syndrome and insulin resistance is not entirely mediated by weight loss. This is evident because 30% of patients with T2DM on oral antiglycemic medications or insulin at the time of admission for Roux‐en‐Y gastric bypass are discharged without these medications postoperatively. ⁵ This effect is thought to be mediated by exclusion of the duodenum, because duodenal hypertrophy has been linked to insulin resistance through increased nutrient presentation and disrupted molecular signaling pathways. ⁶ Even with its impressive results, the invasive nature and risk profile of Roux‐en‐Y gastric bypass are drawbacks, and access to the procedure is limited, because <1% of eligible patients undergo bariatric surgery annually. ⁷ This has led to the emergence of other interventions, such as endoscopic bariatric and metabolic procedures, as a possible less invasive interventional opportunity in this therapeutic area.

DUODENAL MUCOSAL RESURFACING

Duodenal mucosal resurfacing (DMR) is a novel endoscopic procedure that aims to achieve metabolic effects by intervening on the mucosal surface of the duodenum. The procedure is performed under fluoroscopic (Figures 1 and 2) and endoscopic guidance (Figure 3) by introducing a catheter with a balloon into the duodenum. In sections, the balloon inflates, the duodenal mucosa is then lifted by injecting saline into the submucosa, and the ablation is performed by circulating hot and cold water through the balloon. ⁸ These ablation cycles are repeated (Figure 4), with the aim to ablate all duodenal mucosa from 1 cm distal to major papilla to the ligament of Treitz. The goal is to achieve complete circumferential ablation of the postpapillary duodenum covering about 12 cm in length. ⁸ Currently, DMR is investigational in the United States and is not FDA cleared for routine clinical use by the FDA.

FIGURE 1.

Fluoroscopic guidance of duodenal ablation catheter in the duodenum.

FIGURE 2.

Fluoroscopic guidance of duodenal ablation catheter being advanced in the duodenum.

FIGURE 3.

Endoscopic visualization of the ablation catheter in the duodenum.

FIGURE 4.

Endoscopic visualization of postablation duodenum.

DMR FOR T2DM

The first‐in‐human study for DMR in T2DM demonstrated a mean reduction of hemoglobin A1C (HgbA1C) by 1.2% (p < 0.001) at 6 months in 39 participants, with a mean baseline HgbA1C of 9.6%. Patients received circumferential ablation of between 3 and 15 cm of the postpapillary duodenal mucosa. There were no immediate postprocedural complications, but three patients developed duodenal stenosis at 2–6 weeks, which was treated with balloon dilation, with subsequent full resolution of symptoms. Repeat endoscopy at 3 months showed mucosal healing in all study participants. Notably, the effect in weight loss was modest, with most participants returning to their baseline weight at 6‐month follow‐up, indicating that the glycemic improvement is independent of weight loss. ⁸ Another study explored DMR followed by starting liraglutide. In 16 patients with insulin‐dependent T2DM with mean baseline HgbA1c of 7.5%, the mean HgbA1C decreased to 7% (p = 0.009) and 6.7% (p = 0.182) at 6 and 18 months, respectively. Half of the study participants were off insulin at 18 months, but five patients had to be restarted on insulin at 6 months for HgbA1C >7.5%. There were no severe procedure‐related adverse events. ⁹ Another study with a 1‐year follow‐up period included 46 participants with T2DM and baseline HgbA1C of 8.6%. After DMR, there was a mean reduction of 0.9% in HgbA1c in the first 24 weeks, which persisted for the full 1‐year follow‐up (p < 0.001 for both). Notably, mean alanine aminotransferase levels decreased from a mean baseline of 40 U/L to 31 U/L at 24 weeks (p = 0.016) and to 30 U/L at 12‐month follow‐up (p < 0.001). There was one severe adverse event where one patient developed fever and malaise postoperatively, which resolved within 3 days. ¹⁰ A meta‐analysis combined the results from three studies ⁸ , ¹⁰ , ¹¹ on the effect of DMR on HgbA1c at 6 months and showed a 0.9% reduction (I ² = 0%; p < 0.001). ¹²

DMR FOR NAFLD

The most rigorous study to assess DMR for T2DM also assessed liver magnetic resonance imaging proton density fat fraction. In this multicenter (European and Brazilian) double‐blind study that assessed DMR versus sham procedure in patients with T2DM, the results were stratified by region because of significant patient heterogeneity by prespecified interaction testing. ¹¹ In the European cohort (DMR: n = 39; sham: n = 36), modified intention‐to‐treat analysis showed that the median HbA1C at 24 weeks postprocedure was decreased by −6.6 (17.5) mmol/mol in the DMR group compared with −3.3 (10.9) mmol/mol in the sham procedure group (p = 0.033). In patients with baseline liver magnetic resonance imaging proton density fat fraction >5% and baseline fasting plasma glucose (FPG) ≥10 mmol/L, there was an absolute reduction of liver fat content by 7.6% in the DMR group compared with 3.1% reduction in the sham procedure group at 12 weeks (p = 0.001). These results were not replicated in those with baseline FPG <10 mmol/L, suggesting that this intervention is effective only in those patients with NAFLD with higher fasting glucose levels. ¹¹

Even though DMR showed promising results in liver fat reduction, this did not appear to translate to resolution of nonalcoholic steatohepatitis (NASH) in a subsequent study where 14 patients with biopsy‐proven NASH underwent DMR. ¹³ Three patients were excluded from the analysis because of heavy alcohol use or pregnancy. In the 11 patients who were included in the analysis, there was no resolution of NASH on repeat biopsy in any patient at 12‐month follow‐up. Improvement of fibrosis by at least one stage, with no worsening in NASH, was attained in three patients (27%). Notably, there was no significant weight loss or improvement in HgbA1c by the end of the 12‐month follow‐up period, where median hgbA1c was 6.5% and 6.6% at the beginning and end of the study, respectively. ¹³ This suggests that DMR alone may not reverse the effects of NASH.

CONCLUSION

DMR is a novel endoscopic procedure that is well tolerated and with a reasonable safety profile. It may be beneficial as a modality to treat T2DM. The data are limited in the effect of the procedure on liver health, although preliminary signals indicate there may be improvements in liver fat fraction and transaminase levels in patients with NAFLD, but no proven resolution of NASH has been demonstrated. Its future role in the management of NAFLD is yet to be determined. Further studies with larger cohorts and hepatic endpoints are needed to understand the role of DMR in patients with T2DM and NAFLD or NAFLD alone. Furthermore, serial DMR interventions over time may improve the efficacy of the procedure.

CONFLICT OF INTEREST

R.V. and M.A.G. have received research support from Fractyl. M.A.G. has received research support from Allurion Technologies, and consults for Boston Scientific.

Shamseddeen H, Vuppalanchi R & Gromski MA. Duodenal mucosal resurfacing for nonalcoholic fatty liver disease. Clinical Liver Disease. 2022;20:166–169. 10.1002/cld.1255