Specific metabolic impairments indicate loss of sustained liver improvements in metabolic dysfunction-associated steatotic liver disease treatment

Abstract

Background: High liver fat content (LFC) induces increased risks of both hepatic and extrahepatic progression in metabolic dysfunction-associated steatotic liver disease (MASLD), while maintaining a significant decline in magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) (≥30% decline relative to baseline) without worsening fibrosis results in improved histological severity and prognosis. However, the factors associated with the loss of sustained responses to treatment remain unclear, and we aim to identify them.

Methods: Consecutive treatment-naïve MASLD patients between January 2015 and February 2022, with follow-up until April 2023, were included in this prospective cohort study. LFC quantified by MRI-PDFF and liver stiffness measurements (LSM) determined by two-dimensional shear wave elastography (2D-SWE) were evaluated at weeks 0, 24 and 48. MRI-PDFF response was defined as a ≥30% relative decline in PDFF values, and LSM response was defined as a ≥1 stage decline from baseline.

Results: A total of 602 MASLD patients were enrolled. Of the 303 patients with a 24-week MRI-PDFF response and complete follow-up of 48 weeks, the rate of loss of MRI-PDFF response was 29.4%, and multivariable logistic regression analyses showed that 24-week insulin resistance (IR), still regular exercise and caloric restriction after 24 weeks, and the relative decline in LFC were risk factors for loss of MRI-PDFF response. Loss of LSM response at 48 weeks occurred in 15.9% of patients, and multivariable analysis confirmed 24-week serum total bile acid (TBA) levels and the relative decline in TBA from baseline as independent predictors. No significant association was found at 48 weeks between loss of MRI-PDFF response and loss of LSM response.

Conclusions: MASLD patients with IR and high TBA levels are at higher risks of subsequent diminished sustained improvements of steatosis and fibrosis, respectively.

Keywords: Metabolic dysfunction-associated steatotic liver disease (MASLD); liver stiffness measurements response (LSM response); loss of response; magnetic resonance imaging-based proton density fat fraction response (MRI-PDFF response).

Figure 1

Comprehensive management flow of MASLD patients. The cardiovascular risk and LDL-C targets of MASLD patients were determined according to the American Heart Association blood cholesterol clinical practice guideline. MASLD, metabolic dysfunction-associated steatotic liver disease; MRI-PDFF, magnetic resonance imaging-based proton density fat fraction; 2D-SWE, two-dimensional shear wave elastography; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; SUA, serum uric acid; FBG, fasting blood glucose; OGTT, oral glucose tolerance test; HbA1C, hemoglobin A1c; ACEI/ARB, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers; CCB, calcium channel blockers; GLP-1R, glucagon-like peptide 1 receptor; DPP-4, dipeptidyl peptidase 4; SGLT-2, sodium-dependent glucose transporters 2; PCSK9, proprotein convertase subtilisin/kexin type 9; BP, blood pressure.

Figure 2

Flowchart showing the flow of participants through the study. MASLD, metabolic dysfunction-associated steatotic liver disease; MRI-PDFF, magnetic resonance imaging-based proton density fat fraction; 2D-SWE, two-dimensional shear wave elastography; LFC, liver fat content; LSM, liver stiffness measurement.

Figure 3

Dynamic changes in LFC measured by MRI-PDFF and LSM measured by 2D-SWE in MASLD patients without or with loss response status. Evolution of hepatic steatosis (A) and fibrosis (B) from study enrollment to 48-week follow-up in the whole cohort. Violin plots showing the change trends of LFC (C) or LSM (D) in the two groups at 0, 24 and 48 weeks. Boxplots showing the relative decline ratio of LFC (E) or LSM (F) in the two groups at both 24 and 48 weeks. Nonparametric tests were employed for comparisons at each time point. *, P<0.05; **, P<0.01; ***, P<0.001. F0, liver fibrosis stage 0; F1−2, liver fibrosis stages 1 to 2; F3−4, liver fibrosis stages 3 to 4. ns, not significant; LFC, liver fat content; LSM, liver stiffness measurement; MRI-PDFF, magnetic resonance imaging-based proton density fat fraction; 2D-SWE, two-dimensional shear wave elastography; MASLD, metabolic dysfunction-associated steatotic liver disease.

Figure 4

Dynamic changes in LFC measured by MRI-PDFF and LSM measured by 2D-SWE in MASLD patients who completed a 48-week follow-up, stratified by insulin resistance (A,B) or total bile acid levels (C,D). The changes (95% CI) from baseline were noted, and comparisons at each time point were performed using nonparametric tests. *, P<0.05; **, P<0.01; ***, P<0.001. IR_0w(−), without insulin resistance at baseline; IR_0w(+), with insulin resistance at baseline; IR_24w(−), without 24-week insulin resistance; IR_24w(+), with 24-week insulin resistance; HTBA_0w(−), without high total bile acid levels (≥4.1 μmol/L) at baseline; HTBA_0w(+), with high total bile acid levels (≥4.1 μmol/L) at baseline; HTBA_24w(−), without high total bile acid levels (≥4.1 μmol/L) at 24 weeks; HTBA_24w(+), with high total bile acid levels (≥4.1 μmol/L) at 24 weeks. ns, not significant; LFC, liver fat content; MRI-PDFF, magnetic resonance imaging-based proton density fat fraction; LSM, liver stiffness measurement; 2D-SWE, two-dimensional shear wave elastography.

Figure 5

Multivariable logistic regression analysis for the loss of response in hepatic steatosis and fibrosis at 48 weeks among MASLD patients without (A) or with (B) weight loss of ≥5.0% at 0–24 weeks and among those without (C) or with (D) insulin resistance at baseline, respectively. MRI-PDFF, magnetic resonance imaging-based proton density fat fraction; LFC, liver fat content; 24w, 24 weeks; 95% CI, 95% confidence interval; FFA, free fatty acid; TBA, total bile acid; FBG, fasting blood glucose; LSM, liver stiffness measurement; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; WC, waist circumference; ALT, alanine aminotransferase; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; FINS, fasting insulin; ALP, alkaline phosphatase.