Effect of colesevelam on liver fat quantified by magnetic resonance in nonalcoholic steatohepatitis: a randomized controlled trial

Abstract

Bile acid sequestrants (BAS) lower plasma low density lipoprotein levels and improve glycemic control. Colestimide, a BAS, has been claimed by computed tomography to reduce liver fat. Therefore, we examined the efficacy of colesevelam, a potent BAS, to decrease liver fat in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liver fat was measured by a novel magnetic resonance imaging (MRI) technique, the proton-density-fat-fraction (PDFF), as well as by conventional MR spectroscopy (MRS). Fifty patients with biopsy-proven NASH were randomly assigned to either colesevelam 3.75 g/day orally or placebo for 24 weeks. The primary outcome was change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Compared with placebo, colesevelam increased liver fat by MRI-PDFF in all nine segments of the liver with a mean difference of 5.6% (P = 0.002). We cross-validated the MRI-PDFF-determined fat content with that assessed by colocalized MRS; the latter showed a mean difference of 4.9% (P = 0.014) in liver fat between the colesevelam and the placebo arms. MRI-PDFF correlated strongly with MRS-determined hepatic fat content (r(2) = 0.96, P < 0.0001). Liver biopsy assessment of steatosis, cellular injury, and lobular inflammation did not detect any effect of treatment.

Conclusion: Colesevelam increases liver fat in patients with NASH as assessed by MRI as well as MRS without significant changes seen on histology. Thus, MRI and MRS may be better than histology to detect longitudinal changes in hepatic fat in NASH. Underlying mechanisms and whether the small MR-detected increase in liver fat has clinical consequences is not known.

Fig. 1

Chart of study enrollment and study flow. In all, 77 subjects were screened and 50 subjects were eligible for randomization. Twenty-five subjects were randomized to either colesevelam or placebo. There were two dropouts in the colesevelam and three dropouts in the placebo groups.

Fig. 2

Effect of colesevelam on hepatic fat content assessed by MRI in patients with NASH. The longitudinal trend of liver fat fraction as measured by MRI-PDFF for each subject is shown in the placebo (right) and colesevelam (left) groups. Each small circle represents an individual patient at weeks 0 and 24. The average MRI-PDFF increased by 2.8% in the colesevelam group (P = 0.011) as shown by red lines and decreased by 2.7% in the placebo group (P = 0.065) as shown by black lines with a mean difference between the two groups of 5.6% (P = 0.002).

Fig. 3

(A) Whole liver fat mapping with MRI-PDFF for a single patient. MRI-PDFF measurements of liver segments 1, 2, 4a, 7, and 8 in the superior plane (upper panel), and of liver segments 3, 4b, 5, and 6 in the inferior plane (lower panel) are shown at week 0 (left column) and 24 (right column) for a patient in the placebo group. The fat fraction in a single liver segment is calculated by averaging three MRI-PDFF ROIs. Using 27 ROIs, the calculated total liver fat fraction average at week 0 is 29% and this decreased to 18% at week 24. MRI-PDFF data from all nine liver segments gives a fat map for the entire liver where longitudinal within-segment changes of liver fat can be appreciated. (B) MRS measured fat fraction in the same patient. MRS measurements from a 2 × 2 × 2 cm³ cube (voxel) within the right liver lobe of the same patient in which MRI-PDFF were performed in (A) are shown at week 0 (left column) and week 24 (right column). The corresponding MRS fat fraction at week 0 is 28% and this decreased to 20% at week 24.