Dysregulated Neurovascular Control Underlies Declining Microvascular Functionality in People With Non-alcoholic Fatty Liver Disease (NAFLD) at Risk of Liver Fibrosis

Abstract

Background/aims: Increasing evidence shows that non-alcoholic fatty liver disease (NAFLD) is associated with dysregulation of microvascular perfusion independently of established cardio-metabolic risk factors. We investigated whether hepatic manifestations of NAFLD such as liver fibrosis and liver fat are associated with microvascular hemodynamics through dysregulation of neurovascular control.

Methods: Microvascular dilator (post-occlusive reactive hyperemia) and sympathetically mediated constrictor (deep inspiratory breath-hold) responses were measured at the forearm and finger, respectively, using laser Doppler fluximetry. Non-linear complexity-based analysis was used to assess the information content and variability of the resting blood flux (BF) signals, attributable to oscillatory flow-motion activity, and over multiple sampling frequencies.

Results: Measurements were made in 189 adults (113 men) with NAFLD, with (n = 65) and without (n = 124) type 2 diabetes mellitus (T2DM), age = 50.9 ± 11.7 years (mean ± SD). Microvascular dilator and constrictor capacity were both negatively associated with age (r = -0.178, p = 0.014, and r = -0.201, p = 0.007, respectively) and enhanced liver fibrosis (ELF) score (r = -0.155, p = 0.038 and r = -0.418, p < 0.0001, respectively). There was no association with measures of liver fat, obesity or T2DM. Lempel-Ziv complexity (LZC) and sample entropy (SE) of the BF signal measured at the two skin sites were associated negatively with age (p < 0.01 and p < 0.001) and positively with ELF score (p < 0.05 and p < 0.0001). In individuals with an ELF score ≥7.8 the influence of both neurogenic and respiratory flow-motion activity on LZC was up-rated (p < 0.0001).

Conclusion: Altered microvascular network functionality occurs in adults with NAFLD suggesting a mechanistic role for dysregulated neurovascular control in individuals at risk of severe liver fibrosis.

Keywords: NAFLD; blood flow; flow-motion; liver fibrosis; microcirculation; non-linear complexity analysis; skin; sympathetic nervous system.

FIGURE 1

Skin microvascular (A) dilator response to reactive hyperemia (RH) measured at the forearm and (B) constrictor response to deep inspiratory breath-hold (IBH%) measured at the finger in individuals with NAFLD with an ELF score of <7.8 (open circles n = 89) and ≥7.8 (filled circles n = 92).

FIGURE 2

Spectral-domain analysis of resting blood flux signals measured at the forearm and finger. (A) Individual (dotted) and mean (solid) spectra of spectral density across the five frequency bands corresponding to endothelial (0.0095–0.02 Hz), sympathetic (0.02–0.06 Hz), myogenic (0.06–0.15 Hz), respiratory (0.15–0.4 Hz), and cardiac (0.4–1.6 Hz) activity in individuals with ELF score <7.8 (black n = 89) and ELF score ≥7.8 (red n = 92). (B) Relative power spectral density (PSD) contribution of each of the spectral bands to total power for ELF score <7.8 (open circles n = 89) and ELF score ≥7.8 (filled circles n = 92). Bar = median. *p < 0.05, **p < 0.01.

FIGURE 3

(A) Lempel-Ziv complexity index (LZC-index) and (B) Sample entropy index (SE-index) of the blood flux signals measured at the forearm and finger in individuals with NAFLD with an ELF score <7.8 (open circles n = 89) and ≥7.8 (closed circles n = 92). Horizontal bar = median.

FIGURE 4

Spearman correlations between BF signal LZ complexity and PSD contribution of the five frequency bands corresponding to endothelial (0.0095–0.02 Hz) (black), sympathetic (0.02–0.06 Hz) purple), myogenic (0.06–0.15 Hz) (green), respiratory (0.15–0.4 Hz) (blue), and cardiac (0.4–1.6 Hz) (red) activity with increasing sampling frequency, measured in the resting forearm BF signal in individuals with an ELF score <7.8 (n = 89) and ≥7.8 (n = 92).