Liver Fibrosis and Steatosis in Alström Syndrome: A Genetic Model for Metabolic Syndrome

Abstract

Alström syndrome (ALMS) is an ultra-rare monogenic disease characterized by insulin resistance, multi-organ fibrosis, obesity, type 2 diabetes mellitus (T2DM), and hypertriglyceridemia with high and early incidence of non-alcoholic fatty liver disease (NAFLD). We evaluated liver fibrosis quantifying liver stiffness (LS) by shear wave elastography (SWE) and steatosis using ultrasound sonographic (US) liver/kidney ratios (L/K) in 18 patients with ALMS and 25 controls, and analyzed the contribution of metabolic and genetic alterations in NAFLD progression. We also genetically characterized patients. LS and L/K values were significantly higher in patients compared with in controls (p < 0.001 versus p = 0.013). In patients, LS correlated with the Fibrosis-4 Index and age, while L/K was associated with triglyceride levels. LS showed an increasing trend in patients with metabolic comorbidities and displayed a significant correlation with waist circumference, the homeostasis model assessment, and glycated hemoglobin A1c. SWE and US represent promising tools to accurately evaluate early liver fibrosis and steatosis in adults and children with ALMS during follow-up. We described a new pathogenic variant of exon 8 in ALMS1. Patients with ALMS displayed enhanced steatosis, an early increased age-dependent LS that is associated with obesity and T2DM but also linked to genetic alterations, suggesting that ALMS1 could be involved in liver fibrogenesis.

Keywords: Alström syndrome; FIB-4; NAFLD; diabetes; fibrosis; liver/kidney ratio; metabolic syndrome; obesity; shear wave elastography.

Figure 1

Liver fibrosis and steatosis in patients with ALMS: (A) liver stiffness evaluated by shear wave elastography in patients with ALMS and in controls (CTRLs); (B) liver steatosis quantified by the L/K in patients with ALMS and in CTRLs. Results are presented as a box plot, with 25th and 75th percentiles and median values. ID 1 (white triangle), ID 2 (white circle), and ID 5 (white square) patients had clinical signs of portal hypertension and are described in detail in Table 3. Statistical analysis was performed using the Mann–Whitney U-test.

Figure 2

Correlation analysis of the liver stiffness and the sonographic hepatorenal ratio in patients with ALMS. The simple correlations between liver stiffness and FIB-4 (A), liver stiffness and age (B), and steatosis evaluated by L/K and TG levels (C) were performed by Spearman’s correlation in the 18 patients with ALMS. Data are reported on a logarithmic scale in (C).

Figure 3

Relationships between liver stiffness and liver steatosis in patients with ALMS: (A) liver stiffness evaluated by the shear wave elastography in patients with ALMS divided into two subgroups on the basis of the L/K cut-off value (non-steatosis subgroup with L/K of <1.6 and steatosis subgroup with L/K of >1.6). Results were presented as a box plot, with 25th and 75th percentiles and median values. ID 1 (white triangle), ID 2 (white circle) and ID 5 (white square) patients had clinical signs of portal hypertension and are described in detail in Table 3. Statistical analysis was performed using the Mann–Whitney U-test; (B) the simple correlation between liver stiffness evaluated by the shear wave elastography and liver steatosis evaluated by L/K, was performed by Spearman’s correlation in patients with ALMS.

Figure 4

Liver stiffness and metabolic complications in patients with ALMS: (A) liver stiffness evaluated by shear wave elastography in patients with ALMS divided into subgroups according to the presence of obesity; (B) liver stiffness evaluated by shear wave elastography in patients with ALMS divided into subgroups according to the presence of type 2 diabetes mellitus (T2DM). Data are reported as a box plot with 25th and 75th percentiles and median values. ID 1 (white triangle), ID 2 (white circle), and ID 5 (white square) patients had clinical signs of portal hypertension and are described in detail in Table 3. Statistical analysis was performed using the Mann–Whitney U-test.

Figure 5

Correlation analysis of the liver stiffness and biomarkers of metabolic complications in patients with ALMS. The simple correlations between liver stiffness evaluated by the shear wave elastography and waist (n = 15) (A), and homeostasis model assessment (HOMA; n = 15) (B), and glycated hemoglobin 1Ac (Hb1Ac) (n = 14) (C) were performed by Spearman’s correlation in the indicated patients with ALMS. Data were transformed into logarithmic values in (B).