Liver fibrosis in type I Gaucher disease: magnetic resonance imaging, transient elastography and parameters of iron storage

Abstract

Long term liver-related complications of type-1 Gaucher disease (GD), a lysosomal storage disorder, include fibrosis and an increased incidence of hepatocellular carcinoma. Splenectomy has been implicated as a risk factor for the development of liver pathology in GD. High ferritin concentrations are a feature of GD and iron storage in Gaucher cells has been described, but iron storage in the liver in relation to liver fibrosis has not been studied. Alternatively, iron storage in GD may be the result of iron supplementation therapy or regular blood transfusions in patients with severe cytopenia. In this pilot study, comprising 14 type-1 GD patients (7 splenectomized, 7 non-splenectomized) and 7 healthy controls, we demonstrate that liver stiffness values, measured by Transient Elastography and MR-Elastography, are significantly higher in splenectomized GD patients when compared with non-splenectomized GD patients (p = 0.03 and p = 0.01, respectively). Liver iron concentration was elevated (>60±30 µmol/g) in 4 GD patients of whom 3 were splenectomized. No relationship was found between liver stiffness and liver iron concentration. HFE gene mutations were more frequent in splenectomized (6/7) than in non-splenectomized (2/7) participants (p = 0.10). Liver disease appeared more advanced in splenectomized than in non-splenectomized patients. We hypothesize a relationship with excessive hepatic iron accumulation in splenectomized patients. We recommend that all splenectomized patients, especially those with evidence of substantial liver fibrosis undergo regular screening for HCC, according to current guidelines.

Figure 1. Study flow chart.

Figure 2. MRE: selection of region of interest (ROI) in the liver.

ROIs are drawn manually on the elastograms, in the lateral part of the right liver lobe while avoiding liver margins and large hepatic vessels. The mean elasticity value within the ROI in this example (Sx GD patient) is 2.3 kPa (colored bar represents kPa). The corresponding stiffness measured with TE was 7.2 kPa.

Figure 3. Comparison of quantitative imaging results and distribution of HFE mutations.

Solid black horizontal lines represent median values. Presence and distribution of HFE mutations in GD patients are shown in red and green. (A) MR-liver iron concentration (Gandon). Dashed line represents upper limit of normal (60 µmol/g). Median (range) in µmol/g: controls (n = 7) 30 (5–66); non-Sx GD (n = 7) 35 (20–90); Sx GD (n = 7) 35 (10–250). (B) Transient elastography results. Dashed line represents cutoff value for the presence of substantial liver fibrosis (Metavir ≥ F2). Median (range) in kPa: controls (n = 7) 4.9 (3.9–5.9); non-Sx GD (n = 7) 4.8 (3.4–7.2); Sx GD (n = 7) 8.8 (3.5–16.0). (C) MR elastography results. Median (range) in kPa: controls (n = 7) 1.69 (1.53–1.84); non-Sx GD (n = 7) 1.47 (1.32–2.03); Sx GD (n = 4) 2.32 (2.12–2.42).

Figure 4. T2* maps of the liver.

(A) Healthy control with a normal liver T2* value of 26 ms (LIC-Gandon: 20±20 µmol/g). (B) Sx-GD patient with severe iron overload: T2* value in the liver is short: 3.2 ms; the corresponding LIC measured with the Gandon method was high: 250±50 µmol/g.

Figure 5. Correlations between study parameters.

A–C: correlations between MR-LIC and 1/T2* (n = 21), TE (n = 21) and ferritin concentration (n = 14). D–F: correlations between TE and MRE (n = 18), Chitotriosidase activity (n = 14) and ACE (n = 14).