Non-invasive screening for liver fibrosis by acoustic radiation force impulse in patients with ciliopathies

Abstract

Primary cilia are antenna-like structures on the surface of epithelial cells involved in multiple signaling pathways. Their malfunction can cause a heterogenous group of diseases called ciliopathies with a broad spectrum of organ involvements, including liver fibrosis. The aim of this exploratory study was to evaluate elastography measurement via ultrasound based acoustic radiation force impulse imaging (ARFI) as a screening tool for liver fibrosis in ciliopathies. In a prospective cohort of 51 patients with ciliopathies (aged between 2 months and 66 years) from the NEOCYST registry stiffness of the right liver lobe and spleen was measured via ARFI and results were then compared with laboratory parameters, endoscopic, ultrasonographic and histological findings. ARFI screening of the liver identified 27 patients without increased liver stiffness suggesting no or insignificant fibrosis, 11 with intermediate fibrosis, and 12 with liver fibrosis F4. Four patients showed increased spleen stiffness in ARFI. In all 10 patients with histologically confirmed fibrosis, ARFI results perfectly matched fibrosis stages. In the ARFI-based overall fibrosis subgroup, ALT, AST, GGT and spleen size were significantly increased, whereas platelets were significantly decreased compared to the no fibrosis subgroup. Normal GGT excluded ARFI-defined F4 fibrosis (negative predictive value 100%). Gene variants in PKHD1, TMEM67, and TULP3 were primarily detected in our patients with liver fibrosis whereas NPHP1 and HNF1B were not associated with increased liver stiffness. ARFI is a valuable screening tool for the detection of liver involvement in ciliopathies and may be useful in addition to laboratory and clinical parameters alone.Trial registration: NEOCYST registry DRKS00011003, registered 06.09.2016, https://drks.de/search/en/trial/DRKS00011003 .

Keywords: Ciliopathies; Congenital hepatic fibrosis; Liver elastography; Liver stiffness measurement; Spleen stiffness measurement.

Fig. 1

Individual association of ARFI velocities of liver and spleen with histological, clinical and imaging parameters for liver fibrosis and portal hypertension in patients with ciliopathies. Each column indicates one patient’s data. Portosystemic shunt procedure includes transjugular intrahepatic portosystemic shunt and shunt surgery.

Fig. 2

Comparison of different indicators of liver involvement in ciliopathies. Contingency tables showing the relation of liver ARFI results with AST, ALT, GGT, APRI, platelets and splenomegaly (for reference values refer to methods). ARFI values exceeding 1.34 m/s in liver were assessed as indicators for liver fibrosis (equaling F2-F4 fibrosis in adults and F1-F4 fibrosis in children). Panel G: comparison of diagnostic accuracy for different indicators of liver involvement defined by liver ARFI.

Fig. 3

Receiver operating characteristics (ROC) curves for prediction of ARFI-based liver fibrosis by liver enzymes (AST, ALT, GGT), APRI and platelet levels. Area under curves (AUC) and p-values were calculated for each parameter. ARFI values exceeding 1.34 m/s in liver were assessed as indicators for liver fibrosis (equaling F2-F4 fibrosis in adults and F1-F4 fibrosis in children).

Fig. 4

Specific genes are associated with ARFI-based liver fibrosis in ciliopathies. Each bar represents an individual patient grouped by affected gene and coded by ARFI measurements of liver and spleen. Portal hypertension (PH) was defined as pathologic splenic ARFI.