In our prospective study, 18F-FAPI PET/CT could be applied to accurately evaluate early-stage liver fibrosis in LT recipients and patients with CHB (AUROC:0.92, 0.94). Compared with TE, 18F-FAPI PET/CT was comparable in detecting early-stage liver fibrosis with the additional advantages in whole-liver evaluation.
Liver cirrhosis and hepatocellular are standard endpoints of various chronic liver diseases, among which liver fibrosis is the critical pathological stage[19].
Early detection and monitoring of the progression of liver fibrosis are crucial for reflecting the prognosis of LT recipients and patients with chronic liver diseases. At present, non-invasive methods such as serum biomarkers, TE, Point Shear-wave Elastography (pSWE), and Magnetic resonance elastography (MRE) have demonstrated good accuracy in detecting significant liver fibrosis[20–23].
In a previous study, Niklas Verloh et al. calculated the liver-to-blood ratios (LBRs) of 37 patients either with or without liver fibrosis/cirrhosis by analyzing their 18F-fluorodeoxyglucose (FDG) PET/CT scans. They finally found that patients with liver fibrosis or cirrhosis showed a significantly higher LBR than patients with normal liver parenchyma (1.53 ± 0.35 VS 1.08 ± 0.23; P = 0.004). However, the LBR of patients with liver cirrhosis was lower than that of patients with advanced liver fibrosis(1.32 ± 0.14 VS 2.00 ± 0.40)[24]. FAPI PET/CT is a new functional imaging technique. Many studies have shown that, compared with 18F-FDG PET/CT, 68Ga-FAPI PET/CT and 18F-FAPI PET/CT have better imaging sensitivity for various tumors[25, 26]. Besides, in the recent study of Yue Zhou et al., it was found that as the degree of renal fibrosis gradually increased, the SUVmax values gradually increased (P = 0.03) by conducting renal biopsy and 68GA-FAPI PET/CT scan in 13 patients with chronic kidney disease[27], which showed that 68Ga-FAPI PET/CT has a specific value for diagnosing and evaluating of renal fibrosis in addition to tumors. And Manuel Röhrich et al. found that 68Ga-FAPI PET/CT imaging had potential clinical value for monitoring fibrotic interstitial lung diseases (fILD) by analyzing 68Ga-FAPI PET/CT scans of 15 patients with field and suspected lung cancer[28]. Ali Pirasteh et al. established five swine models that underwent baseline FAPI PET/MRI and liver biopsy, followed by liver parenchymal embolization, eight weeks of oral alcohol intake, endpoint FAPI PET/MRI, and autopsy. Their study finally demonstrated that liver FAPI uptake strongly correlated with the fibrosis stages of the liver (P < 0.001)[29]. On these bases, the prospective study on the evaluation of liver fibrosis in LT recipients and patients with CHB was carried out, which found that the cut-off value of SUVmax of 18F-FAPI PET/CT yielded 100% sensitivity and 66.7% specificity (AUROC = 0.93, P < 0.001) was 2.0 for diagnosing liver fibrosis. Although it was a preliminary study with a small sample, 18F-FAPI PET/CT showed significant efficacy and feasibility in evaluating early-stage liver fibrosis among LT recipients and CHB patients. A foreign study reported a 22% incidence of moderate to severe liver fibrosis in LT recipients with a median postoperative time of 5.1 (1.75–10.7) years[11]. In the study of Kenji Yoshino et al. about the development of liver fibrosis after LT, it was reported that severe liver fibrosis could be found in 23.7% of 278 LT recipients at the median 8.3 ± 6.8 years after LT[30]. In this study, moderate to severe liver fibrosis was not found in LT recipients at the median time of 2.9 (1.6-4.0) years after LT, which might be related to the small sample size, insufficient follow-up time, and the strict selection of liver biopsy. Nevertheless, it was found in our study that, based on the results of liver biopsy, 18F-FAPI PET/CT performed well in diagnosing early-stage liver fibrosis and had comparable diagnostic accuracy compared with TE. Diagnostic accuracy for distinguishing early stages of fibrosis was higher with 18F-FAPI PET/CT than with TE (AUROC 0.92 and 0.80, respectively). Though TE is much simpler and less expensive, FAPI PET/CT has several key potential advantages for evaluating liver fibrosis compared with liver biopsy and non-invasive techniques. It can offer imaging and overall assessment of liver fibrosis and could be applied as a supplementary examination method for diagnosing liver fibrosis to reduce the sampling error of liver biopsy. 18F-FAPI PET/CT might raise the prospect of an image-based noninvasive assessment of liver fibrosis with complex comorbidities.
This study has some limitations. Firstly, this study was conducted in a single center, and the sample size was relatively small. The sampling error and the evaluation error of liver biopsy represent the significant limitations of our study. The needle liver biopsy is only a finite portion of an organ with potential variability in the expression of liver fibrosis, which may cause an underestimate of the degree of hepatic fibrosis. Although two experienced pathologists were applied to analyze the identical specimens, the inter-/intra-observer variability could not be avoided entirely. Secondly, the small sample size may influence our results. In addition, considering the high risk of liver biopsy for severe fibrosis, poor diversity of liver fibrosis degrees and lack of data on patients with severe liver fibrosis were inevitable. Future studies with a larger sample size are needed to explore the potential value of FAPI PET/CT in evaluating liver fibrosis in LT recipients and patients with CHB, especially in moderate and severe liver fibrosis. Moreover, our data yielded only findings that 18F-FAPI PET/CT could detect liver fibrosis with comparable accuracy. 18F-FAPI PET/CT’s potential would have to be confirmed in independent validation cohorts. Additionally, it was found in our study that the uptake of the overexpressed FAP in aHSCs was correlated to liver fibrosis by FAPI PET/CT. However, the causality between FAP and fibrosis was not proved. Finally, further studies on the prognostic value of 18F-FAPI PET/CT in LT recipients combined with liver fibrosis were needed. We anticipate 18F-FAPI PET/CT will be implemented in LT patients with elevated liver enzymes, such as acute or chronic rejection, and CMV reactivation to test its capacity to distinguish early fibrosis from more specific changes. And future studies could concentrate on developing a prognostic model integrated with TE by 18F-FAPI PET/CT in distinguishing patients at high risk of liver fibrosis complications after LT.
In conclusion, our preliminary results suggested that 18F-FAPI PET/CT might represent a promising non-invasive procedure for assessing early-stage liver fibrosis in LT recipients and CHB patients. In the follow-up, monitoring the development of liver fibrosis by 18F-FAPI PET/CT was available in clinical practice. Future studies could focus on expanding the scope of 18F-FAPI PET/CT for monitoring liver fibrosis and predicting complications of chronic liver disease.