Our investigation of ultrasound imaging features in patients diagnosed with PBC went beyond the conventional markers characterized in previous studies. The scope of observation was expanded by taking advantage of both high- and low-frequency ultrasound measurements, which allowed us to uncover unique ultrasound features in PBC patients. Using this approach, we identified characteristic patterns of change in the LHLD that take place during PBC progression. Notably, we observed that the PVW thickness and PHB width were increased in more advanced PBC stages. These novel findings will be immensely valuable to enhance the assessment of disease progression in patients with PBC.
We observed the presence of a PHB in the liver ultrasound images from patients diagnosed with either PBC or CHB. While the presence of a PHB alone is not a definitive indication of PBC, it is nevertheless more frequently present and wider in PBC cases, particularly as the disease progresses. In the course of our investigation, we performed pathological analysis of a rare PBC patient who underwent transplantation. Our findings revealed inflammatory cell infiltration, the presence of fibrous tissue, and mild cholestasis within the PHB range surrounding the portal area. In the early stages of PBC, inflammation was minimal, and the degree of fibrosis was not significant. However, as the disease progressed, the gradual damage to the bile duct epithelium led to the accumulation of lymphocytes in the portal area, resulting in cholestasis, necrosis, and varying degrees of fibrosis. Therefore, we believe that it is more meaningful in the diagnosis of progressive stages of PBC according to the degree of widening of PHB. We speculate that the wider PHB observed in PBC patients could be attributed to differences in the degree of inflammation and cholestasis around the portal area. Furthermore, patients in our study having middle to advanced stage PBC exhibited a thickened intrahepatic duct wall with enhanced echogenicity. The enhanced thickness of the intrahepatic duct wall was quantitatively confirmed in the study. It is vital to note that the contrast between the PHB and thickened PVW can cause confusion among observers and lead to misinterpretation of the enhanced echogenicity of the intrahepatic duct wall. Although the determination of enhanced echogenicity of the intrahepatic portal vein wall was subjective, this was additionally confirmed using MRI data. Moreover, a previous study by Kovač and colleagues reported that, out of 44 PBC patients, 72.7% exhibited periportal hyperintensity [5], which is consistent with our findings.
As PBC progresses, the excessive accumulation and toxic effect of bile acid can lead to a decline in liver cell function, resulting in the compensatory regeneration of the liver. In the early stages of the disease, approximately 70–80% of PBC patients experience hepatomegaly, and in the end stage, approximately 20% develop splenomegaly [17]. A previous study reported that 75% of PBC patients had hepatic left lobe enlargement, and splenomegaly was only observed in the presence of significant hepatic fibrosis [18], which is consistent with our findings. In our investigation, we not only identified hepatosplenomegaly in PBC patients but also observed distinct patterns of changes in the LHLD and spleen area at different stages of the disease. Specifically, we observed a significant increase in LHLD at PBC stages II and III, and a significant increase in spleen area at stages III and IV. As PBC progresses, the portal vein diameter does not differ significantly from that observed in all stages of CHB; however, we noted that the increase in splenic area and the widening of the splenic vein occur earlier in PBC compared to CHB patients. This suggests that portal hypertension may manifest earlier in these patients. Recent studies have demonstrated that portal hypertension in PBC can exhibit up to a 40% increase over a 10-year period [19], and it can occur much earlier in the course of the disease, well before the rise in serum bilirubin and the development of cirrhosis. This phenomenon is linked to portal area and hepatic sinusoid lesions [20].
It has been reported that the liver surface, echogenicity, and liver edge of patients with chronic liver disease undergo regular changes as the disease progresses [3]. In our study, we noted similar changes in patients with PBC. Nonetheless, it is noteworthy that the liver surface of PBC patients remained smoother than that of CHB patients as the disease progressed. Furthermore, during the cirrhosis period, the ultrasound images of PBC patients differed from those of most chronic liver disease patients, who typically manifest more regenerative nodules in the liver parenchyma [21]. In our study, we observed that among the 25 patients with stage IV PBC, only 4% showed a small number of regenerative nodules. In contrast, 30.8% of patients with stage F4 CHB presented nodular manifestations in their imaging data. In general, the progression of CHB to cirrhosis is characterized by macronodular cirrhosis, whereas regular micronodular cirrhosis dominates in PBC [17, 22]. Importantly, Aishima et al. proposed that the lower degree of interlobular bile duct loss in PBC could lead to macronodular cirrhosis with more acini, whereas severe interlobular bile duct loss could result in the separation of individual acini, leading to micronodular cirrhosis [22]. In this study, the incidence of intrahepatic nodules assessed by ultrasound imaging was lower in PBC than in CHB patients. Two plausible reasons could account for this finding. Firstly, 96% of PBC patients with cirrhosis were identified based on clinical symptoms. As a result, their condition may have been severe at the time of diagnosis, and they might have already developed a substantial number of severe interlobular bile duct defects that could manifest as small nodular cirrhosis. Secondly, the size of the nodules in PBC patients was either equal to or smaller than the liver lobules, which meant that the ultrasound imaging resolution may not be sufficient to detect them. Patients with advanced disease often present with typical manifestations of portal hypertension, ascites, and collateral circulation. Our study findings showed that 20.0% of patients with PBC presented with gallbladder stones or gallbladder polyps, while 12.0% had enlarged abdominal lymph nodes. Furthermore, approximately 60.9% of patients with advanced (stage IV) PBC developed esophagogastric varices (EGV), which is a higher percentage than what has been previously reported by Gao et al. (50.9%) [23]. This may be because our study only considered the incidence of EGV in patients with stage IV PBC.
The main methods for non-invasive PBC staging based on ultrasound elasticity are transient elastography, shear-wave elastography (SWE), and real-time elastography (RTE). The clinical guidelines from the European Association for the Study of the Liver (EASL) state that vibration-controlled transient elastography (VCTE) plays an irreplaceable role in determining disease progression in PBC. An international multi-center study of 3,985 patients with PBC showed that liver stiffness measurements were independently associated with poor clinical outcomes and that 8 kPa and 15 kPa were the optimal diagnostic thresholds for risk stratification into low-, intermediate-, and high-risk populations [24]. SWE reliably distinguishes between mild, moderate and severe liver fibrosis and cirrhosis, with areas under the ROC curve of 95.3%, 87.4%, 85.3%, and 95.3%, respectively [25]. Koizumi et al. found that the diagnostic accuracy of RTE in the diagnosis of severe liver fibrosis was higher than that of VCTE [26]. Ultrasound imaging features of PBC correlate with histological staging, although there is a considerable degree of subjectivity in the observation of liver surface, liver echogenicity, and liver edge. Liver echogenicity, in particular, appears to be less consistent, and therefore we recommend PHB, PVW, LHLD and splenic area as the most appropriate ultrasound imaging features to determine disease progression in PBC patients. The different elastography techniques have their own advantages in the monitoring of PBC progression, and ultrasound measurement of two-dimensional images may provide a simple and quick complementary assessment method for a subset of PBC patients whose elastography results may have been affected by factors such as rib space stenosis, elevated bilirubin, or abdominal distension.
Our study had two limitations that need to be taken into account. Although we applied strict inclusion criteria, our sample size was relatively small, and the study was conducted in its early stages. Therefore, we need to expand our research by increasing the total number of participants and including additional healthcare centers, to more comprehensively explore the changes in ultrasound imaging according to the disease stage and to identify additional distinctive ultrasound features that could assist in this evaluation. Furthermore, we need to expand our research to determine whether these typical ultrasound features are generalizable to other etiologies that cause liver progression.
In summary, we conducted a thorough analysis of ultrasound imaging changes among patients with progressive PBC. Our findings revealed that this technique is a highly precise method for assessing the extent to disease progression in PBC patients. Furthermore, our study suggests that ultrasound imaging may provide crucial clinical reference values for the prediction of the histological stage of the disease.