Hepatic nodular ultrasound appearance in Wilson’s disease: association with ultrasound-derived fat fraction but not fibrosis markers

Introduction

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism that affects multiple organ systems, including the liver, nervous system, psychiatric function, and ocular structures (1-3). Progressive liver involvement is a hallmark of the disease. With appropriate treatment, survival rates are comparable to those of the general population (4); however, delayed diagnosis or inadequate management may result in cirrhosis and liver failure (5). Therefore, early and accurate assessment of hepatic injury severity is essential for optimal clinical management.

Ultrasound is the first-line imaging modality for evaluating hepatic involvement in WD because of its accessibility and cost-effectiveness. In most chronic liver diseases, the presence of hepatic parenchymal nodularity on imaging is closely associated with advanced fibrosis and disease progression (6-9). However, clinical practice has revealed that a considerable proportion of patients with WD demonstrate nodular parenchymal changes on ultrasound, and some exhibit multiple nodules in the absence of sonographic features suggestive of advanced fibrosis, such as capsular irregularity, portal vein dilation, or ascites. This apparent discrepancy raises important clinical questions regarding the significance and underlying mechanisms of nodular imaging findings in WD. At present, the clinical implications of hepatic nodularity in WD remain unclear. As WD is a rare disease, available studies are limited and often outdated. Moreover, liver biopsy is no longer routinely required for the diagnosis of WD (10), and investigations with histopathological correlation are scarce. In current clinical practice, noninvasive approaches—including imaging-based assessment and serum fibrosis indices such as aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4)—are increasingly used to evaluate liver injury (11). Accordingly, the present study aimed to determine whether nodular hepatic appearance on ultrasound in patients with WD is associated with more severe liver injury and to further explore its potential pathophysiological basis. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2300/rc).

Methods

Patients

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Ethics Committee of Anhui University of Chinese Medicine (approval No. 2024AH-82). As this was a retrospective study with anonymized patient data, the requirement for informed consent was waived by the ethics committee. A total of 188 patients with WD who underwent ultrasound examinations between June 2024 and April 2025 were consecutively screened for eligibility. After application of the predefined exclusion criteria, 175 patients were ultimately included in the final analysis.

Inclusion criteria

Patients were eligible if they met all of the following criteria:

• Diagnosis of WD according to established diagnostic guidelines (10,11);
• No concomitant viral hepatitis or autoimmune hepatitis;
• No history of excessive alcohol consumption (defined as ethanol intake ≤140 g/week for females and ≤210 g/week for males);
• No rheumatic diseases associated with secondary liver fibrosis.

Exclusion criteria

Patients were excluded if they met any of the following criteria:

• Missing ultrasound-derived fat fraction (UDFF), Shear wave elastography (SWE), or routine ultrasound data;
• Poor image quality of UDFF or SWE due to massive ascites, limb tremor, or inability to cooperate with breath-holding, which could compromise measurement reliability.

Ultrasonography

Routine B-mode ultrasound and SWE were performed using a Mindray Resona R9G ultrasound system (Mindray, Shenzhen, China) equipped with SC6-1U (1–6 MHz) and L15-3 (3.8–15.4 MHz) probes. Patients fasted for at least 8 hours prior to the examination and were positioned supine with both arms elevated to widen the intercostal spaces. Conventional ultrasound was performed using the SC6-1U low-frequency probe to assess liver size and morphology, parenchymal echogenicity, nodular appearance, portal vein diameter (PVD), portal vein velocity (PVV), spleen size, and the presence of ascites. The L15-3 high-frequency probe was additionally used to evaluate detailed hepatic parenchymal echotexture. For SWE measurements, a region in segment V or VIII of the right hepatic lobe was selected. The measurement depth was ≤6 cm, and a 4 cm × 3 cm sampling frame was positioned 1–2 cm beneath the hepatic capsule, avoiding large vessels and the gallbladder. Patients were instructed to hold their breath for 3–5 seconds during acquisition. Images were obtained when the motion stability index (M-STB index) met the predefined quality control threshold (≥ ****). Liver stiffness was measured using a 20-mm circular region of interest (ROI) (Figure 1). At least five valid measurements were acquired, and results were considered reliable when the interquartile range-to-median ratio (IQR/M) was ≤30%.

Figure 1 SWE. The M-STB index and confidence index are used as quality control parameters for SWE. An M-STB index value ≥ **** indicates adequate tissue stability relative to the probe, thereby reducing motion-related measurement variability. LSM, liver stiffness measurement; M-STB, motion stability; RLB, reliability; SD, standard deviation; SWE, shear wave elastography.

UDFF measurements were performed using an ACUSON Sequoia ultrasound system (Siemens Healthineers, Issaquah, WA, USA) equipped with a 5C1 convex probe and a deep-penetration DAX probe. Patients were positioned supine with the right arm elevated to widen the intercostal spaces. A measurement site in segment V or VIII of the right hepatic lobe was selected, ensuring that the probe was perpendicular to the skin surface. The ROI was placed 1.5–2 cm beneath the hepatic capsule, with the sampling line oriented parallel to the capsule. The ROI size was fixed at 3 cm × 3 cm and contained 15 automatically generated sub-ROIs. Areas with minimal vascular structures and homogeneous parenchyma were preferentially selected. Patients were instructed to hold their breath during image acquisition. Once image stability was achieved, the system automatically calculated the UDFF value (Figure 2). For quality control, at least five repeated measurements were obtained. Measurements were considered valid when the IQR/M was ≤0.30. Each UDFF value represented the mean of the 15 sub-ROIs, and the final UDFF was defined as the median of five valid measurements that satisfied the predefined quality criteria.

Figure 2 UDFF. A ROI was positioned parallel to the hepatic capsule in segment V of the liver, avoiding major intrahepatic vessels. The corresponding UDFF value is shown in the upper-left corner of the image. ROI, region of interest; UDFF, ultrasound-derived fat fraction.

Grouping and observation indicators

Three board-certified abdominal radiologists (each with more than 10 years of experience in hepatic ultrasonography) independently reviewed all ultrasound images under blinded conditions. Patient identifiers, clinical diagnoses, and group assignments were concealed during image interpretation. Patients with WD were classified according to the presence or absence of hepatic nodules on ultrasound.

• Nodular group: ultrasonography demonstrated a smooth hepatic capsule with diffusely coarsened or increased parenchymal echotexture, accompanied by either diffusely distributed round or irregular hypoechoic nodules (Figure 3A) or multiple well-defined hyperechoic nodules (Figure 3B).
• Non-nodular group: the hepatic parenchyma showed normal findings, isolated coarsened echotexture (Figure 3C), or diffusely increased echogenicity without discrete nodules (Figure 3D).

Figure 3 Hepatic parenchymal echotexture types in WD. (A) Scattered round hypoechoic nodules. (B) Scattered round and irregular hyperechoic nodules. (C) Coarsened parenchymal echotexture without discrete nodules. (D) Diffusely increased echogenicity without nodules, resembling hepatic steatosis. WD, Wilson’s disease.

Comparisons between groups were performed to evaluate the association between nodular ultrasound appearance and liver injury. The following parameters were analyzed: (I) demographic variables: age, sex, and body mass index (BMI); (II) ultrasound parameters: routine ultrasound findings, liver stiffness measurement (LSM), and UDFF; (III) serum fibrosis indices: APRI and FIB-4; (IV) serum fibrosis biomarkers: type IV collagen (COL IV), hyaluronic acid (HA), laminin (LN), and procollagen III N-terminal peptide (PIIINP); (V) liver function parameters: albumin (ALB) and platelet (PLT) count.

Data analysis and statistical methods

Statistical analyses were performed using SPSS version 26.0 and R software (version 4.1.3). Normally distributed continuous variables are presented as mean ± standard deviation (SD), whereas non-normally distributed variables are expressed as median [interquartile range (IQR)]. Categorical variables are reported as counts and percentages. Between-group comparisons were conducted using the independent-samples t-test, Mann-Whitney U test, or Pearson’s Chi-squared test, as appropriate. Multivariate logistic regression analysis was performed to identify independent factors associated with hepatic nodular appearance in patients with WD. The diagnostic performance and optimal cutoff value of UDFF were evaluated using receiver operating characteristic (ROC) curve analysis. A two-sided P value <0.05 was considered statistically significant.

Results

Demographic characteristics of study population

This retrospective study initially enrolled 188 consecutive patients with WD. Thirteen patients were excluded according to the predefined exclusion criteria, six due to poor-quality UDFF and SWE measurements caused by uncontrolled limb tremor or inability to cooperate with breath-holding, which failed to meet quality control requirements, and seven due to incomplete biochemical data. Ultimately, 175 patients were included in the final analysis, comprising 107 males and 68 females, with a median age of 26 years. Of these, 138 were classified into the non-nodular group and 37 into the nodular group, with nodular cases accounting for 21% of the study population.

The nodular group was further stratified based on nodule echogenicity into a hyperechoic subgroup (n=15) and a hypoechoic subgroup (n=22) (Table 1). One patient with hypoechoic hepatic nodules (Figure 4) underwent two contrast-enhanced ultrasound (CEUS) examinations and a percutaneous liver biopsy. SonoVue was used as the contrast agent for the first CEUS examination, and Sonazoid for the second. Both examinations demonstrated homogeneous iso-enhancement of the liver parenchyma throughout all vascular phases, with no definite focal enhancing lesions identified. Histopathological evaluation of the biopsy specimen revealed mild chronic hepatitis with mild hepatic steatosis (Figure 5).

Figure 4 Ultrasonographic appearance of hepatic nodules in WD. WD, Wilson’s disease.

Figure 5 Histopathological findings of liver biopsy specimens from a nodular lesion in WD. Hematoxylin and eosin staining; magnification, ×40. WD, Wilson’s disease.

As shown in Table 1, no significant differences were observed between the hyperechoic and hypoechoic subgroups across the evaluated parameters. Therefore, these subgroups were combined into a single nodular group for subsequent analyses.

Before performing multivariate logistic regression, univariate comparisons were conducted between the nodular and non-nodular groups. BMI, UDFF, and COL IV differed significantly between the two groups, whereas the remaining variables showed no significant differences (Table 2).

Multivariate regression analysis of factors closely associated with hepatic nodular imaging in WD

As shown in Table 3, after adjustment for potential confounding factors, UDFF remained independently associated with hepatic nodular appearance in WD. UDFF values were significantly higher in the nodular group than in the non-nodular group. In contrast, markers reflecting liver fibrosis—including LSM, APRI, FIB-4, and serum fibrosis markers—as well as liver function parameters [ALB, total bilirubin, and PLT count] were not independently associated with nodular findings. The distributions of LSM, UDFF, APRI, and FIB-4 between the two groups are illustrated in Figure 6.

Figure 6 Scatter plots of UDFF, LSM, APRI, and FIB-4 distribution between groups. APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis-4 index; LSM, liver stiffness measurement; UDFF, ultrasound-derived fat fraction.

ROC curve analysis demonstrated that the optimal UDFF cutoff value for predicting hepatic nodularity was 4.85%, with a sensitivity of 0.77, specificity of 0.72, and an area under the ROC curve (AUROC) of 0.75 [95% confidence interval (CI): 0.674–0.833] (Figure 7).

Figure 7 ROC curve analysis of UDFF for hepatic nodular imaging in WD. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic; UDFF, ultrasound-derived fat fraction; WD, Wilson’s disease.

Discussion

In this retrospective study of 175 consecutive patients with WD, we systematically evaluated the relationship between hepatic nodular ultrasound appearance and the severity of liver injury using multimodal ultrasonography in combination with noninvasive biochemical markers. After adjustment for potential confounders—including age, sex, BMI, and triglyceride (TG) levels—multivariate logistic regression analysis identified UDFF as the only independent factor associated with hepatic nodular appearance in WD (odds ratio =1.254, P=0.007). In contrast, parameters reflecting liver fibrosis severity—including LSM, APRI, FIB-4, and serum fibrosis markers—were not independently associated with nodular findings. These results suggest that hepatic nodular appearance in WD is more likely related to heterogeneous fatty infiltration rather than to fibrosis progression. This observation differs from the conventional understanding in chronic viral hepatitis or alcoholic liver disease, in which hepatic nodularity typically reflects regenerative nodules associated with advanced fibrosis and disease progression. The discrepancy may be attributable to the distinct metabolic and pathological mechanisms underlying WD.

WD is a multisystem disorder caused by mutations in the ATP7B gene (11-14). Excess copper accumulation promotes the generation of reactive oxygen species through the Haber-Weiss and Fenton reactions, triggering cuproptosis and iron-dependent ferroptosis, which ultimately result in hepatocellular injury and multi-organ dysfunction (15). Histopathological studies have demonstrated heterogeneous patterns of liver injury in WD, with reported prevalences of cirrhosis (37%), hepatic fibrosis (36%), and steatosis (54%) (16). Hepatic steatosis has been suggested to represent an early pathological manifestation of WD (17). UDFF, as a noninvasive quantitative technique, has shown good agreement with MRI-derived proton density fat fraction (MRI-PDFF) and histopathological findings for the assessment of hepatic steatosis (18-22). In the present study, UDFF was independently associated with hepatic nodular appearance in WD, and median UDFF values were significantly higher in the nodular group than in the non-nodular group (6% vs. 4%, P<0.001). These findings support the hypothesis that nodular ultrasound appearance in WD may be related to more pronounced hepatic steatosis.

Notably, the median UDFF value in the nodular group (6%) approached the diagnostic thresholds previously reported for hepatic steatosis. To further explore its discriminative performance, we performed ROC curve analysis to determine the optimal UDFF cutoff value for predicting hepatic nodular appearance in WD. The optimal cutoff was 4.85%, yielding a sensitivity of 77%, specificity of 72%, and an AUROC of 0.75 (95% CI: 0.674–0.833). Previous studies have reported UDFF cutoff values ranging from approximately 5% to 8% for the diagnosis of hepatic steatosis. For example, Chen et al. (21) identified a threshold of 5.5% (AUC 0.95) in a Bama minipig model of nonalcoholic fatty liver disease (NAFLD); Labyed et al. (20) reported a cutoff of 6.34% based on histopathological and MRI-PDFF correlation in NAFLD; and Huang et al. (18) determined a threshold of 7.6% for mild steatosis (MRI-PDFF ≥5%) in a cohort of 300 adults. In the present study, the UDFF cutoff identified for nodular WD was close to the thresholds reported for hepatic steatosis in previous literature. This finding supports the notion that patients in the nodular group may exhibit early or localized steatotic changes. However, due to the heterogeneous distribution of fat infiltration in WD, steatosis may present as scattered hyperechoic or hypoechoic nodular patterns on B-mode ultrasound rather than as diffuse fatty infiltration.

The heterogeneous pattern of fatty infiltration observed on ultrasound in patients with WD may be explained by the distinct pathological mechanisms of the disease. In WD, hepatic steatosis occurs secondary to copper accumulation, and copper deposition within the liver is itself unevenly distributed (23). Previous studies have demonstrated a positive correlation between the severity of copper deposition and the degree of local steatosis (16,24), leading to spatial heterogeneity characterized by multifocal fat accumulation (25-28). On ultrasonography, this heterogeneity may manifest as scattered hyperechoic nodules within a relatively hypoechoic parenchymal background (Figure 3B), representing focal areas of increased fat deposition. Conversely, in some patients, scattered hypoechoic nodules can be seen within a diffusely hyperechoic liver (Figure 3A), corresponding to areas of relative fat sparing against a steatotic background. This imaging appearance reflects localized variations in fat distribution rather than true structural nodularity related to fibrosis.

Several limitations should be acknowledged. First, this study lacked large-scale histopathological confirmation to definitively determine the nature of hepatic nodular appearance in WD. However, liver biopsy is no longer routinely indicated for the assessment of hepatic injury in WD, and ethical considerations limit the feasibility of obtaining biopsy samples solely for research purposes. To mitigate this limitation, we strengthened the analysis by comprehensively comparing nodular and non-nodular groups using noninvasive modalities, including multimodal ultrasonography and serum-based fibrosis markers. Second, although BMI and TG levels were incorporated into the multivariate model to adjust for the potential confounding effect of metabolic dysfunction-associated steatotic liver disease (MASLD) on UDFF, residual confounding cannot be entirely excluded. Future studies incorporating more comprehensive metabolic parameters may further refine the analysis. Finally, prospective investigations incorporating MRI-PDFF, CEUS, and, where clinically indicated, histopathological correlation would provide more robust validation. In addition, evaluating the role of UDFF in longitudinal follow-up of patients with WD to monitor disease progression and treatment response warrants further exploration.

Conclusions

In the present study, hepatic nodular ultrasound appearance in patients with WD was independently associated with UDFF but showed no significant association with LSM, APRI, FIB-4, or serum fibrosis markers. These findings indicate that nodular imaging features in WD are more likely attributable to heterogeneous fat distribution rather than to fibrosis progression. Heterogeneous fatty infiltration may therefore represent the underlying pathological basis of this nodular appearance. From a clinical perspective, this interpretation may help reduce unnecessary concern and avoid unwarranted invasive procedures in patients with WD presenting with nodular ultrasound findings. Nevertheless, careful evaluation remains essential. Although the overall incidence of hepatobiliary malignancies, including hepatocellular carcinoma (HCC), is extremely low in WD—even among patients with cirrhosis—and lower than that reported in other chronic liver diseases (29,30), malignant lesions cannot be entirely excluded. WD patients with ultrasound-detected nodules demonstrating a clear mass effect suggestive of malignancy or progressive enlargement during follow-up should undergo further contrast-enhanced imaging. When clinically indicated, histopathological evaluation should be performed to avoid overlooking rare malignant cases.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2300/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2300/dss

Funding: This study was supported by the Key Project of Anhui Provincial Department of Education (No. 2025AHGXZK31324) and Key Project of Traditional Chinese Medicine Inheritance and Innovation of Anhui Province (No. 2024CCCX011).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2300/coif). All authors report this study was supported by the Key Project of Anhui Provincial Department of Education (No. 2025AHGXZK31324) and Key Project of Traditional Chinese Medicine Inheritance and Innovation of Anhui Province (No. 2024CCCX011). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Ethics Committee of Anhui University of Chinese Medicine (Approval No. 2024AH-82). As this was a retrospective study with anonymized patient data, the requirement for informed consent was waived by the ethics committee.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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