Insights into the coexistence of Wilson’s disease and chronic hepatitis B: A retrospective propensity score matched study for improving clinical practice

Abstract

Background and aims: Early and accurate diagnosis of the coexistence of Wilson’s disease (WD) and chronic hepatitis B (CHB) presents a significant challenge for clinicians. The objective of this study was to retrospectively analyse the characteristics of such patients to improve clinical practice and provide a reference for clinical management.

Methods: From January 2011 to December 2022, 35 patients with concurrent CHB and WD (CHB + WD group) were identified. A total of 127 patients with CHB (CHB group) and 168 patients with WD (WD group) were included in the control group between January 2016 and December 2021. Propensity score matching (PSM) was performed to balance the baseline values between groups. The Kaplan-Meier (K-M) survival analysis and log-rank test were performed to compare the prognoses.

Results: In the cohort of 35 patients with concurrent CHB and WD, 74.3% of patients (26 patients) faced a substantial delay of up to 10 years (range: 0-40 years) in WD diagnosis following their CHB diagnosis. Twenty-three (65.7%) patients had cirrhosis at the time of WD diagnosis, and 26 (74.3%) patients experienced liver failure. The levels of serum copper and uric acid were lower in patients in the CHB + WD group than in those in the CHB group. Patients in the CHB + WD group presented higher alanine transaminase and total bile acid levels compared to those in the WD group. K-M survival analysis indicated that patients with CHB and WD had poorer outcomes than those with CHB alone; however, the outcomes were similar to those of individuals with WD alone. The optimal cut-point of serum ceruloplasmin (CP) in identifying WD in CHB patients was 0.10 g/L before PSM and after PSM.

Conclusions: The present study emphasizes the importance of clinicians being vigilant for concurrent CHB and WD diagnoses, as delays in WD diagnosis may adversely affect patient outcomes. CHB patients with serum CP below 0.10 g/L are highly recommended to screen for WD.

Keywords

Chronic hepatitis B (CHB) / Wilson’s disease (WD) / Coexistence / Ceruloplasmin (CP) / Clinical practice / Prognosis

Authors’ contributions

Jiahui Pang and Shuru Chen contributed equally to this work. Jiahui Pang: Methodology, Data curation, Formal analysis, Writing-original draft. Shuru Chen: Formal analysis, Data curation, Writing-original draft. Yingfu Zeng: Data curation, Methodology. Yutian Chong: Funding acquisition, Supervision. Weiqiang Gan: Investi-gation, Conceptualization, Writing-original draft, Writing-review & editing. Xinhua Li: Project administration, Conceptualization, Funding acquisition, Writing-review & editing.

Data availability statement

The data presented in this study are available upon request from the corresponding authors.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This study was supported by the Guangdong Key Field R&D plan (No. 2019B020228001), 5010 Project of Sun Yat-sen University (No.2018024), and Guangdong Rural Science and Technology Pro-gram (No.KTPYJ2022012).

References

[1] Chen S, Li J, Wang D, Fung H, Wong LY, Zhao L. The hepatitis B epidemic in China should receive more attention. Lancet. 2018;391:1572. https://doi.org/10.1016/S0140-6736(18)30499-9.

[2] Cżonkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4:21. https://doi.org/10.1038/s41572-018-0018-3.

[3] Vieira Barbosa J, Fraga M, Saldarriaga J, et al. Hepatic manifestations of Wilson’s disease: 12-year experience in a Swiss tertiary referral centre. Swiss Med Wkly. 2018;148:w14699. https://doi.org/10.4414/smw.2018.14699.

[4] Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47:2089-2111. https://doi.org/10.1002/hep.22261.

[5] Mazi TA, Shibata NM, Medici V. Lipid and energy metabolism in Wilson disease. Liver Res. 2020;4:5-14. https://doi.org/10.1016/j.livres.2020.02.002.

[6] Jeng WJ, Papatheodoridis GV, Lok ASF. Hepatitis B. Lancet. 2023;401: 1039-1052. https://doi.org/10.1016/S0140-6736(22)01468-4.

[7] Scheinberg IH, Sternlieb I. Wilson’s Disease. Philadelphia: W.B. Saunders; 1984. https://doi.org/10.1002/ana.410160531.

[8] Yamaguchi H, Nagase H, Tokumoto S, et al. Prevalence of Wilson disease based on genome databases in Japan. Pediatr Int. 2021;63:918-922. https://doi.org/10.1111/ped.14565.

[9] Coffey AJ, Durkie M, Hague S, et al. A genetic study of Wilson’s disease in the United Kingdom. Brain. 2013;136:1476-1487. https://doi.org/10.1093/brain/awt035.

[10] Gao J, Brackley S, Mann JP. The global prevalence of Wilson disease from next-generation sequencing data. Genet Med. 2019;21:1155-1163. https://doi.org/10.1038/s41436-018-0309-9.

[11] Wallace DF, Dooley JS. ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Hum Genet. 2020;139:1065-1075. https://doi.org/10.1007/s00439-020-02161-3.

[12] Sandahl TD, Laursen TL, Munk DE, Vilstrup H, Weiss KH, Ott P. The prevalence of Wilson’s disease: an update. Hepatology. 2020;71:722-732. https://doi.org/10.1002/hep.30911.

[13] Xie JJ, Wu ZY. Wilson’s disease in China. Neurosci Bull. 2017;33:323-330. https://doi.org/10.1007/s12264-017-0107-4.

[14] Steindl P, Ferenci P, Dienes HP, et al. Wilson’s disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology. 1997;113: 212-218. https://doi.org/10.1016/s0016-5085(97)70097-0.

[15] Cauza E, Maier-Dobersberger T, Polli C, Kaserer K, Kramer L, Ferenci P. Screening for Wilson’s disease in patients with liver diseases by serum ceru-loplasmin. J Hepatol. 1997;27:358-362. https://doi.org/10.1016/s0168-8278(97)80182-1.

[16] Gong A, Leitold S, Uhanova J, Minuk GY. Non-Wilson’s disease-associated hypoceruloplasminemia. J Clin Exp Hepatol. 2020;10:284e289. https://doi.org/10.1016/j.jceh.2019.11.008.

[17] Xu R, Jiang YF, Zhang YH, Yang X. The optimal threshold of serum cerulo-plasmin in the diagnosis of Wilson’s disease: a large hospital-based study. PLoS One. 2018;13:e0190887. https://doi.org/10.1371/journal.pone.0190887.

[18] LaRusso NF, Summerskill WH, McCall JT. Abnormalities of chemical tests for copper metabolism in chronic active liver disease: differentiation from Wil-son’s disease. Gastroenterology. 1976;70:653-655.

[19] Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23:139-142. https://doi.org/10.1034/j.1600-0676.2003.00824.x.

[20] Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67:1560-1599. https://doi.org/10.1002/hep.29800.

[21] European Association for Study of L. EASL clinical practice guidelines: Wilson’s disease. J Hepatol. 2012;56:671-685. https://doi.org/10.1016/j.jhep.2011.11.007.

[22] Inherited Metabolic Liver Disease Collaboration Group, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the diagnosis and treatment of hepatolenticular degeneration (2022 edition) (in Chinese). Zhonghua Gan Zang Bing Za Zhi. 2022;30:9e20. https://doi.org/10.3760/cma.j.cn501113-20211217-00603.

[23] Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383: 1749-1761. https://doi.org/10.1016/s0140-6736(14)60121-5.

[24] Sarin SK, Choudhury A, Sharma MK, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatol Int. 2019;13:353e390. https://doi.org/10.1007/s12072-019-09946-3.

[25] Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464-470. https://doi.org/10.1053/jhep.2001.22172.

[26] Wong RJ, Gish R, Schilsky M, Frenette C. A clinical assessment of Wilson disease in patients with concurrent liver disease. J Clin Gastroenterol. 2011;45: 267-273. https://doi.org/10.1097/MCG.0b013e3181dffaa5.

[27] Machado A, Chien HF, Deguti MM, et al. Neurological manifestations in Wil-son’s disease:report of 119 cases. Mov Disord. 2006;21:2192-2196. https://doi.org/10.1002/mds.21170.

[28] Dzie_zyc-Jaworska K, Litwin T, Cżonkowska A. Clinical manifestations of Wilson disease in organs other than the liver and brain. Ann Transl Med. 2019;7:S62. https://doi.org/10.21037/atm.2019.03.30.

[29] Berman DH, Leventhal RI, Gavaler JS, Cadoff EM,Van Thiel DH. Clinical differentia-tion of fulminant Wilsonian hepatitis from other causes of hepatic failure. Gastro-enterology. 1991;100:1129-1134. https://doi.org/10.1016/0016-5085(91)90294-u.

[30] Ferenci P, Stremmel W, Cżonkowska A, et al. Age and sex but not ATP7B ge-notype effectively influence the clinical phenotype of Wilson disease. Hep-atology. 2019;69:1464-1476. https://doi.org/10.1002/hep.30280.

[31] Beinhardt S, Leiss W, Stättermayer AF, et al. Long-term outcomes of patients with Wilson disease in a large Austrian cohort. Clin Gastroenterol Hepatol. 2014;12:683-689. https://doi.org/10.1016/j.cgh.2013.09.025.

[32] Pang J, Chen S, Gan W, et al. A novel nomogram based on routine clinical in-dicators for screening for Wilson’s disease. Liver Res. 2023;7:82e89. https://doi.org/10.1016/j.livres.2023.02.003.

[33] Wang H, Zhou Z, Hu J, et al. Renal impairment in different phenotypes of Wilson disease. Neurol Sci. 2015;36:2111-2115. https://doi.org/10.1007/s10072-015-2322-y.

[34] Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology (Bethesda). 2005;20:125-133. https://doi.org/10.1152/physiol.00039.2004.

[35] Wilson DM, Goldstein NP. Renal urate excretion in patients with Wilson’s disease. Kidney Int. 1973;4:331-336. https://doi.org/10.1038/ki.1973.125.

[36] Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012; 3. https://doi.org/10.7554/eLife.00049,10.7554/eLife.

[37] Eller C, Heydmann L, Colpitts CC, Verrier ER, Schuster C, Baumert TF. The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B, C and D viruses. Cell Mol Life Sci. 2018;75:3895-3905. https://doi.org/10.1007/s00018-018-2892-y.

[38] Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000;64: 51-68. https://doi.org/10.1128/mmbr.64.1.51-68.2000.

[39] Paternostro R, Pfeiffenberger J, Ferenci P, et al. Non-invasive diagnosis of cirrhosis and long-term disease monitoring by transient elastography in pa-tients with Wilson disease. Liver Int. 2020;40:894-904. https://doi.org/10.1111/liv.14368.

[40] Lai JC, Liang LY, Wong GL. Noninvasive tests for liver fibrosis in 2024: are there different scales for different diseases? Gastroenterol Rep (Oxf). 2024;12: goae024. https://doi.org/10.1093/gastro/goae024.