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Adverse Events with d-penicillamine Therapy in Hepatic Wilson’s Disease: A Single-Center Retrospective Audit

Clinical Drug Investigation volume 42, pages 177–184 (2022)Cite this article

A Correction to this article was published on 23 February 2022

This article has been updated

Abstract

Background and Objective

There are limited data on the adverse events of d-penicillamine in Wilson's disease (WD) that can result in dose modification or treatment discontinuation. The objective of this study was to observe the adverse events related to d-penicillamine in patients with hepatic WD.

Methods

A retrospective audit of prospectively registered hepatic WD patients at a tertiary care center between December 2006 and January 2020 was carried out. Demographic variables, laboratory parameters, and details of treatment were noted. Adverse events (AEs) related to d-penicillamine treatment, the timing and management of these AEs were analysed.

Results

The study included 112 patients with hepatic WD on d-penicillamine. d-penicillamine intolerance was seen in 28/112 (25%) over 179 person-years. Of the 28 AEs, severe AEs leading to permanent d-penicillamine discontinuation occurred in 16 (57%) [never reintroduced 12 (43%), discontinued after intolerant to rechallenge, 4 (14%)], temporary cessation followed by reintroduction to initial dose 13 (46%) and continuation with reduced dose in 3 (11%) patients. Overall, most common AEs were hematological [16, 57% (pancytopenia n = 8, bicytopenia n = 5 and hemolytic anemia n = 3)] while renal adverse events (n = 7, 25%) constituted the most common indication for permanent discontinuation. Cytopenias developed beyond 12 months of d-penicillamine initiation whereas hemolytic anemia developed within first 3 months. Following d-penicillamine discontinuation in 25 patients, it was reintroduced to initial dose in 13/25 (52%), switched to trientine due to neurological worsening in 2/25 (8%) and switched to zinc in 10/25 (40%). In patients with reintroduction, gradual dose escalation was tolerated in 9/13 (69%) with a recurrence of AEs leading to permanent discontinuation in 4/13 (31%).

Conclusion

D-penicillamine treatment is associated with significant AEs mainly related to blood, kidney, and skin. Temporary cessation of drug with reintroduction at a lower dose is an effective and safe option.

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References

  1. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky M. Wilson’s disease. Lancet. 2007;369:397–408.

    CAS  Article  Google Scholar 

  2. Gitlin JD. Wilson disease. Gastroenterology. 2003;125:1868–77.

    Article  Google Scholar 

  3. Medici V, Trevisan CP, D’Incà R, Barollo M, Zancan L, Fagiuoli S, Martines D, Irato P, Sturniolo GC. Diagnosis and management of Wilson’s disease: results of a single center experience. J Clin Gastroenterol. 2006;40(10):936–41.

    Article  Google Scholar 

  4. Walshe JM, Yealland M. Wilson’s disease: the problem of delayed diagnosis. J Neurol Neurosurg Psychiatry. 1992;55(8):692–6.

    CAS  Article  Google Scholar 

  5. Nagral A, Sarma MS, Matthai J, Kukkle PL, Devarbhavi H, Sinha S, Alam S, Bavdekar A, Dhiman RK, Eapen CE, Goyal V, Mohan N, Kandadai RM, Sathiyasekaran M, Poddar U, Sibal A, Sankaranarayanan S, Srivastava A, Thapa BR, Wadia PM, Yachha SK, Dhawan A. Wilson’s Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. J Clin Exp Hepatol. 2019;9(1):74–98.

    Article  Google Scholar 

  6. Bayes F, Karim A, Helaly L, Bayes F, Rukunuzzaman M, Ahmed S, Alam S. Spectrum of hepatic presentation of Wilson’s disease in children attending a tertiary care centre of Dhaka City. Bang J Child Health. 2014;38(2):86–93.

    Article  Google Scholar 

  7. Wu F, Wang J, Pu C, Qiao L, Jiang C. Wilson’s disease: a comprehensive review of the molecular mechanisms. Int J Mol Sci. 2015;16(3):6419–31.

    CAS  Article  Google Scholar 

  8. Hanif M, Raza J, Qureshi H, Issani Z. Etiology of chronic liver disease in children. J Pak Med Assoc. 2004;54(3):119–22.

    CAS  PubMed  Google Scholar 

  9. Czlonkowska A, Gajda J, Rodo M. Effects of long-term treatment in Wilson’s disease with d-penicillamine and zinc sulphate. J Neurol. 1996;243(3):269–73.

    CAS  Article  Google Scholar 

  10. Pandit A, Bavdekar A, Bhave S. Wilson’s disease. Indian J Pediatr. 2002;69:785–91.

    Article  Google Scholar 

  11. Kalra V, Khurana D, Mittal R. Wilson’s disease–early onset and lessons from a pediatric cohort in India. Indian Pediatr. 2000;37(6):595–601.

    CAS  PubMed  Google Scholar 

  12. Brewer GJ. Wilson’s disease: A clinician’s guide to recognition, diagnosis, and management. Boston: Kluwer Academic Publishers; 2001.

    Book  Google Scholar 

  13. Lin L, Wang D, Ding N, et al. Hepatic manifestations in Wilson disease: report of 110 cases. Hepatogastroenterol. 2015;62:657–60.

    Google Scholar 

  14. Weiss KH, Thurik F, Gotthardt DN, et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013;11:1028–35.

    CAS  Article  Google Scholar 

  15. Wiggelinkhuizen M, Tilanus ME, Bollen CW, et al. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther. 2009;29:947–58.

    CAS  Article  Google Scholar 

  16. Członkowska A, Litwin T, Karliński M, Dziezyc K, Chabik G, Czerska M. D-penicillamine versus zinc sulfate as first-line therapy for Wilson’s disease. Eur J Neurol. 2014;21(4):599–606.

    Article  Google Scholar 

  17. Chang H, Xu A, Chen Z, et al. Long-term effects of a combination of D-penicillamine and zinc salts in the treatment of Wilson’s disease in children. Exp Ther Med. 2013;5:1129–32.

    CAS  Article  Google Scholar 

  18. Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut. 2007;56(1):115–20.

    CAS  Article  Google Scholar 

  19. Kay AG. Myelotoxicity of D-penicillamine. Ann Rheum Dis. 1979;38(3):232–6.

    CAS  Article  Google Scholar 

  20. Jaffe IA. Adverse events profile of sulfhydryl compounds in man. Am J Med. 1986;80(3):471–6.

    CAS  Article  Google Scholar 

  21. Gromadzka G, Wierzbicka D, Litwin T, Przybyłkowski A. Iron metabolism is disturbed, and anti-copper treatment improves but does not normalize iron metabolism in Wilson’s disease. Biometals. 2021;34(2):407–14.

    CAS  Article  Google Scholar 

  22. DeSilva RN, Eastmond CJ. Management of proteinuria secondary to penicillamine therapy in rheumatoid arthritis. Clin Rheumatol. 1992;11:216–9.

    CAS  Article  Google Scholar 

  23. Kay A. European league against rheumatism study of adverse reactions to D-penicillamine. Br J Rheumatol. 1986;25:193–8.

    CAS  Article  Google Scholar 

  24. Habib GS, Saliba W, Nashashibi M, Armali Z. Penicillamine and nephrotic syndrome. Eur J Intern Med. 2006;17(5):343–8.

    CAS  Article  Google Scholar 

  25. Brewer GJ, Terry CA, Aisen AM, et al. Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch Neurol. 1987;44:490–3.

    CAS  Article  Google Scholar 

  26. Kalita J, Kumar V, Chandra S, Kumar B, Misra UK. Worsening of Wilson Disease following penicillamine therapy. Eur Neurol. 2014;71:126–31.

    CAS  Article  Google Scholar 

  27. Ranucci G, Di Dato F, Spagnuolo MI, et al. Zinc monotherapy is effective in Wilson’s disease patients with mild liver disease diagnosed in childhood: a retrospective study. Orphanet J Rare Dis. 2014;9:41–51.

    Article  Google Scholar 

  28. Walshe JM, Munro NA. Zinc-induced deterioration in Wilson’s disease aborted by treatment with penicillamine, dimercaprol, and a novel zero copper diet. Arch Neurol. 1995;52:10–1.

    CAS  Article  Google Scholar 

  29. Linn FH, Houwen RH, van Hattum J, van der Kleij S, van Erpecum KJ. Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients. Hepatology. 2009;50(5):1442–52.

    CAS  Article  Google Scholar 

  30. Hölscher S, Leinweber B, Hefter H, Reuner U, Günther P, Weiss KH, Oertel WH, Möller JC. Evaluation of the symptomatic treatment of residual neurological symptoms in Wilson disease. Eur Neurol. 2010;64:83–7.

    Article  Google Scholar 

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Acknowledgments

The authors convey their greatest gratitude to Dr. Devesh Kumar for performing statistical analysis.

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Authors and Affiliations

  1. Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India

    Sanjay Kumar, Biswa Ranjan Patra, Mohammed Irtaza, Praveen Kumar Rao, Suprabhat Giri, Harish Darak, Amrit Gopan, Aditya Kale & Akash Shukla

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  1. Sanjay Kumar
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  2. Biswa Ranjan Patra
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Correspondence to Akash Shukla.

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No funding was received to conduct this study.

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The authors declare that they have no conflict of interest.

Ethics approval

The study was approved by the Institutional Ethics committee, Seth GS Medical college & KEM Hospital (EC/OA 63/2020).

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Informed consent was obtained from all individual participants included in the study.

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Kumar, S., Patra, B.R., Irtaza, M. et al. Adverse Events with d-penicillamine Therapy in Hepatic Wilson’s Disease: A Single-Center Retrospective Audit. Clin Drug Investig 42, 177–184 (2022). https://doi.org/10.1007/s40261-022-01117-x

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  • DOI: https://doi.org/10.1007/s40261-022-01117-x