We read with interest “A Case to Tear One's Hair Out: Trichotillomania in Wilson's Disease.” 1 Lagrand and colleagues report a case of Wilson's disease (WD) with trichotillomania who received combined therapy with zinc and trientine. This well‐written article serves as anecdotal evidence for an issue about which we have been pulling our own hairs out: the growing popularity of combined therapy in WD despite a lack of evidence or robust clinical experience to back it up.
WD treatment has been a challenge all over the world. The available oral drugs have different mechanisms. 2 Penicillamine and trientine chelate copper from the tissues, elevating free copper levels relying on the kidneys to increase urinary excretion. Zinc salts stimulate the production of the copper‐binding protein, metallothionein in intestinal mucosal cells, and hepatocytes, antagonizing copper absorption and promoting its excretion via the stool. Chelators are still considered the gold standard, but zinc has been recommended as an acceptable surrogate for asymptomatic patients, for the maintenance phase, or for use on limited resource settings where chelators are of limited availability. 2 , 3 , 4
The robust body of literature supporting the use of these drugs in monotherapy contrasts with the recent hype about an alternative approach combining zinc with any of the 2 chelating agents. 3 The charming notion that the mechanisms of action could be complementary glosses over the fact that zinc itself might bind to the chelator. 3 That means an interval of at least 1 hour is needed between administering zinc and chelators, increasing the number of daily doses of medication and potentially decreasing compliance. 4 Furthermore, concomitant administration might decrease the efficacy of each drug alone. Combined therapy also precludes monitorization of treatment efficacy via its most reliable marker, urinary copper, because the expected curve of urinary copper excretion produced by chelators is marred by zinc salts that do not promote urinary excretion. 2
Despite being reported as successfully used in rare cases of liver failure, a recent systematic review outlined that combined therapy has an effectiveness rate lower and an adverse effect rate higher than monotherapy regimens in hepatic patients, echoing more traditional opinions on the matter. 4 , 5 , 6
We strongly advise caution when starting combined therapy for selected cases and suggest future studies should investigate the matter further.
Author Roles
Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
C.A.‐S.: A
E.R.B.: B
L.S.‐M.: A
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board and patient consent was not required for this work.
Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Lagrand TJ, McLaughlin L, Lehn AC. A case to tear one's hair out: Trichotillomania in Wilson's disease. Mov Disord Clin Pract 2022;9:829–831. 10.1002/mdc3.13514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Brewer GJ, Yuzbasiyan‐Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson's disease with zinc: XI. Interaction with other anticopper agents. J Am Coll Nutr 1993;12(1):26–30. 10.1080/07315724.1993.10718278 [DOI] [PubMed] [Google Scholar]
- 3. Schilsky ML. Treatment of Wilson's disease: what are the relative roles of penicillamine, trientine, and zinc supplementation? Curr Gastroenterol Rep 2001;3(1):54–59. 10.1007/s11894-001-0041-4 [DOI] [PubMed] [Google Scholar]
- 4. Aggarwal A, Bhatt M. The pragmatic treatment of Wilson's disease. Mov Disord Clin Pract 2014;1(1):14–23. 10.1002/mdc3.12003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Chen JC, Chuang CH, Wang JD, Wang CW. Combination therapy using chelating agent and zinc for Wilson's disease. J Med Biol Eng 2015;35(6):697–708. 10.1007/s40846-015-0087-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Yonetani L, Walshe JM. Surviving Wilson's disease. Clin Med 2001;1(1):72–74. 10.7861/clinmedicine.1-1-72 [DOI] [PMC free article] [PubMed] [Google Scholar]