Combination Treatment With Chelators and Zinc for Wilson Disease: A Double-edged Sword

Appropriate pharmacological treatment of Wilson disease (WD) can reverse chronic liver or neurological disease and prevent symptomatic disease when treatment is instituted early. The available options include chelators and Zinc salts. There are variations in the use of these drugs between clinicians. One of the variable practices involves the use of chelators in combination with Zinc, more often cited in the context of advanced liver disease.¹ Panda et al. retrospectively analyse their outcomes using a combination of chelators (penicillamine/trientine) and zinc acetate in children with WD.² They assess outcomes concerning the normalisation of serum transaminases to <1.5 times normal, normal serum albumin and international normalized ratio (INR), 24-h urinary copper excretion (UCE) values of <500 mcg/day and low serum non-caeruloplasmin-bound copper (NCC). They conclude that combination therapy (CT) is superior to monotherapy with chelators by comparing the proportion of patients in their cohort with 24-h UCE values of <500 mcg/day at 2-year follow-up, with that reported in other small series where monotherapy is used specifically in advanced decompensated liver disease. The study reaffirms valuable data on the time to normalisation of biochemical parameters on chelator therapy, including copper studies on follow-up in children. The authors also advocate the wider use of CT over chelator monotherapy. This recommendation merits discussion.

The use of a combination of chelator with a zinc salt has been described in literature, in the context of decompensated advanced liver disease. The basis of use has been case reports and series, including one from our centre.^{1,3, 4, 5} The use of CT is prompted by the possibility that the use of two drugs with different mechanisms of action is possibly better than the use of a single chelator alone. It remains to be proven that the addition of zinc provides a clinically significant benefit when the chelators are capable of inducing a strong cupriuresis. Our team has moved away from using CT due to challenges in combined administration that could impact adequate chelation, adherence to medication, quality of life, impact on families, and the added cost in the face of questionable benefits. The absorption of chelators and zinc is affected by food, and their administration has to be spaced out from food. In addition, they must be administered at different times to avoid chelator binding to zinc in the intestine, eventually decreasing the efficacy of both drugs. Children, especially young and sick children, tend to eat in small multiple feeds rather than in regulated schedules. Sick children with decompensated liver disease and altered sleep patterns may struggle with the detailed scheduling of a CT. After accounting for the different timepoints for chelators, zinc, food, and sleep times, CT has been viewed as impractical in our clinical practice. This is more so in the sicker children with liver disease where the benefits of CT have been advocated. The cost of the better-tolerated zinc acetate preparation used by Panda et al. is substantial in the Western context to drive cost-conscious prescribing.⁶ The data from Panda et al. seem to suggest that they use CT in all their patients rather than exclusively in children with decompensated liver disease.² They report a poor compliance of 25.6% with their regimen. Although the contribution of drug burden and cost-related non-adherence is not known, there is an opportunity to improve adherence by switching to chelator monotherapy. Any adherence to the complexity of combination regimen in the Western context may be challenging to sustain in the long term and would be at the expense of parental stress. Future comparisons of these regimens should also assess the quality of life and impact on family.⁷

Panda et al. demonstrate an improvement in serum total bilirubin, serum transaminases, INR and serum albumin in the first year of therapy with further improvement of INR and serum albumin in the second year. They demonstrate significant progressive improvement in cupriuresis by 24-h UCE measurement in the first two years of treatment. This is a valuable affirmation of similar data published in adults and children,^{8, 9, 10, 11, 12} yet the evidence that the authors provide in favour of their primary hypothesis of the superiority of CT over chelator monotherapy is not convincing. They base their argument on the fact that the 2-year 24-h UCE of 307.5 (interquartile range IQR: 169.0–447.7) mcg/day in their study is lower compared to the median 24-h UCE of 507.5 (range: 277.2–2290.2) in the study by Pfeiffenberger et al.⁹ and median 24-h UCE of 587 (IQR: 217.8–831.6) in the study by Chanpong et al.^{9, 10} in the study by Pfeiffenberger et al.⁹and median 24-h UCE of 587 (IQR: 217.8–831.6) inc series. There is neither a raw data analysis nor the cases matched for their baseline severity of illness. The authors do not have a control group within their study on chelator monotherapy. There are significant interindividual variations in 24-h UCE for it to be reliably used as a comparison tool, especially across studies.⁹ If we were to use the same tools as the authors for comparison, other studies with children on chelator monotherapy show low levels of 24-h UCE on par with that shown by Panda et al.^2,11,12 These are not cited by the authors. The authors also cite the fact that 28.5% had their 2-year follow-up UCE values lower than 200 mcg/day and consider this as a demonstration of over-chelation that proves the superiority of CT. A UCE value of <200 mcg/day could also be due to non-compliance, and the authors have not provided data on the proportion of patients with UCE values <200 mcg/day who had non-compliance or raised transaminases. Normal or low NCC in the presence of UCE values <200 mcg/day does not sufficiently indicate normal or low total-body copper, given the limitations in the calculation of NCC arising from erroneous serum caeruloplasmin measurements. Hence, the superiority of CT over chelator monotherapy remains unproven.

The authors have appropriately focussed on follow-up copper studies while monitoring children being treated for WD. Twenty-four-hour UCE involves cumbersome urine collection which is often incomplete in very young children, those with neurological manifestations, and adolescents where the collection is often incomplete. This poses challenges in monitoring. NCC estimation has been advocated as a modality to differentiate inadequate chelation vs over-chelation in the face of 24-h UCE values being <200 mcg/day while on chelators. The overestimation of serum caeruloplasmin by immunological assays leads to underestimation of calculated NCC, including negative values, as also evident from the author's data.^2,13 Consequent to this underestimation, a normal or low NCC has no clinical relevance, whereas a high value indicative of excessive total-body copper may have clinical relevance for decision-making. Yet, for the same reasons mentioned earlier, the sensitivity for NCC to detect excessive copper load is likely to be low. Exchangeable copper estimation promises to be a valuable tool in monitoring patients in follow-up and assisting in decision-making but is not widely available and is expensive.¹¹

Panda et al. also suggest that the combination of biochemical normalisation of liver function tests and a 24-h UCE value of <500 mcg/day should be validated as a criteria. These parameters are already used in clinical practice to revisit the adequacy of chelation and compliance. Validation of such cut-offs will be useful only if they were to be used as mandatory triggers for change in therapy. It is well-documented in the literature that a proportion of WD may not normalise their serum transaminases in follow-up, despite adequate chelation.¹⁴ Also, adequate clinical and biochemical normality at 2-year follow-up can be achieved with a 24-h UCE value of just over 500 mcg/day without necessitating a change in therapy.

Although Panda et al. suggest switching to zinc monotherapy after 2 years in those who have achieved adequate chelation to avoid the long-term side-effects of chelators, our practice differs.² We continue with chelators without further escalation in doses or sometimes with a decrease in dose where over-chelation is suspected. Even with the same dose, growth and weight gain result in the patient receiving lower weight-based doses with time. This practice has not resulted in any concerning long-term adverse events. The more intense monitoring and the greater attention to diet that is required on zinc monotherapy is often not preferred by patients.

Of the 135 children with a diagnosis of WD, 23 died and 17 underwent transplantation. Although the article does not describe the clinical presentation or cause of death, the mortality of 17% with the availability of transplantation is a stark reminder of the serious manifestations of WD. There is a need for early identification of children who will benefit from timely liver transplantation in children presenting with acute-on-chronic liver failure or a presentation mimicking acute liver failure.

There is a need to rethink the role of CT with chelators and zinc in the treatment of WD. It may not necessarily be the right tool for the job when treating advanced liver disease and certainly not as a blanket option for all cases of WD. Its superiority over chelator monotherapy remains unproven. It may increase the complexity of therapy at the expense of adherence, cost, and parental stress with the potential to result in poorer chelation than what could be achieved with chelator monotherapy.

Credit authorship contribution statement

All authors contributed to the manuscript and approved the final manuscript.

Conflicts of interest

The authors declare no conflicts of interest.

Funding

The authors have no financial relationships relevant to this article to disclose.