A little while back I wrote a blog reviewing some of the evidence regarding zinc (Read it here) and one of the suggestions I made in the conclusion was for a systematic review on the topic. Well, somebody must have heard me as this has been carried out and published so I thought I would summarise its findings.
As I mentioned in the last blog, there is no doubt that zinc is an important element in human physiology with around 2 – 4 grams being stored in the body, the vast majority of it being stored in the bones and muscle, with just 5% in the skin. Published work has demonstrated that zinc is required for lipid and protein metabolism along with nucleic acid transcription. It is required for normal function within the innate and adaptive immune systems. Zinc deficiency has been shown to significantly affect T & B cells, Langerhans cell, neutrophil and macrophage function (1). It is well known the human papilloma virus has a suppressing effect on many of the normal immune operations in the skin (2) so the question is - can zinc be used therapeutically as a treatment for warts?
A team of Chinese researchers have recently undertaken and published a systematic review of the clinical trials examining the benefit of zinc in treating viral warts (3). Published in the Journal of Dermatological Treatment, they undertook a systematic review of published papers which examined the use of zinc (either orally, injected intra-lesionally or topically) as a treatment in immunocompetent patients diagnosed with warts. They followed the PRISMA guidelines (4) – a checklist which aims to ensure that papers are reviewed objectively covering all the main aspects of the research process to identify the quality of the evidence.
From 265 studies they initially reviewed, it was whittled down to 16 clinical trials:
6 trials examining oral zinc therapy alone in treating warts.
2 trials examining the effect on oral zinc supplementation alongside other wart therapies.
5 trials reviewing intra-lesional zinc sulphate injections.
3 studies examining topical zinc treatment for warts.
Oral Zinc for warts
The six studies reviewed were predominantly from the Middle East showing remarkable response rates to zinc with clearance rates of 76-87%. However, as the authors point out there were considerable flaws within the studies which could adversely affect the results such as dropout and high withdrawal rates. Only one study from Mexico showed no significant difference between oral zinc and placebo, with the study appearing to have a stronger protocol design than the others in this group.
When using oral zinc to supplement wart treatments, the two trials from Iran showed little or no benefit when used alongside cryotherapy. In one study, there was a high rate of side effects – nausea and stomach pain, leading to a high dropout rate.
Intralesional zinc injections for warts
The authors report 5 studies which examined the use of zinc intralesionally either as the sole agent or comparing to saline or vitamin D3. The zinc injection method was tested against a saline injection in 100 patients with 623 plantar warts. The clearance rate again was heavily in favour of zinc sulphate 98.2% versus 8.3% clearance at 10 weeks but once again the randomisation process and blinding in the study were questionable. In addition, side effects of zinc injection included erythema, scarring, hyperpigmentation and significant pain. These side effects were also observed in other trials as well where zinc was injected.
A three-armed study compared saline with zinc or vitamin D injections in 105 patients. Subjects were administered an injection every two weeks for two months (8 injections in total). The results showed that vitamin D3 cleared 62.9% compared to 71% of the zinc group and just 40% cleared completely in the saline group (40%), but pain was severe pain on injection was reported by almost half of the zinc injected patients.
Topical Zinc
A review of the three studies using topical (20%) zinc cream showed clearance rates close to salicylic acid and lactic acid when compared head-to-head. Other studies showed high clearance using a 10% zinc solution, but all of these studies focused on plane and flat warts but not plantar lesions so its difficult to suggest them for plantar lesions.
What does this all mean?
For the practising podiatrist looking for a new modality, the jury is still out on the effects of zinc. The methodological quality of many of these studies was probably too weak to generate any meaningful results with high dropout rates in some studies and lack of blinding or randomisation in others. In addition, few studies focussed on plantar lesions. Although the injectable zinc studies suggested high clearance with plantar lesions, high levels of pain were experienced by many patients undergoing treatment. In addition, the majority of these studies were conducted in the Middle East where zinc deficiency is much more common amongst the general population and so could have been a confounding factor affecting the resolution rate. Ultimately, more research is required to plug this knowledge gap with subjects who are not zinc deficient using a robust randomised controlled trial methodology with proper blinding to ensure the results are meaningful.
References
1. Gao H, Dai W, Zhao L, Min J, Wang F. The Role of Zinc and Zinc Homeostasis in Macrophage Function. Journal of Immunology Research. 2018;2018:11.
2. McBride AA. Human papillomaviruses: diversity, infection and host interactions. Nature Reviews Microbiology. 2022;20(2):95-108.
3. Song D, Pan L, Zhang M, Wang S. Clinical use of zinc in viral warts: a systematic review of the clinical trials. Journal of Dermatological Treatment. 2022;33(4):1878-87.
4. Moher D, Liberati A, Tetzlaff J, Altman D. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. : The Prisma Group; 2009 [Available from: http://www.prisma-statement.org/2.1.2%20-%20PRISMA%202009%20Checklist.pdf.