Introduction
Plantar warts continue to be a challenge for the clinician with an array of currently available treatments. I was recently discussing this with a colleague who mentioned that a patient of his had been advised to take oral zinc as an adjunct whilst undergoing wart treatment. A quick look through PUBMED revealed a number of publications which had investigated the use of oral zinc for this purpose. In this blog, I will be reviewing the papers to see if it would be of benefit to our patients to be taking this supplement.
Zinc in its natural form
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What the papers say
I undertook a search of the last twenty years published literature on the subject. The earliest paper of that period was published in 2002, in the respected British Journal of Dermatology (BJD). In a study from Baghdad in Iraq, Al-Gurairi and colleagues (1) studied 80 patients with plane, common and plantar warts. Half were given oral zinc, the other half a glucose pill. The zinc was dosed at 15mg/kg per day (up to a maximum of 600mg daily) for up to six months. The study showed a clear effectiveness over the placebo curing 86% in the active treatment compared with a 0% response rate in the placebo group. At first, it may sound amazing but dig deeper and you realise that there was a high dropout rate of nearly fifty percent which was not adjusted for correctly within the statistical analysis. Moreover, the average age for this cohort was young at just 20 years of age which arguably will have skewed the results. The pivotal aspect of this seemingly astonishing high response rate is to look at the zinc levels in these patients before and after treatment. As the authors report, all of the subjects were found to be zinc deficient at the start of the study, with normal levels at the conclusion.
This work was eventually followed up in the Journal of Clinical and Experimental Dermatology (CED) in 2009 by Lopez-Garcia (2). In their work, they deliberately attempted to design a study which would solve the flaws in the Iraqi study, seven years earlier. Fifty patients, with normal zinc levels, were randomised and prescribed 10mg/kg of daily zinc (up to 600mgs) or a placebo starch pill. This time the results were very different. The complete responses were similar in both the zinc and placebo groups (7 pts v 6 pts respectively) as were the non-responses (18 pts v 19 pts respectively).
In the same year, Sadigha (3) undertook a two month study of 26 subjects split into two groups - one taking a 10mg/kg dosage (up to a maximum of 600mg/day) of zinc, the other a placebo pill. After two months, ten subjects in the zinc group had resolved their warts whilst only 1 within the control group had. Of interest in this study was the average age of subjects – just 15 years of age. Another study in 2009 showed similar pattern (4). A cohort of 32 patients were treated with zinc sulphate (as in the previous study) and compared after two months therapy to a placebo group of 23 patients. Blood zinc levels were measured before and after the study in all patients. The complete response rate was 78% (25 patients) in the treated group versus just 13% (3 patients out of 23) in the placebo arm. In both groups blood levels of zinc were around 55µg/100ml at the commencement of the study. Afterwards, the control groups zinc level remained the same whilst in the treatment arm it was shown that of those that responded (25 patients or 78%) their zinc levels rose to 199 µg/100ml compared with just 77 µg/100ml in the non-responsive patients taking zinc (7 patients or 22% of the treatment arm).
The most recent published study was undertaken in 2011 by Mun et al., and published in the Journal of Dermatology (5). Again, the authors acknowledge previous work being confounded by potential zinc deficiency and high drop out rates. In this work they recruited 31 patients but didn’t randomise, instead they went for an open label design on a cohort of patients with an average of 26 (range 6-54 years of age) and no control group. All patients had tried other remedies without success and had at least five warts. Three patients had plantar lesions. All had blood zinc levels assessed and were given zinc sulphate at 10mg/kg up to 600mg daily for two months and assessed at the end of the study. They were either categorised as complete responder (all warts resolved) or non-responder.
At the end of the study, 26 subjects had completed the study (84%). Zinc profiles suggested 18 of 31 patients (58%) showed a low serum zinc level (<70 µg⁄100 mL). The mean serum zinc level was 69µg⁄100 mL in this group. The overall response rate was complete resolution in 50% (13 patients). However, there was no correlation between initial zinc levels and outcome in the patients with lower zinc levels.
Where’s the science in this?
Zinc as an element has been studied and it is known that an average human body contains around 2-4 grams of zinc. Around 90% is in muscle and bone with just 5% being located in the skin. Zinc is found in the diet being particularly abundant in meat and eggs. It is also present in legumes and cereals, but this is not so readily absorbed by the body. The element is ingested and absorbed through the intestine and secreted by the kidney and to a lesser extent in sweat. Around one-third of the world is reported to be deficient in zinc – areas such as south-east Asia, Sub-Saharan Africa and the middle east (Egypt, Turkey, Iran and Iraq) (6). The recommended daily intake is around 10mg in males and 7mg in females.
Studies have shown the importance if the element, zinc, for lipid and protein metabolism and 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 (7). In the skin, in addition to Langerhans cell function, it is an important regulator of skin barrier function as not only is it essential for cell apposition but it also plays a role in the metabolism of filaggrin – a key molecule in skin hydration, defence and repair (8).
Effectively, the literature shows that zinc deficiency can adversely affect immune function and relating this to viral infections like HPV, lack of the element can profoundly affect the function of cytotoxic T lymphocytes which are also vital for wart clearance (9).
What are the risks?
It is important to highlight what was also reported in the studies regarding the side effects of taking zinc at these dosages (10mg/kg daily up to 600mg/daily). Studies frequently reported gastro-intestinal effects such as nausea, vomiting and abdominal pain in subjects.
What is the bottom line?
The bottom line is that there is little doubt that zinc levels can affect the immune system and as two of the earlier studies demonstrated, giving a zinc supplement to a zinc-deficient patient can certainly improve the clearance of warts. This seems to be more evident in the younger patients. The question is though, how many of our patients are really zinc deficient? There are blood tests to measure this but there is still some questions around what is a normal, healthy level and indeed some observers questioning the validity of the test as zinc levels naturally may fluctuate (7). A systematic review on this topic suggested zinc maybe of value, particularly in those with suspected low zinc levels (10). Is zinc as effective for plantar warts as flat and plain warts found elsewhere on the skin? The data from all these studies isn’t much help as only a small number of plantar warts were included in the data.
In the UK, I also came across a leaflet from the Oxford Department of Dermatology (Click to download here) for patients giving information on zinc supplements (11). In the leaflet its suggested that it’s used in patients who have warts that have failed to respond to standard treatments. The dosage it recommends is much lower than in any of the studies at between 15mg – 45mg daily (for adults and children above five stones [around 30kg] in weight) and therefore this should reduce the likelihood of any side effects observed frequently in the published studies.
So, for the podiatrist, is it worth suggesting this to patients? Patients generally will always seek simple and straightforward ways to treat their warts. Taking a supplement is straightforward, convenient and can be easily bought at a health food shop. There is evidence to suggest it maybe helpful and by taking a lower dose, as suggested in the Oxford leaflet, perhaps there is little to lose by trying. As I have found from time to time this can be effective for a few but isn’t going to replace any other of our current treatments quite yet.
Note: Before taking any supplements, patients should always be advised to always read the label and not to exceed the dose stated.
References
1. Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in the treatment of recalcitrant viral warts: randomized placebo-controlled clinical trial. Br J Dermatol. 2002;146(3):423-31.
2. López-García DR, Gómez-Flores M, Arce-Mendoza AY, Fuente-García Adl, Ocampo-Candiani J. Oral zinc sulfate for unresponsive cutaneous viral warts: too good to be true? A double-blind, randomized, placebo-controlled trial. Clin Exp Dermatol. 2009;34(8):e984-e5.
3. Sadighha A. Oral zinc sulphate in recalcitrant multiple viral warts: a pilot study. J Eur Acad Dermatol Venereol. 2009;23(6):715-6.
4. Yaghoobi R, Sadighha A, Baktash D. Evaluation of oral zinc sulfate effect on recalcitrant multiple viral warts: A randomized placebo-controlled clinical trial. J Am Acad Dermatol. 2009;60(4):706-8.
5. Mun J-H, Kim S-H, Jung D-S, Ko H-C, Kim B-S, Kwon K-S, et al. Oral zinc sulfate treatment for viral warts: An open-label study. The Journal of Dermatology. 2011;38(6):541-5.
6. Gupta M, Mahajan VK, Mehta KS, Chauhan PS. Zinc Therapy in Dermatology: A Review. Dermatol Res Pract. 2014;2014:11.
7. 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.
8. Ogawa Y, Kinoshita M, Shimada S, Kawamura T. Zinc in Keratinocytes and Langerhans Cells: Relevance to the Epidermal Homeostasis. Journal of Immunology Research. 2018;2018:11.
9. Overbeck S, Rink L, Haase H. Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases. Arch Immunol Ther Exp (Warsz). 2008;56(1):15-30.
10. Simonart T, de Maertelaer V. Systemic treatments for cutaneous warts: a systematic review. The Journal of dermatological treatment. 2012;23(1):72-7.
11. Oxford Hospitals. Oral zinc for warts - information for patients.