Aluminium in dermatology – Inside story of an innocuous metal

Introduction

Aluminium is the third most abundant element in the earth’s crust, the unique properties of this lightweight metal (symbol: Al; atomic number: 13; weight: 26.98; density: 2.7 g/cm³) and its alloys make it a versatile and economical metal with various uses.¹ Despite its ubiquity, aluminium was long considered virtually innocuous to humans but has gained importance in the recent past. This review discusses the role of aluminium in various dermatological conditions and its use in diagnostic and therapeutic modalities.

(I) Therapeutic applications of aluminium

1) Anti-perspirant

Aluminium salts are effective antiperspirants used in the treatment of axillary and palmoplantar hyperhidrosis of all grades of severity. This aluminium-containing agent can be either prescription based or available over the counter (OTC) whose differences are elucidated in Table 1. The mechanism of action of aluminium chloride hexahydrate (ACH) as an anti-perspirant is elucidated in Figure 1.² ACH is the most frequently used agent, starting at a lower concentration (10%) for palmar and axillary hyperhidrosis and at a higher concentration (20%) for plantar hyperhidrosis [Figure 2].³ A prolonged administration of this agent is often needed to prevent recanalisation of injured eccrine duct epithelium, thereby providing a sustained hypohidrotic effect.^4–6 A randomised half-side trial for assessing the efficacy of aluminium chloride for plantar hyperhidrosis found that clinical score decreased by 38.9% at two weeks from baseline with an additional 7.9% reduction at 6 weeks.⁷ According to a systematic review, the efficacy of aluminium chloride in axillary hyperhidrosis showed striking difference in Hyperhidrosis Disease Severity Scale (HDSS) response rates in two trials (33% and 72%).⁸

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Figure 1:

Mechanism of antiperspirant action of aluminium-based compounds.

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Figure 2:

Prescription-based antiperspirant (20% aluminium chlorohydrate).

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Aluminium chloride (AlCl₃) can also be added to iontophoresis to amplify the anhidrotic effect due to better penetration of aluminium salts into sweat glands.⁹ The addition of 2% salicylic acid gel to 15% ACH has better efficacy and tolerability due to the keratolytic, antiperspirant and astringent properties of salicylic acid.¹⁰

Apart from hyperhidrosis, ACH can also be used for bromhidrosis, transient aquagenic keratoderma, trichomycosis axillaris, epidermolysis bullosa simplex, gustatory hyperhidrosis and local hyperhidrosis associated with eccrine naevi.¹¹ The adverse effects of using aluminium-based antiperspirants include pain, pruritus, hyperpigmentation, irritation, fissuring, scaling and pustules. Factors like high chloride content, low pH and anhydrous alcohol vehicles contribute significantly to the irritant effects of aluminium.¹² In mouse models, the use of AlCl₃ as an antiperspirant has resulted in axillary granular parakeratosis. It was proposed to be due to aluminium-induced apoptosis resulting in keratinisation arrest at the granular layer of the epidermis.¹³

2) Topical haemostatic agent

Aluminium chloride (AlCl₃) (20–40%) in isopropyl alcohol, ether or glycerol works as an effective chemical haemostatic agent, especially in minor dermatological procedures including skin biopsy. Low cost, easy utility and storage at room temperature attract its usage as a haemostatic agent.^14,15 The application of AlCl₃ with a cotton-tipped applicator in a twisting motion perpendicular to the skin surface helps establish sufficient haemostasis.¹⁴ The advantages of AlCl₃ over Monsel solution and electrocautery for haemostasis include less pigmentation and less tissue charring, respectively. The mineral zeolite (microporous crystalline aluminosilicate) and clay minerals such as kaolin and smectite (a combination of octahedral aluminate sheets and tetrahedral silicate in a ratio of 1:1 and 2:1, respectively) have also been used as haemostatic agents.^16–19 The mechanisms of action of aluminium chloride, zeolite and clay minerals as topical haemostatic agents are depicted in Table 2.^19,20

Table 2: Mechanisms of action of aluminium based compounds as topical haemostatic agents

3) As an astringent

Aluminium acetate (Burow’s solution) is prepared by combining aluminium sulphate, acetic acid, tartaric acid and calcium carbonate. It is an effective astringent and antiseptic used for exudative lesions like eczemas, pompholyx and tinea pedis, especially if vesiculation or maceration is present and for chronic exudative ear infections.²¹ Aluminium, with a high degree of protein-precipitating properties, alters the ability of proteins to swell and hold water, and draws water out of the cell, leading to the drying up of exudative lesions.^22,23 AlCl₃, due to its astringent action, has proved efficacious even in post-surgical hypergranulation tissue by its ability to contract and retract the tissues.²⁴

4) Bentonite in contact dermatitis and eczema

Bentonite (colloidal hydrated aluminium silicate) is an insoluble, odourless, white, yellow, pink or grey powder forming a homogenous, viscous gel or colloidal suspension mixed with 10 parts of water. It is incompatible with mineral acids and salts, thus displaying thixotropy.²⁵ It is reported to be effective in hand eczema and diaper dermatitis by causing reduced percutaneous allergen absorption and skin barrier function improvement.^26,27

5) Wound healing

Anodic aluminium oxide (AAO) is found to enhance wound healing by acting as a membrane for the firm attachment of cells aiding in the migration and proliferation of epithelial cells.²⁸

6) As sanitizer for controlling transmission of COVID-19 (SARS-CoV-2)

Bentonite clays carrying a net negative charge and positive charge on edges with high cation exchange capacity act as an excellent adsorbent for SARS-CoV-2 preventing COVID-19 transmission.²⁹

7) Role of aluminium in calciphylaxis and treatment of calcinosis cutis

A close relationship is observed between calcium phosphorus products in plasma and the tendency for ectopic calcification. Administration of aluminium hydroxide (2.8 g/100 mL- 15 to 20 mL four times a day) leads to the formation of insoluble aluminium phosphate, decreasing intestinal absorption of phosphorus and thereby reducing the calcium phosphorus product in plasma.^30,31 Aluminium hydroxide (1.8–2.4 g/day) has been used to treat idiopathic calcinosis cutis, calcinosis universalis, calcinosis associated with juvenile dermatomyositis, systemic sclerosis and systemic lupus erythematosus.³² There are no accepted standard treatment protocols or algorithms for the use of aluminium hydroxide in calcinosis cutis, since the recommendations are based on individual case reports with a low quality of evidence.³²

Weenig et al., in a retrospective study, noted a fourfold increase in the risk of developing calcific uremic arteriolopathy (CUA) with elevated serum aluminium levels (>25 ng/mL).³³ A case-control study conducted at the Mayo Clinic identified serum aluminium concentration as a significant factor for calciphylaxis in patients with end-stage renal disease.³⁴ The speculative causes of aluminium overload in calciphylaxis could be attributed to poor urinary excretion of aluminium, low serum transferrin levels resulting in competition for transferrin binding sites between iron and aluminium, and mobilisation of aluminium from bone stores due to high bone turnover in secondary hyperparathyroidism.^35–37

8) Role in photodynamic therapy for cutaneous malignancies

Aluminium-chloride-phthalocyanine (AlClPc), a second-generation photosensitising agent, is used for photodynamic therapy with the advantages of high photodynamic efficiency and low cutaneous photosensitivity.^38,39 Aluminium (III) phthalocyanine chloride tetra sulphonate (AlPcS4Cl) is another aluminium-based photosensitizer used.⁴⁰

9) Aluminium adsorbed allergen preparation for honey bee venom allergy

Venom immunotherapy (VIT), a type of allergen-specific immunotherapy or systemic allergen immunotherapy is a highly effective treatment for protecting honey bee venom (HBV) allergic patients from anaphylaxis. In this, aluminium hydroxide (75%) as an adjuvant is mixed with the honey bee venom extract, and the mixture is administered subcutaneously, which protects patients from developing systemic allergic symptoms if re-stung.⁴¹ The injections are given in gradually increasing quantities of the allergen until immunological tolerance is achieved.⁴² Comparative trials show that aluminium hydroxide adsorbed extracts are better tolerated than non-purified extracts, particularly in severe reactions.⁴³

10) Nd YAG and Er Yag laser

Crystals of aluminium garnet and yttrium are doped with neodymium to produce Nd: YAG laser that is used for pigment removal and vascular lesions like telangiectasia, spider veins and hemangioma. Aluminium is a desirable laser host material due to its stability, hardness and optically isotropic nature.⁴⁴

11) Aluminium oxide crystals for microdermabrasion

Aluminium oxide crystal microdermabrasion (AOCM) was initially developed in 1985 in Italy.⁴⁵ Aluminium oxide is the most commonly used abrasive in microdermabrasion because of its coarse, uneven surface and chemically inert nature [Figure 3]. AOCM has been found to enhance lipid barrier function through decreased transepidermal water loss (TEWL) and increased hydration in the stratum corneum. The bactericidal property of AOCM has the advantage of treating acne, as acne is associated with bacterial proliferation.⁴⁶ It has a lower propensity to cause bleeding and allergic contact dermatitis. The hazards associated with AOCM are pain, redness of the eyes, photophobia, epiphora, adherence of crystals to the cornea, and flares of herpes simplex infections.⁴⁵

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Figure 3:

Aluminium oxide crystals used in microdermabrasion.

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12) Topical antibiotic

French green clay, rich in iron-smectite, has been used for Buruli ulcers caused by Mycobacterium ulcerans due to its antibacterial properties. It is usually applied in a paste form to the ulcers, left for a week and reapplied again, resulting in wound debridement and regeneration of healthy tissue.¹⁷ It was found that the pH and oxidation state buffered by the surfaces of clay minerals control the solution chemistry and redox related events occurring at the bacterial cell wall.¹⁷

13) Bentonite as a component of calamine lotion

During the preparation of calamine lotion, bentonite (Al₂O₃. 4SiO₂. xH₂O) is added to the powders prior to the addition of water. The main function of bentonite in shake lotions like calamine is to act as a stabiliser/suspending agent.⁴⁷

14) Aluminium in sunscreens

Aluminium is found to be a component of sunscreens, wherein they help in preventing the agglomeration of titanium dioxide particles. However, due to its pro-oxidant effect, it exaggerates the oxidative damage induced by the chronic use of sunscreens.⁴⁸

15) Aluminium in friction blisters

A double-blind placebo-controlled trial found that the topical application of 20% ACH applied three times on three different days reduced friction blisters in those involved in hiking.⁴⁹ The mechanism proposed was reduced sweating by ACH decreases the friction between the skin and the contact surface, thereby reducing the incidence of friction blisters.⁴⁹

The uses of aluminium in dermatology are summarised in Table 3.

16) Aluminium as an allergen

Contact with aluminium in the environment is inevitable due to the widespread use of aluminium metal as mentioned in Table 4. Aluminium was first identified as an allergen by Hall in 1944 among aircraft workers.⁵⁰ The “allergen of the year” award for 2022 has been awarded to aluminium by the American Contact Dermatitis Society (ACDS).¹ In a systematic review, the prevalence of aluminium contact allergy was found to be 5.6% and 0.4% in children and adults, respectively.⁵¹ ACD to aluminium can present as eczematous dermatitis (localised in hands, legs, axilla or widespread systemic contact dermatitis).¹ A report of contact urticaria secondary to aluminium-containing coins has been reported.⁵² The aluminium salts reported to have allergic potential include aluminium chloride hexahydrate, aluminium lactate, alum, aluminium hydroxide, aluminium phosphate and aluminium acetotartrate.⁵³

17) Granulomatous conditions

a) Aluminium granuloma

Aluminium salts are used in various vaccines as adsorbents to enhance a specific and long-lasting immune response to antigens [Table 5]. The rationale behind using aluminium as an adjuvant points out theories like “depot theory” (slow elimination of aluminium precipitated antigens) and “antigen targeting theory” (particulate nature of adjuvants favouring phagocytosis and subsequent activation).⁵⁴ Aluminium salts (aluminium hydroxide, aluminium phosphate and alum) are one of the few adjuvants formulated for the SARS-CoV-2 COVID vaccines. Alum binds with the receptor binding domain (RBD) of S-protein to induce the production of neutralising antibodies, thus offering protection against SARS-CoV-2.⁵⁵ Aluminium adjuvants mediate inflammation through two pathways, namely NLRP3 inflammasome and NLRP3 independent pathways leading to immune responses and cytokine production.⁵⁶ The subcutaneous administration of aluminium-containing vaccines is known to produce granuloma by either of the two mechanisms; i) delayed hypersensitivity reaction, and ii) non-allergic reaction to such as direct toxicity. It is estimated that around 1% of all vaccinated children develop vaccine granuloma which appears from 2 weeks and 13 months after injection and persists for an average of 4.6 years.^51,57

Clinically, it may present as asymptomatic or pruritic erythematous subcutaneous nodules. Associated hypertrichosis and hyperpigmentation may be observed. The aluminium-containing Td vaccine has resulted in recurrent interconnected sterile abscesses.⁵⁸ The exacerbating factors for vaccine granuloma in children include infections, consumption of tin-foiled or canned food and the use of aluminium-containing sunscreens.⁵⁷ The aluminium granulomas can result in poor quality of life among children.⁵⁹ The various histopathological features observed in aluminium granuloma include necrobiotic granuloma with surrounding histiocytes, panniculitis, pseudolymphoma and granuloma annulare like patterns.⁶⁰

b) Tattoo granuloma

Localised aluminium-induced delayed hypersensitivity granulomatous reactions in tattoos have been observed, proposed to be due to delayed type hypersensitivity.⁶¹ Granulomatous reactions are observed in 26.3% of the patients getting tattooed.^61,62 Similar reactions following blepharopigmentation with aluminium-silicate have been reported.⁶³

c) Foreign body granuloma

Aluminium is one of the inciting agents for foreign body granulomatous reactions in cutaneous sarcoidosis as evidenced by the electron probe microanalysis revealing aluminium peaks in the foreign bodies.⁶⁴

18) Podoconiosis

Aluminium from the soil that penetrates the skin gets engulfed by the macrophages, resulting in inflammation and fibrosis of the vessel’s lumen thereby blocking lymphatic drainage and resulting in podoconiosis.^65,66 A study conducted in the Great Rift Valley in Kenya found that aluminium at a concentration of 10303.82 mg/kg in the soil was significantly associated with the log of expected counts of podoconiosis cases.⁶⁷

19) Uraemic pruritus

In patients undergoing haemodialysis, exposure to aluminium occurs with the water used for dialysate solution and aluminium-containing phosphate binders. Higher aluminium levels in serum are more associated with uraemic pruritus.⁶⁸ A ten-fold increase in serum aluminium was associated with a 5.6 fold increase in the risk of developing uraemic pruritus.⁶⁹ Serum aluminium levels ≥2 µg/dL were significantly associated with a greater risk of uraemic pruritus.⁶⁹

20) Malignancies

The use of aluminium-containing antiperspirants in the axilla has been implicated in breast cysts and malignancies.^70,71 Aluminium by producing DNA alterations, epigenetic effects and interfering with the function of oestrogen receptors can predispose to breast malignancies in the upper outer quadrant.⁷⁰ The side effects of aluminium in Dermatology are summarised in Table 6.

(II) Diagnostic applications

1) Finn chamber

Finn chamber made of aluminium is the most preferred test chamber system in patch testing [Figure 4].⁷² The amount of aluminium released from an empty Finn chamber corresponds to a skin dose of 0.03% to 0.5% ACH applied in a plastic chamber.¹ Aluminium salts, including ACH, aluminium hydroxide, aluminium sulphate, aluminium lactate, aluminium acetate and aluminium acetotartrate, have been used for patch testing instead of elemental aluminium, with petrolatum as the predominant vehicle.⁵³ Studies suggest that patch testing with 10% ACH is better than 2% ACH to detect aluminium allergy, although 2% ACH is sufficient for patch testing in children younger than 7 to 8 years.⁷³ In a study analysing positive patch test results for elemental/metallic aluminium (empty Finn chamber) and 2% ACH in petrolatum in 366 children with vaccine-induced persistent itching nodules, it was found that 31% of children showed positive patch test to 2% ACH with a negative patch test to elemental aluminium.⁷⁴ Hence, patch testing with elemental/metallic aluminium (empty Finn chamber) is not recommended since it is less sensitive than 2% ACH in petrolatum to diagnose aluminium hypersensitisation.¹

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Figure 4:

Finn chamber (containing aluminium salts as the predominant vehicle) used in patch testing.

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2) As a contrast agent for confocal microscopy

AlCl₃ is used as a contrast-enhancing agent in reflectance confocal microscopy (RCM). Tannous et al., utilised 20% AlCl₃ as a contrast-enhancing agent in RCM for performing Mohs micrographic surgery for basal cell carcinoma. The AlCl_3-stained tumour cells exhibited intensely bright nuclei with excellent contrast.⁷⁵ In a study by Flores et al., it was found that in keratinocyte carcinomas, when AlCl₃ was applied topically post-surgically to wounds, it provided a consistently enhanced contrast of tumour morphology at a cellular level.⁷⁶

Conclusion

The role of aluminium and its salts has gained importance over the past few years in various fields of medicine. Aluminium is a vintage metal that has potential applications in various diagnostic and therapeutic armamentariums in dermatology. The emergence of aluminium as an allergen and its use in cosmetic products require special concern for both producers and consumers.