Introduction:

              Eczema is a common skin condition characterized by severe itching and inflammation of the skin. However, as common as it is, the exact cause of eczema has not been pinpointed. Instead, a range of factors including genetics have been studied in relation to eczema. In particular, the relationship between eczema and pH has been studied considerably. There are many promising and exciting avenues of study in this field. The implications of this research include guidelines for products eczema patients use. It has been shown that many products commonly marketed as “gentle” and for “sensitive skin” are very alkaline which could have harmful effects on the skin¹. This review will present an overview of the research done to determine the relationship between eczema and pH and the future of this field of study.

              The pH scale is a scale from 0 to 14 that measures the concentration of hydrogen ions in a solution. 7 is neutral, meaning the concentration of hydrogen ions equals the concentration of hydroxide ions which neutralizes the positive charge of the hydrogen ions. Anything below 7 is considered acidic, meaning the concentration of hydrogen ions is more than that of hydroxide ions. Anything above 7 is considered basic, meaning the concentration of hydrogen ions is less than that of hydroxide ions.

Increased skin pH, meaning more basic pH, has been associated with increased dryness, increased skin roughness, and decreased stratum corneum hydration21. pH is especially important in the uppermost layer of the skin which is called the epidermis. The epidermis contains something known as the “acid mantle” which has a normal pH of between 4 and 6. This acid mantle protects the skin’s native microbiota, leads to healthy desquamation (flaking) of the skin, and maintains proper lipid biosynthesis². Atopic dermatitis, more commonly known as eczema, has been correlated with an alkaline skin pH.  One study found that a pH of 4 had a small but detectable increase on the mobility of the stratum corneum, the uppermost layer of the epidermis, in pigs’ ears because keratin and the lipids in the SC have the best mobility at pH 415. The effects of a higher skin pH are far ranging and will be discussed in depth in the later sections. One of the most impactful effects is that higher pH leads to increased skin permeability. Increased skin permeability causes more particles to be able to pass through the skin surface which can irritate the skin and cause eczema.

Therefore, research on the origin of the acid mantle is important. The origin of the acid mantle has been studied and found to be a combination of diffusion of acidic material from the surface and cornification-related organic acids. Specifically, in a study done on ichthyosis, it was found that a decrease in acidic products from the breakdown of profilaggrin and accumulated cholesterol sulfate both contributed to a higher pH and abnormal function24. Understanding the mechanisms of the acid mantle of the skin is important to creating treatments that target these mechanisms.

Many factors including the methods of measurement affect pH. The most common way to measure skin pH is using a flat glass electrode but this method can produce different results than a dry pH meter11 . Thus, more accurate measurement methods of pH may be necessary so there are no discrepancies over the readings. pH itself is unique to different parts of the body. The environment can also have a significant impact on skin pH. One study compares skin pH and other skin factors in two Indonesian cities, Jakarta, which sits at a low altitude, and Bandung, which sits at a high altitude. It was found that low altitude caused more redness, higher sebum level (secretion of oils from the sebaceous gland through pores on the skin) in the forehead, and lower pH. At high altitudes, there was higher pH, greater elasticity, and brighter skin25. Another study found that outdoor exposure lowers pH in the summer because sweat-derived lactic acid acidifies the stratum corneum28. Thus, the implications of pH in personalized medicine are important to treating eczema and other skin conditions with a person’s unique pH levels in mind.

Microbial and Fungal Growth Caused by Increased Skin pH

Increased skin pH has been found to allow harmful microbes and fungi to proliferate on the skin. These microbes and fungi can be triggers for itching, causing eczema. In one study, the effects of surgical dressings were observed. Participants wore an occlusion on their forearm for three days. After removal, skin moisture increased from 20% to 75%, skin pH increased from 4.9 to 7.1, and staph bacteria and Corynebacterium increased 4-5 logs due to the occlusion6. The increased skin moisture and pH allowed the bacteria to proliferate.

A similar phenomenon occurs with yeast. For example, the opportunistic yeast, Malassezia sympodialis, a trigger factor for eczema, is almost nine times more expressed when skin pH is 6.1 than when skin pH is 5.513. A similar study tested occluded forearms for C. albicans, another opportunistic yeast, using buffers of 4.5 and 6.0. Lesions resulting from the yeast were more pronounced in the arms buffered at 6.0, suggesting that higher skin pH provided a more ideal environment for the C. albicans to proliferate10. Thus, an alkaline skin pH can irritate the skin and trigger an eczematic attack.

Filaggrin’s Role in Eczema

              The FLG gene is of particular importance in the case of eczema. FLG codes for a protein in the epidermis of the skin called profilaggrin which breaks down into smaller filaggrin molecules. These filaggrin molecules further break down into their amino acids which are hygroscopic, meaning they absorb water from the atmosphere. These hygroscopic amino acids are NMFs, or natural moisturizing factors17 so they help moisturize the skin. Furthermore, one of the amino acids is histidine, whose role is to further help make urocanic acid and pyrrolidone 5 carboxylic acid which acidify the stratum corneum17. Thus, the FLG gene has a starring role in the maintenance of healthy skin pH.

              One experiment compared a FLG-deficient skin construct with a healthy skin construct because filaggrin deficiency or mutations in FLG have been associated with atopic dermatitis17. As expected, the levels of urocanic acid and pyrrolidone 5 carboxylic acid were significantly less in the FLG-deficient construct. Initially in the FLG-deficient skin construct, NHE1, officially known as the sodium and hydrogen exchanger 1, was upregulated to compensate for the lack of acidic filaggrin breakdown products. This allowed the construct to maintain a healthy skin pH of 5.5. At day 14 of the study, secretory phospholipase A2 (sPLA2), whose role is to convert phospholipids into fatty acids, was significantly more active in the FLG-deficient construct. This caused an accumulation of fatty acids in this construct which led to less organization of lipids in the skin. Disorganization of the skin barrier caused increased skin permeability and barrier dysfunction, a possible explanation for one of the mechanisms that leads to sensitivity to eczema. The FLG-deficient construct had a more hexagonal assembly of lipids rather than the normal lateral structure. The absorption of testosterone was observed to test skin permeability because testosterone is lipophilic. There was increased testosterone absorption in the FLG-deficient construct, meaning that there were less phospholipids and more fatty acids, leading to increased barrier permeability. The increased free fatty acids contributed to barrier dysfunction and inflammation. The trigger for the disorganization of lipids and barrier dysfunction could have been triggered by localized changes in pH or a response to the abnormal levels of certain products17.

              Another study had conflicting conclusions about the role of filaggrin deficiency in the development of eczema. The spontaneous development of eczema in newborn mice in conventional conditions was observed while no eczema development was observed in mice placed in specific-pathogen-free conditions. Over time, the pH of the eczematic mice increased while the pH of the mice in the specific-pathogen-free conditions decreased to normal levels. The alkalinization of the eczematic mice in the conventional conditions resulted in more kallikrein 5 and activated protease activated receptor 2 which secrete thymic stromal lymphopoietin. Simply, this causes T-cell proliferation, leading to inflammation and trans epidermal water loss. The pathway identified is known as the KLK5-PAR2-TSLP pathway. Weak acidification via a treatment of 2.5% or 5% lactobionic acid led to a reduction in eczema via a reduction in TSLP, PAR2, and KLK5. Notably, there was no noted filaggrin deficiency in the eczematic mice though. However, there was impaired function of NHE1, which is a pH regulator, in these mice. The eczematic mice did not have increased NHE1 to compensate for the alkalinization. The study concludes that prolonged alkalinization of eczema patients could be due to the suppression of NHE1 by an overactive immune system.

              Clearly, further research must be conducted to identify the degree to which FLG and NHE1 function contribute to the development of eczema. However, it is evident that while impaired function of one or the other may not definitively cause eczema, each can be a trigger or contributor of eczema.

Neonatal Acidification and the Origins of the Acid Mantle

              The acid mantle of the skin is not present immediately after birth. In fact, mammals have a neutral pH at birth but gradually, acidification occurs. The acidification process occurs as the skin barrier forms through the processing of lipid products that act as a structural barrier. Allergies and atopic dermatitis have been known to set in while the stratum corneum is undergoing acidification. One study observed the developing acid mantle in neonatal rats using fluorescence lifetime imaging. There was a periderm layer on the newborn rats’ skin the first few days after birth that eventually acidified in the first three days and then disappeared on day 4. This is a remnant of the periderm of the uterus which is a barrier between the epidermis and the amniotic fluid in the uterus. This layer acts as a barrier between the baby’s epidermis and its environment the first few days of life, and could potentially be important in the development of healthy skin. Acidification of the lower stratum corneum occurred three days after birth and the acidification spread outward to the surface along with the construction of mature extracellular lamellar membranes, otherwise called the skin barrier8.  Within one week, the rats’ skin surface had adult pH levels. The acidification process takes several weeks in human babies, which implies that the first few weeks of a baby’s life are crucial to the development of a healthy skin barrier.  This study also highlights the potential significance of the periderm layer in babies in the development of eczema.

              Treatments have also been studied for neonatal skin in the prevention of eczema. One study22 looked at the effect of oil baths and facial fat creams as treatments for xerosis, or dry skin, for babies aged six months in Norway. Babies with dry skin from a well-baby clinic were involved in the treatment while babies from five other clinics served as controls. Oil baths were given between 2-7 times a week. The results showed that the treatments improved the skin of the babies with xerosis by restoring the defective lipid bilayer. The defective lipid bilayer was attributed to increased skin surface pH due to a Western lifestyle of excessive soap use.

              Another interesting area of research regarding eczema and infant pH is umbilical artery pH. The umbilical artery is found in the umbilical cord between the mother and baby. A study conducted of two hundred twenty-two asthmatic Finnish children and one hundred eighty-three Finnish children studied the correlation between umbilical artery pH at birth and the development of asthma, allergic rhinitis, and eczema at the age of 5-6. Babies that had an umbilical artery pH greater than 7.30 had a 0.41-fold lower risk of eczema than those with a pH between 7.26 and 7.30. This study shows that while acidified skin may be healthier, a more basic umbilical artery could be healthier for babies. The implications of umbilical artery pH must be studied in greater depth.

              The link between skin wetness, skin pH, and diaper dermatitis has also been studied27. Diaper dermatitis is a rash caused by increased skin hydration due to diaper wear. Increases in skin wetness and skin pH of the diaper covered area were correlated with increased diaper dermatitis through statistical analysis. The difference in pH between healthy skin and diaper dermatitis- affected skin was pH 5.3 and pH 5.9. This difference resulted in increased permeability and increased activity of fecal enzymes which irritate the skin. Enzyme activity is known to be pH dependent, another important implication of skin surface pH in the development of eczema.

Eczema Treatments Related to pH

              Finding the mechanisms of the acid mantle is interesting but equally exciting are the applications of pH-focused treatments for eczema. One of these treatments involves electron ionized water. One such treatment was used for a patient in her late twenties who came to the hospital with severe face and body eczema14. The reason this novel treatment was used was because infection had set in as well because of the exposed skin wounds. The patient was given an herbal medicine tablet and an oral antihistamine, a steroid ointment, and vitamins E and A topically, allergy injections, and electrolyzed water and electrolytic reduction ion water lotion for disinfection and skin care. ERI and electrolyzed water were applied twice a day and emulsified the patient’s skin. The patient’s swelling, redness and lesions improved greatly over the next few months even as the steroid was decreased. The electrolyzed water had a pH of 2-3 and is considered very safe because it is used in the food industry and the dental industry as a sterilizer, and promisingly in the medical field in wound healing.

              Another line of treatment is hyper-acidification. One study3 tested skin buffered skin products with pH below 4.5 in the acidification and hydration of the skin of subjects over 50. Vitamin C Spheres, Collagen Spray, and Collagen Mask were tested. The criteria measured were skin surface pH, skin hydration, and barrier integrity over the course of four weeks. The Vitamin C Spheres acidified the skin while the other two products maintained the physiological skin pH. In subjects with a higher-than-normal pH, the products acidified their skin. This is important because with age, the pH of the skin increases, raising the risk of eczema. Acidification of the skin could aid in preventing eczema with age.

              The buffering capacity of the skin itself has also been explored. In one study7, the buffering capacities of the stratum corneum, epidermis, and dermis were observed. The skin was obtained from a skin bank. Each layer was injected with solutions of NaOH, a common base, and HCl, a common acid, at different concentrations and were washed with deionized water after 30 minutes. pH and trans epidermal water loss were measured at intervals between the injections and the washings. The dermis demonstrated the best immediate buffering capacity, meaning the pH did not increase as much as in the other layers, but over time, the stratum corneum was better at buffering because it reestablished the basal pH the fastest. The dermis had the greatest trans epidermal water loss while the SC had the least. Interestingly, it was found that buffering was faster after HCl was applied than after NaOH was applied. This shows that alkalinization of the skin is dangerous because it takes a while for the skin to reestablish basal pH, allowing time for eczema to set in. This study is important because it emphasizes that buffering of the stratum corneum does not occur immediately after an induced change in pH. This draws attention to the need for an immediate application or treatment if a patient’s skin has been alkalinized, such as after the shower.

Models for Studying Eczema and pH

              There are many models that are used to study the mechanisms behind pH and eczema. One such model4 found that a specific peptide amphiphile in the skin is flat and tape-shaped at pH 3 and pH 7, twisted and right-angled at pH 4, and circular at pH 2. An amphiphile is water loving at one end and fat loving at the other. The twisted structures which occur at pH 4 are likely the “normal” structures because the normal skin pH is between 4 and 6.  Hydrophobic and electrostatic interactions determine the self-assembly of this peptide amphiphile, which is derived from collagen. Thus, this model provides an interpretation for some of the physical changes created by a diversion from the normal skin pH. In biology, pH is important to the shapes of proteins because specific R-groups are acidic or basic and this influences the shape of the protein. If there is a change in pH, as in this study, the shape of the protein changes, just as the peptide amphiphile did.

              Many models that study eczema and pH are animal models, particularly mice. In one study19, hyper acidification of mouse stratum corneum with two polyhydroxy acids, lactobionic acid and gluconolactone was tested. Hyper acidification proved beneficial because the skin barrier was able to maintain homeostasis better and some of the deeper layers of the stratum corneum were acidified. In addition, ceramide generated enzymes and lipid processing enzymes in the stratum corneum were activated by hyper acidification. This caused the maturation of lamellar bilayers, the lipid structures that make up the skin barrier. Accordingly, the integrity of the stratum corneum improved because of the acidification. Most importantly, though, the acidification did not cause irritation of the mice. This study highlights the potential for hyper acidification of layers of the stratum corneum as a treatment to help strengthen the skin barrier of eczematic patients.

              Outside of animal testing, other models are used to study eczema as outlined in one review article12. For example, 2D cultures of cells like keratinocytes are used for basic studies and 3D skin disease models are used for more complex ones. Co-cultures can also be used; for example, skin cells and immune cells can be co-cultured to see the relationship between eczema and the immune system. Reconstructed human epidermis is another approach to studying eczema without live patients.

              To take research on eczema and pH to the next level though, requires looking for other viable options. For example, microfluidic body on a chip systems have been explored and need to be further explored for studying eczema. These devices can study the relationship of the skin to other organs in the body. Specifically to pH, one angle of research could be studying the effects of changes in pH of other organs or internal pH on eczema. Microfluidic systems could be the medium of research for such a field of inquiry. The review article mentioned also highlighted the need for skin models with vasculature and models that include shear stress and mechanical stresses. These novel methods of studying skin could open a larger field of questions that can be asked about eczema and pH.

New Wearable Technologies

              Wearable technologies are a rapidly growing field of research. There have been studies on wearable technologies to monitor skin pH for eczema and related conditions.  One way to determine skin surface pH via wearable technology is through the monitoring of skin volatile emissions. A study tested wearable colorimetric sensors that monitored volatile emissions of nitrogen compounds like ammonia from the skin16.  This was a novel approach because it did not involve microneedles that could irritate the skin, as had been used previously. The sensors had bromocresol green pH indicator dye which changed color when it sensed a volatile emission from the skin. The color changes had a strong correlation with skin surface pH.  Ammonia is produced when bacteria in the intestine break down proteins. The ammonia is transported by the blood to the liver where it is converted to urea and excreted. However, the remaining ammonia in the blood diffuses to the stratum corneum where it is emitted in eccrine sweat as ammonia or the ammonium ion. The volatile emission of gaseous ammonia was measured because the equilibrium between ammonia and the ammonium ion is pH dependent since the ammonium ion just has an extra hydrogen ion. Thus, low emission of ammonia was correlated with low skin pH because that means that there was more ammonium ion, and therefore more hydrogen ions. This study highlighted that skin surface pH greatly differs between males and females and between different parts of the body, emphasizing the need for a holistic approach to skin conditions that considers these multiple factors.

              Another investigation studied volatile skin emissions, but this time of fatty acids18. The relationship between volatile fatty acid (VFA) emissions and skin surface acidity was found to be that the lower the pH, the greater the VFA emissions. In addition, peaks of VFA emission were correlated with the hydrogen ion concentration at a specific site. The proposed reason for this phenomenon was that the more ordered structure of fatty acids under low pH conditions leads to greater VFA emission. This study also used colorimetric sensors with bromocresol green dye.

              Another approach to wearable technologies for eczema is bandages that monitor skin pH to direct treatment of the wound. A low-cost, bandage potentiometric sensor was developed to monitor skin pH by monitoring the levels of common ions20. The bandage can handle mechanical stress that would occur from day-to-day activities. This technology is based on the fact that wounds have a neutral to basic pH, but different pH levels are necessary at different stages of the wound healing process. Thus, continuous monitoring of the wound’s pH would be useful for customizing the treatment of the wound. Wound conditions were simulated in the experiment using human sebum buffers at different pH values. A noteworthy anion that would affect the wound pH is SO42- so this anion was tested. The bandage was able to sense rapid changes in pH of the wound without getting cross contaminated. One of the issues that came up was that sterilization of the wound affected the pH sensing, so this is an area that needs to be addressed.

              A sustainable bandage has also been developed using red cabbage extract inside alginate nanoparticles30. Red cabbage extract is a natural pH sensor because it changes color with pH changes. A solution was used to simulate a wound a decrease in pH caused a change of color from purple to pink. It also has antifungal, antiviral, anti-inflammatory, and antioxidant properties so it is a beneficial contribution to the wound environment. The four stages of wound healing- haemostasia, inflammation, proliferation, and remodeling- each have a different ideal pH. pH monitoring is especially important in wounds because it can alert of bacterial contamination.   

              Artificial skin grafts with an acidic pH have also been studied. One such skin graft was made using a chitosan/agarose film26. Chitosan, which is obtained from chitin (found in plant cell walls), and agarose (found in seaweed) are carbohydrates. The combination of these two carbohydrates was used to develop a regenerative skin graft that could substitute skin. A new method to combine the two using agarose in sodium hydroxide and chitosan in acetic acid was used to obtain a pH of 5.98 which is known to support regeneration. This pH value was obtained because it allows for fibroblasts to be cultured on the film for regeneration of the skin. The film is also biodegradable in the enzymatic wound environment. The film showed promising characteristics of a skin substitute including elasticity comparable to human skin. This study is important in exploring the importance of considering pH for skin regeneration and wound healing.

Next Steps

              It is evident that pH plays a major role in the cause for eczema. This field of study has a lot of research from different angles, and yet, there is still so much to be learned about skin pH and its role in eczema. There are some key areas of research that could lead to valuable discoveries on the pathogenesis of eczema. One takeaway is that more skin constructs and microfluidic systems should be used in research related to eczema. This will reduce the use of animal testing which is often harmful to the animals. Microfluidic systems are particularly intriguing because they can analyze the intersection between the skin and other body parts. Specifically related to pH and eczema, some internal body parts of interest are the liver, the stomach, and the blood. It was found that stomach extract of cod and other fish effectively degrades human epidermal keratin which causes hand eczema in people who handle fish material23. Pepsin in the stomach, which degrades proteins, works optimally to degrade keratin at pH 3.3-3.4, indicating that too acidic pH can cause eczema as well. This shows that treatment based on pH can be used on an individual basis, even as far as taking occupation and location into account. In addition, a study found high hydrogen ion concentration in inflamed skin of rats. This acidic pH excites nociceptors, sensory neurons that signal pain to the brain29. This study could indicate that acidic pH causes the area of skin to be more sensitive to inflammation, which could alert the body early on about if the area of skin is vulnerable to an eczematic attack. Thus, the relationship between the skin pH, neurons, and the brain is also an important area of research.

              It is important to take into consideration a person’s sex, the body part being considered, the environment, and other factors to develop a comprehensive and accurate view of how pH affects the person’s skin. The research on skin pH and eczema also shows that skin pH should be considered for prevention of eczematic attacks by monitoring and maintaining a healthy skin pH, but also for the treatment of eczema and the wounds caused by it.

References:

1. ajol.info/index.php/sajchh/article/view/164488

2. onlinelibrary.wiley.com/doi/full/10.1111/ics.12721

3. scirp.org/journal/paperinformation.aspx?paperid=107702

4. pubs.rsc.org/en/content/articlehtml/2013/sm/c3sm51029h

5. sciencedirect.com/science/article/pii/S0022202X15000147

6. file:///C:/Users/yasti/Downloads/Hartmann1983_Article_EffectOfOcclusionOnResidentFlo.pdf

7. file:///C:/Users/yasti/Downloads/Skin%20Research%20and%20Technology%20-%202011%20-%20Zheng%20-%20Buffering%20capacity%20of%20human%20skin%20layers%20%20in%20vitro.pdf

8. sciencedirect.com/science/article/pii/S0022202X15302852

9. jiaci.org/issues/vol22issue1/7.pdf

10. medicaljournals.se/acta/download/10.1080/000155500300012819/

11. ipcbee.com/vol81/001-ICBET2015-B0002.pdf

12. file:///C:/Users/yasti/Downloads/Experimental%20Dermatology%20-%202018%20-%20L%20wa%20-%20Alternatives%20to%20animal%20testing%20in%20basic%20and%20preclinical%20research%20of%20atopic.pdf

13. file:///C:/Users/yasti/Downloads/Allergy%20-%202006%20-%20Selander%20-%20Higher%20pH%20level%20%20corresponding%20to%20that%20on%20the%20skin%20of%20patients%20with%20atopic%20eczema%20%20stimulates.pdf

14. ddtjournal.com/downloadpdf/395

15. sciencedirect.com/science/article/pii/S0927776520308328

16. sciencedirect.com/science/article/pii/S2214180422000022

17. sciencedirect.com/science/article/pii/S0022202X15366744

18. iopscience.iop.org/article/10.1088/1752-7163/abf20a/pdf

19. sciencedirect.com/science/article/pii/S0022202X15346741

20. analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/elan.201300558

21. file:///C:/Users/yasti/Downloads/skin-surface-ph-stratum-corneum-hydration-trans-epidermal-water-loss-and-skin-roughness-related-to-atopic-eczema-and-skin-dryness-in-a-population-of-primary-school-children-clinical-report.pdf

22. sciencedirect.com/science/article/abs/pii/S0301054614001311

23. file:///C:/Users/yasti/Downloads/BF00417716.pdf

24. jidonline.org/article/S0022-202X(15)40244-1/fulltext

25. file:///C:/Users/yasti/Downloads/J%20of%20Cosmetic%20Dermatology%20-%202016%20-%20Lee%20-%20Comparison%20of%20skin%20properties%20in%20individuals%20living%20in%20cities%20at%20two%20different.pdf

26. file:///C:/Users/yasti/Downloads/1-s2.0-S0141813020338538-main.pdf

27. onlinelibrary.wiley.com/doi/epdf/10.1111/j.1525-1470.1994.tb00066.x

28. file:///C:/Users/yasti/Downloads/Acad%20Dermatol%20Venereol%20-%202019%20-%20Kim%20-%20Influence%20of%20exposure%20to%20summer%20environments%20on%20skin%20properties.pdf

29. file:///C:/Users/yasti/Downloads/3982.full.pdf

30. file:///C:/Users/yasti/Downloads/1-s2.0-S0141813022010315-main.pdf