Alpha-Hydroxy Acids
by Dr. Dennis T Sepp, As published in Les Nouvelles Esthetiques, December, 1998

General Background

Long before the chemical structure, or even the existence, of alpha-hydroxy acids (AHA's) were known, they were unknowingly being used as an ingredient for improving the condition of skin. Egyptian women took baths in sour milk in order to improve their skin. French women in the court of Louis XIV washed their faces with old wine for the same reasons. Old fashioned facial masks made from fruit, honey or yogurt were also unknowingly taking advantage of AHAs as their active ingredients.

Alpha-hydroxy acids are commonly found and isolated from fruits of all sorts. That is why they are referred to as fruit acids. For example, malic acid is found in apples, citric acid can be isolated from most all citrus fruits and glycolic acid is commonly found in honey or sugar cane. Another source of AHAs is from the fermentation of natural products. Lactic acid is found in milk that has soured, and tartaric acid can be isolated from fermented grapes (wine). It is this natural, feel good origin of alpha-hydroxy acids that make them so appealing. Couple this with the genuine hi-tech biochemistry that they exhibit and it is no mystery as to why they are so popular today.

A Little Chemistry:  Organic vs. Mineral Acids

Chemically speaking, an alpha-hydroxy acid is a low molecular weight organic acid. Most people associate the word "acid" with potent and dangerous acids like hydrochloric and sulfuric. These acids are called mineral acids and are indeed potent and dangerous. Most are strong enough to dissolve metals. An organic acid however, differs greatly from a mineral acid. Organic acids are much, much milder than mineral acids and occur quite commonly in everyday life. Acetic acid, for example, is the organic acid that gives vinegar its characteristic sour taste.

An organic acid is chemically defined as a molecule that possesses a carboxylic acid (-COOH) group:

Acetic Acid (CH3-COOH);  Glycolic Acid (CH2OH-COOH)   Lactic Acid (CH3-CHOH-COOH)    Beta Hydroxy Acid (CH2OH-CH2-COOH)

An AHA such as glycolic or lactic acid has a hydroxyl group (-OH) present on the carbon atom immediately adjacent to the acid group. This position is defined as "alpha" (first letter of the Greek alphabet) because it is the first carbon next to the acid group. Beta-hydroxy acids are thus molecules where the hydroxy group is on the second carbon next to the acid group. Glycolic Acid is the most commonly used AHA. Because of its small molecular weight and size, it is presumed to have a better capacity to penetrate skin. Lactic acid on the other hand, has a larger molecular weight than glycolic acid but is capable of being converted in vivo to pyruvic acid (an alpha keto acid) which is presumed to be a more effective exfoliating agent. It should be noted that neither salicylic acid nor retinoic acid are alpha-hydroxy acids.

Current Uses

Today, alpha-hydroxy acids are used extensively in cosmetic dermatology (1). At concentrations lower than 10%, they are regularly formulated into everyday use creams. At these levels, skin benefits result from continuous use and result in a gradual reduction in fine lines and an overall improvement in skin texture brought about by accelerated desquamation (exfoliation). At higher concentrations, AHAs function as peeling agents which act more rapidly and at a deeper level (7). Glycolic acid peels at concentrations of 20-70% are commonly used by dermatologists and plastic surgeons to remove severe acne scarring and skin pigmentation irregularities. Their effectiveness depends on the contact time of the acid and the number of peeling sessions (2). Milder peels (10-40%) can be carried out in skin care salons. Peels, in general, are being used more frequently to treat the wrinkles and skin discoloration resulting from solar damaged skin (actinic aging). They are also finding more and more use as anti-aging ingredients to combat the loss of smoothness and skin elasticity associated with chronological aging. The war against wrinkles seems to be never ending.

How AHAs Work

The full mechanism of action of alpha-hydroxy acids is not yet fully understood (3). It is known however, that they function in two distinct fashions: First, they can act as a simple humectant that absorbs moisture from the atmosphere. When applied to the skin, these hydrated AHAs act to increase the water content of the skin and thus moisturize the outer layer of the epidermis (the stratum corneum) and consequently make the skin softer and more flexible. The second method by which AHAs are thought to act is by reducing corneocyte adhesion and accelerating cell proliferation within the deeper basal layer of the skin (4,5,6). This exfoliating action of AHAs occurs as a result of their ability to break the bonds between dead skin cells that form at the surface of the skin. Skin normally has a dead layer of cells at its surface (the corneocyte layer), and AHAs can speed up the normal process of skin cell regeneration and sloughing. This results in increased flexibility of the skin as well as decreased formation of large dry skin flakes at the surface of the skin. When applied in the high concentrations of a peel, AHA's operate at a deeper level and cause detachment of keratinocytes and epidermolysis. At lower concentrations, AHAs primarily reduce intercorneocyte cohesion thus promoting exfoliation and thinning of the stratum corneum. A thinner stratum corneum is more compact and flexible (8).

Sun damaged skin is becoming more and more of a problem in our society. Prematurely aged skin brought about by long term UV radiation exposure (actinic aging), is in part caused by a thickening of the stratum corneum resulting from increased corneocyte cohesion (9). Long term UV radiation exposure also degrades collagen in the dermis layer of the skin. There is also evidence that excessive amounts of abnormal elastic fibers also tend to accumulate within the dermis of photodamaged skin (10). Glycolic acid at low concentrations works well to decrease corneocyte cohesion by promoting exfoliation of the outer layers of the stratum corneum (11,12). This is especially relevant since most pigmentation alterations associated with photodamage can be attributed to the thickening of the stratum corneum (10).

Most of the evidence on how AHAs work seems to point to exfoliation and the resulting turnover of new cells in the outer epidermal layer of the skin. There is increasing evidence however, that AHAs may be working at a much deeper level. There may well be increases in procollagen and Type I collagen that occur in the deeper dermis layer brought about by long term treatment with AHAs (13). One interesting study showed that topical treatment twice a day for 3 months with a 5% glycolic acid cream, at pH 2.8, affected surface and epidermal changes, while the same treatment, but with a 12% cream, reached deeper and influenced both the epidermis and the deeper dermis layer, and resulted in increased epidermal and dermal firmness and thickness. Both showed clinical improvement in skin smoothness and in the appearance of lines and wrinkles (15). Another interesting study showed that AHAs may thin the outer stratum corneum, but actually end up increasing the overall thickness of the epidermis. This thickening is accompanied by increased synthesis of glycosaminoglycans and collagen (14). It is becoming apparent that alpha-hydroxy acids may do more than just increase exfoliation and skin cell turnover.

Requirements for Effectiveness

The efficacy of an alpha-hydroxy acid when used as an exfoliating agent depends upon the concentration of the AHA and the pH of the medium in which it is used. But surprisingly, it does not depend upon the specific AHA that is used. For example, glycolic acid and lactic acid applied at equal concentrations and at the same pH have just about the same cell renewal rates (16). Furthermore, this same study showed that just about all of the small organic acids tested had similar cell renewal rates. It did not seem to matter whether you were testing alpha-hydroxy acids, beta-hydroxy acids or even the non-hydroxy acids like acetic or pyruvic acid. Only trichloroacetic acid was measurably more potent. All acids tested however, showed an increase in cell renewal stimulation with increased concentration. And all acids tested showed a marked decrease in cell renewal with increasing pH. The optimum pH for cell renewal stimulation was at about 3.0. At a pH above 6.0 very little stimulation was observed for any of the acids. In general, AHAs at a pH of 6.0 or greater behave more like moisturizers than exfoliating agents. There is, of course, no optimum concentration for the use of an AHA. It depends upon how it is being used, whether by a physician using it as a peel (up to 70%), or by a consumer using an over-the-counter cream (about 10%). Safety is the primary consideration for determining at what concentration an AHA should be used.

The relationship between the strength of an AHA and the pH at which it is being used cannot be overestimated. Intuitively one can recognize that a higher concentration of AHA should be more potent. But the effect of pH on potency is more subtle. It must be recognized that it is the free acid form of the AHA molecule that is responsible for cell renewal stimulation. It is generally accepted that 4% free acid is usually the threshold minimum for this effect (17). It can be mathematically calculated that in order to have 4% free acid available at a pH of 3.8 one needs to start with 8% alpha-hydroxy acid. If the pH of the same preparation were lowered to approximately 1.0, the available free acid would increase to greater than 7%. And conversely, if the pH were increased to 6.0 or greater, the available free acid would drop well below 1%. Thus it can be seen that the same 8% AHA formula could work as a truly potent (but very irritating) skin cell renewal stimulator if the pH were 1.0. Or, it could end up as just a mild moisturizer if formulated at pH 6.0 or higher. It is for this reason that an alpha-hydroxy acid preparation sold to the public should be labeled with not only the identity of the AHA used, but also with its concentration and the pH of the preparation.

Long Term Effects and Safety Concerns

Although alpha-hydroxy acids appear to be the miracle cosmetic ingredients of the 90s, there are genuine safety concerns associated with their extended use. The FDA is directly concerned with two primary issues: sun sensitivity and the long term effects brought about from the usage of a skin irritant.

Does the use of AHAs make the user more sensitive to sunlight and consequently more at risk for photodamage and photocarcinogenity? The Cosmetic & Ingredient Review (DRI), an independent panel formed by the CTFA (Cosmetic, Toiletry and Fragrance Association), conducted a study on the safety of glycolic acid and lactic acid. They concluded that on a professional level (skin salons) these AHAs could safely be used at a concentration 30% or less and at a pH of 3.0 or greater. The CTFA study also recommended that retail products contain 10% or less AHA and maintain a pH of 3.0 or greater. In both cases they recommended that the person treated with AHA's should use sun protection of at least SPF 15 (18). Although this study did not find that AHAs promoted sun sensitivity, they did find that people with light hair and fair skin do experience increased sunburn-cell levels when exposed to sunlight using a 10% solution of AHA. It was felt however, that this result was not significant since people with this kind of skin are predisposed to sun damage.

The effects of long term usage of alpha-hydroxy acids is just now being addressed. Any answers will have to wait until someone determines how alpha-hydroxy acids actually work. As yet there are no definitive studies from either industry or academia and the FDA has started a study on their own. The fact that the FDA is genuinely interested is evident from this statement by Dr. John Bailey, director of the FDA's Office of Cosmetics & Colors: "The fact that these are chemical irritants that are being sold and directed to be used over a long time raises the issue of chronic irritation and potential adverse effects." (3)

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References:

1. WP Coleman and JM Futrell, J. Dermatol Surg Oncol 20 76-80 (1994)
2. LS Moy, H Murad and RL Moy, Surg Oncol 19 243-246 (1993)
3. Cosmet & Toil, 112 (3) page 9 1997
4. M Takahashi, et al, J Soc Cosmet Chem 36 177-187 (1985)
5. Ej Van Scott, et al, J Am Acad Dermatol, 11 867-879 (1984)
6. E J van Scott, et al, Arch Dermatol 100 586-590 (1985)
7. BA Gilchrest, Brit J Dermatol 135 867-875 (1996)
8. C Fox, Cosm & Toil 113 p. 25 1998 March.
9. EJ VanScott and RJ Yu, Cutis 43 222-229 (1986).
10. JJ Leyden, Br J Dermatol 35 1-3 (1990)
11. BE Katz, Cosmet Dermatol 8 24-36 (1995)
12. EJ VanScott, et al, J Am Acad Derma 5 867-879 (1984)
13. BC Kwak, et al, J Inv Dermatol 108 (4) 572 Abstract 207 (1997)
14. CM Ditre et al, J Am Acad Dermatol 35 287-295 (1996)
15. WP Smith, J Am Acad Dermatol 35 388-391 (1996)
16. WP Smith, Cosm & Toil 105 (11) 39-48 (1990)
17. GS Hahn, DCI January 1998, 18-22