15 Dry Skin

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15 Dry Skin

N.Y. Schürer

Flaking, scaling, fissuring and roughness of the skin’s surface is termed “dry skin.” Synonyms are “xerosis,”

“xeroderma,” “rough skin,” “chapping skin,“ “asteato- sis,” and “winter eczema.” These terms are based on the description of symptoms and physical signs, when light is scattered on a rough surface (Fig. 15.1).

Although dry skin is very common, little is known about its etiology: A lack of moisture seems to be the underlying cause as well as a lack and/or imbalance of lipids or even a combination thereof. Consequently, the literature currently lacks a reproducible definition of dry skin [46]. The following presents an attempt to bring current findings about dry skin pathology into context.

Fig. 15.1. Under normal conditions, the turnover time of the stratum corneum in humans is 4 weeks, the physiological pH ranges between 4.5 and 5.5, a balanced protein–intercellular lipid matrix composition allows barrier homeostasis and normal smooth skin appearance

15.1

The Stratum Corneum

The human stratum corneum is a two-compartment system of protein-enriched corneocytes embedded in a lipid-enriched, intercellular matrix. The epidermal barrier resides in the stratum corneum and depends on the presence and balance of intercellular substances (lipids and water) as well as the strong cohesion between individual corneocytes [6, 32]. The stratum corneum is viewed as a dynamic and metabolically interactive tissue, reacting to environmental forces as well as to changes in the organism itself. However, when the stratum corneum is damaged, a series of pro- cesses are immediately accelerated to achieve barrier recovery [36]. This process includes synthesis and pro- cessing of stratum corneum lipids and proteins.

15.1.1

Intercellular Lipids

The stratum corneum intercellular matrix may be con- sidered as a multiphase system consisting of a complex mixture of lipids, enzymes, low-molecular-weight hydrophilic substances, and water [15]. This unique organization imparts its (a) impermeability, (b) capacity to trap water, (c) selective permeability for lipophil- ic substances, and (d) abnormal desquamation occur- ring in inherited or acquired disorders of epidermal lipid metabolism.

Stratum corneum intercellular lipids are devoid of phospholipids, but enriched in ceramides, free sterols, and free fatty acids (40 %, 25 %, 20 %, respectively, by weight). Despite the absence of phospholipids, these intercellular lipids form membranous lamellae using the amphipathic qualities of the ceramides. However, ceramides located in the intercellular space only form

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bilayers in conjunction with cholesterol, free fatty acids, ionized at a physiological low pH. The physical state of these lipid chains in the apolar regions of the bilayers is essential [56]. Long-chain saturated fatty acids (LCFA) of these ceramides provide protection against excessive transepidermal water loss (TEWL).

Very LCFA (VLCFA) are highly hydrophobic and have a higher ability to prevent TEWL than short-chain fatty acids (FA). Further, saturated FA are more resistant to oxidation than unsaturated FA [21].

Human stratum corneum also contains covalently bound ceramides and FA, which can be analyzed only after strong alkaline extraction [70]. The K -hydroxy ceramides are attached by ester linkage of their K -hydroxy group to involucrin, a structural protein of the epidermal cornified envelope [62]. Together with K -hydroxy fatty acids, these K -hydroxy ceramides form a lipid monolayer surrounding the corneocytes.

This structure is relevant for proper barrier function and control of TEWL [30, 61].

15.1.2

Physiology of Desquamation

The stratum corneum typically comprises about 20 corneocyte cell layers, which differ in size, thickness, packing of keratin filaments, and number of corneoso- mes, depending on the body site [41]. There are excep- tions, such as the face and genitals or palms and soles, where the stratum corneum is extremely thin or thick [74]. Under healthy conditions, the thickness of the stratum corneum is constant at a given body site.

Therefore, the most superficial parts of the stratum corneum continuously shed at the same rate as corneocytes are produced de novo. Under normal conditions, the turnover time of the stratum corneum in humans is approximately 4 weeks (Fig. 15.2). This process of desquamation employs invisible shedding of individual corneocytes. Therefore, the smooth appearance of the skin surface is associated with a normal, healthy skin condition.

15.1.3

Stratum Corneum Hydration

The skin’s smooth and flexible appearance is partly due to the water-binding capacity of the stratum corneum, even in a dry environment. The stratum corneum water-holding capacity relies on:

Fig. 15.2. Dry skin, i.e., the accumulation of only partially detached corneocytes or aggregates, may be the consequence of an imbalance of the intercellular lipid matrix composition, a pH > 5.5 and/or changes in proteinaceous structures

1. The content and composition of intercellular lipids [24]

2. Sebaceous gland lipids covering the skin surface [37]

3. Natural moisturizing factors (NMF), e.g., water-sol- uble amino acids [43].

Within the stratum corneum, hydrophilic nitrogenous compounds hold in moisture. These NMF, i.e., amino acids, urea, urocanic acid, and 2-pyrrolidone-5-car- boxylic acid, make up about 10 % of the stratum corneum dry weight [43]. These compounds derive from filaggrin breakdown products, which are precisely timed with barrier formation.

Corneocytes do not have a nucleus and no de novo protein or de novo lipid synthesis. Therefore, reactions to irritation must lead to structural and functional changes of the stratum corneum and cell signaling.

When the surface of the skin is injured, a variety of sig- nal cascades are initiated, for example, cytokines, growth factors, and lipid mediators are upregulated [36]. This initiates not only epidermal changes, but also inflammatory events in deeper skin layers. This process can be disturbed, either by increased production of corneocytes or a decreased rate of cell shedding, or decreased/disturbed intercellular material. The accumulation of only partially detached corneocytes or aggregates may result. Concomitantly, the stratum corneum thickens. The intensity of this disturbance may vary from modest to very pronounced, from barely visible scaling combined with a feeling of roughness and dryness to severe corneocyte shedding (Fig. 15.3).

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Fig. 15.3. Clinical appearance of dry skin, i.e., when light is scattered of a rough, flaky skin surface

15.2

Pathophysiology of Dry Skin

15.2.1

Content and Composition of Intercellular Lipids

Changes in epidermal lipid content and composition have been linked with dry skin, i.e., stratum corneum abnormality, which may not be a secondary phenome- non, but a critical trigger of inflammation [15]. Light and electron microscopic studies showed disturbed extrusion of lamellar bodies, epidermal hyperkeratosis, focal parakeratosis, low-grade acanthosis, focal spongiosis and a slight perivascular infiltrate in dry skin [13].

Essential fatty acids are crucial for stratum corneum function. Replacement of linoleic acid with oleic acid esterified with ceramide I is associated with ultrastruc- tural stratum corneum lipid perturbation and disorders of cornification. Imokawa noted the importance of intercellular sphingolipids as well as other neutral lipids for water-retention properties in the stratum corneum [23]. Ceramide I levels are reduced in atopic eczema and xerosis. Moreover, deficiencies in ceramide I and K -hydroxy ceramides have been correlated with dry skin conditions in young adults [55]. De novo ceramide synthesis may be stimulated by nicotinamide via the upregulation of serine palmitoyltransferase and free fatty acid levels in the stratum corneum. An improved permeability barrier, decreased TEWL, and clearance of dry skin may result [66].

15.2.2

Stratum Corneum Proteins

Proteinaceous structures are involved in stratum corneum cell cohesion. Desquamation depends upon cor- neodesmosomal degradation, involving the stratum corneum chymotryptic enzyme, which has an alkaline pH optimum, but is also active at pH 5.5, i.e., at the physiological pH of the upper stratum corneum. This enzyme is expressed in the suprabasal layer of the epidermis. At this level, the enzyme was found in association with the lamellar bodies. Upon the stratum granulosum/stratum corneum transition, the enzyme is extruded into the extracellular space together with the lamellar bodies [59].

Trypsin-like and chymotrypsin-like inhibitors inhibit spontaneous cell dissociation in the stratum corneum. Therefore, trypsin-like and chymotrypsin- like enzymes may degrade intercellular cohesive structures in the stratum corneum, leading to tissue remo- dulation and desquamation [64].

However, many other proteases present in the stratum corneum, for example a 30-kD serine protease, might be complementary to that of stratum corneum chymotryptic enzyme degradation. Furthermore, the 30-kD serine protease might activate the stratum corneum chymotryptic enzyme precursor. All these recently described mechanisms of protein degradation are important for normal invisible cell shedding. Any disturbance thereof may lead to a decreased rate of cell shedding and eventually to visible scaling. Further- more, delayed desmosomal degradation contributes to the accumulation of squames: more intact transmem- brane desmosomal glycoprotein desmoglein 1 has been extracted from dry than normal skin [50].

In dry compared to normal skin, the expression of the differentiation-related epidermal keratins K1 and K10 are decreased and the associated suprabasal keratins K5 and K14 are increased [12]. These findings allow the assumption of a hyperproliferative disorder.

Furthermore, a premature expression of involucrin was observed in dry skin. Age-related differences were not demonstrated.

15.2.3

Sebaceous Gland Lipids

The importance of sebaceous gland lipids for the etiology of dry skin remains controversial. However, the

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content and distribution of sebaceous gland lipids in dry skin were examined in several studies, reporting decreased or normal contents of sebaceous lipids [48, 75, 76]. Analysis of sebum-derived lipids present in the stratum corneum revealed a significant decline in free fatty acids in dry skin as compared to age-matched healthy controls, and a similar decline in triglycerides in these three groups when compared to younger controls [1].

15.2.4

Environmental Effects

Environmental humidity has been shown to contribute to the appearance of the outermost surface of the skin.

Employing a mouse model, the effects of the environmental humidity on the skin’s pathology was studied [26]. A dry environment leads to a drastic decrease of amino acid, i.e., filaggrin generation, and then to a stratum corneum imbalance and skin surface dryness.

15.2.4.1

Seasonal Changes

During the winter season, dry skin appears to be more frequent and/or enhanced. Decreased skin surface/

stratum corneum lipids have been reported in winter xerosis of Caucasians [45]. Winter-dependent decreases in skin temperature may influence the over- all biosynthesis capacity of the epidermis, leading to decreased lipid biosynthesis [1]. Depletion of ceramide 1 linoleate in winter may contribute to the formation of an intrinsically weaker stratum corneum with an increased susceptibility to xerosis. An elevation of esterified oleic acid and a decrease in linoleic acid and long-chain saturated fatty acids was found in Cauca- sian women, leading to greater fatty acid desaturation, making the skin’s outermost skin surface more vulner- able to lipid peroxidation [8, 45]. However, a seasonal change in TEWL was not described. The reduction in lipids may in turn reduce the water content of the stratum corneum, which may influence the activity of the stratum corneum proteases involved in desquamation and will interfere with the generation of NMFs. Fur- thermore, a decreased amino acid content has been found in dry skin [43].

In winter, dry skin degradation of corneodesmosomes has been found to be abnormal compared to normal controls [58]: the amounts of corneodesmosin,

desmoglein 1, and plakoglobin detected were significantly higher in winter dry skin compared with normal skin extracts. Furthermore, during the cold winter months, risk factors for the development of occupa- tional irritant hand dermatitis are increased [69]. The incidence of hand dermatitis is associated with low temperature and low absolute humidity. Thus, environmental factors influence the incidence of occupa- tional hand eczema and must therefore be taken into account in the field of dermatology.

15.2.4.2 UV Irradiation

Stratum corneum absorbs about 50 % of UVA and UVB. Lipid peroxidation and protein oxidation may be induced by UV radiation [68]. Twenty-four hours after UVB irradiation, a decrease in stratum corneum hydration was observed [33]. However, neither abnormal barrier function nor changes in the skin surface were found after repeated UV irradiation over several years. However, in UV-radiated skin of 80-year-olds (upper surface of the lower arms), a higher incidence of xerosis was detected in the skin exposed to the environment over a lifetime than in the protected body parts [57]. Further, UV-exposed dry skin was more irritable to 0.1 N NaOH than chronologic aged unex- posed skin (unpublished personal observations).

15.2.4.3 Irritants

Acute disruption of the skin barrier by tape stripping or treatment with an organic solvent or detergent elic- its a repair response in the epidermis, which rapidly results in restoration of the barrier homeostasis. In addition, acute disruption of the barrier results in an increase in epidermal DNA synthesis [42] and cytokine production [27]. Even if the barrier’s damage is slight, when it is repeated or occurs under low environmental humidity [9, 65], the damage induces an obvious epidermal hyperplasia, inflammation, and visible skin dryness.

The response to an irritant is followed by an extrusion of newly formed lamellar bodies in the intercellular space, leading eventually to a recovery of the barrier function [14]: sodium lauryl sulfate (SLS) may induce an increase in TEWL, reaching maximal values 24 – 48 h after application. The rough and scaly appear-

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ance of SLS-induced mild irritant contact dermatitis may be due to the binding of this surfactant to stratum corneum keratins, including the disturbance of keratinocyte lipid metabolism and NMF denaturation [71].

Topical application of magnesium and calcium chloride in water improves this condition. The mechanisms of efficacy might induce barrier repair from the damage by SLS. Ions such as magnesium and calcium play an important role in various biological functions within the stratum granulosum, where concentration was found to be the highest [27]. Calcium plays a role in stratum corneum desquamation. Abnormal ion distribution might cause hyperproliferative dermatoses. The effects of calcium chelating agents (EDTA, AHA) on increased desquamation (chemical peeling) suggest that divalent ions such as calcium may play a role in the regulation of desquamation.

In addition, development of dry and/or irritated skin has been observed with frequent swimming in public pools. Indeed, in vivo studies showed that the water-holding capacity of the stratum corneum in atopic patients is more sensitive to free residual chlorine exposure than that in normal controls. Free residual chlorine exposure may play a role in the development or exacerbation of xerosis and inflammation [53].

15.2.5

Diseases Associated with Dry Skin 15.2.5.1

Atopic Disposition

The noninvolved skin of atopic dermatitis (NIAD) is frequently characterized by xerosis and an impaired barrier function of the stratum corneum, as sometimes indicated by an increased TEWL. The total lipid content in atopic stratum corneum is reduced compared to normal controls [24]. The stratum corneum of atopic dry skin also contains smaller amounts of NMF than that of normal controls. The water content of the stratum corneum and the skin surface lipids are reduced in patients with atopic dermatitis compared with healthy controls [52]. Therefore, the moisture and lipid levels should be regarded as complementary factors and summarized as a hydro-lipid film of the skin.

Previous studies have demonstrated that the barrier impairment of atopic dermatitis (AD) coincides with marked alterations in the amount and composition of stratum corneum ceramides: the quantities of free extractable ceramides were significantly decreased in

atopics [5, 10, 29, 31]. The percentage of ceramide 1 is decreased compared with healthy controls [29]. In AD, the levels of ceramide 1 and 3 are significantly lower and values of cholesterol and phospholipids significantly higher compared to those in normal skin [10, 54]: ceramide/cholesterol ratios may be responsible for functional abnormalities of the skin of patients with AD [10]. Further, in the dry skin of patients with AD, protein-bound K -hydroxy ceramides are deficient and K -hydroxy fatty acids were increased [28]. In healthy epidermis, K -hydroxy ceramides comprise 46–53 wt%

of total protein-bound lipids, whereas in NIAD they decrease to 23 – 28 wt %, and in lesional skin of AD patients it is as low as 10 – 25 wt %.

Macheleidt and co-workers compared the proliferation rate and the amount of newly synthesized free ceramides during the proliferation stage [28]. In vitro, the proliferation of AD keratinocytes was lower and the amount of newly synthesized free ceramides reduced compared to keratinocytes from healthy controls.

[¹⁴C]-serine incorporation in the total ceramide frac- tion of the lesional skin of AD patients was decreased by 46 % compared to the skin of healthy controls.

Free fatty acids are essential for epidermal barrier function. In lesional and NIAD, the total amount of free fatty acids was unchanged; however, that of free VLCFA (> 24 carbon atoms) was remarkably reduced to about 25 % of the amount determined in healthy control skin [28]. A decreased amount of total ceramides (especially ceramide 1) and VLCFA may be responsible for functional abnormalities of the skin of AD patients.

A decreased stratum corneum ceramide content could be due to altered glucosylceramide and sphingomyelin metabolism. To elucidate the enzyme activity of major enzymes in ceramide production and degradation, ceramidases, glucocerebrosidases, and sphingo- myelinases were examined: The activities of the two catabolic enzymes, glucocerebrosidase, and sphingomyelinase, as well as alkaline ceramidase were essen- tially unchanged in epidermal AD compared with age- matched normal controls [25]. In AD, the activity of acid ceramidase is significantly downregulated compared with healthy controls [3, 19]. Therefore, sphingosine is significantly decreased in the stratum corneum of patients with AD compared with healthy controls.

The enzyme sphingomyelin deacylase is expressed in AD dry skin [35]. This enzyme hydrolyzes sphingomyelin at the acyl site to yield its lyso-form sphingosylphosphorylcholine and free fatty acids instead cerami-

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des. The sphingomyelin deacylase activity of lesional and NIAD skin is at least three to five times higher than of healthy controls [19]. In the lesional and NIAD skin, the sphingosylphosphorylcholine content is increased over that of healthy control subjects. A reciprocal relationship between an increase in sphingosylphosphorylcholine and a decrease in Stratum Corneum (SC) ceramides was observed [38]. In contrast, SC from contact dermatitis and chronic eczema patients shows levels of sphingomyelin deacylase similar to healthy controls. Furthermore, no significant difference in the activity of sphingomyelinase has been found between AD patients and healthy controls. These data suggest a physiological relevance of sphingomyelin deacylase function in vivo in the ceramide deficiency found in AD.

In conclusion, imbalances of stratum corneum sphingolipid metabolism may be one of the underlying factors for dryness of NIAD. Furthermore, despite a shorter turnover time shedding smaller corneocytes, the number of stratum corneum cell layers in atopic dry skin is higher than that of controls.

15.2.5.2

Ichthyosis and Psoriasis

An accumulation of corneocyte aggregates on the skin’s surface may be due to an increased production of corneocytes, as in psoriasis [34], or to a delayed desquamation, as in lamellar ichthyosis [40]. In psoriatic plaques, the ceramide 1 concentration is significantly decreased, permitting the assumption that the increased TEWL is based on an alteration of the ceramide distribution [34].

The elucidation of the molecular genetics of X- linked ichthyosis (RXI) has had a major impact on our understanding of stratum corneum turnover. For equi- librium cholesterol sulfate, catalyzing cholesterol sulfate to cholesterol and free sulfate is required. An accumulation of cholesterol sulfate, as it is the case in RXI, lead to disturbances in desquamation. Application of cholesterol sulfate on mouse skin causes increased scaling, possibly by inhibition of serine proteases [50].

Mutations of the gene for epidermal transglutamin- ase, which catalyzes the cross-linking of proteins to form the cornified envelope, lead to recessive autoso- mal lamellar ichthyosis.

15.2.5.3

Associated Systemic Diseases

In association with systemic diseases, skin that appears dry has been described. Hypothyroidism, for example, affects 4 % – 10 % of women, and dry skin is one of the frequently described symptoms [44]. Further, eating disorders are frequent in Western countries. Particu- larly young women feel obliged to meet fashion demands in terms of weight. Dermatological examination of 24 anorexia nervosa women revealed xerosis in nearly 60 % [63]. A possible explanation might in part be an inadequate consumption of vitamin C or chronic zinc deficiency. Cutaneous findings of adult scurvy present with follicular hyperkeratosis and xerosis [20].

Diabetes mellitus induces pathophysiological skin changes, including a dry appearance. Patients com- plain about pruritus. Furthermore, a decreased skin elasticity is measurable in diabetes mellitus patients [73]. Employing a type I diabetes mouse model, a reduced stratum corneum water content with unchanged TEWL was observed [49]. While the stratum corneum triglyceride content was lower than in normal controls, levels of ceramides, cholesterol, and fatty acids were comparable. Epidermal turnover was reduced with unchanged epidermal differentiation marker proteins.

Approximately 20 % of HIV-infected patients com- plain of increasing dryness of the skin. Typically, the xerosis is most prominent on the anterior lower legs. In winter, skin dryness is more severe in HIV-infected patients, manifesting as itching with areas of erythem- atous papules and fine scaling on the posterior arms and lower legs. Patients with an atopic diathesis are even more predisposed. Excessive or frequent bathing with soaps precipitates this condition. Premature expression of involucrin has been reported as a feature of xerosis [12]; however, in HIV xerosis the epidermal distribution of involucrin was comparable to normal controls [47].

In uremic patients, dry, itchy skin reveals a decreased water content compared to healthy controls.

However, no correlation between xerosis and pruritus could be revealed [39]. Dry skin has also been described in other systemic diseases, such as Hodgkin’s disease, mycosis fungoides, sarcoidosis, myeloma, and carcinoma.

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15.2.6 Medication

Medication that is involved in the lipid metabolism might also affect epidermal lipid metabolism and eventually lead to dry skin. These drugs include nicotinic acid, butyrophenones, cimetidine, triparanol, and reti- noids, such as isotretinoin and etretinate. Mild to mod- erate cutaneous peeling, xerosis, and erythema are indeed experienced by a majority of patients undergoing retinoid (tretinoin) therapy [2].

15.2.7 Skin Aging

Dry skin, known to frequently affect the elderly [60], is linked to changes in stratum corneum lipid content and composition [11], reduced water binding capacity [45], and seasonal influences [58]. Basal barrier function is not perturbed in the elderly skin; however, when subjected to stress and irritation, a delay in barrier recovery has been observed [17]. Barrier function of the aged epidermis is less resistant to external stressors than young epidermis [16, 17]. This might reflect the slower keratinocyte metabolism of the aged, leading to a decreased biosynthetic capacity. Decreased lipid generation seems to be one of the key defects underlying the permeability abnormalities in aged skin. The intercellular lipids as well as total surface lipids are decreased in senile xerosis [16]. Comparing 20-year- olds to 60-year-olds, total lipid levels decrease by 30 % [45]. Age and skin surface lipid levels correlate in males. Women do not show such correlation, especially after menopause, as a result of the decreased andro- gens [76].

Therefore, the decreased ability of the aged epidermis to repair following habitual types of injury, such as the daily use of detergents, rubbing the skin surface with a rough towel to remove superficial stratum corneum layers and regular application of alcoholic solu- tions containing menthol, may eventually induce barrier perturbation, reactive increased production of corneocytes, and finally visible scaling combined with a feeling of dryness of the skin’s surface. Barrier perturbation, i.e., imbalance of stratum corneum constitu- ents followed by visible scaling, has been discussed [18].

Many elderly people suffer from dry skin and expe- rience exacerbation more frequently in the winter, i.e.,

under dry and cold environmental conditions. Epider- mal changes in a dry environment have been shown [7, 9]. Although the observed decrease in the stratum corneum lipids in older people may well explain the high incidence of winter dry skin, the progression toward asteatotic eczema cannot be accompanied solely by a quantitative decrease in lipids, suggesting that the evo- lution of dry skin is also associated with other moisturizing factors and/or environmental stimuli [1]. Immu- nohistochemical examination of the aged facial skin revealed an unchanged filaggrin content [4, 67]. In contrast to facial skin, low profilaggrin biosynthesis has been attributed to xerosis of the lower leg [22].

15.3 Conclusion

The elucidation of the pathophysiology of skin diseases associated with increased desquamation and xerosis might help to understand dry skin on a molecular level.

A better understanding of desquamation and the mechanisms involved may eventually lead to a uniform reproducible definition of dry skin and then allow evidence-based treatments for skin disorders associated with dryness.

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