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Review

Critical assessment of diabetic


xerosis
Gerald E Pierard, Claudine Pierard-Franchimont & Andre Scheen

1. Introduction University Hospital of Lie`ge, Department of Dermatopathology, Laboratory of Skin Bioengineering
and Imaging (LABIC), Lie`ge, Belgium
2. Structure and function of the
stratum corneum Introduction: Diabetes mellitus is commonly responsible for skin changes
3. Xerosis severity grading including discrete to mild xerosis.
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4. Corneodynamics Areas covered: This review focuses on some selected relevant bioinstrumental
methods assessing diabetes xerosis. Peer-reviewed articles on objective non-
5. Global electrometric
invasive methods were scrutinized. The reviewed methods address i) the xero-
assessment and skin
sis severity grading scale, ii) corneodynamics referring to the desquamation
capacitance mapping
rate, iii) electrometric assessment of skin hydration including skin capacitance
6. Imperceptible perspiration
mapping and iv) implication of the imperceptible perspiration. The subjective
7. Emollient effects clinical assessment often fails to disclose diabetic xerosis with confidence and
8. Conclusion precision. By contrast, a multipronged biometrological approach identifies a
9. Expert opinion cluster of diabetic patients who experience alterations in the structural and
functional maturation of the stratum corneum.
Expert opinion: A multipronged biometrological approach helps identifying
the changes in the stratum corneum of diabetic xerosis. There is a continuum
between the dry skin feeling, xerosis and ichthyosiform presentations,
For personal use only.

particularly on the shins and feet of diabetic patients.

Keywords: dermoscosmetics, diabetes, neuropathy, skin, stratum corneum, xerosis

Expert Opin. Med. Diagn. (2013) 7(2):201-207

1. Introduction

It has been reported that a majority of diabetic patients presented with skin changes
at some periods in their life [1,2]. A cluster of the diabetes-associated skin conditions
results from the direct metabolic dysfunctions. Accumulation of advanced glycation
end products, as well as progressive damages to the vascular, neural and immune
systems contribute to other skin disorders [3]. One of the most common diabetes-
related condition corresponds to a discrete dry skin feeling potentially evolving
to more severe xerosis, ichthyosiform conditions and callus formation [1,4,5], which
in turn is at the origin of diabetic foot ulceration.
The keratinization, more properly called cornification process, exerts a key role in
the hydration physiology of the stratum corneum (SC). This process covers both
morphological and molecular events taking place in the living keratinocytes ahead
of the formation of dead anucleated corneocytes of the SC. On most body parts,
the SC typically consists of 12 -- 20 layers of flattened corneocytes. Each of these
cells is about 1 m thick and covers an area averaging approximately 1000 m2.
However, the average corneocyte surface area is commonly influenced by age,
anatomical site and any change altering the epidermal renewal. When the average
corneocyte size increases such as with aging [6], it is assumed that the corneocyte
transit time is prolonged in the SC.
This review focuses on selected non-invasive methods applicable to diabetic
xerosis. They explore its physiopathology and the corrections brought by some
dermocosmetic products.

10.1517/17530059.2013.728585 2013 Informa UK, Ltd. ISSN 1753-0059, e-ISSN 1753-0067 201
All rights reserved: reproduction in whole or in part not permitted
G. E. Pierard et al.

3. Xerosis severity grading


Article highlights.
. Xerosis corresponding to a structural alteration of the Xerosis grading is important for a proper clinical management
stratum corneum is a common ailment in diabetic patients. because emollients, urea-based formulations, salicylic acid prep-
. Current clinical grading systems of diabetic xerosis lack arations, chitin-glucan-enriched creams are indicated and active
specificity and objectivity.
.
in only a part of the whole spectrum of diabetic xeroses.
A series of non-invasive or minimally invasive
biometrological methods provide accurate information Clinical assessments of the SC aspect commonly rely on
about xerosis severity, the rate of desquamation, the ordinal grading scales [11]. Most of them suffer from vague
hydration level of the stratum corneum and the and overlapping definitions. Indeed, subjective clinical assess-
imperceptible perspiration. ments referring to visual and tactile scoring show variability
. The effects of emollients and keratolytic-enriched
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due to inconsistencies from grade to grade, and from limita-


formulations are better appreciated using dermometrology.
. The strategy directed to diabetic xerosis should help tions in reproducibility. Variations in the environmental con-
preventing and treating some ailments including the ditions commonly jeopardize such grading systems because
dry skin feeling and pruritus. They contribute to reduce hydration swells the outer SC and often camouflages
the risk of the diabetic foot syndrome. low-grade dryness/roughness, xerosis and scaling.
One of the ancillary method designed to study the outer SC
This box summarizes key points contained in the article.
layers relied on tape stripping. The use of casual sticky tapes
often proved to be unreliable for quantitative assessments
2. Structure and function of the stratum because considerable variation prevailed in the adhesion of
corneum different batches to the SC. During the past decades, investi-
gators strived relentless to provide more precise evaluation
The primary function of the SC is to act as a physicochemical tools for xerosis rating. In this field, bioinstrumentation
semi-permeable barrier against both the environment and the reduced grading uncertainties and interobserver inconsisten-
transepidermal water loss (TEWL) from the body. In addi- cies. It yielded better distinction between xerotic conditions
For personal use only.

tion, the water-holding capacity of the SC is crucial for the by increasing the accuracy, sensitivity, specificity and repro-
control of the global epidermal homeostasis and differentia- ducibility of data. Bioinstrumentation typically provided
tion. The water-holding capacity governs the SC plasticity increased positive predictive value. Hence, the power of the
and prevents physiological harsh/dry skin conditions [7,8]. majority of these methods appears superior to subjective
The turnover and assembly of corneocytes are important fac- scoring and regular clinical grading. Currently, the standard
tors controlling the water flux and retention inside the SC, operating procedures in many laboratories rely on two mini-
thus governing the overall level of SC moisturization. At the mally invasive sampling methods, namely the cyanoacrylate
molecular level, the SC is a selective lipidic barrier. Its perme- skin surface strippings (CSSS) and strippings with adhesive
ability largely depends on the nature, integrity and assembly coated discs (SACD) under controlled pressure. In vivo con-
of the intercorneocyte lipid layers. trolled optical visualization of the skin surface is further
Each corneocyte contains a water-insoluble protein scaffold used with camera recordings and image analysis.
made predominantly of a highly organized keratin microfi-
brillar matrix. This meshwork is encapsulated in a protein- 3.1 Cyanoacrylate skin surface stripping
and lipid-enriched shell showing variable maturation among CSSS sampling consists of harvesting a uniform continuous
corneocytes. Two distinct types of cornified cell envelopes sheet of SC using a cyanoacrylate bond with a transparent
were contrasted as fragile and rigid, also called immature plastic strip. After a 15 -- 30 s polymerization time, the sample
and mature [9]. Each corneocyte is further embedded in a is lifted off. It is stained by a variety of microscopical stains
hydrophobic domain formed by lipid bilayers. The global and examined under a low-power magnification.
structure guarantees the SC water-holding capacity, and limits Several grades of diabetes-related orthokeratotic hyperkera-
the trans-SC water flux, thus preventing dessication of the tosis are possibly distinguished using CSSS [12]. Grade 0 corre-
living epidermis. Both the SC structure and TEWL result sponds to the absence of hyperkeratosis, except for some
from dynamic processes that are possibly altered in diabetes discrete focal accumulations of corneocytes in the primary
mellitus. Accordingly, the SC homeostasis and hydration are order lines of the skin. Grade 1 corresponds to a continuous
commonly altered in this disease. linear hyperkeratosis confined to the primary lines or to spotty
Any xerotic process is a combination of SC thickening, tidy hyperkeratosis predominating at adnexal openings, either at
corneocyte assembly with lowered flexibility, harsh surface and hair follicles or acrosyringia. Grade 2 corresponds to focal
lowered hydration of the uppermost SC layers [10]. Weathering hyperkeratosis of the skin surface plateaus covering less than
xeroses (related to surfactants, cold, dry, windy environment, 30% of the sampling surface. Grade 3 is similar to grade 2,
friction, pressure, etc.) and metabolic xeroses (related to diabetes but with a xerotic area extending over 30% of the CSSS. Grade
neuropathy and peripheral vascular disease, atopy, ichthyosiform 4 is defined by an homogeneous and diffuse hyperkeratosis
conditions, aging, etc.) are conveniently distinguished. with persistence of the primary order lines. Grade 5 resembles

202 Expert Opin. Med. Diagn. (2013) 7(2)


Critical assessment of diabetic xerosis

grade 4, but hyperkeratosis is uneven with loss of the pattern of called the squamometry index (SQMI), which refers to the
the primary lines. The excessive SC thickening results from a Chroma C* corresponding to (a*2 + b*2).
multilayered stacking of corneocytes. Squamometry is currently used for several purposes.
Accordingly, different names were coined and defined,
3.2 Ultraviolet light-enhanced visualization including squamometry X, which specifically refers to the
Similar aspects are provided in vivo using a CCD camera assessment of xerosis [15]. A linear correlation exists between
equipped with an internal UV-emitting unit (VisioScan the amount of harvested corneocytes and SQMI. Data are
VC98, C+K electronic, Cologne, Germany). The video sensor influenced by the presence of parakeratotic cells.
chip is closely applied to the skin surface in order to avoid
shadows. The uniform lighting of the SC brings out a sharp 4. Corneodynamics
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picture of a 6*8 mm skin area. The high resolution of the


equipment allows close assessments of the SC. The digitaliza- The SC is subject to constant self-renewal. Diabetes com-
tion unit configures the image in 256-gray-level pixels, where monly slows down the turnover time of the SC, and alters
0 is black and 256 is white. This procedure leads to the so- the evenness of this process [4,7]. CSSS are conveniently used
called UV-light enhanced visualization (ULEV) method [13,14]. for objectively assessing the rate of SC renewal. For the pur-
The ULEV pictures conveniently reveal any hyperkeratotic and pose of corneodynamics assessment, the SC has to be stained
scaly aspect of the skin surface. The lesions look whitish, down to its deeper layers. After a lag period lasting about
contrasting with the gray aspect of the normal-looking skin [13]. 10 days, a CSSS is collected to be examined under light or
fluorescence microscopy according to the staining compound.
3.3 Surface evaluation of living skin Dansyl chloride is a time-honored fluorescent compound
The SELS (surface evaluation of living skin) method is an for the SC. For years, the test relied on daily assessments of
additional way, allowing direct and non-invasive measure- the decline in the clinical fluorescence [16]. The rate of SC
ment of the skin topography using the VisioScan camera. renewal was determined by the duration of the fluorescence
The actual skin picture can be presented with false colors persistence. However, this clinical test was difficult to inter-
For personal use only.

and viewed either two-dimensionally or tridimensionally. pret because it was uneasy to accurately determine the time
Different parameters are displayed in the evaluation of the point when fluorescence was lost. This was in part due to
skin surface. For instance, the scaliness parameter (SEsc) the uneven fade out of fluorescence at the skin surface. The
aims at representing the xerosis grade [14]. CSSS procedure is a variant method performed at a fixed
time after dansyl chloride application. The fluorescence pat-
3.4 Strippings with adhesive coated discs tern is quantified using image analysis under the fluorescence
Groundbreaking work using the SACD method has reached microscope [17].
recognition for fundamental research, clinical experimenta- A number of topical products extract dansyl chloride from
tion and applied dermocosmetology [6,8,15]. The SACD the SC [18]. Hence, for testing the product efficacy on xerosis
sampling device is a crystal-clear pressure-sensitive while avoiding any dansyl chloride extraction, the in vivo test
adhesive-coated disc (D-squame, Cuderm Corp., Dallas, should begin with the application of the test product for a
TX; Corneofix, C+K Electronic). Such specific sampling dozen of days. In a second step, dansyl chloride should be
material exhibits adequate rigidity and adhesion to uni- applied without any further application of the test product.
formly harvest loose corneocytes from a fixed area of the A risk of contact allergy and systemic resorption of dansyl
SC. The disc is applied to the skin surface using a gauge chloride was reported [19]. Hence, there is some limitation
spring dynamometer to ensure a calibrated pressure usually for its use, particularly in subjects involved in a series of
in the range 100 -- 250 g/cm2. Both the pressure and the similar tests. Dihydroxyacetone was offered as a surrogate
time of application of the disc influence the amount of SC SC marker [20].
removed. A short-time (5 s) SACD application harvests less
corneocytes from the stratum disjunctum than a longer 5.Global electrometric assessment and skin
time (1 h) application. Such difference is due to the occlu- capacitance mapping
sion time modifying the SC hydration and cohesion between
corneocytes. Seasonal and other environmental variations Skin electrical properties are influenced by i) the surface
alter the amount of harvested SC [10]. texture and microrelief together with ii) the water and electro-
A wealth of applications have benefited from a 1-min lyte content inside the SC and iii) the sweat production.
staining procedure using toluidine blue and basic fuchsin in Measuring electrical capacitance is a convenient although
30% ethanol at pH 3.4. Such samples are suitable for both indirect way to appreciate any changes in these physiological
microscopic examination and reflectance colorimetry. This parameters [21-23]. The capacitance method is rooted on the
latter assessment was coined squamometry [15]. For that pur- permittivity of water (" = 81), which is higher than for most
pose, the color of each specimen is measured using reflectance other molecules. Thus, the dielectric characteristics of the
colorimetry. The most convenient colorimetric parameter was SC mainly depend on its water content. According to the

Expert Opin. Med. Diagn. (2013) 7(2) 203


G. E. Pierard et al.

location of the measurement site, sources of error and varia- a combination of two or more patterns of sweating abnor-
tion in the data are encountered, including sweat production, malities and even from global anhidrosis. The extent in body
occlusion of the sweat ducts and density in vellus hairs, as well surface anhidrosis was reported to be correlated with the seve-
as the electrolyte content of the SC and some artifacts from rity of clinical dysautosomia [30,31]. Fine-tuning the objective
topically applied xenobiotics. Regular devices devoted to skin assessments of discrete sweat gland dysfunction in diabetes
capacitance measurements provide average electrometric values has not received much attention so far using recent sensitive
for the global skin area covered by the sensor probe. Hence, biometrological methods [28].
there is no information about the possible heterogeneity in At rest, water evaporation from each sweat pore at the
the measured physical parameter over the test area. skin surface is added to the regular TEWL for creating the
Over the past few years, a new advance was made, with the so-called insensible perspiration corresponding to the global
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skin capacitance mapping/imaging (SCM) method, represent- skin surface water loss (SSWL) [32]. This latter parameter is
ing a unique type of non-optical skin surface imaging [24,25]. not perceptible at the clinical observation. The literature is
This method relies on fine-tuned electrometric measurements occasionally quite confusing regarding the clear-cut distinc-
of the skin surface properties. It represents a physiological and tion between TEWL and SSWL. The imperceptible perspira-
medical application of the silicon image sensor technology tion is conveniently observed using SCM. Tiny black dots
initially designed for identifying fingerprints in security pro- mark the discretely active sweat gland openings and the SC
cedures. The same electrometric assessments of the upper appears dull. This aspect has little influence on the casual
layers of the SC represent a convenient non-invasive way TEWL determinations. When sweating is more active, SCM
assessing the SC hydration. Such properties are closely related black dots become larger and some merge to form irregular
to a series of specific SC structures and functions. dark puddles. Because sweat appears as black dots, it is possi-
The SCM method currently relies on the unique ble to measure its contribution to the SCM-derived mean
SkinChip device (ST microelectronics, Geneva, Switzerland gray level by thresholding the values.
and LOreal, Paris, France). This specific sensor is dedicated At rest, diabetic subjects exhibit symmetrical sweating with-
for computer recordings of both the skin surface hydration out any significant difference between both forearms and legs.
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and microrelief. It contains a network of 92,160 microcapaci- No significant differences were found in both the Corneome-
tors orderly dispersed on a 18*12.8 mm plate protected by a ter average capacitance (CMAC) value and TEWL between
thin silicon oxide layer. The probe must be closely applied the upper and lower limbs. By contrast, the mean SCM was
to the skin surface for approximately 5 s in order to collect significantly lower on the legs compared with the forearms.
relevant information without interfering with both the water In addition, the mean SCM on the forearms was significantly
flux through and water collection inside the SC. higher in diabetic patients than in healthy subjects [28].
In practice, the real-time SCM images are acquired and Diabetic neuropathy predominantly affects the distal por-
displayed on the computer screen. They provide simultaneous tions of the sensory motor innervation [30,31]. As a result,
SC capacitance measurements every 50 m over the test area. eccrine hypohidrosis develops in time on the legs, and a reac-
Capacitance values of the superficial SC appear as pixels in a tional hyperhidrosis is expected to occur on the upper body
range of 256 gray levels. The darker pixels correspond to high regions [28]. Such conditions become obvious in severe cases
capacitance (hydrated) spots, whereas the clear ones represent of diabetic neuropathy and during psychological stress or
the lower capacitance (dry) values. In addition, other specific increased body temperature such as after intense physical exer-
skin parameters are characterized. On a flat skin surface, the cise. Globally, after discrete physical exercise, SSWL, CMAC
mean gray level of the image represents the average SC hydra- and the mean SCM remain positively correlated [28,29].
tion. The SC commonly exhibits an heterogeneous pattern of
corneocyte hydration, particularly during aging [26,27] and in 7. Emollient effects
diabetic xerosis of mild-to-moderate intensity as well [28].
Many consumers believe that emollients, moisturizers and
6. Imperceptible perspiration hydrating creams actively increase the water content in the
SC. By contrast, a number of physicians perceive moisturizers
Eccrine sweating is under the control of the cholinergic sympa- as emollients softening the SC and removing its uppermost
thetic innervation. It plays an essential role in regulating body layers [4,33,34]. Indeed, the term moisturizer does not imply
temperature in physiological and pathological conditions [29]. that water is being added to the SC [35]. Traditionally, SC
This function is altered by some systemic diseases including moisturization is expected to follow reduction in TEWL by
diabetic neuropathy, which commonly involves the distal sen- occlusion. However, such claim is rarely supported by exper-
sorimotor innervation [30,31]. The resulting peripheral sweating imental evidence in clinical settings. In fact, moisturizers are
deficit is responsible for unequivocal abnormalities of length- used to fill in some tiny cracks at the skin surface and to
dependent thermoregulatory sweating. Other sweating changes provide the SC surface with a soothing protective film. The
in diabetes include segmental hypohidrosis and more rarely a products help the process of corneodesmolysis while keeping
set of dermatome involvement [31]. Some patients suffer from it in the physiological range [35-40]. Indeed, some moisturizers

204 Expert Opin. Med. Diagn. (2013) 7(2)


Critical assessment of diabetic xerosis

improve the appearance and tactile properties of the skin, the imperceptible perspiration. This function in unstimulated
including diabetic xerosis [4]. As an inert epicutaneous layer, conditions is clearly observed using SCM. Any correlation
they are thought to redistribute water in the superficial layers with other consequences of diabetes complications merits to
of the SC and to reduce skin friction. Of note, emollients be investigated.
probably represent a first approach to prevent the callus for- Emollients represent the current preventive and therapeutic
mation in the diabetic foot syndrome [37,41]. management of diabetic xerosis.

8. Conclusion 9. Expert opinion

Most dedicated dermometrology assessments of diabetic xerosis During the past decades, much progress has been made in the
are valuable because their sensitivity and objectivity often appear
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design of dermometrological methods allowing objective and


undisputable. However, their respective specificity is much accurate measurements of skin changes. Some of the methods
weaker and should not dismiss the global evaluations best are useful in the management of related conditions encompass-
obtained by the non-instrumental expertise. The global three- ing the dry/rough skin feeling, xerosis, ichthyosiform presenta-
pronged approach using instruments, trained assessors and tion and the diabetic foot syndrome. In addition, they help the
self-assessments provides a good opportunity to evaluate the preventive and therapeutic managements of these conditions.
xerotic status and increases the confidence of the evaluations. The cluster of xerotic presentations appears to be particu-
Data gained by instruments add quantification to the sub- larly related to the microangiopathy and neuropathy affecting
jective perception by the patient and/or the physician. Non- diabetic patients. Possible correlations between xerotic mani-
invasive measurements reveal changes in the functional prop- festations, the duration of diabetes and the poor glycemic con-
erties of the skin, which are not readily accessible at the visual trol have not been searched so far. Similarly, any association
and tactile examinations. This situation represents an advance with nephropathy and retinopathy remains unsettled. Some
in knowledge when it describes a relevant clinical aspect. studies could be initiated introducing xerosis biometrology
Unfortunately, it may represent hype in some instances. in the assessment procedures.
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Any significant difference yielded by instrumental methods An extensive arsenal of emollients is available. Emollients
between two conditions, but lacking clinical relevance sug- still have a pivotal role to fulfill in this field of pathology
gests discrepancies between the two assessments regarding because the biological origins of diabetic xerosis are out of
their sensitivity and specificity. access for any current drug. Moisturizers basically act on the
In some instances, surrogate parameters are used to assess water concentration gradient in the SC in two ways: i) by
the efficacy of therapies. This approach does not represent a restoring, retaining or increasing moisture in the SC allowing
direct measure of the benefit of treatment. However, carefully the addition of water from the dermis and stratum Malpighi
chosen and validated surrogate parameters provide insights to or conversely from the applied product and ii) by occluding
queries that would typically require much complicated trials if the skin surface, impeding TEWL and causing a buildup of
the specific targeted end point had to be assessed. One exam- moisture in the SC. These modes of action are commonly
ple of such a surrogate parameter is the determination of skin combined in the same product. There are, however, excep-
electric properties as a measure of the SC hydration. tions, such as petrolatum or floating (spreading) bath oils
Some diabetic patients suffer from xerosis similar to senile that are considered to work only by forming a semi-
xerosis. The skin condition ranges from a dry/rough skin feeling occlusive layer on the SC. Some of the formulations are
to obvious xerosis and even to an ichthyosiform presentation. designed for a general use in the population irrespective of
When severe, it participates to the diabetic foot syndrome [36,37]. the diabetic status or not. Other products claim to be specifi-
Due to its high prevalence and potential severity, this contin- cally targeting diabetic xerosis. Ongoing research and deve-
uum of disorders is not trivial and should be properly managed. lopment activities should be focusing on novel types of
Bioinstrumentation is useful, particularly in the assessment formulations. In addition, it would be worth to evaluate the
of the shins and feet of diabetic patients suffering from effects of age and environmental conditions on diabetic
microangiopathy and peripheral neuropathy. xerosis in order to design adequately preventive measures.
Grading the xerosis severity is important both for defining
the skin changes and assessing the effects of treatment or pre- Acknowledgments
vention. Objective comparisons of the emollient effects
become possible. Corneodynamics is a method bringing a The authors appreciate the excellent secretarial assistance of
dynamic information about the renewal rate of the SC. Any I Leclercq and M Pugliese.
boosting effect of medications on this parameter would prob-
ably be welcome in diabetic xerosis. Among the electrometric Declaration of interest
assessments of the SC moisture, SCM appears to be the most
promising tool in diabetic patients prone to xerosis. The The authors state no conflict of interest and have received no
impairment in autonomic innervation of sweat glands alters payment in preparation of this manuscript.

Expert Opin. Med. Diagn. (2013) 7(2) 205


G. E. Pierard et al.

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