[CASE REPORT AND LITERATURE REVIEW]

Overcoming the Barrier Treatment of Ichthyosis

A Combination-therapy Approach
SUSUN BELLEW, DO; JAMES Q. DEL ROSSO, DO, FAOCD
Valley Hospital Medical Center, Las Vegas, Nevada

ABSTRACT
Ichthyosis vulgaris is an inherited disorder of keratinization that results in asteatotic scales on extensor surfaces of the
arm, legs, and trunk. A combination-therapy approach with a physiological lipid-based barrier repair topical emulsion and
ammonium lactate 12% lotion applied topically was shown to be effective at four-week follow up without any untoward
side effects. This combination therapy addresses the importance of caring for both the corneocytes (“bricks”) and the
intercellular lipid bilayer (“mortar”) for optimal benefit. (J Clin Aesthetic Dermatol. 2010;3(7):49–53.)

A
10-year-old boy presented with a long-standing
history of very dry skin involving the arms, legs,
and trunk (Figures 1 and 2). Prior treatment
regimens for the current condition were limited to use of
over-the-counter moisturizers with limited success. The
patient was in general good health with no known drug
allergies and was using no medications. Family history was
noncontributory except for his mother and one sibling
having dry skin. Physical examination exhibited dry, fine,
scaly patches on the trunk (Figure 1) and both the upper
and lower extremities (Figure 2) with sparing of the
flexural surfaces, including the popliteal, antecubital,
axillary, and inguinal regions. A diagnosis of ichthyosis
vulgaris (IV) was rendered based on the clinical features
and history. The patient was treated with a combination
regimen including ammonium lactate (AL) 12% lotion
(Lac-Hydrin 12% Lotion, Ranbaxy Laboratories,
Jacksonville, Florida), followed by a physiological lipid-
based barrier repair cream (Ec) containing ceramides,
cholesterol, and free fatty acids in a 3:1:1 ratio designed to
simulate the normal intercellular lipid bilayer (EpiCeram®
Skin Barrier Emulsion, Promius Pharma LLC,
Bridgewater, New Jersey). Both formulations were
applied sequentially twice daily diffusely to the skin
including the affected areas. At the one-month follow-up
visit, the patient had essentially complete resolution of
ichthyotic scaling and xerosis (Figures 3–5). The patient
remained clear with continued use of the ensuing weeks
and was subsequently lost to follow up.
DISCUSSION
IV is an autosomal semidominant disorder characterized
by visible scaling and dryness with noticeable sparing of
the flexural surfaces along with palmar and plantar
hyperlinearity (Figure 6).1–3 The term semidominant
refers to heterozygous individuals having a milder
phenotypic form of the disease with incomplete
penetrance as opposed to homozygotes who have a more
severe manifestation.1,3 Individuals with IV have frequent
nonsense mutations in the filaggrin gene (FLG), which
alters the expression of profilaggrin, a high-molecular
weight filaggrin precursor.3 Profilaggrin is housed in the
granular layer of the epidermis by keratohyalin granules,
which are reduced in number or completely absent in
patients with IV (Figure 7).3–5 Subsequently, these
alterations lead to reflexive epidermal hyperplasia,
“clumping” of corneocytes, and abnormal desquamation
resulting in the clinical manifestation of scaling.6
The role of filaggrin in the differentiation of the
epidermis as well as in the maintenance of epidermal
barrier function is a crucial one. Upon terminal
differentiation, profilaggrin is proteolytically cleaved into
multiple filaggrin peptides that aggregate keratin
filaments, thus the name filaggrin or filament aggregating
protein.3,4 In many patients with IV, there is concurrent
association with atopic dermatitis (AD).7,8 In fact, studies
show that FLG mutations found in IV are also strongly
associated with atopic dermatitis and secondary allergic
diseases.7

DISCLOSURE: Dr. Bellew reports no relevant conflicts of interest. Dr. Del Rosso is a consultant, speaker, and or researcher for Allergan, Coria,
Galderma, Graceway, Intendis, Medicis, Onset Therapeutics, Ortho Dermatology, PharmaDerm, Promius, Quinnova, Ranbaxy, SkinMedica, Stiefel,
Triax, Unilever, and Warner Chilcott.
ADDRESS CORRESPONDENCE TO: James Q. Del Rosso, DO; E-mail: jqdelrosso@yahoo.com

49 [ July 2010 • Volume 3 • Number 7] 49

Figure 1. Dry, scaly patches on the trunk
Figure 3. Response to treatment (one-month follow up)
“MAJOR PLAYERS” OF THE STRATUM CORNEUM
Our understanding of the complexity of the stratum
corneum (SC) has come a long way from the SC being
considered an inactive “plastic film.” Advances in benchtop
research have led to our recognition that the SC is a
structurally and biochemically dynamic entity essential to
maintaining the homeostatic function of the epidermal skin
barrier.9 In healthy skin, the SC is essentially an
impermeable membrane to the environment. It only allows
for small amounts of physiological transepidermal water
loss (TEWL), enough to maintain hydration of the corneal
layer. Adequate SC hydration is needed to maintain skin for
flexibility with avoidance of microfissuring, to catalyze
hydrolytic enzyme activity involved in normal corneocyte
maturation and physiological desquamation, and desmolysis
allowing for shedding of individual corneocytes.10 To
simplify this highly specialized structure, the SC has been
compared to a brick wall consisting of protein-enriched
corneocytes or terminally differentiated keratinocytes
(bricks) enveloped by a surrounding intercellular lipid
bilayer membrane (mortar).11 The corneocytes are “spot-
welded” by corneodesmosomes at several points and
stacked on top of one another.12
The corneocyte bricks constitute a scaffold framework
50 [July 2010 • Volume 3 • Number 7]
Figure 2. Dry, scaly patches on both the upper and lower
extremities with sparing of flexural surfaces
Figure 4. Response to treatment (one-month follow up)
around which the intercellular lipid bilayer is able to wrap
itself in a continuous fashion.6 The intercellular lipid bilayer
also provides a tortuous pathway preventing excessive
TEWL and acts as a physical barrier for environmental
stresses.6 Corneocytes mainly consist of protein-rich keratin
filaments encapsulated within a protein/lipid polymer
structure, referred to as the cornified cell envelope (CE).13
The lipid component of the CE interacts directly with the
lipid-rich intercellular mortar.13
Another important player in maintaining epidermal
barrier integrity and function is natural moisturizing factor
(NMF) found within corneocytes. NMF, which is derived
from filaggrin, comprises a mixture of amino acids, lactic
acid, urea, citrate, sugar, and inorganic ions, and functions
to serve as the inherent humectant of the epidermis
(“nature’s humectants”).14 Mechanistically, NMF absorbs
atmospheric water and retains necessary hydration that is
vital for proper functioning and turnover of the SC.15 NMF
is produced by proteolysis of filaggrin during corneocyte
maturation, and its release is tightly regulated by
environmental humidity as well as the filaggrin/keratin
complex.15 This complex is resistant to proteolysis and
ultimately prevents premature degradation of filaggrin.15
The intercellular lipid bilayer (mortar) has the arduous
Figure 5. Response to treatment (one-month follow up)
task of acting as the permeability barrier of the skin
consisting mainly of ceramides (approximately 50% by
mass), cholesterol (25%), and free fatty acids (10–20%)
(Figure 8).16–18 This ratio is crucial as deficiencies in any of
the intercellular lipid components can result in epidermal
barrier dysfunction, characterized by an increase in
TEWL, subsequent impairment of physiological
desquamation with development of scaling, and reduced
skin plasticity leading to micro- and macrofissuring of the
skin.12 The majority of lipids are derived from lamellar
bodies (LBs) in the stratum granulosum layer of the
epidermis.10 During terminal differentiation, LBs bud off in
a trans-Golgi-like network and secrete their precursor
lipid contents into the interface of the stratum granulosum
and the SC where they are cleaved by co-secreted
enzymes to generate ceramide-dominant lipid membrane
structures.19 These lipids then bind to form the
intercellular lipid bilayer membrane, referred to as the
mortar, of the SC.
RATIONALE FOR COMBINATION TREATMENT FOR
ICHTHYOSIS VULGARIS
There is limited information available regarding effective
therapies for IV. Most conventional treatment regimens for
IV, and even for xerosis, focus on either the bricks or the
mortar components of the SC. A limitation of this approach
is failure to address the functional interdependence of both
the brick and mortar components. It seems more prudent to
incorporate therapy aimed at treating both components of
the epidermal barrier, that is the corneocytes and the
intercellular lipid bilayer membrane. The current case
illustrates the combined use of AL 12% lotion and Ec cream
which resulted in resolution of IV.
Much of the evidence supporting the combination topical
therapy approach selected for treatment of this patient is
derived from research in patients with AD who also have
similar FLG mutations leading to filaggrin deficiencies.
Although inflammation is not inevitable or generally visible
clinically in IV, the common association of AD and IV in the
same individuals is both a clinical and biological link. The
most immediate response to deficiencies in filaggrin as seen
in patients with IV and AD is decreased corneocyte
51 [ July 2010 • Volume 3 • Number 7]
Figure 6. Palmar hyperlinearity in ichthyosis vulgaris
hydration.20 To this end, the ability of AL to enhance SC
hydration in the treatment of IV has been extensively
studied.21–24 AL is lactic acid (an alpha-hydroxy acid)
buffered with ammonium hydroxide to provide a pH of 4.4
to 5.5.25 As mentioned earlier, lactic acid was identified as
one of the major constituents of NMF, and thus is used as
moisturization therapy for xerotic skin conditions.22
Further studies found that AL has additional properties
beyond its role as a humectant. In-vivo studies indicate
that the L-isomer of lactic acid stimulates ceramide
biosynthesis, thus treating the mortar component by
enhancing the intercellular lipid bilayer.26 Furthermore,
topical AL was shown to reduce cutaneous atrophy induced
by application of potent topical corticosteroids, with AL
counteracting both the epidermal thinning and the decrease
in dermal matrix seen with continued corticosteroid use.27
It has been illustrated that a topical AL 2 to 10% solution
increased dermal glycosaminoglycans.24 Moreover, a study
that compared AL 5%, AL 12%, and a nonlactate emollient
showed that patients who applied AL 12% lotion exhibited
a slower relapse of xerotic skin changes during the
regression period after treatment was discontinued.28
When stratum corneum barrier integrity is disrupted, a
repair sequence is rapidly initiated to reinstate
homeostasis.29 Studies have shown that application of
complete physiological lipid mixtures containing ceramides,
cholesterol, and fatty acids in the proper ratio facilitates the
barrier recovery mechanism. In contrast, key lipids applied
individually, and not as a physiologically rational mixture,
can actually prolong the barrier repair process.30
Physiological lipid mixtures, such as Ec cream, traverse the
epidermis and the individual lipid components may be
incorporated into lamellar bodies at the granular layer after
application. Nonphysiological occlusive agents (i.e.,
petrolatum ointment) remain localized and primarily
restricted to the superficial stratum corneum.31
As a result, an occlusive agent, such as petrolatum, may
create a rapid decrease in TEWL; however, a sustained
effect on barrier repair is limited. On the contrary, a
physiological lipid mixture, such as Ec cream, may be
slower in onset; however, the therapeutic impact on barrier
repair and recovery is greater in benefit and of more
51

Figure 7. Molecular abnormalities in ichthyosis vulgaris
Figure 8. Relative concentrations of individual lipid
components of the intercellular lipid membrane
Figure 9. Physiologic vs. nonphysiologic lipids. Epidermal
barrier recovery time course. Adapted from Elias PM. Physiological
lipids for barrier repair in dermatology. In: Draelos Z, ed. Procedures in
Cosmetic Dermatology. Cosmeceuticals. Elsevier, Inc. 2005:63–70.
sustained duration than an occlusive agent or
nonphysiological lipid formulation (Figure 9).
Ec cream is a ceramide dominant barrier repair cream
containing all three key lipids (ceramide, cholesterol, free
fatty acids) in an optimized 3:1:1 molar ratio, thereby
increasing the lipid bilayer and ultimately treating the
mortar component of the barrier.32,33 In a multicenter,
52 [July 2010 • Volume 3 • Number 7]
randomized, investigator-blinded, clinical trial of 121
patients with moderate-to-severe AD, Ec cream was found
to have comparable efficacy to a mid-strength topical
corticosteroid with a favorable safety profile.33 Ec cream
was approved by the United States Food and Drug
Administration in April 2006 for treatment of burning and
itching associated with dry skin conditions, such as AD,
irritant contact dermatitis, radiation dermatitis, and other
dermatoses.34
SUMMARY
IV is an autosomal semidominant inherited disorder of
keratinization characterized by dry, fine scales on the
extremities and trunk with sparing of the flexural surfaces.
IV is associated with FLG mutation leading to altered
profilaggrin production and subsequent decreases in
filaggrin. Treatment should be directed toward caring for
both bricks and mortar components of the stratum
corneum. The combination therapy of Ec and AL 12% lotion
addresses both elements in order to optimize treatment for
the IV patient.
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