Celiac Disease and Dermatologic Manifestations: Many Skin Clue to Unfold Gluten-Sensitive Enteropathy

Abstract

Cutaneous manifestations of intestinal diseases are increasingly reported both in the adult and in the children, and this association cannot longer be considered a simple random. Besides the well-known association between celiac disease (CD) and dermatitis herpetiformis (DH), considered as the cutaneous manifestation of gluten-dependent enteropathy, is more frequently reported also the association with other mucocutaneous diseases. Among these there are both autoimmune, allergic, and inflammatory diseases, but also a more heterogeneous group called miscellaneous. The knowledge about pathogenic, epidemiological, clinical, and diagnostic aspects of CD is increasing in recent years as well as those about DH, but some aspects still remain to be defined, in particular the possible pathogenetic mechanisms involved in the association between both CD and DH and CD and other immunological skin diseases. The aim of this paper is to describe the skin diseases frequently associated with CD, distinguishing them from those which have a relationship probably just coincidental.

Full text

Hindawi Publishing Corporation
Gastroenterology Research and Practice
Volume 2012, Article ID 952753, 12 pages
doi:10.1155/2012/952753
Review Article
Celiac Disease and Dermatologic Manifestations:
Many Skin Clue to Unfold Gluten-Sensitive Enteropathy
Marzia Caproni,1Veronica Bonciolini,1Antonietta D’Errico,1
Emiliano Antiga,1, 2 and Paolo Fabbri1
1Division of Dermatology, Department of Medical and Surgical Critical Care, University of Florence, 50129 Florence, Italy
2Department of Clinical Physiopathology, University of Florence, 50139 Florence, Italy
Correspondence should be addressed to Marzia Caproni, marzia.caproni@unifi.it
Received 12 January 2012; Revised 13 March 2012; Accepted 5 April 2012
Academic Editor: Govind K. Makharia
Copyright © 2012 Marzia Caproni et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Cutaneous manifestations of intestinal diseases are increasingly reported both in the adult and in the children, and this association
cannot longer be considered a simple random. Besides the well-known association between celiac disease (CD) and dermatitis
herpetiformis (DH), considered as the cutaneous manifestation of gluten-dependent enteropathy, is more frequently reported
also the association with other mucocutaneous diseases. Among these there are both autoimmune, allergic, and inflammatory
diseases, but also a more heterogeneous group called miscellaneous. The knowledge about pathogenic, epidemiological, clinical,
and diagnostic aspects of CD is increasing in recent years as well as those about DH, but some aspects still remain to be defined,
in particular the possible pathogenetic mechanisms involved in the association between both CD and DH and CD and other
immunological skin diseases. The aim of this paper is to describe the skin diseases frequently associated with CD, distinguishing
them from those which have a relationship probably just coincidental.
1. Introduction
In recent years, the knowledge about pathogenic, epidemio-
logical, clinical, and diagnostic aspects of celiac disease (CD)
has rapidly increased.
CD, also known as celiac sprue or gluten-sensitive entero-
pathy, can be defined as a permanent intolerance to wheat
gliadins and other cereal prolamins in the small bowel
mucosa in genetically susceptible individuals. The main
expression of the disorder consists in characteristic, though
not specific, small intestine lesions that impair nutrient
absorption and improve upon withdrawal of the responsible
cereals. Nevertheless, the clinical presentation of the disease
can often be misleading as highly variable from one patient to
another, leading to frequent delays in diagnosis [1], thus it is
important to take into account both the distinction between
classical (typical), subclinical (atypical or mono-symptoma-
tic), silent (asymptomatic) and potential/latent CD [2]as
well as the extraintestinal manifestations of the disease
and/or the different associated disorders affecting different
organs and systems recently classified as autoimmune,
idiopathic, chromosomal, and miscellaneous. Among them
there are many mucocutaneous diseases. In 2006, Humbert
et al. proposed to classify skin diseases associated with CD
in those improved by gluten-free diet and those occasionally
associated with CD, dividing them into four categories:
autoimmune, allergic, inflammatory, and miscellaneous [3]
(Tab l e 1 ).
In the present paper, the main features of the skin and
oral diseases with a proven association with CD and those
that improve after a gluten free-diet were described. More-
over, other skin conditions sporadically associated with CD
as well as dermatologic manifestation secondary to nutri-
tional deficiencies due to the enteropathy were briefly report-
ed.
2. Dermatitis Herpetiformis
The most important skin disease closely associated with CD
is dermatitis herpetiformis (DH), currently considered as

2Gastroenterology Research and Practice
Tab l e 1: Skin diseases associated with CD (adapted from Humbert et al. [3].
Proved
association
Improvement in skin disease by gluten free-diet
or/and presence of serologic markers in several data
Fortuitous association
(sporadic cases reports)
Autoimmune
diseases
Dermatitis
herpetiformis
Alopecia areata
Cutaneous vasculitis
IgA linear dermatosis
Dermatomyositis
Vitiligo
Lupus erythematosus
Lichen sclerosous
Allergic diseases Urticaria
Atopic dermatitis Prurigo nodularis
Inflammatory
diseases Psoriasis
Palmoplantar pustolosis
Pytiriasis rubra pilaris
Erythroderma
Miscellaneous
diseases
Oral mucosa
Chronic ulcerative stomatitis
Necrolytic migratory erythema
Cutaneous amyloidosis
Annular erythema
Partial lipodystrophy
Generalized acquired cutis laxa
Ichthyosis
Transverse leukonychia
the cutaneous manifestation of gluten-dependent enteropa-
thy. DH, initially described by Louis Duhring in 1983 [4], is
considered an autoimmune skin disease with an estimated
prevalence range from 1,2 to 39,2 per 100.000 and an incid-
ence range of 0,4 to 2,6 per 100.000 per year with geograph-
ical variability. Males have a higher prevalence of DH [5]. In
fact, most population-based studies to date have found male-
to-female ratios ranging from 1,5 : 1 to 2 : 1 [6]. Interestingly,
the opposite has been shown about gender prevalence of CD,
with female-to-male ratios ranging from 2 : 1 to 4 : 1. The
time of onset of the disease is variable. Cases of childhood
DH are currently more often reported than in the past, but
the average age at presentation varies from 30 to 40 years
old [7,8]. A recent epidemiological study conducted by
Salmi et al. [9] in Finland reported some interesting results
about the increasingly rarity of DH. Although the rates of
incidence and prevalence of DH, in the Finnish population
in the thirty years between 1980 and 2009, were higher
than those of previous studies conducted elsewhere, in the
course of time there was a downward trend especially in the
90s. In particular, the estimated prevalence rate was 75,3
per 100000, while annual incidence rates were respectively
5,2 per 100000 in 1980–1989, 2,9 per 100000 in 1990–1999
and 2,7 per 100000 in 2000–2009, with a decrease in incid-
ence rate between the first and second 10-year period that
was statistically significant. In the study of Salmi et al. [9]
emerged a ratio between DH and CD of 1 : 8, that result-
ed lower than 1 :5 showed in previous studies [10]. Theoreti-
cally, the risk of a celiac patient to develop DH remains high,
but, being the diagnosis of the enteropathy and therefore the
adoption of gluten-free diet ever earlier, the risk of DH is
drastically reduced [9] as postulated also by Fry [11].
DH lesions show a typical polymorphism consisting of
erythema, urticarial plaques, papules, grouped vesicles and
blisters associated with intense itch and therefore followed
by erosions, excoriations, and hyperpigmentation (Figure 1).
In addition to the morphology, also the symmetrical
distribution of the lesions on the extensor surfaces of the
upper and lower extremities, elbows, knees, scalp, nuchal
area, and buttocks is considered a hallmark of the disease. At
times face and groins may be involved. DH is rarely observed
in darker-skinned individuals [12,13]; however, there were
no significant clinical differences compared to those North
European.
Since 1971, sporadic cases of DH presenting as palmo-
plantar purpura were reported. This uncommon skin mani-
festation is usually observed in the children, but a number of
adult cases have been described. [14–16]
Since clinical presentation of DH is often atypical, espe-
cially in early and later stages in which prevailing scratching
lesions, this diagnosis may not come to mind. DH must be
differentiated from atopic dermatitis, scabies, papular urti-
caria, and impetigo in children, whereas eczema, other auto-
immune blistering diseases (especially linear IgA bullous dis-
ease and bullous pemphigoid), prurigo nodularis, urticaria,
and erythema multiforme should be considered in adults
[17].
The diagnosis of DH is based on physical examination,
histopathology, immunofluorescence studies, and serologic
testing.
Routine histopathology of lesional skin of DH, that
should ideally contain an intact vesicle or should be taken in
the vicinity of early blisters [18], can be evocative, but not
diagnostic, and nonspecific. Furthermore, the lesions pre-
sent characteristic histopathological changes, in fact the
initial inflammatory event is variable edema in the papillary
dermis with discrete subepidermal vacuolar alteration and
neutrophils along the dermal-epidermal junction. As the
lesion develops, neutrophils, to a lesser extent eosinophils,
and fibrin accumulate within the dermal papillae and form
microabscesses. These become confluent resulting in a sub-
epidermal blister. In early stages of the disease, the inflam-
matory infiltrate contains mostly neutrophils, but in later
stages, variable numbers of eosinophils can be present [19].

Gastroenterology Research and Practice 3
(a)
(b)
(c)
(d) (e)
Figure 1: Erythematous, popular, and vesiculosus lesions in a patient with DH.
However, a prevalent lymphocytic infiltrate was also reported
by Warren et al. [20] probably corresponding to a later stage
of the disease.
However, direct immunofluorescence (DIF) on perile-
sional skin should be considered the gold standard for the
diagnosis [21,22].
In particular, two different patterns of DIF are possible:
(a) granular deposits in the dermal papillae and (b) granular
deposits along the basement membrane. Sometimes, a
combination of both patterns, consisting in granular IgA
deposition along the basement membrane with accentuation
at the tips of the dermal papillae, may be present [23,24].
Recently Ko et al. suggested the existence of a third different
pattern of IgA deposition at DIF, the fibrillar pattern, that
may be related to a clinical variant of DH [25].
Also serologic tests, and in particular IgA antitissue
transglutaminase antibodies (anti-tTG) and IgA endomysial
autoantibodies (EMA), have become relatively sensitive and
specific tools for detection of gluten-sensitive diseases and
therefore of DH in subjects on a diet free. Other serologic
tests for the diagnosis of DH include the detection of
antibodies directed to epidermal TG (eTG), that is currently
considered the key autoantigen in DH, as well as antideami-
dated gliadin peptides antibodies (IgA and IgG), that are
particularly reliable in children under two years old, and
antibodies against to the covalent complex tTG-deamidated
gliadin peptides, that was coined as neoepitope [26,27].
Currently, the diagnosis of CD in patients also affected by
DH not requires further investigation because skin disease is
sufficient for diagnosis of CD [28].
To date, the first-line therapy of DH, as well as CD, is
gluten-free diet, that should not be considered as a mere
symptomatic approach and therefore continue without inter-
ruption even after clinical remission [29]. Generally, several
months are necessary to obtain the control of the skin dis-
ease. For this reason, other treatment may be used as sympto-
matic agents such as dapsone, sulfasalazine and sulphame-
thoxypyridazine, topical potent or very-potent corticoster-
oids, and antihistamines.
Since 1950, when the first report on successful use of
dapsone in the treatment of DH was published [30], dap-
sone became the best tolerated symptomatic pharmacologic
therapy for DH in both adults and children. In particular,
the anti-inflammatory properties of this drug are linked to
inhibition of neutrophil recruitment and local neutrophil-
and eosinophil-mediated tissue injury.
Dapsone represents a valid therapeutic option during the
1- to 2-year period until the GFD is effective; dosages of
1/mg/kg/day can control itching and blister development.
The commonest side effect of dapsone is haemolysis and

4Gastroenterology Research and Practice
Figure 2: Erythematous scaly lesions of the buttocks in a patient
affected by psoriasis.
patients should be seen within 2 weeks after starting the drug
as haemolysis may be acute in some individuals [17].
Sulfasalazine and sulphamethoxypyridazine might pro-
vide an effective alternative to dapsone especially when it fails
to control the disease or the therapy is complicated by adverse
events [17].
3. Psoriasis
Among the inflammatory skin diseases improved by gluten-
free diet, psoriasis is one of the most important. Psoriasis
is a common chronic relapsing inflammatory disease of the
skin, which affects about 2% of general population and cha-
racterized by scaling, erythema, and less commonly postula-
tion (Figure 2). Some patients have affected nails and joints
(psoriatic arthritis) with an obvious decline in quality of life
[31].
Psoriasis is an immunological disease with an important
genetic predisposition linked to HLA-Cw∗0602 [32], which
is characterized by hyperproliferation of keratinocytes medi-
ated by T cells [33]. In particular, Th1 and Th17 lymphocytes
contribute to the pathogenesis of psoriasis through the
release of inflammatory cytokines that promote further
recruitment of immune cells, keratinocyte proliferation, and
sustained inflammation. The inflammatory environment
seems to be amplified due to the plasticity of T regulatory
cells [34], that can convert into IL-17 producing cells. More-
over genetic, experimental and therapeutic evidences have
highlighted a central role for the innate immune system in
the pathogenesis of psoriasis [35].
The pivotal role of immune system in psoriasis patho-
physiology is also confirmed by the frequent association with
other immunological diseases.
The treatment of psoriasis is often difficult, although CD
patients usually show an improvement only adopting the glu-
ten-free diet, as stated above, and then suggesting patho-
genetic differences compared to nonceliac-psoriatic patients.
About the association between P and CD, we must consider
a recent cohort study developed by Ludvingsson et al. that
showed an increased risk of psoriasis both before and after
CD diagnosis. Specifically, they showed that the absolute
risk of future psoriasis in patients with CD was 135/100,000
person-years, with an excess risk of 57/100,000. The hazard
ratio (HR) for psoriasis remained around 1.7 also when they
excluded the first year of followup. Even 5 years after CD
diagnosis we did detect more than 60% increased risk for
psoriasis in patients with CD [36]. Several studies suggest-
ed a correlation between psoriasis and CD [37,38], showing
an improvement in psoriatic skin lesions after 3–6 months of
gluten-free diet without other pharmacological approaches
[39,40]. However, at present the relationship between CD
and psoriasis remains controversial since there are few data
available in the literature, and this association is consider-
ed to be coincidental by some authors [41–43]. To our know-
ledge, no epidemiological studies are currently available
demonstrating the prevalence of psoriasis in celiac patients.
In 2001, Ojetti et al. showed a prevalence of CD of 4,34%
in 92 psoriatic patients [37], while Zamani et al. denied the
increase prevalence of CD in Iranian psoriatic patients with
respect to general population as the estimated prevalence
was 0,3% [44]. However, in 2009, a new study by Birkenfeld
et al. confirmed the increased prevalence of CD also in
Asian population affected by psoriasis with a prevalence rate
varying from 0 to 29% against 0–11% of controls [45]. Fin-
ally, the most recent study of Montesu et al. showed a celiac
prevalence of 2% in patients with psoriasis, confirming an
increase than in the general population [46].
The mechanisms implicated in the possible association
between CD and psoriasis, and consequently the effect of
gluten-free diet on psoriatic skin lesions are currently not
known. Three different hypotheses have been proposed:
(1) abnormal small intestinal permeability, frequently
present both in psoriatic [47] and in CD patients
[48], could be a triggering factor between CD and
psoriasis;
(2) T cells play an important role in the pathogenesis of
both psoriasis and CD. An increased number of T
CD4+ cells in the blood, in the dermis, and in the
epidermis of psoriatic patients have been document-
ed [49]. In CD patients, gliadin induces a sensitiza-
tion of T CD4+ cells [50], and this may play a role in
the pathogenesis of psoriatic skin lesions [51];
(3) psoriatic lesions in CD patients could be related to
vitamin D deficiency, which is present both in CD
[52] and in psoriasis [53,54].
Moreover, recent observations of Troncone and Jabri [55].
suggested that psoriasis could be considered as a part of
gluten sensitivity at least in a subgroup of patients. In those
patients, the site of immunization against gluten may be
extraintestinal and or TG is probably not the main target
antigen, since 16% of patients with psoriasis have been found
to present high levels of IgA and or IgG antibodies to gliadin
in the absence of anti-TG antibodies, showing a significant
reduction when they were put on a gluten-free diet [56].
4. Alopecia Areata
Alopecia areata (AA) is an autoimmune disease that presents
as nonscarring hair loss, with a frequency ranging from 0.7%

Gastroenterology Research and Practice 5
Figure 3: AA of scalp, beard, eyelashes, and eyebrows in patient
affected by CD.
to 3.8% of their patients [57,58]. Although some studies
showed a significant male preponderance in adult age group,
others demonstrated the opposite, indicating that AA likely
affects males and females equally, as our personal clinical
experience may suggest [59–61]. The disease prevalence
peaks between the second and fourth decades of life [62], and
pediatric reports are common accounting for 20% of all cases
[63](Figure 3).
For the first time, in 1995 Corazza et al. [64]described
the association between AA and CD in 3 patients and devel-
oped a prospective screening program to ascertain whether
this novel association could be real or coincidental. The esti-
mated prevalence rate of CD in patients with AA was 1 in 85
[64], and therefore CD was included among the autoimmune
diseases that may be associated with AA, in particular among
those affecting the intestinal wall together with ulcerative
colitis. By contrast, in 2008 Neuhausen et al. [65] considered
the co-occurrence of CD and other autoimmune diseases
both in celiac and their first-degree relatives in the North
American population without finding an increased incidence
of AA different from other autoimmune diseases such as
insulin-dependent diabetes mellitus, juvenile rheumatoid
arthritis/juvenile idiopathic arthritis, and hypothyroidism.
Our review of the literature showed that the reported cases
of association between these two conditions are few but,
being often more severe variant of AA, in particular alopecia
universalis, also as only clinical presentation of CD, an active
search for CD using serological screening tests should be per-
formed to diagnose the numerous cases of subclinical CD
and avoid uncomfortable gastrointestinal and extraintestinal
manifestations.
Although remission and recurrence may be observed
during the clinical course of AA, many patients on gluten-
free diet showed complete regrowth of scalp and other body
hair and no further recurrence of AA at followup. The
positive effects of gluten-free diet on the pattern of autoim-
mune conditions, such as AA, associated with CD have been
attributed to a normalization of the immune response [66].
Figure 4: Pink-to-red edematous lesions, that have pale centers
localized on the back of a patient affected by urticaria.
5. Chronic Urticaria
Urticaria is a common disorder, occurring in 15–25% of
individuals at some point in life [67]. It is characterized by
recurrent, itchy, pink-to-red edematous lesions that often
have pale centers. The lesions can range in size from a few
millimeters to several centimeters in diameter, and are often
transient, lasting for less than 48 hours [68–71](Figure 4).
Approximately 40% of patients with urticaria also experience
angioedema [68].
Urticaria is generally classified as acute (AU) or chronic
(CU) depending on the duration of symptoms. AU refers to
lesions that occur for less than 6 weeks, while CU to lesions
that occur for more than 6 weeks; it is usually assumed that
the lesions are present most days of the week [72]. Most cases
of urticaria are acute; however, approximately 30% go on
to become chronic. AU and CU are also distinguished by
the prognosis, as AU can generally be easily managed and
is associated with a good prognosis, while CU is often asso-
ciated with significant morbidity and a diminished quality of
life [70].
In 1987, Hautekeete et al.first described the association
between CD and CU [71], although this is a matter still
under debate [73]. Indeed, the relationship between the two
diseasesisnotclear[74], but it can be speculated that auto-
immunity induced by gliadin or by other unknown antigens
may link CU and CD. The increased permeability of intesti-
nal mucosa allows the passage of antigens that are respon-
sible for CU pathogenesis by the formation of circulating
immunocomplexes [75]. Both CD and urticaria are immune-
mediated disorders, but they have a different pathogenesis.
In fact, while CD is a Th1-mediated autoimmune response to
gluten, urticaria could be supported by different mechanisms
that range from Th2-driven response to allergens to Th1
autoimmunity [76]. In particular, autoimmune urticaria is
related to autoantibodies against the αsubunit of the high-
affinity IgE receptor FcεR1 or against the αsubunit of IgE.
These antibodies are able to induce the mast cells degranula-
tion and the consequent formation of anaphylatoxin [76].
However, the only epidemiologic study assessing the pre-
valence of CD in a population of adult idiopathic CU (ICU)
patients was published in 2005 by Gabrielli et al. [73] without
demonstrating an increased risk of CD in patients with ICU.

6Gastroenterology Research and Practice
These data, obtained on a population of 80 subjects affected
by ICU and 264 healthy controls, were not confirmed by
larger and more detailed epidemiological studies and are in
contrast not only with several case reports, but also with
the results of a recent study by Confino-Cohen et al. [77].
This study considered all autoimmune diseases potentially
associated to CU finding thyroid diseases the most common
one and also CD the more frequent among female affected
by CU. In particular, when comparing women with CU with
women in the control group, the odds of having CD was 57,8,
and in most cases the diagnosis of CD followed that of CU,
emphasizing that a screening through the determination of
the serological markers of CD in patients suffering from CU
may improve the prognosis of these patients.
Furthermore, even if no meta-analysis is still available,
in some cases of CU the adoption of a gluten-free diet has
proven effective in controlling the skin lesions [74,76], fur-
ther confirming that CU may be a cutaneous manifestations
of CD and not only a chance association.
6. Hereditary Angioneurotic Edema
Hereditary angioneurotic edema (HANE) is a rare autosomal
dominant genetic disorder resulting from an inherited defi-
ciency or dysfunction of the C1 inhibitor, a plasma protease
inhibitor that regulates several proinflammatory pathways.
Three phenotypic variants of HANE have been defined: type
I HANE, that is characterized by a quantitative and func-
tional deficiency of C1 inhibitor (80–85% of cases); type II
HANE, which is associated with normal C1 inhibitor levels,
but low function (15–20% of cases); type III HANE, that
includes rare cases, usually female, in which there are no
alterations of quantity and functions of C1 inhibitor and
the genetic defect in most cases involves the expression of
factor XII (Hageman) resulting in increased production of
bradykinin [78,79].
Clinically, HANE is characterized by recurrent episodes
of angioedema, without U or pruritus, which most often
affect the skin or mucosal tissues of the gastrointestinal and
upper respiratory tracts. Although generally benign condi-
tions, laryngeal involvement can rapidly lead to fatal asphyx-
iation if left untreated. HANE usually presents in late child-
hood or adolescence in otherwise healthy subjects, and a
familial history is present in approximately 75% of cases.
These epidemiological features are useful for the differen-
tial diagnosis with acquired angioneurotic edema (AANE),
which is not associated with a family history, and usually
develops in older patients (fourth decade of life) with an
underlying lymphoproliferative or autoimmune disease [80].
Cases of HANE associated with ulcerative colitis and
Crohn’s disease have been reported by Brickman et al. in
1986 [81] and after by Farkas et al.in 1999. In 2002,
Farkas et al. first described the simultaneous occurrence of
HANE and CD in a 14-year-old white male, which adopted
gluten-free diet three years before following the diagnosis of
CD, but represented similar clinical manifestations that was
hardly ranked as HANE [82]. The knowledge and the ability
to diagnose HANE is important not only for its frequent
association with CD, particularly because of their confusion
as Farkas et al. [83] reiterated in 2011. The aim of their study
was to assess the prevalence of immunoregulatory disorders
within the patient population affected by HANE, including
CD, and contrary to other, CD was actually more common,
with a prevalence of 3,1% in patients with HANE against that
in healthy controls of 0,64%. Furthermore, according to the
authors, similarities between the symptoms of HANE, and
CD may cause difficulties in differential diagnosis, as well as
in choosing the appropriate therapy, suggesting the screen-
ing for CD in HANE patients in whom abdominal attacks
or neurological symptoms persist despite adequate manage-
ment.
The classic activation pathway of the complement system
plays a potential role in the immune regulation of both dis-
orders, since C1 inhibitor is deficient in HANE and gluten is
considered potent activator of the alternative pathway of the
complement in CD [84]. Nevertheless, there might also be a
genetically determined etiology of both diseases [85]. Com-
plement testing is justified whenever the gastrointestinal
symptoms of CD persist despite restoration of damaged
mucous. Conversely, HANE unresponsive to adequate pro-
phylaxis should prompt for complete gastrointestinal group
tests [86].
In the literature, there are no data available about the
effectiveness of the gluten-free diet.
7. Cutaneous Vasculitis
In the literature, there are sporadic reports about the asso-
ciation between cutaneous vasculitis (CV) and CD [86–88].
Vasculitis (V) is defined as inflammation directed at
vessels, which compromises or destroys the vessel wall lead-
ing to haemorrhagic and/or ischaemic events. The skin is
the most common involved organ, and clinical manifesta-
tions include U, infiltrative erythema, petechiae, purpura,
purpuric papules, haemorrhagic vesicles and bullae, nodules,
livedo racemosa, deep (punched out) ulcers, and digital gan-
grene. These varied morphologies are a direct reflection of
size of the vessels and extent of the vascular bed affected,
ranging from a V affecting few superficial, small vessels in
petechial eruptions to extensive pan-dermal small-vessel V in
haemorrhagic bullae to muscular vessel V in lower extremity
nodules with livedo racemosa [89]. Aetiologically, vasculitis
can be separated into primary V (idiopathic, including
cutaneous leukocytoclastic angiitis, Wegener’s granulomato-
sis, Churg-Strauss syndrome, and microscopic polyangiitis),
secondary V (a manifestation of connective tissue diseases,
infection, adverse drug eruption, or a paraneoplastic phe-
nomenon), or incidental V (a histological finding that is the
consequence of another pathological process such as trau-
matic ulceration or diffuse neutrophilic infiltrates) [90].
Some items may help to explain how so many different
diseases can coexist, in fact leukocytoclastic V is often
due to immunocomplex deposition on the vessel wall, and
the antigen may be either exogenous or endogenous [91].
Therefore, increased intestinal permeability being present in
CD, antigens can penetrate and form immunocomplexes,
that can circulate because of the impaired phagocytic
function of reticular endothelium system and be deposited in

Gastroenterology Research and Practice 7
Tab l e 2: Dermatological manifestation secondary to nutritional deficiencies.
Zinc deficiency Crusty-erythematous-squamous dermatitis localized to periorificial regions, genitals and flexures,
associated with diffuse alopecia, stomatitis, balanitis, vulvar, and proctitis
Iron deficiency Atrophy and dryness, itching, hair loss, atrophic glossitis, angular stomatitis, and koilonychia
Vitamin A deficiency Pytiriasis rubra pilaris-like
Vitamin B12 and folic acid deficiency Angular stomatitis, glossitis, and oral mucosa ulcers, hyperpigmentation
VitaminPPdeficiency Pellagra
the skin [90]. Alternatively, an autoimmune sensitization
may result because of the release of endogenous antigens
from damaged small bowel mucosa [92].
Tr ea t m e n t o f l e u ko c y t o c la s t i c V i s o f te n d ifficult; how-
ever, the use of corticosteroids and mostly the adoption of
gluten-free diet in patients with CD has proved of great help
as reported also by Marsh and Stewart [90].
8. Atopic Dermatitis
Atopic dermatitis (AD) is a very common inflammatory skin
disease in childhood, that has a large impact on the quality
of life both of children and their families. In developed coun-
tries, AD is affecting 15–20% of the children [93,94], and its
cumulative incidence at the age of 6 based on the criteria of
Hanifin and Rajka, determined in a recent population-based
prospective birth cohort study in Denmark of 562 children,
was 22.8% [95]. AD usually starts within the first 6 months
of life. Remission during life occurs before the age of 15 years
in 60–70% of cases, although some will relapse later. Most
of the children have a family history of atopic diseases, and
a high percentage of the children with AD are sensitized to
food- and/or aero-allergens [96].Thereisalargevariability
in the severity of the disease: most children have mild disease
(70–84%) and are treated by general practitioners [97–99].
However, young age at onset (first year of life), coexistent
respiratory allergy and urban living may be considered as
factors of disease severity [100].
Genetic factors are thought to be involved in the devel-
opment of AD involving several susceptibility loci.
The clinical manifestations of AD vary with age. It is
often difficult to differentiate AD from other skin conditions
such as scabies, contact dermatitis, seborrheic dermatitis,
and also to those that we have already described among those
more frequently associated with CD, such as DH and psori-
asis [101].
As already mentioned above, CD is considered to arise
from an inappropriate T-cell-mediated immune response
against ingested gluten in genetically predisposed subjects
[102] and therefore different from allergic, IgE-mediated
reactions, in which the Th2-type lymphocytes are mostly
involved [103]. Thus, one would hypothesize that Th1- and
Th2-type immunity are present in a distinct patient popu-
lation, but this is still a matter of controversy [101,104]. In
fact, some reports have suggested that allergy manifestations
are more frequent in patients with CD [105], and asthma
incidence is increased in celiac disease diagnosed in child-
hood [106]. Atopic disorders were more frequently found in
children [107] and adult patients with CD and their relatives
than in normal control subjects [108,109]. Zauli et al. first
showed that CD prevalence in Italian population of atopic
patients was 1%, significantly higher than in general popu-
lation [110]. On the contrary, one single case control study
in children with CD denies the link between CD and allergy
[111]. However, in 2004 Ciacci et al.considered both patients
with and without malabsorption and showed that AD is
about 3 times more frequent in patients with CD and 2 times
more frequent in their relatives than in controls [112]. Unfor-
tunately no data are available about efficacy of gluten-free
diet in atopic patients with CD, because followup in the study
conducted by Ciacci et al. was limited to 1 year and did not
abate allergic manifestations, even if it cannot be excluded
that a longer period of diet may have some effects [112].
9. Other CD-Associated Skin Conditions
As reported by Humbert et al. in 2006 [3], in addition to
skin diseases with proven association with CD and those
improved by gluten-free diet and/or with positivity of celiac
serological markers, there are also fortuitous associations
with other skin conditions. After a detailed review of the
literature, we selected all the reported associations between
CD and skin conditions. Although in none of these cases has
been effectively demonstrated a pathogenetic link between
the diseases, some of these associations are more common.
Particularly lupus erythematosus [113], dermatomyositis
[114], vitiligo [115], Behc¸et disease [116], linear IgA bullous
dermatosis [117], and also both skin and mucosal manifest-
ations of lichen [118,119] are the most frequently reported,
while prurigo nodularis [120], erythema nodosum [121],
necrolytic migratory erythema [122], porphyria [123], cuta-
neous amyloidosis [124], pityriasis rubra pilaris [125], ery-
throderma [126], partial lipodystrophy [127], generalized
acquired cutis laxa [128], ichthyosis [129], atypical mole syn-
drome, and congenital giant nevus [130] result very rare.
In addition to those listed above, there are also dermato-
logical manifestations secondary to a deficiency of absorp-
tion of various nutrient in the intestine. The first and only
case of pellagra associated with CD was reported in 1999 by
Schattner [131], but CD patients may also present nonspe-
cific dermatological disorders, that only a specialist can be
traced to a specific vitamin or oligoelement. Therefore, in
Tab l e 2 , we reported the main dermatological manifestations
related to specific nutritional deficiencies, that a CD patient
can develop during the course of the disease.
Finally, also oral cavity may be involved in course of
CD by both dental disorders or oral mucosa manifesta-
tions. Recently, Rashid M et al. described oral and dental

8Gastroenterology Research and Practice
manifestations of CD, consisting in enamel defects, delayed
eruption, recurrent aphthous ulcers, cheilitis, and atrophic
glossitis and stressed that “the diagnosis of celiac disease can
sometimesbemadefromasmile”[132].
10. Conclusion
Despite the knowledge about pathogenic, epidemiological,
clinical and diagnostic aspects of CD is rapidly increased in
the recent years, the possible mechanisms involved in the
association with other diseases and in particular with the
dermatological ones remain still unclear. Several hypotheses
have been proposed depending on the type of the association,
but the most probable may involve both a genetically con-
ditioned lack of mechanisms for the maintenance of immu-
nological tolerance, that consequently predisposes to auto-
immunity and an abnormal small intestinal permeability,
which may allow the crossing of endogenous or exogenous
antigens and may provoke the immunological response, vas-
cular alterations and, lastly, vitamin and aminoacid defi-
ciency secondary to malabsorption in patients with CD.
Besides the importance of the diagnosis of DH, that is
virtually always associated to CD and can be considered
a specific marker of the disease, even the identification of
the other dermatological conditions associated with gluten-
sensitive enteropathy could be significant, highlighting the
importance of a close collaboration between gastroenterolo-
gists and dermatologists. In fact, many skin diseases reported
in this paper are actually more common in the celiacs or show
atypical clinical presentation often associated with resistance
to standard therapies in those patients. As a consequence, we
suggest the screening for CD in patients affected by psoriasis,
AA, CU, HANE, and AD, especially in cases resistant to first-
line therapies.
Acknowledgments
This work was supported by the Ministry of Instruction,
University and Research of the Italian Government (PRIN
2008EW3FHK).
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