American Journal of Gastroenterology ISSN 0002-9270


C 2006 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2006.00423.x
Published by Blackwell Publishing

Dermatological Manifestations in Primary Biliary

Cirrhosis Patients: A Case Control Study
Meri Koulentaki, M.D., Ph.D.,1 Despina Ioannidou, M.D.,2 Maria Stefanidou, M.D.,2 Sofia Maraki, M.D.,3
I. Drigiannakis, M.D.,1 Philippas Dimoulios, M.D.,1 Jean Marie Enele Melono, M.D.,1 Androniki Tosca, M.D.,
Ph.D.,2 and Elias A. Kouroumalis, M.D., Ph.D.1
1
Department of Gastroenterology, 2 Department of Dermatology, and 3 Department of Microbiology, University
Hospital, Crete, Greece

OBJECTIVES: Primary biliary cirrhosis (PBC), a disease of probable autoimmune etiology that affects the small
intrahepatic bile ducts of mainly middle-aged women is commonly associated with pruritus,
xanthomatous lesions, and melanosis. We conducted a prospective study to systematically describe
the skin disorders of a group of PBC patients.
METHODS: A prospective evaluation and analysis of dermatological manifestations including oral and genital
lesions was carried out, in 49 PBC patients (45 females and 4 males). Median age 63 yr (range
35–87 yr). They were compared with 45 age and sex matched controls, selected among persons
attending the dermatologic outpatient clinic.
RESULTS: A total of 330 skin disorders were found in the 49 PBC patients versus 76 in the 45 controls; 31.5%
of all lesions were skin fungal infections. Of all lesions analyzed with the Bonferonni rule of multiple
comparisons significantly more common in PBC patients were plantar mycoses, onychomycoses,
and interdigital mycoses. Pruritus was found in 69.3% of patients versus 22.2% of controls, xerosis
in 69.3% versus 2.2%, dermographism in 57.1% versus 4.4%, and melanosis in 46.9% versus 0%.
In 38.7% of the PBC patients the dermatologic lesion was the presenting symptom.
CONCLUSIONS: PBC patients present with a wide variety of cutaneous manifestations varying in severity. Multiple
skin fungal infections have been found even in the early stages. Since in more than one third of our
PBC patients the dermatologic lesion was the presenting sign or symptom leading to diagnosis we
believe that physicians should be aware so that a prompt and early diagnosis may be achieved.
(Am J Gastroenterol 2006;101:541–546)

INTRODUCTION before. In an attempt to describe the cutaneous and mucosal

Primary biliary cirrhosis (PBC) is a disease of probable au-
toimmune etiology that affects the small intrahepatic bile
ducts of mainly middle-aged women. In approximately 95%
of the cases M2 anti-mitochondrial antibodies (AMA, M2)
are present. The AMA negative cases are also known as au-
toimmune cholangitis (AIC) and do not differ histologically
or clinically from the AMA positive cases. PBC has four
histological stages from inflammation to cirrhosis. Dermato-
logic manifestations commonly associated with PBC are xan-
thomatous lesions (1) and melanosis (2). At the late stages,
nonspecific skin lesions usually seen in patients with ad-
vanced liver disease can also be found. Various case reports
exist in the literature describing a more frequent association
of PBC with lichen planus (3, 4), scleroderma (5, 6), and
CREST syndrome (calcinosis cutis, Raynaud’s phenomenon,
esophageal dysfunction, sclerodactyly, and teleangiectasia)
(1, 7). To our knowledge a systematic description of the skin
disorders of a group of PBC patients has not been published
involvement of our PBC patients we designed this prospective
study.
PATIENTS AND METHODS
A prospective evaluation and analysis of dermatological man-
ifestations including oral and genital lesions was carried out
at the Department of Gastroenterology, in a series of 49 con-
secutive PBC patients (45 females and 4 males) between
February 2001 and May 2004 seen as inpatients or outpa-
tients in the Liver Outpatient Clinic. Median age was 63 yr
(range 35–87 yr).
All patients had histologically confirmed PBC, 45 were
AMA positive, 4 AMA negative, 24 were stage I–II, 9 were
stage III, while 16 were stage IV. They were all followed up
regularly in the outpatient Liver Clinic since their diagnosis,
with a mean follow-up of 7.94 yr (range 1–20 yr). All patients
were treated with ursodeoxycholic acid 13–15 mg/kg/day

541
542 Koulentaki et al.
since their initial diagnosis. Cirrhotic patients were addi-
tionally treated with diuretics, propranolol hydrochloride,
vitamins, and calcium as clinically indicated. One of the pa-
tients had undergone liver transplantation a year before and
was also receiving steroids, ciclosporin, and mycophenolate
mofetil.
Forty-five age- and sex-matched controls were compared
with the patients. They were selected on the same period
among patients attending the dermatology outpatient clinic
who consented to be included in the study. Persons with any
known systemic disease, previous medical history, or any
drug intake were excluded.
All patients and controls underwent a complete skin exam-
ination by two different experienced dermatologists that were
aware of patients’ diagnosis. A skin biopsy was performed
when clinically indicated. Skin specimens were stained
with hematoxylin and eosin and examined, while some of
them were specially stained for bacteria, mycobacteria, and
fungi.
Statistical Analysis
The results were reported as percentages, and comparisons
were carried out between the two groups. Statitistical signif-
icance for differences between groups was assessed by the
Pearson’s χ 2 test or by Spearman’s rho test. A p value of 0.05
was considered significant. The Bonferroni rule for correc-
tion of statistical significance for multiple comparisons was
applied to the results. Statistical analysis was performed with
the SPSS package V13.
RESULTS
All 49 PBC patients had manifestations of two or more skin
lesions with or without symptoms. A total of 330 skin disor-
ders were found in the PBC patients versus 76 skin disorders
in the 45 controls referred in detail in Table 1.
Spearman’s rho analysis revealed significant difference in
the presence of: seborrheic keratoses ( p < 0.02, Fig. 1),
cherry hemangiomas ( p < 0.02, Fig. 2), varicose veins ( p <
0.002, Fig. 3), inguinal epidermophytoses ( p < 0.002), inter-
digital mycoses ( p < 0.0001, Fig. 4), plantar mycoses ( p <
0.0001, Fig. 5), onychomycoses ( p < 0.0001, Figs. 6 and 7),
angular cheilitides ( p < 0.02), hand and foot eczema ( p <
0.02), atopic dermatitis ( p < 0.005), xanthelasmas ( p <
0.05), senile lentigines ( p < 0.05, Fig. 7), and melanosis
( p < 0.0001, Figs. 3 and 8), in the PBC patients. When the
Bonferroni correction for multiple comparisons was applied,
the statistical significance was restricted to interdigital my-
coses, plantar mycoses, onychomycoses, and melanosis.
Forty-three out of the 49 patients had dermatologic symp-
toms, versus 14 of the 45 controls. A comparison between
PBC patients and controls concerning symptoms and signs
revealed significant differences in the incidence of pruritus
( p < 0.0001), xerosis cutis ( p < 0.0001, Fig. 8), and der-
mographism ( p < 0.0001, Fig. 2), while erythema did not
differ between the two groups. These results remained sig-
nificant after correction by the Bonferroni rule (Table 2).
Xerosis cutis was present in 79.4% of patients with pruritus
( p < 0.02), while dermographism coexisted in 70.6% of them
( p < 0.001). All three symptoms were present in 46.9% of
the PBC patients.
Based on the medical records of the PBC patients, 19 of
the 49 PBC patients (38.7%) presented with dermatological
symptoms (pruritus, hyperpigmentation, xerosis) or asymp-
tomatic lesions at least 9 wks before the diagnosis of PBC
was established. In the remaining patients, dermatological
lesions followed the diagnosis of PBC.
No significant correlations were found between the pres-
ence of specific lesions or symptoms and patients’ age, dura-
tion of the disease, ANA presence, and Ludwig histological
stage.
DISCUSSION
Our case control study revealed a number of differences on
the incidence of a wide variety of skin lesions, between our
PBC patients and controls. It is obvious that our control
group, being selected from the dermatology outpatient clinic
does not reflect the incidence of skin disorders in the general
population, nevertheless our study leads to certain interesting
conclusions.
Multiple coinciding skin lesions were observed in all PBC
patients. Fungal skin infections (31.5%) were the most fre-
quent skin disorders observed in the PBC patients, followed
by neoplastic lesions (18.4%), dermatitis-urticaria (15.7%),
and disturbances of pigmentation (12.4%). Fungal infections
are reported to be frequent in cirrhotic patients (8), acute
liver disease (9), or advanced liver failure (10). We have pre-
viously reported that urine fungal infections are frequent in
advanced stage PBC patients (11), but as far as we know it
is the first time that fungal skin infections are reported to be
frequent even in the early stages of PBC patients. This high
incidence of skin mycosis in our series is probably due to im-
paired cellular immunity of these patients but it needs further
clarification.
Differences between the two groups in seborrheic ker-
atosis, cherry hemangiomas, varicose veins, venous lakes,
hand and foot eczema, atopic dermatitis, senile lentigines,
inguinal epidermophytoses, angular cheilitis, and xanthelas-
mas although not significant, should be kept in mind since
this could be the result of the relative small number of pa-
tients included in the study. Indeed the association of xan-
thelasmas with PBC is well documented (12). Our results
confirm the high incidence of melanosis as reported in the
literature. Lichen planus and scleroderma although present in
some patients are not as common and no CREST was found.
It should be stressed that all PBC patients were treated with
ursodeoxycholic acid, while D-penicillamine was never used.
This might account for the rarity of lichen planus lesions in
our series compared to those reported in the literature since
 Dermatological Manifestations in PBC Patients 543

Table 1. The Cutaneous Manifestations of 49 PBC and 45 Control Patients

Dermatologic Lesions PBC No. Controls No. p
Neoplastic lesions 61 (18.4%) 32 (42.1%)
Osteoma 1 0 NS
Epidermal cyst 2 1 NS
Seborrheic keratosis 12 9 p < 0.02/NS∗
Cherry hemangioma 15 7 p < 0.02/NS∗
Milia 3 0 NS
Melanocytic nevus 4 1 NS
Congenital nevus 2 2 NS
Dysplastic nevus 1 3 NS
Blue nevus 2 1 NS
Epidermal nevus 1 0 NS
Achromicnevus 2 0 NS
Skin tag 4 3 NS
Lipoma 2 0 NS
Actinic keratoses 4 3 NS
Basal cell carcinoma 3 2 NS
Dermatofibroma 3 0 NS
Drug related 1 (0.3%) 0
bullus eruption 1 0 NS
Vascular related 31 (9.3%) 5 (6.5%)
Varicose veins 11 1 p < 0.002/NS∗
Livedo reticularis 3 1 NS
Venous lakes 6 0 p < 0.05/NS∗
Senile purpura 3 1 NS
Telangiectesia 8 2 NS
Infections 104 (31.5%) 10 (13.1%)
Vulvovaginitis 6 2 NS
Oral candidiasis 2 0 NS
Pityriasis vescicolor 2 0 NS
Inguinal epidermophytoses 12 1 p < 0.002/NS∗
Interdigital mycosis 20 1 p < 0.0001∗
Intertrigo 4 1 NS
Plantar mycoses 19 0 p < 0.0001∗
Onychomycoses 24 1 p < 0.0001∗
Paronychia 3 1 NS
Verruca vulgaris 5 3 NS
Angular cheilitis 7 0 p < 0.02/NS∗
Dermatitis/urticaria 52 (15.7%) 17 (22.3%)
Neurodermatitis circumscripta 6 0 NS
Hand and foot eczema 9 4 p < 0.02/NS∗
Contact dermatitis 7 2 NS
Prurigo 2 1 NS
Atopic dermatitis 11 2 p < 0.005/NS∗
Seborrheic dermatitis 7 2 NS
Urticaria 9 5 NS
Angioedema 1 1 NS
Disorders of metabolism 9 (2.7%) 0
Xanthelasmas 7 0 p < 0.05/NS∗
Eruptive xanthoma 2 0 NS
Inflammatory dermatoses 18 (5.4%) 4 (5.2%)
Psoriasis 3 3 NS
Lichen planus 5 0 NS
Oral lichen planus 4 0 NS
Vulvar lichen sclerosus and atrophus 2 1 NS
Lichen sclerosus and atrophus 3 0 NS
Localized scleroderma 1 0 NS
Disturbances of pigmentation 41 (12.4%) 4 (5.2%)
Lentigo senile 9 3 p < 0.05/NS∗
Ashy dermatoses 4 0 NS
Melanosis 23 0 p < 0.0001∗
Idiopathic guttated hypomelanoses 5 1 NS
(continued)
544 Koulentaki et al.

Table 1. Continued
Dermatologic Lesions PBC No. Controls No. p
Others 13 (3.9%) 4 (5.2%)
Vasculitis 2 0 NS
Hypodermatitis 1 1 NS
Graft versus host disease 1 0 NS
Hypertrichosis 2 0 NS
Ichtyosis 2 0 NS
Sarcoidosis 2 0 NS
Bullous pemphigoid 1 1 NS
Erythema multiforme 0 1 NS
Lupus erythematosus 2 1 NS
∗
Statistically significant with the Bonferroni correction.

Figure 1. Seborrheic keratosis (sharply defined, raised and pig- Figure 3. Dilated varicose veins and melanosis at the inner surface
mented, black-brown, keratotic benign tumor with irregular, of the thigh.
bunched verruciform surface).

Figure 2. Dermographism (linear wheal formation and redness after

mechanically stroking the skin) and cherry hemangiomas (bright Figure 4. Interdigital mycosis caused by trichophyton mentagro-
red, smooth, dome shaped benign tumors). phytes.
 Dermatological Manifestations in PBC Patients 545

Figure 5. Tinea pedis caused by trichophyton rubrum: plantar scal- Figure 8. Xerosis of the skin and melanosis.
ing that accentuates the flexural creases.

Figure 9. Graft versus host disease (reticulated poikilodermatous

hyperpigmentation).

Figure 6. Onychomycosis. Yellow discoloration and subungual hy-
perkeratosis of the distal edge of the nail plate.
there are references that connect this lesion to the use of this
drug (3, 4). Graft versus host disease was one out of the 11
other lesions found in the only transplanted patient included
in this series, and probably was due to the transplantation
itself (Fig. 9).
Signs or symptoms like pruritus (69.3%), xerosis (69.3%),
and dermographism (57.1%) were experienced by more than
half of the PBC patients examined and in 46.9% were coexist-
ing. Interestingly a high percentage of PBC patients (38.7%)
appeared with a dermatologic involvement as their presenting
symptom leading to the diagnosis.
In conclusion, PBC patients present a wide variety of cuta-
neous manifestations, and therefore dermatologists and gen-
eral practitioners should be aware of them in order to achieve
a prompt and early diagnosis.

Table 2. Signs and Symptoms of 49 PBC and 45 Control Patients

PBC Controls Significance
Pruritus 34 (69.3%) 10 (22.2%) <0.0001
Xerosis cutis 34 (69.3%) 1 (2.2%) <0.0001
Erythema 4 (8.1%) 1 (2.2%) NS
Figure 7. Multiple senile lentigines on the back of the hands and
Dermographism 28 (57.1%) 2 (4.4%) <0.0001
onychomycosis caused by Candida albicans.
546 Koulentaki et al.
STUDY HIGHLIGHTS
What is Current Knowledge
r Pruritus and xanthelasmas are commonly associated
with primary biliary cirrhosis (PBC).
r Case reports describe the presence of only a few other
dermatological lesions in PBC patients.
What is New Here
r A case control study systematically describes the der-
matological manifestations of a group of PBC patients.
r Multiple skin fungal infections correlated with early
stage liver disease.
r In more than one third of the PBC patients, the der-
matologic lesion was the presenting sign or symptom
leading to diagnosis.
Reprint requests and correspondence: Meri Koulentaki, M.D.,
Ph.D., Department of Gastroenterology, University Hospital, Her-
aklion, PO Box 1352, 71110 Heraklion, Crete, Greece.
Received July 8, 2005; accepted October 17, 2005.
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