LIVER FAILURE AND LIVER DISEASE

LIVER DISEASE

High Frequency of Cholestasis in Generalized Pustular

Psoriasis: Evidence for Neutrophilic Involvement of the
Biliary Tract
Manuelle Viguier,1 Matthieu Allez,2 Anne-Marie Zagdanski,3 Philippe Bertheau,4 Eric de Kerviler,3 Michel Rybojad,5
Patrice Morel,5 Louis Dubertret,1 Marc Lémann,2 and Hervé Bachelez1

Generalized pustular psoriasis is a rare form of psoriasis that is sometimes associated with
extracutaneous manifestations. Evidence for biliary involvement has been suggested in iso-
lated cases. We investigated the prevalence and nature of liver abnormalities occurring in this
disease. Twenty-two patients consecutively admitted for generalized pustular psoriasis who
underwent liver biological tests at the time of the attack and during the following weeks were
included. Twenty patients (90%) had at least one abnormal biological liver parameter.
Eleven patients (50%) had pronounced abnormalities: jaundice (4/22), gammaglutamyl
transferase higher than 5 times the normal value (10/22), alkaline phosphatase higher than
twice the normal value (7/22), and/or aminotransferases higher than 3 times the normal
value (7/22). These abnormalities returned to normal range at the time of remission of
pustular psoriasis, suggesting that severe liver abnormalities could be associated with severe
cutaneous disease. Neutrophilic cholangitis was observed on liver biopsy. Persistent mag-
netic resonance cholangiopancreatography features similar to those observed in sclerosing
cholangitis were found in 3 of the 4 patients studied. No causal factor other than pustular
psoriasis could be identified. In conclusion, our results demonstrate the high frequency of
liver abnormalities in patients with generalized pustular psoriasis. Biliary involvement re-
lated to neutrophilic cholangitis should be added to the spectrum of extracutaneous mani-
festations of this disease, and physicians should be aware of such a complication.
(HEPATOLOGY 2004;40:452– 458.)

G
eneralized pustular psoriasis (GPP) of the von
Zumbusch variety is a generalized life-threaten-
ing form of psoriasis characterized by dissemi-
nated pustular skin lesions following an acute course and
often associated with high fever and hyperleukocytosis.
The attacks may be induced in some cases by triggering
Abbreviations: GPP, generalized pustular psoriasis; CRP, C-reactive protein;
GGT, ␥-glutamyltransferase; ALP, alkaline phosphatase; AST, aspartate amino-
transferase; ALT, alanine aminotransferase; ERCP, endoscopic retrograde cholan-
giopancreatography; MRCP, magnetic resonance cholangiopancreatography; PSC,
primary sclerosing cholangitis.
From the Departments of 1Dermatology 1, 2Gastroenterology, 3Radiology, 4Pa-
thology, and 5Dermatology 2, Hôpital Saint-Louis, Assistance Publique-Hôpitaux
de Paris and Université Paris 7, Paris, France.
Received December 11, 2003; accepted April 6, 2004.
Address reprint requests to: Dr. Manuelle Viguier, Service de Dermatologie I,
Hôpital Saint-Louis, 1 Avenue Claude-Vellefaux, 75475 Paris Cedex 10, France.
E-mail: mviguier@libertysurf.fr; fax: ⫹33 1-42-49-46-20.
Copyright © 2004 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.20305
452
factors such as infections, drugs, sunlight, or preg-
nancy.1,2 Since the first description of the disease in 1910,
there have been reports of patients with GPP who present
with extracutaneous manifestations, which consist mostly
of mucous membranes lesions and arthritis.3,4 Evidence of
liver involvement of unknown physiopathology has been
suggested in isolated case reports.5– 8 Recently, we re-
ported a case of neutrophilic cholangitis associated with
GPP in a 42-year-old woman presenting with cholestasis
following an acute evolution paralleling the course of skin
disease.9 Recognizing the hypothesis that neutrophilic
cholangitis could represent an extracutaneous manifesta-
tion of GPP, we investigated the prevalence and the na-
ture of liver abnormalities occurring in patients with
GPP.
Patients and Methods
We conducted a study on all patients consecutively
admitted for a GPP attack in one of the two departments
HEPATOLOGY, Vol. 40, No. 2, 2004
of dermatology of the Saint-Louis Hospital, Paris, be-
tween 1995 and 2001. To be included, patients had to
fulfill the following criteria: (1) at least one attack of GPP,
defined as sheets of erythema and pustulation spreading in
waves, progressively involving the whole body surface
within a few days, associated with general symptoms in-
cluding fever higher than 38°C, and/or leukocytosis
higher than 10,000/mm3; or (2) liver biological tests
available at the time of GPP attack and during the follow-
ing weeks. The clinical criteria were validated by two der-
matologists, and the diagnosis of GPP had to be
ascertained on the basis of the histological analysis of a
skin biopsy showing changes consistent with pustular
psoriasis (i.e., acanthosis, parakeratosis, and spongiosis
with subcorneal and intraepidermal collections of neutro-
phils).
Extracutaneous clinical manifestations during the at-
tack were noted, including fever, mucous membrane le-
sions, abdominal pain, jaundice, arthritis, and
pneumonitis. Biological investigated parameters were the
value of peripheral blood absolute leukocyte count, C-re-
active protein (CRP), bilirubin, ␥-glutamyltransferase
(GGT), alkaline phosphatase (ALP), aspartate amino-
transferase (AST), and alanine aminotransferase (ALT)
serum levels during the acute episode. These parameters
were considered abnormal if the highest value was above
the normal upper limit.
A subset of patients with abnormal liver tests was exten-
sively investigated: search for drugs intake, serological detec-
tion of hepatitis B virus and hepatitis C virus infection,
abdominal ultrasound examination, liver histology, endo-
scopic retrograde cholangiopancreatography (ERCP) or
magnetic resonance cholangiopancreatography (MRCP).
Because histological analysis of liver samples gave confirma-
tion of a specific involvement in two initial cases, liver biopsy
was not performed in further enrolled patients because of
potential complications associated with this invasive tech-
nique. Moreover, ERCP was substituted in the last studied
patients by MRCP, which is a noninvasive technique previ-
ously shown to be both as sensitive and specific as ERCP for
the detection of extrahepatic bile duct lesions in diseases such
as primary sclerosing cholangitis (PSC).10 –15 MRCP was
performed using a 1.5-T unit (Siemens Magnetom Sym-
phony, Erlangen, Germany). Heavily T2-weighted se-
quences (single-shot turbo spin echo) were used with
multiple coronal oblique thick slabs (3- to 5-cm section).
Contiguous thin (7-mm) slices were also obtained in the
axial plane using the same parameters. Results from MRCP
were independently analyzed by two radiologists.
The evolution of clinical and biological liver abnormal-
ities, in relation to skin and general symptoms of GPP,
were assessed, as well as the outcome of liver involvement
VIGUIER ET AL. 453
after cutaneous healing and during further relapses of
GPP.
Statistical analysis was performed using Student’s t test
or linear regression analysis with Statview software (SAS
Institute, Cary, NC).
Results
Characteristics of Patients and Psoriasis History.
From an initial population of 26 patients admitted for a
GPP attack, a total of 22 patients were enrolled. The 4
remaining patients were excluded because results from
liver tests were lacking. There were 16 women and 6 men
(sex ratio F/M: 2.7). The median age, at the time of the
studied GPP attack, was 45 years (range, 21–98). While
the studied GPP attack was the first one in the psoriasis
history of most patients, 7 of them had experienced at
least one attack prior to inclusion. Pustular psoriasis at-
tacks occurred as an evolutive complication of the usual
clinical variety of psoriasis in 17 patients (77%): psoriasis
vulgaris in 12 of them, acral pustular psoriasis (pustular
palmoplantar psoriasis or acrodermatitis continua) in 3
cases, localized pustular psoriasis (1 patient), and erythro-
dermic psoriasis (1 patient). Four other patients suffered
from GPP of the von Zumbusch type since childhood,
while the GPP attack occurring at the time of inclusion
was the initial manifestation of psoriasis history in 1 pa-
tient.
Extracutaneous Manifestations Observed During
Attacks. Twenty-one patients (95.4%) had a severely
altered general condition, with malaise, chills, and a high-
grade fever (median, 39°C; range, 37°C– 40°C). Extracu-
taneous manifestations were observed in 13 patients
(59%) including epigastric pain in 4, jaundice in 4, poly-
arthritis in 3, interstitial pneumonitis in 2, mucous mem-
brane lesions involving the tongue or the gums in 2, otitis
media in 1, aseptic pyuria in 1, and aseptic leucorrhea in
1. All these extracutaneous manifestations were transient
and remitted in parallel with cutaneous involvement.
Laboratory Investigations. Nineteen patients (86%)
had a neutrophil absolute count exceeding 10,000/mm3
(median, 16,650/mm3; range, 7,600 –33,900). Consider-
ing the highest biological value observed during the attack
of GPP compared with the upper limit of normal value at
our laboratory (N), 20 of the 22 patients (90%) had at
least one abnormal biological liver parameter. Seventeen
patients (77%) had an abnormal GGT level (median, 3.3
N; range, 1–14.6 N). An abnormal ALP value was ob-
served in 13 patients (59%; median, 1.2 N; range, 1–5.6
N), while abnormal AST and ALT values were found in
12 patients (median AST count, 1.2 N, range, 1–14 N;
median ALT count, 1.5 N, range, 1–22.3 N). The biliru-
454 VIGUIER ET AL. HEPATOLOGY, August 2004

Table 1. Biological Variables, Histological and Morphological Findings in Studied Patients

Neutrophil Bilirubin Count
Patient Count (/mm3) (␮mol/L) GGT ALP AST ALT Liver Biopsy ERCP MRCP

1 — 88 6.4 N 3 N 3.4N 2 N Neutrophilic cholangitis Normal —

2 18,100 67.1 8.9 N 5.6N 2.6N 3.35N Neutrophilic cholangitis — Unique stricture of CBD
3 19,100 45.8 6.3 N 2.1N 2.3N 1.9 N — — Normal
4 21,000 — 8 N 3 N — 1.5 N — — —
5 19,900 221.5 7.8 N 1.8N 14 N 22.3 N — — —
6 17,000 54 8 N N 2.8N 3.6 N — — —
7 33,900 ⬍16 2 N N N N — — —
8 29,000 ⬍16 3.4 N 1.2N 1.2N N — — —
9 7,600 22.8 N N 2.1N N — — —
10 15,100 ⬍16 1.1 N N N 1.6 N — — —
11 14,600 ⬍16 2.2 N 2.3N 2.2N 3.3 N — — —
12 21,500 ⬍16 1.6 N N N 1.5 N — — —
13 9,700 ⬍16 N 1.1N N N — — —
14 10,400 ⬍16 3.25N N N N — — —
15 11,500 ⬍16 5.2 N 2 N 1.6N 1.6 N — — —
16 19,100 ⬍16 2.5 N N N N — — —
17 16,200 25.9 11.5 N 5.5N 3 N 4 N — — —
18 10,400 ⬍16 N N N N — — —
19 16,300 ⬍16 6.8 N 1.4N 1.3N N — — Strictures of PBD
20 16,700 21.6 14.6 N 1.5N 1.2N 3 N — — Strictures of CBD and PBD
21 14,200 ⬍16 N N N N — — —
22 22,400 ⬍16 N 1.2N N N — — —

NOTE: The highest value observed during the episode has been selected and compared with the normal upper limit (N). —, not done.
Abbreviations: CBD, common bile duct; PBD, peripheral bile duct.

bin value was higher than 16 ␮mol/L, which is the normal
limit at our laboratory, in 8 patients (36%; median, 1;
range, 1–14 N) (Table 1). Pronounced liver abnormalities
were observed in 11 out of 22 patients (50%): bilirubin
superior to 50 ␮mol/L (4 patients), GGT levels higher
than 5 times the normal value (10 patients), ALP values
higher or equal to twice the normal value (7 patients),
and/or aminotransferase (AST and/or ALT) values higher
or equal to 3 times that of normal (7 patients) (see Table
1). No statistical difference was evidenced regarding age,
gender, or presence of other extracutaneous manifesta-
tions between these patients and the remaining ones (Stu-
dent’s t test, data not shown).
We further investigated whether or not a relationship
could be established between the severity of liver/biliary
alterations and the severity of cutaneous disease. The se-
verity of GPP could not be directly assessed because the
psoriasis area severity index is not useful in this variety of
psoriasis.16 We studied in all patients the correlation be-
tween different parameters reflecting the severity and/or
the duration of the GPP attack (highest temperature re-
corded, maximum values of neutrophil count and of
CRP, duration of hospitalization) and the highest value of
the different biochemical liver tests (bilirubin, GGT,
ALP, AST, and ALT values). A significant correlation was
found between CRP and ALP values (r ⫽ 0.616, P ⫽ .01)
and between CRP and bilirubin levels (r ⫽ 0.551, P ⫽
.05). In contrast, there was no significant correlation be-
tween biochemical liver tests and fever, duration of hos-
pitalization, or neutrophil count.
The maximal peripheral blood leukocyte absolute
count was observed 6 days after the onset of the GPP
attack (range, 1–15), while the peak value for liver abnor-
malities occurred at day 6 for bilirubin (range, 2– 46), day
11 for ALP (range, 7–23), day 15 for GGT (range, 6 – 40),
day 16.5 for ALT (range, 5– 40), and day 16 for AST
(range, 11– 44). For all of these values, the median one is
given.
Investigations in Patients With Liver Alterations.
All but 2 patients (cases 16 and 21) required systemic
treatment for GPP attack consisting in acitretin (n ⫽ 13),
cyclosporine (n ⫽ 5), methotrexate (n ⫽ 3), or isotreti-
noin (n ⫽ 1) taken alone or in combination. Drug-in-
duced toxicity was excluded in 17 out of 20 patients
(85%) because liver abnormalities were observed prior to
the intake of these drugs and returned to normal ranges
despite continuation of drug therapy.
Serologies for hepatitis B virus and hepatitis C virus
were performed in 15 out of the 20 patients having at least
one abnormal biological liver parameter; all but one case
yielded negative results. This latter case (patient 5) was
positive for hepatitis B surface antigen but negative for
hepatitis B virus deoxyribonucleic acid, excluding hepati-
tis B virus infection as a causal factor for liver abnormal-
ities. Abdominal ultrasonography was performed in 14
patients and was normal in 8 (57%). Homogenous hep-
HEPATOLOGY, Vol. 40, No. 2, 2004
Fig. 1. Bile duct strictures in 3
patients (MRCP). (A) Moderate nar-
rowing of the common hepatic bile
duct (arrow) in patient 2. (B, C) In
patient 20, MRCP shows two stric-
tures of the common hepatic bile
duct (arrows) and succession of
strictures (arrowheads) and dila-
tions of intrahepatic bile ducts (B,
left view; C, right view). (D) A stric-
ture of the left central hepatic bile
duct (arrow) with proximal dilatation
and irregularities of the left intrahe-
patic bile ducts (arrowhead) are ob-
served in patient 19.
atomegaly with features of steatosis was observed in 3
cases, whereas uncomplicated vesicular lithiasis was
shown in 1 case. A slight dilatation of the biliary tract and
a thickened biliary tract were observed in patients 3 and
19, respectively.
ERCP was performed in one case and was normal (pa-
tient 1). Four patients underwent MRCP during one of
the acute episodes. MRCP correctly showed the common
bile duct in all cases and the intrahepatic bile ducts in all
but one case. Bile duct strictures— defined as narrowing
of the bile duct with dilatation of the proximal segment—
were found in 3 of the 4 patients. One of them had a
unique stricture of the common bile duct (Fig. 1A). An-
other one had 2 strictures involving the common bile duct
and multiple peripheral bile duct strictures (Fig. 1B and
1C). The remaining patient had 3 peripheral bile duct
strictures (Fig. 1D).
Two patients (patients 1 and 2) with pronounced ab-
normalities on liver tests underwent a liver biopsy at the
time of GPP attack. Histological examination showed no
architectural change. In the two cases, a polymorphonu-
clear leukocyte infiltrate was observed in the portal con-
nective tissue as well as within the epithelial layer of
interlobular bile ducts, without epithelial cell degenera-
VIGUIER ET AL. 455
tion (Fig. 2). No polymorphonuclear leukocyte was seen
in the bile duct lumen or in the hepatic lobules. There was
no cholestasis, no portal edema, and no periductal fibro-
sis. A mild bile ductular proliferation was observed in
patient 1. Associated liver abnormalities consisted of mild
lymphocytic portal infiltration, mostly composed of
CD8⫹ T cells, without lymphocytic bile duct exocytosis.
There were few liver cell necroses in periportal areas and a
mild steatosis. Recently, another patient was directly re-
ferred to our gastroenterology department from an exter-
nal dermatology department for jaundice, acute abnormal
liver tests, and normal abdominal ultrasound examina-
tion during a GPP attack. We did not include this patient
in the present series, because the recruitment method was
different. Liver biopsy revealed alterations very similar to
those described above. A mild bile ductular proliferation
was also observed in this patient (data not shown).
Outcome of Liver Alterations. Liver tests returned to
normal values within the month following the peak value
after recovery of the cutaneous lesions in all but 1 patient.
In all 6 patients who presented with further GPP attacks
during follow-up, a relapse of liver alterations with a sim-
ilar course was observed. The 3 patients who had abnor-
malities evidenced by MRCP underwent a follow-up
456 VIGUIER ET AL.
Fig. 2. Histological views of portal tracts showing neutrophilic cholangitis in 2 patients. Polymorphonuclear leukocytes are observed in the portal
spaces, as well as within the epithelial layer of interlobular bile ducts (arrows), but not in the bile duct lumen or within the hepatic lobules
(hematoxylin-eosin; original magnification ⫻400).
MRCP examination 6, 9, and 27 months after the initial
one, respectively. Abnormal features were persistent in all
cases.
Discussion
GPP of the von Zumbusch variety is a severe form of
psoriasis that may be associated with life-threatening
complications such as sepsis or metabolical, hemody-
namic, and thermoregulatory disturbances related to se-
vere alterations of the epidermal barrier. Although
cutaneous involvement is always the predominant fea-
ture, extracutaneous localizations have also been de-
scribed, and liver involvement has only been reported in
isolated cases prior to this study.5– 8,17–23 However, the
incidence of liver damage has not been previously inves-
tigated in published series of patients with GPP.1,2,24 –27
The results presented herein provide evidence for a high
frequency of liver involvement in patients with GPP. In-
deed, we have shown that clinical symptoms (epigastric
pain and/or jaundice) were present in 32% of cases, while
the prevalence of at least 1 abnormal biological liver test
was 90%. Pronounced abnormalities on liver tests were
observed in 50% of patients. Liver test abnormalities usu-
ally occurred within the 2 weeks following the onset of
cutaneous symptoms and 1 week after the peak of leuko-
cytosis. A significant correlation was found between CRP
and ALP values at one hand and between CRP and bili-
rubin levels on another hand. This suggests that the sever-
ity of liver alterations could be associated with a more
severe cutaneous flare. Nevertheless, this needs to be con-
firmed in further prospective studies designed to assess
both inflammatory biological markers and different clin-
ical parameters that were not investigated in the present
study (e.g., the duration of pustulation and erythro-
derma).
Abnormal liver tests usually resolved when the skin
healed and relapsed during further GPP attacks in all
HEPATOLOGY, August 2004
cases. The evidence that the course of liver alterations
paralleled the evolution of both skin lesions and neutro-
philic hyperleukocytosis strongly supports a specific in-
volvement of the biliary tract. No other cause of liver
and/or biliary disorder such as viral infection, toxic shock
syndrome, cardiac failure, or obstruction or infection of
the biliary tree were found in our patients. No potentially
hepatotoxic drug, such as acitretin or methotrexate, was
taken by our patients before occurrence of liver abnormal-
ities in 85% of them (data not shown). Biliary involve-
ment can be considered an extracutaneous manifestation
of GPP in view of histological alterations observed in liver
biopsies from 3 patients showing a neutrophilic infiltra-
tion of the portal tract and of the epithelium of the bile
ducts, which is consistent with the diagnosis of neutro-
philic cholangitis. MRCP revealed intra- or extrahepatic
bile duct strictures in 3 out of 4 patients analyzed. These
latter features were still observed several months after the
initial investigation in these 3 patients. Biliary involve-
ment related to GPP was not limited to small ducts, but
also affected large biliary ducts with strictures, sharing
features similar to those observed in PSC. Interestingly, a
case of GPP has been previously mentioned in a series of
56 children with PSC.28 However, no histological
changes characteristic of PSC (e.g., concentric layers of
connective tissue surrounding bile ducts29) or changes
associated with large duct obstruction (e.g., cholestasis,
portal edema, or presence of polymorphonuclear leuko-
cytes in the bile duct lumen29) were observed in the 3 liver
biopsies we examined, one of them having being per-
formed in a patient who had a unique stricture of the
common bile duct (case 2). Moreover, patients with ste-
nosis on MCRP did not develop progressive cholestasis, as
liver tests remained normal between GPP attacks with a
follow-up now exceeding 4 years for patient 2. Neverthe-
less, specific pathological signs of PSC are seen in only a
minority of percutaneous liver biopsies, and it is more
HEPATOLOGY, Vol. 40, No. 2, 2004
common to find nonspecific fibrosis and inflammation in
the portal tracts, especially at the early onset of disease.29
On the other hand, there are reports of patients with PSC
diagnosed by cholangiography or MRCP who had nor-
mal liver tests.29,30 Altogether, the presence of PSC in
GPP patients remains uncertain and follow-up studies
will be warranted to clarify further the prognosis of biliary
duct stenosis in patients with GPP.
Case reports of liver abnormalities occurring during
GPP attacks have been previously published, consisting
mostly of liver test abnormalities with or without jaun-
dice.5,6,8,17–23 The hypothesis that liver abnormalities in
patients with GPP could be related to the inflammatory
pathogenic process characterized by a predominant neu-
trophilic activation has already been raised by several au-
thors.5,6,8 In the reported cases, ultrasonography,
tomodensitometry explorations,5,8,22 ERCP,8 or MRCP22
showed no significant change. However, a specific in-
volvement was supported by histological alterations
found by liver biopsy which was performed in four cases,
showing evidence of cholestasis with portal fibrosis and
proliferation of ductules,8 periportal infiltrates of poly-
morphonuclear leukocytes, and lymphocytes with focal
necrosis of liver cells.5,6 These alterations differed from
histopathological findings of our series regarding the lack
of duct epithelial cell damage, but these differences may
reflect different stages during the course of liver involve-
ment.
Neutrophilic infiltration, as found in the portal tract of
our patients, is a predominant feature of cutaneous and
extracutaneous lesions of pustular psoriasis, notably those
involving the mucous membranes3 and the synovial
membranes in patients with polyarthritis.4 Other extracu-
taneous manifestations of GPP include ocular involve-
ment resulting in conjunctivitis, uveitis, or corneal
ulceration,31,32 as well as bone lytic lesions due to multi-
focal sterile osteomyelitis.33 Pneumonitis with occasion-
ally acute respiratory distress syndrome has also been
reported, but neutrophilic involvement of the bronchial
tract has not been documented in published cases.19,34 –37
Interestingly, one case of neutrophilic cholangitis associ-
ated with Sweet’s syndrome—a variety of neutrophilic
dermatosis— has also been reported.38
So far, it remains unclear whether neutrophilic infiltra-
tion of the biliary tract is an initial event or more likely is
secondary to the influx of activated T cells and macro-
phages, as suggested by Shelley5 and Craig,6 in a similar
way as what is observed for skin lesions.39 In future stud-
ies, immunohistochemical analysis of T cell subsets and
investigations of the local secretion of neutrophil-recruit-
ing chemokines (e.g., interleukin 8 and Gro-␣) will be
warranted to deal with this issue.
VIGUIER ET AL. 457
In conclusion, the results of the present study strongly
support that neutrophilic cholangitis should be added to
the spectrum of extracutaneous manifestations of GPP.
Such a complication should be known to avoid both use-
less invasive liver investigations and withdrawal of drugs
with potentially deleterious consequences on the course of
the disease. Further prospective studies are warranted to
understand more accurately the mechanism of biliary in-
volvement in GPP.
Acknowledgment: The authors are indebted to Dr.
Ewa Guigné (Department of Dermatology, Hôpital
Henri Mondor, Créteil, France) for referring a patient.
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