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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.)

eneralized pustular psoriasis (GPP) of the von factors such as infections, drugs, sunlight, or preg-
Zumbusch variety is a generalized life-threaten- nancy.1,2 Since the first description of the disease in 1910,
ing form of psoriasis characterized by dissemi- there have been reports of patients with GPP who present
nated pustular skin lesions following an acute course and with extracutaneous manifestations, which consist mostly
often associated with high fever and hyperleukocytosis. of mucous membranes lesions and arthritis.3,4 Evidence of
The attacks may be induced in some cases by triggering 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
Abbreviations: GPP, generalized pustular psoriasis; CRP, C-reactive protein; GPP in a 42-year-old woman presenting with cholestasis
GGT, ␥-glutamyltransferase; ALP, alkaline phosphatase; AST, aspartate amino- following an acute evolution paralleling the course of skin
transferase; ALT, alanine aminotransferase; ERCP, endoscopic retrograde cholan-
giopancreatography; MRCP, magnetic resonance cholangiopancreatography; PSC, disease.9 Recognizing the hypothesis that neutrophilic
primary sclerosing cholangitis. cholangitis could represent an extracutaneous manifesta-
From the Departments of 1Dermatology 1, 2Gastroenterology, 3Radiology, 4Pa- tion of GPP, we investigated the prevalence and the na-
thology, and 5Dermatology 2, Hôpital Saint-Louis, Assistance Publique-Hôpitaux
de Paris and Université Paris 7, Paris, France.
ture of liver abnormalities occurring in patients with
Received December 11, 2003; accepted April 6, 2004. GPP.
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:; fax: ⫹33 1-42-49-46-20. Patients and Methods
Copyright © 2004 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience ( We conducted a study on all patients consecutively
DOI 10.1002/hep.20305 admitted for a GPP attack in one of the two departments
HEPATOLOGY, Vol. 40, No. 2, 2004 VIGUIER ET AL. 453

of dermatology of the Saint-Louis Hospital, Paris, be- after cutaneous healing and during further relapses of
tween 1995 and 2001. To be included, patients had to GPP.
fulfill the following criteria: (1) at least one attack of GPP, Statistical analysis was performed using Student’s t test
defined as sheets of erythema and pustulation spreading in or linear regression analysis with Statview software (SAS
waves, progressively involving the whole body surface Institute, Cary, NC).
within a few days, associated with general symptoms in-
cluding fever higher than 38°C, and/or leukocytosis Results
higher than 10,000/mm3; or (2) liver biological tests
available at the time of GPP attack and during the follow- Characteristics of Patients and Psoriasis History.
ing weeks. The clinical criteria were validated by two der- From an initial population of 26 patients admitted for a
matologists, and the diagnosis of GPP had to be GPP attack, a total of 22 patients were enrolled. The 4
ascertained on the basis of the histological analysis of a remaining patients were excluded because results from
skin biopsy showing changes consistent with pustular liver tests were lacking. There were 16 women and 6 men
psoriasis (i.e., acanthosis, parakeratosis, and spongiosis (sex ratio F/M: 2.7). The median age, at the time of the
with subcorneal and intraepidermal collections of neutro- studied GPP attack, was 45 years (range, 21–98). While
phils). the studied GPP attack was the first one in the psoriasis
Extracutaneous clinical manifestations during the at- history of most patients, 7 of them had experienced at
tack were noted, including fever, mucous membrane le- least one attack prior to inclusion. Pustular psoriasis at-
sions, abdominal pain, jaundice, arthritis, and tacks occurred as an evolutive complication of the usual
pneumonitis. Biological investigated parameters were the clinical variety of psoriasis in 17 patients (77%): psoriasis
value of peripheral blood absolute leukocyte count, C-re- vulgaris in 12 of them, acral pustular psoriasis (pustular
active protein (CRP), bilirubin, ␥-glutamyltransferase palmoplantar psoriasis or acrodermatitis continua) in 3
(GGT), alkaline phosphatase (ALP), aspartate amino- cases, localized pustular psoriasis (1 patient), and erythro-
transferase (AST), and alanine aminotransferase (ALT) dermic psoriasis (1 patient). Four other patients suffered
serum levels during the acute episode. These parameters from GPP of the von Zumbusch type since childhood,
were considered abnormal if the highest value was above while the GPP attack occurring at the time of inclusion
the normal upper limit. was the initial manifestation of psoriasis history in 1 pa-
A subset of patients with abnormal liver tests was exten- tient.
sively investigated: search for drugs intake, serological detec- Extracutaneous Manifestations Observed During
tion of hepatitis B virus and hepatitis C virus infection, Attacks. Twenty-one patients (95.4%) had a severely
abdominal ultrasound examination, liver histology, endo- altered general condition, with malaise, chills, and a high-
scopic retrograde cholangiopancreatography (ERCP) or grade fever (median, 39°C; range, 37°C– 40°C). Extracu-
magnetic resonance cholangiopancreatography (MRCP). taneous manifestations were observed in 13 patients
Because histological analysis of liver samples gave confirma- (59%) including epigastric pain in 4, jaundice in 4, poly-
tion of a specific involvement in two initial cases, liver biopsy arthritis in 3, interstitial pneumonitis in 2, mucous mem-
was not performed in further enrolled patients because of brane lesions involving the tongue or the gums in 2, otitis
potential complications associated with this invasive tech- media in 1, aseptic pyuria in 1, and aseptic leucorrhea in
nique. Moreover, ERCP was substituted in the last studied 1. All these extracutaneous manifestations were transient
patients by MRCP, which is a noninvasive technique previ- and remitted in parallel with cutaneous involvement.
ously shown to be both as sensitive and specific as ERCP for Laboratory Investigations. Nineteen patients (86%)
the detection of extrahepatic bile duct lesions in diseases such had a neutrophil absolute count exceeding 10,000/mm3
as primary sclerosing cholangitis (PSC).10 –15 MRCP was (median, 16,650/mm3; range, 7,600 –33,900). Consider-
performed using a 1.5-T unit (Siemens Magnetom Sym- ing the highest biological value observed during the attack
phony, Erlangen, Germany). Heavily T2-weighted se- of GPP compared with the upper limit of normal value at
quences (single-shot turbo spin echo) were used with our laboratory (N), 20 of the 22 patients (90%) had at
multiple coronal oblique thick slabs (3- to 5-cm section). least one abnormal biological liver parameter. Seventeen
Contiguous thin (7-mm) slices were also obtained in the patients (77%) had an abnormal GGT level (median, 3.3
axial plane using the same parameters. Results from MRCP N; range, 1–14.6 N). An abnormal ALP value was ob-
were independently analyzed by two radiologists. served in 13 patients (59%; median, 1.2 N; range, 1–5.6
The evolution of clinical and biological liver abnormal- N), while abnormal AST and ALT values were found in
ities, in relation to skin and general symptoms of GPP, 12 patients (median AST count, 1.2 N, range, 1–14 N;
were assessed, as well as the outcome of liver involvement median ALT count, 1.5 N, range, 1–22.3 N). The biliru-

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 tween biochemical liver tests and fever, duration of hos-
limit at our laboratory, in 8 patients (36%; median, 1; pitalization, or neutrophil count.
range, 1–14 N) (Table 1). Pronounced liver abnormalities The maximal peripheral blood leukocyte absolute
were observed in 11 out of 22 patients (50%): bilirubin count was observed 6 days after the onset of the GPP
superior to 50 ␮mol/L (4 patients), GGT levels higher attack (range, 1–15), while the peak value for liver abnor-
than 5 times the normal value (10 patients), ALP values malities occurred at day 6 for bilirubin (range, 2– 46), day
higher or equal to twice the normal value (7 patients), 11 for ALP (range, 7–23), day 15 for GGT (range, 6 – 40),
and/or aminotransferase (AST and/or ALT) values higher day 16.5 for ALT (range, 5– 40), and day 16 for AST
or equal to 3 times that of normal (7 patients) (see Table (range, 11– 44). For all of these values, the median one is
1). No statistical difference was evidenced regarding age, given.
gender, or presence of other extracutaneous manifesta- Investigations in Patients With Liver Alterations.
tions between these patients and the remaining ones (Stu- All but 2 patients (cases 16 and 21) required systemic
dent’s t test, data not shown). treatment for GPP attack consisting in acitretin (n ⫽ 13),
We further investigated whether or not a relationship cyclosporine (n ⫽ 5), methotrexate (n ⫽ 3), or isotreti-
could be established between the severity of liver/biliary noin (n ⫽ 1) taken alone or in combination. Drug-in-
alterations and the severity of cutaneous disease. The se- duced toxicity was excluded in 17 out of 20 patients
verity of GPP could not be directly assessed because the (85%) because liver abnormalities were observed prior to
psoriasis area severity index is not useful in this variety of the intake of these drugs and returned to normal ranges
psoriasis.16 We studied in all patients the correlation be- despite continuation of drug therapy.
tween different parameters reflecting the severity and/or Serologies for hepatitis B virus and hepatitis C virus
the duration of the GPP attack (highest temperature re- were performed in 15 out of the 20 patients having at least
corded, maximum values of neutrophil count and of one abnormal biological liver parameter; all but one case
CRP, duration of hospitalization) and the highest value of yielded negative results. This latter case (patient 5) was
the different biochemical liver tests (bilirubin, GGT, positive for hepatitis B surface antigen but negative for
ALP, AST, and ALT values). A significant correlation was hepatitis B virus deoxyribonucleic acid, excluding hepati-
found between CRP and ALP values (r ⫽ 0.616, P ⫽ .01) tis B virus infection as a causal factor for liver abnormal-
and between CRP and bilirubin levels (r ⫽ 0.551, P ⫽ ities. Abdominal ultrasonography was performed in 14
.05). In contrast, there was no significant correlation be- patients and was normal in 8 (57%). Homogenous hep-
HEPATOLOGY, Vol. 40, No. 2, 2004 VIGUIER ET AL. 455

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 tion (Fig. 2). No polymorphonuclear leukocyte was seen
cases, whereas uncomplicated vesicular lithiasis was in the bile duct lumen or in the hepatic lobules. There was
shown in 1 case. A slight dilatation of the biliary tract and no cholestasis, no portal edema, and no periductal fibro-
a thickened biliary tract were observed in patients 3 and sis. A mild bile ductular proliferation was observed in
19, respectively. patient 1. Associated liver abnormalities consisted of mild
ERCP was performed in one case and was normal (pa- lymphocytic portal infiltration, mostly composed of
tient 1). Four patients underwent MRCP during one of CD8⫹ T cells, without lymphocytic bile duct exocytosis.
the acute episodes. MRCP correctly showed the common There were few liver cell necroses in periportal areas and a
bile duct in all cases and the intrahepatic bile ducts in all mild steatosis. Recently, another patient was directly re-
but one case. Bile duct strictures— defined as narrowing ferred to our gastroenterology department from an exter-
of the bile duct with dilatation of the proximal segment— nal dermatology department for jaundice, acute abnormal
were found in 3 of the 4 patients. One of them had a liver tests, and normal abdominal ultrasound examina-
unique stricture of the common bile duct (Fig. 1A). An- tion during a GPP attack. We did not include this patient
other one had 2 strictures involving the common bile duct in the present series, because the recruitment method was
and multiple peripheral bile duct strictures (Fig. 1B and different. Liver biopsy revealed alterations very similar to
1C). The remaining patient had 3 peripheral bile duct those described above. A mild bile ductular proliferation
strictures (Fig. 1D). was also observed in this patient (data not shown).
Two patients (patients 1 and 2) with pronounced ab- Outcome of Liver Alterations. Liver tests returned to
normalities on liver tests underwent a liver biopsy at the normal values within the month following the peak value
time of GPP attack. Histological examination showed no after recovery of the cutaneous lesions in all but 1 patient.
architectural change. In the two cases, a polymorphonu- In all 6 patients who presented with further GPP attacks
clear leukocyte infiltrate was observed in the portal con- during follow-up, a relapse of liver alterations with a sim-
nective tissue as well as within the epithelial layer of ilar course was observed. The 3 patients who had abnor-
interlobular bile ducts, without epithelial cell degenera- malities evidenced by MRCP underwent a follow-up

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 cases. The evidence that the course of liver alterations
one, respectively. Abnormal features were persistent in all paralleled the evolution of both skin lesions and neutro-
cases. philic hyperleukocytosis strongly supports a specific in-
volvement of the biliary tract. No other cause of liver
Discussion and/or biliary disorder such as viral infection, toxic shock
GPP of the von Zumbusch variety is a severe form of syndrome, cardiac failure, or obstruction or infection of
psoriasis that may be associated with life-threatening the biliary tree were found in our patients. No potentially
complications such as sepsis or metabolical, hemody- hepatotoxic drug, such as acitretin or methotrexate, was
namic, and thermoregulatory disturbances related to se- taken by our patients before occurrence of liver abnormal-
vere alterations of the epidermal barrier. Although ities in 85% of them (data not shown). Biliary involve-
cutaneous involvement is always the predominant fea- ment can be considered an extracutaneous manifestation
ture, extracutaneous localizations have also been de- of GPP in view of histological alterations observed in liver
scribed, and liver involvement has only been reported in biopsies from 3 patients showing a neutrophilic infiltra-
isolated cases prior to this study.5– 8,17–23 However, the tion of the portal tract and of the epithelium of the bile
incidence of liver damage has not been previously inves- ducts, which is consistent with the diagnosis of neutro-
tigated in published series of patients with GPP.1,2,24 –27 philic cholangitis. MRCP revealed intra- or extrahepatic
The results presented herein provide evidence for a high bile duct strictures in 3 out of 4 patients analyzed. These
frequency of liver involvement in patients with GPP. In- latter features were still observed several months after the
deed, we have shown that clinical symptoms (epigastric initial investigation in these 3 patients. Biliary involve-
pain and/or jaundice) were present in 32% of cases, while ment related to GPP was not limited to small ducts, but
the prevalence of at least 1 abnormal biological liver test also affected large biliary ducts with strictures, sharing
was 90%. Pronounced abnormalities on liver tests were features similar to those observed in PSC. Interestingly, a
observed in 50% of patients. Liver test abnormalities usu- case of GPP has been previously mentioned in a series of
ally occurred within the 2 weeks following the onset of 56 children with PSC.28 However, no histological
cutaneous symptoms and 1 week after the peak of leuko- changes characteristic of PSC (e.g., concentric layers of
cytosis. A significant correlation was found between CRP connective tissue surrounding bile ducts29) or changes
and ALP values at one hand and between CRP and bili- associated with large duct obstruction (e.g., cholestasis,
rubin levels on another hand. This suggests that the sever- portal edema, or presence of polymorphonuclear leuko-
ity of liver alterations could be associated with a more cytes in the bile duct lumen29) were observed in the 3 liver
severe cutaneous flare. Nevertheless, this needs to be con- biopsies we examined, one of them having being per-
firmed in further prospective studies designed to assess formed in a patient who had a unique stricture of the
both inflammatory biological markers and different clin- common bile duct (case 2). Moreover, patients with ste-
ical parameters that were not investigated in the present nosis on MCRP did not develop progressive cholestasis, as
study (e.g., the duration of pustulation and erythro- liver tests remained normal between GPP attacks with a
derma). follow-up now exceeding 4 years for patient 2. Neverthe-
Abnormal liver tests usually resolved when the skin less, specific pathological signs of PSC are seen in only a
healed and relapsed during further GPP attacks in all minority of percutaneous liver biopsies, and it is more
HEPATOLOGY, Vol. 40, No. 2, 2004 VIGUIER ET AL. 457

common to find nonspecific fibrosis and inflammation in In conclusion, the results of the present study strongly
the portal tracts, especially at the early onset of disease.29 support that neutrophilic cholangitis should be added to
On the other hand, there are reports of patients with PSC the spectrum of extracutaneous manifestations of GPP.
diagnosed by cholangiography or MRCP who had nor- Such a complication should be known to avoid both use-
mal liver tests.29,30 Altogether, the presence of PSC in less invasive liver investigations and withdrawal of drugs
GPP patients remains uncertain and follow-up studies with potentially deleterious consequences on the course of
will be warranted to clarify further the prognosis of biliary the disease. Further prospective studies are warranted to
duct stenosis in patients with GPP. understand more accurately the mechanism of biliary in-
Case reports of liver abnormalities occurring during volvement in GPP.
GPP attacks have been previously published, consisting
Acknowledgment: The authors are indebted to Dr.
mostly of liver test abnormalities with or without jaun- Ewa Guigné (Department of Dermatology, Hôpital
dice.5,6,8,17–23 The hypothesis that liver abnormalities in Henri Mondor, Créteil, France) for referring a patient.
patients with GPP could be related to the inflammatory
pathogenic process characterized by a predominant neu- References
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