Juvenile Systemic Lupus

Erythematosus and cholecystitis: Case

reports and review of literature

Rivas-Larrauri Francisco, MD,* Gómez-

Hernández Noemi, MD,** Yamazaki-
Nakashimada Marco Antonio, MD,***
Rodríguez-Jurado Rodolfo, MD,****
Hernández-Bautista Víctor Manuel,
MD,***** Ramírez-Mayans J, MD,******
Rodríguez-Lozano Ana Luisa,
MD*******

* Pediatric Immunologist, Immunology

Service Staff.
** Immunology Fellow.
*** Pediatric Immunologist,
Immunology Service Staff.
**** Pathologist, Pathology Service
Staff.
***** Pediatric Immunologist,
Immunology Chief Service.
****** Pediatric Gastroenterologist,
Gastroenterology Staff.
******* Corresponding author. Instituto
Nacional de Pediatría, México, D.F.
1
Abbreviations
SLE: Systemic Lupus Erythematosus
JSLE: Juvenile Systemic Lupus
Erythematosus
APS: Antiphospholipid Antibody
Syndrome
AAC: Acute acalculous cholecystitis
OVII: Occlusive venous mesenteric
inflammatory illness
US: Ultrasound
ALC: Acute lithiasic cholecystitis
AMLC: Acute microlithiasic
cholecystitis
ANA: Anti Nuclear Antibodies
ACA: Anticardiolipin antibodies
AntiB2GP: Anti-B2 Glycoprotein
Anti-PS: Anti- Phosphatidylserine
Corresponding author:
Ana Luisa Rodríguez Lozano, MD
Pediatric Rheumatologist, Medical
Researcher Immunology Service.
Instituto Nacional de Pediatría
Insurgentes Sur 3700-C Col.
Insurgentes Cuicuilco
2
04530 México City, México
Tel/Fax +52 55 1084 0900 ext 1337
E-mail: [email protected]

Resumen

Palabras clave:

Abstract

Juvenile Systemic Lupus

Erythematosus (JSLE) is an
autoimmune, multi-systemic disease
with a wide range of clinical
manifestations, however, the
gallbladder disease is not well
documented in the pediatric patients,
there are few cases of cholecystitis in
patients with JSLE in the world
literature. We present three JSLE
patients from the Immunology Service
of the Instituto Nacional de Pediatría
who developed cholecystitis during
their evolution. We emphasize the
awareness of this complication in these
patients.
3
Key words: Juvenile systemic lupus
erythematosus, cholecystitis,
abdominal pain.

Introduction

Systemic Lupus Erythematosus (SLE)

is an autoimmune, multi-systemic
disease with an unpredictable course
and a wide range of clinical
manifestations.1 It is known that the
incidence of abdominal manifestations
in adults is from 8 to 40% and acute
cholecystitis represents 15% of them.2
There are few reports of
gastrointestinal manifestations in
children, Richer and cols., evaluated
the frequency of gastrointestinal
manifestations in French children with
SLE (JSLE) and found an incidence of
19%, reporting only one case of
cholecystitis in 201 evaluated
patients.3 Vesicular pathology is an
unusual complication in patients with

4
SLE, even though there are diverse risk
factors for developing it in this disease.
We present three JSLE patients from
the Immunology Service of the
Instituto Nacional de Pediatría who
developed cholecystitis during their
evolution.

Case presentation

Case 1

A ten year-old female became ill 8

months prior to her hospitalization
with malar rash, arthralgia,
photosensitivity and muscular
weakness. Diagnostic approach was
initiated and met criteria for SLE
(photosensitivity, discoid lupus, oral
ulcers, proteinuria 5.4 g, ANA diffuse
pattern 1:320, positive anti-DNAn,
anti-SM > 100 U). She had
hypocomplementemia C3 29.6 mg/dL,
C4 < 6.18 mg/dL and dyslipidemia,
1,964 mg/dL triglycerides, 418 mg/dL
cholesterol, negative serology for
5
Antiphospholipid Antibody Syndrome
(APS), which was treated with pulse
methylprednisolone. During her
hospitalization, she had acute
abdominal pain associated to the
ingestion of cholecystokinetic food,
which was accompanied by nausea
and biliary vomiting. Initial evaluation
was normal, but because of persistence
of pain in the right hypochondrium, an
abdominal US was performed, showing
thickening of the vesicular wall with
biliary sludge, she had a conservative
treatment and because of lupus was
initiated with methylprednisolone and
cyclophosphamide pulses, with good
lupus evolution and remission of the
abdominal symptoms.
As the result of recurrent cholecystitis
the patient required laparoscopic
cholecystectomy, the histopathology
showed slight edema and inflammatory
infiltrate composed of lymphocytes and
plasma cells at the muscle layer, there
was no evidence of lithiasis or
vasculitis. The patient is currently
6
under treatment with
cyclophosphamide pulses for nephritis,
and has remained stable.

Case 2

A thirteen year-old male was initiated

with asthenia, weight and hair loss,
facial erythema, photosensitivity and
intense generalized cephalea
accompanied by nausea and conduct
disorders. The patient met SLE criteria
(malar erythema, oral ulcers,
photosensitivity, arthritis, ANA 1:160,
positive anti-DNAn, lymphopenia,
hemolytic anemia, and 0.9 g
proteinuria) and also had
hypocomplementemia and
hypergammaglobulinemia (IgG 2,009
mg/dL). The patient needed
methylprednisolone pulses because of
the activity and also received
prednisone, azathioprine and
hydroxychloroquine, and showed
satisfactory progress.

7
Three years later, he presented to the
emergency room for abdominal pain in
the right hypochondrium. Initial
laboratory showed: triglycerides 465
mg/dL, cholesterol 214 mg/dL, HDL
22.3 mg/dL, LDL 144 mg/dL, VLDL
47.2 mg/dL. During inpatient
evolution proteinuria, hematuria,
hypocomplementemia and positive
anti-DNAn were observed. An
infectious process was discarded and
an abdominal ultrasound was
performed, in which free liquid was
saw in the right iliac fossa and a 7 mm
thickening of the gallbladder wall with
no evidence of lithogenesis. The
decision was made to initiate
methylprednisolone pulses as a result
of the activity data, with notable
improvement of lupus activity and the
cholecystitis, with no need for surgery.
The patient continues to receive
cyclophosphamide pulses due to
neurolupus and nephritis. He has not
had cholecystitis episodes and
maintains a normal lipid profile.
8
Case 3

A fourteen year-old female began ill

with arthritis, 5 kg weight loss and
purpuric lesions in the lower
extremities. Pleural effusion was
detected and the patient was
diagnosed with SLE (lymphopenia,
hemolytic anemia, pleural effusion,
oral ulcers, ANA 1:320 and
proteinuria). She was treated initially
with azathioprine, cyclophosphamide
and methylprednisolone pulses.
However, since the proteinuria
persisted, the decision was made to
change to mycophenolate mofetil 60
mg/kg/d. Two years later a thyroid
dysfunction was detected, triglycerides
859 mg/dL, cholesterol 434 mg/dL,
HDL 40.3 mg/dL, LDL 241 mg/dL,
VLDL 171 mg/dL and positive Anti B2
glycoprotein were documented for
which treatment with levothyroxine
and levastatin was initiated.

9
After 6 months the patient entered
with 2 days of abdominal pain in the
epigastric region accompanied by
alimentary vomiting, and positive
Murphy’s sign. Normal pancreatic
enzymes were reported and her
cholesterol was 387 mg/dL,
triglycerides 358 mg/dL. The
abdominal US showed a cholelith in
the gallbladder. She had lymphopenia
and proteinuria of 4.6 g during her
stay, for which it was decided to
administer methylprednisolone pulses,
and she showed improvement of the
activity of the illness and cholecystitis
symptoms. She is currently receiving
65 mg/kg/d of mycophenolate mofetil,
is asymptomatic and on a
cholecystokinetic-free diet.

Discussion

The ubiquitous gastrointestinal

manifestations in patients with SLE
consist of oral ulcers, abdominal pain,
gastroesophageal reflux, peritonitis,
10
pancreatitis and hepatitis. Among less
frequent manifestations are dysphagia
and cholecystitis.4,5
Abdominal pain is a diagnostic and
therapeutic challenge in these patients
because it could have an autoimmune
source secondary to concomitant
illnesses, the side effects of the
immunosuppressant treatment,4,5 and
less common due to serositis.15
Patients with SLE are prone to the
formation of biliary sludge and lithiasis
because of the presence of biliary
dyskinesia caused by ischemia of the
gallbladder.7 Reshetnyak et al., also
found in patients with SLE the
relationship between the use of
corticosteroids and a metabolic lipid
disorder, which predisposes the
formation of biliary calculi.8
Acute acalculous cholecystitis (AAC),
which is non-distinguishable from
litiasic cholecystitis, is present in 5-
10% of the patients with acute
cholecystitis. It has been reported in
patients with burns, severe trauma,
11
infectious processes, prolonged
parenteral nutrition, diabetes mellitus,
APS and vasculitis. In vasculitis,
patients with poliarteritis nodosa are at
greater risk of presenting CAA.
Echographic criteria proposed for
diagnosing CAA include thickening of
the gallbladder wall, edema around the
gallbladder and the absence of liths.8-10
There are two main causes for
gallbladder ischemia in SLE: vasculitis
and thrombosis. Gallbladder vasculitis
is characterized by the presence of
acute periarterial fibrotic arteritis.9,10
Chen et al., separate gallbladder
vasculitis into 3 groups: 1) vasculitis
with manifestations of poliarteritis
nodosa, 2) vasculitis occurring in
ailments associated to vasculitis, such
as systemic lupus erythematosus and
3) idiopathic vasculitis.11 Thrombosis is
more characteristic of SLE patients
and is presented more frequently in
patients with antiphospholipid
antibodies. Histologically, multiple
thrombi are appreciated in the veins of
12
the gallbladder with no evidence of
vasculitis.9-11
Occlusive venous mesenteric
inflammatory illness (OVII) is an
infrequent cause of ACC in SLE with
unknown etiology. Lie et al., reported
that OVII belonged to a new category of
vasculitis, in which inflammation is
limited and affects intestinal veins and
venules, specifically the mesenteric
vein and its branches. Histologically,
lymphocytic inflammatory with a
necrotizing, granulomatous or mixed
infiltrates and thrombosis are
observed.12,13
In 2006, we reported the case of a 17
year-old patient with SLE who
reentered one year later for intense
cramping abdominal pain, hemolytic
anemia, proteinuria and lymphopenia.
Elevated hepatic and pancreatic
enzymes were also reported. The
abdominal US (ultrasound) showed
microlithiasic cholecystitis and
pancreatitis. An open cholecystectomy
was performed and the histopathology
13
reports showed segmental necrotizing
vasculitis. Treatment was started with
pulse methylprednisolone and
cyclophosphamide and the patient
showed improvement. Because of the
histopathological findings and data
regarding clinical activity, it was
considered that the cholecystitis was
part of the damage caused by the
disease’s activity.14
In 1983, Swanepoel17 was the first to
describe the association between CAA
and SLE, since then different reports
have been issued.18-22 In table I
summarizes the main alterations our
patients share with cases reported
previously. It attracts our attention
that the 3 cases reported here and the
one reported previously14 by our
Institute have lupus nephritis and
hypertriglyceridemia, in comparison to
only two of the rest of the reports. On
the other hand, the presence of
hemolytic anemia in two of the patients
associated to other activity data on the
disease, as could be the increase in
14
proteinuria, leads to conclude that: 1.
Patients with juvenile SLE go through
a more aggressive illness, with greater
multi-organ affliction, 2. In patients
with disease activity that present
abdominal pain, cholecystitis should
be suspected. As mentioned by
Mendoca et al., it is possible that
acalculous cholecystitis is under
diagnosed since the abdominal
ultrasound is not part of the routine
examination for patients with SLE. It is
also important to comment that it is
possible that data on vasculitis could
not appear in the histopathological
report of the first case because the
patient received immunosuppressant
treatment and was surgically
intervened during a sub-acute stage.
Conclusions
Cholecystitis causes unsuspected and
rather unrecognized abdominal pain in
SLE patients. In the Institute’s Lupus
Clinic, we treat 119 patients, and only
4 of them have shown this entity. It
15
attracts attention that in patients we
reported and in 1 of the pediatric
patients reported in the literature
(Table I), developed cholecystitis and
lupus nephritis, for which more
studies should be done to conclude
that a direct relationship does exist.
Despite the multiple risks factors
known in the SLE patients to develop
cholecystitis, the fact is this entity is
very uncommon in JSLE patients in
large series, this is why it is a
remarkable finding that three patients
presented with activity of their illness,
hypertrigliceridemia and
hypercholesterolemia developed
cholecystitis, more studies are need to
determine if the activity illness and/or
dyslipidemia could be the trigger, and
permit identify this patients as high
risk of complications.
To our knowledge this is the first cases
reported in Mexican children with
JSLE and cholecystitis.
We believe that acute cholecystitis,
especially acalculous, should be
16
suspected in SLE patients with
abdominal pain, particularly those
showing activity of the illness, and an
abdominal US should be ordered as
soon as possible.
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Hebert D, Harvey E et al. Clinical and
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emerging and unsuspected cause of
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Prieto A, Cordoba R, Yamazaki M.
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Masumaya I, Yoshio T, Okasaki H et
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Hemorrhagic acalculous cholecystitis
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Table I. Summary of SLE patients with

cholecystitis.
Author Gender Age Diagnosis Morbidity

Case 1 F 10 SLE Lupus neph

AAC Hypertriglyc

21
Case 2 M 13 SLE Lupus neph
AAC Hypertriglyc
Hemolytic a
Neuro LES
Case 3 F 14 SLE Lupus neph
ALC Hemolytic a
Hypertriglyc
De Leon et F 17 SLE Lupus neph
al. (2006) AMLC Hypertriglyc

Swanepoel F 22 SLE Lupus neph

et al.
(1983)
Newbold F 28 SLE
et al. APS
(1987)
Newbold F 38 SLE
et al.
(1987)
Kamikura F 27 SLE
et al.
(1998)

22
Rhoton et F 22 SLE
al. (1993)
Raijman F 34 SLE
et al.
( 1989)

Nolen et F 22 SLE
al. (1994)
Desailloud F 29 SLE
et al.
(1998)
Shin et al. F 39 SLE
(2002) Sjögren
APS
Bando et F 43 SLE
al. (2003)

Kara et al. M 65 APS

(2004)
Baristaina M 10 SLE Lupus neph
et al.
(2006)
Mendoça F 12 SLE
et al.
(2009)

23
SLE: Systemic Lupus Erythematosus,
APS: Anti Phospholipid Syndrome,
AAC: Acute Acalculous Cholecystitis,
ALC: Acute lithiasic cholecystitis,
AMLC: Acute microlithiasic
cholecystitis. ANA: Anti Nuclear
Antibodies, ACA: Anticardiolipin
antibodies, AntiB2GP: Anti-B2
Glycoprotein, Anti-PS: Anti-
Phosphatidylserine.

24