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REVIEW
Lupus protein-losing enteropathy (LUPLE): A systematic review
Sultan M. Al-Mogairen
Received: 17 October 2010 / Accepted: 30 January 2011 / Published online: 23 February 2011
� Springer-Verlag 2011
Abstract Lupus protein-losing enteropathy (LUPLE) is a
well reported but a rare manifestation of systemic lupus
erythematosus (SLE). The main objectives of this study are
to raise awareness of LUPLE that can be easily missed by
internist, rheumatologist, gastroenterologist and nephrolo-
gist, and then to be considered in any patient with unex-
plained edema, ascites, and hypoalbuminemia. A systematic
review was performed with 112 patients who met the eligi-
bility criteria and were critically appraised. The LUPLE was
ultimately diagnosed by either Tc-99m albumin scintography
(99mTc-HAS) or fecal alpha-1-antitrypsin clearance test.
Clinical features of patients, at the time of LUPLE diagnosis,
were as follows: age was 34 ± 14.2 years; the female
to male ratio was 5.8:1; the mean time to development of
LUPLE after diagnosis of SLE was 4.19 ± 4.7 years. There
was a predominance of Asian (64.7%) while 29.5% were
white or Hispanic patients. Eighty percent had peripheral
edema, 48% had ascites, 38% had pleural effusion, and 21%
had pericardial effusion. Forty-six percent had diarrhea, 27%
had abdominal pain, 22% had nausea, and 19% had vomit-
ing. Hypoalbuminemia was the most common characteristic
laboratory finding (96%). A 24-h urine protein was less than
0.5 gm in (71%). Almost all patients (96%) had positive
ANA with predominant speckled patterns (55%) and hypo-
complementemia (79%). Colonoscopy showed mucosal
thickening in 44% of patients, and the majority of patients
(52%) revealed no abnormalities; on the other hand, intes-
tinal histology either revealed mucosal edema, inflammatory
cell infiltrate, lymphangiectasia, mucosal atrophy or vascu-
litis in 80% of patients. All patients were started on steroids.
Thirty-four percent responded to steroids alone. Sixty-six
percent were started with other immunosuppressive thera-
pies, which include cyclophosphamide (46%), azathioprine
(33%), and a combination of cyclophosphamide and aza-
thioprine (7%). A few reported cases responded to either
cyclosporine or etanercept. Prognosis was very good with
steroids combined with immunosuppressive therapy. This is
the first systematic review of LUPLE and should be con-
sidered as an etiology of unidentified edema, ascites, and
hypoalbuminemia.
Keywords Systemic lupus erythematosus (SLE) �Hypoalbuminemia � Ascites � Unexplained edema �Protein-losing enteropathy (PLE) � Alpha-1-antitrypsin
Introduction
Autoimmune protein-losing enteropathy (APLE) is a very
important and unusual complication of autoimmune dis-
eases. It is characterized by leakage of serum proteins from
the gastrointestinal tract with profound generalized edema
and hypoalbuminemia without proteinuria [1–54]. Protein-
losing enteropathy (PLE) can occur as an idiopathic dis-
order but it can also develop as a manifestation of various
diseases. These include Crohn’s disease, sarcoidosis,
intestinal lymphoma, infectious diseases such as tubercu-
lous or parasitic infection, and autoimmune diseases such
as SLE, scleroderma, Sjogren, RA, and allergic gastroen-
teritis [55–63]. There are two reported cases of PLE
associated with pemphigus vulgaris [64]. Lupus Protein-
losing enteropathy (LUPLE) is a well reported but rare
manifestation of SLE. Most previous reports involved
isolated cases or small series of patients [19, 27, 55]. Its
prevalence is 3.2% in Chinese SLE population [39, 62].
S. M. Al-Mogairen (&)
Rheumatology Division, Department of Medicine,
King Saud University, Riyadh, Saudi Arabia
e-mail: [email protected]
123
Rheumatol Int (2011) 31:995–1001
DOI 10.1007/s00296-011-1827-9
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Although the cause and precise mechanism of this
condition are unknown, several theories have been postu-
lated. One theory claims mesenteric and intestinal vessel
vasculitis leading to increased intestinal vascular perme-
ability to protein. A second theory states the pathogenesis
complement conversion or cytokine-mediated damage with
associated vasodilation and increased vascular permeabil-
ity. A third theory pertains to intestinal lymphangiectasia,
which has been observed in several cases without evidence
of an increased central venous pressure or lymphatic
obstruction [38, 39, 62–64].
This review is the first systematic review of LUPLE
based on 112 cases from 54 studies. This review will
include the following: Methods (including search strategy,
selection criteria, statistical analysis, and role of funding
source), Results (including clinical features, laboratory
with diagnostic features, and therapy with prognosis), and
Discussion.
The objective of this review article is to increase the
awareness of a disease that is often undetected and should
be considered in patients with unexplained edema and
hypoalbuminemia.
Methods
Search strategy and selection criteria
The inclusion criteria included patients who were reported
to have SLE or who had at least four out of eleven (C4/11)
criteria of SLE (Based on the 1997 revised criteria for the
classification of SLE). Patients who did not meet at least
four criteria were excluded. Literature research was per-
formed using PubMed from National Library of Medicine
with the key words ‘‘protein losing enteropathy in systemic
lupus erythematosus’’ (limit: humans) and unlimited date
range and languages. The Literature research resulted in 64
articles related to our topic but only 55 papers were found
to meet our inclusion and exclusion criteria. Out of these
55 papers, 43 were published in English (our reference
numbers 1–43) and 12 were published in language other
than English (see below). References lists from above 55
papers were manually scanned to identify other relevant
reported cases and we picked up five more papers (our
reference numbers 44–48). PubMed MeSH database was
also searched by combining the MeSH terms ‘‘Protein-
losing Enteropathies’’ and ‘‘Lupus Erythematosus, Sys-
temic’’ (limit: humans), which provided 58 citations related
to our topic; of which, all satisfied our inclusion and
exclusion criteria and were included in the above-men-
tioned 60 references. Science Direct was used with key
words ‘‘Protein losing enteropathy in systemic lupus ery-
thematosus,’’ which resulted in the same citations as in
PubMed. OvidSP Medline was searched with the ‘‘basic
search’’ option, which resulted in 9,761 citations using the
key words ‘‘protein losing enteropathy in systemic lupus
erythematosus’’ (limit: humans). The first 51 papers of this
search are included in the 60 articles mentioned above. Key
words were modified to ‘‘protein losing in lupus’’ (limit:
humans) to increase the specificity. The search resulted in
2,150 citations; first 58 of which are related to our topic
and are all included in the above-mentioned 60 articles. All
articles available online from among the 2,150 citations
were read, and we found one more reference that is not
included in the 60 articles mentioned in this study (Wang
et al. 2000, our ref# 49), making it a total of 61 references.
OvidSP Medline was searched with ‘‘advanced search’’
option by combining the search terms ‘‘Protein-losing
Enteropathies’’ and ‘‘Lupus Erythematosus, systemic’’
(Limit: humans), which resulted in 54 citations related to
our topic which are all included in the 61 references we
retrieved. Of the 12 non-English language articles, five are
included in our study (our reference numbers 50–54: four
French papers and one German paper). The other seven
full-text articles (our reference numbers 55–61: four
French and three Japanese papers) were neither available in
the King Saud Faculty of Medicine Library nor in the
British library (www.bl.uk). A search for registered but not
yet published protein-losing enteropathy was performed in
Google and yahoo Searches with key words ‘‘Rheumatol-
ogy conferences and protein losing-enteropathy,’’ ‘‘Rheu-
matology symposiums and protein losing-enteropathy,’’
and ‘‘unpublished protein-losing enteropathy,’’ which did
not yield any single unpublished Luple case.
Therefore, the total number of publications with repor-
ted cases for the systematic review is 54 papers (references
[1–54]).
Statistical analysis
Data were analyzed by the statistical software SPSS,
version 12. Descriptive statistics was computed and the
results are presented as means ± SD (standard deviation)
and percentages.
Results
Clinical features
This systematic review has identified 112 cases of LUPLE
reported from 54 studies. It was found that the mean age at
presentation was 34.3 ± 14.2 (range 6–79 years) (total
number 79 cases). See the distribution of cases according to
age (Table 1).
996 Rheumatol Int (2011) 31:995–1001
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This review showed that 89/112 (80%) had peripheral
edema, 54/112 (48%) had ascites, 42/112 (38%) had
pleural effusion, and 24/112 (21%) had pericardial effu-
sion. The current review also showed 30/112 (27%) had
abdominal pain, 25/112 (22%) had nausea, 21/112 (19%)
had vomiting, and 51/112 (46%) had diarrhea. Diarrhea in
LUPLE was generally loose or liquid in nature, and fre-
quency was ranged from 2 to 10 times a day. In six severe
cases, diarrhea was as frequent as twenty times a day. PLE
was the initial presentation of SLE in 53/109 (48.6%) and
the mean time to development of PLE after the diagnosis of
SLE was 4.19 ± 4.7 (range 0.2–14 years in 29 cases). The
female to male ratio was 5.8:1 with the female percentage
being 85.2% and the male percentage being 14.8% in 108
reported cases. In terms of ethnicity, there was a predom-
inance of Asian 44/68 (64.7%). The remaining patients
were comprised of 5 (7.4%) Hispanics, 4 (5.9%) blacks,
and 15 (22.1%) whites. Percentage of patients had con-
comitant disease activity in other organs (summarized in
Table 2).
Laboratory and diagnostic features
In this review, total numbers of shown up stool cultures
were 19, and no evidence of positive culture for ova, par-
asites, or bacteria were found.
There was no reported case of significant liver disease.
The mean serum albumin (g/dl) was 1.8 ± 0.82 (range
0.5–3.90 g/dl). Hypoalbuminemia was reported in 72/75
(96%) cases. Three of these LUPLE patients had mild
hypoalbuminemia (serum albumin 3–3.49 g/dl). On the
other hand, three cases were reported to have normal serum
albumin (3.5–5.5 g/dl) (see Tables 3, 4). The 24-hour urine
protein (see Table 5) was less than 0.5 gm in 36/51 (71%)
of cases and more than 0.5 gm in 15/51 (29%) patients.
Eight cases of these achieved [ 1 gm/24 h. However, their
protein-losing enteropathy diagnosis was confirmed with a
24-h stool a1 antitrypsin clearance of 99mTc HAS scan with
or without intestinal histology. The kidney histopathology
results were reported in only 16 out of 112 cases (see
Table 6). Diagnosis was confirmed by 99mTc HAS scan or
24-h fecal excretion of alpha-1-antitrypsin.
In this review, 67 cases underwent 99mTC HAS. Protein
leakage was positive in all above cases although the site of
leakage was only identified in 58 cases. The most common
protein leakage site was small intestine in 49/58 (84%)
cases, and the least common was the stomach, only 5/58
(9%). (See Table 7). A 24-hour stool specimen is preferable
compared to a spot sample. Twenty patients underwent this
test and all showed a positive fecal alpha-1-antitrypsin
clearance test.
Ultrasonographies were conducted in 35 cases. Twenty-
three of 35 (66%) showed ascites and 3/35 (9%) revealed
Table 1 Distribution of protein-losing enteropathy (LUPLE) cases
according to age
Age in years No. % out of 79 cases
B16 9 11.4
[16–50 62 78.5
[50 8 10.1
Table 2 Concomitant lupus disease activity at presentation of pro-
tein-losing enteropathy
Manifestations No. of cases % out of 54 cases
Malar rash 13 24
Photosensitivity 7 13
Alopecia 9 17
Oral ulcer 2 4
Raynaud’s phenomenon 8 15
Arthritis 24 44
Neuropsychiatric 8 15
Lupus nephritis 8 15
Leukopenia 1 2
Hemolytic anemia 18 33
Thrombocytopenia 9 17
Table 3 Range of serum albumin in Lupus protein-losing enteropa-
thy (LUPLE)
Serum Albumin (g/dl) No. of cases % out of 75 cases
\3.0 69 92
3.0–\3.5 3 4
3.5–5.5 3 4
[5.5 0 0
Table 4 Total serum protein in Lupus protein-losing enteropathy
(LUPLE)
Serum T protein (g/dl) No. of cases % out of 37 cases
\5 30 81
5–8 7 19
[8 0 0
Table 5 A 24-h urine protein reading of 51 Lupus protein-losing
enteropathy (LUPLE) cases
24 h Urine protein/day No. of cases % out of 51 cases
\0.2 gm 13 25
0.2–\0.5 gm 23 45
C0.5–\1 gm 7 14
[1 gm 8 16
Rheumatol Int (2011) 31:995–1001 997
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bowel thickening. Contrast CT scanning of the abdomen
was performed in 28 patients; all revealed ascites. Other
features are found in Table 8. Upper GI endoscopies were
done in 37 patients and it showed gastritis in eight cases
(22%), duodenitis in three cases (8%), and thickened
mucosa in five cases (14%). The majority of the cases,
25/37 (68%), showed normal features.
Similarly, majority of patients 14/27 (52%) who
underwent colonoscopies did not reveal significant lesions.
In 12 (44%) patients, the colonoscopic feature was mucosal
thickening while only one patient had purpura lesions
(4%).
Barium meal and follow-through showed the following:
mucosal edema and thickening 14/45 (31%), loss of
mucosal folds 6/45 (13%), non-specific changes 2/45 (4%),
intestinal ulcers 1/45 (2%), intestinal inflammation 4/45
(9%), gastritis 4/45 (9%), duodenitis 6/45 (13%), and
normal appearance 9/45 (20%).
Sixty-two intestinal tissue biopsies were reported in this
review, which revealed the following: mucosal edema
42/66 (64%), inflammatory cell infiltrate 48/66 (73%),
lymphangiectasia 10/66 (15%), mucosal atrophy 2/66
(3%), vasculitis 1/66 (2%), and normal features 13/66
(20%). This review showed positive antinuclear antibody
(ANA) in 64/67 cases (96%) with predominant speckled
pattern in 16/29 (55%) cases and homogenous pattern in
9/29 (31%) cases. Serology revealed positive anti-dsDNA
38/64 (59%), anti-Ro 20/26 (77%), anti-La 6/18 (33%),
anti-RNP 9/17 (53%), anti-Smith Ab 5/21 (24%), hypo-
complementemia 45/57 (79%), and positive anticardiolipin
9/17 (53%).
Therapy and prognosis
Treatment consists of two measures
a. Nutritional replacement using high-protein diet and
medium-chain triglycerides [5, 39].
b. Treatment of underlying disease.
In this review, the details of therapy were reported for
93 patients. All LUPLE patients (93/93, 100%) were
treated with steroids. Thirty-two of 93 (34%) responded to
steroids alone, and 61/93 (66%) were also started with
other immunosuppressive therapy. Twenty cases (20/61,
33%) responded to azathioprine; two of them supported by
hydroxychloroquine. Twenty-eight (28/61, 46%) patients
remitted with IV cyclophosphamide. One of these patients
was refractory to azathioprine. Four 4/61 (7%) cases
responded to both azathioprine and cyclophosphamide, and
one patient responded to cyclosporine and hydroxychlo-
roquine. Three patients were refractory to cyclophospha-
mide, two died, and one responded to etanercept.
The total number of doses of IV cyclophosphamide
courses was reported only in seven cases ranging from 3
doses to 24 doses. Prognosis with combination of steroid
with immunosuppressive therapy was quite good.
Discussion
In this review, the mean age at presentation was
34.3 ± 14.2. In contrast, the study by Mok et al. (2006)
reported 16 cases with a mean age of 36.2 ± 8.7 years.
Another study by Zheng et al. (2007) reported 15 cases
with a mean age of 40.1 ± 15.4 years [39, 41].
The most common clinical presentation was peripheral
edema (80%) followed by ascites (48%) and diarrhea
(46%). This showed that almost half of LUPLE patients do
not have diarrhea. There were no reported cases of bloody
diarrhea.
In LUPLE, infective causes should be excluded [39].
The presence of severe diarrhea and marked hypoalbumi-
nemia was without significant proteinurea, which should
Table 6 Renal histopathological results shown up based on World
Health Organization (WHO) of Lupus protein-losing enteropathy
(LUPLE)
WHO Class Number of cases % out of 16 cases
I 2 12
II 6 37
III 3 19
IV 2 12
V 2 12
Normal 1 6
Table 7 Protein leakage site in 99mTc HAS Scan Lupus protein-
losing Enteropathy (LUPLE)
Protein leakage site No. of cases % out of 58 cases
Small intestines 40 69
Large intestines 9 16
Small and large intestines 4 7
Stomach and small intestines 1 2
Stomach, small and large intestines 4 7
Table 8 Abdominal CT scan finding lupus protein-losing enteropa-
thy (LUPLE)
Findings No. of cases % out of 35 cases
Ascites 28 80
Lymphadenopathy 2 6
Edema 1 3
Bowel thickening 3 8
Portal vein thrombosis 1 3
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raise the suspicion of PLE. In order to establish a diagnosis
of PLE, in addition to the demonstration of protein loss
from the gastrointestinal tract, significant loss from other
sources such as urinary tract and reduced protein intake and
synthesis due to malnutrition or severe liver diseases
should be excluded [39]. Hypoalbuminemia is usually the
typical characteristic laboratory findings, and it was
reported in 96% of patients and normal serum albumin was
rarely present. Therefore, despite the presence of PLE,
normal serum albumin does not exclude the diagnosis of
LUPLE.
Established diagnosis of LUPLE in the presence of
proteinurea more than 0.5 gm a day in 29% of patients
signalized a coexisting LUPLE and lupus renal disease
proved in some of them by kidney biopsy. In systemic
rheumatic diseases, one can find multiple contributing
factors for hypoalbuminemia in a single patient.
In recent years, 99mTc Albumin scintography (99mTc-
HAS) has become the most frequently used diagnostic
method and can be used to monitor the efficacy of treat-
ment. In this technique, the albumin was labeled with99mTc and intravenously introduced into patients. Then, the
distribution of 99mTc is traced at particular intervals. The
location of leakage can be observed if there is leakage of
albumin into the intestinal lumen.99mTc albumin scintigraphy is non-invasive, fast, safe,
and convenient in demonstrating gastrointestinal loss of
blood protein to the intestinal lumen. It also has the
potential of localizing protein leakage [41–43, 49–62].99mTc HAS with serial scanning for up to 24 h was reli-
able. The sensitivity was 96% and the specificity was
100% and yields results within 24 h [27–34, 47, 48].99mTc albumin scintigraphy is the best quantitative study
for the following disease activity, though one report has
suggested that fecal alpha-1-antitrypsin clearance also can
monitor response to therapy. Possible drawbacks to mea-
suring alpha-1-antitrypsin clearance measurement are the
test that does not distinguish between gastric and small
intestinal protein loss, and alpha-1-antitrypsin is appar-
ently degraded by the acidic gastric juice below pH 3.5. In
such case, we need cimetidine infusion of any other acid
blockage [41].
A reasonable percentage of LUPLE patients had normal
histopathological features, which indicate that an autoim-
mune enteropathy is most likely a patchy or segmental
disease. In LUPLE, ANA might be negative at presenta-
tion. The above intestinal histopathological results and the
autoantibodies positivity indicate that the autoimmune
inflammatory response is the most likely mechanism of
LUPLE and the lymphangiectasia is an occasional histo-
phathological finding while the vasculitis is a rare one.
Corticosteroids were very effective, and prognosis to
combination of steroid with immunosuppressive therapy
was quite good. Mok et al.’s (2006) study reported that
because of the lack of controlled trials, treatment is purely
anecdotal. There was not much information available on
the relapse rate from historical cases because most reports
only concentrated on the short-term treatment response
[39].
It appears that relapse is more common in patients
receiving maintenance therapy with low-dose prednisolone
alone than in those receiving maintenance therapy with a
combination of prednisolone and immunosuppressive
therapy. Mok et al.’s (2006) study [39] also reported that
the experience suggests relapse of PLE is uncommon with
long-term maintenance treatment consisting of low-dose
prednisolone and AZA. However, whether the long-term
efficacy of combining corticosteroid and AZA is better
than that of corticosteroid alone in APLE needs to be
establish through further randomized controlled trials.
Supplemental therapies including serum albumin infusion
and diuretics should be given at the same time. In addition,
octreotide could reduce intestinal microvascular blood
flow, decrease local lymph formation, and ameliorate
lymphatic dilation [33, 41].
Acknowledgments I would like to acknowledge the intense support
and contribution of my research assistant Dr. Najma Khalil, Dr.
Hamdani, Mr. Karim as well as the secretarial assistance of S. Seno
and Joann Octubre. I would also like to extend my thanks to Faculty
of Medicine at King Saud University.
Conflict of interest We declare that we have no conflict of interest
and Ethical committee has approved this study.
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