sle

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

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

123

http://www.bl.uk

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

123

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

998 Rheumatol Int (2011) 31:995–1001

123

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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