Protein-losing enteropathy is rarely seen in patients with systemic lupus erythematosus. This clinical condition should be suspected in the presence of persistent hypoalbuminemia despite normal liver function, adequate protein intake, and no significant proteinuria. We report the case of a 48-year-old female with weight loss, cavity effusions (ascites and pleural effusion), and lower extremity edema. The diagnosis of lupus was established based on the presence of lymphopenia, proteinuria, ANA, and positive autoantibodies (anti-Sm, anti-DNA, and anti-Ro). Because hypoalbuminemia persisted even with corticosteroid therapy at the dose of 1 mg/kg, protein-losing enteropathy was diagnosed by use of Tc-99m albumin scintigraphy. After adding azathioprine to the treatment, the symptoms subsided and serum albumin levels improved.A enteropatia perdedora de proteínas raramente pode ser observada em pacientes com lúpus eritematoso sistêmico. Essa situação clínica deve ser suspeitada quando houver hipoalbuminemia persistente, na presença de uma função hepática preservada, ingesta proteica adequada e ausência de proteinúria significativa. Descrevemos o caso de uma paciente de 48 anos com perda ponderal, derrames cavitários (ascite e derrame pleural) e edema de membros inferiores. O diagnóstico de lúpus foi firmado a partir da presença de linfopenia, proteinúria, FAN e autoanticorpos positivos (anti-Sm, anti-DNA e anti-Ro). Houve persistência de hipoalbuminemia mesmo com corticoterapia na dose de 1 mg/kg de peso, sendo diagnosticada enteropatia perdedora de proteínas por meio da cintilografia com albumina 99mTc. A melhora clínica e laboratorial da paciente veio após a associação da azatioprina com corticosteroide.Hospital Geral César Cals de OliveiraUniversidade Federal do Ceará Curso de MedicinaUFCHospital Geral César Cals de Oliveira Departamento de Clínica MédicaUniversidade Federal de São Paulo (UNIFESP)Hospital Geral César Cals de Oliveira Serviço de ReumatologiaUniversidade Estadual do CearáUNIFESPSciEL

Aguiar, Fernando Moreira Batista

Correia, José Walter

Correia, Júlio Marcus Sousa

Costa, Débora Maia da

Menescal, Zilaís Linhares Carneiro

Paiva, José Gerardo Araújo

Revista Brasileira de Reumatologia

Paiva, José Gerardo Araújo [UNIFESP]

Repositório Institucional UNIFESP

CASE REPORT 956 Rev Bras Reumatol 2012;52(6):956-964Received on 04/14/2011. Approved on 09/05/2012. The authors declare no conﬂ ict of interest.Hospital Geral César Cals de Oliveira.1. Resident Physician in Internal Medicine, Hospital Geral César Cals de Oliveira2. Medical School student, Universidade Federal do Ceará – UFC3. PhD in Medical Sciences, UFC; Chief of the Department of Internal Medicine, Hospital Geral César Cals de Oliveira4. Master’s degree in Rheumatology, Universidade Federal de São Paulo − Unifesp; Preceptor of the Rheumatology Service, Hospital Geral César Cals de Oliveira5. Physician Specialized in Nuclear Medicine; Associated Professor, Universidade Estadual do Ceará − UECECorrespondence to: Fernando Moreira Batista Aguiar. Rua Dr. Joaquim Frota, 540 – José de Alencar. CEP: 60830-132. Fortaleza, CE, Brazil.   E-mail: fernandombaguiar@hotmail.comProtein-losing enteropathy in systemic lupus erythematosus: case reportFernando Moreira Batista Aguiar1, Zilaís Linhares Carneiro Menescal1, Débora Maia da Costa2, José Walter Correia3, José Gerardo Araújo Paiva4, Júlio Marcus Sousa Correia5ABSTRACTProtein-losing enteropathy is rarely seen in patients with systemic lupus erythematosus. This clinical condition should be suspected in the presence of persistent hypoalbuminemia despite normal liver function, adequate protein intake, and no signifi cant proteinuria. We report the case of a 48-year-old female with weight loss, cavity effusions (ascites and pleural effusion), and lower extremity edema. The diagnosis of lupus was established based on the presence of lymphopenia, pro-teinuria, ANA, and positive autoantibodies (anti-Sm, anti-DNA, and anti-Ro). Because hypoalbuminemia persisted even with corticosteroid therapy at the dose of 1 mg/kg, protein-losing enteropathy was diagnosed by use of Tc-99m albumin scintigraphy. After adding azathioprine to the treatment, the symptoms subsided and serum albumin levels improved. Keywords: systemic lupus erythematosus, protein-losing enteropathies, technetium Tc-99m albumin aggregates.© 2012 Elsevier Editora Ltda. All rights reserved.INTRODUCTIONSystemic lupus erythematosus (SLE) is an autoimmune dise-ase that affects several systems, including the gastrointestinal tract.1,2 The gastrointestinal manifestations most commonly reported are as follows: gastroesophageal refl ux; dysphagia; abdominal pain; constipation; diarrhea; intestinal pseudo--obstruction; perforation; and hemorrhage.1 Protein-losing enteropathy is a rare gastrointestinal condi-tion that has been related to SLE and should be investigated in the presence of persistent hypoalbuminemia and lack of the following: signifi cant proteinuria; liver disease; malabsorption syndrome; and defi cient protein intake.1−3 That enteropathy can manifest clinically with edema or cavity effusions, depen-ding on serum levels of albumin. In addition, the following symptoms can be present: nausea; vomiting; abdominal pain; diarrhea; and anorexia.2 We report the case of a female patient with SLE and protein-losing enteropathy. The diagnostic ap-proach and treatment used are also discussed. CASE REPORTThe patient is a 48-year-old female of mixed heritage, who worked as housemaid. She reported that edema of her lower limbs and deterioration of her general state of health began in December 2009. She sought medical care in July 2010, when bilateral pleural effusion was evidenced, and thoracocentesis and pleural biopsy (discrete chronic and unspecifi c pleuritis) were performed. In September 2010, she was admitted to a regional hospital complaining of pain and increased abdominal volume, being then referred to our service in October 2010.On admission, she complained of diffuse abdominal pain, increased abdominal volume, dyspnea on mild exertion, and asthenia. She reported signifi cant weight loss (approximately 25 kg in 10 months). The physical examination showed an emaciated, tachycardic, tachypneic patient, with reduced re-spiratory sounds in both pulmonary bases, diffuse abdominal pain on palpation, shifting dullness and positive fl uid wave test, and edema of lower limbs. Protein-losing enteropathy in systemic lupus erythematosus: case report957Rev Bras Reumatol 2012;52(6):956-964Table 1Major results of the laboratory tests with respective reference valuesVariable Result ReferenceHemogramHemoglobin (g/dL)Hematocrit (%)Mean corpuscular volume (fL)Mean corpuscular hemoglobin (pg)9.4327.886.829.412–1736–5080–10028–32Leukocytes (/µL)NeutrophilsLymphocytes6,3605,316 (83%)625 (9%)4,000–11,00045%–70%20%–45%Platelets (/µL) 80,400 150,000–450,000Prothrombin time (s) 13.2 12.7–15.4Partial thromboplastin time (s) 33.7 26.3–39.4Urea (mg/dL) 42 10–50Creatinine (mg/dL) 0.7 0.6–1.2Erythrocyte sedimentation rate (mm/h) 4 ≤ 20C-reactive protein (mg/dL) 4.3 ≤ 6Protein electrophoresisAlbumin (g/dL)Gamma globulin (g/dL)Aspartate transaminase (U/L)Alanine transaminase (U/L)1.611.89 (polyclonal)24174.30–5.100.60–1.107–4112–38UrinalysispHDensityProteinsHemoglobinRed blood cells (cells/fi eld)Leukocytes (cells/fi eld)Urinary casts6.01.020++106Absent4.5–8.01.010–1.025AbsentAbsent0–30–5Absent24-hour proteinuria (mg/24h) 264 30–300Ascitic fl uidCells (cells/µL) Neutrophils Lymphocytes Monocytes Mesothelial cellsSerum-ascites albumin gradient (SAAG)Acid-fast bacillusCultureAdenosine deaminase (ADA, U/L)Oncotic cytology9559%27%8%6%0.8NegativeNegative12.0Negative0≥ 1.1 = portal hypertension< 1.1 = probable peritoneal diseaseNegativeNegative≤ 40NegativeANA1:1,280Homogeneous nuclearNo reactionAnti-Sm Reaction No reactionAnti-dsDNA 1:320 No reactionAnti-Ro Reaction No reactionAnti-La No reaction No reactionComplementC3 (mg/dL)C4 (mg/dL)CH-50 (u/CAE)23.88.54190–17012–36≥ 60Aguiar et al.958 Rev Bras Reumatol 2012;52(6):956-964Diagnostic investigation was initiated, and the major diagnostic hypothesis was neoplasm of unknown origin. The laboratory tests are shown in Table 1. Upper digestive endos-copy and colonoscopy ruled out neoplasm of the upper and low digestive tract. The chest, abdomen, and pelvis tomographies showed large volume ascites, bilateral pleural effusion, and pericardial effusion. The diagnosis of systemic lupus erythematosus was estab-lished based on abnormal antinuclear antibody (ANA) titers, presence of specifi c autoantibodies (anti-Sm and anti-DNA), serositis, and lymphopenia. Prednisone, at the dose of 1 mg/kg, was initiated. Initially, the lower limb edema and ascites worsened, requiring repeated relief paracentesis. Due to sig-nifi cant and persistent hypoalbuminemia, with no signifi cant proteinuria, normal liver function tests, and adequate protein intake, protein-losing enteropathy was investigated by use of Tc-99m albumin scintigraphy. Protein leakage was confi rmed in the right lower abdominal quadrant four hours after begin-ning the study and in the subsequent images (6, 8, and 24 hours) (Figure 1).Azathioprine at the dose of 100 mg/day was added for four weeks, and the cavity effusions and lower limb edema subsided, and her serum albumin levels normalized. DISCUSSIONProtein-losing enteropathy is a condition characterized by excessive protein loss via the gastrointestinal tract, resulting in hypoproteinemia, edema, and, sometimes, cavity effu-sions.4 It has been related to erosive gastrointestinal disorders (infl ammatory bowel disease, pseudomembranous colitis, sarcoidosis, intestinal lymphoma, erosive gastropathy), non-erosive gastrointestinal disorders (celiac disease, microscopic colitis, rheumatic disorders, tropical sprue, Whipple’s disease, hypertrophic gastropathy), and disorders involving increased interstitial pressure (intestinal lymphangiectasia, congestive heart failure, portal hypertension, intestinal lymphatic fi stula, retroperitoneal fi brosis, and mesenteric tuberculosis).4,5Protein-losing enteropathy should be considered in the presence of hypoalbuminemia whose most common causes have been ruled out, such as massive proteinuria, malnutrition, and decreased protein synthesis due to liver disease. The clini-cal manifestations vary, being determined by the underlying disease.5 Diarrhea and other gastrointestinal symptoms might not be present.4 From the laboratory viewpoint, in addition to hypoalbuminemia, the following can be found: hypercholes-terolemia due to the hepatic response to hypoalbuminemia; Figure 1Tc-99m albumin scintigraphy showing leakage of the radiotracer in the right lower abdominal quadrant (4-hour static images), which increased in subsequent images.Protein-losing enteropathy in systemic lupus erythematosus: case report959Rev Bras Reumatol 2012;52(6):956-964hypogammaglobulinemia (IgA, IgG, and IgM); and decreased transferrin, ceruloplasmin, and fi brinogen, because the intesti-nal loss depends on neither protein load nor protein molecular weight, similarly to that of nephrotic syndrome.2,4,5Some reviews have already described protein-losing enter-opathy as a condition secondary to lupus.1–3 One review carried out in Asia has shown predominance of female patients aged around 30 years, the disorder being, in most cases, the initial manifestation of lupus.2 The Asian study by Mok et al.6 has reported a 3.2% prevalence of protein-losing enteropathy in patients with lupus. Similar data have been reported by Zheng et al.7 and Kim et al.8In our patient, the criteria for diagnosing systemic lupus erythematosus9 were as follows: serositis (pleural and pericardial effusion); hematological changes (lym-phopenia); immunological changes (positive anti-dsDNA and anti-Sm); and abnormal ANA titers. However, there is no characteristic autoantibody to identify protein-losing enteropathy in patients with lupus. Those laboratory findings are related to lupus, and not necessarily to the protein-losing enteropathy.6 A mechanism that might justify protein-losing enteropathy in connective tissue diseases is the increased permeability of the intestinal microvasculature.2 Some cytokines, such as INF-γ, IL-6, and TNF-α,  have been implicated in that process, but controlled studies on the relation of those cytokines and disease activity and therapeutic response still lack.7,10 Other mechanisms reported are immune complex-mediated vasculi-tis, lymphatic dilation, and mucosal injury, which are diffi cult to demonstrate microscopically.2,6Two methods are used for diagnosing protein-losing enteropathy: 24-hour fecal clearance of alpha-1-antitripsin; and Tc-99m albumin scintigraphy. The former is non-invasive and can monitor the treatment response of the underlying disease.4,5,11 Its normal value is 2.6 mg/g of stools, refl ecting an intestinal clearance < 13 mL/day. Diarrhea and gastroin-testinal bleeding can result in falsely elevated values. Alpha-1-antitripsin is degraded at a gastric pH < 3.5, interfering with the result. The fecal clearance of alpha-1-antitripsin does not defi ne whether the site of protein leakage is gastric or intestinal.5We used the Tc-99m albumin scintigraphy, which enables locating the site(s) of protein leakage.2 It is less expensive than other radiotracers (111In-chloride or 111In-transferrin), has in vivo stability, high sensitivity, and rare side effects (nausea, vomit-ing, dyspnea, tachycardia, confusion, and abdominal pain). False-positive results occur in the presence of gastrointestinal bleeding. Serial images should be obtained up to 24 hours, increasing protein loss detection rate, possibly because of the intermittent nature of the process.12The association of protein-losing enteropathy with lupus requires identifying the clinical and laboratory characteristics of the disease and ruling out other conditions by use of echocardiog-raphy, abdominal tomography, endoscopy, and colon biopsy.13There is no controlled study for the treatment of protein-losing enteropathy in lupus. Reports have suggested that therapy should be initiated with corticosteroid alone. In case of no response, the association of immunosuppressants (cy-clophosphamide, azathioprine or cyclosporine) provides rapid and long-lasting results. Relapses have been more frequently reported when corticosteroids were used in isolation, and those relapses have responded well to an increase in corticosteroid doses.2,6,7,13Protein-losing enteropathy should be considered whenever patients with lupus have unexplained hypoal-buminemia. Those patients respond well to treatment with corticosteroids and immunosuppressants, and, in most cases, the prognosis is good. Enteropatia perdedora de proteínas no lúpus eritematoso sistêmico: relato de caso963Rev Bras Reumatol 2012;52(6):956-964REFERENCESREFERÊNCIAS 1. Xu D, Yang H, Lai CC, Li P, Zhang X, Yang XO et al. Clinical analysis of systemic lupus erythematous with gastrointestinal manifestations. Lupus 2010; 19(7):866−9.2. Chng HH, Tan BE, Teh CL, Lian TY. Major gastrointestinal manifestations in lupus patients in Asia: lupus enteritis, intestinal pseudo-obstruction, and protein-losing gastroenteropathy. Lupus 2010; 19(12):1404−13.3. Sultan SM, Ioannou Y, Isenberg DA. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology 1999; 38(10):917−32.4. Umar SB, DiBaise JK. Protein-losing enteropathy: case illustrations and clinical review. Am J Gastroenterol 2010; 105(1):43−9.5. Milovic V, Grand RJ. Protein-Losing Gastroenteropathy. In: Basow DS (ed.). UpToDate. Waltham, MA, 2010.964 Rev Bras Reumatol 2012;52(6):956-964Aguiar et al.6. Mok CC, Ying KY, Mak A, To CH, Szeto ML. Outcome of protein-losing gastroenteropathy in systemic lupus erythematosus treated with prednisolone and azathioprine. Rheumatology 2006; 45(4):425−9.7. Zheng WJ, Tian XP, Li L, Jing HL, Zeng XF, Li F et al. Protein-losing enteropathy in systemic lupus erythematous: analysis of the clinical features of fi fteen patients. J Clin Rheumatol 2007; 13(6):313−6.8. Kim YG, Lee CK, Byeon JS, Myung SJ, Oh JS, Nah SS et al. Serum cholesterol in idiopathic and lupus-related protein-losing enteropathy. Lupus 2008; 17(6):575−9.9. Borba EF, Latorre LC, Brenol JCT, Kayser C, Silva NA, Zimmermann AF et al. Consenso de lúpus eritematoso sistêmico. Rev Bras Reumatol 2008; 48(4):196−207.10. Yazici Y, Erkan D, Levine DM, Parker TS, Lockshin MD. Protein-losing enteropathy in systemic lupus erythematosus: report of a severe, persistent case and review of pathophysiology. Lupus 2002; 11(2):119−23.11. Wang SJ, Tsai SC, Lan JL. Tc-99m albumin scintigraphy to monitor the effect of treatment in protein-losing gastroenteropathy. Clin Nucl Med 2000; 25(3):197−9.12. Chiu NT, Lee BF, Hwang SJ, Chang JM, Liu GC, Yu HS. Protein-losing enteropathy: diagnosis with 99mTc-labeled human serum albumin scintigraphy. Radiology 2001; 219(1):86−90.13. Castro GRW, Appenzeller S, Bértolo MB, Costallat LTL. Protein-losing enteropathy associated with systemic lupus erythematosus: response to cyclophosphamide. Rheumatol Int 2005; 25(2):135−8.

Protein-losing enteropathy in systemic lupus erythematosus: case report

A enteropatia perdedora de proteínas raramente pode ser observada em pacientes com lúpus eritematoso sistêmico. Essa situação clínica deve ser suspeitada quando houver hipoalbuminemia persistente, na presença de uma função hepática preservada, ingesta proteica adequada e ausência de proteinúria significativa. Descrevemos o caso de uma paciente de 48 anos com perda ponderal, derrames cavitários (ascite e derrame pleural) e edema de membros inferiores. O diagnóstico de lúpus foi firmado a partir da presença de linfopenia, proteinúria, FAN e autoanticorpos positivos (anti-Sm, anti-DNA e anti-Ro). Houve persistência de hipoalbuminemia mesmo com corticoterapia na dose de 1 mg/kg de peso, sendo diagnosticada enteropatia perdedora de proteínas por meio da cintilografia com albumina 99mTc. A melhora clínica e laboratorial da paciente veio após a associação da azatioprina com corticosteroide.Protein-losing enteropathy is rarely seen in patients with systemic lupus erythematosus. This clinical condition should be suspected in the presence of persistent hypoalbuminemia despite normal liver function, adequate protein intake, and no significant proteinuria. We report the case of a 48-year-old female with weight loss, cavity effusions (ascites and pleural effusion), and lower extremity edema. The diagnosis of lupus was established based on the presence of lymphopenia, proteinuria, ANA, and positive autoantibodies (anti-Sm, anti-DNA, and anti-Ro). Because hypoalbuminemia persisted even with corticosteroid therapy at the dose of 1 mg/kg, protein-losing enteropathy was diagnosed by use of Tc-99m albumin scintigraphy. After adding azathioprine to the treatment, the symptoms subsided and serum albumin levels improved.Hospital Geral César Cals de OliveiraUniversidade Federal do Ceará Curso de MedicinaUFCHospital Geral César Cals de Oliveira Departamento de Clínica MédicaUniversidade Federal de São Paulo (UNIFESP)Hospital Geral César Cals de Oliveira Serviço de ReumatologiaUniversidade Estadual do CearáUNIFESPSciEL

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

A enteropatia perdedora de proteínas raramente pode ser observada em pacientes com lúpus eritematoso sistêmico. Essa situação clínica deve ser suspeitada quando houver hipoalbuminemia persistente, na presença de uma função hepática preservada, ingesta proteica adequada e ausência de proteinúria significativa. Descrevemos o caso de uma paciente de 48 anos com perda ponderal, derrames cavitários (ascite e derrame pleural) e edema de membros inferiores. O diagnóstico de lúpus foi firmado a partir da presença de linfopenia, proteinúria, FAN e autoanticorpos positivos (anti-Sm, anti-DNA e anti-Ro). Houve persistência de hipoalbuminemia mesmo com corticoterapia na dose de 1 mg/kg de peso, sendo diagnosticada enteropatia perdedora de proteínas por meio da cintilografia com albumina 99mTc. A melhora clínica e laboratorial da paciente veio após a associação da azatioprina com corticosteroide.Protein-losing enteropathy is rarely seen in patients with systemic lupus erythematosus. This clinical condition should be suspected in the presence of persistent hypoalbuminemia despite normal liver function, adequate protein intake, and no significant proteinuria. We report the case of a 48-year-old female with weight loss, cavity effusions (ascites and pleural effusion), and lower extremity edema. The diagnosis of lupus was established based on the presence of lymphopenia, proteinuria, ANA, and positive autoantibodies (anti-Sm, anti-DNA, and anti-Ro). Because hypoalbuminemia persisted even with corticosteroid therapy at the dose of 1 mg/kg, protein-losing enteropathy was diagnosed by use of Tc-99m albumin scintigraphy. After adding azathioprine to the treatment, the symptoms subsided and serum albumin levels improved

Fernando Moreira Batista Aguiar

Zilaís Linhares Carneiro Menescal

Débora Maia da Costa

José Walter Correia

José Gerardo Araújo Paiva

Júlio Marcus Sousa Correia

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Enteropatia perdedora de proteínas no lúpus eritematoso sistêmico: relato de caso Protein-losing enteropathy in systemic lupus erythematosus: case report

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Protein-losing enteropathy in systemic lupus erythematosus: case report

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