Protein-losing enteropathy as initial presentation of pediatric systemic lupus erythematosus: A rare case report from Vietnam and literature review

Abstract

Protein-losing enteropathy (PLE) is a rare but recognized manifestation of systemic lupus erythematosus (SLE). As an initial presentation of SLE, PLE is exceptionally uncommon, particularly in pediatric patients. We report the case of a 15-year-old Vietnamese girl with no significant past medical or family history, who presented with PLE as the initial manifestation of SLE. Clinical features included bilateral eyelid and lower extremity edema, ascites, and hypoalbuminemia, in the absence of nephrotic-range proteinuria, hepatic dysfunction, or malnutrition. Stool α1-antitrypsin concentration was markedly elevated at >231 mg/dL (normal <26.8 mg/dL), supporting the diagnosis of PLE in conjunction with clinical features and therapeutic response. Immunological evaluation revealed positive antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) antibody, and lupus anticoagulant, hypocomplementemia, along with proteinuria equivalent to >0.5 g/24 h, fulfilling the 2019 EULAR/ACR classification criteria for SLE. The patient also developed cerebral venous sinus thrombosis. Treatment with corticosteroids, hydroxychloroquine, and warfarin resulted in significant clinical improvement. At 7 months of follow-up, she remained clinically stable, with normalized serum albumin levels and resolution of thrombosis. This case highlights the challenges of diagnosing PLE as an initial symptom of SLE in resource-limited settings. Heightened awareness of this rare presentation can facilitate early diagnosis and optimal management, improving patient outcomes.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with the potential to affect multiple organ systems. When SLE presents before the age of 18, it is classified as childhood-onset SLE (cSLE). Compared to adult-onset SLE, cSLE is typically associated with a more aggressive disease course, including a higher frequency and severity of organ involvement and complications. Gastrointestinal involvement in cSLE is uncommon, and limited data are available regarding its presentation and outcomes. Gastrointestinal manifestations can affect any segment of the gastrointestinal tract and can result directly from active disease, secondary complications, or adverse effects of therapy. ¹

Protein-losing enteropathy (PLE) is characterized by excessive loss of serum protein through the gastrointestinal tract, leading to hypoalbuminemia and edema. ² While PLE is a recognized manifestation of SLE, it is an unusual presentation and is even rarer as an initial symptom.^2–4 Most of the documented cases involve adults, highlighting the scarcity of reported pediatric cases.^5–7 Herein, we describe the case of a 15-year-old girl who presented with PLE as the initial manifestation of cSLE.

Case presentation

A 15-year-old Vietnamese girl presented with progressive swelling of both upper eyelids over the preceding 3 months. The swelling was bilateral and non-tender, without redness or eye pain. Additionally, she experienced occasional diffuse, dull headaches but denied dizziness, lightheadedness, or limb weakness. Her past medical history was unremarkable, with no significant prior conditions, and her family history revealed no notable illnesses.

On examination, the patient was alert, pubescent, and normal-developed (142 cm, 38 kg) with stable vital signs (BP 105/60 mmHg, HR 88/min, RR 22/min, afebrile). She had bilateral upper eyelid edema, pitting edema of the lower extremities, and ascites, without hepatosplenomegaly or stigmata of liver disease. Breath sounds were clear bilaterally, heart sounds were normal without murmurs, and neurological examination unremarkable. No skin rashes, oral ulcers, alopecia, joint abnormalities, or other systemic findings were noted. Initial laboratory evaluations revealed hypoalbuminemia with a serum albumin level of 20.1 g/L and total protein of 48.2 g/L. Renal function was normal, with a serum creatinine of 39 µmol/L and serum urea of 2.5 mmol/L. Urinalysis showed no hematuria, and normal pH (6.2), but the urinary protein-to-creatinine ratio (UPCR) was persistently elevated, consistently above 50 mg/mmol across multiple samples, with a peak value of 68.2 mg/mmol—below the nephrotic range, thus ruling out significant proteinuria as the primary cause of hypoalbuminemia. Liver function tests were within normal limits, with aspartate transaminase (AST) at 27 U/L, alanine transaminase (ALT) at 11 U/L, and a prothrombin time (INR) of 0.87. Abdominal ultrasound confirmed ascites but showed no signs of portal hypertension or liver disease. Cardiac and respiratory evaluations, including chest X-ray and echocardiography, were unremarkable. Other laboratory results showed normal inflammatory markers and hematologic parameters, including a white blood cell count of 8.8 × 10⁹/L, hemoglobin of 123 g/L, platelet count of 201 × 10⁹/L, and C-reactive protein of 3.2 mg/L. Electrolytes and plasma osmolality were also within normal limits: sodium 133 mmol/L, potassium 3.6 mmol/L, chloride 101 mmol/L, and osmolality 284 mOsm/kg H₂O.

The clinical diagnosis of PLE was strongly suspected (Figure 1). Further confirmation was obtained by measuring stool α1-antitrypsin (A1AT), which was significantly elevated at >231 mg/dL (normal range <26.8 mg/dL), supporting excessive protein loss through the gastrointestinal tract and reinforcing the diagnosis of PLE. Upper gastrointestinal endoscopy revealed gastritis, with gastric biopsies showing non-specific inflammation within normal limits. Colonoscopy with multiple biopsies demonstrated chronic nonspecific ileitis (Figure 2). There was no evidence of intestinal lymphangiectasia, ulceration, inflammatory bowel disease, vasculitis, or malignancy on macroscopic view and histology. Microbiological tests for HIV, HbsAg, Quantiferon, EBV-IgM, and CMV-IgM were all negative. Immunological investigations revealed hypocomplementemia (C3: 4.8 g/dL, reference range: 9–18 g/dL; C4: 0.7 g/dL, reference range: 1–4 g/dL), positive antinuclear antibody (ANA) at a titer of 1:100 (homogeneous pattern), and positive anti-double-stranded DNA (anti-dsDNA) at 30.4 U/mL. Lupus anticoagulant (LA) was also detected, while anti-Smith, anti-cardiolipin, and anti-beta-2 glycoprotein antibodies were negative. These findings yielded a total score of 16, fulfilling the 2019 EULAR/ACR classification criteria for SLE. The patient was diagnosed with lupus-associated protein-losing enteropathy (LUPLE).

Figure 1.

Trends in key laboratory parameters during treatment monitoring.

Figure 2.

A biopsy from the terminal ileum reveals chronic mucosal inflammation with mild epithelial degeneration and erosion; numerous lymphocytes and few polymorphonuclear leukocytes infiltrate the stroma. No evidence of lymphangiectasia, inflammatory bowel disease, vasculitis, or malignancy was observed.

To investigate her headache, a brain MRI was performed, revealing partial thrombosis in the right transverse sinus and bilateral sigmoid sinuses, with no parenchyma or cranial nerve abnormalities (Figure 3). Coagulation studies demonstrated a hypercoagulable state, with prolonged APTT (60.2 s; normal 25–35 s), elevated fibrinogen (5.82 g/L; normal 2.0–4.0 g/L), and increased D-dimer (3.5 mg/L; normal <0.48 mg/L), while factor VIII and IX activities were within normal ranges. These findings suggest LA-associated hypercoagulability in the setting of SLE, contributing to cerebral venous sinus thrombosis.

Figure 3.

Partial thrombosis of the right transverse sinus, characterized by hyperintensity on FLAIR and DWI sequences, hypointensity on T2* imaging, and the lack of contrast enhancement after gadolinium administration (blue arrows).

The patient was treated with high-dose intravenous methylprednisolone (1000 mg/1.73 m²/day) for 3 days, followed by oral prednisolone (1 mg/kg/day) with gradual tapering. Hydroxychloroquine was also used at 5 mg/kg/day. Oral warfarin (target INR of 2–3) was also initiated to manage cerebral venous sinus thrombosis. Symptom improvement was noted within 1 week. She transitioned to outpatient care and remained stable over 7 months, with no recurrence of edema, headache, or other SLE symptoms. Serum albumin levels normalized (Figure 1), and repeat stool A1AT at 2 months was within normal range (6.3 mg/dL). Follow-up brain MRI at 4 months confirmed thrombosis resolution, and warfarin was replaced with low-dose aspirin (81 mg/day).

Discussion

PLE is a diagnosis of exclusion and should be considered in patients with unexplained edema and hypoalbuminemia after ruling out other causes such as inadequate protein intake, decreased protein synthesis, or excessive protein loss. Our patient had a normal BMI, adequate dietary intake, and normal liver function, making malnutrition and hepatic causes unlikely. Although urinary protein loss was mildly elevated (UPCR = 68 mg/mmol), it was insufficient to account for her significantly low plasma albumin levels. Thus, the possibility of PLE was strongly considered. This was further supported by a significantly elevated stool A1AT level (>231 mg/dL; normal <26.8 mg/dL), indicating gastrointestinal protein loss. A1AT is a glycoprotein similar in size to albumin, resistant to intestinal degradation, and neither secreted nor reabsorbed in the gut, making it a reliable marker of PLE when detected in high concentrations in stool. ⁸ The combination of clinical features, markedly elevated stool A1AT, and a favorable response to therapy strongly supported the diagnosis of PLE in this patient.

SLE is an autoimmune disease that can affect any organ system. According to the 2019 EULAR/ACR criteria, our patient met the entry criterion of a positive ANA at a titer of 1:100 on Hep-2 cells. She also fulfilled one clinical criterion: proteinuria >0.5 g/24 h (4 points); and three immunology criteria: LA positivity (2 points), low C3 and low C4 (4 points), and anti-dsDNA antibody positivity (6 points). Proteinuria >0.5 g/24 h is defined in the 2019 EULAR/ACR 2019 criteria as proteinuria >0.5 g/24 h on a 24-hour urine collection or an equivalent spot urine protein-to-creatinine ratio (UPCR)—around >50 mg/mmol (or 0.5 mg/mg),^9,10 which aligns with our patient’s findings. Furthermore, due to the patient’s need for anticoagulation therapy with warfarin, a renal biopsy to assess histopathological kidney involvement was not performed to assess for histopathological kidney involvement. With a total score of 16 points (⩾10 points required), the patient fulfilled the 2019 EULAR/ACR classification criteria for SLE. Additionally, gastrointestinal pathologies and common infections known to be associated with PLE (HIV, tuberculosis, EBV, and CMV) were systematically excluded. Based on these findings, a diagnosis of lupus-associated protein-losing enteropathy (LUPLE) was established.

LUPLE is a rare but recognized manifestation of SLE. Its pathogenesis is variable and may involve mucosal erosions, non-necrotizing intestinal vasculitis, vascular epithelial damage induced by cytokines or complement activation, and lymphangiectasia.^2,3 However, the mechanism of protein loss appears to differ on a case-by-case basis. In the present case, the absence of vasculitis, lymphangiectasia, or significant mucosal abnormalities on macroscopic and histological examination, combined with decreased serum complement levels, the presence of autoantibodies, and a favorable response to corticosteroid treatment, suggests that complement activation is a likely cause of increased vascular permeability. This mechanism implies that complement-associated cytotoxic reactions may contribute to tissue damage through autoantibody activity, excessive immune complex formation, and cytokine-mediated effects. Such processes could lead to capillary hyperpermeability, enabling protein leakage into the intestinal lumen. ¹¹

Glucocorticoids and other immunosuppressants are the cornerstone treatments for LUPLE. According to a systematic review by Williamson et al., ¹² induction therapies commonly involve glucocorticoids, such as 1 mg/kg/day of intravenous methylprednisolone or prednisolone, or a regimen of 1 g of intravenous methylprednisolone daily for 3 days. Maintenance therapy typically consists of continued use of prednisolone or intravenous methylprednisolone. Additionally, some authors have advocated for the use of immunosuppressants like azathioprine, cyclosporine, or mycophenolate mofetil, either alongside glucocorticoids from the beginning of treatment or when glucocorticoid monotherapy does not achieve a complete response. Adjunct therapies often include anticoagulation, nutritional support (featuring a high-protein, low-fat medium-chain triglyceride diet or elemental diet), diuretics, and octreotide. ¹² The prognosis for LUPLE is generally favorable, with 88% of patients achieving a complete response to corticosteroids, and mortality is exceedingly rare. ² This underscores the critical importance of early diagnosis to ensure timely treatment and achieve optimal outcomes.

Despite the overall strength of the diagnostic approach in this case, certain limitations inherent to our clinical setting should be acknowledged. The diagnosis of PLE in this case was primarily based on suggestive clinical features and a markedly elevated stool A1AT level, without additional confirmatory testing. Although definitive confirmation can be achieved by identifying protein loss sites through nuclear imaging techniques such as Technetium-99m labeled Human Serum Albumin (Tc-99m HSA) scintigraphy, these modalities were unfortunately unavailable in our resource-limited setting. Additionally, the diagnosis of SLE in this patient relied on a single clinical criterion (proteinuria), without other classical features such as arthritis, rash, or Raynaud’s phenomenon, which may raise concerns regarding specificity. However, after careful evaluation of both clinical and immunological domains, the patient fulfilled the 2019 EULAR/ACR classification criteria for SLE, and alternative diagnoses were systematically excluded. Importantly, she demonstrated a sustained and complete clinical and laboratory response to standard SLE therapy during a 7-month follow-up period. These findings not only support the validity of the diagnosis but also underscore the utility of the updated EULAR/ACR criteria in recognizing non-classical or organ-dominant manifestations of lupus, such as LUPLE.

While PLE is linked to various underlying conditions, its association with SLE is uncommon and even rarer as an initial manifestation. To the best of our knowledge, most reported cases involve adults, with only seven documented cases occurring in children. We have reviewed and summarized the clinical features, diagnostic findings, and treatment of pediatric SLE patients presenting initially with PLE in Table 1.^{5–7,13–16}

Table 1.

Summary of pediatric SLE cases presenting initially with PLE.

Ref	Authors (reported year)	Age; gender	Clinical manifestation of PLE	Albumin (g/L)	Associated conditions	Autoantibodies	Complement	Diagnostic test for PLE	Histological findings	Treatment for PLE
13	Tsukahara et al. (1980)	12Y; M	Generalized edema, pleural effusion, ascites.	13.2	Facial butterfly rash	ANA, anti-DNA	Low C3 and C4	I131-PVP	—	Steroids
6	Chase et al. (1982)	12Y; F	Periorbital and leg edema, ascites	12	Lupus nephritis, Libman-Sacks endocarditis	ANA, anti-DNA	—	Cr51-labeled albumin	Ileal lymphangiectasia	Steroids
14	Edworthy et al. (1990)	16Y; F	Periorbital and leg edema	22	Lupus nephritis, hematological involvements	ANA, anti-DNA	—	—	Ileal lymphangiectasia	Steroids
15	Molina et al. (1996)	13Y; F	Abdominal pain, diarrhea, edema	7	Pericarditis, myocarditis	ANA, anti-SSA, anti-SSB	—	A1AT clearance	Minimal villous blunting at small intestine	Steroids + AZA
7	Park et al. (2004)	11Y; F	Periorbital edema, pleural effusion, abdominal pain, diarrhea	23	Lupus nephritis, pericarditis, oral ulcers	ANA, anti-dsDNA, anti-SSA, anti-SSB, anticardiolipin	Low C3 and C4	A1AT clearance and Tc-99m has	Mild, chronic duodenitis	Steroids + CTX
16	Ranawaka et al. (2012)	13Y; F	Generalized edema, ascites, diarrhea	18	Hematological involvements, malar rash, neuropsychiatric lupus	ANA	Low C3 and C4	—	Normal	Steroids + AZA; Steroid + MMF
5	Naddei et al. (2019)	10Y; M	Generalized edema	Not detectable	Hematological involvements	ANA, anti-dsDNA, anti-SSA/SSB	—	Stool A1AT and Tc-99m HSA	Chronic gastritis and colitis, lymphangiectasia	Steroids + AZA
	Present case (2024)	15Y; F	Periorbital and leg edema, ascites	20.1	Cerebral venous sinus thrombosis, Lupus nephritis	ANA, anti-dsDNA, LA	Low C3 and C4	Stool A1AT	Chronic gastritis and ileitis	Steroids

ANA: antinuclear antibody; anti-dsDNA: anti-double-stranded DNA; anti-SSA: anti-Sjögren’s syndrome-related antigen A; anti-SSB: anti-Sjögren’s syndrome-related antigen B; LA: Lupus anticoagulant; A1AT: α1-antitrypsin; I¹³¹-PVP: Iodine-131 labeled polyvinylpyrrolidone; Tc-99m HSA: Technetium-99m labeled Human Serum Albumin; AZA: Azathioprine; CTX: Cyclophosphamide; MMF: Mycophenolate Mofetil.

Conclusion

This case highlights the importance of considering PLE in the differential diagnosis of unexplained edema and hypoalbuminemia, especially in the context of autoimmune diseases. The initial presentation of SLE with PLE is exceptionally rare in children and poses diagnostic challenges, particularly in resource-limited settings. This report contributes to the growing recognition of lupus-associated PLE as an important clinical entity and emphasizes the need for heightened awareness among clinicians.