Pediatric Gastrointestinal Sarcoidosis Presenting With Protein‐losing Enteropathy

Abstract

INTRODUCTION Sarcoidosis is a disease of undetermined cause that primarily affects adults and is characterized by the formation of noncaseating granulomas. Although sarcoidosis is a multisystem disease, the involvement of the alimentary tract is rare; when present, it is often an asymptomatic finding in a patient with widely disseminated disease (1). Gastrointestinal sarcoidosis (involving the esophagus, small intestine, large intestine and, most commonly, the stomach) has been described in adults; however, prominent and symptomatic gastrointestinal involvement is rare (2–4). Pediatric gastrointestinal sarcoidosis is exceedingly rare, with only 1 case reported in the literature (5). We report the case of an 11-year-old girl with a history of poor growth and protein-losing enteropathy due to gastrointestinal sarcoidosis. Biopsies of the lung, esophagus and colon all show typical features of sarcoid. This is the youngest case of gastrointestinal sarcoidosis yet reported and is remarkable in its presentation without pulmonary, ocular or skin symptoms. CASE REPORT An 11-year-old white girl presented in September 2004 for evaluation of poor growth. She had been growing at the 15th to 25th percentile for weight and at the 50th percentile for height until the age of 8 years, when she began to fall off her growth curves. At age 11, 1 week after treatment of pinworms, the patient reported a 7-month history of nonbloody diarrhea associated with diffuse abdominal pain that was relieved by defecation. Dietary changes did not result in improvement and, unexpectedly, the patient's diarrhea and abdominal pain resolved spontaneously in December 2003. She denied experiencing fatigue, constitutional symptoms, vomiting, fevers, arthritis, visual changes, anorexia, rashes, or respiratory infections. There was no heavy metal exposure. Her medical history was remarkable for an allergy to animal dander that induced bronchospasm, 2 pinworm infections (1998 and 2003) and admission for bronchiolitis at the age of 3 months. There was no known family history of inflammatory bowel disease, celiac disease, autoimmune disorders and cystic fibrosis. Physical examination revealed an articulate, pleasant young girl, who was less than the third percentile for weight and from 5th to 10th percentile for height. Her body mass index was 14.5. Vital signs were normal. Examination of the head, ears, eyes, nose, throat, and the respiratory, cardiovascular, orthopedic, ophthalmologic and integumentary systems was within reference ranges. The abdomen was mildly distended but was soft and nontender with no masses or hepatosplenomegaly. Rectal examination revealed normal anal tone and an anterior skin tag. Stools were negative for occult blood. The laboratory examination was remarkable for an elevated white blood cell count of 12,500 cells/μL with a normal differential cell count, an elevated platelet count of 804,000 cells/μL, and an elevated erythrocyte sedimentation rate (ESR) of 47 mm/h. She had a hemoglobin level of 11.9 g/dL, hematocrit of 36.6% and mean corpuscular volume of 71.5 fL. Iron level was low at 22 μg/dL, iron saturation was low at 5.3%, and total iron-binding capacity and ferritin level were within reference ranges at 414 μg/dL and 46.8 mg/mL, respectively. A mildly low serum albumin level (3.6 g/dL) and elevated stool α1-antitrypsin level (105 ng/dL) suggested a protein-losing enteropathy. Quantitative immunoglobulin levels were normal (immunoglobulin G [IgG] = 1360 mg/dL; immunoglobulin A [IgA] = 277 mg/dL; immunoglobulin M = 106 mg/dL). Although gliadin IgG concentration was elevated at 29.5 U/mL, the remainder of the celiac screening to include gliadin IgA, endomysial and tissue transglutaminase antibodies showed negative results, indicating that celiac disease was unlikely. Tests for antibodies associated with inflammatory bowel disease (perinuclear antineutrophil cytoplasmic antibodies, antiouter membrane protein C and anti-Saccharomyces cerevisiae IgA and IgG) showed negative results. Infectious disease testing included a negative result for purified protein derivative of tuberculin and a negative result for rapid plasma reagin. The stool test for enteric pathogens, including giardia and ova and parasites, showed negative results. Other unremarkable laboratory findings included negative antinuclear antibody, rheumatoid factor and C-reactive protein; aspartate aminotransferase level of 23 U/L, alanine aminotransferase level of 18 U/L, total bilirubin level of 0.2 mg/dL, calcium level of 9.4 mg/dL and thyrotropin level of 1.34 μIU/mL. Delayed hypersensitivity skin testing did not demonstrate anergy. Overall, these laboratory findings suggested an inflammatory process (elevated white blood cells count, platelets count and ESR), associated with a protein-losing enteropathy (elevated stool α1-antitrypsin and low level of serum albumin). A radiological upper gastrointestinal/small bowel follow-through (UGI/SBFT) examination demonstrated multiple areas of fold thickening, wall thickening and abnormal separation of loops of small bowel (Fig. 1A). On upper endoscopy, aphthous lesions were noted in the distal esophagus (Fig. 1B), whereas the duodenum seemed inflamed. Colonoscopy revealed edematous and nodular mucosa, and the aphthous lesions were scattered throughout the colon (Fig. 1C).FIG. 1: A, Small bowel barium contrast study demonstrating multiple areas of fold thickening, wall thickening and abnormal separation of loops of small bowel. B, Endoscopic view of esophagus showing multiple punctate white lesions. C, Endoscopic view of rectum showing aphthous lesions and granular, nodular mucosa. D, High-resolution chest computed tomography (CT) image demonstrating multiple, small nodules in a centrolobular distribution within the acini of both lungs.Biopsy revealed that the esophageal epithelium had reactive changes overlying submucosal, noncaseating granulomas with giant cell formation and a moderate submucosal inflammatory infiltrate (Fig. 2A). Mild chronic inflammation was noted on antral biopsies, whereas the duodenal biopsies findings were normal. Colonic biopsies showed multiple, intramucosal, noncaseating granulomas associated with sparse to moderate chronic inflammation (Fig. 2B, C). The giant cells in the granulomas often contained concentric calcifications (Schaumann bodies) and/or polarizable calcifications (Fig. 2C). The glandular architecture was preserved. There was no cryptitis or crypt abscess formation. Special stains for acid-fast and fungal microorganisms showed negative results.FIG. 2: Endoscopic biopsies from the esophagus (A) and the large intestine (B-C). D, Transbronchial biopsy. A, B and D are at ×200 magnification; C is at ×400 magnification with a polarizing filter. Noncaseating granulomas with giant cells are indicated by vertical arrows in A and B; concentric calcifications (Schaumann bodies) are indicated by arrowheads in C and D; and a polarizable calcification is indicated by a horizontal arrow in C.Although the patient had no respiratory complaints and the chest radiograph was unremarkable, pulmonary function testing revealed evidence of mild interstitial and restrictive lung disease with recruitment of reserve volumes. Plethysmography demonstrated a total lung capacity of 2.69 L (87%), but a reduced inspiratory capacity of 1.25 L (62%) and a slightly reduced expiratory reserve volume of 0.77 L (77%) with normal residual volume. The diffusing capacity for carbon monoxide was mildly reduced at 12.5 mL/mmHg/min (75%), suggesting interstitial thickening. The forced expiratory flows (FEFs) were mildly reduced, with forced expiratory volume in 1 second (FEV1) of 1.71 L (80%) and FEF25%–75% of 1.77 L/min (67%). The FEV1 and forced vital capacity ratio was normal at 0.82. The serum angiotensin-converting enzyme level was within reference ranges on the 2 occasions it was tested (43 and 73 U/L, respectively, with normal values of 13–100 U/L). A high-resolution CT scan of the chest demonstrated multiple, small, centrolobularly distributed nodules within the acini of both lungs and involving all lung segments (Fig. 1D), consistent with the diagnosis of pulmonary sarcoidosis. At bronchoscopy, the transbronchial biopsies revealed peribronchial granulomas with sparse chronic inflammation and prominent giant cells containing birefringent calcifications and Schaumann bodies (Fig. 2D). These findings were the same as those in the esophageal and colonic biopsies and were morphologically consistent with the diagnosis of sarcoidosis. The bronchoalveolar lavage analysis revealed no organisms, including a negative pneumocystis direct fluorescent antibody test, and the cultures of the fluid were negative for fungal and acid-fast bacterial organisms. Flow cytometry was nondiagnostic for sarcoidosis. Tests for serum antibodies against Bartonella quintana, B henselae, Histoplasma capsulatum and Coccidioides immitis showed negative results. The combination of sarcoidlike histological findings in the lungs, esophagus and large intestine, lack of characteristic inflammatory bowel disease histological findings and negative workup for infectious disease of the lungs and the gastrointestinal tract suggested systemic sarcoidosis with significant gastrointestinal involvement. The patient began receiving daily administration of steroids at a dosage of 1 mg/kg/d in December 2004, resulting in a rapid resolution of all gastrointestinal symptoms. In February 2005, she began receiving doses of methotrexate, which was gradually increased to 15 mg every week, whereas the dosage of prednisone was weaned to 5 mg every other day. With treatment, there was normalization of the patient's complete blood cell count, sedimentation rate, albumin level and iron level. The angiotensin-converting enzyme level remained normal at 66 U/L, whereas a spot stool α1-antitrypsin level was normal at less than 10 mg/dL. At follow-up, the patient seemed healthy and, anthropometrically, was at the 5th to 10th percentile for weight and at the 10th percentile for height, whereas the body mass index increased to 16.3. Her examination was unremarkable, including ophthalmological examinations that revealed no evidence of uveitis. She did not develop joint or skin involvement. The repeat chest CTs performed at 4 and 12 months after diagnosis showed a significant interval decrease in pulmonary nodular interstitial disease and no hilar or mediastinal adenopathy. The serial pulmonary function testing revealed significant increases in total lung capacity to 3.56 L (104%), inspiratory capacity to 1.78 L (83%), FEV1 to 2.20 L (94%), FEF25%–75% to 2.34 (79%) and diffusing capacity for carbon monoxide to 17.5 mL/mmHg/min (97%). These findings indicated reversal of the mild restrictive and interstitial defects noted before treatment. The result of an upper endoscopy 1 year into treatment was grossly and histologically normal. On colonoscopy, a few scattered rectal ulcers were seen; otherwise, the terminal ileum, down to the sigmoid colon, seemed grossly healthy. Histologically, focal granulomas were present in tissue from the ascending colon to the rectum. The granulomas were significantly fewer than before medical management; however, the biopsies still demonstrated giant cells with intracytoplasmic material. DISCUSSION Although there is precedent for sarcoid-induced protein-losing enteropathy in adults (6,7), this is the youngest case of gastrointestinal sarcoidosis yet reported; therefore, the diagnosis must be made with caution. Because clinical, endoscopic, radiological and pathological features of Crohn disease and sarcoidosis overlap, it can be a challenge to differentiate these 2 diseases (8–16). However, a diagnosis of gastrointestinal sarcoidosis has been made in this case because of the following distinctive features: prominent intramucosal rather than sparse submucosal granulomas; lack of intestinal crypt involvement or deformity; lack of overall mucosal architectural distortion and acute inflammation; and particular morphological features of the granulomas to include prominence of giant cells rather than a loose aggregation of mononuclear histiocytes. Furthermore, Schaumann bodies and birefringent calcifications are commonly observed in sarcoidosis, but rarely in Crohn disease (17). Finally, the presence of typical sarcoid granulomas in the lung similar to those observed in the esophagus and colon lends strong support for a diagnosis of sarcoidosis. Differentiating gastrointestinal sarcoidosis from Crohn disease is further complicated by the apparent clinical overlap between sarcoidosis and inflammatory bowel disease. Patients with pulmonary sarcoidosis can have altered bowel mucosal permeability; conversely, patients with Crohn disease can have “metastatic” granulomatous lesions in the lungs (8–12). Case reports have identified patients with coexistent inflammatory bowel disease and sarcoidosis (13,14). These facts may point to a spectrum of disease that includes inflammatory bowel disease and sarcoidosis. Evidence in support of this idea includes common immunological features of the 2 diseases (14,15). It has been postulated that both diseases may result from immune dysregulation after antigenic exposure (3,4,14,15) and that gastrointestinal sarcoidosis and Crohn disease represent a spectrum of systemic granulomatous disease(13). However, this term is too vague to adequately express the striking sarcoidlike morphology observed in the present case. Other granulomatous processes could conceivably be responsible for the findings in this patient, including Wegener granulomatosis, Behçet disease, Reiter syndrome and chronic granulomatous disease. Wegener is characterized by necrotizing granulomas with vasculitis; Behçet disease presents with multiorgan involvement, usually with aphthous ulcers; Reiter disease involves arthritis, uveitis and urethritis; and chronic granulomatous disease manifests as recurrent infections and gastrointestinal involvement consisting of granulomas with marked inflammation (18,19). The current case is clearly distinct from these clinicopathological entities. Gastrointestinal sarcoidosis is exceedingly rare. There is only 1 previously reported pediatric case, which involved a 15-year-old boy with sarcoidosis causing duodenal obstruction (5). In this patient, sarcoidosis presented in the lacrimal gland and caused proptosis before the intestinal involvement. In contrast, the patient described in the current report was not suspected to have sarcoidosis before the onset of protein-losing enteropathy. In summary, we report an 11-year-old girl presenting with poor growth and protein-losing enteropathy who was subsequently diagnosed with pulmonary and gastrointestinal sarcoidosis. This case is illustrative of 2 important points: first, gastrointestinal sarcoidosis should be considered in the differential diagnosis of diarrhea and protein-losing enteropathy; second, the clinicopathological overlap between sarcoidosis and Crohn disease may lead to a misdiagnosis of Crohn disease in cases of pediatric gastrointestinal sarcoidosis.