Malrotation of the Intestine and Chronic Volvulus as a Cause of Protein-Losing Enteropathy in Infancy Aglaia Zellos, Diagoras Zarganis, Stelios

Ypsiladis, Dimitris Chatzis, Georgia Papaioannou and Christos Bartsocas Pediatrics; originally published online January 23, 2012; DOI: 10.1542/peds.2011-0937

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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CASE REPORT

Malrotation of the Intestine and Chronic Volvulus as a Cause of Protein-Losing Enteropathy in Infancy
AUTHORS: Aglaia Zellos, MD,a,b Diagoras Zarganis, MD,b Stelios Ypsiladis, MD,b Dimitris Chatzis, MD,a,b Georgia Papaioannou, MD,c and Christos Bartsocas, MDb
Department of Pediatrics, University of Athens School of Medicine, Athens, Greece; bDepartment of Pediatrics, Mitera Childrens Hospital, Athens, Greece; and cDepartment of Radiology, Mitera Childrens Hospital, Athens, Greece KEY WORDS children, chronic midgut volvulus, intestinal malrotation, proteinlosing enteropathy ABBREVIATIONS IgAimmunoglobulin A IgEimmunoglobulin E IgGimmunoglobulin G IgMimmunoglobulin M MRAmagnetic resonance angiography PLEprotein-losing enteropathy UGIupper gastrointestinal Dr Zellos is the rst author and wrote the paper and collected and interpreted the data. Drs Zellos and Bartsocas were the attending physicians responsible for the patient in this case report. Drs Zarganis, Ypsiladis (the operating surgeon), Papaioannou, Chatzis, and Bartsocas participated in the clinical care of the patient, assisted in editing the draft. In addition, Drs Ypsiladis and Papaioannou provided all the images. All authors have participated in the concept and design, analysis and interpretation of data, drafting or revising of the manuscript, and they have approved the manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2011-0937 doi:10.1542/peds.2011-0937 Accepted for publication Sep 16, 2011 Address correspondence to Aglaia Zellos, MD, First Department of Pediatrics, University of Athens School of Medicine, Aghia Sophia Childrens Hospital, Thivon and Levadias Street, Athens, Greece 11527. E-mail: eglie1@aol.com, azellos@otenet.gr PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2012 by the American Academy of Pediatrics
aFirst

abstract
Protein-losing enteropathy in children is caused by intestinal metabolic, inammatory, or infectious processes, or by lymphatic obstruction (intestinal lymphangiectasia). In this report, a 17-month-old child is presented with protein-losing enteropathy due to intestinal malrotation and chronic midgut volvulus causing lymphatic obstruction and spillage of lymph in the intestine and the peritoneum. This report should alert the pediatrician that intestinal malrotation should be added to the wide list of possible causes of protein-losing enteropathy in children. Pediatrics 2012;129:515518

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Protein-losing enteropathy (PLE) is a clinical entity dened by abnormal protein loss from the digestive tract resulting in decreased concentration of serum proteins such as albumin, a1-antitrypsin, ceruloplasmin, brinogen, transferrin, and hormone-binding proteins with concomitant hypogammaglobulinemia and lymphocytopenia.1 PLE in children is caused by intestinal metabolic, inammatory, or infectious processes, or by primary or secondary lymphatic obstruction (intestinal lymphangiectasia).1,2 In this report, a 17-month-old child with PLE caused by intestinal malrotation and chronic midgut volvulus, resulting in lymphatic obstruction and spillage of lymph in the peritoneum in the absence of bilious vomiting, is presented. Thus, intestinal malrotation should be added to the differential diagnosis of PLE in infancy and childhood.

CASE REPORT
A 17-month-old boy from Albania was admitted to our hospital with hypoalbuminemia, peripheral edema, diarrhea, and failure to thrive since 9 months of age. At age 3 weeks, he developed bilious vomiting caused by jejunal duplication diagnosed by laparotomy and resected without complications in his home country. He was exclusively breastfed up to 12 months when cows milk supplementation was added. Solids and gluten were introduced gradually at 6 months. His growth up to 9 months of age was normal. At age 9 months, he developed watery diarrhea and poor weight gain that resulted in multiple hospitalizations. Although stool cultures were negative for bacteria and parasites, he received a 15-day course of oral metronidazole for presumed giardiasis without improvement. Because pediatric endoscopy was unavailable in his country, he was treated empirically with albumin infusions, antiplasmin therapy with trans-4-aminothylcyclohexamine carboxylic acid (tranexamic acid) and 1
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mg/kg daily prednisone for 1 month without discernible improvement. At presentation to our hospital, his weight was 9.0 kg (less than the third percentile for age), his height was 78 cm (less than the third percentile for age), and his head circumference was 46.5 cm (less than the third percentile for age). He had facial and peripheral extremity edema. The cardiac and respiratory systems were normal. The abdomen was nontender and mildly distended with hyperactive bowel sounds, without hepatosplenomegaly or ascites. Laboratory tests revealed the following values: serum albumin was 2.2 g/dL, total protein 4.5 mg/dL, serum glutamic oxaloacetic transaminase 47 U/L, serum glutamic pyruvate transaminase 38 U/L, g-glutamyltransferase 20 U/L, alkaline phosphatase 117 U/L, cholesterol 144 mg/dL, triglycerides 60 mg/dL. His white blood cell count was 16 130/mL, with marked lymphopenia of 11%. His platelet count was 828 000/ mL, hemoglobin level was 15.8 g/dL, and hematocrit level was 47.6%. Serum immunoglobulins IgG, IgM, and IgA were all decreased. Serum IgE level was 12 IU/mL (normal for age ,49). A urinalysis did not reveal proteinuria. Serology results for systemic lupus erythematosus were negative. The results of a cardiac echogram and a chest x-ray were normal. There was elevated stool a1-antitrypsin. The results of stool cultures for known pathogens and parasites were negative. The prednisone dose was gradually decreased and stopped. An upper gastrointestinal (UGI) endoscopy excluded Menetrier disease, Helicobacter pylori gastritis, and celiac disease. There were no signs of intestinal lymphangectasia or duodenal villous atrophy, but eosinophilic duodenitis was noted with an eosinophil count in the lamina propria of 35per high-power eld. Colonoscopy excluded inammatory bowel disease. Skin prick and atopy patch testing showed allergy to

milk, wheat, oats, bananas, and pears. For the next 2 weeks, he received a diet without these food antigens and a hypoallergenic milk formula with medium-chain triglycerides; his diarrhea improved, but his serum albumin remained low. A 99mTc human serum albumin scan showed diffuse loss of albumin in the colon and excluded a focal leakage related to previous surgical resection (blind loop). An abdominal ultrasound was performed but was not diagnostic because of increased bowel gas. Subsequently, a MRI of the abdomen was ordered to exclude a retroperitoneal mass causing lymphatic system obstruction. Computed tomography was avoided for reasons of radiation protection in this multiply hospitalized child. Apart from extended mesenteric edema, appearances of whirlpool sign were noted in the superior mesenteric vessel branches which became more conspicuous in the additionally performed magnetic resonance angiography (MRA) (Fig 1). The latter emphasized a relevant dilatation of the superior mesenteric vein branches, which could explain both the mesenteric edema and the clinical manifestations of venous obstruction. In addition, MRA suggested incomplete vascular volvulus. Differential diagnosis included malrotation of the intestine or acquired noncomplete small-bowel volvulus. A UGI contrast study conrmed this nding, because the duodenum was dilated, the jejunum was partially obstructed, and the ligament of Treitz was located in the right side of the abdomen. During laparotomy, chronic midgut volvulus was found with 180 twisting of the jejunum and the superior mesenteric vessels (Fig 2) causing lymphatic obstruction and spillage of milky white lymph into the cut surfaces of the mesentery. The mesenteric lymph nodes were enlarged, and there was no bowel ischemia. No signs of previous surgery were found, with the exception

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CASE REPORT

TABLE 1 Differential Diagnosis of ProteinLosing Enteropathy in Children

Gastrointestinal mucosal injury 1. Inammatory bowel disease: Crohn disease and ulcerative colitis 2. Infections Bacterial: Salmonella, Shigella, Campylobacter, Clostridium difcile Parasitic: Giardia lamblia, Strongyloides stercoralis Viral: rotavirus, cytomegalovirus, measles 3. Gastrointestinal tumors Esophageal, gastric, colonic adenocarcinomas Lymphoma, Burkitt lymphoma Lymphangioma Kaposi sarcoma Hemangioma Gastrointestinal tract involved Langerhans cell histiocytosis 4. Juvenile polyposis 5. NSAID enteropathy 6. Graft versus host disease 7. Post liver transplant lymphoproliferative disease 8. Necrotizing enterocolitis 9. Hypertrophic gastropathy (Menetrier disease) 10. Eosinophilic gastroenteritis, food-induced enteropathy 11. Celiac disease 12. Other intestinal: paraduodenal hernia, intestinal stenosis, stagnant loop, small intestinal bacterial overgrowth, anastomotic ulceration or ischemia, superior mesenteric artery dissection, and thrombosis 13. Vasculitic disorders: systemic lupus erythematosus, Henoch-Schonlein purpura Lymphatic system abnormalities 1. Primary intestinal lymphangiectasia Congenital hypoplasia of the mesenteric lymphatic system 2. Secondary intestinal lymphangiectasia Obstructive: Crohn, sarcoidosis, lymphoma, retroperitoneal tumors (neuroblastoma) Elevated lymph pressure: congestive heart failure, pericarditis, post-Fontan procedure Syndromal: Turner, Noonan, Hennekam, Klippel-Trenaunay Metabolic: congenital disorders of glycosylation, enterocyte heparin sulfate deciency, infantile sialic acid storage disease
Sources: Sylvester,1 Braamskamp et al,2 Sparks et al,3 Shima et al,4 Yamashita et al,5 Lou et.al,6 Kirchner,7 Younes et al,8 and Stormon et al.9

FIGURE 1
A whirlpool sign was noted in the superior mesenteric vessels branches (A and B) which became more conspicuous in the additionally performed MRA (C). The results of the MRA suggested incomplete vascular volvulus and dilatation of the superior mesenteric vein branches, which could explain both the mesenteric edema and the clinical manifestations of venous obstruction.

FIGURE 2
Laparotomy image of the intestinal malrotation with twisting 180 of the jejunum, superior mesenteric artery, and vein, causing partial intestinal, venous, and arterial obstruction.

that should be considered by the pediatrician when faced with a child with suspected PLE.111 Two surgical case reports published in the 1980s12,13 indicated that intestinal malrotation caused PLE in two Japanese infants, yet this diagnosis has not been included in previous reviews on PLE in children.1,2 In this report, we presented yet another case of chronic midgut volvulus causing PLE in a child, in the absence of bilious emesis and abdominal pain. After PLE is diagnosed by increased fecal a1-antitrypsin clearance, renal protein loss, cardiac disorders, and liver disorders should be excluded. Bacterial, viral, and parasitic infections should be considered.14 Esophageal, gastric, and intestinal mucosal pathology should be examined by endoscopy. UGI endoscopy and colonoscopy are essential in ruling out all causes of mucosal inammation as listed in Table 1, and biopsies should be obtained from all anatomic sites. Occasionally, as in our case, the duodenal biopsies may not identify intestinal lymphangiectasia, especially if not preceded by a fatty meal. Recently, wireless capsule endoscopy and doubleballoon enteroscopy have been useful in detecting sites of chylous leakage in the more distal parts of the small bowel not reached by UGI endoscopy, the latter allowing for diagnostic biopsies.15 A UGI contrast study may help identify hypertrophic gastritis, intestinal malrotation, and intestinal

of an appendectomy. The volvulus was untwisted, the Ladd bands were resected, and the ligament of Treitz was mobilized. After surgery, the childs serum albumin concentration gradually increased to normal levels and remained stable 6 months after the operation. He remains on hypoallergenic diet pending reevaluation by the allergist.

DISCUSSION
PLE is a rare condition characterized by protein loss from the gastrointestinal tract presenting at any age from the neonatal period into adolescence. Children with PLE typically present with facial, palpebral, or peripheral edema and diarrhea, and laboratory investigations show lymphopenia, serum hypoalbuminemia, and hypogammaglobulinemia, rendering them vulnerable to infections. Table 1 presents the variety of known-to-date disorders

blind loops. The most commonly used 99m Tc human serum albumin scan may help dene abnormal lymphatic vessel anatomy and focal lymph loss into the intestine.16 In our case, the magnetic resonance study ordered to rule out a retroperitoneal mass led to the diagnosis of malrotation and chronic midgut volvulus.
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Our patient presented with bilious vomiting in the neonatal period and was operated on immediately for presumed small-bowel intestinal duplication. The parents were not aware of any associated bowel anomalies. After the operation, the infant was asymptomatic until age 9 months when he developed diarrhea and failure to thrive. The typical ndings of intestinal malrotation and volvulus, such as bloody stools, colicky abdominal pain, and bilious emesis, were not present; therefore, the diagnosis was not suspected by the pediatricians. The subsequently diagnosed eosinophilic duodenitis and food allergy may have been triggered by chronic gut ischemia and could have contributed to the infant s PLE; however, a food exclusion diet did not improve

his hypoalbuminemia. Similarly, the small-bowel bacterial overgrowth often accompanying intestinal obstruction may have contributed to this childs symptoms; however, treatment with oral metronidazole did not ameliorate his condition. Intraoperatively, the dilated lymphatic vessels and the leakage of chylous uid into the peritoneum clearly identied lymphatic obstruction as the etiology of PLE. Chronic midgut volvulus is less common than acute volvulus, and symptoms may be less prominent. Bilious vomiting is typical, but it may not always be present. Nonbilious vomiting may also be a symptom due to gastroduodenal distention. Recurrent abdominal pain and malnutrition are frequent presentations.

Imamoglu et al17 presented four children with diarrhea and malabsorptionlike symptoms secondary to chronic midgut volvulus. Vascular compromise may occur from proximal occlusion of the superior mesenteric vessels, but it is often alleviated by the development of collaterals.18 If further twisting occurs, chronic volvulus may evolve into catastrophic ischemia and loss of bowel. In conclusion, intestinal malrotation and chronic midgut volvulus resulting in lymphaticand venousobstruction should be added to the differential diagnosis of PLE in infancy and childhood. Early suspicion and detection by the pediatrician may prevent catastrophic bowel ischemia and life-threatening infections, severe malnutrition, and lymphedema.

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1. Sylvester FA. Protein-losing enteropathy. In: Wyllie R, Hyams J, eds. Pediatric Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 3rd ed. Philadelphia, PA: Saunders, Elsevier; 2006:507515 2. Braamskamp MJAM, Dolman KM, Tabbers MM. Clinical practice. Protein-losing enteropathy in children. Eur J Pediatr. 2010;169 (10):11791185 3. Sparks SE, Krasnewich DM. Congenital disorders of glycosylation overview. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993 2005 Aug 15 [updated Sep 01, 2009] 4. Shima H, Takahashi T, Shimada H. Proteinlosing enteropathy caused by gastrointestinal tract-involved Langerhans cell histiocytosis. Pediatrics. 2010;125(2):e426 e432 5. Yamashita K, Saito M, Itoh M, et al. Juvenile polyposis complicated with protein losing gastropathy. Intern Med. 2009;48(5): 335338 6. Lou Z, Zhang W, Mei Z, Fu C. Protein-losing enteropathy caused by spontaneous superior mesenteric artery dissection with thrombosis. Acta Gastroenterol Belg. 2010; 73(3):411412 7. Kirchner L, Kircher S, Salzer-Muhar U, Paschke E, Birnbacher R, Stckler-Ipsiroglu S. Infantile sialic acid storage disease and protein-losing gastroenteropathy. Pediatr Neurol. 2003;28(4):313317 8. Younes BS, Ament ME, McDiarmid SV, Martin MG, Vargas JH. The involvement of the gastrointestinal tract in posttransplant lymphoproliferative disease in pediatric liver transplantation. J Pediatr Gastroenterol Nutr. 1999;28(4):380385 9. Stormon MO, Mitchell JD, Smoleniec JS, Tobias V, Day AS. Congenital intestinal lymphatic hypoplasia presenting as non-immune hydrops in utero, and subsequent neonatal protein-losing enteropathy. J Pediatr Gastroenterol Nutr. 2002;35(5):691694 10. Tainaka T, Ikegami R, Watanabe Y. Left paraduodenal hernia leading to proteinlosing enteropathy in childhood. J Pediatr Surg. 2005;40(2):E21E23 11. Rudd PT. Protein-losing enteropathy with small intestinal stenoses and a stagnant loop in a nine-year-old boy. Acta Paediatr Scand. 1982;71(3):515516 12. Iida F, Wada R, Sato A, Yamada T. Clinicopathologic consideration of protein-losing enteropathy due to lymphangiectasia of the intestine. Surg Gynecol Obstet. 1980;151 (3):391395 13. Tamamoto F, Takeuchi N, Shindou N, Sumi Y, Katayama H. A case of infantile protein losing gastroenteropathy due to chronic volvulus [in Japanese]. Rinsho Hoshasen. 1988;33(4):511514 14. Umar SB, DiBaise JK. Protein-losing enteropathy: case illustrations and clinical review. Am J Gastroenterol. 2010;105(1):4349, quiz 50 15. Fritscher-Ravens A, Scherbakov P, Buer P, et al. The feasibility of wireless capsule endoscopy in detecting small intestinal pathology in children under the age of 8 years: a multicentre European study. Gut. 2009;58(11):14671472 16. Lan JA, Chervu LR, Marans Z, Collins JC. Protein-losing enteropathy detected by 99m Tc-labeled human serum albumin abdominal scintigraphy. J Pediatr Gastroenterol Nutr. 1988;7(6):872876 17. Imamoglu M, Cay A, Sarihan H, Sen Y. Rare clinical presentation mode of intestinal malrotation after neonatal period: Malabsorption-like symptoms due to chronic midgut volvulus. Pediatr Int. 2004;46(2): 167 170 18. Mori H, Hayashi K, Futagawa S, Uetani M, Yanagi T, Kurosaki N. Vascular compromise in chronic volvulus with midgut malrotation. Pediatr Radiol. 1987;17(4):277281

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Malrotation of the Intestine and Chronic Volvulus as a Cause of Protein-Losing Enteropathy in Infancy Aglaia Zellos, Diagoras Zarganis, Stelios Ypsiladis, Dimitris Chatzis, Georgia Papaioannou and Christos Bartsocas Pediatrics; originally published online January 23, 2012; DOI: 10.1542/peds.2011-0937
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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