Edema is defi ned as abnormal accumulation of fl uid in the interstitium. Diff erential diagnosis of generalized edema is very broad.
Most often, renal and cardiac causes lead to generalized edema. The potential gastrointestinal causes of edema are liver failure and
protein losing enteropathy including celiac disease and protein malnutrition. Generalized edema is rarely an initial manifestation of
celiac disease. Hereby, we present a case of a 3-year-old boy with celiac disease, initially presented with generalized edema and hypoproteinemia.Edemi nastaju zbog abnormalnog nakupljanja tekućine u intersticiju. Diferencijalna dijagnoza edema je vrlo široka. Bubrežni i srčani
uzroci su najčešći uzroci generaliziranih edema. Mogući gastrointestinalni uzroci edema su zatajenje jetre, enteropatija uzrokovana
gubitkom proteina, uključujući celijakiju i proteinsku neishranjenost. Generalizirani edemi su rijetka prva manifestacija celijakije.
Prikazujemo slučaj trogodišnjeg dječaka s celijakijom koji se inicijalno prezentirao generaliziranim edemima i hipoproteinemijom

Goran Palčevski

Ivona Butorac Ahel

Mirna Šubat Dežulović

English

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181 Paediatr Croat. 2015;59:181-4PRIKAZ BOLESNIKA / CASE REPORTwww.paedcro.comhttp://dx.doi.org/10.13112/PC.2015.27Generalized edema with hypoproteinemia as initial presentation of celiac disease in a 3-year-old boy: case reportIvona Butorac Ahel, Mirna Šubat Dežulović, Goran Palčevski*Edema is defi ned as abnormal accumulation of fl uid in the interstitium. Diff erential diagnosis of generalized edema is very broad. Most often, renal and cardiac causes lead to generalized edema. The potential gastrointestinal causes of edema are liver failure and protein losing enteropathy including celiac disease and protein malnutrition. Generalized edema is rarely an initial manifestation of celiac disease. Hereby, we present a case of a 3-year-old boy with celiac disease, initially presented with generalized edema and hy-poproteinemia.Keywords: celiac disease; edema; hypoalbuminemia; child* Clinical Hospital Centre Rijeka, Krešimirova 42, 51000 RijekaCorrespondence to:Ivona Butorac Ahel, dr. med., Clinical Hospital Centre Rijeka, Krešimirova 42, 51000 Rijeka, e-mail: ivonabuah@gmail.comPrimljeno/Received: 15. 2. 2015., Prihvaćeno/Accepted: 10. 4. 2015. INTRODUCTIONEdema is defi ned as a clinical condition characterized by  abnormal fl uid accumulation in the interstitium, resulting in generalized or peripheral tissue swelling. There are several mechanisms of edema formation, i.e. altered capillary hemodynamic, impaired lymphatic transport, and renal salt and water retention. Altered capillary hemodynamic results in shifting of fl uid from the vascular space into the interstit-ium due to increased capillary hydrostatic pressure, de-creased capillary oncotic pressure, or increased capillary permeability. Impaired lymphatic transport may be a conse-quence of abnormal development, dysfunction or obstruc-tion of the lymphatic system. Renal retention of sodium and water may be primary or secondary and results in hyper-volemia and increased vascular hydrostatic pressure (1). Dif-ferential diagnosis of generalized edema is very broad. The most common causes of edema in children, based on the pathogenesis, are shown in Table 1.Celiac disease (CD) is a chronic immune-mediated disease of the small intestine that occurs in genetically susceptible individuals and is characterized by an aberrant response to gluten. Originally considered as a malabsorption syndrome of childhood, CD is nowadays recognized as a disease that can be diagnosed at any age and presents itself through various symptoms (2-5).CASE REPORTA 3-year-old boy was admitted to the hospital because of generalized edema that had fi rst appeared on his eyelids and legs with an increase in body mass over the previous two weeks. Urine output was reduced. Stools were of nor-mal consistency and frequency. His parents were healthy and unrelated; his 6-year-old sister was also healthy. He was born from normal pregnancy and delivery, his birth weight was 4.1 kg, and he had normal postnatal course and regular weight gain. He was not breastfed; since birth he was fed an adapted formula based on cow’s milk. At the age of 6 months, cereals were introduced in his diet but without any reaction. However, since his second year of life, his mother noticed diff erent skin reactions with rashes to various food products and generalized urticaria provoked by peanuts. Skin prick tests undertaken for nutritive allergens excluded milk protein allergy, but were positive for peanuts, which were thus excluded from his diet. At the age of 2.5 years, taking peanuts by mistake resulted in development of Quincke’s edema that was treated with steroids by his pedi-182BUTORAC AHEL I. ET AL. GENERALIZED EDEMA AS INITIAL PRESENTATION OF CELIAC DISEASE. PAEDIATR CROAT. 2015;59:181-4atrician. Since then, he was treated with steroids several times because of obstructive bronchitis, with the last treat-ment only a week before current admission.At admission, the examination showed signifi cant edema of the eyelids and pitting edema of both hands, legs and per-igenital region. The abdomen was not distended. He was afebrile with normal vital signs. His weight was on the 75th and his height on the 95th percentile for his age. He was on the 95th weight for height percentile. Laboratory fi ndings including blood count, renal parameters, liver tests and co-agulation tests were within the normal ranges, except for hypoproteinemia, hypoalbuminemia, hypoglobulinemia and hypercholesterolemia. Plasma concentrations of urea and creatinine were normal. Urinalysis showed mild pro-teinuria with normal microscopy of urine sediment. Spot urine was analyzed several times confi rming mild proteinu-ria (the urinary protein/creatinine ratio was 0.02-0.03 g/mmol). The results of laboratory investigations are shown in Table 2. The initial treatment consisted of intravenous ad-ministration of albumin, diuretics and fl uid restriction. Ultra-sound of the abdomen and echocardiography were unre-markable, without ascites or cardiac eff usion. Pleural ultra-sound showed minimal pleural eff usion of 1 mm. Based on previous medical history, earlier treatment with steroids, the fi ndings of generalized edema with mild proteinuria, hy-poalbuminemia and hypercholesterolemia, renal biopsy was performed for suspicion of nephrotic syndrome, which is the most common cause of generalized edema in pre-school children. Renal biopsy, including light microscopy and immunofl uorescence, was normal without podocyte reaction and without complement and immune deposits. Excluding cardiac and renal pathology as the most com-mon cause of generalized pitting edema, additional workup was performed. Other potential causes of hypoalbumine-mia and edema, such as cystic fi brosis, hereditary angioede-ma and celiac disease were taken into consideration. Sweat test was negative; C3 and C4 levels and C1 inhibitor level were normal. The measurement of stool alpha-1-antitrypsin was not available in our hospital. Test for tissue transglutam-inase IgA antibodies was 156 RU/mL (normal range <20 RU/mL), indicating the need of small intestine biopsy. Ultimate-ly, the small intestine biopsy confi rmed the diagnosis of CD. According to Marsh’s classifi cation, histologic features were typical for stage 3B: villous atrophy, crypt hypertrophy and intraepithelial lymphocytes (6) (Figure 1). The results of test-ing for human leukocyte antigen (HLA) DQ2 were positive and for DQ8 negative. The patient was diagnosed to have CD and a gluten-free diet was recommended. After starting the gluten-free diet, edema started to disappear gradually, followed by normalization of serum albumin concentration. Since the diagnosis of CD, the boy has been regularly fol-lowed up every six months. With a gluten-free diet, he has no symptoms characteristic of CD and the value of tissue transglutaminase IgA antibodies normalized after six months. Before hospital discharge and one month after TABLE 1. Etiology and pathopysiology of edema in childrenGeneralized edemaIncreased capillary hydrostatic pressureHeart failurePrimary renal diseaseNephrotic syndromeAcute glomerulonephritisRenal failureLiver cirrhosisDecreased capillary oncotic pressureNephrotic syndromeLiver failureProtein losing enteropathyProtein malnutritionIncreased capillary permeabilitySepsisBurnsTABLE 2. Results of laboratory investigations performed at diagnosisSerum At diagnosis Reference valuesErythrocite (x1012/l) 5.45 4.0-5.0Hemoglobin (g/l) 117 109-138Leukocytes (x109/l) 12.1 5.0-13.0Platelets (x109/l) 850 150-450Urea (mmol/l) 2.7 1.8-6.0Creatinine (μmol/l) 43 35-62Sodium (mmol/l) 139 134-143Potassium (mmol/l) 4.5 3.5-6.0Albumin (g/l) 20.1 28-48Total protein (g/l) 35 55-80AST (U/l) 28 24-49ALT (U/l) 13 9-20GGT (U/l) 5 4-22Cholesterol (mmol/l) 4.8 < 4.7Triglycerides (mmol/l) 2.5 0.3-1.1C3 (g/l) 1.29 0.9-1.8C4 (g/l) 0.31 0.1-0.4IgG (g/l) 1.8 4-16IgM (g/l) 0.4 0.5-2IgA (g/l) 0.5 0.2-1.3Coagulation tests:PTINR0.952.10.7-1.32.0-3.5AST = aspartate aminotransferase, ALT = alanine aminotransferase, GGT = γ-glutamyl-transpeptidase, PT = prothrombin time, INR = International Normalised Ratio183PAEDIATR CROAT. 2015;59:181-4 BUTORAC AHEL I. ET AL. GENERALIZED EDEMA AS INITIAL PRESENTATION OF CELIAC DISEASE.urine spot was analyzed, proteinuria was not recorded. Screening of the family for CD revealed the diagnosis of CD in his mother and older sister, confi rmed by positive specifi c autoantibodies and biopsy of the small intestine in his sister. DISCUSSIONDiff erential diagnosis of generalized edema is quite broad and diagnostic approach is based on the pathogenesis of edema. Based on laboratory fi ndings of hypoalbuminemia, it was assumed that generalized edema was the result of hypoalbuminemia and decreased capillary oncotic pres-sure. The possible causes of hypoalbuminemia in childhood are nephrotic syndrome, liver failure, protein losing enter-opathy, and protein malnutrition. Nephrotic syndrome is one of the most common causes of generalized edema in childhood. Besides generalized edema, the syndrome is characterized by marked proteinuria, hypoalbuminemia and hyperlipidemia. Although the patient did not show marked proteinuria, his medical history (taking steroids) and marked hypoalbuminemia with generalized pitting edema were suggestive of renal etiology. The results of renal biopsy including light and immunofl uorescence studies were un-remarkable and excluded renal pathology. Based on the normal hepatic function test and coagulation tests, liver dis-ease was excluded as well. Initially, as the patient’s body mass and height were within the normal range for his age, protein malnutrition was not considered as a possible cause of generalized edema. Protein losing enteropathy is a di-verse group of disorders associated with excessive loss of serum protein through the gastrointestinal tract. The most aff ected protein is albumin, although other proteins such as immunoglobulin and ceruloplasmin are also aff ected. It is important to emphasize that before considering protein losing enteropathy as a potential cause of hypoproteine-mia, other causes of hypoproteinemia mentioned above had to be excluded. There are two mechanisms behind the increased protein loss through the intestinal tract, i.e. mu-cosal injury and abnormalities of the lymphatic system. Lymphatic abnormalities responsible for protein losing en-teropathy are primary and secondary intestinal lymphangi-ectasia. Numerous conditions can induce injury of intestinal mucosa and protein loss, such as infl ammatory bowel dis-ease, infections, gastrointestinal malignancy, milk protein allergy, celiac disease and Menetrier’s disease. A test for tis-sue transglutaminase IgA antibodies was performed and the fi ndings were suggestive of CD. Intestinal biopsy con-fi rmed the diagnosis of CD. Protein loss in CD is a result of the loss of villi and surface epithelium, which ease the leak-age of plasma proteins (7).Celiac disease is considered to be the most common ge-netically predetermined condition with a prevalence of 1% in many European countries (4-8). The understanding of this disease has changed from gastrointestinal disease to a mul-tisystem immune disorder (9).Clinical presentation of CD varies, including cases of either typical gastrointestinal features manifesting during the fi rst two years of life or atypical extraintestinal features manifest-ing later in life. Typical symptoms of CD are diarrhea, ab-dominal distention, weight loss, failure to thrive, anorexia and irritability. Atypical presentation includes extraintestinal symptoms such as isolated anemia, short stature, delayed puberty, hepatitis, arthritis, ataxia, headache, depression, dermatitis herpetiformis and altered bone metabolism (9). Also, patients may present some gastrointestinal symptoms that were considered highly unusual for CD, such as consti-pation, vomiting and recurrent abdominal pain. Several re-cent studies have shown that typical symptoms of CD are absent in half of the newly diagnosed cases (9-12). One in four patients with CD does not report any gastrointestinal symptomatology, as in our case.Nowadays, attention is focused on the symptoms that were until recently considered unusual for the diagnosis of CD (13). Whilst some features of CD have become more accept-able and recognizable as part of CD presentation, general-ized edema caused by severe hypoalbuminemia in CD is rare. Kuloglu et al. report on the 9.5% prevalence of hypoal-buminemia and 3.5% of peripheral edema in CD patients (14). In another report, CD presented with generalized ede-ma in two patients with coexisting CD and intestinal lym-phangiectasia (15).In our patient, CD coincided with urticaria. Urticaria is an immunoglobulin (Ig)-E-mediated allergic reaction, while CD is an immune-mediated enteropathy caused by aberrant response to gluten in genetically susceptible individuals. FIGURE 1. Biopsy of duodenum: complete villous atrophy associated with hyperplasia of glandular crypts; increased number of intraepithelial lymphocytes. (HE, X10)184BUTORAC AHEL I. ET AL. GENERALIZED EDEMA AS INITIAL PRESENTATION OF CELIAC DISEASE. PAEDIATR CROAT. 2015;59:181-4Besides CD, gluten can cause wheat allergy and gluten sen-sitivity.Because of the fact that the fi rst-degree relatives of celiac patients are at a higher risk of CD, the patient’s parents and his older sister underwent screening too. Although com-pletely asymptomatic, his mother and older sister had silent CD confi rmed by positive specifi c autoantibodies and bi-opsy of the small intestine.In conclusion, clinical presentation of CD is very heteroge-neous and the diagnosis of CD should be considered even in the presence of atypical symptoms.NOVČANA POTPORA/FUNDINGNema/NoneETIČKO ODOBRENJE/ETHICAL APPROVALNije potrebno/NoneSUKOB INTERESA/CONFLICT OF INTERESTAutori su popunili the Unifi ed Competing Interest form na www.icmje.org/coi_disclosure.pdf (dostupno na zahtjev) obrazac i izjavljuju: nemaju potporu niti jedne organizacije za objavljeni rad; nemaju fi nancijsku potporu niti jedne organizacije koja bi mogla imati interes za objavu ovog rada u po-sljednje 3 godine; nemaju drugih veza ili aktivnosti koje bi mogle utjecati na objavljeni rad./All authors have completed the Unifi ed Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the cor-responding author) and declare: no support from any organization for the sub-mitted work; no fi nancial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have infl uenced the submitted work. REFERENCES 1. Kimura G. Pathogenesis of edema and its classifi cation. Nihon Rinsho. 2005;63:11-6. 2. Catassi C, Anderson RP, Hill ID, et al. World perspective on celiac disease. J Pediatr Gastroenterol Nutr. 2012;55:494-9. doi: 10.1097/MPG.0b013e318272adf4. 3. Husby S, Koletzko S, Korponay-Szabó IR, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease. J Pediatr Gastroenterol Nutr. 2012;54:136-60. 4. Mišak Z, Hojsak I, Jadrešin O, Kekez AJ, Abdović S, Kolaček S. Diagnosis of coeliac disease in children younger than 2 years. J Pediatr Gastroenterol Nutr. 2013;56:201-5. doi: 10.1097/MPG.0b013e3182716861. 5. Alaedini A, Green PH. Narrative review: celiac disease: understanding a complex autoimmune disorder. Ann Intern Med. 2005;142:289-98. 6. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol. 1999;11:1185-94. 7. Braamskamp MJ, Dolman KM, Tabbers MM. Clinical practice. Protein losing enteropathy in children. Eur J Pediatr. 2010;169:1179-85. doi: 10.1007/s00431-010-1235-2. 8. Rewers M. Epidemilogy of celiac disease: What are the prevalence, incidence and progression of celiac disease? Gastroenterology. 2005;128:S47-S51. 9. Roma E, Panayiotou J, Karantana H, et al. Changing pattern in the clinical presentation of pediatric celiac disease: a 30-year study. Digestion. 2009;80:180-91. doi: 10.1159/000227275.10. Steens RF, Csizmadia CG, George EK, Ninaber MK, Hira Sing RA, Mearin ML. A national prospective study on childhood celiac disease in the Netherlands 1993–2000: an increasing recognition and a changing clinical picture. J Pediatr. 2005;147:239-43.11. Ravikumara M, Tuthill DP, Jenkins HR. The changing clinical presentation of coeliac disease. Arch Dis Child. 2006;91:969–71.12. Garampazzi A, Rapa A, Mura S, Capelli A, Valori A, Boldorini R, Oderda G. Clinical pattern of celiac disease is still changing. J Pediatr Gastroenterol Nutr. 2007;45:611–4.13. Green PH, Jabri B. Coeliac disease. Lancet. 2003;362:383-91.14. Kuloğlu Z, Kirsaçlioğlu CT, Kansu A, Ensari A, Girgin N. Celiac disease: presentation of 109 children. Yonsei Med J. 2009;50:617-23. doi: 10.3349/ymj.2009.50.5.617.15. Perisic N, Kokai G. Coeliac disease and lymphangiectasia. Arch Dis Child. 1992;67:134-6.S A Ž E T A KGeneralizirani edem s hipoproteinemijom kao prva prezentacija celijakije u 3-godišnjeg dječakaI. Butorac Ahel, M. Šubat Dežulović, G. PalčevskiEdemi nastaju zbog abnormalnog nakupljanja tekućine u intersticiju. Diferencijalna dijagnoza edema je vrlo široka. Bubrežni i srčani uzroci su najčešći uzroci generaliziranih edema. Mogući gastrointestinalni uzroci edema su zatajenje jetre, enteropatija uzrokovana gubitkom proteina, uključujući celijakiju i proteinsku neishranjenost. Generalizirani edemi su rijetka prva manifestacija celijakije. Prikazujemo slučaj trogodišnjeg dječaka s celijakijom koji se inicijalno prezentirao generaliziranim edemima i hipoproteinemijom.Ključne riječi: celijakija; edemi; hipoalbuminemija; dijete

Generalizirani edem s hipoproteinemijom kao prva prezentacija celijakije u 3-godišnjeg dječaka

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