A Rare Cause of Protein Losing Enteropathy in an Adult Patient Cláudio Martins1, Alice Gagnaire2, Florian Rostain2 and Côme Lepage2 1Department of Gastroenterology

Home , Enteropathy, Hypoalbuminemia, Hypoproteinemia, Lymphangiectasia

CASE REPORT

Waldmann’s disease: a rare cause of protein losing enteropathy in an adult patient Cláudio Martins1, Alice Gagnaire2, Florian Rostain2 and Côme Lepage2 1Department of Gastroenterology. Centro Hospitalar de Setúbal. Hospital de São Bernardo. Setúbal, Portugal. 2Department of Hepatogastroenterology and Digestive Oncology. Centre Hospitalier Universitaire de Dijon. Dijon, France

ABSTRACT formation or secondary obstruction of intestinal lymphatic drainage (1). As lymphatic fluid contains a lot of proteins, Primary intestinal lymphangiectasia or Waldmann’s disease fat and lymphocytes, leakage of lymph will cause hypo- is an uncommon cause of protein losing enteropathy with an proteinemia, lymphopenia and decreased serum levels of unknown etiology and is usually diagnosed during childhood. It is characterized by dilation and leakage of intestinal lymph vessels immunoglobulins (2). leading to hypoalbuminemia, hypogammaglobulinemia and Depending on the cause of the disease, it can be clas- lymphopenia. Differential diagnosis should include erosive and non- sified into primary or secondary. Primary intestinal erosive gastrointestinal disorders, conditions involving mesenteric lymphangiectasia (PIL) or Waldmann’s disease, original- lymphatic obstruction and cardiovascular disorders that increase ly described by Waldmann in 1961 (3), is a rare cause of central venous pressure. Since there are no accurate serological or radiological available tests, enteroscopy with histopathological PLE, whose prevalence and etiology are unknown. The examination based on intestinal biopsy specimens is currently the diagnosis is generally established before the third year of gold standard diagnostic modality of intestinal lymphangiectasia. life but can be rarely seen in adults (4). The gold-standard We report a rare case of a primary intestinal lymphangiectasia in diagnostic modality is enteroscopy with the respective his- a 60-year-old Caucasian female who presented with asymptomatic tological examination of the intestinal biopsy specimen. hypoalbuminemia and hypogammaglobulinemia. After the diagnosis of a protein losing enteropathy, the patient underwent The confirmation of the primary nature of disease requires an enteroscopy and biopsies were taken, whose histological the exclusion of secondary causes (4). Main differential examination confirmed dilated intestinal lymphatics with diagnosis includes congestive cardiac failure, constrictive broadened villi of the small bowel. Secondary causes of intestinal pericarditis, intestinal lymphoma, Crohn’s disease, intes- lymphangiectasia were excluded and the diagnosis of Waldmann’s disease was recorded. The patient was put on a high-protein and tinal tuberculosis, sarcoidosis, Whipple’s disease, human low-fat diet with medium-chain triglyceride supplementation with immunodeficiency virus (HIV)-related enteropathy, cyto- improvement. megalovirus (CMV)-related enteropathy or systemic scle- rosis. Key words: Protein losing enteropathy. Primary intestinal A low-fat diet associated with medium-chain tri- lymphangiectasia. Single-balloon enteroscopy. glycerides (MCT) supplementation is the cornerstone of PIL medical management (5). We report an uncommon case of PIL diagnosed in an INTRODUCTION adult asymptomatic female during etiological investigation of hypoproteinemia. Protein losing gastroenteropathies, characterized by an excessive loss of serum proteins into the gastrointestinal tract, are an important cause of hypoproteinemia, and CASE REPORT their diagnosis should be considered in patients when other causes of hypoproteinemia have been excluded, such We present a 60-year-old Caucasian female that was as malnutrition, heavy proteinuria and impaired protein referred to our Department due to asymptomatic hypoal- synthesis due to liver diseases. A high fecal alpha-1-anti- buminemia and hypogammaglobulinemia. She reported a trypsin clearance suggests exudative enteropathy. medical history of hypothyroidism, hypercholesterolemia Intestinal lymphangiectasia is an uncommon cause of and gastroesophageal reflux disease under treatment with protein losing enteropathy (PLE) due to congenital mal- levothyroxine, simvastatin and omeprazole. There was no

Received: 08-09-2016 Accepted: 01-12-2016 Martins C, Gagnaire A, Rostain F, Lepage C. Waldmann’s disease: a rare Correspondence: Cláudio Martins. Department of Gastroenterology. Centro cause of protein losing enteropathy in an adult patient. Rev Esp Enferm Dig Hospitalar de Setúbal. São Bernardo Hospital. Rua Camilo Castelo Branco. 2017;109(5):385-388. 2910 Setúbal, Portugal DOI: 10.17235/reed.2017.4593/2016 e-mail: [email protected] 386 C. MARTINS ET AL. Rev Esp Enferm Dig

history of diarrhea, limb swelling, abdominal pain, fever, vomiting, anorexia, weight loss, skin rash or urinary symptoms. Physical examination was unremarkable. Initial laboratory tests showed no anemia (hemoglobin 13.6 g/dL), normal total white blood cells count (4.18 x 109/L) with normal lymphocytes (1,720/uL) and platelet count (200,000/uL); protein electrophoresis with hypoproteinemia (4.6 g/dL), hypoalbuminemia (2.9 g/dL) and hypogammaglobulinemia (2.6 g/L); normal calcium levels, liver and kidney function tests. Further investigations showed no proteinuria and fecal alpha-1-antytripisin clearance was increased. These results were consistent with a PLE. In order to clarify the etiology of exsudative enteropathy, the patient underwent an upper gastrointestinal endoscopy with gastric and duodenal biopsies which were normal. Computed tomography (CT) scan enterography and magnetic resonance imaging (MRI) enterography revealed dif- Fig. 2. Enteroscopy showing the jejunum covered by diffuse white spots fuse and regular thickening throughout the jejunum; there with a “snowflake” appearance. were no adenopathies (Fig. 1). A single-balloon enteroscopy was performed and scattered white spots with a “snowflake” appearance overlying the jejunum were observed and low-fat diet with supplementation of medium chain (Fig. 2). These findings were consistent with diffuse intes- triglyceride with good response. tinal lymphangiectasia. Multiple biopsies were taken and the histopathological examination revealed broadened villi with dilated lymphatic channels in mucosa and submucosa. DISCUSSION To exclude secondary causes of intestinal lymphangiectasia an additional study was performed. Coprocultures, Intestinal lymphangiectasia, an uncommon but import- parasitological stool sample examination, serological test- ant cause of protein losing enteropathy, is characterized ing for HIV and CMV and interferon-gamma release assay by an impaired small intestinal lymph drainage associated were negative. Antinuclear antibodies, anti-double strand- with dilated lymphatic channels. It can be due to prima- ed DNA and immunoglobulin A (IgA) anti-tissue transglu- ry disorders of intestinal lymphatics or due to second- taminase were negative. Erythrocyte sedimentation rate ary causes. Regardless of the cause, the impaired flow and serum beta-2 microglobulin were normal. Immuno- and increased pressure in intestinal lymphatics lead to phenotypic analysis of peripheral blood revealed no atyp- decreased absorption of fat-soluble vitamins (A, D, E and ical cells. Transthoracic echocardiogram was normal. K), reduced recirculation of intestinal lymphocytes into the These findings were fully consistent with PIL (Wald- peripheral circulation and leakage of intestinal lymph into mann’s disease). The patient was put on a high-protein the intestinal lumen (6). PIL, first described in 1961 by Waldmann et al. (3), is a rare disorder whose prevalence and etiology are unknown. A B After 1961, as per available literature, less than 200 cases have been reported. It is mainly seen in pediatric patients, usually diagnosed before three years of age, with an equal incidence in both genders (4). Although most cases are sporadic, PIL has been reported in multiple siblings of several families, suggesting a genetic contribution. Fur- thermore, PIL can occur as an isolated disorder or as a part of a syndrome such as Von Recklinghausen, Turner, Noonan, Klippel-Trenaunay-Weber, Hennekan and yel- low-nail syndrome. In a retrospective analysis of 84 cases in 2010, the most common symptoms were limb edema, diarrhea, ascites and lymphedema, present in 78, 62, 41 and 22%, respective- ly (7). Other non-specific symptoms are fatigue, abdom- Fig. 1. Diffuse thickening through the jejunum seen on CT (A) and IRM inal pain, nausea, vomiting, weight loss, failure to thrive, enterography (B). iron deficiency anemia, obstructive ileus, steatorrhea and

Rev Esp Enferm Dig 2017;109(5):385-388 2017, Vol. 109, N.º 5 WALDMANN’S DISEASE: A RARE CAUSE OF PROTEIN LOSING ENTEROPATHY IN AN ADULT PATIENT 387

fat-soluble vitamin deficiency (2). Due to leakage from the tract but may also be seen in the retroperitoneum and the ruptured lymph vessels, other major features are lymph- mediastinum. Recurrent and opportunistic infections are not openia, hypoalbuminemia and hypogammaglobulinemia. rare due to moderate or severe hypogammaglobulinemia and However, in a few cases, patients are asymptomatic and lymphopenia (e.g., Streptococcus G, meningitis, cryptococ- the diagnosis is made during etiological investigation of cus, cytomegalovirus) (9,10). hypoproteinemia (13). In our case, enteroscopy reveals scattered white spots In this report, we present a rare case of a PIL in an with a “snowflake” appearance, which are the typical asymptomatic adult patient diagnosed during etiological findings of intestinal lymphangiectasia. Histopathological investigation of hypoproteinemia, hypoalbuminemia and examination of their biopsies confirmed diagnostic suspi- hypogammaglobulinemia. Taking into account the high cion. Regarding the length, and also taking into account fecal alpha-1-antitrypsine clearance and after excluding IRM enterography findings, the disease involved the entire other causes of hypoproteinemia, such as malnutrition, jejunum. After the exclusion of secondary causes of intesti- proteinuria and liver disease, a PLE was considered. nal lymphangiectasia, the diagnosis of Waldmann’s disease Currently, diagnosis of intestinal lymphangiectasia is was recorded and the patient was put on a high protein and based on typical findings during enteroscopy with further low-fat diet with medium-chain triglyceride supplementa- confirmation by histopathological examination of corre- tion with a good response. sponding biopsy specimens (4). Other tests proposed to In conclusion, PIL is a rare condition that can be demonstrate the abnormal intestinal lymphatic vessels asymptomatic or appear with common features such as are albumin scintigraphy, contrast lymphangiography and limb edema, diarrhea, hypoproteinemia and hypogamma- magnetic resonance lymphangiography. However, their globulinemia. Careful endoscopic examination and metic- sensitivity and specificity have not been studied in a suffi- ulous histopathological evaluation is mandatory to achieve cient number of patients to justify routine use. a correct pathological diagnosis and, thus, to decide the The definitive diagnosis of Waldmann’s disease requires proper treatment plan. It can be severe, affecting the entire the exclusion of secondary causes of intestinal lymphan- small bowel, persistent and difficult to manage, leading to giectasia, which includes erosive and non-erosive intesti- lifetime disease. The risk of cancer in these cases should nal disorders, conditions involving mesenteric lymphatic be taken into account. On the other hand, the disease can obstruction and cardiovascular disorders that increase be mild, affecting part of the bowel, transient and easy to central venous pressure. Therefore, the main differential manage with dietary interventions. diagnoses are constrictive pericarditis, intestinal lymphoma, lymphenteric fistula, Whipple’s disease, Crohn’s disease, sarcoidosis, intestinal tuberculosis, systemic scle- REFERENCES rosis, radiation and/or chemotherapy with retroperitoneal fibrosis, HIV and CMV-related enteropathy and Fontan 1. Vignes S, Bellanger J. Primary intestinal lymphangiectasia (Wald- mann’s disease). Orphanet J Rare Dis 2008;3:5. DOI: 10.1186/1750- operation to treat cardiac malformations. 1172-3-5 Lifelong dietary modification with high protein, fat 2. Freeman HJ, Nimmo M. Intestinal lymphangiectasia in adults. World J restriction and substitution with MCT and vitamin supple- Gastrointest Oncol 2011;3:19-23. DOI: 10.4251/wjgo.v3.12.19 ments remains the cornerstone in the management of PIL. 3. Waldmann TA, Steinfeld JL, Dutcher TF, et al. The role of the gastrointestinal system in “idiopathic hypoproteinemia”. Gastroenterol Exclusion of long-chain fatty acids prevents the engorge- 1961;41:197-207. ment and rupture of malformed lymphatics while MCT 4. Lai Y, Yu T, Qiao XY, et al. Primary intestinal lymphangiectasia get directly absorbed into the portal venous circulation. In diagnosed by double-balloon enteroscopy and treated by medium- patients not responding to a low fat diet, enteral nutritional chain triglycerides: A case report. J Med Case Rep 2013;7:19. DOI: 10.1186/1752-1947-7-19 therapy (elemental, semi-elemental and polymeric diets) 5. Jeffries GH, Champan A, Sleisenger MH. Low fat diet in intestinal may be required. In a few severe cases, total parenteral lymphangiectasia: Its effect on albumin metabolism. N Engl J Med nutrition is warranted (8). Alternative treatment options 1964;270:761-6. DOI: 10.1056/NEJM196404092701503 6. Davidson NO. Intestinal lipid absorption. In: Textbook og Gastroen- with variable efficacy are discussed in several publications. terology. Yamada T, Alpers DU, Kaplowitz N (Eds.). Philadelphia: JB They include antiplasmin therapy, octreotide, corticoste- Lippincott; 2003. p. 413 roids, small bowel resection, albumin infusions, peritone- 7. Wen J, Tang Q, Wu J, et al. Primary intestinal lymphangiectasia: Four ovenous (Levine) shunt and intestinal transplant. case reports and a review of the literature. Dig Dis Sci 2010;55:3466- 72. DOI: 10.1007/s10620-010-1161-1 The prognosis of PIL is highly variable depending on the 8. Aoyagi K, Iida M, Matsumoto T, et al. Enteral nutrition as a primary age of onset, extent and severity of disease and response to therapy for intestinal lymphangiectasia: Value of elemental diet and therapy. Regarding the main complications, it is not clear if polymeric diet compared with total parenteral nutrition. Dig Dis Sci 2005;50:1467-70. DOI: 10.1007/s10620-005-2863-7 malignancy, especially lymphoma, is fortuitous or related to 9. Hallevy C, Sperber AD, Almog Y. Group G streptococcal empyema the disease. Among 84 PIL patients reviewed in 2010, four complicating primary intestinal lymphangiectasia. J Clin Gastroenterol (5%) had malignant lymphoma, and the average time from 2003;37:270. DOI: 10.1097/00004836-200309000-00015 PIL onset to lymphoma diagnosis was 31 years (range 19-45 10. Cole SL, Ledford DK, Lockey RF, et al. Primary gastrointestinal lymphangiectasia presenting as cryptococcal meningitis. Ann Allergy Asth- years) (7). Lymphoma mainly affects the gastrointestinal ma Immunol 2007;98:490-2. DOI: 10,1016/s1081-1206(10)60765-X

Rev Esp Enferm Dig 2017;109(5):385-388