Primary intestinal lymphangiectasia (Waldmann's disease)

1750-1172-3-5 1750-1172 Review Primary intestinal lymphangiectasia (Waldmann's disease) Vignes Stéphane stephane.vignes@hopital-cognacq-jay.fr Bellanger Jérôme j-bellanger@wanadoo.fr

Department of Lymphology, Centre de référence des maladies vasculaires rares, Hôpital Cognacq-Jay, 15, rue Eugène Millon, 75015 Paris, France

Department of Gastroenterology and Nutrition, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France

Orphanet Journal of Rare Diseases 1750-1172 2008 3 1 5 http://www.ojrd.com/content/3/1/5 18294365 10.1186/1750-1172-3-5 26 7 2007 22 2 2008 22 2 2008 2008 Vignes and Bellanger; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective treatments have been proposed for PIL patients, such as antiplasmin, octreotide or corticosteroids. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. PIL outcome may be severe even life-threatening when malignant complications or serous effusion(s) occur.

Disease name and synonyms

Primary intestinal lymphangiectasia (PIL).

Waldmann's disease.

History and definition

In 1961, Waldmann et al. described the first 18 cases of "idiopathic hypercatabolic hypoproteinemia" 1. These patients had edema associated with hypoproteinemia, low serum albumin and gammaglobulin levels. The total exchangeable albumin pool, assessed with radio-labeled ¹³¹I-albumin, was low in all patients. Daily fecal excretion of ¹³¹I was twice the highest value obtained in controls. Microscope examination of the small intestine biopsies showed variable degrees of dilation of the lymph vessels in the mucosa and submucosa. The authors also proposed the term "intestinal lymphangiectasia".

Epidemiology

The prevalence of clinically overt PIL is unknown. However, PIL can be asymptomatic; it primarily affects children (generally diagnosed before 3 years of age) and young adults but may be diagnosed later in adults 23. Very rare familial forms of Waldmann's disease have been reported 14.

Clinical description

A. Edema

Peripheral edema of variable degree, usually symmetrical, from moderate (lower limb edema) to severe, including the face and external genitalia, is the main clinical feature, which accounts for 95% of PIL clinical manifestations 4. Moderate serous effusions (pleural effusion, pericarditis, chylous ascites) are common, and life-threatening anasarca may occur rarely throughout the course of the disease 15. The edema is pitting because the oncotic pressure is low due to hypoalbuminemia resulting from exsudative enteropathy. PIL may be suspected at birth or during pregnancy based on ultrasonography images, which can detect fetal ascites or lower limb lymphedema 6.

B. Childhood particularities

In children, PIL is generally diagnosed before 3 years of age 578 and may be complicated by fatigue, abdominal pain, nausea, vomiting and weight loss, inability to gain weight and growth retardation 5. Malabsorption may cause fat-soluble vitamin deficiencies and hypocalcemia leading to convulsions 5.

C. Other clinical findings

- Lymphedema is a rare disorder which is usually not associated with another disease, but it may be associated with intestinal lymphangiectasia. Clinical features of lymphedema are specific (Figure 1). Lymphedema is less pitting than edema due to hypoproteinemia, and is localized to the lower limbs (foot, ankle, calf, rarely thigh) and predominantly bilateral. Upper limb with hand and forearm involvement, lymphedema of breast and external genitalia (with skin thickening) may also be present 9. In most patients with lymphedema, edema as a consequence of hypoproprotidemia has also been observed. The two types of edema are not always easily distinguished. Stemmer's sign is an important element to confirm the diagnosis and differentiate lymphedema from edema: i.e., it is impossible to lift and wrinkle the dorsal skin on the second toe because of skin-thickening as the result of fibrosis.

Figure 1

A 23-year-old woman with PIL since infancy

A 23-year-old woman with PIL since infancy. Note the bilateral lower limb lymphedema, with accentuation of the dorsal flexion folds of the toes.

- Moderate or discontinuous diarrhea is the main digestive symptom 10.

- An abdominal mass was found in the epigastrium and right upper quadrant of a 12-year-old girl. Ultrasonography failed to confirm an abdominal mass but the mass was attributed to small bowel edema 11.

- A malabsorption syndrome may be encountered in the elderly 12.

- Mechanical ileus of the small intestine caused by localized edema leading to intestinal wall-thickening and lumen diminution. It may be visualized as a segmental mass requiring resection (histological findings: dilation of submucosal lymphatics, extensive pseudocysts in the jejunal wall, intramural lymph edema, secondary bleeding, tight stenosis of the jejunal lumen) 13.

- Chylous reflux into the skin of the right flank resembles lymphangioma circumscriptum with multiple dome-shaped vesicles filled with milky-white fluid, which is discharged into the surrounding skin 14.

- Chyle can also backflow into the skin of the lower limb, perineum or external genitalia 15.

- An association with celiac disease has been reported in children 16.

- Iron deficiency with anemia occurs secondary to chronic blood loss resulting from non-specific multiple ulcers in the small intestine 17.

- Necrolytic migratory erythema can be seen 18.

- Recurrent hemolytic uremic syndrome has been described 19.

- Osteomalacia resulting from vitamin D deficiency was reported in a 63-year-old woman 20.

- It remains open to debate whether recurrent gastrointestinal bleeding is indeed a manifestation of PIL 21.

D. Syndromes associated with intestinal lymphangiectasia

First described in 1964 by Samman and White, the yellow nail syndrome is a very rare condition which may be associated with PIL. Dystrophic yellow nails with ridging and loss of lunula on the hands are associated with lymphedema and pleural effusions 22.

Five syndromes are associated with intestinal lymphangiectasia: von Recklinghausen, Turner (X0) or Noonan, Klippel-Trenaunay and Hennekam 23. In general, these syndromes are easily distinguishable by the presence of facial abnormalities (Turner, Noonan, Hennekam), mental retardation (Hennekam, Noonan), seizures (Hennekam), severe limb and/or face lymphedema (Hennekam), neurofibromas and other tumors (von Recklinghausen), and hemihypertophy of the limbs associated with vascular malformations (Klippel-Trenaunay).

Etiology and pathogenesis

To date, PIL etiology is unknown. Intestinal lymphangiectasia is responsible for lymph leakage into the bowel lumen, which leads to hypoalbuminemia and lymphopenia. Edema is the consequence of hypoprotidemia with decreased oncotic pressure. Several genes, such as VEGFR3 (vascular endothelial growth factor receptor 3), prospero-related homeobox-transcriptional factor PROX1, forkhead transcriptional factor FOXC2 and SOX18 are implicated in the development of the lymphatic system. In a recent paper, Hokari et al. reported inconsistently changed expressions of regulatory molecules for lymphangiogenesis in the duodenal mucosa of PIL patients 24.

Diagnosis and diagnostic methods

PIL diagnosis is confirmed by the presence of intestinal lymphangiectasia based on endoscopic findings with the corresponding histology of intestinal biopsy specimens (Figure 2). Macroscopic abnormalities are usually obvious with creamy yellow of jejunal villi corresponding to marked dilation of the lymphatics within the intestinal mucosa. The density of lymphangiectasia varies and their size ranges from mm to cm. Histological examination of duodenum-jejunum and ileum biopsies confirms the presence of lacteal juice, dilated mucosal (from moderate to severe) and submucosal lymphatic vessels (and also in the serosa) with polyclonal normal plasma cells. Intestinal lymphatics may be dilated in many villi or only a few. Intestinal abnormalities may be slight; small bowel mucosa also appears edematous but not creamy. That neither villous atrophy nor microorganisms are found in biopsies is underlined in pathology reports. Endoscopy may be negative when intestinal lesions are segmental or localized. In such cases, videocapsule endoscopy, easier to use than enteroscopy, is a useful tool to detect the presence of intestinal lymphangiectasia and to specify its localization (Figure 3) 252627. Videocapsule endoscopy is also feasible to appreciate the extent of lymphangiectasia in children 28.

Figure 2

Duodenal biopsy: note the markedly dilated lymphatic ducts (periodic acid Schiff staining)

Duodenal biopsy: note the markedly dilated lymphatic ducts (periodic acid Schiff staining).

Figure 3

Capsule endoscopy (M2A, Given Imaging, Yoqneam, Israel): note the edematous aspect of the jejunum mucosa with whitish, swollen villi

Capsule endoscopy (M2A, Given Imaging, Yoqneam, Israel): note the edematous aspect of the jejunum mucosa with whitish, swollen villi.

Indirect biological abnormalities are suggesting of PIL, such as hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia with low IgG, IgA and IgM levels or lymphocytopenia. Exsudative enteropathy is confirmed by the high 24-h stool α1-antitrypsin clearance due to enteric protein loss. Functional absorption tests, e.g., such as D-xylose test results are normal in PIL.

Complementary examinations

Although various methods have been proposed to investigate PIL, none of them can replace histological examination of biopsies to confirm the diagnosis.

A. Albumin scintigraphy

^99mTechnetium-labeled human serum albumin (^99mTc-HSA) scintigraphy may show marked enhancement in the bowel, which indicates protein leakage into this region 23. Serial scanning for up to 24 h is required to detect protein loss from the gut, perhaps because of the intermittent nature of protein loss. ^99mTc-HSA scintigraphy has high sensitivity and is able to identify the site of protein loss (large and/or small bowel localization, stomach) 29. The α1-antitrypsin method has replaced ^99mTc-HSA scintigraphy, which is more costly, less readily available and also uses a human product potentially carrying an infectious risk.

B. Ultrasound

Indirect features may suggest PIL in children and adults. Ultrasonographic findings may show dilation of the intestinal loops, regular and diffuse thickening of the walls, plical hypertrophy and severe mesenteric edema and, in some cases, ascites 3031.

C. Computed tomography (CT) scans

Axial abdominal CT images are obtained with oral and intravenous contrast medium enhancement. CT appearance of PIL is similar in adults and children. Typically, there is diffuse, nodular, small bowel wall-thickening and edema, which are a consequence of the dilated lymphatics within the villi, along with some degree of small bowel dilation, with, in few cases, a "halo sign" due to swelling and edema 323334. CT may be useful to identify localized intestinal lymphangiectasia 35.

D. Lymphoscintigraphy

Lymphoscintigraphy is an effective tool for identifying abnormal lymphatic tree in the upper or lower limb and also to confirm limb lymphedema, when the limb images are abnormal. In limb lymphedema, isotope-uptake seen on the lymphogram shows an absence of visible lymph nodes which indicates either peripheral lymphatic obliteration or inability of the vessels to transport lymph up the limb through incompetent lymphatic vessels 36. ^99mTc-radio-labeled rhenium sulfur colloid and albumin colloid are the two isotopes currently used in limb lymphoscintigraphy. At present, lymphoscintigraphy is not a routine and useful methodology for PIL diagnosis. Indeed, in one study, So et al. reported that intestinal lymphoscintigraphy (after subcutaneous injection of ^99mTc-antimony sulfide colloid into the two first toe spaces) only detected the presence of radioactivity in less than half of patients with histologically proven PIL 37.

Immunological abnormalities

PIL patients have immunological abnormalities involving both the B-cell and T-cell lineages of the immune system. The B-cell defect is characterized by low immunoglobulin levels (IgG, IgA and IgM) and poor antibody responses 383940. The T-cell defect is characterized by lymphocytopenia, prolonged skin-allograft rejection and impaired in vitro proliferative responses to various stimulants (anti-CD3, anti-CD28) 41. Furthermore, PIL patient's peripheral blood samples contain extremely low counts of CD4⁺T cells, especially naïve, CD45RA⁺CD62L⁺, while CD45RO⁺memory cells, are only moderately below normal. CD45RA⁺and CD45RO⁺CD8⁺T cells are moderately below normal 41.

Differential diagnosis

The differential diagnosis is of special importance for subjects suspected of having PIL. Some secondary causes of intestinal lymphangiectasia have been identified as diseases responsible for anatomical or dynamic alterations of the lymphatic flow. Protein-losing enteropathies associated with intestinal lymphangiectasia may arise secondary to constrictive pericarditis 424344, intestinal lymphoma 4546, lymphenteric fistula 47, Whipple's disease 48, Crohn's disease 49, sarcoidosis 50, intestinal tuberculosis 51, systemic sclerosis 52, radiation and/or chemotherapy with retroperitoneal fibrosis 53, human immunodeficiency virus-related enteropathy 54 or the Fontan operation to treat cardiac malformations 55.

Many diseases are associated with excessive enteric loss of plasma proteins but do not include lymphatic lymphangiectasia, such as Menetrier's disease or inflammatory states of systemic lupus erythematosus in adults and children 56575859.

Complications

A. Malignant transformation

It is not clear whether the occurrence of malignancy, especially lymphomas, is fortuitous or related to PIL. Indeed, only a few lymphomas associated with PIL have been reported. Among 50 PIL patients reviewed, 3 had malignant lymphomas, that arose 3 to 25 years after the initial diagnosis 60. The interval from PIL diagnosis to lymphoma diagnosis was even 39 and 40 years in a study 61. Some lymphomas were confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum), i.e. in PIL involved sites, while in other patients they were extra-intestinal (retroperitoneum, mediastinum, bone) 60616263. In the well-described histological and immunological studies, only B-cell lymphomas (large cells, small cells, centroblastic, immunoblasts) were encountered 61. Chemotherapy achieved regression of the exsudative enteropathy in only two of those previous cases 6263.

Lymphoma may be related to PIL as a consequence of several mechanisms: (1) long-standing protein-losing enteropathy may be resolved after treatment (chemotherapy and/or radiotherapy) 626364; (2) lymphoma may cause secondary intestinal lymphangiectasia, (3) lymphoma in PIL could be associated with an immune deficiency. Indeed, a primary deficiency of B cells and/or helper T cells has been proposed in PIL, in combination with a secondary immune deficiency resulting from the loss of immunoglobulins and lymphocytes 3940. But no clear evidence of depressed intestinal immunity was found in PIL patients compared to those with other primary immunodeficiencies and having gut infections, like giardiasis.

B. Cutaneous warts

PIL patients were reported to have diffuse and multiple cutaneous warts in association with lymphoma 6566. Widespread viral warts may be associated with a primary immune deficiency in PIL or secondary to lymphoma.

C. Infections

Although PIL patients have moderate-to-severe hypogammaglobulinemia and lymphopenia, their risk of pyogenic bacterial infection is not significantly elevated and opportunistic infections are uncommon. Only one case of a severe infection with group G streptococcal empyema was reported 67 and another had cryptococcal meningitis 68.

D. Gelatinous transformation of the bone marrow

It is an uncommon disorder characterized by the replacement of hematopoietic cells and adipocytes by amorphous extracellular material composed of acid mucopolysaccharides. The only reported case of a gelatinous transformation of the bone marrow in a PIL patient was attributed to the malnutrition resulting from malabsorption 69.

Management including treatment

A. Low-fat diet associated with medium-chain triglycerides

Low-fat diet associated with supplementary medium-chain triglycerides (MCT) is the cornerstone of PIL medical management 70. It is likely that the absence of fat in the diet prevents engorgement of the intestinal lymphatics with chyle, thereby preventing their rupture with its ensuing protein and T-cell loss. MCT are directly absorbed into the portal venous circulation and thus provide nutrient fat but avoid lacteal engorgement. After a few weeks, this treatment may lead to reversal of clinical and biochemical signs (albuminemia, immunoglobulin levels and lymphocyte counts) 71. In patients not responding to a low-fat diet, enteral nutritional therapy (elemental, semi-elemental and polymeric diets) may be required. In a few very severe cases, total parenteral nutrition is warranted 72. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. Long-term PIL monitoring essentially concerns its predominant clinical manifestation (edema). Laboratory analyses (albuminemia, lymphocyte counts, immunoglobulin levels) are required when lower limb edema becomes more pronounced.

B. Other treatments

In the literature, other treatments have been proposed to treat PIL. They can be used after or in combination with a low-fat diet associated with MCT supplementation. Their efficacy is variable and insufficiently evaluated.

1) Antiplasmin

A few authors reported that PIL patients responded to tranexamic acid (1 g, 3 times a day) 7374, but these responses were heterogeneous with only partial disease attenuation. It was hypothesized that increasing plasma fibrinolysis might enhance lymphatic permeability to plasma proteins. Under antiplasmin treatment, a lower percentage of T lymphocytes became normalized together with serum immunoglobulin values. In addition, the therapy resulted in the disappearance endoscopically observed duodenal lesions 73.

2) Octreotide

In 1998, Ballinger and Farthing reported the efficacy of octreotide in one PIL patient 75. To date, few publications have supported the contribution of octreotide in PIL. Octreotide (150–200 μg, twice a day or the slow-release formulation) might lead to clinical, biochemical (albuminemia) and histological improvement 7677. The mechanism of action of the somatostatin analog on the gastrointestinal tract remains unclear. It has been shown that octreotide induces short-lasting splanchnic vasoconstriction in healthy volunteers and cirrhotic patients, and inhibits the absorption of triglycerides 78. Furthermore, somatostatin inhibits thoracic lymph flow in dogs 79. Octreotide may be useful in PIL patients in combination with a low-fat diet.

3) Surgery

Small bowel resection is useful in the rare cases in which intestinal lymphangiectasia is segmental and localized (duodenum) 8081. Recurrent and/or bulky pleural effusions may lead to unilateral or bilateral surgical pleurectomy or talc pleurodesis 5.

4) Corticosteroids

Steroids were prescribed to patients with intestinal lymphangiectasia secondary to inflammatory disease with variable efficacy 82 and also to systemic lupus erythematosus patients with protein-losing enteropathy 58

5) Albumin infusion

Albumin infusion is a symptomatic treatment proposed in patients with important serous effusion or uncomfortable lower limb edema. Repeated albumin intravenous supplementation may be useful to reduce edema and improve albuminemia but its efficacy is transient resulting from persistent lymph leakage into the bowel lumen.

Prognosis and long-term outcome

PIL is a chronic debilitating disorder requiring constraining long-term dietary control based on a low-fat regimen associated with supplementary MCT. Lower limb edema is usually the main clinical manifestation but lymphedema may be associated. Lower limb lymphedema had its own particularities, including infectious complications (e.g., cellulitis) and requires specific long-term management (low-stretch bandage, manual lymph drainage, skin care, elastic hosiery) 83. These two conditions deteriorate the quality of life (difficulty to put on shoes, unattractive aspect of leg). PIL outcome may be severe even life-threatening when malignant complications (lymphoma) or serous effusion(s) (pleural, pericardic) occur.

The role of the gastrointestinal system in "idiopathic hypoproteinemia" Waldmann TA Steinfeld JL Dutcher TF Davidson JD Gordon RS Gastroenterology 1961 41 197 207 13782654 Lymphangiectasies intestinales primitives (maladie de Waldmann) révélées par un lymphœdème des membres Boursier V Vignes S J Mal Vasc 2004 29 103 106 15229406 Intestinal lymphangiectasia long-term results with MCT diet Tift WL Lloyd JK Arch Dis Child 1975 50 269 276 50050 Maladie de Waldmann familiale Le Bougeant P Delbrel X Grenouillet M Leou S Djossou F Beylot J Lebras M Longy-Boursier M Ann Med Interne 2000 151 511 512 Intestinal lymphangiectasia: a reappraisal Vardy PA Lebenthal E Shwachmann H Pediatrics 1975 55 842 850 1134884 Isolated fetal ascites caused by primary lymphangiectasia: a case report Schmider A Henrich W Reles A Vogel M Dudenhausen JW Am J Obstet Gynecol 2001 184 227 228 10.1067/mob.2001.106756 11174507 Maladie de Waldmann: lymphangiectasies intestinales primitives Misery L Lachaux A Chambon M Faure M Claudy A Ann Dermatol Venereol 1996 123 567 568 9615110 Suivi de long cours des lymphangiectasies intestinales primitives de l'enfant. A propos de six cas Munck A Sosa Valencia G Faure C Besnard M Ferkdadji L Cézard JP Mougenot JF Navarro J Arch Pediatr 2002 9 388 391 10.1016/S0929-693X(01)00799-0 11998426 Bilateral breast edema in intestinal lymphangiectasia [letter] Goktan C Pekindil G Orguc S Coskun T Serter S Breast J 2005 11 360 10.1111/j.1075-122X.2005.21578.x 16174162 Chronic diarrhoea in infants and young children: causes, clinical features and outcome Lee WS Boey CC J Paediatr Child Health 1999 35 260 263 10.1046/j.1440-1754.1999.00356.x 10404446 Intestinal lymphangiectasia presenting as abdominal mass Rao R Shashidhar H Gastrointest Endosc 2007 65 522 3 discussion 523 10.1016/j.gie.2006.10.026 17321261 Usefulness of jejunal biopsy in the study of intestinal malabsorption in the elderly Lobo B Casellas F de Torres I Chicharro L Malagelada JR Rev Esp Enferm Dig 2004 96 259 264 15117239 Acute jejunal ileus in intestinal lymphangiectasia Lenzhofer R Lindner M Moser A Berger J Schuschnigg C Thurner J Clin Investig 1993 71 568 571 10.1007/BF00208483 8374252 Chylous reflux into abdominal skin simulating lymphangioma circumscriptum in a patient with primary intestinal lymphangiectasia O'Driscoll JB Chalmers RJ Warnes TW Clin Exp Dermatol 1991 16 124 126 10.1111/j.1365-2230.1991.tb00322.x 2032374 Primary lymphoedema associated with xanthomatosis, vaginal lymphorrhoea and intestinal lymphangiectasia Karg E Bereczki C Kovacs J Korom I Varkonyi A Megyeri P Turi S Br J Dermatol 2002 146 134 137 10.1046/j.1365-2133.2002.04477.x 11841381 Coeliac disease and lymphangiectasia Perisic VN Kokai G Arch Dis Child 1992 67 134 136 1739329 Clinicopathologic consideration of protein-losing enteropathy due to lymphangiectasia of the intestine Iida F Wada R Sato A Yamada T Surg Gynecol Obstet 1980 151 391 395 7404312 Erythème nécrolytique migrateur au cours d'une maladie de Waldmann Baricault S Soubrane JC Courville P Young P Joly P Ann Dermatol Venereol 2006 133 693 696 17053741 Recurrent hemolytic uremic syndrome associated with intestinal lymphangiectasia Kalman S Bakkaloglu S Dalgic B Ozkaya O Soylemezoglu O Buyan N J Nephrol 2007 20 246 249 17514630 Osteomalacia in a patient with primary intestinal lymphangiectasis (Waldmann's disease) Sahli H Ben Mbarek R Elleuch M Azzouz D Meddeb N Chéour E Azzouz MM Sellami S Joint Bone Spine 2008 75 73 75 10.1016/j.jbspin.2007.01.045 17900962 A case of recurrent gastrointestinal bleeding and protein-losing gastroenteropathy Herfarth H Hofstädter F Feuerbach S Jürgen Schlitt H Schölmerich J Rogler G Nat Clin Pract Gastroenterol Hepatol 2007 4 288 293 10.1038/ncpgasthep0812 17476211 The "yellow nail" syndrome Samman P White WF Br J Dermatol 1964 76 153 157 10.1111/j.1365-2133.1964.tb14499.x 14140738 Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation Hennekam RC Geerdink RA Hamel BC Hennekam FA Kraus P Rammeloo JA Tillemans AA Am J Med Genet 1989 34 593 600 10.1002/ajmg.1320340429 2624276 Changes in regulatory molecules for lymphangiogenesis in intestinal lymphangiectasia with enteric protein loss Hokari R Kitagawa N Watanabe C Komoto S Kurihara C Okada Y Kawaguchi A Nagao S Hibi T Miura S J Gastroenterol Hepatol 2007 2007 Nov 14 Videocapsule endoscopy is useful for the diagnosis of intestinal lymphangiectasia Chamouard P Nehme-Schuster H Simler JM Finck G Baumann R Pasquali JL Dig Liver Dis 2006 38 699 703 10.1016/j.dld.2006.01.027 16527553 Intérêt de l'entéroscopie par vidéocapsule dans le diagnostic des lymphangiectasies intestinales primitives Vignes S Bellanger J Rev Med Interne 2007 28 173 175 17229491 A primary intestinal lymphangiectasia patient diagnosed by capsule endoscopy and confirmed at surgery: a case report Fang YH Zhang BL Wu JG Chen CX World J Gastroenterol 2007 13 2263 2265 17465517 Use of capsule endoscopy in children with primary intestinal lymphangiectasia Rivet C Lapalus MG Dumortier J Le Gall C Budin C Bouvier R Ponchon T Lachaux A Gastrointest Endosc 2006 64 649 650 10.1016/j.gie.2006.03.008 16996365 Protein-losing enteropathy: diagnosis with 99mTc-labeled human serum albumin scintigraphy Chiu NT Lee BF Hwang SJ Chang JM Liu GC Yu HS Radiology 2001 219 86 90 11274540 Sonography of intestinal lymphangiectasia Dorne HL Jequier S J Ultrasound Med 1986 5 13 16 3511270 Ultrasonographic features of long-standing primary intestinal lymphangiectasia Maconi G Molteni P Manzionna G Parente F Bianchi Porro G Eur J Ultrasound 1998 7 195 198 10.1016/S0929-8266(98)00037-8 9700215 Primary intestinal lymphangiectasia: clinical and CT findings Fakhri A Fishman EK Jones B Kuhadja F Siegelman SS J Comput Assist Tomogr 1985 9 767 770 4019833 The CT halo sign: a new finding in intestinal lymphangiectasia Stevens RL Jones B Fishman EK J Comput Assist Tomogr 1997 21 1005 1007 10.1097/00004728-199711000-00029 9386299 Congenital intestinal lymphangiectasia: CT demonstration in a young child Mazzie JP Maslin PI Moy L Price AP Katz DS Clin Imaging 2003 27 330 332 10.1016/S0899-7071(02)00588-0 12932684 Localized lymphangiectasia: CT findings. Localized intestinal lymphangiectasia: CT findings Yang DM Jung DH AJR Am J Roentgenol 2003 180 213 214 12490507 Value of isotope lymphography in the diagnosis of lymphoedema of the leg Burnand KG McGuinness CL Lagattolla NR Browse NL El-Aradi A Nunan T Br J Surg 2002 89 74 78 10.1046/j.0007-1323.2001.01964.x 11851667 Different patterns of lymphoscintigraphic findings in patients with intestinal lymphangiectasia So Y Chung JK Seo JK Ko JS Kim JY Lee DS Lee MC Nucl Med Commun 2001 22 1249 1254 10.1097/00006231-200111000-00013 11606892 Intestinal lymphangiectasia: a protein-losing enteropathy with hypogammaglobulinemia, lymphocytopenia and impaired homograft rejection Strober W Wochener RD Carbone PP Waldmann TA J Clin Invest 1967 46 1643 1656 292913 4168730 Impaired lymphocyte transformation in intestinal lymphangiectasia: evidence for at least two functionally distinct lymphocyte populations in man Weiden PL Blaese RM Strober W Block JB Waldmann TA J Clin Invest 1972 51 1319 1325 292269 4554185 10.1172/JCI106928 Immunological study in primary intestinal lymphangiectasia Heresbach D Raoul JL Genetet N Noret P Siproudhis L Ramee MP Bretagne JF Gosselin M Digestion 1994 55 59 64 7509299 Intestinal lymphangiectasia, a disease characterized by selective loss of naive CD45RA+ lymphocytes into the gastrointestinal tract Fuss IJ Strober W Cuccherini BA Pearlstein GR Bossuyt X Brown M Fleisher TA Horgan K Eur J Immunol 1998 28 4275 4285 10.1002/(SICI)1521-4141(199812)28:12<4275::AID-IMMU4275>3.0.CO;2-P 9862365 Protein-losing gastroenteropathy in congestive heart-failure Davidson JD Waldmann TA Goodman DS Gordon RS Jr Lancet 1961 1 899 902 10.1016/S0140-6736(61)91768-8 13720056 Protein-losing enteropathy in constrictive pericarditis Petersen VP Hastrup J Acta Med Scand 1963 173 401 410 13942764 Reversible protein-losing enteropathy with intestinal lymphangiectasia secondary to chronic constrictive pericarditis Wilkinson P Pinto B Senior JR N Engl J Med 1965 273 1178 1181 5847556 Protein-losing gastroenteropathy in patients with gastrointestinal cancer Sum PT Hoffman MM Webster DR Can J Surg 1964 7 1 5 14103417 The distribution and enteric loss of 51Cr-labelled lymphocytes in normal subjects and in patients with coeliac disease and other disorders of the small intestine Douglas AP Weetman AP Haggith JW Digestion 1976 14 29 43 10.1159/000114723 955324 Intestinal lymphangiectasia mechanism of enteric loss of plasma protein and fat Mistilis SP Skyring AP Stephen DD Lancet 1965 42 77 79 10.1016/S0140-6736(65)91657-0 14234205 Albumin metabolism in patients with Whipple's disease Laster L Waldmann TA Fenster LF Singleton JW J Clin Invest 1966 45 637 644 292741 4160668 10.1172/JCI105379 The mechanism of hypoproteinemia in patients with regional enteritis and ulcerative colitis Steinfeld JL Davidson JD Gordon RS Jr Grenne FE Am J Med 1960 29 405 415 10.1016/0002-9343(60)90036-X 13834226 Sarcoidosis and protein losing enteropathy Popovic OS Brkic S Bojic P Kenic V Jojic N Djuric V Djordjevic N Gastroenterology 1980 78 119 125 7350018 Intestinal lymphangiectasia in intraabdominal tuberculosis Ploddi A Atisook K Hargrove NS J Med Assoc Thai 1988 71 518 523 3249186 Intestinal lymphangiectasia in systemic sclerosis van Tilburg AJ van Blankenstein M Verschoor L Am J Gastroenterol 1988 83 1418 1419 3195550 Intestinal lymphangiectasia secondary to radiotherapy and chemotherapy Rao SS Dundas S Holdsworth CD Dig Dis Sci 1987 32 939 942 10.1007/BF01296718 3608736 Duodenal biopsies of HIV-infected patients with diarrhoea exhibit epithelial barrier defects but no active secretion Stockmann M Fromm M Schmitz H Schmidt W Riecken EO Schulzke JD AIDS 1998 12 43 51 10.1097/00002030-199801000-00006 9456254 Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group Mertens L Hagler DJ Sauer U Somerville J Gewillig M J Thorac Cardiovasc Surg 1998 115 1063 1073 10.1016/S0022-5223(98)70406-4 9605076 Systemic lupus erythematosus and intestinal venulitis Weiser MM Andres GA Brentjens JR Evans JT Reichlin M Gastroenterology 1981 81 570 579 7018990 Protein-losing enteropathy in systemic lupus erythematosus. Observations by magnifying endoscopy Kobayashi K Asakura H Shinozawa T Yoshida S Ichikawa Y Tsuchiya M Brown WR Dig Dis Sci 1989 34 1924 1928 10.1007/BF01536713 2689113 Protein-losing enteropathy in systemic lupus erythematosus associated with intestinal lymphangiectasia Edworthy SM Fritzler MJ Kelly JK McHattie JD Shaffer EA Am J Gastroenterol 1990 85 1398 1402 2220736 Severe hypoalbuminaemia in a systemic lupus erythematosus-like patient Gattorno M Buoncompagni A Barabino A Barbano G Loy A Toma P Picco P Marmont AM Eur J Pediatr 2002 161 84 86 10.1007/s00431-001-0868-6 11954757 Immunodeficiency disease and malignancy Waldmann TA Strober W Blaese RM Ann Intern Med 1972 77 605 628 4581908 Very late onset small intestinal B cell lymphoma associated with primary intestinal lymphangiectasia and diffuse cutaneous warts Bouhnik Y Etienney I Nemeth J Thevenot T Lavergne-Slove A Matuchansky C Gut 2000 47 296 300 1728014 10896925 10.1136/gut.47.2.296 Resolution of longstanding protein-losing enteropathy in a patient with intestinal lymphangiectasia after treatment for malignant lymphoma Broder S Callihan TR Jaffe ES DeVita VT Strober W Bartter FC Waldmann TA Gastroenterology 1981 80 166 168 7450403 Remission of malabsorption in congenital intestinal lymphangiectasia following chemotherapy for lymphoma Shpilberg O Shimon I Bujanover Y Ben-Bassat I Leuk Lymphoma 1993 11 147 148 10.3109/10428199309054743 8220148 Remission of protein-losing enteropathy after nodal lymphoma treatment in a patient with primary intestinal lymphangiectasia Laharie D Degenne V Laharie H Cazorla S Belleannee G Couzigou P Amouretti M Eur J Gastroenterol Hepatol 2005 17 1417 1419 10.1097/00042737-200512000-00024 16292099 Malignant lymphoma and extensive viral wart formation in a patient with intestinal lymphangiectasia and lymphocyte depletion Ward M Le Roux A Small WP Sircus W Postgrad Med J 1977 53 753 757 604991 Aggressive bowel lymphoma in a patient with intestinal lymphangiectasia and widespread viral warts Guma J Rubio J Masip C Alvaro T Borras JL Ann Oncol 1998 9 1355 1356 10.1023/A:1008496900822 9932170 Group G streptococcal empyema complicating primary intestinal lymphangiectasia Hallevy C Sperber AD Almog Y J Clin Gastroenterol 2003 37 270 10.1097/00004836-200309000-00015 12960729 Primary gastrointestinal lymphangiectasia presenting as cryptococcal meningitis Cole SL Ledford DK Lockey RF Daas A Kooper J Ann Allergy Asthma Immunol 2007 98 490 492 17521035 Gelatinous transformation of the bone marrow: an uncommon manifestation of intestinal lymphangiectasia (Waldmann's disease) Marie I Lévesque H Héron F Courtois H Callat MP Am J Med 1999 107 99 100 10.1016/S0002-9343(99)00035-2 10403358 Low fat diet in intestinal lymphangiectasia: its effect on albumin metabolism Jeffries GH Champan A Sleisenger MH N Engl J Med 1964 270 761 766 14107315 Stable reversal of pathologic signs of primitive intestinal lymphangiectasia with a hypolipidic, MCT-enriched diet Alfano V Tritto G Alfonsi L Cella A Pasanisi F Contaldo F Nutrition 2000 16 303 304 10.1016/S0899-9007(00)00223-9 10758368 Enteral nutrition as a primary therapy for intestinal lymphangiectasia: value of elemental diet and polymeric diet compared with total parenteral nutrition Aoyagi K Iida M Matsumoto T Sakisaka S Dig Dis Sci 2005 50 1467 1470 10.1007/s10620-005-2863-7 16110837 Intestinal lymphangiectasia markedly improved with antiplasmin therapy Mine K Matsubayashi S Nakai Y Nakagawa T Gastroenterology 1989 96 1596 1599 2714582 Primary intestinal and thoracic lymphangiectasia: a response to antiplasmin therapy MacLean JE Cohen E Weinstein M Pediatrics 2002 109 1177 1180 10.1542/peds.109.6.1177 12042562 Octreotide in the treatment of intestinal lymphangiectasia Ballinger AB Farthing MJ Eur J Gastroenterol Hepatol 1998 10 699 702 9744700 Primary intestinal lymphangiectasia successfully treated with octreotide Kuroiwa G Takayama T Sato Y Takahashi Y Fujita T Nobuoka A Kukitsu T Kato J Sakamaki S Niitsu Y J Gastroenterol 2001 36 129 132 10.1007/s005350170142 11227670 Type I intestinal lymphangiectasia treated successfully with slow-release octreotide Klingenberg RD Homann N Ludwig D Dig Dis Sci 2003 48 1506 1509 10.1023/A:1024707605493 12924644 Somatostatin Reichlin S N Engl J Med 1983 309 1495 1501 6139753 Effect of somatostatin on the flow rate and triglyceride levels of thoracic duct lymph in normal and vagotomized dogs Nakabayashi H Sagara H Usukura N Yoshimitsu K Imamura T Seta T Diabetes 1981 30 440 445 6112179 Protein-losing enteropathy and malabsorption in regional enteritis: cure by limited ileal resection Warshaw AL Waldmann TA Laster L Ann Surg 1973 178 578 580 1355735 4748296 10.1097/00000658-197311000-00004 Surgical resection of duodenal lymphangiectasia: a case report Chen CP Chao Y Li CP Lo WC Wu CW Tsay SH Lee RC Chang FY World J Gastroenterol 2003 9 2880 2882 14669360 Corticosteroid-responsive intestinal lymphangiectasia secondary to an inflammatory process Fleisher TA Strober W Muchmore AV Broder S Krawitt EL Waldmann TA N Engl J Med 1979 300 605 606 763272 Lymphoedema Framework: Best practice for the management of lymphoedema. International consensus London: MEP Ltd 2006