Pediatrics

Intestinal Lymphangiectasia

Overview: What every practitioner needs to know

Are you sure your patient has intestinal lymphangiectasia? What are the typical findings for this disease?

Intestinal lymphangiectasia, also known as Protein Losing Enteropathy (PLE), is characterized by an abnormal dilatation of the lymphatic structures in the mucosa, submucosa or subserosa of the small intestine leading to an excessive loss of serum proteins and lymphocytes into the gastrointestinal tract. The disease occurs either as an idiopathic primary condition known as Waldmann’s disease or it may be secondary to lymphatic obstruction or elevated lymphatic pressure.

Typical findings include peripheral edema, variable intestinal symptoms such as diarrhea, abdominal pain, vomiting and nausea. Failure to thrive may be prominent in the primary form of intestinal lymphangiectasia. The mean age of presentation is 11 years in the primary form of lymphangiectasia but symptoms may begin at any time between infancy and childhood.

Symmetrical pitting edema of the lower extremities is secondary to severe hypoalbuminemia from the massive loss of albumin in the GI tract. In some cases the lymphangiectasia is associated with lymphatic abnormalities elsewhere in the body. In these cases, lymphedema may be non-symmetrical and more fibrous, fixed, and non-pitting in character, and may involve the extremities or other body part such as the breast.

Gastrointestinal manifestations are variable in both frequency and severity and include nausea, vomiting, feeding intolerance, abdominal pain, diarrhea and occasionally frank steatorrhea. Growth failure secondary to malnutrition is common. Gastrointestinal bleeding has been reported as a consequence of ulcerated lymphangiectasia. Venous thrombosis with embolic events can occur as the result of intestinal loss of coagulation factors with antithrombin III depletion causing a hypercoagulable state.

Chylothorax or chylous ascites are seen in some cases of intestinal lymphangiectasia and must be differentiated from the pleural effusions and ascites caused by decreased intravascular oncotic pressure due to the hypoproteinemia.

Gathering a detailed patient history and conducting a physical examination is the first step in confirming diagnosis. Intestinal lymphangiectasia should be considered in patients with peripheral edema and hypoalbuminemia who do not have proteinuria. Clinical suspicion is increased in patients who have a condition known to be associated with lymphatic abnormalities (e.g., Turner syndrome or Noonan syndrome). Non-selective loss of protein into the intestines which results in both hypoalbuminemia and hypoglobulinemia are also suggestive.

Immunoglobulin and lymphocyte losses can potentially lead to immune deficiencies but this is seldom clinically a problem.

What other disease/condition shares some of these symptoms?

Other causes of gastrointestinal protein loss include idiopathic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis), milk protein allergy, eosinophilic gastroenteropathy, celiac disease, bacterial enteritides (salmonella, shigella, campylobacter, Ecoli and C difficile), intestinal lymphoma, hypertrophic gastritis (childhood Ménétrier’s disease), immunodeficiency diseases including HIV, vasculitides (lupus or Henoch-Schönlein purpura), radiation enteritis, intestinal polyposis syndromes and tropical sprue.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A low serum albumin, alone or together with a low serum globulin level, in the absence of proteinuria should raise suspicion for PLE.

PLE can be confirmed by the presence of an elevated fecal alpha-1-antitrypsin level in a random stool sample.

A CBC showing lymphopenia may suggest loss of lymphocytes. In association with protein losing enteropathy, this is characteristic of loss of lymphatic fluid from the intestinal tract.

The definitive diagnosis of intestinal lymphangiectasia requires small intestinal biopsy and histological examination of the tissue specimen. Characteristic features include wide villi with dilated lacteals in the mucosa and enlarged submucosal lymphatics in the absence of an inflammatory cell infiltrate or signs of mucosal atrophy.

Would imaging studies be helpful? If so, which ones?

Barium contrast studies may demonstrate thickening of the small intestinal folds or a disorganized spicular configuration with punctate lucencies. Dilution of the barium and dilatation of the bowel lumen may occur. These are non specific findings and can also be seen in other malabsorption syndromes.

Abdominal computed tomography (CT) scan with oral and intravenous contrast may show diffuse or segmental nodular thickening of the small bowel mucosa associated with dilatation of the small bowel. These findings are not specific for lymphangiectasia.

Upper GI endoscopy or wireless capsule endoscopy may be helpful in cases where the lymphangiectasia is segmental as opposed to being diffuse. The presence of dilated lymphatics is suspected when areas of mucosa have edema with scattered white spots, white tipped villi, and a chyle-like substance covering the mucosa.

Lymphangiography may reveal various abnormal patterns but is technically difficult to perform and hence seldom used.

If you are able to confirm that the patient has intestinal lymphangiectasia, what treatment should be initiated?

Treatment of primary intestinal lymphangiectasia mainly involves dietary manipulation. In rare cases where the disorder is localized as opposed to diffused, surgical resection of the affected segment of small intestine may be curative. Pharmacological agents have been used with reported improvement in a few instances.

A low fat diet supplemented with medium chain triglycerides (MCT’s) is the mainstay of therapy to prevent distension and subsequent rupture of the intestinal lymphatics. The MCT’s directly enter the portal venous system and hence bypass the intestinal lacteal system. Some patients require supplemental calcium salts and water soluble forms of fat-soluble vitamins. Lifelong treatment through dietary modification is usually necessary although spontaneous remission has occurred in rare cases.

There is a long-term risk for deficiencies of other nutrients including essential fatty acids, fat soluble vitamins and minerals which may need supplemental replacement. In severe and refractory cases there is risk of serious malnutrition and parenteral nutrition may be required.

Octreotide at a dose of 20-200 µg given subcutaneously twice daily has been used with success in some cases. Slow release octreotide LAR 20-30 mg by intramuscular injection every 4 weeks has also been used with some success. Antiplasmin or trans-4-aminothylcyclohexamine carboxylic acid (tranexamic acid), an antifibrinolytic hemostatic agent used in hemophilia, has been used in some cases who were unresponsive to treatment with diet or octreotide.

Surgical resection of portions of small intestine in cases of segmental lymphangiectasia has been used with success. Small bowel transplantation has been proposed for severe refractory cases associated with complications.

Treatment of lymphangiectasia that is secondary to elevated lymphatic pressure involves correction of the underlying disorder.

What are the adverse effects associated with each treatment option?

Adverse effects of MCT Oil include sedation, narcosis, hepatic encephalopathy in patients with cirrhosis ketosis, nausea, vomiting, abdominal pain, diarrhea, or borborygmi.

Octreotide-based treatment have a number of adverse effects associated with its use that include constitutional symptoms, cardiovascular, central nervous system, endocrine system, and gastrointestinal issues.

General constitutional symptoms may include fatigue, malaise, fever, dizziness, or pruritus alopecia.

Cardiovascular effects include sinus bradycardia, chest pain, hypertension, or arrhythmia. Central nervous system side effects include headache, anxiety, confusion, hypoesthesia, insomnia, or dizziness.

Endocrine system problems may include hyperglycemia or hypothyroidism. Finally, gastrointestinal symptoms that might arise include abdominal pain, nausea, diarrhea, flatulence, cholelithiasis, biliary sludge, constipation, vomiting, biliary duct dilatation, anorexia, tenesmus, dyspepsia, steatorrhea, feces discoloration. Neuromuscular side effects may include back pain, arthropathy and myalgia.

Tranexamic acid treatments may cause hypersensitivity reactions, venous and arterial thrombosis or thromboembolism, ophthalmic toxicity, color vision change, visual loss, or conjunctivitis.

What are the possible outcomes of intestinal lymphangiectasia?

Intestinal lymphangiectasia is a chronic and debilitating condition. Skin infections and ulcerations may occur as a result of the lymphedema. Those with ascites are at risk for spontaneous bacterial peritonitis. Pain and difficulty with ambulation may occur with severe edema of the lower extremities. Patients are at risk for venous thromboses and thrombotic emboli. In rare cases spontaneous remission has been reported.

What causes this disease and how frequent is it?

The prevalence of primary intestinal lymphangiectasia is unknown but the condition is relatively rare. Secondary forms are probably more common but go unrecognized as the features are overshadowed by the findings related to the underlying condition.

Little is known about the genetics of primary intestinal lymphangiectasia. Most cases are sporadic although in some cases there is clustering in families suggesting a genetic component. Intestinal lymphangiectasia does occur in some well known genetic disorders such as Turner and Noonan syndrome but it is unclear whether the relationship is coincidental.

How do these pathogens/genes/exposures cause the disease?

Abnormalities in the expression of regulatory molecules for lymphangiogenesis in the duodenal mucosa of idiopathic intestinal lymphangiectasia have been identified. Vascular endothelial growth factor receptor 3 (VEGFR3) and lymphatic vessel endothelial hyaluronan receptor1 (LYVE-1) levels are increased on the mucosal surface corresponding to widely dilated lymphatic vessels while they are decreased in the deeper mucosal layers. VEGFR3 mRNA expression was significantly increased in primary lymphangiectasia while expression of VEGF-C and –D mRNA was significantly suppressed compared to controls. Precisely how these findings are involved in the production of lymphangiectasia is not known.

What complications might you expect from the disease or treatment of the disease?

Intestinal lymphangiectasia can lead to several complications including combined B- and T-cell immunodeficiency induced by the lymphopenia which can increase the risk for infections such as pneumococcal empyema, cryptococcal meningitis or cytomegalovirus.

Malignant conditions such as lymphoma, mesenteric angiosarcoma and neuroblastoma have also been associated to intestinal lymphangiectasia.

A hypercoagulable state due to antithrombin deficiency leading to venous thromboses and thromboembolic events has been described in some cases. Hypocalcemic seizures has been described in young infants and newborns due to the vitamin D deficiency associated with lymphangiectasia.

Acute severe gastrointestinal bleeding has been reported from localized mucosal ulceration in intestinal lymphangiectasia.

Necrolytic migratory edema presenting as annular lesions with peripheral scaling has been reported in adults with intestinal lymphangiectasia. This condition improved with the institution of a MCT enriched diet.

What is the evidence?

Clinical findings in IL:

Moller, A, Kalhoff, H, Reuter, T. "Congenital intestinal lymphangiectasia: a rare differential diagnosis in hypoproteinemia in infants". Klin Padiatr. vol. 218. 2006. pp. 224-5.

(Case report and review of Intestinal lymphagiectasia.)

Vardy, PA, Lebenthal, E, Shwachman, H. "Intestinal lymphangiectasia: a reappraisal". Pediatrics. vol. 55. 1975. pp. 842-51.

(A case series reviewing the clinical findings and histologic features of Intestinal lymphangiectasia.)

Boursier, V, Vignes, S. "Limb lymphedema as a first manifestation of primary intestinal lymphangiectasia (Waldmann's disease)". J Mal Vasc. vol. 29. 2004. pp. 103-6.

(Case report and review.)

White, SM. "Operative ascitic drainage in a patient with primary intestinal lymphangiectasia". Anaesthesia. vol. 58. 2003. pp. 396-7.

(Case report and review of surgical approach to therapy.)

Stovicek, J, Keil, R, Palova, S. "Intestinal lymphangiectasia: a rare cause of gastrointestinal bleeding?". Scand J Gastroenterol. vol. 42. 2007. pp. 418.

(Case report and review.)

Lom, J, Dhere, T, Obideen, K. "Intestinal lymphangiectasia causing massive gastrointestinal bleed". J Clin Gastroenterol. vol. 44. 2010. pp. 74-5.

(A case of a massive gastrointestinal bleed caused by IL localized to the jejunum by video capsule endoscopy and subsequently treated with surgical resection.)

Baichi, MM, Arifuddin, RM, Mantry, PS. "Acute gastrointestinal bleeding from focal duodenal lymphangiectasia". Scand J Gastroenterol. vol. 42. 2007. pp. 1269-70.

(Case report and review.)

Herfarth, H, Hofstadter, F, Feuerbach, S. "A case of recurrent gastrointestinal bleeding and protein-losing gastroenteropathy". Nat Clin Pract Gastroenterol Hepatol. vol. 4. 2007. pp. 288-93.

(Case report and review.)

Amtage, F, Marouf, W, Hetzel, A. "Acquired prothrombotic state due to protein-losing enteropathy as a rare cause for ischemic stroke?". Eur J Neurol. vol. 14. 2007. pp. e7-e8.

(Case report and review.)

Calabrese, C, Pironi, L, Di, FG. "Capsule endoscopy revealing small-intestinal lymphangiectasia and GI stromal tumor polyps in neurofibromatosis type 1". Gastrointest Endosc. vol. 64. 2006. pp. 130-1.

(Case report.)

Forzano, F, Faravelli, F, Loy, A. "Severe lymphedema, intestinal lymphangiectasia, seizures and mild mental retardation: further case of Hennekam syndrome with a severe phenotype". Am J Med Genet. vol. 111. 2002. pp. 68-70.

(Case report and review.)

Mazzie, JP, Maslin, PI, Moy, L. "Congenital intestinal lymphangiectasia: CT demonstration in a young child". Clin Imaging. vol. 27. 2003. pp. 330-2.

(Case report and review.)

Pathophysiology:

Waldmann, TA, Steinfeld, JL, Dutcher, TF. "The role of the gastrointestinal system in "idiopathic hypo-proteinemia"". Gastroenterology. vol. 41. 1961. pp. 197-207.

(A general and historical review of the mechanisms whereby gastrointestinal protein loss occurs and leads to hypoproteinemia.)

Macdonald, J, Porter, V, Scott, NW. "Small bowel lymphangiectasia and angiodysplasia: a positive association; novel clinical marker or shared pathophysiology?". J Clin Gastroenterol. vol. 44. 2010. pp. 610-4.

(Pathophysiology of intestinal lymphangiectasia.)

Hokari, R, Kitagawa, N, Watanabe, C. "Changes in regulatory molecules for lymphangiogenesis in intestinal lymphangiectasia with enteric protein loss". J Gastroenterol Hepatol. vol. 23. 2008. pp. e88-e95.

(Pathophysiology.)

Therapy for IL:

Koo, NH, Lee, HJ, Jung, JW. "Primary intestinal lymphangiectasia: a response to medium-chain triglyceride formula". Acta Paediatr. vol. 94. 2005. pp. 982-3.

(Nutritional therapy for IL.)

Biselli, M, Andreone, P, Gramenzi, A. "Acquired intestinal lymphangiectasia successfully treated with a low-fat and medium-chain triacylglycerol-enriched diet in a patient with liver transplantation". Eur J Gastroenterol Hepatol. vol. 18. 2006. pp. 561-4.

(Nutritional therapy for IL.)

Kuroiwa, G, Takayama, T, Sato, Y. "Primary intestinal lymphangiectasia successfully treated with octreotide". J Gastroenterol. vol. 36. 2001. pp. 129-32.

(Treatment of IL.)

Ballinger, AB, Farthing, MJ. "Octreotide in the treatment of intestinal lymphangiectasia". Eur J Gastroenterol Hepatol. vol. 10. 1998. pp. 699-702.

(Treatment of IL.)

Klingenberg, RD, Homann, N, Ludwig, D. "Type I intestinal lymphangiectasia treated successfully with slow-release octreotide". Dig Dis Sci. vol. 48. 2003. pp. 1506-9.

(Treatment of IL.)

Lee, HL, Han, DS, Kim, JB. "Successful treatment of protein-losing enteropathy induced by intestinal lymphangiectasia in a liver cirrhosis patient with octreotide: a case report". J Korean Med Sci. vol. 19. 2004. pp. 466-9.

(Treatment of IL.)

Balboa, A, Perello, A, Mearin, F. "Primary intestinal lymphangiectasia: effectiveness of treatment with slow-release octreotide". Med Clin (Barc ). vol. 123. 2004. pp. 319.

(Treatment of IL.)

MacLean, JE, Cohen, E, Weinstein, M. "Primary intestinal and thoracic lymphangiectasia: a response to antiplasmin therapy". Pediatrics. vol. 109. 2002. pp. 1177-80.

(Treatment of IL.)

Chen, CP, Chao, Y, Li, CP. "Surgical resection of duodenal lymphangiectasia: a case report". World J Gastroenterol. vol. 9. 2003. pp. 2880-2.

(Surgical management of IL.)

Kim, NR, Lee, SK, Suh, YL. "Primary intestinal lymphangiectasia successfully treated by segmental resections of small bowel". J Pediatr Surg. vol. 44. 2009. pp. e13-e17.

(Surgical management of IL.)

Campbell, DI, Beath, SV, Ville de, GJ. "Severe intestinal lymphangiectasia complicated by nephrotic syndrome treated by small bowel, liver, and kidney transplantation". J Pediatr Gastroenterol Nutr. vol. 36. 2003. pp. 278-82.

(Intestinal transplantation for IL.)

Infectious complications of IL:

Hallevy, C, Sperber, AD, Almog, Y. "Group G streptococcal empyema complicating primary intestinal lymphangiectasia". J Clin Gastroenterol. vol. 37. 2003. pp. 270.

Cole, SL, Ledford, DK, Lockey, RF. "Primary gastrointestinal lymphangiectasia presenting as cryptococcal meningitis". Ann Allergy Asthma Immunol. vol. 98. 2007. pp. 490-2.

Hoshina, T, Kusuhara, K, Saito, M. "Cytomegalovirus-associated protein-losing enteropathy resulting from lymphangiectasia in an immunocompetent child". Jpn J Infect Dis. vol. 62. 2009. pp. 236-8.

Non-infectious complications of IL:

Chera, R, Gupta, AA, Bailey, D. "Small intestinal B-cell lymphoma in a patient with lymphangiectasia secondary to abdominal lymphangioma". J Clin Oncol. vol. 26. 2008. pp. 675-8.

Castro, EC, Galambos, C, Shaw, PH. "Primary mesenteric angiosarcoma in a child with associated lymphangiectasia: a case report". Pediatr Dev Pathol. vol. 11. 2008. pp. 482-6.

Lu, YY, Wu, JF, Ni, YH. "Hypocalcemia and tetany caused by vitamin D deficiency in a child with intestinal lymphangiectasia". J Formos Med Assoc. vol. 108. 2009. pp. 814-8.

Baricault, S, Soubrane, JC, Courville, P. "Necrolytic migratory erythema in Waldmann's disease". Ann Dermatol Venereol. vol. 133. 2006. pp. 693-6.

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