eMedicine Specialties > Gastroenterology > Intestine

Intestinal Lymphangiectasia

Anthony Martin, MD, Assistant Professor, Department of Medicine, Division of Gastroenterology, University of Louisville School of Medicine
Richard Wright, MD, Professor and Chief, Department of Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine

Updated: Nov 9, 2009

Introduction

Background

Traditionally, protein-losing gastroenteropathies have been classified into 3 groups (depending on the mechanism of their etiology) that include the following: (1) those causing mucosal damage leading to increased permeability to protein (usually not involving mucosal ulcerations), (2) those with mucosal erosions and/or ulcerations, and (3) those in which protein loss is secondary to mechanical lymphatic obstruction.

While a more detailed discussion on Protein-Losing Enteropathy is presented in another article, this article specifically addresses intestinal lymphangiectasia.

Pathophysiology

Intestinal lymphangiectasia is a disease characterized by hypoproteinemia, edema, and lymphocytopenia, resulting from dilatation of intestinal lymphatics and loss of lymph fluid into the gastrointestinal (GI) tract.¹ This leads to immunologic abnormalities, including hypogammaglobulinemia, anergy, and impaired allograft rejection. In addition to the loss of other serum components (eg, lipids), iron and certain trace metals may also be affected.²

Frequency

United States

Frequency in the United States and internationally is unknown.

Mortality/Morbidity

Morbidity is related to the pathophysiology of this disease. Edema and diarrhea are predominant clinical features; however, the following negative sequelae are also observed:

• Lymphocytopenia, hypogammaglobulinemia
• Hypoalbuminemia, hypocalcemia, trace metal deficiency
• Chylous pleural effusions, ascites (Chylous ascites and transudative ascites are reported.)

Race

No racial predilection exists.

Sex

The male-to-female ratio is 3:2.

Age

Intestinal lymphangiectasia can be primary (ie, congenital), in which case it affects children and young adults (mean age of onset, 11 y). The diagnosis in these cases often occurs during the first decade of life, with the first manifestations being persistent diarrhea and peripheral edema. This condition can also be secondary to other disease states, thus affecting older adults. In a series from Japan, the average age at onset was 22.9 years.

Clinical

History

• Patients usually present in childhood with edema and nonbloody diarrhea. Edema may be unilateral or bilateral, depending on the site of the lesion. Edema in primary intestinal lymphangiectasia is usually bilateral, while the secondary type often manifests as unilateral edema and is caused by various neoplastic, infiltrative, and inflammatory lesions affecting one side of the body.
• Frequently, steatorrhea, malabsorption, lymphocytopenia, and hypogammaglobulinemia are present.
• Ascites (often chylous ascites) and chylous pleural effusions are also reported in patients with long-standing lymphangiectasia.
• If the onset of disease occurs during the early part of the first decade of life, growth retardation usually ensues.
• Despite hypogammaglobulinemia, opportunistic infections rarely occur, although lymphocytopenia predisposes patients to abnormal cellular immunities, including homograft rejection and cutaneous anergy.

Physical

• Primary intestinal lymphangiectasia²
  • Peripheral edema is noted on physical examination in patients with primary intestinal lymphangiectasia.
  • Macular edema on funduscopic examination has been reported and is a cause of reversible blindness. Secondary lymphangiectasia may involve multiple physical findings, depending on the etiology.
• Pachydermoperiostosis has been associated with protein-losing enteropathy due to intestinal lymphangiectasia. Pachydermoperiostosis is a rare hereditary disease characterized by clubbing of the fingers, periostosis, and skin changes.

Causes

• Abdominal or retroperitoneal carcinoma
• Lymphoma
• Cardiac diseases
  • Constrictive pericarditis
  • Congestive heart syndrome
• Crohn disease
• Mesenteric tuberculosis
• Sarcoidosis
• Whipple disease
• Chronic pancreatitis
• Scleroderma
• Celiac disease
• Systemic lupus erythematosus (SLE)
• Retroperitoneal fibrosis
• Intestinal endometriosis
• Sclerosing mesenteritis
• Lymphenteric fistula

Differential Diagnoses

Workup

Laboratory Studies

• Hypoproteinemia: The most common laboratory finding is hypoproteinemia. Hypoalbuminemia is most prominent, and lymphocytopenia and hypogammaglobulinemia (eg, immunoglobulin A [IgA], immunoglobulin G [IgG], immunoglobulin M [IgM]) are also prominent. Cholesterol levels are not usually elevated.
• Alpha1-antitrypsin
  • In random dry stools, alpha1-antitrypsin has been used to indirectly measure protein leakage in the GI tract. Alpha1-antitrypsin is negligibly broken down by intestinal proteases and, thus, is excreted in the stool intact. While measurement of stool alpha1-antitrypsin may serve as a good screening examination for protein loss, several studies show poor correlation between the value of alpha1-antitrypsin in the stool and its clearance measurement. In part, this is because of increased degradation of alpha1-antitrypsin in different milieus. For example, the breakdown of alpha1-antitrypsin is higher in environments where the pH level is less than 3, as in the stomach or small bowel in hyperacidity states.
  • The most specific test for protein loss in the GI tract is direct measurement of alpha1-antitrypsin clearance from plasma. Values greater than 24 cc/d in patients without diarrhea (diarrhea increases alpha1-antitrypsin clearance) and greater than 56 cc/d in those with diarrhea indicate protein loss in the GI tract. GI bleeding has also been shown to increase alpha1-antitrypsin clearance as a result of whole blood loss.

Imaging Studies

• Double-contrast radiographs of the small bowel may be helpful because they may show thickened folds due to intestinal edema from hypoproteinemia, nodular protrusions, and absence of mucosal ulcerations.
• Ultrasound and CT scans are also useful in identifying dilated intestinal loops, regular and diffuse thickening of the intestinal walls, plical hypertrophy, and mesenteric edema. CT scans may help show circumferential thickening of the small bowel wall with low attenuation (<30 H).

Procedures

• Endoscopy
  • Repeatedly, the role of endoscopy has been proven useful. Small bowel enteroscopy not only helps detect mucosal changes suggestive of the disease but also allows acquisition of histologic samples to establish a diagnosis.³
  • White villi and/or spots (dilated lacteals), white nodules, and submucosal elevations are observed.
  • Xanthomatous plaques are often visualized.
•  Capsule endoscopy has also been used to help identify the characteristic changes not reachable with standard endoscopy. 
• Jejunal biopsy
  • This procedure establishes a definitive diagnosis and shows dilation of mucosal and submucosal lymphatic channels.
  • To increase the diagnostic yield, large biopsy forceps should be used when available. In addition, because of the patchy involvement of the small bowel, obtaining multiple biopsy samples from different areas is recommended.

Histologic Findings

Intestinal biopsy results reveal the characteristic dilatation of the lymph vessels of the mucosa and submucosa without any evidence for inflammation.

Treatment

Medical Care

Treatment of patients with primary intestinal lymphangiectasia involves control of symptoms with the use of dietary, pharmaceutical, and behavioral modifications. These include the following:

• Dietary modifications include a low-fat diet and substitution of long-chain fatty acids with medium-chain fatty acids.⁴ A logical step might be to decrease the amount of salt intake, although this has not been proven to decrease edema.
• Medications that may be used include over-the-counter remedies (eg, bulking agents, drugs to control diarrhea). Treatment of secondary causes of lymphangiectasia target the underlying disease. In several reports, octreotide has demonstrated efficacy in refractory cases. A case refractory to octreotide and nutritional manipulations has been successfully treated with tranexamic acid. (This patient presented with refractory anemia due to continued GI blood loss.)
• Treatment of patients with secondary causes of intestinal lymphangiectasia involves management of the underlying disease.

Surgical Care

No role for surgery is evident for patients with primary intestinal lymphangiectasia; however, multiple causes of secondary intestinal lymphangiectasia can be addressed surgically, as follows:

• A gastrectomy improves protein loss caused by giant hypertrophic gastritis (ie, Ménétrier disease).
• Correction of a lymphenteric fistula should eliminate protein loss.
• A pericardiectomy for severe symptomatic constrictive pericarditis should decrease marked protein loss through the GI tract.
• Localized intestinal lymphangiectasia may be treated with surgical resection.⁵

Consultations

Whenever suspicion for protein-losing gastroenteropathy develops, refer the patient to a gastroenterologist.

Diet

Modify the patient's diet to reduce intake of long-chain fatty acids, substituting short-chain and medium-chain fatty acids.² The rationale for this is based on the following 2 principles:

• First, long-chain fatty acids lead to chylomicrons, obstructing lymphatics and increasing lymphatic pressure and lymphocyte loss.
• Second, medium-chain fatty acids are thought to be more water-soluble and, thus, absorbed through portal venous channels rather than through lymphatics.
• In a literature review, Desai et al investigated the efficacy of a medium-chain fatty acid diet in the treatment of primary intestinal lymphangiectasia.⁴ The authors compared the outcomes from 27 patients who were treated with medium-chain fatty acids with those from 28 patients who were not. In the fatty acid group, complete symptom resolution occurred in 17 patients (63%), compared with 10 patients (35.7%) in the other group. In addition, there was 1 death (3.7%) in the fatty acid group, while the second group experienced 5 (17.8%) deaths. The authors concluded that a medium-chain fatty acid diet is a valid option for the treatment of pediatric patients.

Activity

No activity restrictions are suggested. Encourage patients to maintain an active lifestyle as much as their disease allows.

Medication

Two case reports document the use of octreotide to control symptoms in refractory cases. In the first report, octreotide improved symptoms, findings on scintigraphy and endoscopy, and histology of the duodenum in a patient with intestinal lymphangiectasia. The second report showed that octreotide at 200 mcg bid resulted in reduction in enteric protein loss from 16% to 4.1% in 5 days, and albumin infusions, which were necessary to maintain an acceptable level, were eliminated in a single patient with intestinal lymphangiectasia. Additional cases have been reported with the successful use of octreotide, including the long-acting formulation (LAR).

Somatostatin analogs

Used to inhibit effects of GI hormones.

Octreotide (Sandostatin)

Acts in a similar fashion to the hormone somatostatin. Very potent inhibitor of growth hormone, glucagon, and insulin. Markedly decreases splanchnic blood flow and suppresses LH response to GnRH. Has a strong suppressive effect of GI hormones, including gastrin, motilin, secretin, and pancreatic polypeptide. Because of its suppressive effects on GI tract, octreotide is used in a variety of GI diseases, such as VIPoma and carcinoid tumors.

Dosing

Adult

50 mcg bid/tid usually administered SC (IV use also acceptable); titration to higher doses is frequently required

Pediatric

Not established; 1-10 mcg/kg SC recommended and usually tolerated well

Interactions

May reduce effects of cyclosporine; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dosage adjustments

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects are primarily related to altered GI motility and include nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; because of alteration in counter-regulatory hormones (ie, insulin, glucagon, GH), hypo- or hyperglycemia may be observed; bradycardia, cardiac conduction abnormalities, and arrhythmias have been reported; because of inhibition of TSH secretion, hypothyroidism may also occur; exercise caution in patients with renal impairment; cholelithiasis may occur

Antihemophilic agents

Agents like tranexamic acid can competitively inhibit activation of plasminogen to plasmin, diminishing bleeding.

Tranexamic acid (Cyklokapron)

Inhibits plasminogen activators, interfering with fibrinolysis.

Dosing

Adult

25 mg/kg PO tid/qid (dosage recommended for tooth extraction); dose used in case reports for lymphangiectasia 1-2 g PO tid

Pediatric

Administer as in adults

Interactions

Concomitant administration with thrombolytics may reduce efficacy of both drugs

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal impairment, history of thromboembolic disease, or if DIC

Follow-up

Further Outpatient Care

• Although patients are encouraged to maintain a physically active lifestyle, adjustments must be made to minimize peripheral edema.
  • For most patients, postural drainage by elevating the affected extremities above the level of the heart is easy to promote compliance.
  • Suggestions to increase compliance may include the use of recliners in the evenings and the use of elastic support stockings to decrease the potential for cellulitis and lymphangitis.
• Theoretically, limiting the patient's salt intake could decrease edema, although no reports on this subject are known. In addition, the effects are probably not significant because diuretics do not have an important role in controlling edema in patients with primary intestinal lymphangiectasia.

Inpatient & Outpatient Medications

• No maintenance medications for primary intestinal lymphangiectasia are indicated, other than the use of octreotide.
• Patients with secondary intestinal lymphangiectasia should continue the maintenance medications of their primary underlying disease.

Complications

• Primary intestinal lymphangiectasia is associated with an increased risk of lymphoma.
• Fibrotic entrapment of the small bowel is reported in patients with congenital intestinal lymphangiectasia.
• Oral manifestations include gingivitis caused by poor lymphocytic function and enamel defects caused by poor calcium absorption.

Prognosis

• For patients with primary intestinal lymphangiectasia with an onset early in life (usually during the first decade), growth retardation usually occurs.
• The prognosis of patients with secondary intestinal lymphangiectasia depends on the extent and severity of the underlying disease.
• The clinical course is highly variable with about 23% of patients showing improvement and 64% remaining unchanged; the mortality rate is 13%.

Miscellaneous

Medicolegal Pitfalls

• Establishing the diagnosis as early as possible helps the clinician to offer the best treatment possible and to avoid serious consequences.
  • While treatment of primary intestinal lymphangiectasia is limited, especially in young children (growth retardation inevitably occurs), reaching an early diagnosis maximizes the chance of avoiding or minimizing the degree of growth retardation.
  • Identifying the causes of secondary lymphangiectasia is of paramount importance not only to eliminate the symptoms but also to stop, delay, or even reverse the progression of the primary disease and its deleterious sequelae.

References

1. Vignes S, Carcelain G. Increased surface receptor Fas (CD95) levels on CD4+ lymphocytes in patients with primary intestinal lymphangiectasia. Scand J Gastroenterol. 2009;44(2):252-6. [Medline].

2. Vignes S, Bellanger J. Primary intestinal lymphangiectasia (Waldmann's disease). Orphanet J Rare Dis. Feb 22 2008;3:5. [Medline].

3. Safatle-Ribeiro AV, Iriya K, Couto DS, et al. Secondary lymphangiectasia of the small bowel: utility of double balloon enteroscopy for diagnosis and management. Dig Dis. 2008;26(4):383-6. [Medline].

4. Desai AP, Guvenc BH, Carachi R. Evidence for medium chain triglycerides in the treatment of primary intestinal lymphangiectasia. Eur J Pediatr Surg. Aug 2009;19(4):241-5. [Medline].

5. Kim NR, Lee SK, Suh YL. Primary intestinal lymphangiectasia successfully treated by segmental resections of small bowel. J Pediatr Surg. Oct 2009;44(10):e13-7. [Medline].

6. Aoyagi K, Iida M, Yao T, Matsui T, Okada M, Fujishima M. Intestinal lymphangiectasia: value of double-contrast radiographic study. Clin Radiol. Nov 1994;49(11):814-9. [Medline].

7. Aoyagi K, Iida M, Yao T, Matsui T, Okada M, Oh K. Characteristic endoscopic features of intestinal lymphangiectasia: correlation with histological findings. Hepatogastroenterology. Jan-Feb 1997;44(13):133-8. [Medline].

8. Ballinger AB, Farthing MJ. Octreotide in the treatment of intestinal lymphangiectasia. Eur J Gastroenterol Hepatol. Aug 1998;10(8):699-702. [Medline].

9. Bouhnik Y, Etienney I, Nemeth J, Thevenot T, Lavergne-Slove A, Matuchansky C. Very late onset small intestinal B cell lymphoma associated with primary intestinal lymphangiectasia and diffuse cutaneous warts. Gut. Aug 2000;47(2):296-300. [Medline].

10. Filik L, Oguz P, Koksal A, Koklu S, Sahin B. A case with intestinal lymphangiectasia successfully treated with slow-release octreotide. Dig Liver Dis. Oct 2004;36(10):687-90. [Medline].

11. Fuss IJ, Strober W, Cuccherini BA, Pearlstein GR, Bossuyt X, Brown M, et al. Intestinal lymphangiectasia, a disease characterized by selective loss of naive CD45RA+ lymphocytes into the gastrointestinal tract. Eur J Immunol. Dec 1998;28(12):4275-85. [Medline].

12. Kuroiwa G, Takayama T, Sato Y, Takahashi Y, Fujita T, Nobuoka A, et al. Primary intestinal lymphangiectasia successfully treated with octreotide. J Gastroenterol. Feb 2001;36(2):129-32. [Medline].

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17. Rust C, Pratschke E, Hartl W, Kessler M, Weibecke B, Sauerbruch T. Fibrotic entrapment of the small bowel in congenital intestinal lymphangiectasia. Am J Gastroenterol. Oct 1998;93(10):1980-3. [Medline].

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19. Sethuraman G, Malhotra AK, Khaitan BK, Sharma VK, Kumar R, Makharia GK, et al. Familial pachydermoperiostosis in association with protein-losing enteropathy. Clin Exp Dermatol. Jul 2006;31(4):531-4. [Medline].

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Keywords

intestinal lymphangiectasia, lymphangiectasia, protein-losing enteropathy, hypoproteinemia, medium-chain triglycerides, medium-chain fatty acids, medium-chain triglyceride, primary intestinal lymphangiectasia, congenital intestinal lymphangiectasia, Milroy disease, protein-losing gastroenteropathies, lymphocytopenia, hypogammaglobulinemia

Contributor Information and Disclosures

Author

Anthony Martin, MD, Assistant Professor, Department of Medicine, Division of Gastroenterology, University of Louisville School of Medicine
Anthony Martin, MD is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Association of Military Surgeons of the US, Kentucky Medical Association, and Special Operations Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Richard Wright, MD, Professor and Chief, Department of Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine
Richard Wright, MD is a member of the following medical societies: American College of Physician Executives, American College of Physicians, American Gastroenterological Association, American Medical Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Medical Editor

Rajeev Vasudeva, MD, FACG, Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine
Rajeev Vasudeva, MD, FACG is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Columbia Medical Society, South Carolina Gastroenterology Association, and South Carolina Medical Association
Disclosure: Pricara Honoraria Speaking and teaching; UCB Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

We wish to thank Raoul Joubran, MD, for his previous contributions to this article.

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