Intestinal lymphangiectasia is a rare protein-losing gastroenteropathy characterized by dilatation of the intestinal lymphatics and loss of lymph fluid into the gastrointestinal tract, leading to the development of hypoproteinemia, edema, lymphocytopenia, hypogammaglobinemia, and immunologic anomalies.[1]
Traditionally, protein-losing gastroenteropathies have been classified into three groups (depending on the mechanism of their etiology) that include the following[2] : (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.
Although a more detailed discussion on protein-losing enteropathy is presented in another article, this article specifically addresses intestinal lymphangiectasia.
Intestinal lymphangiectasia is a rare, benign disease characterized by hypoproteinemia, edema, and lymphocytopenia, resulting from focal or diffuse dilatation of intestinal mucosal, submucosal, and subserosal lymphatics and loss of lymph fluid into the gastrointestinal (GI) tract.[3, 4] 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.[4]
The United States and international frequency of intestinal lymphangiectasia is unknown.
Race-, sex-, and age-related demographics
No racial predilection exists. However, there is a male-to-female ratio of 3:2.
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, thereby affecting older adults.[1, 5] In a series from Japan, the average age at onset was 22.9 years.
The clinical course of intestinal lymphangiectasia is highly variable with about 23% of patients showing improvement and 64% remaining unchanged; the mortality rate is 13%.
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.
Morbidity/mortality
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.)
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.
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, whereas the secondary type often manifests as unilateral edema and is caused by various neoplastic, infiltrative, and inflammatory lesions affecting one side of the body.
If the onset of disease occurs during the early part of the first decade of life, growth retardation usually ensues.
Frequently, steatorrhea, malabsorption, lymphocytopenia, and hypogammaglobulinemia are present.
Despite hypogammaglobulinemia, opportunistic infections rarely occur, although lymphocytopenia predisposes patients to abnormal cellular immunities, including homograft rejection and cutaneous anergy.
Ascites (often chylous ascites) and chylous pleural effusions are also reported in patients with long-standing lymphangiectasia.
Peripheral edema is noted on physical examination in patients with primary intestinal lymphangiectasia.[6]
Macular edema on funduscopic examination has been reported and is a cause of reversible blindness.[7]
Pachydermoperiostosis has been associated with protein-losing enteropathy due to intestinal lymphangiectasia.[8] Pachydermoperiostosis is a rare hereditary disease characterized by clubbing of the fingers, periostosis, and skin changes.
Secondary lymphangiectasia
Secondary lymphangiectasia may involve multiple physical findings, depending on the etiology.
The most common laboratory finding in intestinal lymphangiectasia 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 levels
In random dry stools, levels of alpha1-antitrypsin has been used to indirectly measure protein leakage in the gastrointestinal (GI) tract. Alpha1-antitrypsin is negligibly broken down by intestinal proteases and, thus, is excreted intact in the stool. However, although measurement of stool alpha1-antitrypsin may serve as a good screening examination for protein loss, several studies have shown 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 mL/day in patients without diarrhea (diarrhea increases alpha1-antitrypsin clearance) and over 56 mL/day 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.
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.
Ultrasonography and computed tomography (CT) scanning 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).
Multidetector CT (MDCT) scanning after direct lympangiography appears to provide an accurate evaluation and diagnosis of primary intestinal lymphangiectasia. In a retrospective study of 55 affected patients, all of whom underwent MDCT after direct lymphangiography, investigators noted that MDCT identified intra-intestinal, extra-intestinal, and lymphatic vessel abnormalities, including different degrees of intestinal dilatation, small bowel wall thickening, ascites, mesenteric edema, mesenteric nodules, lumbar trunk and intestinal trunk reflux.[9]
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.[10, 11, 12]
White villi and/or spots (dilated lacteals), white nodules, and submucosal elevations are observed. Xanthomatous plaques are often visualized.
Capsule endoscopy
Capsule endoscopy has also been used to help identify the characteristic changes of intestinal lymphangiectasia not reachable with standard endoscopy.
Jejunal biopsy
Jejunal biopsy 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.
Treatment of patients with primary intestinal lymphangiectasia involves control of symptoms with the use of dietary, pharmaceutical, and behavioral modifications, such as the following:
Dietary modifications include a low-fat diet and substitution of long-chain fatty acids with medium-chain fatty acids.[13] A logical step might be to reduce 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.[14] In a case report of a 42-year-old man with primary intestinal lymphangiectasia, Troskot et al found that only octreotide provided therapeutic resolution.[15] Following the use of a slow-release form of octreotide, the patient had a partial remission. A case of intestinal lymphangiectasia refractory to octreotide and nutritional manipulations was successfully treated with tranexamic acid. (This patient presented with refractory anemia due to continued gastrointestinal [GI] blood loss.)
Pollack and colleagues reported a case of primary intestinal lymphangiectasia (PIL) in a female patient with tuberous sclerosis complex (TSC) and a TSC2 mutation in whom a trial of the mTOR inhibitor rapamycin was very effective.[16] There was improvement in her clinical symptoms of PIL as well as in abnormal laboratory values. The investigators concluded that these findings suggest that PIL is a rare manifestation of TSC, thereby justifying the use of mTOR inhibitors in future studies.[16] Tan et al also reported a patient in whom PIL was the first manifestation of TSC.[17]
Treatment of patients with secondary causes of intestinal lymphangiectasia involves management of the underlying disease.
Consultations
Whenever suspicion for protein-losing gastroenteropathy develops, refer the patient to a gastroenterologist.
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 gastrointestinal tract.
Localized intestinal lymphangiectasia may be treated with surgical resection.[18]
Modify the patient's diet to reduce the intake of long-chain fatty acids, substituting short-chain and medium-chain fatty acids.[4] The rationale for this is based on the following two principles:
Long-chain fatty acids lead to chylomicrons, obstructing lymphatics and increasing lymphatic pressure and lymphocyte loss.
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 in 27 patients compared to results of 28 control patients.[13] In the fatty acid group, complete symptom resolution occurred in 17 patients (63%), compared to 10 patients (35.7%) in the non-fatty acid group. In addition, there was 1 death (3.7%) in the fatty acid group, whereas 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.[13]
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.
No activity restrictions are suggested. Encourage patients to maintain an active lifestyle as much as their disease allows. However, 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.
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.
Two case reports documented 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.[19] The second report showed that octreotide at 200 mcg twice daily 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.[20]
Additional cases have been reported with the successful use of octreotide, including the long-acting formulation (LAR).[14, 21]
Clinical Context:
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.
Hisham Nazer, MBBCh, FRCP, DTM&H, Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, University of Jordan Faculty of Medicine, Jordan
Disclosure: Nothing to disclose.
Coauthor(s)
Dena Nazer, MD, FAAP, Assistant Professor of Pediatrics, Wayne State University School of Medicine; Chief, Child Protection Team, Children's Hospital of Michigan
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Burt Cagir, MD, FACS, Clinical Professor of Surgery, The Commonwealth Medical College; Director, General Surgery Residency Program, Robert Packer Hospital; Attending Surgeon, Robert Packer Hospital and Corning Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Rajeev Vasudeva, MD, Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine
Disclosure: Received honoraria from Pricara for speaking and teaching; Received consulting fee from UCB for consulting.
Acknowledgements
Raoul Joubran, MD Fellow, Department of Internal Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine
Disclosure: Nothing to disclose.
Anthony E Martin, MD Associate Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Fellowship Training Program Director, University of Louisville School of Medicine
Anthony E Martin, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, 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. 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
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