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.
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. 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.
Frequency in the United States and internationally is unknown.
Morbidity is related to the pathophysiology of this disease. Edema and diarrhea are predominant clinical features; however, the following negative sequelae are also observed:
Hypoalbuminemia, hypocalcemia, trace metal deficiency
Chylous pleural effusions, ascites (Chylous ascites and transudative ascites are reported.)
No racial predilection exists.
The male-to-female ratio is 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, thus affecting older adults. In a series from Japan, the average age at onset was 22.9 years.
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.
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.
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.
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.
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).
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. }[5, 6]
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.
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.
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. 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.
Modify the patient's diet to reduce intake of long-chain fatty acids, substituting short-chain and medium-chain fatty acids. 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. 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.
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).
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.
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.