Intestinal Lymphangiectasia

Updated: Nov 21, 2023
Author: John W Birk, MD, FACG; Chief Editor: Burt Cagir, MD, FACS 

Overview

Background

Intestinal lymphangiectasia is a rare protein-losing gastroenteropathy characterized by impaired drainage of lymph from the small intestine, associated with dilatation of the intestinal lymphatic channels. This leads to inappropriate loss of lymph into the gastrointestinal (GI) tract, causing hypoproteinemia, edema, lymphocytopenia, hypogammaglobinemia, and immunologic dysfunction.[1]

Protein-losing gastroenteropathies have been classified into three groups (depending on the mechanism of their etiology) that include the following[2] : (1) inflammatory-induced mucosal erosions and/or ulcerations (eg, Crohn disease), (2) mucosal damage or abnormalities resulting in increased protein permeability without mucosal erosions or ulcerations (eg, celiac disease), and (3) protein loss stemming from mechanical lymphatic obstruction (eg, intestinal lymphangiectasia).

See protein-losing enteropathy for a more comprehensive discussion on this topic.

Pathophysiology

Protein-losing gastroenteropathy occurs when protein loss into the gastrointestinal (GI) tract exceeds the liver’s production capacity. Intestinal lymphangiectasia is defined by compromised enteric lymph drainage and the presence of dilated lymphatic channels.[3, 4] This condition is categorized into two types: primary and secondary intestinal lymphangiectasia.

Primary intestinal lymphangiectasis (PIL), also known as Waldmann disease, pertains to congenital anomalies. These malformations manifest as extensive or localized dilatations (ectasia) of enteric lymphatics, situated within the mucosa, submucosa, and/or subserosa layers of the intestine. Several genes associated with the development of the lymphatic system have been studied, but none have been conclusively identified as clinically significant contributors to PIL.[5]

Secondary intestinal lymphangiectasia typically results from obstruction. Cardiac diseases can give rise to secondary lymphangiectasia by elevating central venous pressure, subsequently hindering the drainage of the thoracic duct into the left subclavian vein.[6] These conditions encompass structural heart disease such as constrictive pericarditis and cardiomyopathy. Other potential causes of secondary intestinal lymphangiectasia include malignancy (eg, lymphoma), infection (eg, tuberculosis), inflammatory conditions (eg, sarcoidosis), blood clots (eg, mesenteric venous thrombosis), portal hypertension, retroperitoneal fibrosis, and enlargement of retroperitoneal lymph nodes.[7]

Serum proteins commonly impacted include albumin, immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), ceruloplasmin, and fibrinogen. This results in immunologic abnormalities, leading to hypogammaglobulinemia, anergy, and impaired allograft rejection. Other serum constituents can also be lost, including iron, lipids, and trace elements, many of which are bound to proteins.[4]

Etiology

The following conditions can cause secondary intestinal lymphangiectasia:

  • Abdominal or retroperitoneal carcinoma

  • Cardiac disease (eg, constrictive pericarditis, congestive heart failure)

  • Celiac disease

  • Cirrhosis

  • Chronic pancreatitis

  • Crohn disease

  • Enteric-lymphatic fistula

  • Hepatic venous outflow obstruction

  • Intestinal endometriosis

  • Lymphoma

  • Lymphenteric fistula

  • Malignancy involving mesenteric lymph nodes or lymphatics

  • Mesenteric tuberculosis

  • Mesenteric venous thrombosis

  • Portal hypertension

  • Retroperitoneal fibrosis

  • Retroperitoneal lymph node enlargement

  • Sarcoidosis

  • Scleroderma

  • Sclerosing mesenteritis

  • Systemic lupus erythematosus (SLE)

  • Thoracic duct obstruction

  • Whipple disease

Epidemiology

The incidence and prevalence of primary and secondary intestinal lymphangiectasia remains unknown due to rarity.[5]

There is no known racial predilection for this condition.[4] However, there is a male-to-female ratio of 3:2. Intestinal lymphangiectasia can be primary (congenital), typically impacting children and young adults with a mean age of onset at 11 years. In these cases, the diagnosis often occurs during the first decade of life, with initial symptoms such as persistent diarrhea and peripheral edema. Alternatively, this condition can be secondary to other disease states, affecting older adults.[1, 7] In a series from Japan, the average age at onset was 22.9 years.

Prognosis

The clinical course of intestinal lymphangiectasia is highly variable, with approximately 23% of patients experiencing improvement, 64% remaining unchanged, and a mortality rate of 13%.

In patients with primary intestinal lymphangiectasia, especially those with an early onset, which typically occurs during the first decade, growth retardation is a common concern due to malabsorption.[5] On the other hand, the prognosis of patients with secondary intestinal lymphangiectasia depends on the extent and severity of the underlying disease.

Morbidity/mortality

Morbidity in this disease is closely tied to its pathophysiology. Predominant clinical features include edema and diarrhea, but the condition is also associated with the following negative sequelae:

  • Lymphocytopenia, hypogammaglobulinemia

  • Hypoalbuminemia, hypocalcemia, trace metal deficiency

  • Chylous pleural effusions, ascites (Chylous ascites and transudative ascites are reported.)

Complications

Primary intestinal lymphangiectasia is linked to an increased risk of lymphoma.[7] Patients with congenital intestinal lymphangiectasia have reported fibrotic entrapment of the small bowel.[8] Oral manifestations of this condition include gingivitis caused by poor lymphocytic function and enamel defects caused by inadequate calcium absorption.[9]

 

Presentation

History

Patients typically present with pitting edema and nonbloody diarrhea. Primary intestinal lymphangiectasia usually results in bilateral edema, whereas the secondary intestinal lymphangiectasia often leads to unilateral edema, caused by various neoplastic, infiltrative, and inflammatory lesions affecting one side of the body. Onset of the disease during the early party of the first decade of life often results in growth retardation.[5]

Additional symptoms include anasarca, lymphedema, weight loss, fatigue, abdominal pain, steatorrhea, malabsorption (fat-soluble vitamin deficiencies), lymphocytopenia, and hypogammaglobulinemia.[5] Despite the presence of hypogammaglobulinemia, opportunistic infections are rare. However, lymphocytopenia predisposes patients to abnormal cellular immunities, such as homograft rejection and cutaneous anergy.

Patients with long-standing lymphangiectasia may also experience ascites, often chylous ascites, and chylous pleural effusions.[5]

Physical Examination

Primary intestinal lymphangiectasia

Peripheral edema, predominantly bilateral lower limb edema, is a common finding in patients with primary intestinal lymphangiectasia.[10] Other signs include anasarca, including decreased breath sounds due to pleural effusion, distended abdomen from ascites, and weight gain.

In some cases, macular edema observed during funduscopic examination has been reported and can lead to reversible blindness.[11]

Pachydermoperiostosis has been associated with intestinal lymphangiectasia.[12] Pachydermoperiostosis is a rare hereditary disease characterized by clubbing of the fingers, periostosis, and skin changes.

Secondary lymphangiectasia

Secondary lymphangiectasia can present with a spectrum of physical findings, which vary depending on the underlying cause.

 

DDx

 

Workup

Laboratory Studies

Serum protein levels

The most prevalent laboratory finding in intestinal lymphangiectasia is hypoproteinemia. This typically manifests as hypoalbuminemia, and patients may also exhibit lymphocytopenia and hypogammaglobulinemia, involving immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM). Cholesterol levels, however, are not typically elevated in this condition.

Alpha1-antitrypsin levels

In the analysis of random dry stools, alpha1-antitrypsin (AAT) levels are indirect indicators of protein leakage in the gastrointestinal (GI) tract. AAT is resistant to degradation by intestinal proteases and is excreted intact in the stool. However, although measuring stool AAT can be a useful initial screen for protein loss, several studies have revealed a limited correlation between stool AAT and its clearance measurement. This is partially attributed to the variable degradation of AAT in different environments, with higher breakdown observed in conditions where the pH level is less than 3, such as in the stomach or small bowel during states of hyperacidity.

The most precise test for assessing protein loss in the GI tract involves the direct measurement of AAT clearance from plasma. Values exceeding 24 mL/day in patients without diarrhea (as diarrhea can increase AAT clearance) and surpassing 56 mL/day in those with diarrhea indicate protein loss in the GI tract. In addition, GI bleeding has also been shown to increase AAT clearance because of whole blood loss.

Imaging Studies

Double-contrast radiographs of the small bowel can be valuable in diagnosing the condition, as they may reveal thickened folds caused by intestinal edema resulting from hypoproteinemia, nodular protrusions, and an 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.[13] In CT scans, circumferential thickening of the small bowel wall with low attenuation (typically < 30 Hounsfield units) may be observed.

Multidetector CT (MDCT) scanning following direct lymphangiography has proven to be an effective method for evaluating and diagnosing primary intestinal lymphangiectasia. In a retrospective study involving 55 affected patients, all of whom underwent MDCT after direct lymphangiography, investigators noted that MDCT successfully identified various abnormalities, including intra-intestinal, extra-intestinal, and lymphatic vessel issues. These abnormalities included different degrees of intestinal dilatation, small bowel wall thickening, ascites, mesenteric edema, mesenteric nodules, lumbar trunk and intestinal trunk reflux.[14]

Procedures

Endoscopy

Endoscopy has consistently proven its utility in diagnosing intestinal lymphangiectasis. Small bowel enteroscopy allows for the identification of mucosal changes and the collection of histologic samples.[15, 16, 17] During endoscopy, characteristic findings include white villi and/or spots (dilated lacteals), white nodules, submucosal elevations, and xanthomatous plaques.

Capsule endoscopy

Capsule endoscopy has been used to help identify the characteristic changes of intestinal lymphangiectasia, particularly in areas not reachable with standard endoscopy since this condition often occurs at jejunoileum.[18]

Jejunal biopsy

A jejunal biopsy provides a definitive diagnosis, revealing the dilation of mucosal and submucosal lymphatic channels. To enhance diagnostic accuracy, it is advisable to use large biopsy forceps when possible. Given the patchy nature of small bowel involvement, obtaining multiple biopsy samples from different areas is recommended.

Histologic Findings

Intestinal biopsy results display the characteristic dilatation of the lymph vessels of the mucosa, submucosa, and subserosa layers, often without any signs of inflammation. Surface epithelial cells are typically normal.[7] See the image below.

Intestinal villi of normal height with dilated lym Intestinal villi of normal height with dilated lymphatics as usually seen on histology of villi in intestinal lymphagiectasia.
 

Treatment

Medical Care

The treatment of patients with primary intestinal lymphangiectasia (PIL) includes dietary, pharmaceutical, and behavioral modifications. Note the following:

  • Medications to consider include over-the-counter agents (eg, bulking agents like fiber and anti-diarrheal drugs such as loperamide).

  • In several reports, octreotide has shown efficacy in refractory cases, as octreotide theoretically decrease intestinal absorption of fats.[19] Troskot et al reported a case of a 42-year-old man with primary intestinal lymphangiectasia, in which therapeutic resolution was achieved only with octreotide. A slow-release form of octreotide led to partial remission.[20] In another instance, a case of intestinal lymphangiectasia refractory to octreotide and nutritional manipulations was successfully treated with tranexamic acid. The patient had presented with refractory anemia due to ongoing gastrointestinal blood loss.

  • Pollack and colleagues reported a case of PIL in a female patient with tuberous sclerosis complex (TSC) and a TSC2 mutation. A trial of the mTOR inhibitor rapamycin (sirolimus) yielded improvements in her clinical symptoms and abnormal laboratory values.[21] Tan et al also described a case in which PIL was the initial presentation of TSC.[22] Sirolimus and everolimus have proven to be effective for young pediatric patients with extensive lymphangiectasia. Sirolimus affects lymphatic endothelial cells by altering mTOR signaling, suppressing lymphatic sprouting and proliferation, and inducing apoptosis.[23]

  • Tranexamic acid have been used in some cases of refractory lymphangiectasia with clinical improvement.[24] The mechanism of antiplasmin therapy involves normalizing tissue fibrinolytic activity. Elevated fibrinolytic activity, believed to contribute to intestinal protein loss, is considered a factor in this process.[23]

  • Other less substantiated therapies include steroids and intravenous albumin infusions; however, there is insufficient evidence to recommend their routine use for this condition.[7]

The treatment of secondary intestinal lymphangiectasia revolves addressing and managing the underlying disease.[4]

Consultations

Whenever there is a suspicion of protein-losing gastroenteropathy, it is advisable to refer the patient to a gastroenterologist.

Surgical Care

Surgery has no established role in primary intestinal lymphangiectasia. However, surgical interventions may be considered for addressing secondary intestinal lymphangiectasia due to various causes. Note the following:

  • Gastrectomy effectively alleviates protein loss resulting from giant hypertrophic gastritis (eg, Ménétrier disease).

  • Correction of a lymphenteric fistula can eliminate protein loss.

  • Pericardiectomy, when necessary for severe symptomatic constrictive pericarditis, can significantly reduce protein loss through the gastrointestinal tract.

  • Localized intestinal lymphangiectasia may be treated with surgical resection.[25]

Diet

Dietary modifications involve adhering to a low-fat diet and replacing long-chain fatty acids with medium-chain fatty acids.[4, 26] The rationale for this dietary modification includes the following:

  • Long-chain fatty acids result in chylomicron formation, which obstructs lymphatic vessels, elevates lymphatic pressure, and causes lymphocyte loss.

  • Medium-chain fatty acids are considered more water-soluble and are absorbed through portal venous channels instead of lymphatics, thereby decreasing strain on the lacteals.[5]

In a literature review, Desai et al investigated the efficacy of a medium-chain fatty acid diet for treating primary intestinal lymphangiectasia in 27 patients, comparing the results to those of 28 control patients. In the fatty acid group, 17 patients (63%) experienced complete symptom resolution, while in the non-fatty acid group, this figure was 10 patients (35.7%). Moreover, the fatty acid group had 1 death (3.7%), whereas the second group had 5 deaths (17.8%). The authors concluded that a medium-chain fatty acid diet is a viable treatment option for pediatric patients.[26]

For patients who do not respond to a low-fat diet, enteral nutritional therapy (including elemental, semi-elemental, and polymeric diets) may become necessary.[5] In event of severe malnutrition, partial or total parenteral nutrition (TPN) can be considered, although enteral nutrition is usually preferred.[27]

Theoretically, limiting the patient's salt intake could decrease edema, although no known reports address this issue. Moreover, the impact of dietary salt limitation is likely insignificant since diuretics do not play a significant role in controlling edema in patients with primary intestinal lymphangiectasia.

Activity

No specific activity restrictions are recommended. Patients should be encouraged to follow an active lifestyle within the limits of their condition. For patients with peripheral edema, elevating the affected limbs above heart level can improve postural drainage of lymph. Additionally, we recommend using recliners and elastic support stockings to reduce edema and minimize the risk of cellulitis and lymphangitis.

 

Medication

Medication Summary

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.[28] 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.[29]

Additional cases have been reported with the successful use of octreotide, including the long-acting formulation (LAR).[19, 30]

Somatostatin Analogs

Class Summary

Somatostatin analogs are used to inhibit effects of gastrointestinal (GI) hormones.

Octreotide (Sandostatin)

Octreotide (Sandostatin) functions similarly to the hormone somatostatin. It is a highly potent inhibitor of various hormones, including growth hormone, glucagon, and insulin. Octreotide significantly reduces splanchnic blood flow and suppresses LH response to GnRH. It decrease intestinal absorption of fats. Moreover, it exerts a strong suppressive effect on GI hormones, including gastrin, motilin, secretin, and pancreatic polypeptide. Due to its ability to suppress GI hormone activity, octreotide is employed in the treatment of various GI disorders, such as VIPoma and carcinoid tumors.

mTOR inhibitors

Class Summary

Mammalian Target of Rapamycin (mTOR) inhibitors are a class of medications that target the mTOR signaling pathway, which plays an important role in regulating cell growth, proliferation, and survival.

Sirolimus

Within context of primary intestinal lymphangiectasia, sirolimus affects lymphatic endothelial cells by altering mTOR signaling, suppressing lymphatic sprouting and proliferation, and inducing apoptosis.

Antifibrinolytic Agents

Class Summary

Antihemophilic agents like tranexamic acid function by competitively inhibiting the activation of plasminogen to plasmin, thereby reducing or diminishing bleeding. Elevated fibrinolytic activity, believed to contribute to intestinal protein loss, is considered a factor in primary intestinal lymphangiectasia.

Tranexamic acid (Cyklokapron)

Tranexamic acid (Cyklokapron) is an antifibrinolytic agent. It works by inhibiting plasminogen activators, thereby blocking the breakdown of blood clots.