Intestinal lymphangiectasia (OMIM 152800)

Intestinal lymphangiectasia, a rather uncommon condition characterized by diffuse or local dilation of the enteric lymphatics, is the best-known abnormality of the lymphatic system leading to PLE. It can exist as a congenital defect (primary intestinal lymphangiectasia, or PIL) or secondary to other diseases.

Primary lymphangiectasia : The prevalence of clinically overt PIL is unknown but is believed to affect less than 200,000 of the population of the United States. PIL can cause severe, even life-threatening, complications and adopt a chronic or recurrent course in some patients, or present as a mild, transient, or even asymptomatic condition in others.

In some patients, PIL can be associated with different congenital abnormalities of the lymphatic system of variable severity and extent, including peripheral lymphedema and various types of effusions. Five genetic syndromes, including von Recklinghausen, Turner, Noonan, Klippel-Trenaunay, and Hennekam are classically known to be associated with intestinal lymphangiectasia. More recently, it has been shown that CCBE1 mutations over­all can cause a mild form of generalized lymphatic dysplasia, including lymphangiectasia. A mild form of lymphangiectasia is also a salient feature of the group of disorders known as congenital disorders of glycosylation (CDG). These entities are caused by defects in the synthesis of glycans and in the attachment of glycans to other molecules and, in addition to involving the gut, they can determine liver, cardiac, and neurologic developmental involvement. One form of CDG, the CDGIb ( OMIM 602579 ), is dominated by gastrointestinal and liver manifestations, including PLE.

Intestinal lymphangiectasia was first reported by Waldmann et al. in their seminal 1961 paper, as “idiopathic hypoproteinemia.” The structurally abnormal lym­phatics can be located in the mucosa, submucosa, or subserosa, and because of lymph stasis and vessel engorgement, they are constantly prone to rupture, which causes leakage into the gut lumen. Because lymphatic fluid is rich in albumin, globulins, and other proteins as well as chylomicrons, fat-soluble vitamins, long-chain dietary fats, and lymphocytes, its bulk loss leads to a progressive depletion of these elements from the systemic pool and to serious nutritional consequences. Medium- and short-chain fatty acids, on the other hand, are more dependent on the mesenteric venous blood, which transports them to the liver, than on the integrity of the lymphatic flow.

Hypoalbuminemic edema (which is often asymmet­rical) is a hallmark of PIL, other major manifestations or sequelae being, diarrhea, steatorrhea, abdominal pain, nausea/vomiting, chylous effusions, and growth retardation. The core laboratory features of intestinal lymphangiectasia are hypoalbuminemia, hypogammaglobulinemia, and peripheral lymphopenia. These two latter conditions may lead to the development of an immune deficiency state with abnormalities of both the humoral and cellular immune systems. Although this imbalance would theoretically predispose these patients to infections, in practice these are rather unusual.

Diagnosis of PIL is often made before 3 years of age and can usually be documented by the characteristic finding of variable degrees of dilation of the lymph vessels in the mucosa, on endoscopy, and in the submucosa, on small intestinal biopsies ( Figures 33-1 through 33-3 ). Whereas the finding of diffuse lymphangiectasia supports the diagnosis of the congenital PIL, the presence of the focal form would suggest the secondary type of lymphangiectasia. If the endoscopic procedure is carried out after a high-fat meal, typical scattered white spots on the mucosa of the duodenum are visible to the examiner. The use of capsule endoscopy and double balloon endoscopy may be considered in selected patients, when endoscopic findings are not contributory.

Intestinal lymphangiectasia. Prominent valvulae conniventes are present throughout the small bowel.

Endoscopic view of the duodenum showing snowflake-like lesions; histologically these represent dilated lacteals.

Lymphangiectasia. (A) Low-power magnification of expanded villi (V) with dilated lymphatic channels (arrow) (hematoxylin and eosin stain, ×50). (B) Higher-power magnification of a villus with dilated lacteal (arrow) (hematoxylin and eosin stain, ×200).

Secondary lymphangiectasia : Disorders leading to secondary lymphangiectasia act by causing obstruction of the lymph vessels or elevation of the lymph pressure due to raised venous pressure. In the first group, some relevant causes are lymphoma, inflammatory bowel disease, and some connective-tissue disorders, such as sarcoidosis, systemic lupus erythematosus, and amyloidosis, whereas the elevated lymph pressure group is composed mainly of patients with congestive heart failure and constrictive pericarditis. Other proposed mechanisms for secondary lymphangiectasia, as exemplified by Waldenström’s macroglobulinemia, are a high viscosity of the interstitial fluid leading to lymphatic dilation and obstruction, and infiltration, and subsequent distortion, of the mesenteric lymph nodes resulting in the same problem; such a mechanism has been described in low-grade lymphoma.

Cardiac disease was first identified as a cause of PLE in adult patients with constrictive pericarditis and severe cardiac failure. Subsequently, several cases of PLE secondary to constrictive pericarditis were reported in pediatric patients. In this condition, the resulting elevation of central venous pressure leads to congestion of lymphatic vessels in the bowel wall, and to rupture of lacteals in the gut or direct lymph leakage through the surface epithelium into the lumen.

In more recent decades, as reconstructive palliative procedures of previously intractable, complex congenital cardiac disease have become more common, PLE has emerged as a significant complication of this far-reaching surgical approach. As a result, it has added a substantial burden on patients and families already struggling with complicated medical and social issues. Over time, patients undergoing the Fontan operation, a surgical procedure used in children born with a single functional ventricle, due in most cases to a hypoplastic left heart or to defective valves (tricuspid atresia or pulmonary atresia), are at risk of developing PLE, even several years after surgery. Although this outcome occurs in a minority, 2% to 13% of the operated children, it is nevertheless associated with a high degree of morbidity and an ominous prognosis, which entails a 5-year survival rate of 46% to 50%, despite vigorous (and usually frustratingly ineffective) treatment. Risk factors for this complication have been discussed recently.

The various potential complications of the Fontan procedure are rooted in what is regarded as the primary inadequacy of its resulting circulatory arrangement, since the procedure never leads to a physiologically normal hemodynamic state. Although still poorly understood, the complex pathophysiology of PLE in patients with Fontan operations is thought to stem from a spiral of increased lymph production, decreased drainage, and increased thoracic duct pressure with lymphatic stasis and engorgement. This, in turn, apparently involves as major causative mechanisms, an abnormal mesenteric vascular resistance, a low cardiac output secondary to a diminished preload, and an elevated central venous pressure, particularly in the perihepatic interstitium, following the Fontan procedure. The ultimate result is insufficiency and failure of a lymphatic system that operates beyond its physiologic limits. However, the ultimate trigger in the development of PLE remains unclear. It has been proposed that the chain of events is precipitated by the ongoing chronic low cardiac output. The latter, by paving the way to the increased release of inflammatory markers, among them tumor necrosis factor α (TNFα) seems to play an added role in the pathophysiology of PLE. By altering the glycosaminoglycan makeup and the anatomic and electrostatic integrity of epithelial mucosal cells (in like manner to the nephrotic syndrome), TNFα would ultimately allow the abnormal diffusion of albumin and other proteins from the bloodstream into the gut lumen. In vitro models of PLE have lent support to this hypothesis.

Medical management for these cases has included the use of diuretics, periodic albumin infusions, subcutaneous unfractionated heparin, and high-dose corticosteroids, as well as other therapeutic approaches, either alone or in various combinations. These schemes have frequently followed a course where the initial enthusiasm has been tempered by the subsequent recognition of their often-significant side effects and short-lived beneficial impact. Baffle fenestration is another approach that has brought about a temporary improvement in some patients, whereas others have received no benefit. Increased hypoxemia and a greater risk of stroke are known risks of this procedure. Parenteral nutrition support, customarily employed in concert with supplementation with medium-chain triglycerides (MCTs) and other nutrients, is an intuitively rational treatment but it is often as ineffective in the long term as the other approaches already described. Bearing in mind this dismal scenario, an early detection of this complication of the Fontan operation could plausibly help to plan a comprehensive therapeutic strategy. This one, focused on certain crucial interventions, should be applied before irreversible changes in the enteric lymphatic system develop. One early parameter that helps to detect increased gastrointestinal protein loss seems to be A1AT concentration; therefore, it has been proposed that serial measurement of this marker could constitute an early predictor of PLE in patients who have undergone a Fontan procedure.