Developmental Disorders of the Lymphatics

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Sunday, July 23, 2006

Primary Intestinal and Thoracic Lymphangiectasia: A Response to Antiplasmin Therapy

Primary Intestinal and Thoracic Lymphangiectasia: A Response to Antiplasmin Therapy


Lymphangiectasia is a congenital or acquired disorder characterized by abnormal, dilated lymphatics with a variable age of presentation. We describe a case of lymphangiectasia with intestinal and pulmonary involvement in an adolescent female, who presented with many of the classic features including chylous pleural effusions, lymphopenia, hypogammaglobinemia, and a protein-losing enteropathy. She also presented with recurrent lower gastrointestinal bleeding, which is infrequently described. The patient did not improve with bowel rest and a low-fat medium-chain triglyceride diet and had little improvement with octreotide acetate therapy. However, she had a clinical response to antiplasmin therapy, trans-4-aminothylcyclohexamine carboxylic acid (tranexamic acid) in terms of serum albumin and gastrointestinal bleeding. She continues to have exacerbations of her condition, as well as persistent lymphopenia and chronic pleural effusions.

Key Words: lymphangiectasia • anti-plasmin • gastrointestinal bleeding


Primary lymphangiectasia is a congenital disorder of the lymphatic system characterized by marked ectasia of the lymphatic vessels resulting in obstruction and leakage of lymph fluid.1 Intestinal lymphangiectasia is characterized by a protein-losing enteropathy and is diagnosed definitively by small bowel biopsy demonstrating dilated lymphatics in the mucosa, submucosa, and serosa in the absence of coexistent inflammation.24 Symptoms include diarrhea, peripheral edema, lymphedematous limbs, general malaise, and weight loss.2,5 In pulmonary or thoracic lymphangiectasia, dilation of lymphatics in the visceral pleura as well as interlobular septa result in chylothoraces, which may lead to respiratory compromise or failure.1 Intestinal and thoracic lymphangiectasia may occur in isolation or simultaneously in the same patient as part of a generalized lymphatic dysplasia.6

Treatments described for lymphangiectasia have included corticosteroids for patients with primary inflammatory conditions,7 dietary modifications,8 surgical resection for isolated lesions,9 octreotide,10,11 and antiplasmin therapy.12 Successful management with these treatment modalities has been variable with no evidence of specific groups of patients responding to a particular treatment. We report a case of lymphangiectasia associated with intestinal bleeding, a finding that is not commonly described.13 The protein-losing enteropathy was refractory to total parenteral nutrition and a low-fat medium-chain triglyceride diet as well as octreotide, with improvement after starting antiplasmin therapy.

Case Report

A 14-year-old previously healthy girl was transferred from a peripheral hospital with a microcytic anemia requiring transfusion and a large left-sided pleural effusion. She had a 3-week history of fatigue, abdominal pain, nausea, and vomiting, accompanied by a 3-kg weight loss and grossly bloody stools.

On physical examination, her heart rate was 119 beats/min, respiratory rate 36 breaths/min, blood pressure 97/46 mm Hg, and oxygen saturation 99% in room air. She had marked pallor and periorbital edema. Chest examination revealed decreased breath sounds on the left side. A grade II/VI systolic ejection murmur was heard over the left lower sternal border with normal heart sounds. Abdominal examination revealed evidence of ascites with no organomegaly. There was notable peripheral edema but no evidence of lymphadenopathy.

Initial laboratory investigations showed a hemoglobin of 58 g/L and platelets of 248 x 109/L. White blood cell count was 5.9 x 109/L with lymphopenia (0.36 x 109/L lymphocytes). Albumin was 19 g/L with a total protein of 34 g/L and immunoglobulins G, A, and M of 2.4 g/L (normal range: 7.2–15.8 g/L), 0.5 g/L (normal range: 0.5–3.5 g/L), and 0.7 g/L (normal range: 0.2–2.6 g/L), respectively. Urinalysis showed no evidence of proteinuria. The erythrocyte sedimentation rate, amylase, urate, lactate dehydrogenase, transaminases, bilirubin, and -fetoprotein levels were normal with stools positive for blood and markedly elevated stool -1-antitrysin levels.

Chest radiograph showed a large left-sided pleural effusion and a small right-sided effusion (Fig 1). Computerized tomography and magnetic resonance imaging of the chest and abdomen revealed diffuse abnormalities in the mediastinal fat, thickened bowel loops, and mild ascites but no focal mass or lymphadenopathy. An echocardiogram was normal. An endoscopic examination of the small bowel showed diffuse bowel wall thickening with distal nodularity of the ileum. A lymphangiogram demonstrated delayed transit with normal subdiaphragmatic nodal architecture and no entry into the cisterna chyli or thoracic duct.

Thorascopic biopsy of the mediastinal lesion showed grossly fatty vascular tissue that appeared necrotic microscopically without evidence of malignancy. Upper gastrointestinal endoscopy revealed gross white nodules consistent with lymphangiectasia. No focal bleeding sites were seen. Microscopically, there was focal lymphangiectasia in the duodenal cap and gastric antrum. Thoracentesis of the left hemithorax drained 1.8 L of serous fluid with pH 7.0, protein of 20 g/L, glucose of 5.4 mmol/L, and elevated triglycerides of 0.92 mmol/L with chylomicrons present. The white blood cell count of the fluid was elevated at 231 cells/mm3 with a lymphocytic predominance. Routine and mycobacterial cultures were sterile. Cytology showed no malignant cells. Bilateral bone marrow aspirates and biopsy were normal. A gallium scan was normal.

The patient was started on total parenteral nutrition and complete bowel rest. Her albumin remained persistently low despite weekly albumin infusions, and her chest tube continued to drain 1 to 2 L daily. Persistent gastrointestinal bleeding resulted in blood transfusions approximately every 2 weeks. A red blood cell scan and Meckel’s scan were negative with repeat upper and lower intestinal endoscopies showing no signs of active bleeding. Subcutaneous octreotide therapy was initiated 30 days into hospitalization. Although the chest pathology improved with decreased output from the chest tubes, the enteropathy persisted. Repeat endoscopy 5 weeks into hospitalization revealed some pathologic improvement in the duodenum, but multiple focal areas of lymphangiectasia were seen in the terminal ileum. A low-fat medium-chain triglyceride diet was instituted for 4 weeks but did not lead to any improvement. Based on a report showing benefit with antiplasmin therapy, a trial of tranexamic acid (1000 mg by mouth, 3 times daily) was initiated 2.5 months after presentation (Fig 2). At the time, D-dimer levels were elevated at 1770 ng/mL (normal: 0–449 ng/mL) with normal partial thromboplastin time and international normalized ratio. One month later, her albumin had improved to 24 g/L and her immunoglobulin G level was 5.4 g/L. She remained clinically stable for 10 months with normal levels of serum albumin and immunoglobulin G, and she did not have additional intestinal bleeding. Fourteen months after her initial presentation, an exacerbation of her condition occurred with recurrent transfusion dependent lower gastrointestinal bleeding and hypoalbuminemia requiring daily albumin infusions. Repeat endoscopic biopsies again demonstrated lymphangiectasia throughout the small bowel as well as multiple areas of mucosal petechiae. After a 1-month period of parenteral nutrition and bowel rest, increasing the dose of octreotide, and increasing the dose of tranexamic acid to 6 g/d, her condition stabilized with resolution of the intestinal bleeding.


Lymphangiectasias are disorders characterized by abnormal, dilated lymphatics. There is wide variation in the age of onset and extent of disease. Primary lymphangiectasia is a congenital malformation, with the age of presentation ranging from in utero onset to early adulthood. Lymphangiectasia may also be secondary to lymphatic damage from other processes including lymphoma, radiotherapy, and constrictive pericarditis. Although lymphangiectasia can be isolated to the gastrointestinal or pulmonary systems, generalized disease usually shows a predominance of intestinal manifestations.14

We describe a case showing some of the classic features of lymphangiectasia including chylous pleural effusions, lymphopenia, hypoalbuminemia with enteric protein loss, and hypogammaglobulinemia. A thorough investigation excluded potential underlying causes. This case also describes an association with intestinal bleeding thought to be related to latent lymphatic-venous anastomoses, which can rupture under abnormally high lymphatic pressure.13 There was marked clinical improvement, as measured by serum albumin, immunoglobulin levels, and resolution of intestinal bleeding, with the initiation of antiplasmin therapy.

The rarity of lymphangiectasia and the wide variation in its clinical presentation provides a challenge in identifying appropriate therapy. Supportive therapy including albumin infusions, diuretics, thoracentesis, and paracentesis provides transient relief of symptoms. Surgical resection is an option for limited disease of the small bowel.9,15 Dietary modifications are aimed at controlling symptoms and consequences of lymphatic obstruction but not at modifying the underlying disease process. Restriction of dietary fat results in reduction in lymph flow and subsequent leak of protein. Low-fat medium-chain triglyceride diets have been used as sole therapy as well as a part of other treatment regimens. These triglycerides are not reesterified within intestinal cells, thereby bypassing enteric lymphatics. In most patients, dietary modifications need to be continued indefinitely to control symptoms.8 Although it is generally accepted that corticosteroids do not have a role in the treatment of lymphangiectasia, they have been used with success in patients with elevated acute phase reactants, suggesting that there may be a subset of patients with underlying inflammatory disease who may respond to corticosteroids.7,16

Octreotide acetate is a long acting somatostatin analog that may aid in the reduction of lymphatic losses in lymphangiectasia through a variety of mechanisms including reduction of thoracic duct lymph flow17 and reducing lymph fluid excretion in enteric vasculature.18 Octreotide has been reported to be successful in 2 cases refractory to other therapeutic modalities.10,11

Increased fibrinolytic activity, which causes intestinal protein loss, has been proposed as a mechanism responsible for several conditions characterized by protein-losing enteropathy. In a rat protein-losing enteropathy model as well as in patients with Menetrier’s disease and hypertrophic gastritis, Kondo et al19 demonstrated increased tissue fibrinolytic activity in gastric mucosa biopsy specimens. Treatment with antiplasmin therapy, tranexamic acid, led to a resolution of symptoms, laboratory evidence of enteric protein loss, and, in animal models, a normalization of tissue fibrinolytic activity.20

Based on these studies and case reports, Mine et al12 treated a 35-year-old woman with intestinal lymphangiectasia and increased plasma fibrinolytic activity, as measured by euglobin lysis time, with tranexamic acid. The mechanism of action of tranexamic acid has been shown to involve inhibition of conversion of plasminogen to plasmin as well through weak noncompetitive inhibition of plasmin. This patient showed a dramatic clinical response within 6 weeks that was sustained over 8 years, with clinical exacerbations occurring only with discontinuation of the drug and remitting with reinstituting therapy. Two different authors reported 3 subsequent patients, with and without increased plasma fibrinolytic activity, who did not benefit from antiplasmin therapy, and there has not been a subsequent reported case of lymphangiectasia that responded to this therapy. Mine concluded that there is a subset of patients with lymphangiectasia, who may have increased tissue or plasma fibrinolytic activity and may respond to antiplasmin therapy. Our case represents the second apparent beneficial use of this therapy. The elevated D-dimers in our patient may be reflective of increased fibrinolytic activity, which may have a causative role in the protein-losing enteropathy. Tranexamic acid has been used successfully in hereditary hemorrhagic telangiectasia,21 and this condition is also characterized by lesions with increased local fibrinolytic activity caused by an increase in tissue plasminogen activator.22 It is plausible that the multiple areas of mucosal bleeding in our patient represent lesions with increased fibrinolytic activity, and that tranexamic acid modulates the effect of tissue fibrinolysis in these areas. There may be a subset of patients with lymphangiectasia who have gastrointestinal bleeding from diffuse areas of local hyperfibrinolysis and may respond to antiplasmin therapy.

Although it can be argued that our patient’s initial improvement was coincidental to initiation of therapy with tranexamic acid as spontaneous remissions can occur, the timing and nature of the improvement was similar to Mine’s patient. The resolution of gastrointestinal bleeding and the lack of need for any red blood cell or albumin infusions are striking. Our patient has had an exacerbation of her condition which subsequently improved and ongoing lymphopenia which reflects the persistence of the anatomic abnormalities of the lymphatics despite therapy. D-dimers remain elevated, which may be indicative of a persistent fibrinolytic state. The side effect profile of tranexamic acid includes gastrointestinal upset and retinal changes,23 which have not been demonstrated in ongoing surveillance in our patient. Although the long-term outcome of our patient is unclear, it is evident that the improvement in her condition was most likely related to tranexamic acid therapy.

This case underscores the fact that lymphangiectasia is a heterogeneous and poorly understood condition. Some patients with this condition, particularly those with diffuse gastrointestinal bleeding, may respond to antiplasmin therapy. A multicenter surveillance study may aid in our understanding of this uncommon and heterogeneous disorder and provide a more systematic approach to treatment of this complex clinical problem.

Division of Paediatric Medicine The Hospital for Sick Children University of Toronto Toronto, Ontario, Canada M5G 1X8

-->Joanna E. MacLean, MD, Eyal Cohen, MD and Michael Weinstein, MD
Division of Paediatric Medicine The Hospital for Sick Children University of Toronto Toronto, Ontario, Canada M5G 1X8