The basic treatment for primary intestinal lymphangiectasia is dietary therapy. We tried dietary therapy as an initial treatment in all patients, but since dietary therapy was not effective in most of the patients, we became to try various second-line treatments. We made a suggestive treatment guide by evaluating which treatment was effective in patients through classification according to the extent of the lesion and action mechanisms of drugs.
Dietary therapy for our patients consisted of high protein and low fat substituted with MCTs. The exclusion of long-chain fatty acids reduces lymphatic flow and pressure, and thus prevents the rupture of malformed lymphatics, while MCTs are directly absorbed into the portal venous circulation and bypass the enteric lymphatics[11]. Several case reports and articles have introduced the long-term effect of dietary therapy[12-19]. One patient in our study responded to dietary therapy (Table 1) and maintained clinical improvement for more than five years.
Having response to dietary therapy is ideal but some patients are non-responsive to dietary therapy. For that reason, more than 10 reports have introduced secondary therapy like surgery, octreotide, or sirolimus, but there is no consensus on how to choose and apply these therapies to patients who are refractory to dietary therapy[2, 20-32]. We tried to suggest a reasonable choice of second-line therapy because we had several experiences with therapeutic challenges and success with multimodal treatment options. Although no discussion has been made in existing papers on when to start secondary treatment, we think it is sufficient to evaluate the response with two weeks of dietary therapy, given our experience in treatment and other papers on dietary reactions[33].
We emphasize that the initial evaluation of the location and the extra-intestinal extent of abnormal lymphatic lesions is important for a therapeutic strategy. We divided our patients into three groups to distinguish and assess the efficacy of the second-line treatments. We also analyzed other published cases using the same protocol and conducted a review of the literature on second-line therapy (Table 2).
We evaluated capsule endoscopy and MRI after imaging modality has been developed in addition to esophagogastroduodenoscopy. After confirming the locations of the abnormal lymphatic lesions, we considered surgery after dietary therapy failure for the patients with focal abnormal lesions because surgery is the only treatment option with a chance of a complete cure. Cases reporting surgical treatment for patients with focally affected lesions have been published, and all patients showed clinical remission, consistent with our case (Table 2).
With the development of radiologic intervention, we attempted lymphatic embolization instead of surgery in one patient and the result was very successful. This was the first case of recovery from primary intestinal lymphangiectasia and clinical remission in a child or an adult treated with embolization. This procedure minimizes the risk of complications and decreases the treatment period commonly associated with surgery[34-36]. Embolization is a potential therapeutic option for focal lesions of primary intestinal lymphangiectasia in children. Surgery can be considered after embolization treatment failure.
For the patients whose disease extent is too broad to undergo embolization or surgery, medical therapy should be considered for second-line medical therapy. We have treatment experience with octreotide and sirolimus. Choosing the appropriate drug for patients is challenging for all clinicians.
Octreotide is a somatostatin analog whose mechanisms include decreased intestinal absorption of fats, inhibition of gastrointestinal vasoactive peptides, and stimulation of the autonomic nervous system[22]. Because of its mechanisms, we hypothesized that it is optimal for patients who have only intestinal involvement of the abnormal lymphatics with severe diarrhea, but we only have experience using the drug with extensive-type lymphangiectasis. Octreotide had little therapeutic effect in these patients. Ten case reports presenting experience treating with octreotide have been published. Consistent with our experience, octreotide showed little effect in patients with extensive abnormal lymphatic lesions. There are also reports that describe the recurrence of lymphangiectasis after the discontinuation of octreotide. Sari et al. (2010)[30], Prasad et al. (2019)[29], and some other reports described clinical improvement after octreotide treatment but there is no information on the long-term efficacy of octreotide (Table 2)[37, 38]. We analyzed patient characteristics in the aspects of location and extent of lymphangiectasis in reports of clinical outcomes after using octreotide. Like our prediction, patients in reports who have lymphangiectasis only in intestine, responded to octreotide treatment without recurrence after discontinuation. Otherwise, patients in reports who have lymphangiectasis extensively, failed to octreotide treatment (Table 2). In that reason, we made an attempt to use sirolimus initially in patient with extensive lymphangiectasis.
Sirolimus acts on lymphatic endothelial cells and changes mTOR signaling, suppressing lymphatic sprouting and proliferation, and inducing apoptosis[39]. We tried sirolimus in four patients (Patients 4, 5, 6, and 7) who failed to respond to dietary therapy initially and two of them also failed to respond to octreotide therapy (Table 1). Among the four patients, two patients (Patients 6 and 7) with abnormal lymphatic lesions only in the intestine showed clinical improvement after 3 – 4 months of sirolimus treatment, whereas the other two patients (Patients 4 and 5) who had extensive-type lymphangiectasis showed clinical improvement only after on month of sirolimus treatment (Figures 3 and 4). The way sirolimus acts on lymphatic channels resulted in different effect onset times in these two groups. Because sirolimus acts on endothelial cells of the lymphatic channel, not by controlling lymphatic flow like octreotide or dietary therapy, it can affect any lymphatic vessels in the body. We concluded that patients who had the extensive form of abnormal lymphatics channels could be initially considered for sirolimus treatment rather than octreotide for a fast response and cure (Figure 1). One case report of treatment experience with everolimus (an mTOR inhibitor drugs) was published in Japan. Everolimus was prescribed because it was not possible to use sirolimus in the hospital. Their patient characteristics were similar to our patients who had extensive abnormal lymphatic lesions in the body (Table 2). The drug effect was seen after four weeks of use, like in our cases. However, the appropriate drug discontinuation time is debatable because there is no current consensus or guidelines [40, 41]. Incidence of many adverse effects of sirolimus is dose related, and a frequent adverse effect of sirolimus, which is up to 40%, is elevation of creatinine level. Everolimus has an advantage over sirolimus in preserving kidney function, because it is metabolized in the liver via CYP3A4. Another troublesome adverse effect of sirolimus is lymphedema mainly in extremities. There are reports of lymphedema following the use of sirolimus after kidney or liver transplantation. The reported median time between lymphedema onset and the beginning of sirolimus was 52 weeks[42]. Therefore, by this time, the drug concentration should be checked periodically and carefully monitored for side effects.
Only two case reports presented treatment experience with tranexamic acid [27, 29]. Tranexamic acid 25 mg/kg/dose three times a day was used orally (maximum 1,000 mg) for five days [29], and patients showed clinical improvement after one month of treatment [27]. The mechanism of antiplasmin therapy is the normalization of tissue fibrinolytic activity[43]. Increased fibrinolytic activity, which causes intestinal protein loss, has been proposed as a mechanism. Mine et al.[44] suggested that there is a subset of patients with lymphangiectasia who may have increased tissue or plasma fibrinolytic activity and may respond to antiplasmin therapy. Elevated D-dimers may reflect increased fibrinolytic activity. Tranexamic acid can be a choice for patients who present with refractory symptoms of lymphangiectasis.
The primary limitation of our study was its retrospective nature design and the small number of patients. It is practically impossible to perform prospective studies because primary intestinal lymphangiectasia is a very rare disease. We also need more follow-up information after the discontinuation of sirolimus.