Intestinal lymphangectasia (IL), a disorder of impaired lymphatic drainage, clinically presents as protein-losing enteropathy. Described etiologies include primary/congenital, or secondary to pathologies leading to obstructed lymphatic drainage. Whenever possible, underlying predispositions are addressed. Milder cases of hypoalbuminemia and symptoms may be clinically tolerated; however, frequently complementary therapies are necessary. Management may include dietary interventions (high-protein, high medium-chain triglyceride [MCT] formulas), periodic infusions of intravenous (IV) albumin, corticosteroids, and heparin/tranexamic acid/antiplasmin therapy (1). Octreotide is a rarely reported therapy, particularly in pediatrics. We hereby describe a teenage heart transplant recipient who developed severe hypoalbuminemia related to lymphangiectasia arising due to right heart dysfunction, successfully managed with subcutaneous octreotide. Chart review was conducted subsequent to obtaining institutional approval.
A 15-year-old boy of Jamaican origin presented in late 2008 with a 9-month progressive history of hypoalbuminemia. The patient had undergone cardiac transplantation for a fulminant severe dilated cardiomyopathy at 1 year of age. His postoperative years had been complicated by restrictive pericarditis requiring pericardial decortication, 2 episodes of severe cellular rejection, and low-grade rejection on serial biopsies. In 2007, an upper endoscopy had demonstrated increased eosinophilia in the duodenum and chronic gastritis, as well as generalized eosinophilia throughout the colon and terminal ileum. The patient had been found to have positive serology for Strongyloides and thus, despite the possibility of a false-positive result, was treated. Follow-up Strongyloides enzyme-linked immunosorbent assay optical density and immunoglobulin (Ig) G4 had proven negative. Later that year, he had undergone a valvular replacement with biologic prosthesis due to right-sided dysfunction. He had additionally experienced several episodes of aplastic anemia due to chronically active parvovirus infection, for which he was receiving periodic IV immunoglobulin. At the time of presentation with hypoalbuminemia, the patient's active medical issues included stage 3 chronic renal failure, pacemaker (DDD) dependence due to complete heart block, chronic parvovirus infection, and right heart dysfunction. Ongoing medical therapies included the antirejection regimen (corticosteroid, mycophenolate mofetil, and tacrolimus), bumetanide, spironolactone, hydrochlorothiazide, enalapril, darbepoetin, lansoprazole, and micronutrient supplements.
At presentation, the teenager had gained approximately 10 kg weight, developed generalized edema, increased stool frequency during the earlier month (watery, 4–5times per day), abdominal cramping, and a lower extremity cellulitis. At its nadir, blood albumin level decreased to 14 g/L (normal range 31–48 g/L). In addition, hypogammaglobulinemia was noticed and at their nadir, IgM levels were 0.36 g/L (normal 0.38–1.49 g/L), IgA 0.50 g/L (normal 0.86–4.80 g/L), and IgG 1.46 g/L (normal 6.36–17.01 g/L). Investigations revealed an elevated 24-hour α1-antitrypsin stool clearance (1.8 g/L [normal range 0–0.72 g/L] at a time when serum albumin was 18 g/L), confirming the diagnosis of protein-losing enteropathy. Abdominal imaging revealed dilated inferior vena cava and hepatic veins, small bowel wall thickening, a small amount of ascites, and a pleural effusion, without evidence of an overt mass/underlying pathology.
Attempts were made to manage the patient's hypoalbuminemia with dietary interventions (high-protein, high-MCT semielemental formula supplements) as well as periodic 25% albumin infusions with furosemide. Due to failure of this, further investigations were performed. Videocapsule endoscopy showed nonspecific signs of very mild jejunitis and ileitis characterized by scattered foci of mucosal edema and erythema, petechiae, and areas of atrophic, clubbed, or white-tipped villi. Several weeks later, an upper endoscopy revealed a duodenum with a diffuse snowflake pattern, and milky secretions in the duodenal bulb, suggestive of lymphangiectasia (Fig. 1A). Duodenal biopsies confirmed the presence of numerous dilated lymphatics, consistent with a diagnosis of IL (Fig. 1B). There was no recurrence of the earlier eosinophilic infiltrate in the duodenum, nor in the rectosigmoid. Infectious work-up performed at that time, including stool cultures, stool ova and parasites, stool cryptosporidium stain, cytomegalovirus in gastric, rectal, and duodenum biopsies, and Strongyloides enzyme-linked immunosorbent assay optical densities were all negative.
Due to the refractory nature of the hypoalbuminemia during a period of >9 months, the decision was made to institute a trial of subcutaneous octreotide. The patient was hospitalized, IV albumin infusions were provided until normalization of blood albumin levels, and the patient was begun on 50 μg twice a day of subcutaneous octreotide (Fig. 2). Laboratory parameters and vital signs were followed for imbalances related to the octreotide. Subsequent to the initiation of octreotide, albumin infusions were discontinued. The patient's weight decreased from 54.6 to 44.4 kg. The patient's compliance with dietary intervention/specialized formula remained questionable subsequent to this intervention; however, with the use of octreotide injections, compliance of which was ensured by parental administration, the patient maintained a normal albumin level for a period of >18 months.
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IL, a rare form of protein-losing enteropathy, was first described by Waldmann et al (2) in 1961. It may be primary/congenital (type 1), or secondary to lymphatic damage/obstruction from inflammation, abdominal surgery, malignancies, infections, radiotherapy, and cardiac and retroperitoneal diseases (type 2) (1,3). IL may present with nonspecific gastrointestinal complaints, including diarrhea, nausea, vomiting, failure to thrive/weight loss, fatigue, and abdominal distention and discomfort. Other presentations may include shortness of breath or chest discomforts due to complications such as pleural effusion, chylous ascites, and pericardial effusion (1), and increased susceptibility to infections due to impaired neutrophil function and lymphocyte loss (4). Laboratory findings may include elevated 24-hour stool α1-antitrypsin clearance, hypoalbuminemia, hypoproteinemia, edema, lymphopenia, low immunoglobulin levels due to lymphatic leakage/protein losses, and in more severe cases, hypocalcemia and fat-soluble vitamin deficiencies (1,4,5). Upper endoscopy with small bowel mucosal biopsy allows confirmation visually and on histopathology, with the finding of ballooned lacteals with leakage of chyle-like protein-rich fluid (Fig. 1B) (4).
Whenever possible, pathologies leading to secondary IL are managed/corrected to alleviate symptoms. With primary IL, if the area of involvement is limited, surgical resection may be curative. The main medical management of IL consists of a high-protein and low-fat diet, with use of MCT. It is hypothesized that with the direct absorption of MCT via the portal venous system, splanchnic lymph flow is not stimulated, thus avoiding the engorgement of the gastrointestinal lymphatic system and preventing rupture of lymphatics with leakage of proteins, immunoglobulin, and T lymphocytes (1). Difficulty with this type of diet lies in the compliance. In addition, due to the finding that mucosal fibrinolytic activity appears increased in patients with IL, antiplasmin therapy has been reported (5,6).
Octreotide, a long-acting somatostatin analog, also has been used occasionally as a treatment option for refractory IL, leading to the improvement of hypoalbuminemia and controlling clinical symptoms (3,7–16) (Table 1). The known systemic effects of octreotide include suppression of gastrointestinal motility and hormonal secretions by the pancreas, gastrointestinal tract, and pituitary gland. Adverse effects may include pain at the injection site, headaches, fatigue, sinus bradycardia, diarrhea, flatulence, abdominal discomfort, dizziness, nausea and vomiting, and either hyper- or hypoglycemia (17). Long-term effects may include formation of cholesterol gallstones, pancreatitis, and growth restriction (17). There is limited information published regarding the mechanism of action of octreotide in the management of IL. Five human somatostatin receptors (SSTR) have been described. SSTR1 and SSTR5 are the receptors distributed across the gastrointestinal tract and are thought to account for the different effects of somatostatin (14). Somatostatin has been shown to reduce the release of acetylcholine in the intestinal plexus, with potential effects on gastrointestinal motility and absorption (14). Somatostatin also may decrease triglycerides in thoracic duct lymph and intestinal absorption of fats (3). Furthermore, octreotide may inhibit the excretion of lymph by the vascular effect of local SSTRs (7). It has also been speculated that octreotide may function via stimulation of the autonomic nervous system, inhibition of vasoactive peptides (8), reduction in intestinal blood flow, and/or the local release of vasoactive substances due to microscopic inflammatory changes (5). Some have reported a more general effect of octreotide on gastrointestinal functions (motility, digestion, and absorption) and vascular tone by decreasing the secretion of gastrin, motilin, secretin, gastric inhibitory peptide, neurotensin, insulin, glucagons, and pancreatin. Gastrointestinal transit would thereby be delayed, promoting intestinal absorption (18). Any or all of these mechanisms may be responsible for the clinical improvement observed in IL.
Adequately managing secondary lymphangiectasia often proves problematic, and in complex patients, there may be reluctance to add pharmacologic therapy with its own inherent risks and discomforts; however, for certain children, the severity and persistence of clinical symptoms warrant the consideration of rarely used agents. The teenager described presented with a secondary lymphangiectasia with hypoalbuminemia and symptoms resistant to conventional therapy during a period of several months. Despite the possible presence of Strongyloides in 2007, this was followed by normalization of results posttherapy, and neither histology nor serology was suggestive of recurrence in 2009. Hence, the absence of infectious agents being found, the chronologic increase of albumin values immediately after initiation of octreotide and continued good status of the patient longitudinally support that octreotide therapy was the factor responsible for the improvement.
Pediatric IL is a difficult-to-manage condition. The present case is the first description of secondary IL in a transplant recipient successfully treated with octreotide. Given the balance between harm and potential benefit, subcutaneous octreotide should be considered in the therapeutic options available in cases of IL not responding to conventional therapy.
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