Isolated small bowel transplantation for tufting enteropathy.

Abstract

Tufting enteropathy is a chronic malabsorptive syndrome beginning in infancy that is characterized histopathologically by the presence of “tufts” of closely packed surface enterocytes in the bowel, along with features of villous atrophy and crypt hyperplasia (1,2). The significance of these tufts is not fully understood, and there is no effective treatment (3). Patients usually require total parenteral nutrition indefinitely, which can lead to line sepsis, total parenteral nutrition–induced liver failure, and loss of intravenous access. Only one instance of combined liver/intestinal transplantation for tufting enteropathy associated with end-stage liver disease from total parenteral nutrition has been reported (4). The impact of isolated intestinal transplantation on both developing liver disease and the course of the primary disease are unknown. Here we describe the first case in which isolated intestinal transplantation was used to treat tufting enteropathy in a patient with impending liver failure from total parenteral nutrition. CASE REPORT A 3-week-old female infant of Arab descent with persistent diarrhea and failure to thrive could not tolerate breast milk or other enteral formulae. She experienced vomiting and watery diarrhea (>60 mL/kg/d) with any oral intake. She had impaired growth and required parenteral nutrition. There was a history of consanguinity between her parents, but no family history of malabsorptive syndromes. She had an uncomplicated perinatal course and two healthy siblings. Physical examination was normal, and her karyotype was 46XX. Echocardiography, x-ray bone survey, and contrast urinary tract study showed no organ system defects. Stool evaluation showed no pathogens, and result of evaluation for reducing substances was negative. An upper gastrointestinal series and endoscopy were normal. Antienterocyte immunoglobulin G and A antibodies were not detected. Analysis of pancreatic secretions showed a deficiency in lipase enzyme secretions. Trypsin, amylase, and chymotrypsin activities were normal. Activity of lactase, sucrase, maltase, and palatinase in duodenal and jejunal mucosal biopsy specimens was decreased. Proximal intestinal biopsy specimens showed moderate villous atrophy associated with crypt hyperplasia. Tufts within the superficial epithelium covered more than 70% of the specimen (Fig. 1), and lymphocytes and plasma cells in the lamina propria were not increased. Electron microscopy of the specimen revealed a normal microvillous brush border, with no intracytoplasmic inclusions. A diagnosis of tufting enteropathy was made. Colonic biopsy specimens initially showed evidence of tufting enteropathy throughout the colon, but on repeat biopsy 3 months later, only the rectum was involved. Her symptoms remained unchanged during this period.FIG. 1.: Small intestinal mucosal biopsy specimen with partial villous blunting, crypt hyperplasia, and widespread “tufting” (arrows) of the superficial epithelial cells (original magnification, 100×). Higher magnification (inset) shows clumping of the enterocytes, producing a teardrop or micropapillary appearance of the cells (original magnification, 200×). (Hematoxylin and eosin stain.)At 31 months of age, her oral intake was minimal, she had suffered repeated severe line sepsis episodes, including fungal sepsis, and had developed jaundice. She had mild hepatosplenomegaly with no ascites. She had a platelet count of 153 × 109/L, INR of 1.2, bilirubin concentration of 2.9 mg/dL, and ALT concentration of 56 IU/L. Liver biopsy results showed cholestasis and steatosis, but her weight was below the 25th percentile and her height was below the 5th percentile. In the setting of failure to thrive and impending liver failure, intestinal transplantation was planned. At transplantation of a cadaveric graft, her native bowel appeared chronically dilated and thin-walled. The donor graft was anastomosed to the proximal jejunum, a feeding tube was placed, and a Bishop-Koop ileostomy was constructed. Direct mesenteric vascular reconstruction was used. Initially, she was fed a hypotonic elemental formula, which was slowly increased in concentration. Immunosuppression included tacrolimus (15–20 ng/dL for the first 6 weeks), sirolimus (10–15 ng/dL for 6 weeks), basiliximab (10 mg intraoperatively, postoperatively, and on day 4), and steroids. She was discharged home 4 weeks after surgery. Tacrolimus and sirolimus were weaned over 3 months to maintain serum concentrations of 5 to 8 ng/dL. She had a single episode of rejection requiring steroid treatment 2 months after transplant. At 6 months after transplant, her weight was above the 50th percentile, and her ileostomy was closed. Repeat endoscopic biopsy results of her native colon have shown no evidence of tufting, but tufts in the native jejunal remnant persist. At 19 months since transplant, she is on an unrestricted diet, with two to four soft bowel movements daily. Bilirubin and platelet counts have returned to normal, and she has no clinical stigmata of liver disease. DISCUSSION Intractable diarrhea of infancy encompasses several disease conditions, and tufting enteropathy was recognized as one of these by Reifen et al. (2) in 1994. The investigators described three infants with persistent diarrhea and negative stool cultures that did not resolve with removal of dietary antigens or immunosuppressive therapy. Several reports since described the pathognomonic histologic changes associated with this syndrome (3,5), some of which included colonic lesions. Several aspects of this case are noteworthy. Colonic involvement seen on initial biopsy specimens in our patient decreased over time, despite persistence of small intestinal disease. Additionally, even the rectal lesions resolved after transplantation, allowing us to restore colonic continuity. The role of immunosuppression in resolution of colonic lesions remains unclear, although it had no impact on duodenal or proximal jejunal disease. Most patients with tufting enteropathy have been treated with indefinite parenteral nutrition. One of the patients described by Reifen et al. (2) died with persistent diarrhea, and other investigators have reported complications of parenteral therapy, including line sepsis, nutrient deficiencies, and liver failure (6–9). Intestinal transplantation has become a feasible treatment of intestinal failure, with improving results over the past decade (10). Only one report of transplantation for tufting exists (4). The 4-month-old child with tufting developed cholestasis and subsequent cirrhosis. The patient required a combined liver and small bowel transplant and suffered complications related to the liver transplant. Our case demonstrates the feasibility of providing “liver salvage” with isolated intestinal transplantation. Progressive cholestatic liver disease had developed during parenteral nutrition therapy in our patient. The resolution of liver disease on conversion to enteral feeding after transplantation demonstrates that liver disease is not inherent to the underlying tufting defect, at least in some patients. With the high mortality of children awaiting combined liver and intestinal transplantation, early referral for isolated bowel transplantation in such cases is critical. In summary, early diagnosis and timely transplantation allowed liver salvage in this patient, indicating that liver disease is not inherent to the natural history of this entity. Tufting persisted in the short native jejunal remnant after transplantation despite modern intense immunosuppression, although rectal lesions resolved. The remaining upper tract lesions have not caused clinical symptoms, and their persistence strengthens the hypothesis of Abely et al. (5), that tufting enteropathy may be part of a non–immune-mediated disease. As colonic lesions were resolving before transplantation, it is improbable that continued resolution of these lesions was directly caused by institution of immunosuppressive therapy. Adequate colonic function allows reanastomosis and no requirement for a life long stoma. As increased awareness of this disorder leads to earlier diagnosis, close monitoring of such patients for complications of parenteral nutrition should prompt earlier consideration of isolated intestinal transplantation with continuing improved results.