Current Status of Intestinal Failure and Intestinal Transplantation

Home , Bowel resection

pISSN: 2234-8646 eISSN: 2234-8840 http://dx.doi.org/10.5223/pghn.2012.15.3.127 Pediatric Gastroenterology, Hepatology & Nutrition 2012 September 15(3):127-137 Invited Review PGHN Current Status of Intestinal Failure and Intestinal Transplantation

Jae Sung Ko, M.D.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea

Pediatric intestinal failure occurs secondary to short bowel syndrome, motility disorders, or malabsorption. The estab- lishment of an intestinal rehabilitation program and the introduction of innovative surgical and medical treatments, such as the serial transverse enteroplasty procedure and omega-3-containing lipid emulsions, have been major advances in the treatment of intestinal failure. Intestinal transplantation is now established as a therapeutic modality in selected children with irreversible intestinal failure. The improved short to intermediate term survival of intestinal transplant recipients in the last decade can be attributed to immunosuppression with a lymphocyte-depleting agent, control of acute cellular rejection, and comprehensive infection control with careful monitoring of viral pathogens including cytomegalovirus and Epstein-Barr virus. (Pediatr Gastroenterol Hepatol Nutr 2012; 15: 127∼137)

Key Words: Intestinal failure, Short bowel syndrome, Intestinal transplantation, Child, Survival

INTRODUCTION plantation was performed in Boston in 1964. Intestinal transplantation is an established, life-sav- Intestinal failure in infants and children is defined ing modality for patients with intestinal failure who as the inability to achieve adequate weight and develop significant parenteral nutrition-associated growth without supplemental parenteral nutrition complications. [1,2]. It occurs when there is a reduction of functional gastrointestinal mass below the minimal INTESTINAL FAILURE amount necessary for adequate digestion and absorption to maintain appropriate protein-energy, flu- Etiology id, electrolyte, or micronutrient balance. Short bowel SBS is a form of intestinal failure resulting from syndrome (SBS) is the most common cause of in- surgical resection, congenital defect, or diseases asso- testinal failure [3]. Intestinal failure may occur in pa- ciated with the loss of absorptive surface area. The in- tients with apparent normal intestinal anat- cidence of SBS has been estimated to be between 3-5 omy/length secondary to motility disorders and and 24.5/100,000 births per year [4,5]. Advances in malabsorption. The first human intestinal trans- neonatal intensive care, anesthesia, nutrition sup-

Received：August 27, 2012, Revised：September 1, 2012, Accepted：September 3, 2012 Corresponding author: Jae Sung Ko, M.D., Department of Pediatrics, Seoul National University Children's Hospital, 101, Daehak-ro, Jongno-gu, Seoul 110-744, Korea. Tel: +82-2-2072-2197, Fax: +82-2-743-3455, E-mail; [email protected]

Copyright ⓒ 2012 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition This is an openaccess article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY & NUTRITION Pediatr Gastroenterol Hepatol Nutr port, and surgical techniques have improved the sur- growth and, hence, bowel adaptation than full term vival of infants such that the prevalence of SBS has infants. The presence of an ileocecal valve is a marker increased in recent years [6]. The common etiologies for the remaining ileum and this may in fact be the of SBS include necrotizing enterocolitis (NEC), gas- underlying important determinant for weaning from troschisis, intestinal atresia, and midgut volvulus [7]. parenteral nutrition, rather than the presence of the NEC is the most common disorder resulting in SBS valve itself. The loss of colonic length has a relatively and subsequent intestinal failure in children. modest effect on the necessity for long-term paren- Hirschsprung disease involving the small bowel as teral nutrition. In general, the primary function of well as the colon is a cause of SBS. The residual length the colon is fluid and electrolyte absorption [10]. of short bowel, an intact ileocecal valve, and preser- The search for a biomarker to predict the adaptive vation of the right colon are important factors for sur- ability of the intestine is critical with regard to prog- vival and adaptation [1]. nosis and the decision to transplant or continue re- Intestinal failure may occur in patients with appa- habilitative efforts. Plasma citrulline, a nonessential rent normal intestinal anatomy/length secondary to amino acid produced almost exclusively by enter- motility disorders and malabsorption. Chronic in- ocytes, appears to be an excellent biomarker. testinal pseudoobstruction is a heterogeneous group Intestinal failure patients with a serum citrulline lev- of rare disorders, presenting with symptoms and el ＜12 mmol/L are usually unable to wean from pa- signs of intestinal obstruction, but without a me- renteral nutrition [11]. chanical obstruction. They result from a variety of ab- normalities in the enteric nervous system or muscu- Nutritional deficiency lature, and can affect variable segments of the gastro- Maintenance of proper electrolyte balance is intestinal tract. Congenital diseases of enterocyte de- important. Children with SBS and an enterostomy or velopment such as microvillus inclusion disease and poor colonic function lose much more sodium than tufting enteropathy [8] cause intestinal failure. Most potassium in their stool and may have enormous pa- children suffering from congenital enteropathy re- renteral sodium needs. Total body electrolyte levels main permanently dependent on total parenteral nu- (e.g., potassium, sodium, magnesium) may be re- trition (TPN). duced in the face of normal serum levels. Therefore, urinary levels may be a more accurate reflection of Adaptation the total body condition. Sodium should be ad- Adaptation is the spontaneous recovery of in- ministered in TPN in a quantity adequate to maintain testinal function following massive surgical urinary sodium ＞30 mEq/L and sodium to potas- resection. Intestinal adaptation is marked by an in- sium ratios approximating 1：1. Prolonged sodium crease in intestinal epithelial absorptive capacity as a losses lead to growth failure [12]. Low serum bicar- compensatory measure for the loss of functional in- bonate may be managed by increasing acetate in the testinal mass. After surgical resections, adaptation parenteral nutrition. begins almost immediately, but bowel function gen- Hypocalcemia can be a consequence of fat mal- erally cannot improve over time in patients with mi- absorption. Fatty acids bind calcium, leading to the crovillus inclusion disease, tufting enteropathy, and absorption of free oxalate and loss of calcium in the chronic idiopathic intestinal pseudo-obstruction. stool. Free urinary oxalate in large amounts bind in In the absence of any surgical bowel lengthening the renal tubules with calcium to form calcium ox- and tapering procedure, 35 cm of the neonatal small alate stones and decrease the amount of absorbed bowel is associated with a 50% probability of weaning calcium [13]. from parenteral nutrition [9]. Generally, premature Trace element depletion is common among pa- neonates have a greater capacity for intestinal tients with SBS if parenteral administration is

128 Vol. 15, No. 3, September 2012 Jae Sung Ko：Current Status of Intestinal Failure and Intestinal Transplantation inadequate. Adequate parenteral zinc supplementa- deficiency. But, after weaning of TPN, enteral supple- tion is particularly important among patients who mentation is advisable. After transition to full enteral have undergone extensive intestinal resection be- nutrition, the most common micronutrient deficien- cause zinc losses are as high as 17 mg/L in ileostomy cies are vitamin D, zinc, and iron [17]. fluid [14]. Severe zinc deficiency results in acro- Patients with SBS may develop gastric hyper- dermatitis enteropathica, characterized by a rash of secretion [18]. Because most gastrin catabolism the face, hands, feet, and genitalia. It is common for takes place in the small intestine, these patients be- children with SBS to require 300-500 μg/kg/d of come hypergastrinemic and produce excessive gas- zinc. Serum zinc levels tend to be decreased when a tric acid and gastric volume. The volume produced patient is systemically zinc deficient, but serum levels may contribute to fluid and electrolyte losses, and the correlate relatively badly with the deficiency. As zinc hyperacidity may result in peptic ulceration. Acid hy- is a cofactor for alkaline phosphatase synthesis, a sur- persecretion may be associated with deactivation of rogate marker for zinc deficiency is the serum alka- pancreatic enzymes and bile acid precipitation with line phosphatase level, which is likely to be decreased subsequent ineffective micelle formation. For pain patients with the clinical manifestations of zinc tients with excessive enteral fluid losses soon after deficiency. small bowel resection, a trial of acid suppressing Copper deficiency is a trace element deficiency that medications is suggested. The gastric hypersecretion is often iatrogenically induced [15]. It is a common typically resolves during the first few months after dogma that among children with parenteral nu- surgery. trition-associated liver disease (PNLD), hepatic copper retention places an excessive oxidative burden Bacterial overgrowth upon the liver. The common practice is to reduce or Bacterial overgrowth of the small intestine is an eliminate parenteral copper in patients with PNLD. important pathophysiologic change in SBS [19]. This may result in copper deficiency resulting in neu- Adverse effects include deconjugation of bile acids, tropenia, thrombocytopenia, or pancytopenia. If which render them incapable of forming micelles, these findings are present in children on copper-defi- competitive metabolism and use of enteral nutrients cient TPN, copper and ceruloplasmin levels should be and vitamins, synthesis of toxic byproducts such as measured, and copper replaced, if evidence for copper d-lactate, and bacterial translocation to produce deficiency exists. septicemia. Small bowel bacterial overgrowth is usu-

Vitamin B12 levels are of particular concern in pa- ally associated with anorexia, vomiting, diarrhea, tients with an ileal resection. Vitamin B12 assays can cramps, abdominal distention, D-lactic acidosis, and be unreliable, therefore additional screening of urine failure to thrive. In addition, bacterial overgrowth ex- methylmalonic acid, which accumulates in B12 defi- acerbates hepatotoxicity related to parenteral nutri- ciency, is advisable [16]. Vitamin B12 malabsorption tion. A rational antibacterial strategy is to give cycled requires life-long vitamin B12 supplementation, usu- 10-14-day courses of antibiotics specific for their ally accomplished with monthly intramuscular anaerobic spectrum. These could be followed by 14– injections. 20-day rest periods. Antibiotics of choice include Provision of enteral water-soluble vitamins is un- metronidazole and rifaximin [20]. necessary while patients are on parenteral vitamin supplements. But, if adaptation occurs and patients Catheter-related infections are weaned off TPN, enteral provision of most wa- A central venous catheter (CVC) is essential for ter-soluble vitamins is recommended. Fat-soluble vi- children for whom long-term TPN is anticipated. tamin supplementation is delivered via parenteral vi- Strict protocols for line care, for accessing CVCs, and tamins and parenteral lipid, generally preventing for dressing changes are customarily employed to de-

www.kjpgn.or.kr 129 Pediatr Gastroenterol Hepatol Nutr crease the frequency of line-associated compli- a multidisciplinary approach to the management of cations. One of the factors resulting in repeated line parenteral nutrition with a specialized nutritional infections may be the propensity of bacteria to form care team, and aseptic catheter techniques to reduce biofilms adherent to the walls of CVCs that provide sepsis. Fish oil is rich in omega-3 fatty acids that have nutrients to viable, but aggregated bacteria, as well as potential anti-inflammatory effects upon the liver. protection from systemic antibiotics. Bacteria are pe- The use of fish oil containing lipid emulsions (e.g., soy riodically shed from these films and produce sys- bean/medium chain triglyceride/olive oil/fish oil) im- temic infections. proves established cholestasis and may prevent the Any suspicion for catheter-related infections needs onset in premature infants and children [25,26]. to be thoroughly assessed. A child with SBS and Efforts to cycle TPN in an attempt to better mimic in- symptoms of fever, lethargy, irritability, or abdomi- testinal physiologic and hormonal regulation have nal distension may have catheter-related infections. been employed to enhance adaptation as well as im- The most important investigation to confirm catheter prove cholestasis [27]. Oral administration of urso- related infections is a blood culture through the cen- deoxycholic acid may improve bile flow and reduce tral line. If the patient’s clinical presentation is con- gall bladder stasis, although there is little data to sug- gruent with catheter-related infections, broad spec- gest that prophylactic use prevents the onset of PNLD trum intravenous antibiotics are started through the [28]. central line. All patients using long-term parenteral nutrition A promising therapy in the prevention of catheter are at risk for metabolic bone disease (osteoporosis related infections is the use of ethanol locks. Ethanol and osteomalacia) and should have a dual-energy can penetrate biofilms that form on central lines, and x-ray absorptiometry scan performed in their first no bacteria or fungi have been reported to be resistant year [29]. to ethanol. The ethanol lock therapy for the prevention of catheter related infections in pediatric in- Enteral nutrition testinal failure patients significantly decreases blood- Prompt transition to enteral nutrition is the most stream infection rates [21,22]. important intervention in infants with intestinal failure as it obviates PNLD and catheter-related infec- PNLD tion. Maintenance of enteral nutrition is a crucial One of the most devastating disorders in patients step in guaranteeing that the maximal adaptive re- on long-term TPN is PNLD. Patients on TPN are at risk sponse will occur following a resection. An optimal for fatty liver, hepatic fibrosis, and cholestasis. The formula for the provision of calories in pediatric in- pathogenesis is multifactorial and is related to pre- testinal failure has not clearly been established. Both maturity, low birth weight, duration of TPN, SBS re- breast milk and commercially available elemental quiring multiple laparotomies, and recurrent sepsis. formulas are associated with a reduction in the time Other important mechanisms include lack of enteral of parenteral nutrition dependence in infants with feeding that leads to reduced gut hormone secretion, SBS [9]. There is little consensus as to the timing of reduction of bile flow and biliary stasis that leads to initiation of feedings, but evidence suggests that fol- the development of cholestasis, and biliary sludge and lowing surgery for NEC, early feeding is associated gallstones that exacerbate hepatic dysfunction, espe- with no greater recurrence rate but a shorter time to cially in premature neonates with immature hepatic reach full feedings [20]. As soon as 12 hours after ab- function [23]. The use of lipid emulsions, particularly dominal surgery, neonates can tolerate small vol- soy bean emulsions, have been associated with cho- umes of breast milk [30]. Feedings can be initiated as lestasis in children [24]. Management strategies for bolus feedings or continuous feedings via a gastro- the prevention of PNLD include early enteral feeding, stomy or nasogastric tube. Although bolus feedings

130 Vol. 15, No. 3, September 2012 Jae Sung Ko：Current Status of Intestinal Failure and Intestinal Transplantation recapitulate oral feeding through hormonal stim- and lengthening procedures that can improve the ab- ulation, continuous feedings may provide better sorptive capacity of the failing gut and shorten the absorption. duration of parenteral nutrition. Serial transverse en- Limitations to advancing enteral feeding are teroplasty (STEP) creates transverse divisions from stool/stoma output, abdominal distention, and alternating directions resulting in an accordion type vomiting. Stool/stoma output is traditionally limited lengthening of the dilated segment. STEP improves to 40-50 mL/kg per day, although higher volumes are enteral tolerance and results in significant catch-up often tolerated as long as hydration and electrolyte growth [37]. stability can be maintained [31]. Intestinal rehabilitation program Medical and surgical management Although relatively few children suffer from in- Through adaptation, small intestinal surface area testinal failure, the morbidity and mortality asso- and absorptive function may improve over time to fa- ciated with it is high, which can have a profound im- cilitate weaning from parenteral nutrition. Beyond pact upon both healthcare costs and resources. These provision of enteral nutrition, ancillary therapies financial implications as well as the recognized com- such as judicious use of acid suppression, prokinetics plexity of patient needs including medical, nutri- and antidiarrheal agents seem to accelerate the rate tional, psychosocial, surgical, behavioral, and other of adaptation in young children. Clinical studies have aspects of care have led to the development of in- demonstrated improved gastric motility and post- testinal rehabilitation programs designed to support a operative intestinal dysmotility with low-dose multidisciplinary approach to capture individual ex- erythromycin. Oral erythromycin is associated with a pertise in these areas. The goals of each intestinal re- shorter time to full enteral feeds, a decrease in the du- habilitation program are to achieve enteral, if not oral ration of parenteral nutrition requirements, and a re- autonomy, freeing of the child from CVC and enteral duction in the incidence of parenteral nutrition- as- feeding devices; to reduce morbidity and mortality associated cholestasis [32]. Antidiarrheal drugs such as sociated with intestinal failure and its management; loperamide decrease stool output from an ileostomy and to identify those children who will likely not sur- [33]. Recommended dosage for loperamide is vive without intestinal transplantation [38]. 0.08-0.24 mg/kg/day divided two or three times. Cholestyramine often improves diarrhea associated INTESTINAL TRANSPLANTATION with bile salt malabsorption. In parenteral nutrition dependent patients with Indication and type SBS, the use of recombinant human growth hor- Despite appropriate multidisciplinary treatment of mone has led to variable results [34,35]. More re- intestinal failure, 20-40% of children with intestinal cently, the focus has shifted to glucagon-like peptide failure remain parenteral nutrition-dependent and 2 and its analogues (Teduglutide) as a strategy to reg- those who developed parenteral nutrition complica- ulate maintenance and adaptive growth of the small tions, including line sepsis and PNLD, are considered intestinal mucosa. Phase III studies have indicated for an intestinal transplantation [39]. the potential of Teduglutide in reducing the need for There are three major types of grafts: isolated intes- parenteral nutrition in adult patients with SBS [36]. tine; liver-intestine, which usually includes the duo- No studies involving Teduglutide have been inves- denum and head of pancreas to avoid the need for a tigated in the pediatric population. biliary anastomosis; and multivisceral, which con- A combined medical and surgical treatment is a tains intestine with stomach, duodenum, pancreas key factor in successful intestinal adaptation. and possibly colon, with liver (full multivisceral) or Surgical interventions include early stoma closure without liver (modified multivisceral). Isolated in-

www.kjpgn.or.kr 131 Pediatr Gastroenterol Hepatol Nutr testine grafting is indicated for patients with limited three decades has likely contributed to improved venous access, recurrent line infections, reversible graft and patient survival. The recent strategy in liver failure as a result of parenteral nutrition, and many centers is to use a recipient preconditioning unmanageable fluid and electrolyte problems asso- protocol with a lymphocyte-depleting agent, such as ciated with parenteral nutrition. The liver should be rabbit anti-thymocyte globulin (thymoglobulin) or added to an intestine graft when the recipient has ir- alemtuzumab (Campath), a monoclonal anti-CD52 reversible liver damage as a result of parenteral nu- antibody, and to dramatically reduce acute rejection trition, usually manifested by severe fibrosis with or [42]. This has enabled a reduction in posttransplant without portal hypertension and liver dysfunction. tacrolimus, and often withdrawal of steroids, with Multivisceral transplants are indicated for children subsequent minimization of long-term side-effects of with severe motility disorders such as chronic in- immunosuppression. Antithymocyte globulin is giv- testinal pseudo-obstruction or patients with ex- en as a single dose of 5 mg/kg administered over 4-6 tensive abdominal pathology that cannot be safely hours and completed prior to reperfusion of the removed without an evisceration or reconstruction allograft. Alemtuzumab, which has now largely re- with multiple organs (e.g., children with multiple placed thymoglobulin in most centers, is infused as a previous operations and severe portal hypertension) single intravenous dose of 0.5 mg/kg up to a max- [40]. Isolated intestinal transplantation has been imum of 30 mg, infused over 2 hours on induction of more frequently performed in adults (55% of all in- anesthesia. Using this strategy, many patients have testinal transplants) than children (37%), in whom been stabilized on low-dose tacrolimus mono- liver-intestine transplants are required more fre- therapy. quently (50%) due to the greater incidence of PNLD in children. Graft rejection Living donor intestinal transplantation has several Acute cellular rejection occurs in 60% of children potential advantages including elimination of wait- with intestinal transplantation, is severe in over a ing time, elective nature of the procedure, better hu- third, and limits long-term survival [43]. The highly man leukocyte antigen (HLA) matching, and short immunogenic small bowel allograft contains a large cold ischemia time. In particular, the best indication amount of gut-associated lymphoid tissue, of which is probably living donor liver-intestine trans- donor dendritic cells elicit the most potent immune plantation in pediatric patients with intestinal and response from the recipient. hepatic failure. In this setting, the virtual elimination Acute cellular rejection is usually characterized by of waiting time may avoid the high mortality experi- diarrhea and disruption of the gut mucosal barrier, enced by candidates on the deceased waiting list which may lead to bacterial sepsis and fever. A ma- [41]. jority of the episodes occur during the first 90 days, A gastrostomy or jejunostomy feeding tube is when most recipients still have indwelling central ve- placed to facilitate early posttransplant enteral nu- nous lines for fluid management, as the transplanted trition and rehabilitation, and enteral feeding is allograft is adapting to its new environment. started at postoperative day 5 to 7 following reso- Therefore, bacteremia and fever should not be la- lution of the postsurgical ileus. A temporary ileos- beled catheter-related infections alone, but should be tomy (loop or chimney) provides easy access to the considered as manifestations of acute cellular re- intestinal mucosa for routine surveillance biopsies to jection and should lead to endoscopic biopsies to ex- monitor rejection and infection [42]. clude rejection [44]. Early detection and prompt treatment of graft rejection and infections have con- Immunosuppression tributed to the improved results of intestinal Modification of immunosuppression over the past transplantation. Protocol ileoscopies with intestinal

132 Vol. 15, No. 3, September 2012 Jae Sung Ko：Current Status of Intestinal Failure and Intestinal Transplantation biopsies are recommended to monitor the intestine bleeding, and graft malfunction with weight loss. graft after transplant. The surveillance biopsy sched- The pathology of chronic rejection is intimal hyper- ule is biweekly in the first month, weekly during the plasia and obliterative arteriopathy in the sub- second month, and bimonthly during the third mucosal layers. Endoscopic biopsies may show mu- month. The endoscopic findings of acute rejection in- cosal and submucosal fibrosis and atrophy, distorted clude blunted and short villi, edematous and friable villi, crypt damage, and occasionally arteriopathy of mucosa, superficial or deep ulcers, and diffuse mu- small arterioles [48]. However, a full thickness biopsy cosal exfoliation; these findings can be mimicked by is needed to confirm this diagnosis, which is man- infection. The histopathological features of acute cel- ifested by atherosclerotic-type lesions with eccentric lular rejection include a mixed but mostly mono- intimal hyperplasia and concentric fibrous intimal nuclear infiltrate with activated lymphocytes, villus thickening in the large and medium-size arteries. blunting and crypt epithelial cell apoptosis [45]. The Rates of chronic rejection are significantly lower in rejection is graded as indeterminate, mild, moderate patients with liver containing allografts (liver–intes- or severe depending upon the extent of the mucosal tine and full multivisceral) than liver-free allografts, injury and the degree of inflammatory infiltrate and confirming a protective immunomodulating effect of apoptosis. With severe acute rejection, the changes the liver [49]. Patients with recurrent, early, and se- mentioned earlier are accompanied by diffuse mu- vere acute rejection are more susceptible for chronic cosal ulceration and erosion up to a complete loss of rejection and should be carefully monitored to ensure the bowel morphology and mucosal sloughing. optimal immunosuppressive treatment and avoid Treatment of mild acute rejection involves methyl- further episodes of acute rejection. Unlike acute re- prednisolone pulse therapy, with a temporary in- jection, recipient pretreatment does not appear to crease in the tacrolimus dose. Anti-thymocyte glob- protect against chronic rejection. There is no definite ulin or alemtuzumab is reserved for severe or cortico- treatment of chronic rejection because of poor under- steroid unresponsive rejection, and is given for 7-14 standing of the mechanism of this type of rejection, days [42]. and retransplantation is usually the only solution. Acute humoral rejection occurs in a smaller pro- portion, particularly in strongly positive lymphocyto- Infection and posttransplant lymphoprolife- toxic, cross-match transplants [43]. Histolopatho- rative disorder logical features include endothelial swelling, fibrin Infections remain common after transplantation. thrombi in capillaries, ulceration of the mucosa, and It is important to distinguish viral or bacterial enter- the presence of diffuse C4d deposits adjacent to capil- itis from rejection. Most bacterial infection can be lary endothelial cells. These findings correlate with controlled with appropriate antibiotic treatment but the presence of donor specific, anti-HLA antibodies sepsis remains a leading cause of death and accounts (DSA) [44]. Acute humoral rejection is treated with for approximately 50% of the causes of death [40]. In anti-lymphocyte antibody preparations. DSA is also the immediate posttransplant period, prophylactic found in two thirds of acute cellular rejection, and de- systemic antimicrobial and antifungal therapy are clines as rejection episodes resolve [46]. A multi- administered to all recipients. variate analysis of 106 intestinal transplantations A major advance in the reduction of graft failure identified a strong association between DSA and and patient mortality has been improved diagnosis, graft loss [47]. prophylaxis, and therapy of viral infections and their Chronic rejection is observed in about 15% of recip- complications. Cytomegalovirus (CMV) prophylaxis ients, and is the predominant cause of delayed allog- and treatment with intravenous ganciclovir and raft failure and enterectomy [43]. The presentations CMV-specific hyperimmune globulin (cytogam), and include chronic diarrhea, abdominal pain, chronic routine use of polymerase chain reaction (PCR) assay

www.kjpgn.or.kr 133 Pediatr Gastroenterol Hepatol Nutr for early detection, have greatly reduced the adverse This was demonstrated by the results of a 5-year pro- influence of this virus. Monitoring Epstein–Barr virus spective study emerging from the European HPN da- (EBV) by PCR, which might be a prelude posttrans- tabase, which documented a 5-year survival in poten- plant lymphoproliferative disorder (PTLD), enables tial transplant candidates who remained on HPN of reduction of immunosuppression or, in advanced 73%, decreasing to 56% if they had life-threatening cases, the use of the anti-CD20 monoclonal antibody, conditions, such as impending liver failure or des- rituximab [42]. The presence of rising EBV titers on moids tumors [54]. routine surveillance often provides a trigger to reduce Experiences with more than 2,500 cases were re- the dose of maintenance immunosuppression by viewed in the Intestinal Transplant Registry 2011 25-50%. As a result of the use of optimal maintenance Report (http://intestinaltransplant.org). Between immunosuppression, and careful monitoring and 1985 and 2011, 1,277 pediatric intestinal transplants preemptive treatment for EBV, the current incidence have been performed with more than 600 survivors. of PTLD is decreasing to 10% among recipients. Anti-thymocyte globulin or alemtuzumab pretreat- Viral pathogens that usually induce self-limited di- ment-based strategy was associated with significant arrhea in an immunocompetent child can lead to se- improvement in outcome with 1- and 5-year survival vere and prolonged diarrhea in intestinal transplant of 92% and 70%. Despite improvements in short-term recipients. Clinical symptoms and endoscopic find- outcomes, patient survival at 10 and 15 years was on- ings of viral infection and acute rejection overlap. ly 42% and 35%, respectively [43]. Thus, differentiation is often challenging. In addition In one study, the 1-, 3- and 5-year patient survival to hematoxylin and eosin stains, immunohistochem- of 199 children who were transplanted in Pittsburgh istry and use of the PCR may facilitate the identi- in the new era is 95%, 84%, and 77%, respectively. fication of the viruses. Besides common and known Graft survival was 88%, 74%, and 58%, respectively viral pathogens such as CMV, EBV, and rotavirus, [55]. Poor prognostic markers included children other less common enteric viral infection such as ad- younger than 1 year of age, no induction therapy with enovirus and norovirus have emerged in the last dec- interleukin-2 blockers, and waiting in hospital before ade as important pathogens in intestinal transplant transplant [56]. Graft failures have led to retrans- recipients [50,51]. Routine surveillance of CMV, plantation in 7% of pediatric transplants [44]. EBV, and adenovirus in blood and intestinal biopsies Patients can successfully be weaned off TPN within is recommended to ensure early and timely detection a month of intestinal transplantation and maintain of infection. their serum protein parameters and Z-scores for weight in a normal range. However, many have on- Chronic renal failure (CRF) going nutritional deficiencies and demonstrate poor CRF is common after solid-organ transplantation catch-up growth [57]. Most intestinal transplant re- and is a leading cause of posttransplant morbidity and cipients have a good or normal quality of life after mortality. In one study, 8.6% of recipients were on di- transplantation, and their quality of life might be bet- alysis or requiring kidney transplantation for CRF ter than when they were on parenteral nutrition. [52]. Risk factors for CRF include a low preoperative glomerular filtration rate, preoperative intensive care CONCLUSION admission, and high tacrolimus level [53]. Intestinal failure occurs when the functional gas- Outcome trointestinal mass is reduced. A number of manage- Patient and graft survival are now at very least ment strategies are utilized to achieve successful in- equivalent to what would be expected if the patients testinal rehabilitation and maintain adequate were to remain on home parenteral nutrition (HPN). nutrition. These strategies include minimizing the ef-

134 Vol. 15, No. 3, September 2012 Jae Sung Ko：Current Status of Intestinal Failure and Intestinal Transplantation fect of PNLD, limiting catheter complications, and syndrome correlates with clinical outcomes. J Pediatr treating bacterial overgrowth in the remaining small 2001;139:27-33. intestine. Intestinal transplantation is now estab- 10. Gutierrez IM, Kang KH, Jaksic T. Neonatal short bowel syndrome. Semin Fetal Neonatal Med 2011;16:157-63. lished as a therapeutic and cost-effective modality in 11. Fitzgibbons S, Ching YA, Valim C, Zhou J, Iglesias J, selected patients with irreversible intestinal failure. Duggan C, et al. Relationship between serum citrulline As a result of recent surgical advances, control of levels and progression to parenteral nutrition in- acute cellular rejection, and a decrease in lethal independence in children with short bowel syndrome. J fections, survival of intestinal transplant recipients Pediatr Surg 2009;44:928-32. has improved in the last decade. At experienced cen- 12. Schwarz KB, Ternberg JL, Bell MJ, Keating JP. Sodium needs of infants and children with ileostomy. J Pediatr ters, 5-year patient and graft survival rates approach 1983;102:509-13. 80% and 60%, respectively. However, achieving im- 13. Youssef NN, Mezoff AG, Carter BA, Cole CR. Medical proved long-term (＞10 years) graft survival remains update and potential advances in the treatment of pe- a clinical priority. diatric intestinal failure. Curr Gastroenterol Rep 2012;14:243-52. REFERENCES 14. Shulman RJ. Zinc and copper balance studies in infants receiving total parenteral nutrition. Am J Clin Nutr 1. Gupte GL, Beath SV, Kelly DA, Millar AJ, Booth IW. 1989;49:879-83. Current issues in the management of intestinal failure. 15. Hurwitz M, Garcia MG, Poole RL, Kerner JA. Copper Arch Dis Child 2006;91:259-64. deficiency during parenteral nutrition: a report of four 2. Goulet O, Ruemmele F. Causes and management of in- pediatric cases. Nutr Clin Pract 2004;19:305-8. testinal failure in children. Gastroenterology 2006; 16. Green R. Indicators for assessing folate and vitamin 130(2 Suppl 1):S16-28. B-12 status and for monitoring the efficacy of inter- 3. Guarino A, De Marco G; Italian National Network for vention strategies. Am J Clin Nutr 2011;94:666S-72S. Pediatric Intestinal Failure. Natural history of in- 17. Yang CF, Duro D, Zurakowski D, Lee M, Jaksic T, testinal failure, investigated through a national net- Duggan C. High prevalence of multiple micronutrient work-based approach. J Pediatr Gastroenterol Nutr deficiencies in children with intestinal failure: a longi- 2003;37:136-41. tudinal study. J Pediatr 2011;159:39-44. 4. Wallander J, Ewald U, Läckgren G, Tufveson G, 18. Hyman PE, Everett SL, Harada T. Gastric acid hyper- Wahlberg J, Meurling S. Extreme short bowel syn- secretion in short bowel syndrome in infants: associa- drome in neonates: an indication for small bowel trans- tion with extent of resection and enteral feeding. J plantation? Transplant Proc 1992;24:1230-5. Pediatr Gastroenterol Nutr 1986;5:191-7. 5. Wales PW, de Silva N, Kim J, Lecce L, To T, Moore A. 19. Kaufman SS, Loseke CA, Lupo JV, Young RJ, Murray Neonatal short bowel syndrome: population-based esti- ND, Pinch LW, et al. Influence of bacterial overgrowth mates of incidence and mortality rates. J Pediatr Surg and intestinal inflammation on duration of parenteral 2004;39:690-5. nutrition in children with short bowel syndrome. J 6. Schalamon J, Mayr JM, Höllwarth ME. Mortality and Pediatr 1997;131:356-61. economics in short bowel syndrome. Best Pract Res Clin 20. Kocoshis SA. Medical management of pediatric in- Gastroenterol 2003;17:931-42. testinal failure. Semin Pediatr Surg 2010;19:20-6. 7. Squires RH, Duggan C, Teitelbaum DH, Wales PW, 21. Cober MP, Kovacevich DS, Teitelbaum DH. Ethanol- Balint J, Venick R, et al; Pediatric Intestinal Failure lock therapy for the prevention of central venous access Consortium. Natural history of pediatric intestinal fail- device infections in pediatric patients with intestinal ure: initial report from the pediatric intestinal failure failure. JPEN J Parenter Enteral Nutr 2011;35:67-73. consortium. J Pediatr 2012. [Epub ahead of print] 22. Wales PW, Kosar C, Carricato M, de Silva N, Lang K, 8. Ko JS, Seo JK, Shim JO, Hwang SH, Park HS, Kang GH. Avitzur Y. Ethanol lock therapy to reduce the incidence Tufting enteropathy with EpCAM mutations in two of catheter-related bloodstream infections in home pa- siblings. Gut Liver 2010;4:407-10. renteral nutrition patients with intestinal failure: pre- 9. Andorsky DJ, Lund DP, Lillehei CW, Jaksic T, Dicanzio liminary experience. J Pediatr Surg 2011;46:951-6. J, Richardson DS, et al. Nutritional and other post- 23. Kelly DA. Preventing parenteral nutrition liver operative management of neonates with short bowel disease. Early Hum Dev 2010;86:683-7.

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