Kishore Iyer

Teduglutide Reduces Need for Parenteral Support Among Patients With Short Bowel Syndrome With Intestinal Failure

BACKGROUND & AIMS Teduglutide, a glucagon-like peptide 2 analogue, might restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion. These factors could increase fluid and nutrient absorption in patients with short bowel syndrome with intestinal failure (SBS-IF). We performed a prospective study to determine whether teduglutide reduces parenteral support in patients with SBS-IF. METHODS We performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/d; n = 43) or placebo (n = 43) once daily. Parenteral support was reduced if 48-hour urine volumes exceeded baseline values by ≥ 10%. The primary efficacy end point was number of responders (patients with >20% reduction in parenteral support volume from baseline at weeks 20 and 24). RESULTS There were significantly more responders in the teduglutide group (27/43 [63%]) than the placebo group (13/43 [30%]; P = .002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 ± 3.8 L/wk (baseline 12.9 ± 7.8 L/wk) compared with 2.3 ± 2.7 L/wk (baseline 13.2 ± 7.4 L/wk) in the placebo group (P < .001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54%]) than in the placebo group (9/39 [23%]; P = .005). Teduglutide increased plasma concentrations of citrulline, a biomarker of mucosal mass. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3). CONCLUSIONS Twenty-four weeks of teduglutide treatment was generally well tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF; ClinicalTrials.gov Number, NCT00798967.

Improved Adherence and Outcomes for Pediatric Liver Transplant Recipients by Using Text Messaging

OBJECTIVE: The goal was to improve immunosuppressant adherence for pediatric patients with orthotopic liver transplants by using text messaging (TM). METHODS: A prospective study of sending TM reminders to the primary medication administrator (patient or caregiver) for pediatric transplant recipients was performed. Patient records were reviewed, comparing the year before and the year of the study. The SD of serum tacrolimus levels was used as an indicator of adherence. RESULTS: Forty-one patients provided consent. The median age was 15 years (range: 1–27 years), and the median age at the time of transplantation was 2 years (range: 4 months to 23 years). Fourteen patients (34%) were male. In 29 of 41 cases, the medications were self-administered by the patient. The mean duration of study was 13 ± 1.5 months. Twenty-two patients were receiving 1 immunosuppressant, 14 were receiving 2, and 5 were receiving 3. Thirteen patients (37%) stopped the study after 4 months. The mean tacrolimus level SD decreased from 3.46 μg/L before the study to 1.37 μg/L (P < .005). The number of immunosuppressants taken and patient self/caregiver medication administration did not significantly affect the results. The number of acute cellular rejection episodes decreased from 12 to 2 during the study. Risk factors for rejection were older age (17.67 vs 13.28 years) and administration of >1 immunosuppressant. CONCLUSION: We observed significant improvement in medication adherence and a reduction in rejection episodes with TM reminders for pediatric recipients of liver transplants.

Growth Hormone, Glutamine, and an Optimal Diet Reduces Parenteral Nutrition in Patients With Short Bowel Syndrome: A Prospective, Randomized, Placebo-Controlled, Double-Blind Clinical Trial

Objective:To determine if growth hormone (GH) and glutamine (Gln) might allow for a reduction in parenteral nutrition (PN) in individuals with short bowel syndrome. Background Data:Following massive intestinal resection, patients frequently sustain severe nutrient malabsorption and are dependent on PN for life. GH treatment with or without Gln might allow for a reduction in PN. Methods:A prospective, double-blind, randomized, placebo-controlled clinical trial performed in 41 adults dependent on PN. Following screening, patients were admitted to an in-house facility for 6 weeks. After 2 weeks of stabilization and dietary optimization, patients were randomized to one of 3 treatment arms (1:2:2 ratio): oral Gln (30 g/day) + GH placebo (control group, n = 9), Gln placebo + GH (0.1 mg/kg per day, n = 16), or Gln + GH (n = 16). Standard criteria based on clinical and laboratory measurements were followed to determine PN volume and content. After 4 weeks of treatment, patients were discharged and monitored; GH and GH placebo were discontinued, but the diet with Gln or Gln placebo was continued for 3 months. Results:Patients receiving GH + Gln placebo + diet showed greater reductions in PN volume (5.9 ± 3.8 L/wk, mean ± SD), PN calories (4338 ± 1858 calories/wk), and PN infusions (3 ± 2 infusions/wk) than corresponding reductions in the Gln + diet group (3.8 ± 2.4 L/wk; 2633 ± 1341 calories/wk; 2 ± 1 infusions/wk, P < 0.05). Patients who received GH + Gln + diet showed the greatest reductions (7.7 ± 3.2 L/wk; 5751 ± 2082 calories/wk; 4 ± 1 infusions/wk, P < 0.001 versus Gln + diet). At the 3-month follow-up, only patients who had received GH + Gln + diet maintained significant reductions in PN (P < 0.005) compared with the Gln + diet. Conclusions:Treatment with GH + diet or GH + Gln + diet initially permitted significantly more weaning from PN than Gln + diet. Only subjects receiving GH + Gln + diet maintained this effect for at least 3 months.

Intestinal transplant registry report: global activity and trends.

The Registry has gathered information on intestine transplantation (IT) since 1985. During this time, individual centers have reported progress but small case volumes potentially limit the generalizability of this information. The present study was undertaken to examine recent global IT activity. Activity was assessed with descriptive statistics, Kaplan–Meier survival curves and a multiple variable analysis. Eighty‐two programs reported 2887 transplants in 2699 patients. Regional practices and outcomes are now similar worldwide. Current actuarial patient survival rates are 76%, 56% and 43% at 1, 5 and 10 years, respectively. Rates of graft loss beyond 1 year have not improved. Grafts that included a colon segment had better function. Waiting at home for IT, the use of induction immune‐suppression therapy, inclusion of a liver component and maintenance therapy with rapamycin were associated with better graft survival. Outcomes of IT have modestly improved over the past decade. Case volumes have recently declined. Identifying the root reasons for late graft loss is difficult due to the low case volumes at most centers. The high participation rate in the Registry provides unique opportunities to study these issues.

Parenteral nutrition-associated liver disease and the role for isolated intestine and intestine/liver transplantation.

Parenteral nutrition–associated liver disease (PNALD) is the most devastating complication of long‐term parenteral nutrition therapy. Because its progression is typically insidious and its long‐term consequences are generally underappreciated, PNALD is often recognized too late, when liver injury is irreversible. When end‐stage liver disease (ESLD) develops in these patients, most potential interventions are futile and transplantation of both an intestine and a liver becomes the only viable option, despite the relatively poor outcomes associated with this combined procedure. Although likely multifactorial in origin, the etiology of PNALD is poorly understood. Early clinical intervention with a combination of nutritional, medical, hormonal, and surgical therapies can be effective in preventing liver disease progression. If these interventions fail, intestinal transplantation should be performed expeditiously before development of ESLD mandates simultaneous inclusion of a liver graft as well. (HEPATOLOGY 2006;43:9–19.)

A new technique for combined liver/small intestinal transplantation.

The most common application of small bowel transplantation is for the patient with parenteral nutrition-induced liver failure. In this setting, the small intestine is transplanted simultaneously with the liver. We identified three technical problems that we believe contributed to complications in our first eight patients. First, pancreaticoduodenectomy was challenging in the infant donor. Second, the bowel graft was prone to volvulus around the skeletonized donor portal vein. Third, in the pediatric recipient, use of the donor bowel for Roux-en-Y biliary reconstruction was associated with biliary leaks in the early postoperative period. Our surgical technique of liver/small bowel (L/SB) transplantation has evolved since our early experience in 1990. Modifications in the L/SB operation, reported briefly in 1996 and 1997, have led to easier graft preparation and have reduced the incidence of technical complications.

The anatomic pattern of biliary atresia identified at time of kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival

Objective:The goals of this study were to describe the clinical and anatomic features of infants undergoing Kasai portoenterostomy (KPE) for biliary atresia (BA) and to examine associations between these parameters and outcomes. Methods:Infants enrolled in the prospective Childhood Liver Disease Research and Education Network, who underwent KPE were studied. Patients enrolled in a blinded, interventional trial were excluded from survival analysis. Primary endpoints were successful surgical drainage (total bilirubin less than 2 mg/dL within the first 3 months), transplant-free survival (Kaplan-Meier), and time to transplant/death (Cox regression). Results:KPE was performed in 244 infants (54% female; mean age: 65 ± 29 days). Transplant-free survival was 53.7% and 46.7% at 1 and 2 years post-KPE. The risk of transplant/death was significantly lower in the 45.6% of patients who achieved successful bile drainage within 3 months post-KPE (HR: 0.08, P < 0.001). The risk of transplant/death was increased in patients with porta hepatis atresia (Ohi type II and III vs type I; HR: 2.03, P = 0.030), nonpatent common bile duct (Ohi subtype: b, c, and d vs a; HR: 4.31, P = 0.022), BA splenic malformation syndrome (HR: 1.92, P = 0.025), ascites > 20 mL (HR: = 1.90, P = 0.0230), nodular liver appearance compared to firm (HR: = 1.61, P = 0.008), and age at KPE ≥ 75 days (HR: 1.73, P < 0.002). Outcome was not associated with gestational age, gender, race, ethnicity, or extent of porta hepatis dissection. Conclusion:Anatomic pattern of BA, BASM, presence of ascites and nodular liver appearance at KPE, and early postoperative jaundice clearance are significant predictors of transplant-free survival.

Isolated Liver Transplantation in Infants With End-Stage Liver Disease Associated With Short Bowel Syndrome

ObjectiveTo evaluate experience with isolated orthotopic liver transplantation in children with liver failure associated with short bowel syndrome (SBS). Summary Background DataInfants who have liver failure as a result of SBS are frequently referred for consideration for combined liver and small bowel transplantation. In a few patients the liver disease develops despite a seemingly adequate bowel, which if given time and appropriate management has the potential for full enteral adaptation. There is a limited literature suggesting the utility of OLT without replacement of the native bowel. The advantages over combined liver and small bowel transplantation are clear: organ availability is greater, liver-reduction techniques are well established, lower immunosuppression is required, and there is greater experience in the care of children after orthotopic liver transplantation. MethodsEleven infants, considered to have a good prospect of eventual gut adaptation to full enteral nutrition if it were not for their advanced liver disease, underwent isolated orthotopic liver transplantation. Age range was 6.5 to 17.7 months. All patients had been dependent on parenteral feeding but had also shown significant enteral tolerance at some time before listing for transplantation. Advanced liver disease was apparent both clinically and on histologic examination. All were jaundiced and had low albumin levels, and most had coagulopathy. As a group the infants had growth retardation. Estimated remaining length of small bowel beyond the ligament of Treitz was in the range of 25 to more than 100 cm. Six infants retained their ileocecal valve. ResultsThirteen liver transplants were performed in the 11 patients. A combination of whole livers (n = 6) and reduced-size grafts, of which three were from living-related donors, were used. Biliary anastomosis was duct-to-duct in eight instances and involved a short Roux limb in the others. Eight patients are alive with follow-up of 15 to 66 months. Three deaths have occurred after transplantation as a result of sepsis. Of eight surviving patients, only two continue to receive intravenous support and in both there is increasing enteral tolerance. Since transplantation, all surviving children have shown adequate growth with maintenance of pretransplant centiles. ConclusionsIn selected infants with liver failure secondary to short bowel syndrome in whom complete enteral autonomy is anticipated, isolated liver transplantation can offer long-term survival.

Brief Report: Deficits in Health Care Management Skills Among Adolescent and Young Adult Liver Transplant Recipients Transitioning to Adult Care Settings

OBJECTIVE The purpose of the present study was to describe and compare mastery of health care management in adolescent (aged 14-17 years) and young adult recipients of a liver transplant (age ≥ 18 years) expected to transfer from pediatric to adult care settings. METHODS Fifty-two liver transplant recipients completed the Developmentally Based Skills Checklist, which asks how often patients independently engage in specific health care management skills. RESULTS Overall, young adult patients reported greater health care management than adolescents. However, less than half of the young adults surveyed reported consistently managing their liver disease independently, making their own appointments, and understanding insurance issues. CONCLUSIONS Our results suggest that liver transplant recipients display inconsistency with regards to how frequently they engage in health management behaviors. Future work will address intervention development to remedy this first aspect of transition to adulthood such that patients are better prepared before moving to adult care centers.

Use of the Abdominal Rectus Fascia as a Nonvascularized Allograft for Abdominal Wall Closure After Liver, Intestinal, and Multivisceral Transplantation

Introduction. Abdominal wall closure management has become an important challenge during recipient candidate selection, at the time of donor to recipient matching and during the planning of the surgical procedure for intestinal or multiorgan transplantation. Different strategies have been proposed to overcome the lack of abdominal domain: to reduce the graft size or to increase the abdominal domain. Based on the recent concept of using an acellular dermis matrix (Alloderm) and the availability of abdominal wall tissues from the same organ donor, we conceived the idea of using the fascia of the rectus muscle (FoRM) as a nonvascularized tissue allograft. Materials and Methods. This is a retrospective report of a series of 16 recipients of FoRM as part of a liver, intestinal, or multiorgan transplant procedure performed between October 2004 and May 2008 at three different transplant centers. Results. Of the 16 recipients of FoRM, all but one case was performed during their transplantation (four multivisceral, two modified multivisceral, three isolated intestine, and two livers). Five patients underwent a retransplant surgery (two livers, two multivisceral, and one isolated intestine). Abdominal wall infection was present in 7 of 16 cases. Nine patients are still alive. No deaths were related to wound infection. Long-term survival showed complete wound healing and only one ventral hernia. Discussion. The use of a nonvascularized FoRM is a novel and simple surgical option to resolve complex abdominal wall defects in liver/intestinal/multivisceral transplant recipients when it can be covered with the recipient skin.