Liver-intestinal Transplantation Research Articles

Isolated Orthotopic Liver Transplantation for Parenteral Nutrition–Associated Liver Injury

Mild liver dysfunction is common after prolonged use of parenteral nutrition (PN), but end-stage liver failure occurs only rarely. Few treatment options other than combined liver-intestine transplantation exist for patients with liver failure associated with PN use, however. Herein, we report the results of a cohort of patients undergoing isolated orthotopic liver transplantation (OLT) for PN-associated liver injury. A retrospective cohort study of 80 patients (73 pediatric patients and 7 adults) who have undergone isolated OLT for PN-associated liver injury as the primary indication for transplantation was performed. At the time of OLT, the mean total serum bilirubin was 19.5 mg/dL and the mean serum albumin level was 2.9 mg/dL. Severe hepatic encephalopathy was seen in 5%, spontaneous bacterial peritonitis was seen in 6.3%, and respiratory failure requiring mechanical ventilation was seen in 14% of patients at the time of OLT. Overall 1- and 5-year survival rates were 72% and 52%, respectively, with infection being the most common cause of death after OLT. Retransplantation was required in 25% of patients, and the 5-year posttransplant patient survival rate only reached 35% in these cases. Patients with end-stage liver disease associated with PN administration often have very severe liver disease, multiple comorbidities, and poor prognosis by the time they are listed for OLT. Nonetheless, isolated OLT is associated with good long-term survival and should be considered for selected patients with combined intestine-liver failure.

Combined Lung-Liver Transplantation in Patients With Cystic Fibrosis

We agree with Dr. Kotru and colleagues regarding the need for additional studies to better identify the specific indications for combined lung-liver transplantation. This is a difficult task, however, mainly limited by the fact the need for this operation is exceedingly rare. There is simply not enough information available on the efficacy of combined lung-liver transplantation to ethically randomize the treatment of cystic fibrosis patients with lung and liver failure. Non-randomized study designs such as risk-based allocation may represent a more feasible means of proceeding. Alternatively, further analysis of a large single-center experience such as the series from Washington University may help identify factors that predict respiratory morbidity and mortality in isolated lung recipients or hepatobiliary morbidity and mortality in isolated lung recipients. Although isolated liver transplantation may improve lung function in patients with mild to moderate cystic fibrosis-related lung disease, we do not feel it is appropriate for patients with severe respiratory disease. Long waiting times are indeed a problem for combined lung-liver transplant candidates, as they are for many other forms of multi-organ transplantation such as liver-intestine transplantation (1). Unfortunately, there is no formal mechanism to minimize these waiting times; requests for exception points may be the best (and only) option currently available. Cystic fibrosis has previously been associated with bile inspissation and obstruction of the intrahepatic bile ducts. Extrahepatic strictures are less common appear in most cases to be caused by inflammation of the head of the pancreas (2). We agree that transplant surgeons should heed caution in performing a duct-to-duct anastomosis in transplant recipients with cystic fibrosis. We have performed four transplants using duct-to-duct anastomosis in cystic fibrosis patients at our institution, however, and have observed no postoperative strictures. Finally, experimental studies have suggested that transplanting a liver or spleen along with a kidney, heart or lung would lead to a decreased incidence of rejection (3–5). In spite of this, there have been no published reports to suggest that this phenomenon is seen in clinical transplantation. Indeed, the frequency with which acute rejection has been reported in combined heart-liver transplantation, for example, suggests that a liver graft does not induce tolerance to a clinically significant degree (6–10). Nonetheless, the decreased incidence of acute pulmonary rejection and bronchiolitis obliterans is notable and deserves further attention.

New trends in multivisceral transplantation

Purpose of review Intestinal transplantation has become the treatment of choice for irreversible intestinal failure. Within the field of intestinal transplantation, multivisceral transplants have also evolved to include indications other than intestinal failure complicated by parenteral nutrition-induced end-stage liver disease. Recent findings Over the last few years, multiple technical improvements have allowed the surgeon to perform multivisceral transplants in smaller and younger recipients. Gastro-gastric anastomosis, inclusion of the donor spleen and colon are some of the modifications that have been successfully applied to the technique of multivisceral transplants. Induction protocols include Campath 1-H or thymoglobulin and steroid-free maintenance immunosuppression with low-dose tacrolimus. Monitoring of the graft is conducted with repeated endoscopies, though new noninvasive markers of intestinal function, such as citrulline and calprotectin, are being evaluated. Infection and rejection are still the main causes of graft and patient mortality. Multivisceral transplants seem to have a protective effect from rejection compared with isolated intestine or combined liver–intestine transplants. Summary As more centers worldwide develop intestinal transplant programs, multivisceral transplants should be considered an integral part of their surgical armamentarium.

Short bowel syndrome and intestinal transplantation in children

This review summarizes recent knowledge and clinical practice for pediatric patients suffering extensive intestinal resection causing short bowel syndrome. This condition requires the use of parenteral nutrition, as long as intestinal failure persists, and may be, in some selected cases, an indication for intestinal transplantation. Biological evaluation of intestinal failure is becoming possible with the use of plasma citrulline as a marker of intestinal mass. Few epidemiological data are available; some indicate an increased incidence of short bowel syndrome-related gastroschisis and persistent high incidence of necrotizing enterocolitis. Morbidity and mortality data in pediatric patients with short bowel syndrome are limited, while long-term outcome is better documented from recently reported cohorts. Non-transplant surgery is one of the best options for patients with unadapted short bowel syndrome. Isolated liver transplantation may be avoided. The use of trophic factors for enhancing mucosal hyperplasia still remains disappointing. The management should include therapies adapted to each stage of intestinal failure, based on a multidisciplinary approach in centers involving pediatric surgery, pediatric gastroenterology, parenteral nutrition expertise, home-parenteral nutrition program, and liver-intestinal transplantation experience. If managed appropriately, the prognosis of short bowel syndrome is excellent, with limited indications for intestinal and/or liver transplantation. Timing for patient referral in specialized centers remains an issue.

The Importance of Analyzing Graft and Patient Survival by Cause of Failure: An Example Using Pediatric Small Intestine Transplant Data

Although graft and patient survival are vital in reporting overall results of clinical transplant studies, these outcomes do not account for distinct types of graft failure and death, which clearly exist in pediatric small intestine transplantation (Itx). The use of a cause-specific hazard (CSH) approach may provide more precise identification and thus greater insight as to why certain factors are prognostically important. Among 119 pediatric patients who received primary Itx at our center since 1994, Cox model stepwise regression analyses were performed to identify prognostic factors for the following CSH rates: intestinal graft failure (IGF)/death due to rejection, death due to infection not triggered by IGF, and intestinal graft loss/death due to other causes. Two factors were associated with a significantly higher rate of developing IGF due to rejection (23 such failures): receiving an isolated intestine or liver-intestine transplant (P=0.00001) and receiving no induction agent (P=0.006). Conversely, age at transplant <1 year was the single factor associated with a significantly higher death rate due to infection (P=0.0005) (21 such deaths). Two characteristics were associated with a significantly higher death rate due to other causes: being in the hospital pretransplant (P=0.007) and not receiving daclizumab induction therapy (P=0.02) (24 such deaths). Although these four factors (transplant type/age/hospital status/induction therapy) were, for the most part, associated with graft/patient survival, the CSH analysis more precisely identified their prognostic value and achieved greater statistical power. A CSH approach should be used in conjunction with overall outcome analyses.

Study of the Impact of Liver Transplantation on the Outcome of Intestinal Grafts in Children

Successful small bowel transplantation remains a challenge due to the septic and immune content of the gut. The possible beneficial role of the liver was assessed in pediatric recipients of isolated intestinal and liver intestinal combined transplantation, receiving the same immunosuppressive therapy. Fifteen children who underwent small bowel transplantation (seven SbTx) or combined liver-small bowel transplantation (eight LSbTx) at a single center between 1994 and 1998 were retrospectively reviewed and compared with fifteen controls (eight normal and seven appendicitis as inflammatory control). Transplant and patient survival, acute rejection episodes were analyzed and compared. Epithelial apoptotic body counts (ABC) and NF-kB (p65), Caspase-3 and Bax intestinal immunostaining from days 0 to 20 after transplantation were assessed. Graft and patient survivals at 5 years were respectively 75% and 75% in LSbTx; 43% and 57% in SbTx (NS). Histological analysis showed higher ABC in LSbTx intestinal mucosa (P = 0.05 on day 5, P < 0.01 thereafter). Immunostaining of biopsies on day 0 after reperfusion showed different expression of NF-kB, Caspase-3 and Bax on endothelial (P < 0.05 for NF-kB and Bax), mononuclear (P < 0.05 for Bax) and epithelial cells in LSbTx and SbTx. Our results suggest a protective role of the liver toward intestinal transplantation even in absence of significative difference, probably due to the small number of children. Early changes in NF-kB immunostaining in the biopsies sampled on day 0, pointed to a possible beneficial effect of the liver in the very early phase following transplantation, perhaps through the differential control of ischemia-reperfusion.

Innovative Approaches to Improving Organ Availability for Small Bowel Transplant Candidates

Small bowel transplant candidates have unique features that create special challenges for providing them with organs in a timely manner. More than half of intestinal transplant candidates also need livers. Because there is a greater overall demand for livers than for small bowels, organ allocation in this candidate subset is dictated by the liver allocation policies. However, the extremely high mortality rate associated with patients on the waiting list for combined liver-intestinal transplantation (LIT) attests to the inadequacies of the liver allocation system in recognizing the unique risk factors in patients with intestinal failure who develop end-stage liver disease (ESLD). This report addresses some of the organ allocation issues underlying the discrepancies in waiting list outcomes seen in LIT candidates and discusses possible contributory factors and potential solutions to this problem. The use of living donor and segmental grafts from deceased donors are discussed specifically as potential surgical solutions to the problem, and the potential utility, limitations, and ethical concerns associated with these innovative strategies are discussed.

Causes and Management of Intestinal Failure in Children

Intestinal failure is a condition requiring the use of parenteral nutrition as long as it persists. Causes of severe protracted intestinal failure include short bowel syndrome, congenital diseases of enterocyte development, and severe motility disorders (total or subtotal aganglionosis or chronic intestinal pseudo-obstruction syndrome). Intestinal failure may be irreversible in some patients, thus requiring permanent parenteral nutrition. Liver disease may develop with subsequent end-stage liver cirrhosis in patients with intestinal failure as a consequence of both underlying digestive disease and unadapted parenteral nutrition. Death will occur if combined liver-intestine transplantation is not performed. Catheter-related sepsis and/or extensive vascular thrombosis may impede the continuation of a safe and efficient parenteral nutrition and may also require intestinal transplantation in some selected cases. Thus management of patients with intestinal failure requires an early recognition of the condition and the analysis of its risk of irreversibility. Timing of referral for intestinal transplantation remains a crucial issue. As a consequence, management should include therapies adapted to each stage of intestinal failure based on a multidisciplinary approach in centers involving pediatric gastroenterology, parenteral nutrition expertise, home parenteral nutrition program, pediatric surgery, and liver intestinal transplantation program.

Intestinal Replacement Therapy: Timing and Indications for Referral of Patients to an Intestinal Rehabilitation and Transplant Program

Current treatment options for patients suffering from intestinal insufficiency include all forms of intestinal replacement therapy (IRT). Parenteral nutrition has achieved extended success for the majority of patients requiring interval treatment, however, complications leading to failure of this treatment increases with the duration of therapy. There is currently no consensus as to the appropriate timing for transplantation of the intestine or the timing of referral for evaluation at a center experienced with this therapy. Certain patient characteristics warrant evaluation. Those patients with no jejunoileum who have guaranteed lifelong parenteral dependence, both adult and pediatric, should be immediately referred to a transplant center due to the high likelihood of the development of liver disease. Patients with metastatic infectious complications from catheter sepsis, patients with cholestasis seen intermittently with sepsis episodes, patients who are not successfully weaning and who demonstrate progressive thrombocytopenia, and patients with motility disorder experiencing deterioration should also warrant early referral to an intestinal rehabilitation and transplant program. The objective of evaluation is to maximize the opportunities for rehabilitation while not missing the critical window of opportunity for successful transplantation when needed. We favor an aggressive directed approach to rehabilitation, coupled with psychological preparation for both transplantations and other options. Early referral requires trust between the patient, referring physician, and the transplant team to assure that a rush to judgment will not lead to a premature transplant. The current wait list mortality is high, mandating early referral and listing with an approach aimed at maximizing both the success of gastrointestinal support, as well as of transplantation when necessary.

End‐to‐end portocaval shunt for venous drainage of the native foregut in combined liver–intestinal transplantation

An end-to-side portocaval shunt has been classically described as the standard procedure that needs to be performed to obtain adequate venous drainage of the foregut in combined liver-intestinal transplant. The transplanted organs are placed en bloc in a piggyback fashion on the recipient's vena cava, and graft's porto-mesenteric venous circulation is left intact. Recurrent portal hypertension with hemorrhage has been reported as a complication after such a procedure. In an effort to improve the technical aspects of this complex operation, we began to perform an end-to-end shunt from the recipient portal vein to the infrahepatic donor cava. Here, we describe this new surgical technique and discuss its potential advantages. The new technique is described in detail. Of the 70 intestinal transplants performed in 67 patients at The Mount Sinai Hospital from 1998 to December 2004, three were multivisceral transplants (MVTx) and 28 were combined liver intestine transplants (LITx), post-surgical outcome including recurrent portal hypertension and the presence of splenomegaly and significant thrombocytopenia was retrospectively review between the group that received the classic end-side vs. the new end-end portocaval shunt. Of the 28 LITx, 23 were done with the classic end-side portocaval shunt and in five (one adult, four pediatric) the end-to-end portocaval shunt described in the present study. One patient in this group died on post-operative day 31 (adult); after a mean follow up of 19.5 months there is a 100% patient and graft survival for the pediatric population. Post-operatively there have been no complications related to this technique. Few modifications have been made to the original description of MVTx. This is the first description of this technique that is relatively simple to perform, creating a large vascular conduit with high flow rates and theoretically less turbulence compared with the end-to-side shunt.

Surgical techniques for liver/small bowel and isolated bowel transplants

Purpose of review The aim of this review is to examine the surgical techniques for intestinal transplantation. We will review isolated intestinal transplants and intestinal transplants that are combined with liver and other organs. We will review the established surgical approaches and new ideas that have been reported in the past year. Recent findings The techniques for both isolated intestinal transplant and for combined liver-intestinal transplant have been well established and described. There are modifications on the procedure such as a non-composite simultaneous liver and intestinal transplant. Also the techniques used in intestinal transplantation can be applied to challenging tumor resections with reimplantation of the intestine after ex-vivo tumor resection. Transplantation of the colon and stomach remain controversial. Summary Intestinal transplantation is an accepted therapy for patients with advanced intestinal failure. The surgical techniques have been refined and there continues to be success with intestinal transplantation as a therapeutic option for patients with intestinal failure.

Liver-Induced Immune Tolerance in Recipients of Combined Liver-Intestine Transplants

Liver-Induced Immune Tolerance in Recipients of Combined Liver-Intestine Transplants

Immunosuppressant strategies for intestinal transplantation: a review of a tolerogenic regimen

Intestinal, combined liver-intestinal, and multivisceral transplantation are now considered the standard of care for children and adults with permanent intestinal failure. Early attempts at intestinal transplantation were discouraging because of the high incidence of technical complications, rejection, and infection. Advances in the field of transplantation, including the introduction of tacrolimus, improved surgical techniques, and improvements in postoperative care, have led to a renewed interest in intestinal transplantation since 1990. The most significant achievement, however, has been the effective control of rejection and life-threatening infections. This article focuses on the experience to date of innovative strategies that induce lymphocyte depletion and reduction in the incidence of rejection. In this setting, low-maintenance immunosuppression is clinically achievable with an acceptable rate of allograft rejection. Subsequently, the long-term complications of immunosuppression are significantly reduced with achievement of better long-term survival, and an overall improvement in the quality of life.

Liver-Intestine Transplant from a Pediatric Donor with Unrecognized Mitochondrial Succinate Cytochrome C Reductase Deficiency

The demand for pediatric solid organs for transplantation exceeds the available supply. Transplant surgeons may elect to use organs from a donor whose cause of death is uncertain, especially when the recipient is deteriorating. In such circumstances, it is possible that organs from a patient with a systemic metabolic disorder may be transplanted into the recipient, leading to an adverse outcome. We report the first case in which liver and small bowel were procured from a donor with an unsuspected mitochondrial respiratory transport chain defect (succinate cytochrome C reductase deficiency). We describe the subsequent course of the recipient, who died 10 weeks later of multiorgan failure, and unusual findings at autopsy. In the absence of a clear cause of death in a potential pediatric organ donor, factors such as parental consanguinity should prompt physicians to acknowledge the increased possibility of an inherited metabolic disorder and to take this into consideration before proceeding with the transplant procedure.

Reduced immunosuppression in pediatric liver-intestine transplant recipients with CD8+CD28− T-suppressor cells

Twelve pediatric liver ( n = 7), liver-kidney ( n = 1), and small bowel ( n = 4) transplant recipients, median age 6.5 years (1–21), who received rabbit anti-human thymocyte globulin (rATG) and steroid-free tacrolimus/sirolimus, were screened for the presence of CD8+CD28− T suppressor cells. Four control liver transplant recipients, median age 15 years (5–20), in whom conventional immunosuppression without rATG was successfully discontinued for at least 1 year, were also screened as a reference population. Median time to CD8+CD28− T-suppressor cells analysis was 16 months (2–24) in rATG subjects and 168 months (16–228) in no-immunosuppression subjects. Nine of 16 patients demonstrated the presence of CD8+CD28− T-suppressor cells in the circulation, whereas seven patients did not. CD8+CD28− T-suppressor cells were present in 4/4 children with no immunosuppression, and absent from three of four subjects with acute cellular rejection, all of whom experienced more than one acute cellular rejection episode. In the reduced immunosuppression group ( n = 8), four children demonstrated presence of CD8+CD28− T-suppressor cells in the circulation and four did not. The presence of donor-specific T-suppressor cells in the circulation may characterize transplant recipients, in whom graft function can be maintained with minimal or no immunosuppression. Such assays may also permit safe evaluation of prospective immunosuppression withdrawal strategies.

Spectrum of Imaging Findings After Intestinal, Liver-Intestinal, or Multivisceral Transplantation:Part 1, Posttransplantation Anatomy

1275 ntestinal transplantation is an alternative in patients with irreversible chronic intestinal failure in order to restore enteral absorption of ingested food and fluid. In adults, the most common cause of chronic intestinal failure results from extensive resection of the small bowel because of occlusion of the superior mesenteric vessels, inflammatory bowel disease, or abdominal trauma. In children, the causes of shortbowel syndrome are midgut volvulus, gastroschisis, intestinal atresia, and necrotizing enterocolitis. Intestinal failure infrequently results from permanent intestinal dysfunction despite normal intestinal length. This occurs more frequently in children and includes aganglionosis; malabsorption syndromes, particularly microvillus inclusion disease; and motility disorders, particularly intestinal pseudoobstruction [1]. Intestinal transplantation with cyclosporinebased immunosuppression started in the 1980s in North America [2] and Europe [3] and was followed by multivisceral transplantation [4, 5] and liver–intestinal transplantation [6]. Isolated intestinal transplantation is indicated for patients with irreversible intestinal failure without Spectrum of Imaging Findings After Intestinal, Liver–Intestinal, or Multivisceral Transplantation: Part 1, Posttransplantation Anatomy

Spectrum of Imaging Findings After Intestinal, Liver-Intestinal, or Multivisceral Transplantation:Part 2, Posttransplantation Complications

1275 ntestinal transplantation is an alternative in patients with irreversible chronic intestinal failure in order to restore enteral absorption of ingested food and fluid. In adults, the most common cause of chronic intestinal failure results from extensive resection of the small bowel because of occlusion of the superior mesenteric vessels, inflammatory bowel disease, or abdominal trauma. In children, the causes of shortbowel syndrome are midgut volvulus, gastroschisis, intestinal atresia, and necrotizing enterocolitis. Intestinal failure infrequently results from permanent intestinal dysfunction despite normal intestinal length. This occurs more frequently in children and includes aganglionosis; malabsorption syndromes, particularly microvillus inclusion disease; and motility disorders, particularly intestinal pseudoobstruction [1]. Intestinal transplantation with cyclosporinebased immunosuppression started in the 1980s in North America [2] and Europe [3] and was followed by multivisceral transplantation [4, 5] and liver–intestinal transplantation [6]. Isolated intestinal transplantation is indicated for patients with irreversible intestinal failure without Spectrum of Imaging Findings After Intestinal, Liver–Intestinal, or Multivisceral Transplantation: Part 1, Posttransplantation Anatomy

Intestinal failure

Purpose of review Intestinal failure (IF) has became a specifically defined condition that may be irreversible in some patients. IF requires the use of parenteral nutrition (PN) as long as it persists. As a consequence of both underlying digestive disease and unadapted PN, liver disease may develop with subsequent end-stage liver cirrhosis. Death will occur if combined liver–intestine transplantation is not performed. Catheter-related sepsis and/or extensive vascular thrombosis may impede the continuation of a safe and efficient PN and require intestinal transplantation (ITx). Thus, management of IF patients requires an early recognition of IF and the analysis of its risk of irreversibility. Recent findings Recent literature covered the field of IF management, including therapeutic approaches aiming to avoid extensive intestinal resection, to restore or to develop intestinal function with nutritional or pharmacological treatment and nontransplant surgery in short-bowel patients. Children with extreme short gut, congenital diseases of enterocyte development, or severe motility disorders (total or subtotal aganglionosis or chronic intestinal pseudo-obstruction syndrome) can be diagnosed early as having irreversible IF and are candidates for ITx. Efficient and uncomplicated PN and home PN remain the mainstay of therapy, independent of the nature of IF. When PN limits are reached, ITx is the logical approach because its outcome improved during the last decade. Summary Timing of referral for ITx remains a crucial issue. As a consequence, IF management should include therapies adapted to each stage of IF based on a multidisciplinary approach in centers involving pediatric gastroenterology, PN expertise, home-PN program, pediatric surgery, and liver-intestinal transplantation program. Promotion of basic and applied research in the field should prevent the liver and vascular consequences of IF and long-term PN, respectively.

Organ donation and transplantation trends in the USA, 2003

This summary provides an overview of solid organ transplantation in the USA, produced as part of the 2003 OPTN/SRTR Annual Report. The Annual Report is prepared by the Scientific Registry of Transplant Recipients (SRTR) in collaboration with the Organ Procurement and Transplantation Network (OPTN) under contract with the Health Resources and Services Administration (HRSA). A wide range of activities related to solid organ transplantation in the USA are thoughtfully addressed in this publication with the intention of providing useful information to patients, the transplant community, the public, and the Federal Government.

Application of combined liver-intestinal transplantation as a staged procedure

Liver-intestinal transplantation is a complex surgical procedure that historically has required prolonged operative periods. This report is the first series where liver-intestinal transplantation was performed as a staged procedure. Specifically, allograft reperfusion was followed by resuscitation and stabilization in an intensive care unit before completion of the transplant procedure. Triage of recipients to the intensive care unit following allograft reperfusion was determined at the time of operation and was based upon the clinical condition of the recipient including hemodynamic stability, evidence of coagulopathy, and assessment of early liver function. Medical stabilization was followed by completion of the transplant procedure and definitive abdominal closure within 72 hours. The application of combined liver-intestinal transplantation as a staged procedure demonstrated no effect upon early graft function, incidence of complications, or ability to perform a definitive abdominal closure.