Small Bowel Transplantation

History

Intestine transplantation has become a lifesaving treatment option for patients with intestinal failure. The term intestinal failure encompasses multiple disorders of inadequate intestinal length or function that prevent adequate nutrient absorption. In contrast, enteral autonomy is a term describing the ability of an individual to absorb all nutrient needs from the gastrointestinal tract. For the subset of patients who have intestinal failure because of loss of bowel length, the terms short gut syndrome and short bowel syndrome are used interchangeably. The causes of short bowel syndrome include congenital malformations, traumatic injury, infection, and ischemia. The absolute length of remnant bowel required to sustain nutrient absorption varies among individuals and on the basis of age. As a rule of thumb, however, short bowel syndrome and lack of enteral autonomy are expected after resection of more than 75% of the native intestine.

Intestinal failure may also describe a subset of patients with normal or nearly normal intestinal length but with abnormal function as a result of Crohn disease, motility disorders (such as intestinal pseudo-obstruction and long-segment Hirschsprung disease), or diseases of the enterocytes (such as intestinal epithelial dysplasia). Disorders of intestinal function are less common than short bowel syndrome but share the same devastating consequences, leaving patients unable to absorb nutrients from the gut. In fact, before the 1960s, any cause of intestinal failure was nearly always fatal. Today, however, numerous treatment strategies have been developed, and the management of intestinal failure continues to vary greatly by treatment center. To better understand the natural history and clinical outcomes in these patients, the British Association for Parental and Enteral Nutrition recently established first national intestinal failure registry, which will include surgical outcomes and help define the role for intestinal transplantation as a life-saving therapy in select patients.

The first investigation of intestine transplantation as therapy for intestinal failure is attributed to Alexis Carrel in 1905. Given the lack of understanding of transplant immunology at that time, it was not surprising that these early efforts were unsuccessful. Approximately 50 years later, in 1959 (after the first reports of successful kidney transplantation), Lillehei and colleagues at the University of Minnesota published their successful experimental work transplanting intestines in a canine model. In 1962, Starzl (also working in a dog model) described transplantation of multiple abdominal organs, including the liver and entire gastrointestinal tract (from stomach through colon), termed homotransplantation of multiple visceral organs. Human intestinal transplantation was subsequently attempted by Lillehei and coworkers in 1967. Like Carrel’s work, this effort and several additional attempts during the next two decades were unsuccessful in achieving complete enteral autonomy, although several intestine recipients survived for several months after transplantation. The primary reasons for failure were early technical complications and the inability to control rejection, leading to development of overwhelming infections or posttransplantation lymphoma.

The clinical course of intestinal failure was dramatically altered when Dudrick and associates described hyperalimentation, which is arguably one of the most significant medical breakthroughs of the century. Their work demonstrated that puppies could achieve nearly normal growth patterns while exclusively sustained by hyperalimentation, more commonly referred to currently as total parenteral nutrition (TPN). The clinical introduction of long-term TPN led to increased survival in individuals with intestinal failure, and contemporary studies have now reported overall survival in parenteral nutrition–dependent patients at 84% and 73% in pediatric populations and 88% and 64% in adults at 1 and 5 years, respectively. Given the success of parenteral nutritional support in the early 1970s and the abysmal results after early attempts at intestine transplantation, there was diminished enthusiasm for further clinical trials of intestine transplantation during this era.

Over time, potentially fatal complications associated with TPN administration were identified. These included severe catheter-associated bloodstream infections; technical difficulties in maintaining venous access because of catheter-associated venous thrombosis; and cholestasis leading to liver failure, also referred to as parenteral nutrition–associated liver disease (PNALD) or intestinal failure–associated liver disease (IFALD). Although a formal consensus definition for IFALD is lacking, it is often biochemically characterized as a conjugated bilirubin level greater than 2 mg/dL in patients who have been on TPN for greater than 2 weeks. IFALD develops in approximately 50% of pediatric patients and is closely related to the duration of TPN (>3 months). Risk of IFALD-induced steatosis in adults receiving home parenteral nutrition is lower, with reported rates of 15% to 40%. Once IFALD develops, however, it is associated with a 43% 5-year mortality in patients with remnant jejunum and ileum length of less than 50 cm.

Concurrent with reports of severe TPN-associated complications, cyclosporine immunosuppression was introduced, resulting in marked improvements in kidney and liver allograft survival. With advances in immunosuppression, there was renewed interest in the field of intestine transplantation. The first successful human isolated intestine allograft (with the achievement of enteral autonomy) was reportedly performed by Deltz and colleagues in 1988 with a living donor allograft procured from the sister of the 42-year-old recipient. Although rejection episodes recurred, these episodes were controlled with the use of cyclosporine, bolus steroids, and antilymphocyte treatments, eventually achieving enteral autonomy. A few months later, Grant and coworkers performed the first cadaveric combined liver-intestine transplant to achieve complete enteral autonomy and more than 1-year patient and graft survival using cyclosporine. Despite these individual successes, 1-year expected patient survival after intestine transplantation using cyclosporine immunosuppression was approximately 25%, and failure to achieve enteral autonomy and risk for early death persisted. In the early 1990s, the introduction of tacrolimus immunosuppression improved control of intestine allograft rejection, resulting in improved patient and graft survival after intestine transplantation. While this led to a mild increase in volume, the overall volume and experience with intestine transplantation have been dramatically less than with transplantation of other solid organ allografts. In the United States, the United Network for Organ Sharing (UNOS) has reported that only 3000 intestine transplants have been performed as of December 2018, with 100 performed in the year 2018 ( Fig. 28.1 ).

Indications for Intestine Transplantation

Dependence on parenteral nutrition alone is not considered an indication for intestine transplantation in light of the excellent survival of most patients receiving parenteral nutrition. Indications for transplantation of the intestine were proposed by experts in the field at the Sixth International Small Bowel Transplant Symposium in 2001 and have not changed appreciably since. These include irreversible intestinal failure and one or more of the following : (1) overt or impending liver failure caused by PNALD; (2) multiple thromboses of central veins limiting central venous access; (3) more than two episodes of catheter-related infection requiring hospitalization in any year; (4) single episode of fungal line infection; and (5) frequent and severe episodes of dehydration, despite intravenous (IV) fluid supplementation and TPN. Additional indications for intestine transplantation have subsequently been added, including intestinal failure that typically results in early death despite TPN (e.g., unreconstructible gastrointestinal tract) and diseases for which no alternative therapy is available (such as complete splanchnic venous thrombosis and unresectable benign or slow-growing mesenteric tumors). ^, Other potential indications include patients with high morbidity, poor quality of life, and severe fluid or electrolyte abnormalities that require frequent hospitalization, although these are not uniformly accepted.

The international Intestinal Transplant Registry (ITR) has collected demographic and outcome data on nearly all intestine transplants worldwide since the first successful cases in the late 1980s. The most common primary underlying disease states prompting intestinal transplantation reported by the ITR are shown in Table 28.1 . In both pediatric and adult patients, short gut syndrome accounts for about two thirds of patients, although secondary to different underlying pathologies; in pediatric patients, these include gastroschisis (22%), volvulus (16%), and necrotizing enterocolitis (14%), while in adults, ischemia (24%), Crohn disease (11%), volvulus (8%), and trauma (7%) are more common.

Evaluation