Intestinal and Multivisceral Transplantation

Updated: Apr 06, 2015
  • Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Ron Shapiro, MD  more...
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Overview

Background

Until recently, parenteral nutrition was the standard of care for all patients with intestinal failure. The success of kidney, liver, and heart transplantation has increased with the advent and application of new antirejection medications coupled with improved surgical techniques. Advances in intestinal transplantation, by contrast, have been slow to develop until recently. At the turn of the 20th century, Alexis Carrel demonstrated the technical feasibility of intestinal transplantation; however, acute allograft rejection was an insurmountable obstacle in the absence of immunosuppressive medications. [1] In the 1960s, surgeons demonstrated renewed interest in intestinal transplantation following early successes with kidney transplantation. This interest rapidly waned as the inadequacy of the immunosuppressive medications available at the time became apparent.

Total parenteral nutrition (TPN) became available in 1969, with a number of patients relying on it for complete support. At first, all patients on TPN required continuous hospitalization. Today, TPN is safely used in outpatient management. Pooled data from the North American Home Parental and Enteral Patient Registry show 1- and 4-year survival rates for patients with short bowel syndrome (SBS) who received TPN at home to be 94% and 80%, respectively. Only 5-11% of deaths were directly attributed to TPN, with the vast majority of deaths related to progression of the underlying primary disease.

The success of TPN supplanted the then urgent need to find solutions for the problems with intestinal transplantation, and TPN became the standard of care. Recently, however, intestinal transplantation has been offered to that minority of the patients on long-term TPN who have severe and life-threatening complications related to this therapy. [2, 3] This restricted indication is, however, likely to be broadened as a consequence of the improved patient and graft survival and cost-effectiveness data that have been seen in the last few years.

The complications of long-term TPN are listed below. Those marked (**) are also indications for intestinal transplantation:

  • Infection
    • Catheter sepsis (recurrent**)
    • Exit-site infection
    • Tunnel infection
  • Catheter occlusion
    • Thrombosis (≥2 access sites**)
    • Dislodgment or breakage
    • Mineral or lipid precipitate
  • Hepatic disease (15-40% after 3 y)
    • Hepatic steatosis (most common finding)
    • Cholestasis
    • Phospholipidosis
    • Progressive fibrosis**
    • Cirrhosis**
  • Renal disease
    • Electrolyte disturbance
    • Decreased glomerular filtration rate**
    • Recurrent acute renal failure**
    • Tubular dysfunction
  • Gastrointestinal disease
    • Gastroparesis
    • Bacterial overgrowth
    • Disuse enteritis
    • Intestinal hypoplasia
  • Metabolic bone disease
    • Osteomalacia
    • Osteoporosis
  • Biliary disease (up to 100% after 6 wk)
    • Biliary sludge (almost universal)
    • Gallstones
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History of the Procedure

Intestinal transplantation achieved a clear recognition in the management of complicated total parenteral nutrition (TPN) with Medicare approval (see below). The relatively brief history of this procedure before this included dismal outcomes prior to 1990 and a moratorium during 1994 as a consequence of the high morbidity and mortality associated with the procedure. However, in 1995, rapid improvements in outcomes were seen as results of technical and immunosuppression development.

On the immunosuppression side, the introduction of tacrolimus was one of the cornerstones to success. [4] On the technical side, programs were guided by the recommendations developed by the American College of Surgeons in 1995. Growth since then has been exponential, as is well illustrated in the 2012 report of the Intestinal Transplant Registry.{Ref 164}

Intestine and Combined Liver and Intestine Transplants in the United States by Year (PDF) (www.unos.org)

By and large, this success is a consequence of multiple endeavors. These include progress in immunosuppressive therapy, refinement to surgical techniques, [5] improvement in post-transplant care, better understanding of intestinal immunology, and protocols implemented for anti-infectious monitoring and prophylaxis (primarily against cytomegalovirus [CMV] infection). These actions have translated to improvements in patient and graft survival over the last few years. With this, intestinal transplantation will soon be cost effective; this author believes that intestinal transplantation is not far away from supplanting TPN in the management of short bowel syndrome that requires long-term TPN. Data from Sudan support the cost-effectiveness following 2 years after transplantation.

On October 4, 2000, the US Health Care Financing Administration (HCFA) approved coverage by Medicare for intestinal transplantation. Medicare agreed to cover all types of intestinal transplants for patients with irreversible intestinal failure who have specific life-threatening complications (noted with ** above) from long-term intravenous nutrition and TPN. Medicare's criteria for approved centers include an annual volume of at least 10 intestinal transplants and a 1-year actuarial survival of at least 65%. The decision was important because most state Medicaid and other third-party payers in the United States followed suit and provided reimbursement for intestinal transplantation.

Significant shifts in intestinal transplant programs have been noted along with a significant reduction in the number of transplants in the United States over the last 5 years. Concurrent with this reduction, transplant programs have placed a greater focus on refining and optimizing the management of patients with rehabilitation and are using multidisciplinary approaches to intestinal failure and short bowel syndrome. [6] Evidence supports that this measure has reduced the likelihood of developing an indication for intestinal transplantation; when coupled with refinements in the management of TPN-dependent intestinal failure (with novel agents like teduglutide), the authors feel reductions in overall listings will continue over time.

In 2013, the UNOS Liver and Intestinal Transplantation Committee of the United States revised the organ allocation policy. They sought to reduce what was a high wait list mortality for combined liver and intestinal transplantation (LSBT). The committee gave a priority in the allocation system above the current model for end stage liver disease (MELD) allocation for recipients awaiting LSBT. [7] Interestingly, the percentage of patients removed for death on the wait list over the last 4 years has reduced; this occurred prior to implementation of the new allocation policy.

Wait list removals due to all reasons since the year 2000 are as follows:

  • 2000 - 135
  • 2001 - 192
  • 2002 - 189
  • 2003 - 215
  • 2004 - 226
  • 2005 - 279
  • 2006 - 283
  • 2007 - 293
  • 2008 - 276
  • 2009 - 245
  • 2010 - 205
  • 2011 - 173
  • 2012 - 178
  • 2013 - 156

Wait list removals due to transplant received since the year 2000 are as follows:

  • 2000 - 78
  • 2001 - 111
  • 2002 - 106
  • 2003 - 112
  • 2004 - 145
  • 2005 - 170
  • 2006 - 170
  • 2007 - 193
  • 2008 - 185
  • 2009 - 178
  • 2010 - 150
  • 2011 - 125
  • 2012 - 105
  • 2013 - 99

Wait list removals due to death or transplant-preventing illness since the year 2000 are as follows:

  • 2000 - 30
  • 2001 - 50
  • 2002 - 57
  • 2003 - 56
  • 2004 - 57
  • 2005 - 70
  • 2006 - 67
  • 2007 - 57
  • 2008 - 50
  • 2009 - 36
  • 2010 - 22
  • 2011 - 26
  • 2012 - 20
  • 2013 - 23

Wait list removals due to improved condition since the year 2000 are as follows:

  • 2000 - 7
  • 2001 - 3
  • 2002 - 11
  • 2003 - 20
  • 2004 - 6
  • 2005 - 12
  • 2006 - 15
  • 2007 - 12
  • 2008 - 17
  • 2009 - 17
  • 2010 - 21
  • 2011 - 8
  • 2012 - 29
  • 2013 - 18

Table 1. Intestinal Transplant Programs - 2011. (Open Table in a new window)

Total Number of Programs Number of Programs Doing Transplants Number of Transplants in Largest Center Number of Transplants in Smallest Center
33 19 26 1
  Total Transplants (n=184) Indiana University Health (INIM) Four Centers at 1

 

Over the last 5 years, the total number of transplants and total number of listings for intestinal transplantation has declined.

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Problem

Intestinal failure is a term applied to individuals who are unable to maintain adequate nutrition with an enteric diet. These patients require TPN to maintain energy (caloric) intake. The causes of intestinal failure include anatomic and functional abnormalities and, along with the population affected, are listed as follows:

Patients with SBS have insufficient small bowel length to support energy (caloric) needs; this typically occurs when at least 80% of the small intestine has been resected. Resection of less than 80% of the length of the bowel is generally accompanied by intestinal adaptation and subsequent enteral tolerance. Considerable interindividual variability occurs among patients. Some individuals may require TPN despite having less than 80% of their small intestine resected, while others may not require TPN after more extensive resections. This fact emphasizes the importance of trials of enteral tolerance and nutritional rehabilitation while assessing an individual with SBS (see Intestinal rehabilitation).

Additional factors that may help predict those likely to achieve enteral tolerance include younger age, the presence of an ileocecal valve, and the presence of an ileum. The functional causes of intestinal failure in those with normal bowel length include intestinal aganglionosis, chronic idiopathic intestinal pseudoobstruction, and congenital mucosal abnormalities such as microvillous inclusion disease.

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Indications

Indications for transplantation

The most common cause of death for individuals permanently dependent on TPN is liver failure. Steatohepatitis and cholelithiasis with or without associated cholecystitis are common in patients on TPN and warrant exclusion before the physician makes a diagnosis of TPN-induced liver disease. Advanced TPN-induced liver disease is irreversible; however, when it is identified early it is often reversible with discontinuation of TPN.

Progressive liver disease is more common in young children on TPN and is often associated with a history of multiple resections and recurrent infection. Progressive and irreversible liver disease develops in 2-42% of children and adults with intestinal failure due to SBS. [8, 9, 10, 11, 12] The development of liver disease may be related to enteric stasis, the ability to establish some degree of enteral tolerance, catheter-related sepsis, age, a history of prematurity, the extent of bowel resection, the presence of an underlying inflammatory condition, or the length of time on TPN. [13, 14, 15, 16, 10, 12] The mediators and pathways responsible for the progression of TPN-associated liver disease to end-stage liver disease remain undefined.

Two other causes of life-threatening complications in patients with intestinal failure include recurring sepsis and loss of vascular access due to venous thrombosis. [16, 17] These problems are often concomitant. Sepsis associated with indwelling catheters is more common in children; in some patients, recurrent sepsis is related to gastrointestinal stasis and bacterial overgrowth. Overall, the mortality rate associated with catheter-related sepsis has progressively diminished with the introduction of flexible, silastic, silicone rubber catheters; tunneled, cuffed catheters; and improved line care. [18, 19, 20]

Less common indications for intestinal transplantation include locally invasive desmoid tumors, premalignant conditions (Gardener syndrome), and fluid and electrolyte losses unmanageable with TPN. [21]

In summary, intestinal transplantation is a salvage procedure applied to patients who have either anatomic or functional diseases that preclude enteral tolerance (eg, intestinal failure) and have life-threatening complications of TPN such as progressive liver disease, a history of catheter-related sepsis, or loss of vascular access. [21, 22] It cannot be overemphasized that measures to augment intestinal function and minimize the risk of complications of parenteral nutrition (PN) must be explored in every patient on PN to avoid the need for this procedure. There is not an established role for preemptive intestinal transplantation, ie, transplantation in the absence of complications of PN or invasive intra-abdominal desmoid tumor. There is, however, a very clear indication to refer patients early to centers of excellence in intestinal failure and transplantation in the setting of ultrashort bowel or major catheter-related complications. [23]

To illustrate the problems faced in the setting of intestinal transplantation, an illustration of the variables and the impact of these variables upon the patient's outcome must be remembered.

  • Patients who are admitted from home for their transplant procedure have better survival rates than those who are inpatients at the time they are taken to the transplant procedure.
  • Central vascular access is required for the procedure and in settings in which access is reduced and technical complications and management of posttransplantation complications is increased. Loss of access complicates the procedure by limiting alternative sites for central access should a catheter need to be removed or repositioned. This central access is important for the provision of perioperative PN and is essential for resuscitation, perioperative fluids, and medication maintenance required in the peritransplant period.
  • At some centers, clinicians have decided that the transplantation cannot be performed if all upper and lower central access is lost, which illustrates the necessity for referral if vascular access loss develops. Access loss of 2 major access sites is generally an indication for intestinal transplantation. Patients with a significant loss to central vascular access may lose eligibility for transplantation. This illustrates the necessity for referral if vascular access loss begins to develop.
  • Advanced liver disease may not preclude isolated intestinal transplantation; however, in the presence of advanced liver disease, isolated intestinal transplantation is generally not possible.
  • Waiting list mortality is higher in those awaiting LSBT than in those awaiting isolated liver transplantation or isolated bowel transplantation.
  • In patients who undergo intestinal transplantation and lose their graft and have indications for retransplantation, outcomes in retransplantation are inferior to outcomes for the primary transplantation. [24]

Patient evaluation

The goals of patient evaluation for intestinal transplantation are as follows:

  • Establish the primary diagnosis.
  • Evaluate and document TPN complications experienced by the patient.
  • Establish the length and function of the remnant native intestine.
  • Assess the function of the remnant intestine and potential for establishing enteral tolerance.
  • Determine the degree of liver dysfunction and the potential for reversibility.
  • Identify any comorbid conditions that may impact upon the outcome of intestinal transplantation, and identify potential problems (eg, thrombosis of major vessels).
  • Assess candidate suitability (including families) for the rigors of intestinal transplantation and the ability to comply with the often complex posttransplant regimens. [25]

One critical aspect of the evaluation process is to determine whether the patient's intestinal failure is potentially reversible. Most information regarding nutritional assessment comes from a carefully obtained patient history. Particular attention is given to TPN regimens, prior attempts to achieve enteral tolerance, current enteral feeding protocols, growth, development, and exclusion of nutritional deficiencies. Multidisciplinary consultation with experienced pediatric nutritionists, gastroenterologists, and hepatologists is invaluable before determining the presence or absence of nutritional deficiencies and complications from long-term TPN. Many routine screening studies are listed in Workup.

In addition to a thorough history and review of operative records, evaluation of the length and function of the remnant native bowel is further accomplished through radiographic contrast studies. These studies help delineate the length of the remaining small bowel, its anatomic location, the presence or absence of the ileocecal valve, the caliber of the remaining small and large intestine, and the transit time from the proximal to distal bowel. These studies also may help define surgically correctable diseases that permit enteral tolerance without transplantation. Occasionally, additional motility studies are necessary.

The medical and surgical team must be rigorous when establishing the presence of intestinal failure and when defining its cause because Munchausen syndrome by proxy has been reported in an intestinal transplant recipient. [26] For patients with functional disease, review of histopathologic findings following bowel biopsy is important to confirm the diagnosis and extent of bowel involvement.

During the assessment of TPN complications, the physician must decide whether a patient's TPN-related liver disease is reversible. This decision may be difficult, and considerations include liver biopsy findings and the likelihood of progression during the waiting period. The presence of dense, bridging fibrosis may prompt consideration of LSB transplantation. Minor amounts of fibrosis associated with cholestasis may allow ISB transplantation. However, if rapid progression of the disease is observed and a long waiting period is anticipated (eg, small infants), combined listing for LSB transplantation may be indicated.

An assessment for manifestations of portal hypertension is important, although diminished mesenteric blood flow secondary to the short remnant intestinal length provides protection against varices. Increasing splenomegaly, cytopenia, dilated superficial abdominal veins, and bleeding from gastrostomy sites or stomata provide clues to the presence of portal hypertension. The bilirubin level alone is not a good indicator of whether ISB or LSB transplantation is indicated. ISB transplantation in jaundiced patients has been shown to reverse liver disease, even in patients with a total bilirubin level of 20 mg/dL at the time of transplantation. [27]

Doppler ultrasonography is used to assess venous access and to determine the patency of the central veins. Intestinal transplantation is considered when the patient has lost 2 or more common venous access sites, such as the subclavian or internal jugular veins, or when unconventional sites such as the right atrial, transhepatic, or direct inferior vena caval catheters are required.

Patient history and previous records should reveal the number and type of organisms responsible for previous central venous line infections. Fungal infections requiring mechanical ventilation or vasopressor support are most worrisome. [17, 28] Furthermore, a history of infection with multidrug-resistant organisms should raise concern for future mortality and should be considered in the overall assessment.

Comorbid conditions can greatly increase the likelihood of complications in the posttransplant period. Specific evaluations of other organ systems are dictated by patient history and are further directed by any abnormalities identified from the results of baseline studies. For example, intestinal failure as a consequence of necrotizing enterocolitis may be associated with a history of prolonged neonatal ventilation and bronchopulmonary dysplasia. These conditions are associated with repeated hospitalizations and a propensity for prematurity in infants, which may give rise to behavioral and developmental problems that should be identified and addressed as early as possible. However, controlled trials to support this are lacking. The authors strongly believe that early intervention facilitates posttransplant recovery and that such interventions are important. Portions of these evaluations are incorporated into the psychosocial assessment of the patient and the patient's support system.

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Relevant Anatomy

Relevant donor anatomy

For isolated intestinal transplantation, en bloc removal of the donor intestine commences at the pylorus and proceeds as far as the terminal ileum.

Anatomy of the donor operation, with procurement o Anatomy of the donor operation, with procurement of the liver, small bowel, pancreas, and spleen en bloc (AO, thoracic aorta; HA, hepatic artery; PV, portal vein; CBD, common bile duct; D1, first part of the duodenum; TI, terminal ileum).

Inclusion of the colon in the graft has been associated with worse patient survival, presumably because of increased septic complications as demonstrated by researchers from the University of Pittsburgh. Inclusion of the stomach has been associated with poor gastric motility (personal communications). The superior mesenteric artery and vein provide the blood supply to the organ.

When performing a combined LSB transplantation, the duodenum and head of the pancreas are retained in the allograft. In preparation for multivisceral transplantation, other abdominal organs are obtained at the time of intestinal procurement, most commonly the entire donor pancreas.

The allograft is prepared in the operating room before implantation.

The recipient's requirements dictate which technique should be performed; these requirements are described later. For all recipients, bowel continuity is the ultimate goal, and proximal and distal enteric anastomoses are performed at the time of allograft implantation.

A more comprehensive outline of these procedures is available in the 1999 article by DeRoover and Langnas. [29]

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Contraindications

Although most contraindications to transplantation are relative and a collection of factors might present an absolute contraindication, the following is a list of conditions and situations in which transplantation may be contraindicated:

  • Profound disabilities that are not likely to be corrected by transplantation
  • Severe extraintestinal illnesses that are not likely to be corrected by transplantation
  • Uncontrolled sepsis
  • Immunodeficiency (with the possible exception of immunodeficiency associated with multiple intestinal atresia)
  • Nonresectable or disseminated malignancy (including large hepatoma, desmoid tumour)
  • Complete loss of vascular access or insufficient central access sites (lack of central access during transplantation and during the early posttransplantation period)
  • Absence of psychosocial support or willingness to comply with posttransplant regimens
  • Anatomical elements (size of cavity for the allograft, vascular inflow and outflow)
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