Intestinal and Multivisceral Transplantation

Updated: Feb 22, 2021
  • Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Stuart M Greenstein, MD  more...
  • Print
Overview

Practice Essentials

Parenteral nutrition remains the standard of care for most patients with intestinal failure. Currently, only limited numbers of intestinal transplants are performed in pediatric patients, as a result of advancements in intestinal rehabilitation programs and stagnant long-term outcomes of intestinal transplantation. [1] Similarly, in adults, advances in the medical and surgical treatment of intestinal failure have reduced the need for transplantation, and no significant improvement in survival has been seen in transplant recipients since 2005. [2] Nevertheless, intestinal transplants can be lifesaving in patients with severe complications from parenteral nutrition. See the image below.

Revascularized bowel prior to closure. In the lowe Revascularized bowel prior to closure. In the lower right corner the anastomosis between the donor small bowel and recipient remnant colon can be seen.

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. [3, 4] Currently, TPN is safely used in outpatient management. Pooled data from the North American Home Parenteral and Enteral Patient Registry showed 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. [5]

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. Subsequently, 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. [6, 7] These TPN-related complications include the following [8] :

  • Impending or overt liver failure related to TPN (parenteral nutrition–associated liver disease [PNALD)
  • Impending loss of vascular access for TPN administration
  • Multiple episodes of catheter-related sepsis
  • A single episode of life-threatening catheter-related sepsis
  • Frequent episodes of significant dehydration despite supplemental fluid administration 

Improvements in surgical technique, the monitoring and diagnosis of rejection, and cytomegalovirus (CMV) prophylaxis and the development of improved immunosuppression have paved the way for signiicant improvements in patient and graft survival rates. Most recipients of intestinal transplants are free from TPN and enjoy an excellent quality of life. Compared with TPN, intestinal transplantation is cost-effective within 1–3 years of graft survival. [7]  

In addition to isolated small bowel transplants, other types of gut transplantation include the following:

  • Liver–small bowel transplants
  • Modified multivisceral transplant with exclusion of the liver
  • Full multivisceral transplant (ie, stomach, duodenum, pancreas, intestine, and liver)

See the images below:

Liver–small bowel transplants address liver failure from prolonged TPN, and post-transplant survival rates may be higher in these patients, compared with recipients of isolated intestine transplants, due to the immunologic benefits of the liver. However, most patients with short bowel syndrome, pseudo-obstruction, and Gardner syndrome receive isolated intestinal or modified multivisceral transplantation Furthermore, regression of liver disease after intestine-only transplant has been reported in patients who had significant liver fibrosis. [7]

Rejection and infection are still the most perplexing problems surrounding intestinal and multivisceral transplantation.  Earlier patient referral, the development of new immunosuppressive agents, and the discovery of a serum marker for graft rejection are the keys to continued improvements in graft and patient survival rates.

Next:

Background

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. [9]  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.

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 intestinal transplantation before then included dismal outcomes prior to 1990 and a moratorium during 1994 as a consequence of the high morbidity and mortality associated with the procedure.

Since 1995, however, rapid improvements in outcomes have been seen. By and large, this success is a consequence of multiple endeavors, including the following:

  • Progress in immunosuppressive therapy; in particular, the introduction of tacrolimus [10]
  • Better understanding of intestinal immunology
  • Refinement of surgical techniques [11]
  • Improvement in post-transplant care
  • Implementation of protocols for monitoring and prophylaxis of infection (primarily  cytomegalovirus [CMV] infection)

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 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.

However, after steady increases over the preceding decade, the number of intestinal transplantations in the United States peaked in 2007, at 198 transplants, then stabilized at approximately 100 to 120 cases per year. In 2020, only 91 intestinal transplants were performed in the US. [12] See the image below.

Intestinal transplants by year in the United State Intestinal transplants by year in the United States. Data source: Organ Procurement and Transplantation Network https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#

Along with the decline in intestinal transplants, over the past decade the number of new patients added to the intestine transplant waiting list and the number of intestine donors also decreased. Graft failure plateaued over that period. Patient survival for transplants in 2011-2013 was lowest for adult intestine-liver recipients (1- and 5-year survival 66.7% and 49.1%, respectively) and highest for pediatric intestine recipients (1-and 5-year survival 89.1% and 76.4%, respectively). [13]

Concurrent with the reduction in transplant numbers, 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. [14]  Evidence supports the conclusion that this strategy has reduced these patients' likelihood of developing an indication for intestinal transplantation; when coupled with refinements in the management of TPN-dependent intestinal failure (with novel agents such as teduglutide), continuing reductions in overall listings appear likely.

Previous
Next:

Relevant Anatomy

Relevant donor anatomy

For isolated intestinal transplantation in patients with normal anatomy, the superior mesenteric artery (SMA) of the donor is procured with the aortic cuff. The portal vein is cut above the confluence of the superior mesenteric and splenic vein. If a right replaced hepatic artery from the SMA is present, the SMA is cut distal to the takeoff of the replaced hepatic artery. The SMA of the donor is anastomosed to the recipient SMA or the abdominal aorta. The portal vein of the donor is anastomosed to the portal vein or the inferior vena cava of the recipient.

For liver and intestinal or multivisceral transplantation, the celiac trunk and SMA are procured with the abdominal aorta and thoracic aorta. The inferior vena cava is procured from the iliac vein bifurcation to above the diaphragm. The anastomosis is performed between the donor abdominal aorta and the recipient abdominal aorta in an end-to-side fashion.

Previous
Next:

Pathophysiology

Short bowel syndrome is often the result of extensive intestinal resection for multiple pathophysiologies, such as volvulus, trauma, tumor, and thrombosis. An inadequate absorptive surface results in an inadequate energy intake and malabsorption of vitamin B12 and other vitamins. Calcium and magnesium deficiencies can lead to neurologic complications such as encephalopathy, tetany, and convulsions. Intestinal failure with hyperalimentation causes liver failure. Patient on long-term hyperalimentation usually have complications, including line sepsis, thrombosed veins, and liver dysfunction. [15]

Previous
Next:

Etiology

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. Most often, intestinal failure occurs secondary to surgical resection, leading to short bowel syndrome (SBS), although functional disorders in motility, mucosal defects, obstruction, and fistulae may also result in intestinal failure. [16] The causes of intestinal failure include anatomic and functional abnormalities and, along with the population affected, are listed below.

In pediatric patients, causes are as follows:

In adult patients, causes are 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 followed by intestinal adaptation and subsequent enteral tolerance. Considerable interindividual variability occurs among patients: Some 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 increase the likelihood of achieving enteral tolerance include the following:

  • Younger age
  • Presence of an ileocecal valve
  • Presence of an ileum

The functional causes of intestinal failure in those with normal bowel length include the following:

  • Intestinal aganglionosis
  • Chronic idiopathic intestinal pseudo-obstruction
  • Congenital mucosal abnormalities such as microvillous inclusion disease
Previous
Next:

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. [17, 18, 19, 20, 21] 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. [22, 23, 24, 25, 19, 21] 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. [25, 26] 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. [27, 28, 29]

Less common indications for intestinal transplantation include locally invasive desmoid tumors, premalignant conditions (Gardener syndrome), and fluid and electrolyte losses unmanageable with TPN. [30]

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. [30, 31] It cannot be overemphasized that measures to augment intestinal function and minimize the risk of complications of TPN must be explored in every patient on TPN 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. [32]

To illustrate the problems faced in the setting of intestinal transplantation, the following 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 TPN and is essential for resuscitation, perioperative fluids, and medication maintenance required in the peritransplant period.

  • Loss of 2 major access sites is generally an indication for intestinal transplantation. At some centers, however, 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 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 liver–small bowel transplantation than in those awaiting isolated liver transplantation or isolated bowel transplantation.

  • In patients who undergo intestinal transplantation, then lose their graft and have indications for retransplantation, outcomes in retransplantation are inferior to outcomes for the primary transplantation. [33]

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. [34]

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. [35] 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. [36]

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. [26, 5] 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.

Previous
Next:

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 sepsisImmunodeficiency (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 (eg, size of cavity for the allograft, vascular inflow and outflow)
Previous
Next:

Prognosis

The International Registry for Intestinal Transplantation reports that graft and patient survival rates have improved, with a 69% 1-year patient survival rate and a 55% graft survival rate since 1995. [30]  Trevizol et al studied the procedure over a 5-year period and reported a 1-year patient survival rate of 80%, but survival decreases after the first year to less than 70%. [37]

Of 110 intestinal transplants performed on 101 children from 1994 to 2014, Necker-Enfants malades Hospital in Paris reported graft survival at 5 and 10 years was 44% and 31% for liver-containing graft and 57% and 44% for small bowel transplants.  Among the 55 currently living patients, 21 had a liver-containing graft, 19 a small bowel transplants (17 after induction), and 15 were on parenteral nutrition. Late graft loss occurred in 13 patients, and 7 of 10 retransplanted patients died. The main causes of death and graft loss were sepsis and rejection. [38]

Earlier referral of the patients for intestinal transplantation yields improved survival results. Isolated transplantation is preferable to combined liver-intestinal or multivisceral transplantation from a survival standpoint. Posttransplant prognosis is also improved when transplantation is performed prior to the onset of liver failure and prior to the exhaustion of all routes of vascular access.

Causes of death included the following:

  • Sepsis after rejection
  • Respiratory failure
  • Sepsis
  • Multiple organ failure
  • Arterial graft infection
  • Aspergillosis
  • Posttransplantation lymphoproliferative disorder
  • Intracranial bleeding
  • Fungemia
  • Chronic rejection
  • Graft versus host disease
  • Necrotizing enterocolitis
  • Pancreatitis
  • Pulmonary embolism
  • Viral encephalitis
Previous