Continuing Education Activity

Organ transplantation has quickly developed into a dynamic field in medicine that involves a large multidisciplinary team to manage patients care in the pre and post-transplantation stages. One more recently developing field is that of multi-visceral transplantation (MVT) in the setting of intestinal failure and/or accompanying multisystem organ failure. This activity describes and reviews the role of the interprofessional team in evaluating and treating patients who undergo intestinal multi-visceral transplantation.

Objectives:

• Review the treatment considerations for patients with end-organ dysfunction requiring workup for transplantation.
• Describe the indications for multi-visceral transplantation.
• Identify the most common techniques for organ transplantation.

Introduction

Multivisceral transplantation (MVT) can be categorized into many different organ combinations, but for this review, the focus will be on concurrent transplantation of the intestine, stomach, hepatobiliary system, and the pancreaticoduodenal complex – which can also be performed in a modified fashion by “cherry-picking” different organs that suit the recipient’s condition. Some approach MVT by the replacement of any organ that relies on the superior mesenteric and celiac artery. The concept of a total multi-visceral abdominal transplant was introduced in 1960 by the father of modern transplantation – Thomas Starzl.[1] 

Originally performed on dogs to study the effects of mass denervation of homografts, the concept was not abandoned, and in the 80’s it was attempted again, but this time on humans.  Unfortunately, the first patient suffered post-operative hemorrhage; the following two developed posttransplant lymphoproliferative disorder (PTLD) and never left the hospital.  The first hospital discharge MVT was performed in December of 1989. The patient was able to survive 10 months without parenteral support and ultimately passed from metastatic pancreatic cancer.  To date since 1988, there have been 1,916 intestinal transplantations combined with other organs, most commonly liver-intestine-pancreas (1,105) – with the second most common being liver-intestine (464). With advancements in immunosuppression and post-operative care, the 1-year survival rate has increased from approximately 40% to over 80% since the 1990s, with 5-year survival being around 60%.[2]

Indications

Operative indications vary from children to adults, but intestinal transplant is considered when intestinal failure has led to multi-organ dysfunction.  Gastrointestinal failure is met when the body no longer can maintain the delicate balance of proteins, fats, carbohydrates, electrolytes, fluids, and micronutrients.[3] The most common cause of failure is short bowel syndrome (SBS), which can be present in up to 70% of transplant recipients.[4]  While not every SBS diagnosis ultimately requires MVT, additional variables factor into whether MVT would be indicated.

• Multiple infections parenteral central line (2+ episodes yearly, or single episode of fungemia).
• Organ dysfunction secondary to parenteral nutrition (PN) – most commonly liver.
• Peripheral and central venous thrombosis/stenosis limiting central venous access for PN.
• Frequent dehydration in the setting of concurrent PN and intravenous fluids

Other common indications for MVT:[5][6]

Adults:

• Short bowel syndrome
• Mesenteric ischemia (arterial or venous)
• Abdominal neoplasms
• Inflammatory bowel disease (typically leading to SBS)
• Radiation enteritis
• Trauma

Children:

• Volvulus (most common indication)
• Gastroschisis
• Necrotizing enterocolitis (NEC)
• Intestinal dysmotility diseases (ex: aganglionosis, Hirschsprung's Disease)
• Intestinal atresias
• Short bowel syndrome

Contraindications

Similar to other guidelines laid out for solid organ transplants, the contraindications for MVT can include:[5][7]

• The metastatic disease not treatable with transplantation
• Unmanaged/untreatable systemic or local infections
• Cardiopulmonary disease limiting positive outcomes
• Lack of adequate family or social support
• Active drug or alcohol addiction

Personnel

As with most transplant surgeries, an interdisciplinary team is critical for patient outcomes. Depending on the planned en bloc transplantation, both medicine and surgical evaluation are required in the pre and post-transplant phases. Medical teams can consist of hepatologists, dietitians, case management and social work, transplant nurse coordinator, transplant surgeons, and physical and occupational therapists. Each member plays a vital role in long-term recovery. In some cases, psychiatric evaluation is required in the setting of alcohol/drug use; however, a significant number of transplants are those of children's and may not require formal evaluation.

Preparation

The following workup should be performed:

HLA typing and Blood crossmatching

Laboratory: CBC, CMP, Prealbumin, Coagulation panel

Serologic: CMV, EBV, Hepatitis A, B, and C, HIV

Evaluation of bowel length and function utilizing CT enterography

Venous and arterial duplex of the intraabdominal vascular system. Splenoportography and mesentericography are only required for a select number of patients utilizing the Miami classification. Depending on the class, recipients may also be required to undergo vein and/or arterial angioplasty preoperatively.[8]

Donor liver biopsy. Liver biopsy in recipients in the setting of PN induced liver dysfunction.

Dental and possibly ENT consults to limit infectious sources. Sometimes requires dental extraction. 

Systemic disease evaluation and peri-operative risk modification tailored to the patient. It could include coronary angiography, pulmonary function tests, and nutritional status.

Technique or Treatment

Isolated Intestinal Transplantation (IITx)

IITx is performed more in adults than in children (14) with the ability to also perform the operation with a living donor. The IITx can also be modified to include the pancreaticoduodenal complex. In a deceased donor, the mesenteric arterial supply and venous drainage are identified and dissected clearly. The aorta is cross-clamped and flushed with the University of Wisconsin (UW) solution. The SMA is freed, including a segment of the aorta, and the splenic vein is ligated at the junction of the SMV. Depending on the patient – a segment of the ascending colon, along with the right and middle colic artery, can also be freed. The donor small intestine is inserted in a side to side anastomosis onto the proximal host duodenum/jejunum. The distal end is created with either the native colon or with a segment of the ileocecal complex. Critical to the transplantation an end chimney, or Bishop-Koop, the ileostomy is created that allows frequent transtomal endoscopic access for routine postoperative graft surveillance. The arterial system is then restored with anastomosis to the intrarenal aorta and the venous system to either to the portal vein or infrarenal vena cava.[9][10]

The operation is modified in a living donor to allow both individuals adequate bowel for vitamin and bile absorption. Typically, about 150 cm of an ileal segment of the donor is isolated, along with its vascular pedicle, and removed.  The remaining donor ileum is reconnected in an ileo-ileal anastomosis. The donor vascular pedicle is attached in the end to side onto the recipient ileocolic artery and vein. Depending on the recipient’s anatomy and intra-operative findings, the vascular anastomosis may also be created using the infrarenal aorta and inferior vena cava. The distal ileocecal intestinal complex on the donor remains to allow for adequate B12 absorption.

Combined Liver-Intestine

Patients with compromised liver function, typically secondary to prolonged PN – more commonly seen in children, undergo combined liver-intestine transplants. In the 1990s, the liver and bowel were transplanted in a “separate” fashion, and then a Roux-en-Y choledochojejunostomy reconstruction was performed, restoring the biliary system. This led to a high rate of biliary related complications leading to en bloc transplantation.[10] The organs are harvested as one unit, and the critical structures are identified and cleaned on the back table. The host hepatectomy is performed. Arterial and venous end to side anastomosis is then attached to the host aorta and IVC respectfully. The host duodenum and pancreas are left in place. The donor pancreaticoduodenal complex is placed over the respective anatomical location, and the host distal duodenum is then anastomosed in the end to side fashion to the donor jejunum. As a result, the patient will have two duodena and two pancreata.[11]

Multivisceral

There is no true consensus on what multi-visceral transplant organs are standard, and the concept of a multi-visceral transplant can be considered an umbrella term for all of the variations. The allograft is tailored to the individual patient’s need with exclusion or inclusion of multiple organs (ex. kidney and spleen).  The main difference between the combined liver-intestine is the addition of the stomach into the graft; but, this can be modified to exclude the liver.   Due to the denervation of the stomach graft, a pyloroplasty is performed, which allows for improved gastric emptying. The proximal host esophagus or sometimes a segment of the host stomach is anastomosed to the donor's stomach, and the vascular conduits are restored in a similar fashion as the other types of intestinal transplantation.[12]

Complications

Rejection

Considered to be the largest lymphoid organ, the small bowel creates a substantial lifelong challenge for managing both acute and chronic allograft rejection. The introduction of novel immunosuppression agents in the 1990s catapulted MVT into a viable armamentarium for patients. Graft survival did not significantly change after the introduction of cyclosporin A compared to the improvements seen in other solid organ transplants. It was not until the introduction of tacrolimus in the 1990s that patient outcomes and rejection rates improved.[13] Typical maintenance therapy includes tacrolimus, mycophenolate mofetil, and prednisone. Due to the vague clinical manifestation of rejection symptoms (increased stoma output, abdominal discomfort distension, and weight loss), routine surveillance of rejection is performed in a planned interval on an institutional basis. 

Histologic confirmation of rejection is considered the gold standard for diagnosis. The tissue is obtained through endoscopic transtomal biopsies taken from multiple areas of the graft, with increased suspicion of rejection in ileal segments due to the increased amount of Peyer’s patches. Depending on the surgical approach, biopsies of the transplanted abdominal wall flap can provide a less invasive approach for the diagnosis of rejection. The development of laboratory screening has also played a role in the early recognition of rejection. Low levels of serum citrulline and high fecal calprotectin are emerging as reliable noninvasive measures of allograft rejection.[14][15] There also has been some data to suggest that combined liver-intestinal transplants, compared to intestinal transplantation alone, offer a benefit regarding the reduction of both acute and chronic rejection.[16][17]

Graft versus Host Disease (GVHD)

Graft versus host disease occurs when donor cells recognize the host cells as foreign antigens and begin to mount a donor mediated immune response against the recipient tissue.  Along with the significant concerns of rejection in intestinal transplant, the amount of lymphoid tissue also creates concern for the allograft assaulting the recipient. Thankfully, the incidence is relatively low (approximately 6%), but GVHD carries significant mortality, as high as 70%.[18]  Diagnosis is through polymerase chain reaction (PCR) and immunohistologic staining. Treatment includes increasing immunomodulating drugs and even stem cell therapy.[19] Risk factors for GVHD can include younger age and including spleen in the en bloc transplantation. Although a single-center reporting 100 MVT’s did not see a statistically significant increase in GVHD when transplanting the spleen. Other solid organ transplantations have expressed a theoretical increase in GVHD when combined with a splenic transplant.[20]

Posttransplant Lymphoproliferative Disorder (PTLD)

PTLD is a well-documented complication for many solid organ transplantations and should be briefly mentioned in this review of complications. While not classified as a single disease, but more of a syndromic presentation that involves potentially neoplastic lymphocytic proliferation that can create a difficult and deadly presentation for post-transplant care. The growths are common with B lymphocyte origin that is typically related to Epstein-Barr virus (EBV). Treatment includes reduction of immunosuppression and antiviral therapy; but, this comes with the risk of graft failure secondary to rejection. The median time for development for one institution was 25.3 months, and all patients were able to recover clinically. There has been some data to suggest that the transplantation of the spleen could increase the incidence of PTLD.[21]

Infections

Opportunistic infections, from bacterial to viral, are well-established as a necessary risk in all solid organ transplantations. Subjecting the body to immunosuppression medication opens the body up to life-threatening in otherwise unremarkable infections in immunocompetent individuals. Some institutions make every effort to preserve the native spleen to prevent acquired asplenic opportunistic infections (from encapsulated bacteria) and attempt to reduce the incidence of asplenic sepsis. In the setting of MVT, cytomegalovirus (CMV) is a clinically significant pathogen due to CMV’s higher tropism in gastrointestinal cells and the increased amount of potential cellular hosts (due to the increased lymphoid cells in the small bowel). In one study, up to 94% of MVT patients developed infections post-transplant.[22][23]

Surgical Complications

Post-surgical complications vary depending on the organs transplanted but tend to occur in the early posttransplant period. These can include anastomotic leaks, arterial and venous graft thrombosis, and bleeding. Some are managed non-operatively, but the most feared complication is arterial thrombus creating an emergent relaparotomy. Unfortunately, the graft is often unable to be salvaged in this setting, and retransplantation may be required. Signs of arterial graft thrombosis are like that of acute mesenteric ischemia. In a single institution of 500 transplants, the arterial thrombosis incidence was 3.8%[24]

Clinical Significance

Intestinal and Multivisceral transplant has progressed from a highly morbid surgery in the late 1980s to a life-altering intervention.  A review of 500 transplants show patient survival rates at 1, 5, and 10 years to be 85%, 61%, and 42%, respectfully. Graft survival rates were lower than patient survival rates at 80%, 50%, and 33% respectively.[25] Studies comparing PN to MVT shows a statistically significant increase in functional status, decreased anxiety, and quality of life.[26] Approximately 85% of patients reported having normal functional status.[27]

Enhancing Healthcare Team Outcomes

Multivisceral transplant combines the anatomy and physiology of multiple systems requiring a robust and active multidisciplinary team. Each provider, from dietitian to therapist, plays a critical role in the profound improvement in the quality of life that MVT provides. Leading institutions have been more aggressive at transplanting earlier due to the life-changing improvements. Over the past three decades, patient outcomes have improved by over two-fold – largely due to establishing a dedicated interdisciplinary team. The team must be proactive in following up with pre and post-transplant patients. Patients from lower socioeconomic environments and pediatric populations benefit from close surveillance, this improves compliance and early recognition of potential complications.[28] [Level 5]