Liver‐Intestine/Multivisceral Perspective: Indications, Patient Selection, and Allocation Policy

Watch a video presentation of this article

Abbreviations

IF

intestinal failure

IT

intestine transplantation

MELD

Model for End‐Stage Liver Disease

MVT

multivisceral transplant

PN

parenteral nutrition

PNALD

PN‐associated liver disease

Intestinal failure (IF) exists when the gastrointestinal tract has insufficient function to maintain hydration and nutrition to support life and to modulate electrolyte and fluid balances. In children, this definition also includes the failure of the intestine to support growth and development. The cause of IF most frequently involves loss of intestine length, so‐called short gut, but may also result from neurological or enterocyte dysfunction that prevents normal peristalsis or absorption1 (Table 1).

Table 1.

Common Etiologies of IF

Adult	Pediatric
Noncongenital short gut (Crohn's, adhesions, volvulus, trauma)	Necrotizing enterocolitis
Chronic intestinal pseudo‐obstruction	Gastroschisis
Enteropathies	Malrotation with volvulus
Diffuse portomesenteric thrombosis	Hirschsprung's disease
Slow‐growing benign tumors of the mesenteric root (desmoid, neuroendocrine)

Clinical management of IF requires chronic replacement therapy that may include intravenous fluids or parenteral nutrition (PN). Management of IF is resource intensive and costly. Unlike dialysis, where the average patient receives therapy three times weekly, a large percentage of patients with IF require replacement of fluids and nutrition every day. Long‐term intravenous access is required, resulting in frequent infections, hospital and intensive care unit admissions, home nursing visits, and catheter exchanges, with the additional costs of the PN. A previous analysis estimated that these costs total $200,000 to $300,000 per patient per year, or $2.3 billion annually in the United States.2 Recent advances in the management of long‐term PN have decreased the rate of catheter infections using: (1) tunneled access, (2) daily ethanol dwells in the catheter, and (3) consistent dressing changes by trained personnel two to three times weekly.3 Unfortunately, loss of vascular access remains a life‐threatening issue in patients with IF.

PN‐associated liver disease (PNALD) is a known complication of long‐term PN. Important discoveries in the biochemistry of PN have identified the phytosterols in soybean‐based lipids as the primary culprit of PNALD. Simple lipid minimization, administering lipids only 2 to 3 days per week, has dramatically reduced the incidence of liver injury in this high‐risk population.4 Alternative lipid substitute therapies have also been introduced, many with results similar to lipid minimization.5, 6 Long‐term results from these therapies are still needed to determine the durability of these options in avoiding liver injury. The introduction of glucagon‐like peptide 2 analog (GLP‐2; teduglutide) is an important step forward in the management of IF.7 This agent improves gut absorption in patients with IF, allowing some patients to reduce the number of days per week on PN, whereas some others who require PN only 2 to 3 days per week are able to completely stop PN.

Intestine transplantation (IT) is indicated in patients with IF for whom standard therapies have failed, generally through recurrent episodes of sepsis, loss of vascular access, or PNALD8, 9 (Table 2). IT replaces the full length of intestine, allowing the transplant recipient to take an oral diet. Most patients with IT with good function are able to live independently from supplemental fluids or PN, allowing removal of their central venous catheter. IT also allows removal of the diseased, nonfunctional intestine, reducing the risks for bacterial translocation that may lead to recurrent infections in patients with IF. IT offers the chance for a definitive cure of IF. Other nonstandard indications for IT include surgeries that transplant multiple organs simultaneously (multivisceral transplant [MVT]). Conditions such as diffuse portomesenteric thrombosis, desmoid tumors of the mesenteric root, and abdominal catastrophes resulting in frozen abdomen may be amenable only to complete replacement of the abdominal viscera.10, 11 A standard full MVT includes the en bloc transplant of the liver, intestine, stomach, duodenum, and pancreas.

Table 2.

Indications for IT

Loss of two or more major vascular access sites

Recurrent bloodstream infections

Two or more episodes of bacterial sepsis within 1 year One episode of systemic function infection

Chronic renal dysfunction related to dehydration

Failure of growth and development in children

Liver fibrosis/cirrhosis

Transplants, including both IT and MVT, are reserved for patients who meet criteria and have exhausted standard therapeutic options. Risks associated with transplant include the standard risks of major surgery and lifelong immunosuppression, but transplantation of the intestine is also associated with higher rates of graft rejection, posttransplant renal failure, graft‐versus‐host disease, and posttransplant lymphoproliferative disorder when compared with other organ transplants. Although IT and MVT have been successfully performed since the 1980s, these substantial risks have limited its growth. Now, most IT and MVT patients do successfully undergo the transplant procedure, but they frequently experience posttransplant morbidity or mortality related to immunological complications. Ten‐year patient survival rate after transplant is less than 50%. This result is often considered unacceptable when compared with outcomes for other organs, but should be viewed in the context of a likely 0% 10‐year survival rate for these same patients if they had not undergone transplant.

An important distinction in the field of IT is a comparison of IT and MVT outcomes. The liver is considered to be protective against rejection when cotransplanted with any other organ. This is especially true with IT, in which the 1‐year rate of rejection is 45% to 50% for IT alone, compared with only 10% for the MVT graft. This outcome is then manifest as a better long‐term outcome for MVT (or liver‐intestine grafts), making the MVT a more durable graft over the long term12 (Fig. 1). Because of this clear survival advantage, many centers prefer to perform MVT if the patient meets criteria. Also, if the patient loses his or her IT graft, they are almost always retransplanted with an MVT graft to improve the chances for survival.13

Figure 1.

Posttransplant patient survival comparing intestine only and combined liver‐intestine or multivisceral grafts in the United States.

Transplantation of the intestine reached its peak in 2007 with 198 transplants (about 3% compared with the number of liver transplants) (Fig. 2). In 2017, this number had decreased to only 109 (1.5% compared with livers), with the bulk being done by only 10 centers. This decrease in volume is directly related to improved safety of long‐term PN. Critical advances that have been made in the past decade include decreasing incidence of catheter‐related bloodstream infections and the downstream impact of maintaining better vascular access. Minimization of toxic lipids has dramatically reduced PNALD. Of the current volume of intestine transplants, approximately 50 to 60 annually are liver inclusive. This use of livers equates to 0.7% of the grafts transplanted in the United States.

Figure 2.

Volume of intestine transplants in the United States from 1995 to 2017 (combines both intestine alone and liver‐intestine grafts).

MVT and liver‐intestine patients are currently given a priority position on the liver transplant wait list. However, death while on the wait list continues to be problematic in this population because the Model for End‐Stage Liver Disease (MELD) score does not accurately reflect the severity of disease. Adult candidates awaiting combined liver and intestine transplant have a risk for wait‐list death double to that for liver alone candidates. In the United States, a new liver allocation system has been developed and approved by the United Network for Organ Sharing. This allocation significantly worsens the current position of combined liver and intestine patients on the wait list, providing only a small adjustment to their natural MELD score. This places the United States at odds with Europe, the United Kingdom, and Latin America, where liver‐intestine patients are placed just below the most critically ill patients. Fair allocation of liver allografts is an ongoing debate throughout the world, but the small liver‐intestine subpopulation must still receive preferential listing to optimize survival outcomes and to allow this niche field to remain viable.