Intestinal and Multivisceral Transplantation: Recent Advances

Complications of Short Gut Syndrome

Interruption of enterohepatic circulation after resection of the small intestine often results in progressive liver disease, unlike patients who are receiving parenteral nutrition without short gut. Enteral calories and intravenous lipid derived from fish oil may prevent cholestasis and liver injury. Recent data have demonstrated that omega-3 fatty acids are associated with chemical reversal of parenteral nutrition–associated cholestatic liver disease. Bacterial overgrowth results from excessive bacterial proliferation because of blind loop or absence of ileocecal valve. Symptoms include excessive bloating, flatulence resulting from enterocyte injury, and inactivation of bile acids via deconjugation. It leads to a deficiency of vitamins, especially B ₁₂ , A, D, E, and K. Therapy includes gut decontamination with oral Flagyl or trimethoprim-sulfamethoxazole and gentamicin. Pancreatitis is a well-known complication of TPN that is exacerbated by the development of gallstones. Consequently, patients can develop endocrine and exocrine dysfunction and require replacement therapy with insulin and pancreatic enzymes. Central vein thrombosis and catheter-related bloodstream infection with sepsis, endocarditis, and brain microinfarctions are known complications of prolonged TPN. All of the preceding complications including metabolic derangement and renal insufficiency due to frequent dehydration can be an indication for gut rehabilitation including transplantation.

Medical Management

In the early postoperative period, patients require parenteral nutrition via a peripheral or central line. After resolution of ileus and if there are no confounding factors, enteral feeding is started in the form of formulas and breast milk for infants. Depending on age, nutritional requirements, and ability to take orally, formula and amount of tube feeding are modified with the help of nutritionists who are instrumental in the management of these patients. A well-hydrated patient with rising albumin, weight, reduction in fecal volume, and normal laboratory values on enteral nutrition indicates that TPN weaning is warranted. Care is taken to ensure oral replacements include trace elements and vitamins, and therapy is guided by periodic testing of laboratory values of these. Failure of TPN withdrawal is usually seen in patients with diseased remaining bowel, ultra-short gut length (<40 cm), absence of ileocecal valve, and loss of colon. Thus, failure of enteral therapy, total loss of small bowel, dysmotility, and mucosal disorders are absolute indications for long-term parenteral nutrition at home. This is supported by a multidisciplinary team of providers that includes home nursing, pharmacists, nutritionists, and the gastrointestinal physician.

A multidisciplinary approach is essential to the success of any intestinal rehabilitation program. Patients are evaluated by pediatric gastroenterologists, pediatric general surgeons, intestinal failure nutritionists, pharmacists with advanced training in parenteral nutrition, and social workers ( Fig. 36.1 ). Depending on residual intestinal length, patients may require antimotility agents such as loperamide, diphenoxylate, atropine, or tincture of opium. Cholestyramine and octreotide are of limited benefit. In addition to the standard nutritional measures, enterocyte growth factors have been utilized increasingly to promote gut adaptation.

In selected patients, the use of enterocyte growth factors enhances the adaptation process and increases the chances of achieving nutritional autonomy. Teduglutide is a recombinant analog of human glucagon-like peptide 2 (GLP2) approved in the United States (Gattex) and Europe (Revestive) as the first targeted treatment of short bowel syndrome–associated intestinal failure. It increases crypt epithelial proliferation, reduces epithelial apoptosis, and enhances visceral blood flow and nutrient absorption with the goal of decreasing parenteral nutrition requirements. Parameters of successful gut rehabilitation include enteral autonomy (discontinuation of TPN for more than 3 consecutive months), reduction in parenteral caloric requirements, and reduction in serum-conjugated bilirubin. In a 12-week phase 3 study involving 40 patients (age 1 to 17 years) from 17 intestinal rehabilitation programs in the USA and UK, parenteral volume requirement decreased by 25% to 41% and parenteral calories by 45% to 52% while increasing enteral volume and calories; 4 patients were weaned from PN at the end of the study. However, 2 of them required resumption of PN 4 weeks after termination of the study. Teduglutide was generally well tolerated; the most commonly reported side effect was vomiting, especially in moderate–high dose regimens (0.025 mg/kg/day to 0.05 mg/kg/day) compared to a low dose regimen (0.0125 mg/kg/day). The short study period (12 weeks) did not allow for evaluation of the effects after prolonged treatment and impact on growth.

Surgical Interventions

Failure of supportive and medical therapy, especially in patients with dilated small bowel, is an indication for surgical intervention to enhance gut adaptation to intestinal failure. Small bowel dilatation (≥4 cm) is associated with dysmotility and bacterial overgrowth, predisposing to septic complications from bacterial translocation, D-lactic acidosis, and malabsorption. In addition to the length of remaining small bowel and the presence of the ileocecal valve, small bowel dilatation impacts weaning from PN and survival.

Autologous Reconstruction and Bowel Lengthening

Patients with atretic bands, obstructed bowel loops, and dilated bowel segments need surgical exploration. Oftentimes patients develop enterocutaneous fistulae or intra-abdominal abscesses that need to be surgically repaired or drained, respectively. Successful, calculated surgical intervention can restore native gut function and preclude the need for intestine transplantation.

The technical feasibility of visceral transplantation and improved outcomes has stimulated the introduction of different nontransplantation surgical procedures to treat intestinal failure and complex abdominal pathology, including autologous reconstructive and bowel-lengthening procedures ( Fig. 36.2A–E ). With transplantation being utilized as a rescue therapy, surgical reconstruction has been increasingly applied in patients with multiple entero-cutaneous fistulae and residual bowel function. Dilated segments of the bowel can be lengthened by one of the two well-known and innovative techniques. Both modalities can be successfully performed in patients with dilated bowel loops to reduce transit time, eliminate bacterial overgrowth, and enhance gut absorption. These include longitudinal intestinal lengthening and tailoring (LILT) introduced by Bianchi and serial transverse enteroplasty (STEP) reported by Kim et al. Indications, selection criteria, and outcome measures are summarized in Table 36.1 . In general, the Bianchi procedure requires a minimum of 20 cm of small bowel, whereas the STEP procedure can be performed on any length of bowel. In selected children with short bowel and absent ileocecal valve, tapering surgery increases bowel length by up to 50% and achieves enteral autonomy in 59% to 75%, comparable to patients with longer remnant intestine and retained ileocecal valve not requiring tapering surgery. Repeat STEP can be performed in selected patients to achieve full enteral autonomy. One of the potential complications of STEP is postoperative stricture resulting from excessive reduction (<2 cm) of the intestinal lumen.

Table 36.1

Selection Criteria and Outcome With Bowel Lengthening Procedures

	Longitudinal Intestinal Lengthening and Tailoring, Bianchi	Serial Transverse Enteroplasty, Kim et al.
Indication	Loss of Nutritional Autonomy
Age	Any age, preferably after 6 months	Any age
Recommended anatomy	20–40 cm dilated bowel	Any length
Minimal intestinal diameter and length	3–5 cm along a length of 20 cm	4 m, any length
Associated liver disease	Can be done in the presence of early fibrosis	Can be done in the presence of early fibrosis
Intestinal lengthening	1.25- to 2-fold	1.4- to 2.2-fold
Reversal of liver disease	Yes	Yes
Ability to repeat procedure	None	Possible
Complications	Perforation, ischemia	Bleeding, microperforation

In addition to bowel reconstruction techniques, creative efforts have been made to treat unresectable abdominal malignancies by ex vivo tumor resection and gut auto-transplantation. Failure of autologous intestinal rehabilitation should prompt the need for early transplantation with expected better outcomes. The indications for early referral and transplantation to prevent irreversible neurologic and psychosocial impairments that may have a significant impact on the procedure’s rehabilitative therapeutic indices are summarized in Box 36.2 .

BOX 36.2

Pediatric Criteria for Referral for Visceral Transplantation

• Massive small bowel resection

• Severely diseased bowel and unacceptable morbidity

• Microvillus inclusion disease

• Persistent hyperbilirubinemia

• Venous thrombosis of upper body veins

• Dysmotility

• Portomesenteric thrombosis

Nomenclature

The three main procedures include intestine, liver–intestine, and multivisceral transplantation with the adoption of a new subclassification according to the type of added organs introduced by the senior author of this article (KA). This nomenclature set the stage for future reporting metrics and outcome analysis. It has been accepted by major professional transplant societies ( Fig. 36.3 ).