CHOLESTASIS 1089-3261/99 $8.00 + .OO TOTAL PARENTERAL NUTRITION AND CHOLESTASIS Iqbal S. Sandhu, MD, Catherine Jarvis, PharmD, and Gregory T. Evers...

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1089-3261/99 $8.00

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TOTAL PARENTERAL NUTRITION AND CHOLESTASIS Iqbal S. Sandhu, MD, Catherine Jarvis, PharmD, and Gregory T. Everson, MD

Soon after the introduction of total parenteral nutrition (TI") in the late 1960s, hepatobiliary dysfunction was recognized as a major adverse effect of therapy. Although the incidence and severity of TI"-associated hepatic dysfunction have decreased because of improvements in clinical management, hepatobiliary complications of TI" remain a major cause of morbidity and mortality in these patients. The majority of patients who require TI" have a primary gastrointestinal disorder or other serious medical condition. Hepatobiliary abnormalities may be caused not only by TI" but may reflect underlying disease or effects of pharmacologic agents. Despite these confounding factors, current evidence suggests that TI" contributes to intrahepatic cholestasis and biliary sludge in infants and to steatosis, steatohepatitis, biliary sludge, cholelithiasis and cholestasis in adults. THEORIES OF PATHOGENESIS OF CHOLESTASIS AND LIVER INJURY INDUCED BY TOTAL PARENTERAL NUTRITION

Cholestasis is the most common hepatic complication of TI" in infants; it is less common in adults receiving TPN.9, The origin of TPN-induced cholestasis is not well defined and is probably multifactorial. Despite major advances in the understanding of the molecular

From the Division of Gastroenterology and Hepatology (ISS), the Department of Medicine (GTE), the University of Colorado School of Medicine; and Nutrition Support Services, University of Colorado School of Pharmacy (CJ), Denver, Colorado




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mechanisms that regulate bile there have been no studies of the effects of TPN on biliary secretory transporters, channels, or pathways on a molecular level. Theories of pathogenesis of cholestasis in patients on T I " focus primarily on three concepts (Fig. 1):(1)direct toxicity of TI" on the liver, (2) hepatic nutritional deficiencies resulting from the nutritional inadequacies of TPN, (3) complications related to lack of enteral intake and inadequate stimulation of the enterohepatic circulation and bowel f~nction.~' Toxicity of Total Parenteral Nutrition

Immaturity of the biliary secretory system appears to be a major factor in the development of cholestasis in premature infants, and the events surrounding physioIogic cholestasis may be more pronounced by The decreased size of the bile acid pool the introduction of and the less well-developed hepatic mitochondria1 function may make premature neonates more susceptible to the development of cholestasis.5,16, 33, 94 Recent studies of the cholesterol 7 a-hydroxylase knockout mouse indicate that in rats the cholesterol 27-hydroxylase pathway of bile acid synthesisz3,92 is expressed in the neonatal period and could generate potentially cholestatic monohydroxy bile acids (3 P-hydroxy-548 Abnormal cholenoate, 3 a-hydroxy-5-cholanoate, and lith~cholate).~, regulation or impairment of key enzymes in bile acid biosynthesis,

Figure 1. The three common theories of pathogenesis of total parenteral nutrition (TPN) cholestasis are shown. A, The direct hepatic toxicity of TPN constituents, which potentially could impair bile flow and result in cholestasis. Illustration continued on opposite page



Bile Acid

B Figure 1 (Continued).B, The proposed effect of one nutritional deficiency (taurine). Taurine deficiency reduces the conjugation of bile acids, which then diminish bile secretion and reduce the enterohepatic cycling of bile acids. Illustration continued on following page

related to underlying disease or TPN, may favor the hepatic production of these cholestatic molecules. Many studies have implicated amino acids in TPN cholestasis. Vileisis et a1 compared the effects of two TPN solutions, differing only in protein content, on the development of cholestatic jaundice in 82 infants.91Infants receiving amino acids at a high rate of protein intake (3.6 g/kg/d) developed cholestasis earlier and had a higher peak bilirubin level than a comparable group of infants receiving a lower protein intake (2.3 g/kg/d). The two groups had similar the incidence of cholestasis. The investigators concluded that the severity of cholestasis is directly related to the volume of infused amino acids and the duration of TI" therapy. Long-duration TPN is a risk factor for the development


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Impaired Bile Flow

Increased Endotoxin Lithocholate In Portal Blood

Impaired Barrier Bacterial Overgrowth



Endotoxin Lithocholate

Figure 1 (Continued). C, Some of the effects of inadequate stimulation of the enterohepatic circulation and intestinal function. Inadequate enteral intake diminishes release of cholecystokinin, reducing gallbladder contraction and gut motility. Diminished gut motility favors bacterial overgrowth, which increases intraluminal endotoxin and lithocholate concentrations. Break down of gut mucosal integrity allows translocation of endotoxin and lithocholate into portal venous blood and delivery to the liver. Endotoxin stimulates release of cholestatic cytokines and lithocholate in directly cholestatic.

of cholestasis in both adult and pediatric patients. Individual amino acids implicated in liver injury and cholestasis include tryptophan, alanine, and arginine. Tryptophan, alone or after it is exposed to light or sodium bisulfate, has been shown to promote cholestasis and histologic abnormalities in the livers of rats and gerbils.13,36, 63 Some clinicians have proposed that amino acid solutions should not be administered to neonatal patients to attempt to decrease the risk of cholestasis.16 A consistent pathologic feature in TPN-induced cholestasis is the presence of lipofuscin pigment in Kupffer 's cells. Lipofuscin results from




the peroxidation of subcellular membrane components and is seen in patients with antioxidant defi~iency.~~ Exposure of parenteral nutrition solutions to light in the presence of oxygen generates lipid and other peroxides. Potential sources of peroxides in TPN solutions are vitamins and polyunsaturated fatty acids in lipid emulsions. Neonates or nutritionally depleted adults may have inadequate antioxidant systems, increasing the potential toxicity of peroxide molecules in these patients. Protecting the parenteral nutrition solution from light and supplementing it with antioxidants such as vitamin E may be benefi~ial.~~ Aluminum toxicity has also been implicated in the development of cholestasis. Although aluminum toxicity had been considered a potential problem in the past, it was dismissed as irrelevant to modern TPN therapy. However, recent studies demonstrating contamination of TPN solutions by aluminum have restored awareness of the possibility of aluminum-induced cholestasis. Nutritional Deficiencies Induced by Total Parenteral Nutrition

In contrast with theories of amino acid toxicity, some investigators have suggested that amino acid deficiency, in particular taurine deficiency, may cause cholestasis. Hepatic immaturity in the preterm infant contributes to low activity of hepatic cystathionase and cysteine sulfinic acid decarboxylase, which are rate-limiting enzymes in the biosynthetic pathway of taurine. As a result, taurine, a nonessential amino acid in the adult and mature infant, is an essential amino acid in premature infants." In the neonate, taurine is the principal amino acid utilized by hepatocytes to conjugate bile acids. Taurine supplementation promotes bile flow and protects against lithocholate toxicity.", 38 Taurine supplementation in a guinea pig model prevented the cholestasis induced by lithocholic acid.26Modified amino acid solutions containing taurine have been developed for use in neonates, but there is no clear evidence that their use has resulted in a decline in TI"-associated chole~tasis.~~ Impairment of hepatic methylation reactions, related to deficiencies in methyl-donor molecules, has also been implicated in TPN cholestasis. Supplementing TPN solutions with methyl-donor amino acids, such as serine or methionine, improves bile flow in rats when compared with serine-deficient TPN solutions." Glutamine deficiency commonly occurs in patients on TPN because it is not present in commercially available amino acid solutions. Adding glutamine may protect against TPNrelated hepatic dysfunction by attenuating TPN-associated gut hypoplasia and enhancing gut immunity through prevention of immunoglobulin A depletion. Inadequate Stimulation of the Enterohepatic Circulation and Intestinal Function

Lack of enteral stimulation has many potential implications for the development of cholestasis in infants and adults.89Cholecystokinin, a


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gastrointestinal hormone released in response to oral intake of fat and protein, causes gallbladder contraction and stimulates bile flow. Lack of enteral intake and subsequent lack of cholecystokinin release contributes to production of biliary sludge by decreased emptying of the gallbladder, promoting stasis of bile in the gallbladder.5,20, 46, 78 Small intestinal bacterial overgrowth may result from the intestinal stasis caused by the absence of enteral stimulation. This overgrowth may contribute to the development of cholestasis by promoting formation of the secondary bile acid, lithocholate, from the primary bile acid, chenodeoxycholate. The colonic-type bacteria that colonize the small intestine harbor an enzyme, cholylglycine-hydrolase, which has broad substrate specificity for both taurine and glycine conjugates of bile acids. Free bile acids released by the action of this enzyme are further metabolized by another bacterial enzyme, 7a-dehydroxylase. The action of this enzyme converts the relatively harmless primary bile acid, chenodeoxycholate, to lithocholate, a known hepatotoxin shown to impair bile flow and induce cholestasis in animals.32 Intestinal hypoplasia and decreased gut immunity can also be caused by lack of enteral stimulation.6,8o Intestinal hypoplasia may allow increased absorption of lithocholic acid, thereby promoting lithocholateinduced liver injury and cholestasis. Concomitant bacterial overgrowth, intestinal hypoplasia, and decreased gut immunity promote bacterial translocation across the gut, potentially increasing the concentration of endotoxins in portal blood.81, The lipopolysaccharide component of endotoxins may bind to the CD14 receptor of macrophages and stimulate the release of cytokines injurious to the liver.67,95 Lipopolysaccharide triggers macrophages to release interferon-y, tumor necrosis factor, and transforming growth factor-p (TGF-P). Transforming growth factor-p is known to stimulate hepatic fibrosis and may contribute to the injury, cholestasis, and fibrosis associated with Tl". A similar mechanism is implicated in the development of cholestasis caused by sepsis.85 CLINICAL SYNDROMES

Clinical syndromes caused by TI" are variable; steatosis predominates in adults, and cholestasis is most common in children: Adults NASH-type syndrome Steatosis, phospholipidosis Steatohepatitis Fibrosis Micronodular cirrhosis Cholestasis Intrahepatic Extrahepatic Sludge



Cholelithiasis Choledocolithiasis Acalculous cholecystitis Children Intrahepatic cholestasis Fibrosis Cirrhosis Extrahepatic biliary tract disease Sludge Complications of choledocolithiasis Abdominal pseudotumor (distended gallbladder) Hepatocellular carcinoma (rare) Levels of liver enzymes and bilirubin exhibit marked variability and fluctuate over time, limiting their usefulness as sensitive and specific markers for TI"-related liver dysfunction. Peak levels of liver enzymes have been observed within 1 to 4 weeks after T I " therapy is started; often, enzymes decrease or resolve despite continued administration of 60, 77 Predominant elevations in transaminases suggest steatosis; elevations in y-glutamyltransferase (GGT) or alkaline phosphatase suggest cholestasis. Conjugated hyperbilirubinemia is common in children with TI"-induced cholestasis but is less common in adults, and its presence may suggest other diagnoses, such as sepsis, drugs, viral hepa52, 66 Few studies have correlated titis, and extrahepatic obstru~tion.~~, histology, liver function, and liver test abnormalities. Changes in these tests can result from enzyme induction or may indicate hepatic damage. Liver Dysfunction in Adults Related to Total Parenteral Nutrition

Steatosis is the most common early hepatic abnormality in adult patients receiving TI". It is considered reversible and may not lead to 47* 59, 77 The onset and duration of steatosis are variable, hepatic but it may appear as soon as 1 to 4 weeks after initiation of TI" therapy. The majority of patients maintained on T I " for longer than 3 months exhibit hepatic biochemical abnormalities or steatosis on liver biopsy. Figure 2 presents the authors' recommended treatment for patients with transaminase elevations. The incidence of liver test abnormalities may vary from 25% to 100%. Figure 3 shows the time course of the early changes. The variation results from the diverse patient population that receives TPN. For example, some studies report results from terminal cancer patients, whereas others have studied disorders such as inflammatory bowel disease or trauma patients.l, 65, 93 Moreover, over time, changes have been made in the constituents of TPN, related to changes in standards of practice. In particular, the total TI" calories have been decreased and lipids emulsions have been included in the prescription.', 65, 66, 93 In addition, the


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Elevated AST, ALT

+ Exclude drug reaction

Suspicion of biliary process


US of liver & biliary tree Fig 4, A

Viral serology


A Serial LFTs for 4 weeks




Other disorders

Figure 2. Transaminase elevations in adult patients on total parenteral nutrition (TPN) are suggestive of steatosis or steatohepatitis. Drugs can impair liver function and produce this pattern; they should be carefully evaluated. If biliary symptoms are present, an ultrasound of the abdomen should be ordered to examine the extrahepatic ductal system for stones or obstruction. A, In the absence of biliary symptoms, viral hepatitis should be excluded with viral serologies, including hepatitis A IgM, hepatitis B surface antigen, hepatitis B core IgM and IgG and hepatitis C antibody. After exclusion of viral hepatitis, a period of observation with serial liver test determinations may reveal resolution of the abnormal pattern without discontinuing TPN. 8,Persistence of enzyme abnormalities may necessitate performance of liver biopsy to obtain a specific histologic diagnosis. Steatosis may progress to steatohepatitis (NASH) and fibrosis from the inflammatory process may culminate in cirrhosis.

clinical condition of the patient before TPN therapy may indicate risk of TI"-associated liver disease. Malnutrition before the initiation of TPN therapy has been identified as a risk factor for developing early liver test abnormalitie~.~~ Rather than resolving, steatosis may progress and cause inflammation leading to fibrosis and even to cirrhosis. This progression occurs in 15% of adults on long-term Tl".14 Initial manifestations of cirrhosis include biochemical abnormalities (elevated bilirubin, decreased albumin, and increased protime) and worsening fatigue. Signs of decompensation (ascites, varices, spontaneous bacterial peritonitis, and encephalopathy) indicate severe irreversible liver disease and the possible need for small bowel and liver transplantation. Calculus gallbladder disease occurs commonly in patients on TPN.51 Stasis of bile within the gallbladder may play a major role in the formation of 74 The incidence of sludge increases rapidly from 6% at 3 weeks to 50% between 4 to 6 weeks, and sludge is present in all patients on TPN after 6 weeks.64Nineteen percent to 35% of these










01 1












Weeks on TPN Figure 3. Time course of changes in liver tests after initiating total parenteral nutrition (TPN) in nonseptic patients is shown. AST-aspartate aminotransferase; AP = alkaline phophatase (solid line); Dashed line = AST; dotted line = bilirubin. (Data from Clarke PJ, Ball MJ, Kettlewell MGW: Liver function tests in patients receiving parenteral nutrition. J Parenter Enteral Nutr. 1554, 1991.)

patients develop gallstones as a consequence of TPN; the highest incidence is in patients with preexisting ileal di~ease.6~~ 74 Suspected extrahepatic obstruction from stones or sludge should be evaluated initially with an abdominal ultrasound (Fig. 4). If common bile duct stones are detected, therapeutic interventions with papillotomy and cholecystectomy may be indicated. Patients with biliary sludge may benefit from papillotomy if they experience biliary pain, have abnormal liver tests, or demonstrate reduced gallbladder emptying to fat feeding or cholecystokinin. If ultrasonographic or cholangiographic studies show no obstruction of the common bile duct, patients with typical biliary pain may be candidates for cholecystectomy. Acalculous cholecystitis occurs in about 4% patients who have been on TPN for longer than 3 months.74Patients present with biliary-type pain or unexplained fever and leucocytosis with right upper quadrant abdominal tenderness. Imaging studies fail to reveal gallstones, but sludge is often present. Cholecystectomy is the preferred therapy (Fig. 5). Adults on long-term TPN with a rising alkaline phosphatase level 36, 59, 65, 77 The major risk may show evidence of intrahepatic chole~tasis.'~, factors include presence of length of time on TPN, continuous infusion of TPN, excessive amino acids in TPN, inadequate use of lipid emulsion, and deficiencies of certain nutrients (methionine,'O taurine,", 26, 38, 73 choline,l8 gl~tamine,3~, 57, 58 and carnitine15).Modification of


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Cholestasis Elevated Alk phos, GGT, Bilirubin

US of liver & biliary tree

No cholelithiasis no CBD dialtion

[T Fat feeding

1I '1 Papillotomy

u cholecystectomy

Biliary symptoms


, 4 weeks


Liver biopsy

Figure 4. The first evaluation of adult patients on total parenteral nutrition (TPN) exhibiting a cholestatic pattern is to rule out drug toxicity. A, Extrahepatic obstruction causing cholestasis is initially evaluated by abdominal ultrasonography. Discovery of cholelithiasis or dilation of the common bile duct (CBD) is an indication for ERCP. B, ERCP has both a diagnostic and therapeutic role in management of extrahepatic biliary disease. Papillotomy is performed when a common duct stone is confirmed. C, Sludge (echogenic, non-shadowing, movable material within the gallbladder) that persists despite fat feeding or cholecystokinin administration may be an indication for cholecystectomy when biliary symptoms exist. D, Cholecystectorny is effective in alleviating symptoms. of biliary pain in the presence of stones or sludge. f,Liver tests in patients on TPN may resolve despite continued TPN. Observation for 4 weeks with serial determination of liver tests is recommended. Persistence of liver enzyme abnormalities should be evaluated by histologic examination of liver biopsy.

the TI" prescription or cycling of TI" may resolve cholestasis. If severe cholestatic liver disease does not resolve, small bowel or combined small bowel plus liver transplantation may be indicated. Hepatic Dysfunction in Children Related to Total Parenteral Nutrition

Total parenteral nutrition is administered to children who have lost significant function of the intestine from congenital anomalies of the gut or necrotizing enterocolitis. Complications arising from TPN in this



group are largely confined to the premature and low birth weight inf a n t ~ . ~ ,76 The hepatic dysfunction manifests commonly as cholesta70 The wide variance in reported incidence demonsis.8*9, 12,22, 24, 42, strates the problems inherent in relying on liver tests to make the diagnosis of cholestasis. These abnormalities are first evident within 2 weeks after TPN therapy is initiated and resolve in about 4 weeks following discontinuation of TPN therapy.62,70 Continuance of TPN promotes persistence of cholestasis?, 70 The lack of histologic assessment in these patients may cause the incidence of cholestasis to be underestimated. Continuing TPN in the face of progressive cholestasis eventually leads to cirrhosis. These patients may be candidates for either isolated intestinal transplantation before cirrhosis develops or for combined liver plus small intestinal transplantation if cirrhosis is established. PREVENTION OF LIVER DISEASE RELATED TO TOTAL PARENTERAL NUTRITION

The incidence of TPN-related liver disease has declined with changes in TPN formulations. It has been recommended that decreasing excess amino acids in TPN, adding lipids as an energy source, and cycling of TPN may reduce the risk. Whenever possible, early resumption of oral intake is preferable to TPN. Adding glutamine, a gluconeogenic amino acid, to TI" may stimulate glucagon secretion and decrease the molar ratio of insulin to g l ~ c a g o n .58~ This ~ , hormonal change may decrease hepatic fat uptake and maintain mucosal and immune function. Supplementing TPN with choline and lecithin has been shown to increase choline levels and decrease infiltration of liver by fat.l7rlsCarnitine supplementation for carnitine-deficient patients on TPN has, however, failed to produce any significant change in ~teat0sis.l~ TREATMENT OF LIVER DYSFUNCTION RELATED TO TOTAL PARENTERAL NUTRITION

Interventions similar to those used to prevent TPN-related liver disease can be instituted even after liver test abnormalities have developed (Fig. 6 ) . The caloric needs, constituents such as carbohydrates, proteins, and lipids, and the ratios of carbohydrates to lipids and calories to nitrogen need to be carefully assessed and readjusted. Cycling TPN to mimic physiologic feeding and fasting stages has been shown to resolve liver test abnormalities and reduce hepatomegaly. Patients on TPN who lack the ability to take enteral alimentation experience bacterial overgrowth with a preponderance of gram-negative bacteria. Altered mucosal defense mechanisms,6 and increased bacterial translocations1,82 result in accumulation of hepatotoxic substances, such as endotoxin, bacterial cell wall polysaccharides, platelet activating factor, or tumor necrosis factor. Bowel decontamination in these patients


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Figure 5. A patient with massive bowel resection because of abdominal trauma, who was on long-term total parenteral nutrition, presented with abdominal pain. A, CT scan of abdomen shows absence of bowel and a distended gallbladder with sludge that has the appearance of bright material forming a layer in the lumen. B, The cholangiogram shows echogenic material that exhibits some shadowing (consistent with gallstones) and is present in the lumen of the gallbladder. Illustration continued on opposite page



Figure 5 (Continued). C,Dark pigment stones removed at the time of cholecystectomy.

by treatment with metronidazole or possibly with other antibiotics may decrease hepatic lipid a c c u m ~ l a t i o n31,. ~67~ ~ Ursodeoxycholic acid supplementation enriches the bile acid pool and reduces the potentially toxic lithocholic acid, favorably influencing cholestasis. Ursodeoxycholic acid also improves the fluidity of bile and has proved useful in cholestatic disorders, such as primary biliary cirrhos~s.~O In TPN-related hepatic dysfunction, ursodeoxycholic acid decreases liver enzymes, but its usefulness in reversing cholestasis is unproved. A therapeutic trial may be indicated when other options have failed to improve hepatic dysfunction. Cholecystokinin promotes contraction of the gall bladder and improves flow. In patients on TPN, stasis of bile within the gallbladder results in formation of sludge with eventual stone development. Clinical trials have shown cholecystokinin to reduce bilirubin levels and reduce the severity of cholestasis in infants on TPN. Cholecystokinin can be administered exogenously,28,78 or its endogenous release can be promoted by small amounts of enteral nutrition containing fat or proteinz1


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Short Gut Assess function of GI tract

Overfeeding Reduce TPN calories Optimize carbohydrateht ODtimize ca1ories:nitroaen

Antibiotics Unodeowcholate Glutamine




I Monitor liver function I



I Severe progressive hepatic dysfunction Small bowel transplant +I-

Liver transplant


Figure 6. The function of the gastrointestinal tract must be assessed in all patients on TPN. Entral alimentation is the preferred means of nutritional support in those with a functional gastrointestinal tract and is associated with less complications than parenteral alimentation. A, If the gut is nonfunctional, the caloric needs should be determined and appropriate adjustments made in total parenteral nutrition (TPN) prescription. The ratio of carbohydrate to fat and calories to nitrogen should be optimized to promote resolution of liver test abnormalities. B, If the TPN constituents are ideal then cycling TPN may more closely mimic the physiologic fasting and fed state and bacterial overgrowth may be treated with antibiotics. Ursodeoxycholate has been used to improve bile flow and decrease the amount of lithocholate. Glutamine may promote mucosal growth, integrity and immune function. C,If there is no improvement with the above measures then liver function should be monitored. Progressive hepatic dysfunction should trigger evaluation for small bowel transplantation.


Intestinal transplantation is reserved for patients with irreversible intestinal failure who are permanently dependent upon TPN for their nutritional needsH,35 The current 3-year survival rate for patients on home TI" is 85%. Stable patients who are not experiencing complications should be maintained with TPN and should be considered for transplantation only if they develop serious or life-threatening complic a t i o n ~ .45* ~ ~84, Patients referred for intestinal transplantation usually have suffered complications of TPN, such as frequent hospitalizations, potentially lethal infections, vascular thromboses, metabolic derangement, cholelithiasis, bone disease, or progressive cholestatic liver dis-



ease.3,4, 8, 29, 49, 54, 8 ~ The 8 quality of life for some patients on TPN is extremely poor because the need for prolonged intervenous infusions greatly limits their activities.25,39, 41,@,70,75, 83 In addition to the medical, social, and psychological consequences, TPN is associated with high costs; Medicare estimates the annual cost of TPN, in 1992 dollars, at $150,000 per patient.&Intestinal transplantation is becoming increasingly used as treatment for patients with serious complications or for patients refractory to standard medical management. The most recent update of the experience with small intestinal transplantation is the 1997 Report of the International Registry for Intestinal Transplantation describing results from 33 centers performing 273 transplants in 260 recipient^.^^ Results from the same registry had previously been analyzed in 1996 for 180 transplantations in 170 patients.% There was a progressive increase in the yearly rate of performance of intestinal transplantation from 1985 (N = 1) to 1996 (N = 58). Shortgut syndrome was the most common indication for transplantation, and two thirds of transplantations were performed in children or adolescents. The five diagnoses for which intestinal transplantation was most frequently performed in the pediatric population were volvulus (28%), necrotizing enterocolitis (12%), pseudo-obstruction gastroschisis (~WO), (109'0)~ and intestinal atresia (8%). The five most common diagnoses leading to transplantation in adults were ischemia (21%),Crohn's disease (17%), trauma (15%), desmoid tumor (13%), and other nondesmoid malignancy (13%).Forty-one percent were isolated intestinal transplants, 48% were combined intestinal and liver transplants, and 11% were multivisceral transplants. Graft and patient survival after intestinal transplantation improved during the period of the analysis. Two factors correlated with improved outcome: transplantation after 1991 and performance of the transplantation in centers with experience with more than 10 transplantations. Oneyear graft survival in patients receiving transplantations before 1991 was approximately 30%, compared with 60% for those receiving transplantations after 1991. Patient survival for the whole group by type of transplantation is shown in Table 1. Both graft and patient survival have improved in recent years. Table 2 displays the results in patients receiving transplantations since 1995. Table 1. OVERALL PATIENT SURVIVAL AFTER INTESTINAL TRANSPLANTATION (REGISTRY DATA) Patient Survival (%) Type of Transplant

One Year

Three Year

70 62 45

47 40 40


Isolated intestine Intestine liver Multivisceral


Adapted from Grant D: Intestinal transplantation: 1997 report of the International Registry. Transplantation 671061, 1991; with permission.


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Isolated intestine Intestine + liver Multivisceral

Graft Survival (“A)

One Year

Two Year

One Year

Two Year

69 66 63

45 58 63

55 63 63

38 58 63

Adapted from Grant D Intestinal transplantation: 1997 report of the International Registry. Transplantation 671061, 1991; with permission.

Possible explanations for the improvement in graft survival include improved suppression of rejection with innovative immunosuppression protocols, better recognition of acute cellular rejection and early institution of anti-rejection therapy, better nutritional support, improved management of infectious complications, and reduction in postsurgical complications.2,56, 72 Fifty percent of all patients who have undergone intestinal transplantation have died. Causes of death included sepsis (47%), multiorgan failure (26%), graft thrombosis (lo%), graft rejection (4%), posttransplant lymphoma (lo%), and other causes (4%). Of surviving patients, 77% are completely removed from TPN, 14% require partial TPN, 3% are on TPN with an intact graft, and 6% are on TPN after removal of their graft. Anecdotal reports (personal communication) suggest that isolated intestinal transplantation in patients with early-stage (noncirrhotic)TPN cholestasis may reverse hepatic injury. The improvement in outcome after intestinal transplantation is encouraging, and continued advances in this field may soon increase graft and patient survivals to a level comparable with outcomes for patients on long-term TPN. With continued improvement in graft and patient survival, the indications for intestinal transplantation may broaden and this technique may be more widely used. The possibility of freedom from TPN and resumption of a normal diet make intestinal transplantation an appealing alternative for patients with irreversible intestinal failure. It is the authors’ opinion, however, that additional improvements in patient and graft outcome must be achieved before transplantation is more widely used. References 1. Abad-Lacruz A, Gonzalez-Huix F, Esteve M, et al: Liver function tests abnormalities in patients with inflammatory bowel disease receiving artificial nutrition: A prospective randomized study of total enteral nutrition vs total parenteral nutrition. JPEN J Parenter Enteral Nutr 14:618, 1990 2. Abu-Elmagd K, Fung JJ, Reyes J, et al: Management of intestinal transplantation in humans. Transplant Proc 24:1243, 1992 3. Abu-Elmagd K, Reyes J, Todo S, et al: Clinical intestinal transplantation: New perspectives and immunologic considerations. J Am Coll Surg 186:512, 1998




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