Systemic carnitine deficiency

PREVALENCE OF LIVER DISEASE AND CLINICAL OBSERVATION

Although the components of total parenteral nutrition (TPN) had been used since the 1940s and 1950s, in the late 1960s, Stanley Dudrick, MD, devised what we now know as TPN.1 It was shortly thereafter that the first case of TPN-associated liver disease was reported.2 This infant developed severe cholestasis. Since that time, increased serum hepatic aminotransferase concentrations have been commonly observed within the first 2 to 3 weeks or so of TPN infusion in upwards of two-thirds of patients.3 Typically, this is a transient increase without significant elevation in serum bilirubin, at least in the adult patient. The serum bilirubin concentration often becomes elevated in children, particularly the preterm infant. It is important to recognize, however, that serum hepatic aminotransferase concentration elevations are both insensitive and nonspecific indicators of hepatic dysfunction.4 In fact, it is not uncommon for a patient to have cirrhosis in the face of normal serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations. When patients are followed a longer period of time while receiving TPN, total serum bilirubin concentration tends to increase slightly, but more importantly, the AST often increases significantly beginning after approximately 10 weeks.5 The alkaline phosphatase often increases as well, although some of this increase may relate to the development of concomitant metabolic bone disease. In a study of over 40 long-term TPN patients, some of which had received TPN for up to 16 years at the time of the study in 1991, a significant correlation between TPN duration and the serum alkaline phosphatase observed, although TPN duration and both AST and ALT were not correlated.6

While it is recognized that liver test abnormalities occur during TPN, the question is whether TPN is associated with chronic liver disease. Given that the first case of TPN-associated liver disease was described in a young child, it comes as no surprise the first case of TPN-associated hepatic failure was described in an infant.7 The only case in which the progression of liver disease from steatosis to fibrosis and cirrhosis was monitored by sequential liver biopsies was reported by Robert Craig, MD, from Northwestern in 1980.8 His patient had Crohn's disease and required TPN because of short bowel syndrome. After approximately 11 months of TPN, the patient's liver tests became slightly elevated, and a liver biopsy revealed mild steatosis. Eight months later another biopsy showed progressive steatosis, and a third biopsy 30 months later revealed fibrosis. A final biopsy was performed about 61 months later, and micronodular cirrhosis was found. The patient did not succumb to liver failure however; he had an unrelated myocardial infarction. Investigations have revealed that hepatic steatosis may progress to fibrosis in humans in part related to increased lipid peroxidation.9

The predominant histologic finding in adults with TPN-associated liver disease is steatosis, although signs of cholestasis are usually evident as well.10 Both macro- and microvesicular steatosis are present (Table I). This histologic presentation occurs only in patients with TPN-associated liver disease, acute fatty liver of pregnancy, tetracycline and valproic acid toxicity, and Jamaican vomiting sickness.

Several reported series of patients who developed TPN-associated liver disease, including hepatic failure, have been reported.11-13 Stanco et al13 found the patients with the shortest residual intestine were at the greatest risk to develop eventual liver failure and death. This suggests the degree of malabsorption or the level of TPN dependence are the likely causes of TPN-- associated liver disease.

In France, significant numbers of long-term TPN patients with chronic cholestasis (defined as elevations in ALT, AST, or alkaline phosphatase to > 1.5 times the upper limits of normal for more than 6 months) have been identified when TPN was continued >2 years.14 An even more striking increase in prevalence of TPN-- associated liver disease was observed in patients who had received TPN for at least 4 to 6 years. The investigators also found an increase in the prevalence of complicated liver disease (defined as evidence of portal hypertension, portal fibrosis, or cirrhosis on biopsy, elevation in the serum total bilirubin concentration to >3.5 mg/dL, or hepatic encephalopathy) in patients who had received TPN, and after 8 years, over 40% of their patients had developed complicated liver disease. Other large centers in the United States have not generally observed such a high percentage of patients with clinically significant chronic liver disease, although TPN-associated liver disease has been observed with increasing frequency in all major American home TPN centers. For example, Chan et al15 indicated that approximately 20% of their home TPN patients developed chronic liver disease. The prevalence has increased over time.

In infants, unlike in the adult, the predominant histologic abnormality in the liver is cholestasis, although both micro- and macrovesicular steatosis are generally present.10 The prevalence of TPN-associated liver disease in infants is much greater than in the adult population. Sondheimer et al16 reported that approximately 65% of their infants developed cholestasis and 13% developed hepatic failure after only 6 weeks of TPN. The reported prevalence of TPN-associated cholestasis in the infant is quite variable, with reports ranging from 15% to 85%, depending on the center. The risk of TPN-associated cholestasis in these patients is also related to their prematurity and immature enterohepatic circulation, underlying disease, number of infections, number of surgeries, and number of blood transfusions.17 The question is whether the cholestasis-predominant liver disease seen in the infant (especially the preterm infant) is simply a more severe manifestation of the underlying pathologic process also observed in the adult TPN patients, or whether the cholestasis is a result of a different underlying pathophysiology. The histologic findings in rabbits overfed with IV dextrose were predominately hepatic cholestasis, in association with hyperbilirubinemia.18 Given that overfeeding in the adult human is associated with hepatic steatosis, this study suggests a similar underlying process may result in different hepatic pathology.

POSSIBLE ETIOLOGIES OF TPN-ASSOCIATED LIVER DISEASE

There are many postulated etiologies for TPN-associated liver disease, although data in humans is scarce or nonexistent for many. If one accepts the observation that TPN is associated with development of chronic liver disease, then the question becomes whether TPN causes the liver disease, or whether the disease for which TPN is indicated (such as malabsorption) is the true cause. TPN-related causes can be divided into those in which a nutrient toxicity may develop and those in which a nutrient deficiency may develop (Table II). Two studies, one from France and the other from the United States, have shown that patients with the shortest residual intestine are at greatest risk for the development of liver disease,10,14 This suggests perhaps that the more significant the malabsorption of an hepatic-trophic nutrient, the worse the liver disease. However, it might be equally argued that such patients are the most TPN dependent; and if there is an hepatotoxic substance in TPN, those who receive more of it are at greatest risk for development of liver disease.

NUTRIENT DEFICIENCIES

Kwashiokor (protein malnutrition) is associated with the development of hepatic steatosis because of decreased very-low-density lipoprotein (VLDL) synthesis. 19

Essential fatty acid deficiency occurred before the advent of lipid emulsions and still occurs in patients who do not receive at least 2% to 4% of their total calories as linoleic fatty acid (4% to 8% of calories from the lipid emulsion that is typically 50% linoleic acid). Hepatic steatosis may develop otherwise.20

Carnitine deficiency had been postulated to occur during long-term TPN on the basis of depressed plasma total and free carnitine concentrations. Hepatic steatosis occurs in congenital carnitine and true acquired carnitine deficiency.21 Plasma carnitine concentrations do decrease to about 50% of normal within a few weeks of beginning TPN, but do not decrease further.22,23 Typically, carnitine concentrations approaching 10% of normal are necessary before sequela of carnitine deficiency develops.21 In addition, Bowyer et al24 showed eloquently that plasma carnitine concentration did not correlate with hepatic aminotransferase abnormalities, and carnitine supplementation did not lead to either a decrease in the serum hepatic amino transferase concentrations or in the degree of hepatic steatosis during TPN.25

Low plasma-free choline concentration is found in over 90% of patients that need long-term parenteral nutrition.6 Studies in the rat have indicated that impaired VLDL synthesis and secretion occur in the face of choline deficiency, and hepatic steatosis results. Studies in humans have found a significant association between plasma free choline concentration, hepatic aminotransferase abnormalities, and hepatic steatosis. Initial human trials have demonstrated that hepatic steatosis resolves and hepatic aminotransferase abnormalities improve with choline supplementation.26-28

Why does choline deficiency occur in patients who need TPN? This represents a very interesting example of the difference between absorption of nutrients through the gastrointestinal tract versus the same nutrient when IV infused. Normally, when humans eat, food is taken in through the mouth and into the stomach through the esophagus. Digestion has already begun. Ligual lipase and salivary amylase are already being used to digest fat and carbohydrate, respectively. Epidermal growth hormone (EGF) release is stimulated from the esophagus.29 Food passes through the stomach where various peptidases, gastric acids, and mechanical contractions continue to degrade the food into more easily assimilated particles. Peptides and other molecules are then absorbed through the portal circulation and are transported to the liver for metabolism. After undergoing first pass metabolism, the nutrient remnants are transported to the systemic circulation through the right side of the heart circulation, and finally to the kidney, where some nutrients are reabsorbed and other metabolic products are excreted as waste. When the same nutrient is infused through a central vein, it is first transported to the heart and later to the liver. This route of nutrient assimilation may affect the metabolism of that nutrient and the resultant metabolic products. For example, Steginck and Besten30 showed that when the amino acid methionine (a precursor for choline) is infused IV, cysteine, a product of the hepatic transsulfuration pathway, was nearly undetectable in plasma in normal volunteers. When methionine was infused through a nasogastric tube, there was a small, but nonsignificant, decrease in the plasma cysteine concentration. When the methionine was consumed as part of a meal, plasma cysteine concentration was unchanged from baseline. Similarly, despite the infusion of methinione in TPN, plasma-free choline concentration remains significantly below normal in most patients who need TPN.

Although choline is ubiquitous in nature, patients who need TPN because of malabsorption, either from insufficient bowel or dysfunctional bowel, will malabsorb choline just as with other nutrients. However, unlike those who absorb their nutrients through the portal circulation, patients who receive TPN cannot metabolize methionine effectively through the transulfuration pathway, and choline deficiency develops.31 Potentially, even patients who receive chronic nasoenteric feeding might need additional choline because of the bypass of the orocephalic phase of digestion,31 although the role of this phase of digestion in choline metabolism is not known. There is some choline present in lipid emulsion, and indeed that seems to be a factor in why patients who do receive some lipid emulsion have less abnormal hepatic amino transferase concentrations.32 However, there is relatively little free choline in lipid emulsion.6

Vitamin E deficiency has been suggested as a potential cause for TPN-associated liver disease, especially because vitamin E might mitigate lipid peroxidation and therefore prevent the progression of steatosis to fibrosis. Therefore, it might be expected that during vitamin deficiency, increased hepatic fibrosis might develop. However, there is no evidence that vitamin E deficiency leads to liver disease regardless of whether patients receive TPN or not.33 Selenium's functions are closely related to vitamin E. Decreased plasma selenium concentration has been described in patients with cirrhosis, but selenium deficiency has not been documented.34 Furthermore, there is no evidence that decreased selenium status plays any role in the development of cirrhosis or TPN-associated liver disease.

Plasma glutamine concentration decreases during TPN, and in rats, this has been associated with the development of hepatic steatosis35 and supplementation increases the portal glucagon:insulin ratio,36 leading to decreased steatosis.35 However, this has not been found in all studies37 and has not been studied in humans. In fact, glutamine-supplemented TPN led to significantly increased hepatic aminotransferase concentrations in one study in humans.38

Neonatal TPN is now routinely supplemented with taurine, which increases bile acid secretion.39 Taurine supplementation may result in a decrease in the incidence of TPN-associated cholestasis,40 although this has not been found universally.41 In guinea pigs, oral taurine supplementation increases bile flow and the taurine:glycine ratio of conjugated bile acids and prevents the decrease in bile flow induced by lithocholic acid.42 However, IV taurine supplementation has not been studied in this fashion nor has it been studied in humans. It is entirely possible the decrease in the incidence of TPN-associated liver disease in the neonate may be more related to improvements in overall critical care, including both medical (improved antibiotics for sepsis, improved treatment of hypoxia and hypotension, and the use of early enteral feeding) and surgical therapy.43

NUTRIENT AND OTHER TOXICITIES

Lipid overload (>2.5 to 3.0 g/kg per day) may result in the development of cholestasis.44,45 Retrospective studies have indicated that infusion of lipid emulsion at a dose of >1 g/kg per day may be associated with increased risk of hepatic dysfunction.14,15

Phytosterols are present in significant quantities in lipid emulsion, and the concentrations of these plant sterols are increased in patients who receive TPN.46 However, no correlation with hepatic abnormalities has been demonstrated in humans.

Dextrose overfeeding (>50 kcal/kg per day) has been associated with biochemical evidence of hepatic abnormalities.47 This may relate in art to an increase in the portal insulin:glucagon ratio.48,49

It has been postulated that bacterial overgrowth may contribute to the development of TPN-associated liver disease, predominately steatosis, by increasing intestinal permeability to bacteria, bacterial products, and endotoxin. Studies in rat models have suggested a role for antimicrobial therapy in the treatment of TPN-- associated hepatic steatosis.50,51 However, bacterial translocation does not seem to result in hepatic injury in humans.52 Low-grade endotoxinemia in rat models is not associated with significant hepatic derangements,53 although infusion of lipopolysaccharide during TPN has been associated with the development of hepatic steatosis.54 However, as with bacterial translocation, hepatic dysfunction as a direct result of endotoxinemia has not been conclusively demonstrated in humans. In addition, the formation of lithocholic acid, a secondary bile acid formed by bacterial 7-alpha dehydroxylation of chenodeoxycholic acid, is presumed to have potentially toxic effects on the liver, especially in the neonate, resulting in the development of cholestasis. However, it seems that the neonatal animal is actually more resistant to the effects of lithocholic acid-induced cholestasis than the adult.55 In any case, there is no evidence that lithocholic acid plays any role in the development of TPN-associated hepatic dysfunction in humans.

Manganese toxicity, including hepatic dysfunction, has been described in TPN-dependent patients.56 However, because virtually all manganese is excreted in the bile,57 it is likely the elevated serum concentrations observed were caused by decreased excretion related to cholestasis, rather than the cause for the cholestasis.

Until 1985, the amino acid component of TPN solutions was derived from casein hydrolysate. This solution had significant aluminum contamination. Animal studies have revealed that significant aluminum contamination may lead to the development of cholestasis,58,59 although the level of aluminum infused in these animals was substantially greater than what humans received. Although aluminum contamination is still present in some of the potassium, phosphate, sodium, and calcium components of TPN, the overall degree of aluminum contamination is less than 2% of pre-1985 levels,60 and therefore cannot be considered a factor in the development of TPN-associated liver disease today.

POTENTIAL TREATMENTS

Carbohydrate overfeeding and excessive use of lipid emulsion should be avoided. Otherwise, there are few existing options for either prevention or therapy of TPN-associated liver disease (Table III and IV).

Metronidazole has been used to treat TPN-associated liver disease in humans. Capron et al61 used a dose of 500 mg two times per day versus nothing in a group of Crohn's disease patients that were being treated for active disease. It is unclear to what degree the active Crohn's disease caused liver abnormalities in the patients, and both patient groups were significantly overfed. Nevertheless, ALT, although still significantly abnormal, decreased significantly more with metronidazole after 30 days of treatment. Another study, although retrospective, reported that AST did not increase with metronidazole (1500 mg daily), and the serum alkaline phosphatase increased less than in those patients in whom the medication was not used.62

Ursodeoxycholic acid has been used for the treatment of TPN-associated cholestasis in both adults and neonates. The scientific literature in adults is limited to a single case report63 and a case series of 9 patients.64 In children, there have been two unblinded, open-labeled studies and one retrospective review reported.65-67 Cocjin et al,65 in a preliminary, open-- labeled study in neonates, observed a significant decrease in serum total bilirubin concentration when neonates were provided with 15 to 45 mg/kg per day of ursodeoxycholic acid, although the neonates still remained severely cholestatic.

Choline has been used in three studies to treat TPN-- associated liver disease. The first study used oral lecithin. Although a statistically significant decrease in hepatic steatosis was observed, patients still remained with liver disease.26 A second study, using IV choline chloride-supplemented TPN (2 g/d, which is about 1.2 g/d of choline) led to complete resolution of liver disease in an unblinded study.27 The third study, randomized and placebo-controlled, showed resolution of hepatic steatosis in choline-treated patients and significant declines in serum hepatic aminotransferase concentrations when compared with placebo.28 Steatosis returned after 10 weeks of choline-free TPN. This observation is in agreement with Clark et al,5 who described a significant rise in hepatic aminotransferase concentrations after 10 weeks of TPN. These findings demonstrate that choline is a required nutrient for TPN-dependent patients.

A multicenter study in the United States and England used to evaluate the use of choline-supplemented TPN to prevent liver disease in patients just starting TPN began in late 2001. Inclusion/exclusion criteria for this study can be found at www.gutfailure.com. It is anticipated that a clinical trial involving the use of choline-- supplemented TPN to treat preexistent TPN-associated liver disease will be underway in late 2002 at the same centers.

Isolated intestinal and liver/small bowel transplantation may be the only possibility for patients with significant and progressive liver disease. Isolated intestinal transplantation may be successful in patients who do not yet have evidence of fibrosis or cirrhosis on liver biopsy,68 although the potential benefits of transplantation must be weighed carefully against the potential risks in such patients. Discussion of intestinal and combined intestinal/liver transplantation is the focus of another presentation.

CONCLUSION

The etiology of TPN-associated liver disease is multifactoral. It is fairly common in its milder form and in some instances can progress to cirrhosis and liver failure. There are therapeutic maneuvers that can be done that may minimize its occurrence. Consideration should be given to enrolling patients in investigational studies until the exact etiology of TPN-associated liver disease is better understood. For those patients who develop severe liver dysfunction/failure, liver/small bowel transplantation offers hope for survival.

REFERENCES

1. Dudrick SJ, Wilmore DW, Vars HM, et al: Long-term TPN with growth, development, and positive nitrogen balance. Surgery 64:134-142, 1968

2. Penden VH, Witzleben CL, Skelton MA: TPN. J Pediatr 78:180181, 1971

3. Grant JP, Cox CE, Kleinman LM, et al: Serum hepatic enzyme and bilirubin elevations during parenteral nutrition. Surg Gynecol Obstet 145:573-580, 1977

4. Sax HC, Talamini MA, Brackett K, et al: Hepatic steatosis in TPN: Failure of fatty infiltration to correlate with abnormal serum hepatic enzyme levels. Surgery 100:697-704, 1986

5. Clark PJ, Ball MJ, Kettlewell MGW: Liver function tests in patients receiving parenteral nutrition. JPEN 15:54-59, 1991

6. Buchman AL, Moukarzel AA, Jenden DJ, et al: Low plasma free choline is prevalent in patients receiving long term parenteral nutrition and is associated with hepatic aminotransferase abnormalities. Clin Nutr 12:33-37, 1993

7. Postuma R, Trevenen CL: Liver disease in infants receiving TPN. Pediatrics 63:110-115, 1979

8. Craig RM, Neumann T, Jeejeebhoy KN, et al: Severe hepatocellular reaction resembling alcoholic cirrhosis after massive small bowel resection and prolonged TPN. Gastroenterology 79:131137, 1980

9. MacDonald GA, Bridle KR, Ward PJ, et al: Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3. J Gastroenterol Hepatol 16:599-606, 2001

10. Buchman AL, Ament ME: Liver disease and TPN. In Hepatology, A Textbook of Liver Disease, 3rd ed., Zakim D, Boyer TD (eds). WB Saunders, Philadelphia, PA, 1962, pp 1810-1821

11. Rabeneck L, Freeman H, Owen D: Death due to TPN-related liver failure [abstract]. Gastroenterology 86:1215, 1984

12. Bowyer BA, Fleming CR, Ludwig J, et al: Does long-term home parenteral nutrition in adult patients cause chronic liver disease? JPEN 9:11-17, 1985

13. Stanko RT, Nathan G, Mendelow H, et al: Development of hepatic cholestasis and fibrosis in patients with massive loss of intestine supported by prolonged parenteral nutrition. Gastroenterology 92:197-202, 1987

14. Cavicchi M, Beau P, Crenn P, et al: Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. Ann Intern Med 132: 525-532,2000

15. Chan S, McCowen KC, Bistrian BC, et al: Incidence, prognosis, and etiology of end-stage liver disease in patients receiving home TPN. Surgery 126:28-34, 1999

16. Sondheimer JM, Asturias E, Cadnapaphornchai M: Infection and cholestasis in neonates with intestinal resection and longterm parenteral nutrition. J Pediatr Gastroenterol Nutr 27:131137, 1998

17. Drongowski RA, Coran AG: An analysis of the factors contributing to the development of TPN-induced cholestasis. JPEN 13:586-589, 1989

18. Hata S, Nezu R, Kubota A, et al: Effect of amino acids in TPN on cholestasis in newborn rabbits. J Pediatr Surg 29:892-895, 1994 19. Cook GC, Hutt MSR: The liver after kwashiokor. Br Med J 3:454-457, 1967

20. Reif S, Tano M, Oliverio R, et al: TPN-induced steatosis: Reversal by parenteral lipid infusion. JPEN 15:102-104, 1991

21. Karpati G, Carpenter S, Engel AG, et al: The syndrome of systemic carnitine deficiency: clinical, morphologic, biochemical and pathologic features. Neurology 25:16-24, 1975

22. Dahlstrom KA, Ament ME, Moukarzel A, et al: Low blood and plasma carnitine levels in children receiving long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 11:375-379, 1990

23. Moukarzel AA, Dahlstrom KA, Buchman AL, et al: Carnitine status of children receiving long-term TPN: A longitudinal prospective study. J Pediatr 120:759-762, 1992

24. Bowyer BA, Fleming CR, Listrup D, et al: Plasma carnitine levels in patients receiving home parenteral nutrition. Am J Clin Nutr 43:85-91, 1986

25. Bowyer BA, Miles JM, Haymond MW, et al: L-carnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentration. Gastroenterology 94:434-438, 1988

26. Buchman AL, Dubin M, Jenden D, et al: Lecithin supplementation causes a decrease in hepatic steatosis in patients receiving long term parenteral nutrition. Gastroenterology. 102:13631370,1992

27. Buchman AL, Dubin M, Moukarzel A, et al: Choline deficiency: A cause of hepatic steatosis associated with parenteral nutrition that can be reversed with an intravenous choline chloride supplementation. Hepatology 22:1399-1403, 1995

28. Buchman AL, Sobel M, Dubin M, et al: Choline deficiency causes reversible hepatic abnormalities in patients during parenteral nutrition: Proof of a human choline requirement; a placebocontrolled trial. JPEN 25:260-268, 2001

29. Calabro A, Orsini B, Renzi D, et al: Expression of epidermal growth factor, transforming growth factor-alpha and their receptor in the human esophagus. Histochem J 29:745-758, 1997

30. Steginck LD, Besten LD: Synthesis of cysteine from methionine in normal adult subjects: effect of route of alimentation. Science 178:514-516, 1972

31. Chawla RK, Berry CJ, Kutner MH, et al: Plasma concentrations of transsulfuration pathway products during nasoenteral and intravenous hyperalimentation of malnourished patients. Am J Clin Nutr 42:577-584, 1985

32. Sheard NF, Tayek JA, Bistrian BR, et al: Plasma choline concentration in humans fed parenterally. Am J Clin Nutr 43:219224, 1986

33. Barrow L, Patel HR, Tanner MS: Alpha-tocopherol deficiency fails to aggravate toxic liver injury but liver injury causes alphatocopherol retention. J Hepatol 16:332-337, 1992

34. Burk RF, Early DS, Hill KE: Plasma selenium in patients with cirrhosis. Hepatology 27:794-798, 1998

35. Grant JP, Snyder PJ: Effect of glutamine on total fat content of the liver [abstract]. JPEN 14:85, 1990

36. Li S, Nussbaum MS, McFadden DW, et al: Addition of L-glutamine to TPN and its effects on portal insulin and glucagon and development of hepatic steatosis in the rat. J Surg Res 48:421426, 1990

37. Yeh SL, Chen WJ, Huang PC: Effect of L-glutamine on hepatic lipids at different energy levels in rats receiving TPN. JPEN 18:40-44, 1994

38. Hornsby-Lewis L, Shike M, Brown P, et al: L-glutamine supplementation in home TPN patients: Stability, safety, and effects on intestinal absorption. JPEN 18:268-273, 1994

39. Okamoto E, Rassin DK, Zucker CL, et al: Role of taurine in feeding the low-birth-weight infant. J Pediatr 104:936-940, 1984

40. Desai TK, Reddy J, Kinzie JL, et al: Taurine supplementation and cholestasis during bone marrow transplantation. Gastroenterology 104:A616, 1993

41. Cooke RJ, Whitington PF, Kelts D: Effects of taurine supplementation on hepatic function during short-term parenteral nutrition in the premature infant. J Pediatr Gastroenterol 3:234-238, 1984

42. Dorvil NP, Yousef IM, Tuchweber B, et al: Taurine prevents cholestasis induced by lithocholic acid sulfate in guinea pigs. Am J Clin Nutr 37:221-232, 1983

43. Balistreri WF, Bucuvalas JC, Farrell MK, et al: TPN-associated cholestasis: Factors responsible for the decreasing incidence. In Falk Symposium 63, Pediatric Cholestasis. Novel Approaches to Treatment, Lentze M, Reichen J (eds). Kluwer Academic Publishers, London, 1992

44. Salvian AJ, Allardyce DB: Impaired bilirubin secretion during TPN. J Surg Res 28:547-555, 1980

45. Allardyce DB: Cholestasis caused by lipid emulsions. Surg Gynecol Obstet 154:641-647, 1982

46. Clayton PT, Bowron A, Mills KA, et al: Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology 105:1806-1813, 1993

47. Lowry SF, Brennan MF: Abnormal liver function during parenteral nutrition: Relation to infusion excess. J Surg Res 26:300-307, 1979

48. Blue PR, Burnes JU, Kelly DG: Long-term parenteral nutrition (TPN)-associated hepatobiliary dysfunction: Are there predisposing factors? Gastroenterology 104:A642, 1993

49. Meguid MM, Akahoshi MP, Jeffers S, et al: Amelioration of metabolic complications of conventional parenteral nutrition. Arch Surg 119:1294-1298, 1984

50. Pappo I, Bercovier H, Berry EM, et al: Polymyxin B reduces TPN-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide. JPEN 16:529-532, 1992

51. Freund HR, Muggia-Sullam M, LaFrance R, et al: A possible beneficial effect of metronidazole in reducing TPN-associated liver function derangements. J Surg Res 38:356-363, 1985

52. Riordan SM, McIver CJ, Williams R: Liver damage in human small intestinal bacterial overgrowth. Am J Gastroenterol 93:234-237, 1998

53. Brand HS, Maas MA, Bosma A, et al: Experimental colitis in rats induces low-grade endotoxinemia without hepatobiliary abnormalities. Dig Dis Sci 39:1210-1215, 1994

54. Pappo I, Bercovier H, Berry E, et al: Antitumor necrosis factor antibodies reduce hepatic steatosis during TPN and bowel rest in rats. JPEN 19:80-82, 1995

55. Lewittes M, Tuchwebr B, Weber A, et al: Resistance of the sucking guinea pig to lithocholic acid-induced cholestasis. Hepatology 4:486-491, 1984

56. Masumoto K, Suita S, Taguchi T, et al: Manganese intoxication during intermittent parenteral nutrition: Report of two cases. JPEN 25:95-99, 2001

57. Larsen NA, Pakkenberg H, Damsgaard E, et al: Topographical distribution of arsenic, manganese, and selenium in the normal human brain. J Neurol Sci 42:458-468, 1979

58. Klein GL, Sedman AB, Heyman MB, et al: Hepatic abnormalities associated with aluminum loading in piglets. JPEN 11:293297, 1987

59. Klein GL, Heyman MB, Lee TC, et al: Aluminum associated hepatobiliary dysfunction in rats: Relationships to dosage and duration of exposure. Pediatr Res 23; 275-278, 1988

60. Klein GL: The aluminum content of parenteral solutions: Current status. Nutr Rev 49:74-79, 1991

61. Capron JP, Herve MA, Gineston JL, et al: Metronidazole in prevention of cholestasis associated with TPN. Lancet 26:446447, 1983

62. Lambert JR, Thomas SM: Metronidazole prevention of serum liver enzyme abnormalities during TPN. JPEN 9:501-503, 1985 63. Lindor KD, Burnes J: Ursodeoxycholic acid for the treatment of

home parenteral nutrition-associated cholestasis. Gastroenterology 101:250-253, 1991

64. Beau P, Labat-Labourdette J, Ingrand P, et al: Is ursodeoxycholic acid an effective therapy for TPN-related liver disease. J Hepatol 20:240-244, 1994

65. Cocjin J, Vanderhal A, Sehgal S, et al: Ursodeoxycholic acid therapy for TPN-associated cholestasis. Gastroenterology 104: A615, 1993

66. Spagnuolo MI, Iorio R, Vegnente A, et al: Ursodeoxycholic acid for treatment of cholestasis in children on long-term TPN: A pilot study. Gastroenterology 111:716-719, 1996

67. Levine A, Maayan A, Shamir R, et al: Parenteral nutrition-- associated cholestasis in preterm neonates: Evaluation of ursodeoxycholic acid treatment. J Pediatr Endocrin Metab 12:549-553, 1999

68. Sudan DL, Kaufman SS, Shaw BW, et al: Isolated intestinal transplantation for intestinal failure. Am J Gastroenterol 95:1506-1515, 2000

Alan Buchman, MD, MDPH

From the Department of Gastoenterology and Hepatology, Northwestern University Medical School, Chicago, Illinois

Correspondence and reprint requests: Alan Buchman, MD, MSPH, Northwestern University Medical School, 676 North St Clair Street, Ste 880, Chicago, IL 60611. Electronic mail may be sent to

a-buchman@northwestern.edu.

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