Cholestasis with parenteral nutrition

San Luis VA, Btaiche IF. Ursodiol in patients with parenteral nutrition-associated cholestasis. Ann Pharma-cother2007 41(ll) 1867-72. 

The role of lipid emulsions in cholestasis associated with long-term parenteral nutrition has been investigated retrospectively in 10 children with a total of 23 episodes of cholestasis, associated with thrombocytopenia in 13 cases (104). Changes in lipid delivery, associated with increased daily amounts, preceded complications in more than half the cases, while temporary reduction in lipid administration led to normalization of bilirubin in 17 episodes. The authors concluded that lipid supply is one of the risk factors for cholestasis associated with parenteral nutrition. They recommended that when cholestasis occurs, lipid should be temporarily withdrawn, especially if there is associated thrombocytopenia. 

A fish oil-based intravenous lipid emulsion in the treatment of liver disease associated with parenteral nutrition has been compared with soybean oil in an open study in 42 infants with short bowel syndrome who developed cholestasis [35 ]. There were three deaths and one liver transplantation in those who received the fish oil, compared with 12 deaths and 6 transplants in those who received soybean oil The fish oil was not associated with hypertriglyceridemia, coagulopathy, or deficiency of essential fatty acids. 

Fig. 1 shows a liver biopsy of a 7 week old infant (J.M.) with intestinal atresia, who had been treated with parenteral nutrition for the previous 6 weeks. There is evidence of cholestasis and infiltration of the portal triad. The patient was rebiopsied at 16 weeks of age while still continuing on intravenous nutrition. A round cell infiltrate in the portal area with some fibrous tissue was noted. A third biopsy performed at six months of age while the child was still being maintained on parenteral nutrition revealed the continued presence of fibrous tissue and a round cell infiltrate in the portal triad. 

Biliary tract In a study of 66 infants with cholestasis associated with parenteral nutrition, there were 10 deaths and one referral for liver transplant in the first year of life, all of whom had at least one positive blood culture after the onset of cholestasis [70 ]. Maximum conjugated bilirubin in these 11 infants was 270 pmol/l, compared with 145 pmol/l in babies who recovered. A maximum conjugated bilirubin concentration over 170 pmol/l was a susceptibility factor for death or transplantation. 

The susceptibility factors for cholestasis associated with parenteral nutrition have been studied in 62 premature infants in a neonatal intensive care unit, of whom 11 (18%) developed cholestasis [72 ]. There were significant differences in terms of... 

Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD, Abrams SA. High rates of mortality and morbidity occur in infants with parenteral nutrition-associated cholestasis. JPEN J Parenter Enteral Nutr 2010 34(1) 32-7. 

Forrest, E.H., Oien, K.A., Dickson, S., Galloway, D., Mills, P.R. Improvement in cholestasis associated with total parenteral nutrition after treatment with an antibody against tumour necrosis factor alpha. Liver 2002 22 317-320... 

Messing, B., Colombel, J.F., Heresbach, D., Chazouillres, O., Galian, A. Chronic cholestasis and macronutrient excess in patients treated with prolonged parenteral nutrition. Nutrition 1992 8 30-36... 

Cholestasis from other causes can increase the accumulation of ciclosporin or its metabolites, which in turn worsens hepatic cholestasis. This mechanism has been suggested in patients with bowel diseases who experienced an aggravation of hyperbilirubinemia or an increased incidence of hepatotoxicity from the combination of total parenteral nutrition and ciclosporin (SEDA-19, 348) (288). 

Copper deficiency has been reported in a patient with Crohn s disease after removal of copper from the parenteral nutrition because of severe cholestasis (59). The patient developed pancytopenia with severely depressed serum copper concentrations after 8 weeks. Bone-marrow biopsy confirmed the cause as copper deficiency. Although intravenous replacement of copper improved the patient s anemia and other markers, he suddenly died of cardiac tamponade. 

When oral intake is precluded, the recommended daily parenteral supplementation of manganese is 0.15-0.8 mg. Manganese is mainly excreted in the bile during cholestasis serum manganese levels may rise, and manganese toxicity can result. Hjq)ermanganesemia after parenteral nutrition when first reported was linked to portosystemic encephalopathy. Patients with liver disease were particularly at risk. 

Intestinal transplantation is combined with liver transplantation in 46% of cases, because of terminal liver failure (93). Of 78 patients who had received parenteral nutrition for more than 2 years n — 66) and/ or had short bowel syndrome and could not be weaned from parenteral nutrition (n = 12), 58 developed chronic cholestasis and 37 developed one or more severe liver complication (serum bilirubin concentration 60 pmol/l, factor V (proaccelerin) 50%, portal hypertension, encephalopathy, ascites, bleeding from the gastrointestinal tract, or histological findings consisting of extensive fibrosis and cirrhosis) after 6 (3-132) months and 17 (2-155) months respectively. Liver disease was responsible for deaths in 6.5% of the patients (22% of deaths). 

In a prospective prevalence study of liver disease in 90 patients with permanent intestinal failure receiving parenteral nutrition hver biopsy was performed in 57 (95). Chronic cholestasis developed in 58 patients after a median of 6 (range 3-132) months, and 37 developed comphcated liver disease after a median of 17 (range 2-155) months. Chronic cholestasis was significantly associated with a risk of liver disease independent of parenteral nutrition, a bowel remnant shorter than 50 cm, and a lipid intake of 1 g/kg/day or more hver disease related to parenteral nutrition was significantly associated with chronic cholestasis and a parenteral hpid intake of 1 g/kg/day or more. The authors concluded that the prevalence of hver disease increased with the duration of parenteral nutrition and was one of the main causes of death in patients with permanent intestinal failure. Parenteral intake of long-chain hpid emulsion should be restricted to less than 1 g/kg/day. 

In a retrospective study of the incidence of cholestasis and liver failure in 42 patients with intestinal resection in the neonatal period who subsequently became dependent on parenteral nutrition support, the effect of various associated clinical factors on the incidence and severity of cholestasis was determined (103). Cholestasis developed in 28 while they were receiving parenteral nutrition. In 21 patients, the raised direct bilirubin concentration returned to normal while they continued to receive parenteral nutrition. Seven patients progressed to liver failure. Patients without cholestasis had been dependent on parenteral nutrition for longer than patients with cholestasis. It was clear from this study that cholestasis in neonates with intestinal resection is not simply a function of the duration of exposure to intravenous nutrition. 

Taylor S, Manara AR. Manganese toxicity in a patient with cholestasis receiving total parenteral nutrition. Anaesthesia 1994 49(11) 1013. 

Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 1998 27(2) 131-7. 

Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet JC, Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children. J Parenter Enteral Nutr 2000 24(6) 345-50. 

Two infants with intestinal failure and parenteral nutrition-associated liver disease were given an intravenous fat emulsion containing primarily omega-3 fatty acids instead of the conventional emulsion [30 ]. Biochemical tests of liver function improved significantly. One child was removed from the liver transplantation list because of improved hepatic function, and the second child had complete resolution of cholestasis while solely on parenteral nutrition. 

In a retrospective study of 23 infants with intestinal failure who required parenteral nutrition for more than 6 months and who developed cholestasis, soybean lipid emulsion was replaced by enteral fish oil in 4, which led to improvement [31 J. 

In contrast, in a retrospective analysis of 292 neonates who received parenteral nutrition with lipid emulsions containing omega-3 fatty acids for more than 1 day, 104 (36%) developed cholestasis after a mean of 22 days, with a conjugated bilirubin concentration over 34 pmol/l 31 had a serum conjugated bilirubin concentration over 100 pmoUl and 13 developed liver failure 4 underwent transplantation and 5 died of hepatic disease [385]. The authors suggested that in the absence of definitive evidence of efficacy, as well as increased costs, it is difficult to justify the routine use of lipid... 

Rollins MD, Scaife ER, Jackson WD, Meyers RL, Mulroy CW, Book LS. Elimination of soybean lipid emulsion in parenteral nutrition and supplementation with enteral fish oil improve cholestasis in infants with short bowel syndrome. Nutr Clin Pract 2010 25(2) 199-204. 

Garzbn L, Ledo A, Cubells E, Sdenz P, Vento M. Cholestasis associated with prolonged parenteral nutrition in neonates the role of urso-deoxycholic acid. An Pediatr (Bare) 2009 70(6) 547-52. 

---