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Cholestatic jaundice in newborn infants receiving parenteral nutrition
Semin Neonatal 1996; 1:231-239
Cholestatic jaundice in newborn infants receiving parenteral nutrition Agostino Pierro hIstitute of Child Health and Great Onnond Street Hospital for Children NHS TrtLst, 30 G~dlford Street, London W C I N IEH, UK (EMAIL: A.PIERRO@ICH. UCL.AC.UK)
Key words cholestasis, parenteral nutrition
Hepatic cholestasis is a common complication of long-term parenteral nutrition in infants and children. The factors contributing to the development of this complication are multifactorial and not ye~: completely determined. Neonates, especially those born preterm, are at particular risk. Infection, intestinal bacterial overgrowth and lack of enteral stimulation contribute significantly to the development of the disease. The data on direct toxicity of parenteral nutrients is contradictory and mainly based on experimental animal models that do not reproduce the liver damage observed in infants and children. Enteral feedings should be started as soon as possible to prevent parenteral nutrition-related cholestasis. The efficacy of various drug treatments in preventing parenteral nutrition-related cholestasis have not been proved.
Introduction Parenteral nutrition (PN) is commonly used in newborn infants with congenital or acquired anomalies of the gastrointestinal tract and is often a life-saving procedure. PN permits continuing growth and development and can be used for prolonged periods. PN was introduced into medical practice by Dudrick et al [I]. Considerable refinements of this feeding technique have been achieved during the last 15 years and its use has steadily increased. Approximately 10% of the infants and children treated in children's hospitals receive PN. The benefit of PN needs to be considered against the frequent and occasionally life-threatening complications associated with it. The main complications of PN are infectious, metabolic, mechanical and hepatobiliary. On-going clinical experience with PN and a better understanding of the risk factors involved have considerably reduced some of these complications. The proper management of PN involves preparation of PN solutions in specialized pharmacy units under strict aseptic control, careful assessment of patients" fluid and nutritional requirements, regular multi° 1084-2756/96/030231+09 $12.00
disciplinary reviews, use of softer and less thrombogenic venous catheters and standardized monitoring protocols. All of these measures have reduced the infectious, metabolic and mechanical complications of PN considerably. Unfortunately the hepatobiliary complications related to PN remain serious and often life threatening. The quoted incidence of PN-related cholestasis varies widely from 7.4% to 84% [2, 3]. The aetiological factors in the development of cholestatic jaundice in infants requiring PN remain unclear. Peden et al [4] first reported the development of liver disease in a preterm infant who received PN from birth until death at the age of 71 days. At autopsy the infant's liver revealed cholestasis, bile duct proliferation and early cirrhosis. This association between cholestasis and PN was criticized by Roger et al [5] who, from a series of autopsy studies, concluded that early fasting rather than parenteral supplementation was responsible for impaired hepatobiliary function in the small premature infant. Since these initial reports there have been a number of publications on the aetiology of PN-related cholestasis. The frequency of this complication seems to be diminishing [6]. However, this is probably related to the early © 1996 W. B. Saunders Company Ltd
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initiation of oral feeding rather than to an improvement in the intravenous diet.
Clinical and laboratory findings The clinical presentation of PN-related cholestasis is fairly typical. The infant develops progressive jaundice that is commonly preceded by elevation of non-specific biochemical indicators of hepatic damage, function and excretion. Various clinical factors are thought to contribute to the development of PN-related cholestasis. These include prematurity, low birth weight, duration of PN, immature enterohepatic circulation, intestinal bacterial overgrowth, septicaemia, failure to implement enteral nutrition and the number of operations [7, 8]. Several reports have stressed the association between PN-related cholestasis, prematurity and low birth weight. In a prospective study Touloukian and Seashore [9l found that in eight of 19 (42%) infants receiving total PN for 11-78 days, the serum direct bilirubin was above 2.0 mg/dl. Seven of the eight infants were premature. Beale et al [10] reported intrahepatic cholestasis, which they defined as a direct bilirubin >/1.5 mg/dl, in 23% of premature infants less than 2000 g birth weight receiving total PN. The very low birth weight infants (less than 1000 g) appeared to be at an increased risk of developing cholestasis with an incidence of 50%. Postuma et al [11] reported progressive cholestasis and abnormal elevation of liver enzymes in one third of 92, mostly preterm, newborn infants on total PN. Drongowski et al [7] in a retrospective analysis of 172 neonates requiring total PN for a minimum of 7 days found that the three most significant risk factors for the development of PN-related cholestasis were the number of operations, the number of days the patients received antibiotics and the number of days from birth to the start of enteral feedings. The longer an infant receives PN, the greater the likelihood that PN-related cholestasis will develop. A progressive increase in the prevalence of cholestasis with increasing duration of PN has been reported by Beale et al [10] who found that after 30 days of PN the prevalence of cholestasis was 25%, increasing to 80% at 60 days, and 90% at 90 days. The volumes and duration of enteral feeding in this study were widely variable. Despite knowing the important risk factors, it remains difficult to predict which infants will
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develop cholestasis. Various biochemical tests have been proposed as predictors. Vileisis et al [12] found that the direct bilirubin level was the most sensitive and early indicator of PN-related cholestasis. Postuma et al [11] reported that elevation of the direct bilirubin occurred at 1.8-2.4 weeks of PN and preceded elevation of aspartate aminotransferase levels, which occurred at 4.6 weeks. Serum transaminases levels are usually mildly elevated throughout the course of this disease and are not particularly useful as an indicator. Whitington [13] has suggested that reliance on conventional tests may underestimate the incidence of PN-related cholestasis and that serum levels of y-glutamyl transpeptidase or bile acids may be more sensitive indicators. Radioimmunoassay or enzymatic determination of total or specific bile acid conjugates appear to be useful in the early detection of the hepatic dysfunction [14]. Hypoalbuminaemia and abnormal coagulation studies usually reflect serious hepatic damage. PN-related cholestasis is a diagnosis of exclusion, as no specific marker is yet available. Therefore infants with cholestasis who are receiving or have received PN must have an appropriate diagnostic evaluation to exclude other entities. These include bacterial and viral infections, metabolic diseases and congenital anomalies, including biliary atresia [14]. Comprehensive reviews of the evaluation of neonatal cholestasis are available elsewhere [15, 161. When serial ultrasound examination of liver and gallbladder is performed on infants receiving PN, biliary sludge and cholelithiasis can be detected. Sludge is a dense fluid substance which lies in the dependent portion of the gallbladder, and produces low amplitude echoes [14]. The incidence of sludge formation increases with the duration of PN. In a study by Matos [17], gallbladder sludge appeared in 18 neonates (44%) after a mean period of 10 days of PN. Sludge can progress to 'sludge balls' and gallstones. Asymptomatic infants can develop biliary stones and spontaneous resolution of these stones has been described [17]. Cholecystitis in infants receiving PN is rare. Serial liver ultrasound examinations of neonates and infants receiving PN are advisable to detect abnormalities and/or to follow the abnormal gallbladder content. The disease is progressive unless PN is discontinued and enteral feeding introduced [11]. Hepatosplenomegaly and severe jaundice are characteristic features of advanced disease; neither of these, however, is pathognomonic for this condition and
Cholestatic Jaundice In Newborn Infants
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PN-related cholestasis remains unclear. Different factors may contribute to the development of the disease. These can be classified into four main categories.
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Figure 1. This liver biopsy from an infant on long-term PN shows severe cholestasis in hepatocytes, canaliculi, and Kupffer cells, portal and periportal inflammation, and fibrosis.
haemolytic anaemias, infection and metabolic disease should be excluded [14]. Portal hypertension may develop and is potentially fatal. Although the PN-related cholestasis resolves with time after discontinuation of PN, in a small percentage of patients it remains intractable and progresses to severe hepatic dysfunction and death [18].
Liver histology The literature on paediatric cholestatic liver disease is complicated by the frequent assumption, often without supportive evidence, that abnormal enzyme or bilirubin levels reflect hepatic dysfunction and/or damage [8]. The liver disease early in the course of PN is characterized histologically by centrilobular intrahepatic cholestasis with little evidence of inflammation or necrosis and no evidence of fat accumulation [8]. Liver biopsies taken at the height of PN-related jaundice in infancy showed severe cholestasis accompanied by portal inflammation and mild portal and periportal fibrosis [19] (Figure 1). Half of these biopsies showed scattered loci of hepatocyte necrosis and bile duct proliferation. Fat accumulation was not found. Common findings in liver biopsies also include bile duct proliferation, lymphocyte infiltration and giant cell transformation [20]. The histological features of PN-related cholestasis are non-specific and therefore may mimic those of neonatal hepatitis, extrahepatic biliary obstruction, and biliary atresia.
Pathogenesis In spite of 20 years of clinical experience with PN studies in animals and humans, the aetiology of
• • • •
Toxicity of parenteral nutrients Lack of enteral feeding Mode of delivery of nutrients Host factors
Toxicity of parenteral nutrients PN solutions are usually composed of glucose, crystalline amino acids, triglycerides, electrolytes, vitamins and trace elements. There is evidence from studies in animals and humans that hepatic damage from the components of intravenous diet may result from excessive or inadequate nutrient administration, toxicity of by-products and abnormal metabolism in the neonate.
Carbohydrate Excessive carbohydrate administration during PN causes de novo fat synthesis from glucose [21, 22] and may be responsible for hepatic steatosis [23]. Hepatic steatosis is also seen in humans in a variety of conditions including fatty acid deficiency, protein deficiency, kwashiorkor, diabetes and infections. It is not common in neonates and infants on PN and can be avoided by limiting the intake of carbohydrate to the estimated energy expenditure [22], avoiding fatty acid deficiency and providing an optimal non-protein energy-to-nitrogen ratio [24]. In a full-term neonate stable on total PN the intake of carbohydrate should not exceed 18 glkg per day [22].
Amino acids A considerable number of studies in animals and humans suggests that amino acid solutions may play a role in the development of PN-related cholestasis. Liver perfusion studies demonstrated that bile acid uptake in the hepatocyte can be inhibited by amino acids [25[. Amino acid solutions inhibit bile flow, alter bile composition and increase bile lithogenicity in animals [I4]. Perfusates containing methionine were found to depress biliary flow in isolated liver preparations [26]. In an animal model of total PN, Moss et al [27] found that plasma methionine was elevated without corresponding elevations in its metabolites, cysteine and
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taurine; they speculate that methionine metabolism may be blocked above the level of cysteine synthesis and the excessive circulating methionine may be responsible for the hepatic toxicity. The pathways for the metabolism of sulphur-containing and aromatic amino acids are not mature in the neonate, therefore it is possible that the hepatic toxicity is due to a combined effect of increased administration and decreased metabolism [•4]. Further support to the theory of direct hepatic toxicity of amino acids is given by Vileisis et al [28] who compared the effects of two intravenous diets differing only in the amino acid content, on the development of PN-related cholestasis in 82 infants. The peak bilirubin level was higher and the interval to the onset of jaundice was shorter in those infants receiving the higher amino acid intake. Avoidance of amino acid solutions in the PN diet has been proposed to prevent cholestasis in preterm newborn infants [29]. In contrast with the above studies, which claim direct toxicity from excessive amino acid intake, other studies point to the role of deficiencies of specific amino acids in the pathogenesis of PN-related cholestasis. Belli et al [30] used rats to compare two commonly used amino acid solutions, Vamin (Pharmacia Canad Inc, Dorval, Quebec) and Travasol (Travenol Canad Inc., Mississauga, Ontario), and found impaired bile flow only in the group that received Travasol. Travasol does not contain serine and addition to Travasol of the methyl donor serine, increased bile flow significantly. Taurine deficiency has also been implicated in the pathogenesis of PN-related cholestasis. Taurine is not an essential nutrient for adults, but in neonates supplementation is required because there is a developmental limitation in taurine biosynthesis. This seems to be due to the low levels of activity of hepatic cystathionase and cysteine sulfinic acid decarboxylase. Taurine is present in high quantities in breast milk and is now included in amino acid solutions. It is the principal bile acid conjugate in the neonate and has been shown to promote bile flow; however, its role in preventing cholestasis remains uncertain [31].
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hepatotoxicity [14]. Cottonseed-derived lipid emulsions have been shown to be hepatotoxic and were withdrawn from the market in 1965. Most of the currently used lipid emulsions in paediatrics are based on soybean and safflower oils. In a non-randomized study of adults receiving PN, Allardyce [32] reported progressive cholestatic jaundice in 56% of patients receiving 3 g/kg per day lipid emulsion in comparison with only 6% in patients receiving I g/kg per day of lipid. The cholestatic jaundice improved when the lipid emulsion dosage was reduced. Cholestasis has been reported after switching from Intralipid 20% (KabiVitrum) to Ivelip 20% (Cernepsynthelabo) in four adult patients receiving home longterm PN [33]. The two solutions were both based on soy oil emulsified by egg phospholipids, but the Ivelip emulsion contained smaller lipid droplets and had added sodium oleate; the purification process of lecithin may also be different. Clayton et al [34] observed that plasma concentrations of phytosterols, which are present in lipid emulsions, were higher in children with severe PN-associated liver disease than in those with less severe liver disease. A reduction in the intake of lipid emulsion was associated with a decrease in plasma phytosterol concentrations and an improvement in liver function tests. These authors speculated that a high hepatic concentration of phytosterol can inhibit cholesterol-70t-hydroxylase, the ratelimiting enzyme for bile acid synthesis, and give rise to cholestasis. Minerals, trace elements and contaminants
Increased concentration of calcium, phosphorus and sulphur has been reported in crystals from the biliary tree of patients with PN-related cholestasis [35]. However a relationship between mineral intake in the PN diet and bile mineral concentration has not been demonstrated [36]. Contaminants of the PN solution have also been incriminated in the pathogenesis of PN-related cholestasis. These include aluminium [37], a common contaminant of PN solutions, and tryptophan degradation products contaminated by sodium bisulphite.
Lipid emulsions
Lipid emulsions may have an effect on hepatotoxicity during PN. However, PN-related cholestasis was seen before the introduction of lipids into clinical practice. The source of lipid emulsion used for PN may have a significant effect on
Lack of enteral feeding
Bile is produced by the liver and in the fasting state is stored in the gallbladder. The normal passage of food into the duodenum triggers gallbladder
Cholestatic Jaundice in Newborn Infants
emptying by the release of cholecystokinin. This stimulus to gallbladder activity is not present in patients receiving PN. A recent study from our group has demonstrated that the gallbladder of parenterally fed infants does not contract and its volume is almost four times that of infants receiving bolus enteral feeds [38]. In infancy the gallbladder undergoes a 50% reduction in volume 15 minutes after starting bolus enteral feeding with a return to baseline volume by 90 minutes [38]. In a study of neonatal cholestasis before the introduction of PN in clinical practice, Nakai and Landing [39] concluded that lack of enteral feeding is a possible cause of this condition. The serum levels of various gastrointestinal hormones such as cholecystokinin, gastrin, glucagon, enteroglucagon and gastric inhibitory polypeptide are significantly lower in infants who are parenterally fed compared with those who are enterally fed [14]. Bile flow in humans is induced by active canalicular secretion of conjugated bile acids that generate an osmotic force for the water and filtrable solute to pass across the tight junctions into the biliary ductular lumen [6]. In animals receiving total PN there is a fall in bile acid biosynthesis. Moreover prolonged fasting induces decreased intestinal absorption of bile acids and sequestration of bile salts in the liver and the gallbladder with consequent reduction in bile flow. Gut motility is also reduced leading to bacterial overgrowth and increased production of secondary toxic bile salts. The concomitant delay in colonic transit time may facilitate the colonohepatic recycling of toxic bile acids. These may be even more toxic to the liver during PN because hepatic bile flow is diminished [14, 36]. This phenomenon may potentially lead to cholestasis and/or make the liver more susceptible to other cholestatic factors [36].
Mode of delivery of nutrients The mode of nutrient administration, i.e. continuous versus bolus, may have important bearings on the motility of the extrahepatic biliary tree. We have recently shown in newborn infants that first, continuous enteral feeding impairs gallbladder contractility and leads to an enlarged gallbladder, and secondly, gallbladder contraction is observed immediately after the resumption of bolus enteral feeds and gallbladder volume returns to normal after 4 days [40]. In adults the continuous infusion of PN impairs gallbladder contraction whereas
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Table 1. Patient risk factors for the development of PN-related cholestasis
Age Prematurity Immaturity of biliary secretory system Absence of oral enteral intake Septicaemia Bacterial overgrowth in the small bowel Short bowel length Necrotizing enterocolitis Hypoxia Major abdominal operations General anaesthesia
bolus administration of parenteral amino acids promotes gallbladder motility [41]. More research is needed to clarify the relationship between gallbladder contraction, bile flow and mode of nutrient administration.
Host factors The infant's clinical condition influences the likelihood of PN-related cholestasis development. Table 1 lists the most common risk factors, some of which have already been discussed. PN-related cholestasis has a higher incidence in premature infants than in children and adults. This may be due to the immaturity of biliary secretory system since bile-salt pool size, synthesis and intestinal concentration are lower in premature infants in comparison with full-term infants [42]. Septicaemia and necrotizing enterocolitis have been present in many patients who developed PN-related cholestasis [36]. In both children and adults, septicaemia and urinary tract infection can lead to biochemical cholestasis, even in the absence of PN [43-45]. Manginello and Javitt [46] proposed that the occurrence of cholestasis in infants on PN was related not to the duration of administration or the composition of PN solutions but rather to the presence of sepsis. There are similarities in the liver histology of PN-related liver disease and that associated with Escherichia coli endotoxin [47]. It has been suggested that the cholestatic effects of gram-negative bacterial infections result from the inhibitory effects of endotoxin on bile flow [48]. Animal studies have shown that parenteral nutrition promotes microbial translocation, a process whereby intestinal micro-organisms migrate
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through the mucosal lining into lymph nodes and blood [49]. Pierro et al [50] recently have described microbial translocation in surgical neonates on PN with intestinal overgrowth. All but one episode of microbial translocation occurred in patients with elevated serum bilirubin, indicating PN-related cholestasis. Eradication of microbial overgrowth and neutralization of the intestinal endotoxin pool using selective decontamination of the digestive tract has been shown to reduce sepsis, septicaemia and possibly liver cholestasis [51, 52]. The relationship between microbial translocation and hepatic cholestasis requires further investigation.
Prevention and treatment The clinical care of infants and children who require PN and develop progressive jaundice presents a real challenge. The difficulty is compounded by the lack of understanding of the pathological mechanisms of PN-related cholestasis. None of the experimental animal models for the disease can be extrapolated to the clinical situation, since the histological findings in the liver of animals on PN are not similar to those found in the livers of affected human infants and children. Most of the recommendations for prevention and treatment are therefore empirical and often are not based on substantial clinical evidence. Prevention of PN-related cholestasis is based on the early introduction of enteral feeding and on the administration of intravenous feeding only when appropriate and necessary. In most patients the cholestasis resolves gradually as enteral feedings are initiated and PN is discontinued. Since continuation of PN is usually associated with exacerbation of the liver damage, every effort should be made to introduce entera[ feeding. We have shown that minimal bolus enteral feeding (I ml/kg) during PN in premature infants induces significant gallbladder contraction, and after 3 days of starting minimal enteral feeds the gallbladder volume returns to normal [53]. Unfortunately, as a consequence of gut dysfunction, enteral feeding is often not feasible. In this situation the provision of intravenous calories should not be discontinued since malnutrition and increased risk of infection may result. The calorie needs of the patient should be carefully assessed and overfeeding should be avoided. Maini et al [54] suggested that cycling PN may diminish cholestatic hepatic changes in adults, and this may explain the reduced
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frequency of liver disease in children receiving cyclic PN at home. Experience with this technique in premature infants is extremely limited but encouraging [36, 55]. Rebound hypoglycaemia is a common complication of cyclic PN. Modification of the PN constituents has been proposed but no prospective trial has demonstrated any benefit in reducing or changing the intake of nutrients. Attempts have been made to use drug therapy to treat or prevent PN-related cholestasis. Antibiotics such as metronidazole have been proposed to decrease bacterial overgrowth, formation of secondary toxic bile acids and production of endotoxins [56]. However, metronidazole administration did not prevent development of abnormal liver enzymes in animals receiving PN [57]. Choleretics such as phenobarbital have been used without success [36]. Cholecystokinin has been used to diminish the gallbladder stasis and promote bile flow. Sitzmann et al [58] have demonstrated in a randomized, double-blind controlled study in adults receiving PN that cholecystokinin given intravenously daily prevents stasis and sludge in the gallbladder. Rintala et al [59] reported the reversal of PN-related cholestasis in seven infants by intravenous administration of cholecystokinin three times a day for 3-5 days. However, all the patients except one were completely weaned from PN before treatment with cholecystokinin. In rabbits maintained on total PN, daily infusions of cholecystokinin decreased periportal inflammation and fibrosis, maintained gallbladder emptying capacity and improved organic anion secretion, although bile flow and bile acid secretion were not improved, and hepatocyte damage persisted [60]. Prospective studies are needed to investigate the effects of exogenous cholecystokinin administration on bile flow and cholestatic jaundice in infants and children requiring PN. Ursodeoxycholic acid can be used in infants and children on PN to correct the decreased secretion of endogenous bile acids [6]. Ursodeoxycholic acid is non4oxic and acts as a natural bile acid after conjugation. The efficacy of this treatment has been demonstrated in rabbits and in sporadic case reports. There are no controlled studies showing that ursodeoxycholic acid actually decreases morbidity and mortality in infants on long-term PN [6]. Biliary sludge, cholelithiasis and cholecystitis have been reported with PN. Biliary sludge often resolves with the initiation of enteral feedings and
Cholestatic Jaundice in Newborn Infants
discontinuation of PN. Cholecystectomy is the treatment of choice for patients with acute, symptomatic choleIithiasis and cholecystitis. Rintala et al [61] have proposed laparotomy and operative cholangiography followed by biliary tract irrigation for patients with progressive cholestatic jaundice not responding to medical treatment. In some patients the hepatic disease may progress to cirrhosis, portal hypertension and hepatic failure. In selected cases small bowel and liver transplantation have been used. The introduction of tacrolimus, a new immunosuppressive agent, has allowed intestinal transplantation to become feasible, but infectious and immunological problems still cause significant morbidity and mortality, even 1-3 years after transplantation [62]. The management of cirrhosis, portal hypertension and hepatic failure is beyond the scope of this review. The author's approach to the treatment of PN-related cholestasis is as follows. Once the diagnosis is established and other medical causes of jaundice have been excluded, an ultrasound scan of the liver and extrahepatic biliary tree is obtained to exclude extrahepatic biliary pathology. If cholelithiasis and/or cholecystitis are present, a cholecystectomy with intraoperative cholangiogram is performed. If only biliary sludge is present, an operation is not performed, but the extrahepatic biliary tree is monitored by serial ultrasound to detect stone formation. In the absence of gallbladder disease, the author vigorously attempts to establish at least minimal bolus enteral feeding to stimulate endogenous cholecystokinin production. Elemental formulas containing medium chain triglycerides are used to improve intestinal fat absorption. Surveillance cultures of the throat, rectum and stool are taken to detect bacterial overgrowth; if present, selective decontamination of the digestive tract is carried out [51, 52]. The calorie requirement of the patient is carefully re-evaluated and the carbohydrate intake is limited to the patient's resting energy expenditure (approximately 50 kcal/kg per day in a full-term neonate). The intravenous fat intake is discontinued for 14 days. If there is a drop in serum bilirubin level, the lipid intake is limited to 0.5 g/kg per day on alternative days to provide essential fatty acids. Normal lipid intake is resumed if no changes are observed in serum bilirubin level. Complications from fat-soluble vitamins and/or trace element deficiencies are minimized by proper monitoring and supplementation. Attempts are made to cycle
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the intravenous infusion of nutrients by reducing the daily administration of PN to a maximum of 12 hours. The essential factors are, however, early introduction of enteral feeds and discontinuation of PN at the earliest opportunity.
Acknowledgements I am indebted to Dr H. K. F. van Saene and Mr C. Kimber for reviewing the manuscript, to Dr M. Malone for the liver biopsy shown in Fig. 1 and to Mrs Curig Ghazaros for secretarial help.
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16 Kader HH, Balistreri WF. Neonatal hepatobiliary disease. Semin Gastrointest Dis 1994; 5: 65-77. 17 Matos C, Avni EF, Van-Gansbeke D et al. Total parenteral nutrition (TPN) and gallbladder diseases in neonates. Sonographic assessment. ] Ultrasound Med 1987; 6: 243-248. 18 Hodes JE, Grosfeld JL, Weber TR et al. Hepatic failure in infants on total parenteral nutrition (TPN): clinical and histopathologic observations. ] Pediatr Surg 1982; 17: 463-468. 19 Dahms BB, Halpin TC. Serial liver biopsies in parenteral nutrition-associated cholestasis of early infancy. Gastroenterology 1981; 81: 136--144. 20 Kerner JA. Metabolic complications. In Kerner JA (ed.) Manual of Pediatric Parenteral Nutrition, New York: John Wiley, 1983; 199-216. 21 Pierro A, Carnielli V, Filler RM et al. Metabolism of intravenous fat emulsion in the surgical newborn. ] Pediatr Surg 1989; 24: 95-102. 22 Jones MO, Pierro A, Hammond P e t al. Glucose utilisation in the surgical newborn infant receiving total parenteral nutrition. ] Pediatr Surg 1993; 28: 1121-1125. 23 Sax HC, Talamini MA, Brackett K et al. Hepatic steatosis in total parenteral nutrition: failure of fatty infiltration to correlate with abnormal serum hepatic enzyme levels. Surgery 1986; 100: 697-704. 24 Wolfe BM, Walker BK, Shaul DB et al. Effect of total parenteral nutrition on hepatic histology. Arch Surg 1988; 123: 1084-1090. 25 Bucuvalas JC, Goodrich AL, Blitzer BL et al. Amino acids are potent inhibitors of bile acid uptake by liver plasma membrane vesicles isolated from suckling rats. Pediatr Res 1985; 19: 1298-1304. 26 Preisig R, Rennert O. Biliary transport and cholestatic effects of amino acids. Gastroenterology 1989; 73: 1240. 27 Moss RL, Das JB, Raffensperger JG. Total parenteral nutrition-associated cholestasis: clinical and histopathologic correlation. ] PedhTtrSurg 1993; 28: 1270--1274. 28 Vileisis RA, Inwood RJ, Hunt CE. Prospective controlled study of parenteral nutrition-associated cholestatic jaundice: effect of protein intake. ] Pediatr 1980; 96: 893-897. 29 Brown MR, Thunberg BJ, Golub L et al. Decreased cholestasis with enteral instead of intravenous protein in the very low birth-weight infant. J Pediatr Gastroenterol Nutr 1989; 9: 21-27. 30 Belli DC, Foumier LA, Lepage G e t al. Total parenteral nutrition-associated cholestasis in rats: comparison of different amino acid mixtures. ]PEN 1987; 11: 67-73. 31 Cooke RJ, Whitington PF, KeIts D. Effect of taurine supplementation on hepatic function during short-term parenteral nutrition in the premature infant. ],Pediatr Gastroenterol Nutr 19,54; 3: 234-238. 32 Allardyce DB. Cholestasis caused by lipid emulsion. Surg Gynecol Obstet 1982; 154: 641--647. 33 Gerard-Boncompain M, Claudel JP, Gaussorgues P e t al. Hepatic cytolytic and cholestatic changes related to a change of lipid.emulsions in four long-term parenteral nutrition patients with short bowel. ]PEN 1992; 16: 78-83. 34 Clayton PT, Bowron A, Mills KA et al. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology 1993; 105: 1806-1813.
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35 Nezelof R, Lesec G, Ricour C et al. Cristaux organiques intrah6patiques au cours des nutritions artificielles chez l'enfant. Nouv Presse Med 1977; 6" 3943-3947. 36 Merritt RJ. Cholestasis associated with total parenteral nutrition. ] Pediatr Gastroenterol Nntr 1986; 5: 9-22. 37 Klein GL, Berquist WE, Ament ME et al. Hepatic aluminum accumulation in children on total parenteral nutrition. ] Pediatr GastroenteroI Nutr 1984; 3: 740-743. 38 Jawaheer G, Pierro A, Lloyd DA et al. Gall bladder contractility in neonates: effects of parenteral and enteral feeding. Arch Dis Child 1995; 72: F200--F202. 39 Nakai H, Landing BH. Factors in the genesis of bile stasis in infancy. Pediatrics 1961; 27: 300-307. 40 Jawaheer G, Lloyd DA, Shaw NJ et al. Continuous enteral feeding impairs gallbladder contractility in newborn infants. Proc Nutr Soc 1996; in press. 41 Zoli G, Ballinger A, Healy J e t al. Promotion of gallbladder emptying by intravenous aminoacids. Lancet 1993; 341: 1240-1241. 42 Watkins JB, Szczepanik P, Gould JB et al. Bile salt metabolism in the human premature infant. Gastroenterology 1975; 69: 706--713. 43 Stein H, Isaacson C. Idiopathic cholestasis in the neonatal period. Arch Dis Child 1962; 37: 63--67. 44 Bernstein J, Brown AK. Sepsis and jaundice in early infancy. Pediatrics 1962; 29: 873-882. 45 Zimmerman HJ, Fang M, Utili R et al. Jaundice due to bacterial infection. Gastroenterology 1979; 77: 367-374. 46 Manginello FP, Javitt NB. Parenteral nutrition and neonatal cholestasis. ] Pedialr 1979; 94: 296--298. 47 Utili R, Abernathy CO, Zimmerman HJ. Cholestatic effects of Escherichia eoli endotoxin on the isolated perfused rat liver. Gastroenterology 1976; 70: 248-253. 48 Abernathy CO, Utili R, Zimmerman HJ. Immaturity of the biliary excretory system predisposes neonates to intrahepatic cholestasis. Med Hypotheses 1979; 5: 641647. 49 Alverdy JC, Aoys E, Moss GS. Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 1988; 104: 185-190. 50 Pierro A, van Saene HKF, Donnell SC et al. Microbial translocation in neonates on long-term parenteral nutrition. Arch Surg 1996; 131: I76-179. 51 van Saene HKF, Stantenbeek CP, Faber-Nijholt R et al. Selective decontamination of the digestive tract contributes.to the control of disseminated intra-vascular coagulation in severe liver impairment. ] Pediatr Gastroenterol Nulr 1992; 14: 436-442. 52 Liberati A, Brazzi L, Torri V e t al. Selective decontamination of the digestive tract trialists" collaborative group. Meta-analysis of randomized controlled trials of selective decontamination of the digestive tract. Br Med ] 1993; 307: 525-532. 53 Jawaheer G, Lloyd DA, Shaw NJ et al. Minimal enteral feeding promotes gallbladder contractility in neonates. Proc Nutr Soc 1996; in press. 54 Maini B, Blackburn GL, Bistrian BR et al. Cyclic hyperalimentation: an optimal technique for the preservation of visceral protein. ] Surg Res 1976; 20: 515-525. 55 Ternullo SR, Burkart GJ. Experience with cyclic hyperalimentation in infants. ]PEN 1979; 3 : 5 1 6 (abstract).
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56 Capron JP, Gineston JL, Herve MA. Metronidazole in prevention of cholestasis associated with total parenteral nutrition. Lancet 1983; i: 446-447. 57 Freund HR, Muggia-Sullam M, LaFrance R et al. A possible beneficial effect of metronidazole in reducing TPN-associated liver function derangements. ] Surg Res 1985; 38: 353-363. 58 Sitzmann JV, Pih HA, Steinbom PA et al. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170: 25-31. 59 Rintala RJ, Lindahl H, Pohjavuori M. Total parenteral nutrition-associated cholestasis in surgical neonates may
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be reversed by intravenous cholecystokinin: a preliminary report. ] Pediatr &trg 1995; 30: 827-830. 60 Curran TJ, Uzoaru I, Das JB et al. The effect of cholecystokinin-octapeptide on the hepatobiliary dysfunction caused by total parenteral nutrition. ] PediatrSurg 1995; 30: 242-247. 61 Rintala RJ, Lindahl H, Pohjavuori M et al. Surgical treatment of intractable cholestasis associated with total parenteral nutrition in premature infants. ] Pediatr Surg 1992; 28: 716-719. 62 Furukawa H, Reyes J, Abu-Elmagd K et al. Clinical intestinal transplantation. Clin Nutr 1996; 15: 45-52.
Cholestatic jaundice in newborn infants receiving parenteral nutrition Agostino Pierro hIstitute of Child Health and Great Onnond Street Hospital for Children NHS TrtLst, 30 G~dlford Street, London W C I N IEH, UK (EMAIL: A.PIERRO@ICH. UCL.AC.UK)
Key words cholestasis, parenteral nutrition
Hepatic cholestasis is a common complication of long-term parenteral nutrition in infants and children. The factors contributing to the development of this complication are multifactorial and not ye~: completely determined. Neonates, especially those born preterm, are at particular risk. Infection, intestinal bacterial overgrowth and lack of enteral stimulation contribute significantly to the development of the disease. The data on direct toxicity of parenteral nutrients is contradictory and mainly based on experimental animal models that do not reproduce the liver damage observed in infants and children. Enteral feedings should be started as soon as possible to prevent parenteral nutrition-related cholestasis. The efficacy of various drug treatments in preventing parenteral nutrition-related cholestasis have not been proved.
Introduction Parenteral nutrition (PN) is commonly used in newborn infants with congenital or acquired anomalies of the gastrointestinal tract and is often a life-saving procedure. PN permits continuing growth and development and can be used for prolonged periods. PN was introduced into medical practice by Dudrick et al [I]. Considerable refinements of this feeding technique have been achieved during the last 15 years and its use has steadily increased. Approximately 10% of the infants and children treated in children's hospitals receive PN. The benefit of PN needs to be considered against the frequent and occasionally life-threatening complications associated with it. The main complications of PN are infectious, metabolic, mechanical and hepatobiliary. On-going clinical experience with PN and a better understanding of the risk factors involved have considerably reduced some of these complications. The proper management of PN involves preparation of PN solutions in specialized pharmacy units under strict aseptic control, careful assessment of patients" fluid and nutritional requirements, regular multi° 1084-2756/96/030231+09 $12.00
disciplinary reviews, use of softer and less thrombogenic venous catheters and standardized monitoring protocols. All of these measures have reduced the infectious, metabolic and mechanical complications of PN considerably. Unfortunately the hepatobiliary complications related to PN remain serious and often life threatening. The quoted incidence of PN-related cholestasis varies widely from 7.4% to 84% [2, 3]. The aetiological factors in the development of cholestatic jaundice in infants requiring PN remain unclear. Peden et al [4] first reported the development of liver disease in a preterm infant who received PN from birth until death at the age of 71 days. At autopsy the infant's liver revealed cholestasis, bile duct proliferation and early cirrhosis. This association between cholestasis and PN was criticized by Roger et al [5] who, from a series of autopsy studies, concluded that early fasting rather than parenteral supplementation was responsible for impaired hepatobiliary function in the small premature infant. Since these initial reports there have been a number of publications on the aetiology of PN-related cholestasis. The frequency of this complication seems to be diminishing [6]. However, this is probably related to the early © 1996 W. B. Saunders Company Ltd
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initiation of oral feeding rather than to an improvement in the intravenous diet.
Clinical and laboratory findings The clinical presentation of PN-related cholestasis is fairly typical. The infant develops progressive jaundice that is commonly preceded by elevation of non-specific biochemical indicators of hepatic damage, function and excretion. Various clinical factors are thought to contribute to the development of PN-related cholestasis. These include prematurity, low birth weight, duration of PN, immature enterohepatic circulation, intestinal bacterial overgrowth, septicaemia, failure to implement enteral nutrition and the number of operations [7, 8]. Several reports have stressed the association between PN-related cholestasis, prematurity and low birth weight. In a prospective study Touloukian and Seashore [9l found that in eight of 19 (42%) infants receiving total PN for 11-78 days, the serum direct bilirubin was above 2.0 mg/dl. Seven of the eight infants were premature. Beale et al [10] reported intrahepatic cholestasis, which they defined as a direct bilirubin >/1.5 mg/dl, in 23% of premature infants less than 2000 g birth weight receiving total PN. The very low birth weight infants (less than 1000 g) appeared to be at an increased risk of developing cholestasis with an incidence of 50%. Postuma et al [11] reported progressive cholestasis and abnormal elevation of liver enzymes in one third of 92, mostly preterm, newborn infants on total PN. Drongowski et al [7] in a retrospective analysis of 172 neonates requiring total PN for a minimum of 7 days found that the three most significant risk factors for the development of PN-related cholestasis were the number of operations, the number of days the patients received antibiotics and the number of days from birth to the start of enteral feedings. The longer an infant receives PN, the greater the likelihood that PN-related cholestasis will develop. A progressive increase in the prevalence of cholestasis with increasing duration of PN has been reported by Beale et al [10] who found that after 30 days of PN the prevalence of cholestasis was 25%, increasing to 80% at 60 days, and 90% at 90 days. The volumes and duration of enteral feeding in this study were widely variable. Despite knowing the important risk factors, it remains difficult to predict which infants will
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develop cholestasis. Various biochemical tests have been proposed as predictors. Vileisis et al [12] found that the direct bilirubin level was the most sensitive and early indicator of PN-related cholestasis. Postuma et al [11] reported that elevation of the direct bilirubin occurred at 1.8-2.4 weeks of PN and preceded elevation of aspartate aminotransferase levels, which occurred at 4.6 weeks. Serum transaminases levels are usually mildly elevated throughout the course of this disease and are not particularly useful as an indicator. Whitington [13] has suggested that reliance on conventional tests may underestimate the incidence of PN-related cholestasis and that serum levels of y-glutamyl transpeptidase or bile acids may be more sensitive indicators. Radioimmunoassay or enzymatic determination of total or specific bile acid conjugates appear to be useful in the early detection of the hepatic dysfunction [14]. Hypoalbuminaemia and abnormal coagulation studies usually reflect serious hepatic damage. PN-related cholestasis is a diagnosis of exclusion, as no specific marker is yet available. Therefore infants with cholestasis who are receiving or have received PN must have an appropriate diagnostic evaluation to exclude other entities. These include bacterial and viral infections, metabolic diseases and congenital anomalies, including biliary atresia [14]. Comprehensive reviews of the evaluation of neonatal cholestasis are available elsewhere [15, 161. When serial ultrasound examination of liver and gallbladder is performed on infants receiving PN, biliary sludge and cholelithiasis can be detected. Sludge is a dense fluid substance which lies in the dependent portion of the gallbladder, and produces low amplitude echoes [14]. The incidence of sludge formation increases with the duration of PN. In a study by Matos [17], gallbladder sludge appeared in 18 neonates (44%) after a mean period of 10 days of PN. Sludge can progress to 'sludge balls' and gallstones. Asymptomatic infants can develop biliary stones and spontaneous resolution of these stones has been described [17]. Cholecystitis in infants receiving PN is rare. Serial liver ultrasound examinations of neonates and infants receiving PN are advisable to detect abnormalities and/or to follow the abnormal gallbladder content. The disease is progressive unless PN is discontinued and enteral feeding introduced [11]. Hepatosplenomegaly and severe jaundice are characteristic features of advanced disease; neither of these, however, is pathognomonic for this condition and
Cholestatic Jaundice In Newborn Infants
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PN-related cholestasis remains unclear. Different factors may contribute to the development of the disease. These can be classified into four main categories.
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Figure 1. This liver biopsy from an infant on long-term PN shows severe cholestasis in hepatocytes, canaliculi, and Kupffer cells, portal and periportal inflammation, and fibrosis.
haemolytic anaemias, infection and metabolic disease should be excluded [14]. Portal hypertension may develop and is potentially fatal. Although the PN-related cholestasis resolves with time after discontinuation of PN, in a small percentage of patients it remains intractable and progresses to severe hepatic dysfunction and death [18].
Liver histology The literature on paediatric cholestatic liver disease is complicated by the frequent assumption, often without supportive evidence, that abnormal enzyme or bilirubin levels reflect hepatic dysfunction and/or damage [8]. The liver disease early in the course of PN is characterized histologically by centrilobular intrahepatic cholestasis with little evidence of inflammation or necrosis and no evidence of fat accumulation [8]. Liver biopsies taken at the height of PN-related jaundice in infancy showed severe cholestasis accompanied by portal inflammation and mild portal and periportal fibrosis [19] (Figure 1). Half of these biopsies showed scattered loci of hepatocyte necrosis and bile duct proliferation. Fat accumulation was not found. Common findings in liver biopsies also include bile duct proliferation, lymphocyte infiltration and giant cell transformation [20]. The histological features of PN-related cholestasis are non-specific and therefore may mimic those of neonatal hepatitis, extrahepatic biliary obstruction, and biliary atresia.
Pathogenesis In spite of 20 years of clinical experience with PN studies in animals and humans, the aetiology of
• • • •
Toxicity of parenteral nutrients Lack of enteral feeding Mode of delivery of nutrients Host factors
Toxicity of parenteral nutrients PN solutions are usually composed of glucose, crystalline amino acids, triglycerides, electrolytes, vitamins and trace elements. There is evidence from studies in animals and humans that hepatic damage from the components of intravenous diet may result from excessive or inadequate nutrient administration, toxicity of by-products and abnormal metabolism in the neonate.
Carbohydrate Excessive carbohydrate administration during PN causes de novo fat synthesis from glucose [21, 22] and may be responsible for hepatic steatosis [23]. Hepatic steatosis is also seen in humans in a variety of conditions including fatty acid deficiency, protein deficiency, kwashiorkor, diabetes and infections. It is not common in neonates and infants on PN and can be avoided by limiting the intake of carbohydrate to the estimated energy expenditure [22], avoiding fatty acid deficiency and providing an optimal non-protein energy-to-nitrogen ratio [24]. In a full-term neonate stable on total PN the intake of carbohydrate should not exceed 18 glkg per day [22].
Amino acids A considerable number of studies in animals and humans suggests that amino acid solutions may play a role in the development of PN-related cholestasis. Liver perfusion studies demonstrated that bile acid uptake in the hepatocyte can be inhibited by amino acids [25[. Amino acid solutions inhibit bile flow, alter bile composition and increase bile lithogenicity in animals [I4]. Perfusates containing methionine were found to depress biliary flow in isolated liver preparations [26]. In an animal model of total PN, Moss et al [27] found that plasma methionine was elevated without corresponding elevations in its metabolites, cysteine and
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taurine; they speculate that methionine metabolism may be blocked above the level of cysteine synthesis and the excessive circulating methionine may be responsible for the hepatic toxicity. The pathways for the metabolism of sulphur-containing and aromatic amino acids are not mature in the neonate, therefore it is possible that the hepatic toxicity is due to a combined effect of increased administration and decreased metabolism [•4]. Further support to the theory of direct hepatic toxicity of amino acids is given by Vileisis et al [28] who compared the effects of two intravenous diets differing only in the amino acid content, on the development of PN-related cholestasis in 82 infants. The peak bilirubin level was higher and the interval to the onset of jaundice was shorter in those infants receiving the higher amino acid intake. Avoidance of amino acid solutions in the PN diet has been proposed to prevent cholestasis in preterm newborn infants [29]. In contrast with the above studies, which claim direct toxicity from excessive amino acid intake, other studies point to the role of deficiencies of specific amino acids in the pathogenesis of PN-related cholestasis. Belli et al [30] used rats to compare two commonly used amino acid solutions, Vamin (Pharmacia Canad Inc, Dorval, Quebec) and Travasol (Travenol Canad Inc., Mississauga, Ontario), and found impaired bile flow only in the group that received Travasol. Travasol does not contain serine and addition to Travasol of the methyl donor serine, increased bile flow significantly. Taurine deficiency has also been implicated in the pathogenesis of PN-related cholestasis. Taurine is not an essential nutrient for adults, but in neonates supplementation is required because there is a developmental limitation in taurine biosynthesis. This seems to be due to the low levels of activity of hepatic cystathionase and cysteine sulfinic acid decarboxylase. Taurine is present in high quantities in breast milk and is now included in amino acid solutions. It is the principal bile acid conjugate in the neonate and has been shown to promote bile flow; however, its role in preventing cholestasis remains uncertain [31].
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hepatotoxicity [14]. Cottonseed-derived lipid emulsions have been shown to be hepatotoxic and were withdrawn from the market in 1965. Most of the currently used lipid emulsions in paediatrics are based on soybean and safflower oils. In a non-randomized study of adults receiving PN, Allardyce [32] reported progressive cholestatic jaundice in 56% of patients receiving 3 g/kg per day lipid emulsion in comparison with only 6% in patients receiving I g/kg per day of lipid. The cholestatic jaundice improved when the lipid emulsion dosage was reduced. Cholestasis has been reported after switching from Intralipid 20% (KabiVitrum) to Ivelip 20% (Cernepsynthelabo) in four adult patients receiving home longterm PN [33]. The two solutions were both based on soy oil emulsified by egg phospholipids, but the Ivelip emulsion contained smaller lipid droplets and had added sodium oleate; the purification process of lecithin may also be different. Clayton et al [34] observed that plasma concentrations of phytosterols, which are present in lipid emulsions, were higher in children with severe PN-associated liver disease than in those with less severe liver disease. A reduction in the intake of lipid emulsion was associated with a decrease in plasma phytosterol concentrations and an improvement in liver function tests. These authors speculated that a high hepatic concentration of phytosterol can inhibit cholesterol-70t-hydroxylase, the ratelimiting enzyme for bile acid synthesis, and give rise to cholestasis. Minerals, trace elements and contaminants
Increased concentration of calcium, phosphorus and sulphur has been reported in crystals from the biliary tree of patients with PN-related cholestasis [35]. However a relationship between mineral intake in the PN diet and bile mineral concentration has not been demonstrated [36]. Contaminants of the PN solution have also been incriminated in the pathogenesis of PN-related cholestasis. These include aluminium [37], a common contaminant of PN solutions, and tryptophan degradation products contaminated by sodium bisulphite.
Lipid emulsions
Lipid emulsions may have an effect on hepatotoxicity during PN. However, PN-related cholestasis was seen before the introduction of lipids into clinical practice. The source of lipid emulsion used for PN may have a significant effect on
Lack of enteral feeding
Bile is produced by the liver and in the fasting state is stored in the gallbladder. The normal passage of food into the duodenum triggers gallbladder
Cholestatic Jaundice in Newborn Infants
emptying by the release of cholecystokinin. This stimulus to gallbladder activity is not present in patients receiving PN. A recent study from our group has demonstrated that the gallbladder of parenterally fed infants does not contract and its volume is almost four times that of infants receiving bolus enteral feeds [38]. In infancy the gallbladder undergoes a 50% reduction in volume 15 minutes after starting bolus enteral feeding with a return to baseline volume by 90 minutes [38]. In a study of neonatal cholestasis before the introduction of PN in clinical practice, Nakai and Landing [39] concluded that lack of enteral feeding is a possible cause of this condition. The serum levels of various gastrointestinal hormones such as cholecystokinin, gastrin, glucagon, enteroglucagon and gastric inhibitory polypeptide are significantly lower in infants who are parenterally fed compared with those who are enterally fed [14]. Bile flow in humans is induced by active canalicular secretion of conjugated bile acids that generate an osmotic force for the water and filtrable solute to pass across the tight junctions into the biliary ductular lumen [6]. In animals receiving total PN there is a fall in bile acid biosynthesis. Moreover prolonged fasting induces decreased intestinal absorption of bile acids and sequestration of bile salts in the liver and the gallbladder with consequent reduction in bile flow. Gut motility is also reduced leading to bacterial overgrowth and increased production of secondary toxic bile salts. The concomitant delay in colonic transit time may facilitate the colonohepatic recycling of toxic bile acids. These may be even more toxic to the liver during PN because hepatic bile flow is diminished [14, 36]. This phenomenon may potentially lead to cholestasis and/or make the liver more susceptible to other cholestatic factors [36].
Mode of delivery of nutrients The mode of nutrient administration, i.e. continuous versus bolus, may have important bearings on the motility of the extrahepatic biliary tree. We have recently shown in newborn infants that first, continuous enteral feeding impairs gallbladder contractility and leads to an enlarged gallbladder, and secondly, gallbladder contraction is observed immediately after the resumption of bolus enteral feeds and gallbladder volume returns to normal after 4 days [40]. In adults the continuous infusion of PN impairs gallbladder contraction whereas
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Table 1. Patient risk factors for the development of PN-related cholestasis
Age Prematurity Immaturity of biliary secretory system Absence of oral enteral intake Septicaemia Bacterial overgrowth in the small bowel Short bowel length Necrotizing enterocolitis Hypoxia Major abdominal operations General anaesthesia
bolus administration of parenteral amino acids promotes gallbladder motility [41]. More research is needed to clarify the relationship between gallbladder contraction, bile flow and mode of nutrient administration.
Host factors The infant's clinical condition influences the likelihood of PN-related cholestasis development. Table 1 lists the most common risk factors, some of which have already been discussed. PN-related cholestasis has a higher incidence in premature infants than in children and adults. This may be due to the immaturity of biliary secretory system since bile-salt pool size, synthesis and intestinal concentration are lower in premature infants in comparison with full-term infants [42]. Septicaemia and necrotizing enterocolitis have been present in many patients who developed PN-related cholestasis [36]. In both children and adults, septicaemia and urinary tract infection can lead to biochemical cholestasis, even in the absence of PN [43-45]. Manginello and Javitt [46] proposed that the occurrence of cholestasis in infants on PN was related not to the duration of administration or the composition of PN solutions but rather to the presence of sepsis. There are similarities in the liver histology of PN-related liver disease and that associated with Escherichia coli endotoxin [47]. It has been suggested that the cholestatic effects of gram-negative bacterial infections result from the inhibitory effects of endotoxin on bile flow [48]. Animal studies have shown that parenteral nutrition promotes microbial translocation, a process whereby intestinal micro-organisms migrate
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through the mucosal lining into lymph nodes and blood [49]. Pierro et al [50] recently have described microbial translocation in surgical neonates on PN with intestinal overgrowth. All but one episode of microbial translocation occurred in patients with elevated serum bilirubin, indicating PN-related cholestasis. Eradication of microbial overgrowth and neutralization of the intestinal endotoxin pool using selective decontamination of the digestive tract has been shown to reduce sepsis, septicaemia and possibly liver cholestasis [51, 52]. The relationship between microbial translocation and hepatic cholestasis requires further investigation.
Prevention and treatment The clinical care of infants and children who require PN and develop progressive jaundice presents a real challenge. The difficulty is compounded by the lack of understanding of the pathological mechanisms of PN-related cholestasis. None of the experimental animal models for the disease can be extrapolated to the clinical situation, since the histological findings in the liver of animals on PN are not similar to those found in the livers of affected human infants and children. Most of the recommendations for prevention and treatment are therefore empirical and often are not based on substantial clinical evidence. Prevention of PN-related cholestasis is based on the early introduction of enteral feeding and on the administration of intravenous feeding only when appropriate and necessary. In most patients the cholestasis resolves gradually as enteral feedings are initiated and PN is discontinued. Since continuation of PN is usually associated with exacerbation of the liver damage, every effort should be made to introduce entera[ feeding. We have shown that minimal bolus enteral feeding (I ml/kg) during PN in premature infants induces significant gallbladder contraction, and after 3 days of starting minimal enteral feeds the gallbladder volume returns to normal [53]. Unfortunately, as a consequence of gut dysfunction, enteral feeding is often not feasible. In this situation the provision of intravenous calories should not be discontinued since malnutrition and increased risk of infection may result. The calorie needs of the patient should be carefully assessed and overfeeding should be avoided. Maini et al [54] suggested that cycling PN may diminish cholestatic hepatic changes in adults, and this may explain the reduced
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frequency of liver disease in children receiving cyclic PN at home. Experience with this technique in premature infants is extremely limited but encouraging [36, 55]. Rebound hypoglycaemia is a common complication of cyclic PN. Modification of the PN constituents has been proposed but no prospective trial has demonstrated any benefit in reducing or changing the intake of nutrients. Attempts have been made to use drug therapy to treat or prevent PN-related cholestasis. Antibiotics such as metronidazole have been proposed to decrease bacterial overgrowth, formation of secondary toxic bile acids and production of endotoxins [56]. However, metronidazole administration did not prevent development of abnormal liver enzymes in animals receiving PN [57]. Choleretics such as phenobarbital have been used without success [36]. Cholecystokinin has been used to diminish the gallbladder stasis and promote bile flow. Sitzmann et al [58] have demonstrated in a randomized, double-blind controlled study in adults receiving PN that cholecystokinin given intravenously daily prevents stasis and sludge in the gallbladder. Rintala et al [59] reported the reversal of PN-related cholestasis in seven infants by intravenous administration of cholecystokinin three times a day for 3-5 days. However, all the patients except one were completely weaned from PN before treatment with cholecystokinin. In rabbits maintained on total PN, daily infusions of cholecystokinin decreased periportal inflammation and fibrosis, maintained gallbladder emptying capacity and improved organic anion secretion, although bile flow and bile acid secretion were not improved, and hepatocyte damage persisted [60]. Prospective studies are needed to investigate the effects of exogenous cholecystokinin administration on bile flow and cholestatic jaundice in infants and children requiring PN. Ursodeoxycholic acid can be used in infants and children on PN to correct the decreased secretion of endogenous bile acids [6]. Ursodeoxycholic acid is non4oxic and acts as a natural bile acid after conjugation. The efficacy of this treatment has been demonstrated in rabbits and in sporadic case reports. There are no controlled studies showing that ursodeoxycholic acid actually decreases morbidity and mortality in infants on long-term PN [6]. Biliary sludge, cholelithiasis and cholecystitis have been reported with PN. Biliary sludge often resolves with the initiation of enteral feedings and
Cholestatic Jaundice in Newborn Infants
discontinuation of PN. Cholecystectomy is the treatment of choice for patients with acute, symptomatic choleIithiasis and cholecystitis. Rintala et al [61] have proposed laparotomy and operative cholangiography followed by biliary tract irrigation for patients with progressive cholestatic jaundice not responding to medical treatment. In some patients the hepatic disease may progress to cirrhosis, portal hypertension and hepatic failure. In selected cases small bowel and liver transplantation have been used. The introduction of tacrolimus, a new immunosuppressive agent, has allowed intestinal transplantation to become feasible, but infectious and immunological problems still cause significant morbidity and mortality, even 1-3 years after transplantation [62]. The management of cirrhosis, portal hypertension and hepatic failure is beyond the scope of this review. The author's approach to the treatment of PN-related cholestasis is as follows. Once the diagnosis is established and other medical causes of jaundice have been excluded, an ultrasound scan of the liver and extrahepatic biliary tree is obtained to exclude extrahepatic biliary pathology. If cholelithiasis and/or cholecystitis are present, a cholecystectomy with intraoperative cholangiogram is performed. If only biliary sludge is present, an operation is not performed, but the extrahepatic biliary tree is monitored by serial ultrasound to detect stone formation. In the absence of gallbladder disease, the author vigorously attempts to establish at least minimal bolus enteral feeding to stimulate endogenous cholecystokinin production. Elemental formulas containing medium chain triglycerides are used to improve intestinal fat absorption. Surveillance cultures of the throat, rectum and stool are taken to detect bacterial overgrowth; if present, selective decontamination of the digestive tract is carried out [51, 52]. The calorie requirement of the patient is carefully re-evaluated and the carbohydrate intake is limited to the patient's resting energy expenditure (approximately 50 kcal/kg per day in a full-term neonate). The intravenous fat intake is discontinued for 14 days. If there is a drop in serum bilirubin level, the lipid intake is limited to 0.5 g/kg per day on alternative days to provide essential fatty acids. Normal lipid intake is resumed if no changes are observed in serum bilirubin level. Complications from fat-soluble vitamins and/or trace element deficiencies are minimized by proper monitoring and supplementation. Attempts are made to cycle
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the intravenous infusion of nutrients by reducing the daily administration of PN to a maximum of 12 hours. The essential factors are, however, early introduction of enteral feeds and discontinuation of PN at the earliest opportunity.
Acknowledgements I am indebted to Dr H. K. F. van Saene and Mr C. Kimber for reviewing the manuscript, to Dr M. Malone for the liver biopsy shown in Fig. 1 and to Mrs Curig Ghazaros for secretarial help.
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