Total Parenteral Nutrition-associated Cholestasis Research Articles

Two parenteral amino acid solutions and plasma levels of amino acids in the neonate: A randomized trial.

In neonates on total parenteral nutrition (TPN), amino acids may be a risk factor for developing total parenteral nutrition-associated cholestasis (TPNAC). We aimed, first, to compare methionine, cysteine, and taurine plasma levels between neonates on TPN who were receiving an intravenous amino acid solution based on a breast milk aminogram and those on an intravenous solution of pediatric amino acids based on an umbilical cord aminogram, and second, to determine the frequency of TPNAC. A double-blind randomized controlled trial was conducted. Ninety-four neonates with a birthweight of 1000g or more and a gestational age of 30 wk or older were admitted and enrolled. Blood samples were obtained at 0, 7, and 14 d of TPN, and plasma amino acid concentrations were determined by ultra-high-resolution liquid chromatography. Continuous variables were compared using the Wilcoxon rank-sum test or Student's t test; categorical variables were compared using the Fisher exact test. Thirty-five neonates completed the study (Primene, n = 14; TrophAmine, n = 21). On day 14, methionine plasma concentrations were significantly lower in the Primene group than in the TrophAmine group (27 µmol/L versus 32.9 µmol/L, P = 0.044); the taurine concentration was significantly higher in the same group (72.4 µmol/L versus 45.3 µmol/L, P < 0.0001). There were no differences in TPNAC incidence. Administering an intravenous solution of pediatric amino acids based on the umbilical cord aminogram yielded a higher taurine and lower methionine plasma concentration than did administering a similar solution based on the breast milk aminogram.

Liquid chromatography–mass spectroscopy as a tool in the rapid diagnosis of biliary atresia: a pilot study

IntroductionBiliary atresia (BA) is a neonatal obstructive cholangiopathy requiring rapid intervention to prevent end-stage liver failure and death. Low bile acid levels in stool, detectable with high-performance liquid chromatography–mass spectroscopy, may reflect extrahepatic biliary obstruction in cholestasis. HypothesisStool bile acid content can differentiate BA from non-BA forms of cholestasis. MethodsStool samples from four healthy and nine cholestatic patients were collected following internal review board approval. Bile acids were extracted and separated on a 4000-Q-Trap HPLC-MS system. ResultsTotal bile acid content was highest in samples from healthy relative to cholestatic patients: 3354.01 ± 2102.56, 1476.27 ± 1361.07, and 34.29 ± 10.30 μM/mg of stool in healthy, total parenteral nutrition-associated cholestasis, and BA samples, respectively. Mean cholic acid and chenodeoxycholic acid concentrations in healthy samples (2017.5 ± 1413.6 and 876.83 ± 660.60 μM/mg) were higher than in TPN cholestatic samples (93.99±131.55 and 232.34 ± 293.41 μM/mg). The most dramatic reduction in cholic acid and chenodeoxycholic acid was observed in BA samples (0.65 ± 0.47 and 1.22 ± 0.80 μM/mg). ConclusionBile acid content in stool is reduced in cholestatic patients relative to healthy patients with the most dramatic reduction observed in BA-patients.

Using Volume Index and Lateral Hepatic Angle to Differentiate Biliary Atresia From TPN‐Associated Cholestasis

Differential diagnosis between biliary atresia (BA) and total parenteral nutrition-associated cholestasis (TPN-AC) and early treatment for cholestatic infants are challenges for evaluating neonatal or infantile cholestasis. The aim of our retrospective study was to apply noninvasive indices of magnetic resonance images to differentiate BA from TPN-AC. A total of 44 patients diagnosed as having BA (n = 30) or TPN-AC (n = 14) were included in the present retrospective study and underwent abdominal magnetic resonance imaging to evaluate the possibility of BA. The left lateral hepatic angle was determined from the coronal image of the left portal vein and portal vein of segment II. Adjusted volume indices of the right hepatic lobe (AVIR) and left lateral segment (AVILL) were calculated as the product of 3 diameters (centimeters) divided by each patient's body weight. The left lateral hepatic angles of patients with BA (74° ± 21°) were significantly larger than for patients with TPN-AC (33° ± 9°) and controls (36° ± 5°, P < 0.05). AVILL of the BA (0.037 ± 0.012 cm/g) and TPN-AC groups (0.042 ± 0.030 cm/g) were not significantly different (P = 0.61) but were significantly larger than for controls (0.020 ± 0.011 cm/g) (P < 0.05). The right hepatic lobe to left lateral hepatic segment ratio (RLR) of patients with BA was significantly (P < 0.05) smaller (1.61 ± 0.58) than for patients with TPN-AC (3.08 ± 2.43) and controls (2.98 ± 0.92). Patients with BA could have relative sparing and selective enlargement of the left lateral liver with a resultant lobar difference and blunt left lateral hepatic angle. Noninvasive indices of lobar difference and left lateral hepatic angle help differentiate patients with BA from those with TPN-AC.

Timing of ostomy reversal in neonates with necrotizing enterocolitis.

Most neonates with necrotizing enterocolitis (NEC) requiring laparotomy have bowel resection and intestinal diversion. At present, there is no consensus regarding the best time for enterostomy reversal. Our aim is to determine if there is any difference in outcomes of infants whose enterostomy was reversed early versus late. We retrospectively reviewed medical records of patients with NEC admitted to the neonatal intensive care unit at a large urban children's hospital from 2002 to 2010. The patients underwent operative intervention with creation and subsequent reversal of stomas. Patient characteristics, operative characteristics, and postoperative care were recorded. A total of 206 neonates were diagnosed with NEC and 44 met the inclusion criteria. Seven had ostomies reversed within 8 weeks, 20 underwent reversal 8 to 12 weeks after initial operation, and 17 underwent ostomy reversal greater than 12 weeks from creation. Early reversal did not affect the incidence of total parenteral nutrition-associated cholestasis (p = 0.16), length of parenteral nutrition (p = 0.12), or ability to reach full enteral nutrition (p = 0.30). Ventilator days were not different (p = 0.08). We found no difference in contamination at laparotomy (p = 0.61) or adhesions at reversal (p = 0.73). Mortality rate (p = 0.15) and complications following reversal (p = 0.25) were not different. There is no advantage to early or late enterostomy reversal in the endpoints studied.

Total parenteral nutrition-associated cholestasis and risk factors in preterm infants.

Background/Aim:Development of hepatic dysfunction is a well-recognized complication of total parenteral nutrition in preterm infants. Previous studies reported the incidence of total parenteral nutrition–associated cholestasis and described possible contributing factors to its pathogenesis, but little is done trying to determine its possible predictive risk factors. The aims of this study was to determine the incidence of total parenteral nutrition–associated cholestasis and to develop a possible predictive model for its occurrence.Patients and Methods:A review of medical records of all very low birth weight infants admitted to neonatal intensive care unit at King Khalid University Hospital, Riyadh, Saudi Arabia, between January 2001 and December 2003 was carried out. The infants were divided into two groups: Cholestasis and noncholestasis, based on direct serum bilirubin level >34 μmol/L. A multivariate logistic regression analysis was performed to calculate the statistical significance of risk factors. Receiver–operating characteristic curve was used to determine the optimal cutoff points for the significant risk factors and to calculate their sensitivity and specificity. The level of significance was set at P ≤ 0.05.Results:A total of 307 patients were included in the analysis. The incidence of cholestasis in the whole population was 24.1% (74 patients). Infants with cholestasis had a lower birth weight, 735.4 ± 166.4 g vs. 1185.0 ± 205.6 g for noncholestasis group (P < 0.001), whereas the mean gestational age for the two groups was 25.4 ± 2.1 week and 28.9 ± 2.1 week, respectively (P < 0.001). The significant risk factors for the development of cholestasis were birth weight (P = 0.006) with an odds ratio of 0.99 [95% confidence interval (CI), 0.98, 0.99]; sensitivity of 92%, specificity of 87%; and total parenteral nutrition duration (P < 0.001) with an odds ratio of 1.18 (95% CI, 1.10, 1.27); sensitivity of 96%, specificity of 89%.Conclusions:A lower birth weight and longer duration of total parenteral nutrition were strong predictive risk factors for the development of cholestasis in preterm infants.

Efficacy of US-guided Percutaneous Cholecystocholangiography for the Early Exclusion and Type Determination of Biliary Atresia

To evaluate the efficacy of ultrasonographically (US)-guided percutaneous cholecystocholangiography (PCC) for early diagnosis and characterization of biliary atresia in infants with cholestatic liver disease. Institutional review board approval was obtained for this study. Parental informed written consent was obtained. From October 2003 to August 2010, 22 infants (12 male, 10 female; age range, 1-138 days) were referred to the radiology department for PCC. Indications for PCC were suspected biliary atresia at 24-hour delayed technetium 99m-diisopropyl-phenylcarbamoylmethyl-iminodiacetic acid (DISIDA) scintigraphy because no excretion was observed in the small bowel (n = 17) or when the results of the scan or liver biopsy could not be obtained within 3 days because of a delay in schedule (n = 5). A diagnosis of biliary atresia was excluded when there was contrast material visualized in the gallbladder, biliary system, and passage to the duodenum. Patients with biliary atresia underwent surgery as the reference standard. Among the 18 patients who underwent successful PCC, biliary atresia was excluded in 13, with diagnoses as follows: total parenteral nutrition-associated cholestasis (TPNAC) (n = 6), neonatal hepatitis (n = 4), congenital syphilis (n = 1), neonatal lupus (n = 1), and congenital cytomegalovirus hepatitis (n = 1). Biliary atresia was diagnosed in five patients (four with type IIIb and one with type IIIa) and was confirmed at surgery. In four infants in whom US-guided gallbladder puncture had failed, biliary atresia (n = 2) and TPNAC (n = 2) were diagnosed. PCC is a safe and useful technique for early exclusion when biliary atresia cannot be ruled out after traditional screening tests; in addition, it may be useful for preoperative type determination of biliary atresia. © RSNA, 2011.

Definitive exclusion of biliary atresia in infants with cholestatic jaundice: the role of percutaneous cholecysto-cholangiography

Definitive exclusion of biliary atresia in the infant with cholestatic jaundice usually requires operative cholangiography. This approach suffers from the disadvantage that sick infants are subjected to a time-consuming and potentially negative surgical exploration. The purpose of this study was to determine if percutaneous cholecystocholangiography (PCC) prevents unnecessary laparotomy in infants whose cholestasis is caused by diseases other than biliary atresia. This study is a 10 year retrospective review of all infants with persistent direct hyperbilirubinemia and inconclusive biliary nuclear scans who underwent further evaluation for suspected biliary atresia. A gallbladder ultrasound (US) was obtained in all patients. When the gallbladder was visualized, further imaging by PCC was done under intravenous sedation; otherwise, the standard operative cholangiogram (OCG) was performed, with liver biopsy as indicated. The primary outcome was the diagnostic accuracy of PCC, especially with respect to preventing a laparotomy. There were 35 infants with suspected biliary atresia, with a mean age of 8 weeks (range 1-14 weeks). Nine infants whose gallbladder was visualized by ultrasound underwent PCC that definitively excluded biliary atresia. Of this group, the most frequent diagnosis (five patients) was total parenteral nutrition-associated cholestasis. The other 26 infants with absent or decompressed gallbladder had laparotomy and OCG, which identified biliary atresia in 16 patients (61%). Laparotomy was avoided in all 9 patients who underwent PCC, thus reducing the negative laparotomy rate by 47%. There were no complications associated with PCC. Several alternative techniques to operative cholangiogram have been described for the definitive exclusion of biliary atresia, but many of these have distinct drawbacks. Advances in interventional radiology techniques have permitted safe percutaneous contrast evaluation of the biliary tree. Identification of a normal gall bladder on sonogram is highly predictive of the absence of biliary atresia. Further confirmation can be accurately obtained by a combination of PCC and percutaneous liver biopsy.

Ultrasound-guided Percutaneous Cholecysto-Cholangiography for the Exclusion of Biliary Atresia in Infants

Purpose: The aim of this study is to determine the feasibility and effectiveness of performing an ultrasoundguided percutaneous cholecysto-cholangiogram (PCC) for excluding biliary atresia as the cause of neonatal jaundice. Materials and Methods: Between Oct. 2003 and Feb. 2005, six ultrasound-guided PCC procedures were performed to five jaundiced infants (4 females and 1 male; mean age: 60 days old) for whom possibility of biliary atresia could not be ruled out by the DISIDA scan as the cause of their neonatal jaundice. Gallbladder puncture was performed under ultrasound guidance with a 23-gauge needle. Contrast material injection during fluoroscopic examination was performed after dilatation of the gallbladder lumen with normal saline under ultrasound guidance. The criteria used for excluding biliary atresia were complete visualization of the extrahepatic biliary trees and/or contrast excretion into the duodenum. The complications and final diagnosis was assessed according to the clinical and laboratory findings. Results: The procedures were successful in all the patients without any complication. Biliary atresia could be ruled out in all the patients. The final diagnosis was neonatal cytomegalovirus hepatitis in two patients, total parenteral nutrition-associated cholestasis in two patients, and combined cytomegalovirus hepatitis and total parenteral nutrition-associated cholestasis in one patient. Conclusion: Ultrasound-guided PCC is a feasible and effective method for the early definitive exclusion of biliary atresia as the cause of neonatal jaundice. By the technique of injecting normal saline before contrast injection, PCC can be done even in a totally collapsed or very small gallbladder.

Comparison of total parenteral nutrition-associated cholestasis according to amino acid mixtures in very low birth weight infants

Purpose:The purpose of this study was to evaluate the effect of amino acid mixtures on incidence and severity of total parenteral nutrition associated-cholestasis(PNAC) in very low birth weight infants. Methods:Retrospective review of 63 very low birth weight infants(birth weight ≤1,500 g) who received total parenteral nutrition(TPN) in our neonatal intensive care unit from January 2000 to December 2004 was performed. Patients were divided into 2 groups:Group I(n=32, Jan 2000-Jun 2002) and Group II(n=31, Jul 2002-Dec 2004), where infants in Group II received taurine and glutamic acid-rich amino acid mixtures. PNAC was defined as serum direct bilirubin(DB) level greater than 2.0 mg/dL. The incidence and severity of PNAC were compared between these groups. Results:The incidence of PNAC was significantly lower in Group II than in Group I(21.9% vs 6.5%, P

Taurine and cholestasis associated to TPN. Experimental study in rabbit model

Taurine seems to be essential in the newborn for bile acid (BA) tauroconjugation, and its deficiency has been implicated in total parenteral nutrition-associated cholestasis (TPN-AC). Our purpose was to study the relationship between taurine (Ta) and TPN-AC in rabbits, which have a similar biliary metabolism to that of humans. We used 40 young rabbits, fed for 10 days according to the following four groups: GA [10] given TPN, with amino acid solution (AA) but without taurine (Ta) or its AA-precursors (methionine, cysteine, and serine); GB [10] the same but only without taurine; GC [10] the same but with taurine and its precursors; and GD [10] the control group with oral nutrition and saline infusion. Complete blood and bile analytical data were obtained and analyzed, including plasma AA and BA. Liver samples were studied under optical and electron microscopy. Serum: In GC there was a 20% increase in the AA-precursors, but paradoxically it was greater in GA. Bile: In GC there was 30% more excretion of total and free BA compared with less than 20% in GA and GB. Regarding toxic BA, there was a 15% decline in GLC3S excretion, but more than 20% in LCA excretion, than in GA and GB. Moreover, in GC the glyco-/tauro-conjugate ratio was worse than in the other groups. Histomorphology: While in GA and GB liver steatosis was diffuse (microsteatohepatitis type), in GC there was macrosteatosis with mitochondria-surrounded lipid droplets. In GA and GB, the canaliculi appeared dilated, with abundant bile plugs and loss of microvilli. There are signs that taurine may protect against TPN-AC. The mechanism does not seem to be BA tauroconjugation, but probably taurine's antioxidant, membrane stabilization (with Ca2+ and HCO3-), and/or osmotic effects.

Total Parenteral Nutrition-associated Cholestasis: Prematurity or Amino Acids?

Total Parenteral Nutrition-associated Cholestasis: Prematurity or Amino Acids?

Effect of intravenous lipid emulsions on hepatic cholesterol metabolism.

Total parenteral nutrition offers the chance of survival to children who have had extensive gut resections or gut failure. However, in infants it is often associated with serious complications including cholestatic liver disease. The causes of these complications remain unclear, although it has been suggested that the lipid emulsions used in total parenteral nutrition may be responsible. An in vitro system was developed to study the effect of lipid emulsions on hepatic cholesterol metabolism using cultured hepatocytes. Incubations of Hep G2 cells with medium containing Intralipid (Pharmacia and Upjohn, Milton Keynes, UK) demonstrated that the fat emulsion mediated a powerful dose-dependent but reversible inhibition of cholesterol uptake. In addition Intralipid was shown to stimulate the efflux of cholesterol from Hep G2 cells. The component or components of the Intralipid responsible for these effects and the mechanism by which they act remain to be established. Intravenous lipid emulsions may interfere with hepatic cholesterol metabolism in vivo. This may have implications for the development of total parenteral nutrition-associated cholestasis in neonates.

New approaches to understanding the etiology and treatment of total parenteral nutrition-associated cholestasis.

Total parenteral nutrition-associated cholestasis (TPN-AC) may be a fatal disease. The only known effective treatment is to discontinue TPN and institute full enteral feedings. However, this is not possible for many patients with severe gastrointestinal failure. Current research supports two theories regarding the etiology of TPN-AC. One proposes that the enteral fast disrupts the enterohepatic circulation. Cholestasis, in this hypothesis, results from a combination of altered gut hormone production and endotoxins produced by bacterial translocation. The second theory implicates the direct toxicity of TPN solution. Amino acid solutions and plant sterols in intralipid have generated much interest. Ursodeoxycholic acid and S-adenosyl-L-methionine are promising treatments for TPN-AC. They have been proven to be effective in animals and adult liver diseases. Cholecystokinin also has been investigated as a possible prophylactic agent. However, results from these experiments do not conclusively show a beneficial effect.

Nutritional support of the pediatric surgical patient.

This review discusses the important developments in pediatric surgical nutrition over the past year. Sepsis and total parenteral nutrition-associated cholestasis remain complex problems for patients on total parenteral nutrition. Investigations suggest that total parenteral nutrition may compromise bactericidal activity, increasing the risk of sepsis. Sepsis possibly sensitizes the liver to cholestatic injury. Small volume enteral feeds may restore immune system function. Current research does not support an association between phytosterols in parenteral lipid solutions and total parenteral nutrition-associated cholestasis. Methionine has been identified as a potential hepatotoxin. Ursodeoxycholic acid and S-adenosyl-L-methionine are the most promising treatments of total parenteral nutrition-associated cholestasis. Small bowel transplant is now a reasonable option for patients with irreversible intestinal failure. Patient and graft survival rates have improved with FK-506 (Tacrolimus) immunosuppression. Isolated intestinal grafts have the best survival rate (92% at 1 year). Most surviving graft recipients are weaned off of total parenteral nutrition. The Cox Proportional Hazard model may help to identify candidates for small bowel transplant. This equation predicts the duration of dependence on total parenteral nutrition. Patients with irreversible intestinal failure can then be referred for early small bowel transplantation.

Necrotizing enterocolitis and total parenteral nutrition-associated cholestasis

The proportion of patients with total parenteral nutrition (TPN)-associated cholestasis (TPN-AC) who have necrotizing enterocolitis (NEC) has increased markedly in the past ten years. Little is known about how these diseases affect each other. We retrospectively studied 24 patients with NEC and bowel necrosis or perforation who required surgical intervention. Patients were divided into two groups: those who had received TPN (NEC /s+ TPN, n = 17) and those who had not (NEC, n = 7). As cholestasis was present clinically, or prolonged TPN was anticipated, liver biopsy was done. Bile acid levels were measured in both serum and bile in 13 patients. Six patients, who underwent bowel resection and enterostomy, had a second liver biopsy and measurement of bile acid levels at stoma closure. Our results showed that in 13 patients for whom bile acid levels were measured (NEC /s+ TPN, n = 6) (NEC, n = 7), serum bile acid level was significantly elevated in both groups over normal for age. Biliary bile acid levels were correspondingly depressed in both groups suggesting a failure of bile acid transport. All patients had abnormal liver histology, but the pattern of injury differed between the two groups. Those in the NEC group had biliary statis and mild hepatocyte degeneration. In contrast, 15 of 17 in the NEC /s+ TPN group had advanced injury specific for TPN-AC. All six patients managed on TPN and partial enteral feeding before a second biopsy had no change in bile acid levels and progression of histologic injury. We conclude that NEC alone can cause functional cholestasis and histologic liver injury but does not cause the specific progressive damage caused by TPN. NEC may make the liver more susceptible to the effects of TPN. Partial enteral feeding does not halt or reverse this injury.

Parenteral nutrition related cholestasis: infection as the main risk factor

Total parenteral nutrition-associated cholestasis (TPN-AC) is a clinical problem of special interest in neonates and in other age groups. This retrospective cohort study attempted to determine the incidence and the appearing time of cholestasis in Intensive Care Unit (ICU) patients beyond neonatal period, submitted to total parenteral nutrition (TPN) for more than five consecutive days, focusing on the relation of TPN-AC and severe infection. Data on one hundred and thirteen patients, aged from one month to 14 years, collected over a period of ten years, were analyzed. All patients, followed up to the TPN stop or their death, were classified in two groups: with and without cholestasis. They were evaluated in relation to cholestasis potential risk factors, such as severe infection. Cholestasis was identified by a conjugated bilirubin (DB) and total bilirubin rate equal or superior to 40% and/or a DB equal or superior to 0.5 mg/dl during the TPN laboratory monitoring. Logistic regression analysis was used to control and to adjust for the cholestasis confusion factors. The incidence of cholestasis was 18%, but it was very important in patients younger than 6 months (26% vs 12%) (p=0.06), in patients that use TPN for more than 2 weeks (25% vs 8%) (p=0.01), as well as in patients with severe infection (24% vs 3%) (p=0.02). On the average cholestasis appeared 17.6 days after TPN inception, with a range of 5 to 35 days. Control of the simultaneous effect of age, TPN duration, and severe infection has shown that in patients with less than 6 months the relative risk was 2.6 (NS); in patients with TPN longer than 2 weeks it was 3.1 (p=0.02); and in patients with severe infection it was 7.4 (p=0.006). The results suggest that TPN-AC in children beyond neonatal period is a relatively frequent event (18%), and severe infection is the most important risk factor for cholestasis.

Total parenteral nutrition-associated cholestasis in surgical neonates may be reversed by intravenous cholecystokinin: A preliminary report

Neonatal infants who require total parenteral nutrition (TPN) after major operations are susceptible to total parenteral nutrition-associated cholestasis (TPNAC). A therapeutic dilemma ensues if cholestasis does not resolve after the institution of full enteral nutrition. The authors report the reversal of TPN-associated cholestasis by intravenous cholecystokinin in eight infants who had undergone major surgery during the neonatal period. The indications for surgery were necrotizing enterocolitis in three patients, midgut volvulus in one, gastroschisis in one, diaphragmatic hernia in one, necrosis of the stomach in one, and cardiac anomaly in one. Four of the infants were premature. Median duration of TPN was 25 days (range, 20 to 150 days). Seven patients were weaned from TPN before treatment with cholecystokinin was instituted. Mean duration of pretreatment full enteral nutrition in these seven patients was 35 days (range, 20 to 55 days). One girl with a short gut syndrome tolerated only 10% of her caloric needs via the enteral route. All patients had acholic stools, conjugated hyperbilirubinemia, no excretion of Technetium-labeled HIDA to the biliary tree or duodenum (six patients), and significantly elevated liver enzyme values. In three patients, echography showed biliary sludge or stones in the gallbladder. Porcine cholecystokinin (2 IDU/kg) was administered intravenously for 3 to 5 days. If the stool color did not normalize, cholecystokinin injections were repeated using a larger dose (4 IDU/kg). In seven patients, including the girl with short gut syndrome, the clinical jaundice and conjugated hyperbilirubinemia completely resolved within 1 to 6 weeks. No biliary sludge or stones were seen in the posttreatment echography in any of the patients. HIDA-biligraphy, which was performed 1 to 3 months after the treatment in seven patients, showed normal excretion of the marker to the duodenum in all cases. One patient did not respond to repeated administration of cholecystokinin and underwent operative irrigation of the biliary tree. This preliminary study suggests that TPN-associated cholestasis in neonatal infants who have undergone gastrointestinal operations may be reversed by intravenous cholecystokinin in the majority of patients.

Total parenteral nutrition-associated cholestasis: Clinical and histopathologic correlation

Cholestatic jaundice is the major complication of total parenteral nutrition (TPN) in infants and children. The pathogenesis of this syndrome is poorly understood. The aims of this study were: (1) to define the histologic liver injury in relation to the clinical course of infants on TPN and (2) to determine whether enteral feeding will reverse or halt these changes. We identified 31 infants treated for severe gastrointestinal disease for whom liver histology was available from 1987 to 1991. Clinical records and liver biopsy (23) or autopsy specimens (13) were reviewed. Five patients had biopsies at two subsequent operations. The clinical diagnosis was necrotizing enterocolitis (24), atresia or stenosis (3), midgut volvulus (2), Hirschsprung's disease (1), and sepsis (1). Twenty-one of 31 infants were premature and had a mean birth weight of 1,868 g. Twenty-five of 31 were on TPN and 28 of 31 had received some enteral feeding by the time of the biopsy. Enteral feeding was begun as early as possible in all infants even if continued TPN was necessary for full support. Cholestasis occurred in 71% of premature infants versus 22% of full-term babies. Infants with cholestasis had been on TPN for a longer time (37 days v 18) with a correspondingly shorter period of enteral feeding (17 days v 27). Mean total bilirubin level was 14 in patients with cholestasis and 5 in those without, but the bilirubin level did not correlate with the extent of histological injury and was frequently normal despite marked histological damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Total parenteral nutrition-associated cholestasis after selective damage to acinar zone 3 hepatocytes by bromobenzene in the rat

Total parenteral nutrition is known to cause cholestasis, but the hepatic site of this effect has not been determined. The purpose of our study was to observe the effect of TPN on bile flow and bile salt secretion rate in rats after selective damage to acinar zone 3. Bromobenzene, 3.8 mmol/kg, was injected i.p., and the animals were studied 48 hours later. Experimental groups received either parenteral nutrition or saline for 2 hours. Bromobenzene caused selective damage to acinar zone 3 hepatocytes, and reduced baseline bile flow (23.99±1.09 vs 37.2±1.66, mean±SEM, μl/min/kg, p<0.001). Bromobenzene had no effect on bile salt secretion rate. Total parenteral nutrition decreased bile flow in the bromobenzene treated groups, despite the selective hepatic damage to acinar zone 3 (20.54±1.07 vs 23.28±1.63, mean±SEM, p <0.001). Total parenteral nutrition reduced bile salt secretion rate in healthy animals, but this reduction was not seen in bromobenzene treated rats. Our results suggest that bile flow reduction in response to total parenteral nutrition is mediated through an effect on acinar zones 1 and 2, as this reduction is still observed after zone 3 destruction by bromobenzene. Zone 3 hepatocytes may be involved in the effect of parenteral nutrition on bile salt secretion, as the reduction in secretion rate seen in healthy animals was not observed in bromobenzene treated rats.

Relationship between serum albumin and parenteral nutrition-associated cholestasis.

In a prospective study of 59 patients receiving total parenteral nutrition we found that patients with low serum albumin were more likely to develop cholestasis than patients with normal serum albumin. Only 25% of patients with a normal serum albumin developed cholestasis. Seventy-nine percent of patients with low serum albumin (less than 3.5 g/dl) developed cholestasis (p less than 0.01). In those patients who developed cholestasis, there was a significant correlation (r = 0.63, p less than 0.01) between the serum albumin and the number of days after onset of total parenteral nutrition when cholestasis appeared. The role of hypoalbuminemia in the development of total parenteral nutrition-associated cholestasis deserves further study.