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American Journal of Clinical Nutrition, Vol. 70, No. 1, 70-77, July 1999
© 1999 American Society for Clinical Nutrition

Original Research Communications

Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations1,2,3

J Marleen L de Vree, Johannes A Romijn, Kam S Mok, Lisbeth MH Mathus-Vliegen, Chris P Stoutenbeek, J Donald Ostrow, Guido NJ Tytgat, Hans P Sauerwein, Ronald PJ Oude Elferink and Albert K Groen

1 From the Departments of Gastroenterology and Liver Diseases, Endocrinology and Metabolism, and Intensive Care, Academic Medical Center, University of Amsterdam.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Food in the intestine drives the enterohepatic circulation of bile components.

Objective: We investigated whether parenteral or enteral delivery of nutrients alters serum and biliary lipids in critically ill patients.

Design: Eight intensive care unit (ICU) patients who had received >= 5 d of total parenteral nutrition (TPN) were compared with 8 ICU patients who had fasted for >=5 d. Both groups were studied before and after 5 d of enteral nutrition (EN). Each patient served as his or her own control. Duodenal bile was analyzed for biliary lipid content and serum lipids were determined simultaneously. Duodenal bile samples from 18 healthy persons served as controls.

Results: Bile salt concentrations in all ICU patients were 17% of control values before EN (P < 0.005) and 34% of control values after 5 d of EN (P < 0.005). Phospholipid concentrations were 12% of control before EN (P < 0.0005) but increased almost 4-fold after EN (P < 0.0005). Biliary cholesterol concentrations were 20% of control values before EN (P < 0.001) and did not improve afterward. No difference in bile composition was observed between fasted ICU patients and those who received TPN. The inverse correlation between the severity of illness and biliary lipid concentrations observed before EN disappeared with enteric stimulation. The low serum concentrations of HDL cholesterol and apolipoprotein A-I increased significantly with EN in all ICU patients.

Conclusion: Lack of EN during critical illness was associated with profound decrements in biliary lipid concentrations that normalized partially after 5 d of EN. We hypothesize that loss of enteric stimulation in ICU patients impairs hepatic lipid metabolism.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The liver and the intestine both play key roles in the regulation of cholesterol metabolism. Newly synthesized cholesterol in the liver can be secreted into the circulatory system in the form of lipoproteins and into the intestine as biliary cholesterol and bile salts. Within the intestine, biliary cholesterol accounts for two-thirds of the cholesterol absorbed daily, the remainder being dietary cholesterol. Other bile components such as bile salts are also reabsorbed after secretion into the intestine by an active transport mechanism in the terminal ileum. Only a small amount of cholesterol is lost daily by fecal disposal of bile salts or by epithelial sloughing. The liver replaces this loss of lipids by de novo synthesis of cholesterol (1–4). The cycling of cholesterol and bile salts between the intestine and the hepatobiliary system is a continuous process mediated mainly by the presence of food in the intestine (5). Absence of intraluminal nutrients leads to an interruption of this enterohepatic circulation and may affect hepatic cholesterol metabolism (6–8). In addition to alterations in biliary lipid metabolism, changes in serum cholesterol and lipoprotein turnover may occur (4).

The effect of enteral fasting on biliary lipid metabolism during total parenteral nutrition (TPN) has been investigated in several animal studies (9–12). TPN impaired bile flow and altered bile composition in rats, rabbits, and newborn piglets. Reduced concentrations of all bile constituents were observed and the composition of bile was also changed; phospholipid and cholesterol secretion were relatively more impaired than was bile salt secretion (11). In a model of TPN-induced cholestasis in newborn piglets, TPN produced a state of functional cholestasis that extended into the period after TPN feeding in the animals (10). These observations indicate that interruption of enterohepatic circulation during administration of TPN affects biliary lipid secretion. The effect of TPN on serum cholesterol and lipoprotein concentrations was not analyzed in those studies.

Many patients admitted to an intensive care unit (ICU) are initially starved or given TPN. The interruption of enterohepatic circulation in these patients may alter serum cholesterol and biliary lipid composition. During critical illness, plasma concentrations of cholesterol and lipoproteins are extremely low (13, 14). In addition to lack of enteral nutrition, many factors may operate simultaneously in these critically ill patients: eg, infection, administration of antibiotics, bacterial overgrowth in the intestine, and the development of multiple organ failure (MOF).

We hypothesized that lack of enteral nutrition is an important factor in the alterations in hepatic cholesterol metabolism during critical illness. We therefore compared the effect of a 5-d period of enteric starvation on serum and biliary lipid concentrations in critically ill patients with or without TPN. Subsequently, the effect of a 5-d period of enteral nutrition on biliary and serum lipid concentrations was investigated in the same patients.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This study was approved by the ethical committees of the Academic Medical Center of the University of Amsterdam. After informed consent was obtained from the patients or their closest relatives, patients admitted to our ICU were included in the study. Each patient, in the TPN-fed state or nonfed state for >=5 d, was included in the study the moment enteral nutrition was started via a jejunal feeding tube. The jejunal feeding tube was placed only for the following medical indications: severe gastrointestinal retention, gastroesophageal reflux, or the risk of aspiration pneumonia. Exclusion criteria were acute hepatocellular diseases, cholelithiasis, previous cholecystectomy, administration of hepatotoxic drugs, acute pancreatitis, and age <18 y. Data were collected according to a standardized protocol and included age, sex, the reason for admission to the ICU, the medical indication for placement of the jejunal feeding tube, patient history, and use of medication.

Respiratory, cardiovascular, renal, hepatic, hematologic, and neurologic function were evaluated by the scoring system of Marshall et al (15) at the beginning and end of the study. This MOF score has a maximum of 24 points and gives an impression of the degree of illness in ICU patients. Over 1 y, 20 patients were initially included in the study, of whom 4 were excluded: 2 died, 1 was switched to oral nutrition within 5 d and discharged from the ICU, and 1 patient did not discharge bile into the duodenum after cholecystokinin administration. Data analysis was performed on the results from the remaining 16 patients.

Study design
ICU patients were initially given TPN for >=5 d (TPN-fed; n = 8) or received no nutrition at all other than 5% intravenous glucose (nonfed; n = 8). The TPN-fed patients received 1 L of TPN solution, which contained 70 g amino acids and 240 g glucose per liter, plus minerals, trace elements, and vitamins (Nutriflex; Vifor, Switzerland). In addition, 500 mL lipids (20%, Intralipid; Pharmacia, Woerden, Netherlands) was given every 24 h. All patients were entered into the study just before the initiation of enteral nutrition via a jejunal feeding tube, placed endoscopically. TPN administration was stopped the same day at midnight. Enteral nutrition was started after bile and serum sampling the next morning at 0700. In this way, samples were taken from patients in the postabsorptive state. Enteral nutrition started at a rate of 20 mL/h and was increased by increments of 20 mL/12 h to 80 mL/h within 48 h. Each liter of enteral nutrition contained 40 g amino acids, 123 g glucose, and 39 g fat (Nutrison; Nutricia, Zoetermeer, Netherlands) together with minerals, trace elements, and vitamins. On the fifth day, enteral nutrition was interrupted at midnight and restarted after the second bile sampling at 0700 the next morning. According to this study design, each patient was sampled 2 times, before and after enteral nutrition, and served as his or her own control. Duodenal bile, collected from 18 healthy persons after they fasted overnight, served as control samples (10 men and 8 women with a mean age of 39 y).

Serum and bile sampling
Blood samples were obtained via intraarterial tubes before and after 5 d of enteral nutrition, just before each bile sampling. A double-lumen jejunal feeding tube was specially designed for this study. Two tubes were glued together at a distance such that, with proper positioning, the distal tube (length: 125 cm) was placed beyond the ligament of Treitz for enteral feeding and the proximal tube (length: 100 cm) was placed at the papilla of Vater for bile sampling. The position of the feeding tube was confirmed by X-ray the first day and again after 5 d, before bile sampling. Gallbladder contraction was induced by intravenous injection of cholecystokinin (0.05 µg/kg, Takus; Pharmacia), after which duodenal bile was aspirated. The bile was collected on ice for >1 h in fractions of 10 min each. In each fraction, the pH was determined and lipids were removed from 1 mL bile immediately at the ICU in 3 mL chloroform-methanol (1:3). The bile fraction containing the highest concentration of bile salts was used for lipid analysis. The remaining bile from each fraction was stored at -20°C.

Serum and bile analysis
Serum liver enzyme activities (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and {gamma}-glutamyl- transferase) and total bilirubin and serum lipids (total cholesterol, triacylglycerol, HDL, LDL, and apolipoproteins A-I and B) were determined by routine laboratory tests. Total bile volume and concentrations of bile salts, phospholipids, cholesterol, and total phosphate were measured by using standard procedures (16–18). Bile salt species were analyzed by HPLC as described by Ruben and van Berge-Henegouwen (19) and modified as follows: samples were diluted 1:200 in eluent (60% methanol, 3 mmol K2HPO4/L, pH 3.75) and 20 µL of this sample was injected into the HPLC column (C18 Chromspher, 5 µm; Chrompack with a flow of 800 µL/min; Chrompack, Middelburg, Netherlands). Peaks were quantitated by using an ultraviolet detector set at 205 nm. Cholesterol saturation indexes were calculated according to Carey's critical tables (20) by assuming a total lipid content of 100 g/L.

Statistical analysis
Data are given as means ± SEs. Statistical comparisons between the groups were performed with an unpaired, nonparametric Mann-Whitney two-sample test. A paired, nonparametric Mann-Whitney test was used within each group. Linear regression analysis was performed by using SLIDE WRITE 3.0 for WINDOWS (Advanced Graphics Software, Carlsbad, CA). P < 0.05 was considered to represent statistical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical characteristics
The clinical characteristics of the 16 study patients are given in Table 1Go. Patients in the TPN-fed and the nonfed groups did not differ significantly in age, weight, or sex. Despite the different diagnoses and the various clinical conditions of the individual patients, the MOF scores (15) revealed that there was no difference in the degree of illness between the 2 groups before enteral nutrition at entry into the study. The clinical condition of most patients (13 of 16) improved during their stay at the ICU (mean MOF score improved from 14 to 9), although there was variation between and within the 2 groups. The initially nonfed group tended to improve less (MOF score from 13 to 10) than the TPN-fed group (from 14 to 7), although this difference was not significant.


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  		TABLE 1. Clinical characteristics of the intensive care unit patients1,
 
Serum analyses
Because the serum biochemistry of the TPN-fed and the nonfed groups was not different before and after enteral nutrition, mean (±SE) values of all ICU patients are given together in Table 2Go. Alanine aminotransferase and aspartate aminotransferase activities were not elevated during the stay at the ICU. Serum alkaline phosphatase, {gamma}-glutamyltransferase, bile salts, and total bilirubin concentrations were slightly elevated compared with the reference values of our laboratory. There was not a significant influence of enteral nutrition on any of these values.


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  		TABLE 2. Serum liver enzyme activities of intensive care unit patients before and after 5 d of enteral nutrition1,
 
Serum lipids
The mean serum lipid values of all ICU patients before and after enteral nutrition are shown in Table 3Go. Before enteral nutrition was started, serum total cholesterol, LDL-cholesterol, HDL-cholesterol, and apolipoprotein B concentrations were all below the normal reference range of our laboratory. Apolipoprotein A-I was close to the normal range and serum triacylglycerol was normal. With enteral nutrition, HDL-cholesterol and apolipoprotein A-I concentrations increased significantly (P < 0.02) but serum total cholesterol, LDL cholesterol, apolipoprotein B, and serum triacylglycerol were unaffected.


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  		TABLE 3. Serum lipid concentrations of intensive care unit patients before and after 5 d of enteral nutrition1,
 
Bile analyses
The total bile volume that was collected after cholecystokinin stimulation was 32 ± 8 mL before the start of enteral nutrition and increased to 56 ± 8 mL after 5 d of enteral nutrition. In Figure 1Go (A–C), the bile constituents are given for each ICU patient before and after 5 d of enteral nutrition. There were no significant differences in bile salt (5.79 ± 1.74 compared with 7.71 ± 3.09 mmol/L), phospholipid (0.73 ± 0.30 compared with 1.22 ± 0.39 mmol/L), or cholesterol (0.64 ± 0.26 compared with 0.74 ± 0.23 mmol/L) concentrations in the TPN-fed compared with the nonfed patients before the initiation of enteral nutrition. This did not change with enteral nutrition, although the TPN-fed group had a smaller increase in bile salt concentrations than did the nonfed group (8.83 ± 1.60 compared with 13.71 ± 2.65 mmol/L; NS). Therefore, we combined the data of the 2 groups and compared these with the bile analyses of the 18 healthy control subjects.



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  		FIGURE 1. Duodenal bile composition in intensive care (ICU) patients before and after 5 d of enteral nutrition. A–C: data for individual patients; {square}, ICU patients fed total parenteral nutrition (TPN) (n = 8); {blacksquare}, nonfed ICU patients (n = 8). Mean (±SD) bile salt and phospholipid, but not cholesterol concentrations, increased significantly with enteral nutrition, *P < 0.005, **P < 0.001. D–F: because there was no difference between TPN-fed and nonfed patients, the 2 groups were combined (n = 16) and compared with control subjects (n = 18); {square}, control subjects; {blacksquare}, ICU patients before enteral nutrition; {blacksquare}, ICU patients after enteral nutrition. Bile salts were 83% lower, phospholipids were 88% lower, and cholesterol was 80% lower in ICU patients before enteral nutrition, *P < 0.005.

 
In Figure 1Go (D–F), the concentrations of all biliary lipids in ICU patients were markedly reduced before enteral nutrition compared with control subjects (P < 0.005). Mean bile salt concentrations were 17% of control values before enteral nutrition but more than doubled after 5 d of enteral nutrition (P < 0.005), although they were still <40% of control values. Biliary phospholipid concentrations were initially only 12% of control values but more than tripled after enteral nutrition to 40% of control values (P < 0.005). Breakdown of phospholipids by pancreatic enzymes was minimal because phospholipid concentrations in bile did not differ substantially from total phosphate concentrations. In all ICU patients, biliary cholesterol concentrations were only 20% of control values before enteral nutrition and did not improve significantly afterward.

The total lipid content of bile (combined group of 16 ICU patients) was 4.3 ± 1.0 g/L before enteral nutrition was initiated (Table 4Go). A slight but significant increase in total lipid content was observed with 5 d of enteral nutrition (9.6 ± 1.9 g/L; P = 0.04). Because total lipid content of all bile samples was <2 g/dL (20 g/L) on Carey's critical tables, cholesterol saturation indexes (CSIs) were calculated by assuming a total lipid content of 100 g/L. The elevated CSI in bile (2.18 ± 0.27) normalized with enteral nutrition (1.02 ± 0.07; P = 0.001).


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  		TABLE 4. Cholesterol saturation indexes (CSIs) and total lipids measured in bile of intensive care unit patients before and after 5 d of enteral nutrition1,
 
We investigated whether changes in biliary lipid concentrations in ICU patients could be related to the degree of critical illness in each patient measured by the MOF score. Before enteral nutrition was initiated (in the nonfed or TPN-fed state), critical illness correlated inversely with biliary bile salt concentrations (Figure 2AGo). When illness worsened, bile salt concentrations decreased (regression coefficient of 0.82, P < 0.05). This correlation with illness remained when the data point for an outlier patient was removed from the figure. After 5 d of enteral nutrition, there was no longer a correlation between degree of critical illness and biliary bile salt concentrations (Figure 2BGo).



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  		FIGURE 2. The relation between the severity of illness and biliary bile salt concentrations before (A) and after (B) 5 d of enteral nutrition in intensive care (ICU) patients. The severity of illness was rated with a multiple organ failure (MOF) score (15) based on the function of 6 vital organ systems with a maximum of 24 points. Abscissa values [{square}, patients fed total parenteral nutrition (TPN); {diamondsuit}, nonfed patients] represent the individual total MOF scores of the ICU patients (n = 16). As critical illness worsened before enteric stimulation, biliary bile salt concentrations rapidly declined (A). This correlation disappeared after 5 d of enteral nutrition (B).

 
Phospholipid and cholesterol inactivate the detergent action of bile salts and thereby protect the biliary epithelium (4, 5). An increase in the ratio of bile salts to phospholipids (BS:PL) may therefore lead to hepatobiliary disorders. Before the start of enteral nutrition, the mean BS:PL was considerably elevated in ICU patients compared with that in control subjects (16.3 ± 6.5 compared with 5.0 ± 3.6; P < 0.05) (Figure 3Go), but normalized to control values after 5 d of enteral nutrition (5.7 ± 0.8). The types of bile salts were also analyzed for a change in bile salt composition. There were no significant alterations in bile salt composition, nor in the ratio of glycine to taurine conjugates, before or after enteral nutrition. The reduction in biliary bile salt concentrations was associated with an increase in fasting serum bile salt concentrations, which are normally <5 µmol/L (Figure 4Go).



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  		FIGURE 3. The cytotoxicity of bile, as measured by the ratio of bile salt to phospholipid (BS:PL), before and after 5 d of enteral nutrition in intensive care (ICU) patients. The higher the ratio, the more cytotoxic is the bile. {square}, control subjects; {blacksquare}, ICU patients before enteral nutrition; {blacksquare}, ICU patients after enteral nutrition. Before the start of enteral nutrition, ICU patients (n = 16) had elevated BS:PL compared with control subjects (n = 18). *Significantly different from control subjects and values in ICU patients before enteral nutrition, P < 0.05.

 


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  		FIGURE 4. Bile salt concentrations in bile of intensive care patients (n = 16) versus bile salt concentrations in serum. {blacktriangledown}, before enteral nutrition; {triangleup}, after 5 d of enteral nutrition. Serum values decreased as biliary bile salts increased.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first study in humans to investigate the role of nutrition in biliary and serum lipid composition during critical illness. Our study generated the following conclusions: 1) Compared with control subjects, critically ill patients had profound decrements in biliary lipid concentrations and reduced serum lipid concentrations. 2) These reduced lipid values in serum and bile were not prevented by the administration of TPN. 3) Five days of enteral nutrition partially restored biliary lipid concentrations, irrespective of the clinical condition of the ICU patient.

Before the start of enteral nutrition, biliary bile salt and cholesterol contents were markedly reduced. Serum lipids, except triacylglycerol, were also considerably depressed. Two factors seem to be associated with the observed alterations: the severity of illness and the lack of enteral nutrition. Before the initiation of enteral nutrition, critical illness negatively affected biliary lipid concentrations and bile salt concentrations in bile were negatively correlated with the MOF scores. Despite the range in severity of illness and divergent underlying pathophysiologic conditions, similar alterations in biliary and serum lipids were observed in the ICU patients. Restoration of enteric stimulation with 5 d of enteral nutrition improved biliary lipid concentrations in most patients. Even patients with unchanged status or deteriorating MOF status showed improved biliary lipid concentrations after enteral nutrition. This emphasizes the importance of enteric stimulation during critical illness.

Biliary secretion studies are extremely difficult to perform in ICU patients, so we had to use biliary lipid concentrations as an index of biliary lipid output. Measurements of these biliary lipid concentrations could have been influenced by absorption of water or bile constituents in the gallbladder (21–23), impaired gallbladder emptying, or dilution in the duodenum. Despite these limitations, similar changes in biliary lipid concentrations were observed in the bile of ICU patients before and after 5 d of enteral nutrition.

An explanation for the marked decreases in biliary lipid concentrations in our ICU patients could be that development of MOF during critical illness down-regulates synthesis and secretion of bile salts (24–26). The rate-controlling enzyme in bile salt synthesis, cholesterol 7{alpha}-hydroxylase, is down-regulated by several inflammatory mediators (24). The low cholesterol concentrations in both serum and bile are compatible with a decrease in hepatic synthesis. Hepatocyte sinusoidal bile salt transporters are also down-regulated during sepsis (25, 26). Another mechanism for altered bile composition could be that the interruption of the enterohepatic circulation in these ICU patients results in decreased release of gastrointestinal hormones such as secretin and cholecystokinin. Less cholecystokinin stimulation would lead to diminished gallbladder emptying, sludge formation, or sluggish intestinal motility (27–29). Diminished circulation of bile salts from the gut to the liver would decrease the total pool of bile salts normally secreted into bile. Surprisingly, there was no difference in bile salt composition (various species and conjugates) in these ICU patients with enteral nutrition. The continuous use of broad-spectrum antibiotics in ICU patients may explain this observation.

Before the start of enteral nutrition, reduced amounts of all bile constituents was observed, with a more prominent decrease in phospholipids than in bile salts. Similar changes in bile composition due to lack of enteral nutrition, like during TPN administration, were also observed in several animal studies (10, 11). Molecular evidence for diminished phospholipid transport into bile after 7 d of TPN administration was provided by a 50% reduction in expression of the phospholipid transporter (30, 31). No signs of liver pathology could be detected, however, after this short period of TPN (31). It was postulated in that study that the observed decline in expression of the phospholipid transporter might be an early event in the eventual development of TPN-associated hepatobiliary disorders. In our ICU patients, a similar decline in phospholipid concentration in bile was measured after the relatively short period of 5 d of TPN. The BS:PL more than tripled before enteral nutrition. A relatively short period of 5 d of enteral nutrition normalized the BS:PL again, implying that enteric stimulation also normalizes the relative composition of bile. However, total biliary lipid concentrations remained low. We hypothesize that longer administration of enteral nutrition would have fully normalized biliary lipid output.

The reduced serum total cholesterol and HDL-cholesterol concentrations we found agree with earlier reports of hypolipidemia during critical illness (30, 31). The simultaneous decreases in biliary cholesterol and phospholipid concentrations during our study shed new light on this phenomenon. HDL plays an important role in controlling serum and biliary phospholipid and cholesterol concentrations (32–34). Phospholipids and cholesterol transported by HDL to the liver are mainly secreted into bile (33, 34). Low HDL-cholesterol concentrations observed in the serum of our ICU patients could result in reduced transfer of phospholipids and cholesterol back to the liver and subsequently less secretion into bile. Conversely, the low HDL values in serum might be a consequence of decreased uptake of cholesterol and phospholipids in the intestine due to impaired biliary secretion of cholesterol and phospholipids. The nature of the disturbed relation between the enterohepatic circulation of biliary lipid constituents and serum HDL needs to be clarified in ICU patients.

In conclusion, we investigated biliary and serum lipid composition during critical illness and determined the effects of different nutrition strategies on these variables. Lack of enteral nutrition, irrespective of prior TPN, contributed to markedly reduced concentrations of bile salts, cholesterol, and especially phospholipids in bile, and to hypolipidemia. These effects occurred rapidly and were partially restored after 5 d of enteral nutrition. We hypothesize that loss of enteric stimulation is a major contributing factor in the observed alterations in hepatic lipid metabolism in ICU patients.


   ACKNOWLEDGMENTS
 
We thank all the physicians and nurses of the Department of Gastro-enterology and the Intensive Care Unit for their assistance with this study.


   FOOTNOTES
 
2 Supported by the Dutch Organization for Scientific Research, project no. 902-23-097.

3 Address reprint requests to JML de Vree, Department of Gastrointestinal and Liver Diseases, Academic Medical Center C2-111, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands. E-mail: j.m.devree{at}amc.uva.nl.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 12, 1998. Accepted for publication January 6, 1999.




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