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Am J Physiol Gastrointest Liver Physiol 293: G956-G962, 2007. First published August 23, 2007; doi:10.1152/ajpgi.00366.2006
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LIVER AND BILIARY TRACT

Effect of major liver resection on hepatic ureagenesis in humans

Marcel C. G. van de Poll,1 Stephen J. Wigmore,2 Doris N. Redhead,3 Regina G. H. Beets-Tan,4 O. James Garden,2 Jan Willem M. Greve,1 Peter B. Soeters,1 Nicolaas E. P. Deutz,1 Kenneth C. H. Fearon,2 and Cornelis H. C. Dejong1

Departments of 1Surgery, Nutrition, and Toxicology and 4Radiology, Research Institute Maastricht, University Hospital Maastricht, Maastricht, the Netherlands; and 2Clinical and Surgical Sciences (Surgery), 3Department of Radiology, University of Edinburgh, Royal Infirmary, Scotland, United Kingdom

Submitted 6 August 2006 ; accepted in final form 12 August 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Changes in hepatic ureagenesis following major hepatectomy are not well characterized. We studied the relation between urea synthesis and liver mass before and after major hepatectomy in humans. Fifteen patients scheduled for resection of malignancies in otherwise healthy livers were studied. Pre- and postoperative liver volume was assessed by computerized tomography-volumetry. During surgery, a primed, continuous infusion of [13C]urea was administered intravenously, and arterial blood samples were obtained hourly. Indocyanine green clearance was determined before and after resection. Seven patients underwent major hepatectomy, and eight patients underwent minor [<5% functional liver volume (total volume – tumor volume)] or no resection, serving as controls. Resected functional liver volume in the major hepatectomy group averaged 60%. Urea synthesis per gram of functional liver tissue increased 2.6-fold following major hepatectomy, maintaining whole body urea synthesis. Arterial ammonia remained unchanged throughout the study, whereas following hepatectomy a hyperaminoacidemia occurred. In conclusion, immediately following major hepatectomy, urea synthesis per gram of functional liver tissue increases rapidly and proportionately to the amount of liver tissue resected, maintaining whole body urea synthesis at preoperative levels. This rapid and complete adaptation suggests that the capacity of urea synthesis is not limiting the maximum resectable volume in otherwise healthy livers.

liver function; liver volume; computerized tomography-volumetry; stable isotopes

PARTIAL HEPATECTOMY IS CURRENTLY the only curative treatment option for patients with colorectal liver metastases (23). Only 20% of these patients are eligible for hepatectomy with curative intent, often because radical resection would leave insufficient liver mass, leading to liver failure (21), an almost invariably lethal complication (21, 27). It is believed that diminished ammonia detoxification in this situation, leading to hyperammonemia, is of crucial importance.

In patients without liver disease, resections of up to 70–80% are generally well tolerated (18, 28). In patients with underlying liver disease, however, much smaller resections have been shown to induce liver failure (13). This points out the importance of both remnant liver volume and functional status of the liver following hepatectomy.

Many efforts have been made in the past to develop a tool that identifies patients at risk for liver failure following hepatectomy or that predicts the maximum resectable volume without inducing liver failure. In this respect, both volumetric and functional tests as well as combinations of these have been investigated. The indocyanine green (ICG) clearance test (13) is currently considered to be the best prognostic tool, but its specificity and sensitivity are low (26).

To develop a reliable tool, it is probably necessary to gain insight in changes in liver physiology and mechanisms of liver failure following hepatectomy. In this way, investigations for prognostic tools can be directed at factors that are truly limiting the resectable volume. In addition, awareness of changes in liver physiology following liver resection is crucial to advance postoperative care. We recently showed that the hepatic reticuloendothelial system (RES) undergoes a functional adaptation following major hepatectomy but actually reaches a maximum function per gram liver, resulting in a decrease of total reticuloendothelial function (24).

Hepatocellular adaptation following major hepatectomy is not well characterized. One of the most important hepatocellular functions is the synthesis of urea from ammonia and amino acids. Diminished urea synthesis capacity in liver insufficiency leads to hyperammonemia and hepatic encephalopathy (19). Furthermore, because urea synthesis is a unique liver function (17), whole body urea synthesis can readily be related to the liver volume before and after major hepatectomy. For these reasons, it seemed important to explore the effects of major hepatectomy on urea synthesis.

We have previously demonstrated that pre- and postoperative liver volume can be measured and predicted using three-dimensionally reconstructed computerized tomography (CT) scans (35). These volumetric techniques were applied in the present study to investigate changes in urea synthesis measured by [13C]urea infusion, both on the whole body level and per gram of functional liver tissue.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Patients. Fifteen patients scheduled for hepatectomy for secondary (n = 13) or primary (n = 2) hepatic cancer in otherwise healthy livers were included. This study was started at the Royal Infirmary of Edinburgh, Scotland, where seven patients were enrolled. For practical reasons, the study was finished at the University Hospital Maastricht, the Netherlands, where another eight patients were studied. Surgery was performed after an overnight fast while subjects were on their standard diet in the prestudy period. As part of standard care, all patients had radial artery, jugular vein, and urinary catheters inserted before surgery. Ethical permission for the study was obtained from Ethics Committees in Edinburgh and Maastricht. Written informed consent was obtained from each individual. The protocols were reviewed and approved, bot on Medical Ethical and on Methodological merits, by the Medical Ethical Committees of the Royal Infirmary Edinburgh and the University Hospital Maastricht.

Surgical procedure. Liver resection was performed as detailed previously (3, 5). Briefly, mobilization of the liver was followed by intraoperative ultrasound following which a decision was made regarding the appropriate surgical procedure. Major resection (defined as removal of 3 or more segments) was based on segment-oriented anatomy (5). During the resection, central venous pressure was maintained below 5 mmHg. Liver transection was performed following extrahepatic ligation of portal pedicle structures and hepatic veins using a Cavitron Ultrasonic Surgical Aspirator (CUSA system 200 Macrodissector; Cavitron Surgical Systems, Stamford, CT). Argon beam coagulation (Force GSU System; Valleylab, Boulder, CO), clips, and sutures were used for hemostasis. Only in one case hepatic inflow was temporarily occluded for 15 min, and blood flow was restored 30 min before the hourly arterial sample.

CT imaging and volumetry. Preoperative liver imaging was performed according to local clinical routines. In Edinburgh, computerized tomography angioportography was performed as described before (35). In Maastricht, liver imaging was performed by four-phase spiral CT scans made after the injection of contrast via an elbow vein (120–140 ml; Omnipaque 354, Nycomed Ireland, Cork, Ireland; flow rate = 4 ml/s, scan delay = 25–70-300 s) using a Toshiba Aquillion (Japan) or Elscint Twin RTS Philips Medical Systems (Best, The Netherlands). CT-volumetry was performed as described previously (35). Liver and tumor volumes were calculated, and the model was subjected to virtual resection along anatomical planes according to the intended surgical procedure. Functional liver weight was calculated by subtracting tumor volume from total liver volume, assuming a volume-to-weight ratio of 1 ml:1 g (35).

Isotope studies. Before surgery, baseline blood samples were taken, and a primed continuous infusion of [13C]urea (Eurisotop, Saint Aubin, France) was started and continued for 6 h regardless of the course and duration of the operation (priming dose 36.5 µmol/kg, infusion rate 7.42 µmol·kg–1·h–1). Isotopic steady state was defined as a variation between tracer-to-tracee ratios at three consecutive time points that did not exceed 5.9%, which is the coefficient of variation of the laboratory analysis.

Blood sampling and processing. Arterial blood was sampled hourly and processed as described earlier (20). Briefly, plasma proteins were precipitated using sulfosalicylic acid for amino acid assays and trichloroacetic acid for ammonia and urea assays (20). All samples were stored at –80°C. Samples obtained in Edinburgh were shipped on dry ice to Maastricht for analysis.

Laboratory analysis. Urea tracer-to-tracee ratios were determined using liquid chromatography-mass spectrometry (33). Amino acid concentrations were measured using high-performance liquid chromatography (32), ammonia and urea concentrations with spectrophotometry (Cobas Mira S; Roche Diagnostics, Basel, Switzerland). Arterial pH and HCO3– was measured using an automated analyzer (GEM Premier 3000; Instrumentation Laboratory, Breda, the Netherlands). Amino acids and ammonia levels were measured in the baseline samples and in the samples obtained at the end of the experiment.

Calculations. Isotopic enrichment (E) was calculated by subtracting the tracer-tracee ratio (TTR) at baseline (TTR0) from the TTR at the respective time points during the infusion:

Formula 1(1)
[13C]urea infusion provides an accurate method to measure urea synthesis rate (Q) during steady-state conditions, using a simple standard equation for single-pool steady-state situations (11):

Formula 2(2)
where I is the infusion rate of the tracer. We anticipated that, following major hepatectomy, whole body urea synthesis rate could be decreased. Given the large pool size of urea, prohibiting a fast equilibration towards a new isotopic steady state (8), we applied a non-steady-state approach to calculate the rate of urea synthesis for the second part of the tracer infusion as proposed by Steele (6, 29). This approach takes into account changes in urea enrichment over time [dE(t)/dt] and the mean size of the urea pool [(V x u), where V is the volume of urea distribution (total body water or 0.6 x body mass) and u is the mean urea concentration over time]:

Formula 3(3)
where E is the mean urea enrichment over time. We (4) and others (8) have shown before that this approach is sensitive to relatively minor changes in urea synthesis. It is, however, also valid in steady-state situations, since dE(t) then equals zero, rendering equation 3 equal to equation 2.

Hepatic nitrogen clearance. The ratio between urea synthesis rate and plasma {alpha}-amino nitrogen concentration ([{alpha}-AN]; the sum of all amino acids) was calculated as a reflection of hepatic nitrogen clearance. This approach is a modification of the original calculation of functional hepatic clearance during a nitrogen challenge introduced by Vilstrup (34).

ICG clearance. ICG clearance was measured before and immediately after liver resection. ICG (0.5 mg/kg; Akorn, Buffalo Grove, IL) was administered intravenously, and absorbance of plasma at 805 nm was measured after 10, 15, and 20 min using an Uvikon 923 double-beam UV/VIS spectrophotometer (Kontron instruments, Watford, UK). ICG retention at 15 min (ICGR15) was calculated by expressing the extinction at 15 min as a percentage of the theoretical extinction at 0 min calculated by logarithmic regression analysis.

Statistics. Results are expressed as means ± SE or median (range) as indicated. Statistical tests used were the Mann-Whitney U-test and the Wilcoxon signed ranks test. Values obtained in serial measurements (before hepatectomy, after hepatectomy) were summarized to single means for each individual (16), which were subsequently tested nonparametrically. Correlations were calculated with Spearman's test for nonparametric correlations. Statistical calculations were made using SPSS 11.0 for Windows (SPSS, Chicago, IL). A P value <0.05 was considered to indicate statistical significance.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Patients. Seven patients underwent major hepatectomy, and eight patients underwent either no (n = 4) or only minor (<5%) hepatectomy (Tables 1 and 2). These eight patients were regarded as a control group to correct for the effects of anesthesia and laparotomy. No differences were observed between patients studied in Edinburgh or Maastricht or between major hepatectomy and control patients. There was no major morbidity or mortality in the 15 patients studied, and no liver insufficiency was observed in the major hepatectomy group. Mean ± SE arterial pH was 7.4 ± 0.04 and remained unchanged following hepatectomy; mean ± SE arterial HCO3– concentration was 22.4 ± 0.5 mmol/l and also remained unchanged following hepatectomy.


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  		Table 1. Liver volumes and resected volumes

 

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  		Table 2. Patient characteristics

 
Liver volumes. Mean liver volume in the whole group (n = 15) was 1,989 ± 158 ml, and mean functional liver volume (liver volume – tumor volume) was 1,757 ± 137 ml. In the major hepatectomy group (n = 7), total liver volume was 1,763 ± 249 ml, functional liver volume was 1,512 ± 178 ml, resected functional volume was 896 ± 133 ml (60 ± 6%), and the residual volume was 429 ± 134 ml. In the control group, <5% of functional liver volume was resected (mean 1.3 ± 0.8%). The correlation between predicted and actual resected liver weight (data not shown) was consistent with our previous findings (35).

Urea synthesis rate. In all patients, isotopic steady state was initially present during the experiment (Fig. 1). After 3 h, a small increase of [13C]urea enrichment was found, which was similar in both groups (Fig. 1). Before hepatectomy, mean whole body urea synthesis rate calculated from isotope data was not significantly different between major hepatectomy patients and controls (P = 0.61). Following major hepatectomy, whole body urea synthesis decreased slightly (P = 0.007). The absolute value (P = 0.96) and the decrease in whole body urea synthesis was similar in patients who underwent major hepatectomy (from 223 ± 24 to 203 ± 23 µmol·kg–1·h–1) and in control patients (from 206 ± 20 to 196 ± 19 µmol·kg–1·h–1; P = 0.35; Fig. 2). However, when calculated per gram of functional liver tissue calculated from the CT-scans, urea synthesis per gram of liver increased 2.6-fold (P = 0.02) immediately following major liver resection (Fig. 3). Mean whole body urea synthesis rate at steady state for all patients at baseline was 214.7 ± 8.4 µmol·kg body wt–1·h–1, and mean urea synthesis rate per gram liver at baseline was 9.5 ± 1.3 µmol·g liver–1·h–1.


Figure 1
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  		Fig. 1. Mean ± SE isotopic enrichment in control patients ({blacksquare}) and patients undergoing major hepatectomy ({blacktriangleup}). Arrow indicates the time point of hepatectomy. In all patients, isotopic steady state was achieved before liver resection; thereafter, a small increase of isotopic enrichment occurred. No differences were observed between either group (2-way ANOVA; P = 0.003 for "time effect", P = 0.67 for "group effect," and P = 0.56 for "interaction").

 

Figure 2
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  		Fig. 2. Whole body urea synthesis rate before and after hepatectomy expressed as the mean ± SE of individual means at isotopic steady state. A small but statistically significant difference was observed in both groups, but major hepatectomy did not affect whole body urea synthesis rate compared with the control group. *P < 0.05. BW, body wt; ns, not significant.

 

Figure 3
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  		Fig. 3. Urea synthesis/g liver before and after major hepatectomy. Urea synthesis/g liver increases proportionate to the volume resected (*P = 0.018).

 
Ammonia and urea concentrations. Arterial ammonia concentrations were similar before and immediately after hepatectomy and in both groups (Table 3). Urea concentrations did not change significantly during the study in both groups: from 3.82 ± 0.5 mmol/l to 3.75 ± 0.5 mmol/l in the major hepatectomy group (P = 0.4) and from 3.63 ± 0.3 mmol/l to 3.39 ± 0.2 mmol/l in the control group (P = 0.3).


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  		Table 3. Changes in ammonia, urea, and amino acid plasma concentration

 
Plasma amino acids and nitrogen clearance. Following major hepatectomy, a generalized hyperaminoacidemia (mean [{alpha}-AN] +53 ± 26% from baseline value, P = 0.046) occurred, whereas the {alpha}-AN concentration in the control group decreased (–17 ± 7%, P < 0.05). Urea synthesis rates were significantly correlated with total {alpha}-AN at baseline (Spearman's rho = 0.836, P < 0.001, Fig. 4). This correlation was maintained in control patients, but in patients undergoing major hepatectomy a significant decrease in the ratio between urea synthesis and {alpha}-AN concentration occurred (Fig. 5A), indicating that hepatic nitrogen clearance is impaired following major hepatectomy (Fig. 5B).


Figure 4
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  		Fig. 4. Significant correlation at baseline between {alpha}-amino nitrogen (AN) and urea synthesis rate (Spearman's rho = 0.836, P < 0.001).

 

Figure 5
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  		Fig. 5. Median (range) ratio between {alpha}-AN levels and ureagenesis as a measure for hepatic nitrogen clearance (HNC) on the whole body level (A) and expressed/g functional liver tissue (B). FHNC, functional HNC. Whole body HNC was unchanged in the control group since both {alpha}-AN and ureagenesis decreased. Following major hepatectomy, HNC decreased significantly (P = 0.046), requiring a significant increase in {alpha}-AN levels to maintain urea synthesis. HNC/g liver increased significantly following major hepatectomy, indicating hepatocellular functional adaptation.

 
ICG clearance and hepatic plasma flow. Immediately following major hepatectomy, median (range) ICGR15 was 21.7% (5.7). This was not significantly different from ICGR15 before liver resection [21.6% (6.2)] or from ICGR15 in the control group [22.0% (5.6); Fig. 6]. Because ICG clearance is dependent on and therefore a measure for hepatic plasma flow, it can be concluded that total hepatic plasma flow remains unchanged following major hepatectomy but that hepatic plasma flow per gram liver increased proportionate to the resected volume.


Figure 6
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  		Fig. 6. Indocyanine green (ICG) clearance in 7 patients undergoing major hepatectomy, measured before and immediately after hepatectomy expressed as retention (%) over time. The clearance rate of ICG remained unchanged.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study was designed to investigate changes in nitrogen metabolism and urea synthesis induced by major hepatectomy in humans. We found increased plasma concentrations of, among others, glutamine, alanine, aromatic amino acids, and {alpha}-AN, which are characteristic changes indicative for loss of liver function. Moreover, plasma levels of glutamate, an important product of hepatic amino acid metabolism, decreased significantly following major hepatectomy, also suggesting hepatic dysfunction. Whole body urea synthesis rates, measured 1 h after major hepatectomy, were slightly decreased compared with those measured before major hepatectomy but similar to controls, suggesting that this decrease is because of the gross surgical trauma and not the hepatectomy. Moreover, a functional adaptation occurred, increasing urea synthesis per gram liver up to 2.6-fold, proportionate to the resected volume.

Whole body urea synthesis rate measured by [13C]urea infusion (~215 µmol·kg–1·h–1) is comparable to literature data (11). Urea synthesis rate per gram of functional liver calculated by CT volumetry approximates 10 µmol·g liver–1·h–1. Following resection of 60% functional liver volume, this value increases to ~26 µmol·g liver–1·h–1. This adaptation occurs exceedingly rapidly, at least within 60 min but probably instantaneously. To our knowledge, this is the first study where in vivo in humans absolute values for urea synthesis per gram of liver have been calculated.

Expressing liver function per gram liver and predicting posthepatectomy liver volume may open new perspectives in the preoperative assessment of patients considered for hepatectomy. If the preoperative and the maximum rate per gram liver of a specific function is known, it can be calculated how much liver function per gram will be needed to maintain homeostasis. To successfully apply volumetric and functional assessment as a sensitive preoperative selection tool, it will be necessary to identify liver functions that are truly limiting the maximum resectable volume. From the present observations, it becomes clear that the urea cycle can adapt amply sufficient following major hepatectomy.

The maximum rate of urea synthesis in humans is unknown, but urea synthesis can increase at least 800% in healthy subjects and 600% in patients with liver cirrhosis during an intravenous nitrogen challenge (34). This is very well in concordance with the present study showing that resection of up to 75% of the functional liver volume leads to a rapid and complete adaptation of urea synthesis per gram liver. To force urea synthesis to an 800% increase per gram liver by hepatectomy, however, would require a resection of ~90% of the functional liver volume (Fig. 7), provided that the capacity of urea synthesis per gram liver is maintained following hepatectomy. Clearly such an extensive resection would almost invariably lead to liver insufficiency with potentially lethal consequences (15). We have shown recently that, in patients with a normal liver, resection of 73.4% or more of the functional liver volume is predictive of liver dysfunction following hepatectomy with high positive and negative predictive values (25). Such a "maximal" resection would require an increase of urea synthesis per gram liver of "only" 290%, suggesting that the capacity of urea synthesis is not a priori limiting the maximum tolerated extent of resection in patients with a normal liver. It should be realized, however, that the aforementioned nitrogen challenges (34) were conducted in conscious subjects and that factors like anesthesia, surgical stress, and the metabolic burden of liver regeneration may very well limit the maximum capacity for urea synthesis. Therefore, the actual maximum urea synthesis rate per gram liver following hepatectomy still is unknown. Moreover, it remains unknown whether urea synthesis may be limiting the maximum resectable volume in patients with liver disease. Similar studies as the present one in patients with different grades of cirrhosis could shed light on this issue.


Figure 7
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  		Fig. 7. Increase in urea synthesis/g liver in relation to the resected liver volume. Dots represent individual patients in the present study. From the theoretical prediction line, it can be conceived that beyond 70–80% hepatectomy the demanded functional adaptation increases exponentially, rapidly increasing the risk of liver failure. The value of 74.4% is derived from recent work from our group (25). In that study, a residual functional liver volume of 26.6% or less in patients with a normal liver was found to be predictive of liver insufficiency following hepatectomy. In this case, urea synthesis/g liver has to increase almost 300%.

 
We recently showed that the clearance capacity of the hepatic RES increases per gram liver following liver surgery. Following major hepatectomy, however, this response is only incomplete, resulting in diminished total RES activity (24). Although RES function is not immediately vital for homeostasis, it is important in coping with postoperative endotoxemia and bacteremia. RES dysfunction may predispose for infections and may as such indirectly affect hepatocellular synthetic capacity (25). Regarding its early saturability, it may be an important factor limiting the resectable liver volume.

The mechanism behind the rapid functional adaptation of the liver following hepatectomy has been the subject of many studies. Most of these have focused on changes in gene expression within the first few hours following hepatectomy. It has become clear that there is a reprioritization of liver functions with a downregulation of genes that are not vital for homeostasis or liver regeneration and an upregulation of genes that are (30, 31). Although there is a rapid activation of transcription factors and mRNA expression (7, 14, 31), no changes in protein expression have been observed earlier than 2 h after hepatectomy in the rat (7). The swiftness of the events in the present study demonstrates for the first time that there is no absolute need for gene transcription and protein expression to initiate the metabolic response and to maintain urea homeostasis.

The rate of urea synthesis is directly dependent on nitrogen intake and protein breakdown, reflected by the plasma concentration of {alpha}-AN (1, 9, 22, 34). This was also shown in the present study by the correlation between {alpha}-AN levels and urea synthesis rate. Plasma levels of {alpha}-AN needed to maintain ureagenesis are dependent on liver function and are increased in patients with liver disease. We hypothesize that {alpha}-AN levels increased following major hepatectomy because of an acute temporary reduction of ureagenesis. Simultaneously, these increasing systemic and portal vein {alpha}-AN levels stimulate hepatic ureagenesis, leading to a rapid complete restoration of whole body urea synthesis, apparently within 1 h from liver resection. This effect may be accelerated because all portal blood is now redirected to the small liver remnant. In addition, increased ammonia load to the remnant liver may stimulate glutaminase activity, leading to a feedforward stimulation of urea synthesis (10).

By measuring ICG clearance before and after major hepatectomy, we evidenced an immediate increase in blood flow per gram liver. This probably enhances substrate supply, limiting the increase in plasma {alpha}-AN levels needed to maintain urea synthesis. This view is supported by an increased hepatic nitrogen clearance per gram liver following major hepatectomy. The importance of preservation of hepatic blood flow following major hepatectomy is also supported by clinical data (2, 12).

Arterial ammonia levels remained unchanged in both groups, implying that arterial ammonia is not a driving force for hepatic ureagenesis and that, following major hepatectomy, the liver remains capable of adequately removing intestinal-derived ammonia.

Summary

In this study, we have shown for the first time in humans that liver function and liver volume can simultaneously be assessed in vivo, yielding absolute data on liver function per gram liver tissue. This method is useful to study physiological changes following major hepatectomy and may be applied to assess candidates for major hepatectomy. Following major hepatectomy, urea synthesis per gram liver increases rapidly because of an increased {alpha}-AN plasma concentration and an increased hepatic blood flow per gram liver. Because the adaptive capacity of the urea cycle apparently exceeds the maximum resectable liver volume, it is not likely that urea synthesis limits the maximal extent of hepatectomy.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by grants from The Netherlands Organization for Health Research and Development to M. C. G. van de Poll (920-03-317 AGIKO) and C. H. C. Dejong (907-00-033 Clinical Fellowship). ICG purchase was supported by a grant from the Moray Endowment Fund, Edinburgh.


   ACKNOWLEDGMENTS
 
C. H. C. Dejong expresses his gratitude to the Niels Stensen Foundation, Amsterdam, for financially supporting his stay in Edinburgh.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. C. G. van de Poll, Dept. of Surgery, Univ. Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands (e-mail: mcg.vandepoll{at}ah.unimaas.nl)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
 GRANTS
 REFERENCES
 

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
M. C. G. van de Poll, G. C. Ligthart-Melis, S. W. M. Olde Damink, P. A. M. van Leeuwen, R. G. H. Beets-Tan, N. E. P. Deutz, S. J. Wigmore, P. B. Soeters, and C. H. C. Dejong
The gut does not contribute to systemic ammonia release in humans without portosystemic shunting
Am J Physiol Gastrointest Liver Physiol, October 1, 2008; 295(4): G760 - G765.
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