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Am J Physiol Gastrointest Liver Physiol 295: G760-G765, 2008. First published August 14, 2008; doi:10.1152/ajpgi.00333.2007
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LIVER AND BILIARY TRACT

The gut does not contribute to systemic ammonia release in humans without portosystemic shunting

Marcel C. G. van de Poll,1 Gerdien C. Ligthart-Melis,2 Steven W. M. Olde Damink,1 Paul A. M. van Leeuwen,2 Regina G. H. Beets-Tan,3 Nicolaas E. P. Deutz,1 Stephen J. Wigmore,4 Peter B. Soeters,1 and Cornelis H. C. Dejong1

Departments of 1Surgery and 3Radiology, University Hospital Maastricht, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, the Netherlands; 2Department of Surgery, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands; and 4Department of Surgery, Royal Infirmary of Edinburgh, United Kingdom

Submitted 23 July 2007 ; accepted in final form 2 August 2008


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The gut is classically seen as the main source of circulating ammonia. However, the contribution of the intestines to systemic ammonia production may be limited by hepatic extraction of portal-derived ammonia. Recent data suggest that the kidney may be more important than the gut for systemic ammonia production. The aim of this study was to quantify the role of the kidney, intestines, and liver in interorgan ammonia trafficking in humans with normal liver function. In addition, we studied changes in interorgan nitrogen metabolism caused by major hepatectomy. From 21 patients undergoing surgery, blood was sampled from the portal, hepatic, and renal veins to assess intestinal, hepatic, and renal ammonia metabolism. In seven cases, blood sampling was repeated after major hepatectomy. At steady state during surgery, intestinal ammonia release was equaled by hepatic ammonia uptake, precluding significant systemic release of intestinal-derived ammonia. In contrast, the kidneys released ammonia to the systemic circulation. Major hepatectomy led to increased concentrations of ammonia and amino acids in the systemic circulation. However, transsplanchnic concentration gradients after major hepatectomy were similar to baseline values, indicating the rapid institution of a new metabolic equilibrium. In conclusion, since hepatic ammonia uptake exactly equals intestinal ammonia release, the splanchnic area, and hence the gut, probably does not contribute significantly to systemic ammonia release. After major hepatectomy, hepatic ammonia clearance is well preserved, probably related to higher circulating ammonia concentrations.

liver; kidney; interorgan; hepatectomy

THE GUT IS THE MAJOR ammonia-producing organ in mammals, and consequently intestinal-derived ammonia is regarded as the source of hyperammonemia after ingestion of large amounts of protein or an upper gastrointestinal (GI) bleed (16, 17, 19, 20, 32). However, since the liver has the capability to scavenge portal ammonia either by urea synthesis or by glutamine synthesis, not all intestinal-derived ammonia reaches the systemic circulation.

Hyperammonemia has been associated with an impaired capability of the liver to remove ammonia. This can be attributable to portosystemic shunting, which prohibits exposure of portal blood to the liver cells. In addition, it has been suggested that reduction of hepatocellular functional capacity by chronic or acute liver disease reduces hepatic ammonia clearance and increases splanchnic ammonia release (21). However, although the detrimental effects of portosystemic shunting on hepatic ammonia clearance is evident (13), data on "hepatocellular dysfunction" are less convincing since hepatocytes appear to have a considerable functional reserve. Accordingly, recent studies from our group showed no net splanchnic ammonia release in patients with chronic liver disease (12). Instead, hyperammonemia appeared to be related to increased renal ammonia production. These observations were recognized as an indication that the treatment of hyperammonemia should probably include modulation of renal ammonia metabolism (4, 5, 19). The potential importance of renal ammonia metabolism for systemic ammonia levels is nicely exemplified by the aggravation of hepatic encephalopathy by hypokalemia, which leads to increased ammonia production in the proximal tubule (6, 23).

Presently no data on hepatic and renal ammonia metabolism in humans with a noncirrhotic, nonshunted liver are at hand. This is because of limited accessibility of the portal vein in humans. In patients undergoing liver surgery for colorectal liver metastases, the nontumorous parenchyma is generally well preserved, and no portosystemic shunting is present. Simultaneously the portal, hepatic, and renal veins are relatively easily accessible for blood sampling. Moreover, major hepatectomy provides an excellent opportunity to study the hepatocellular response to an increased metabolic burden after an acute and substantial loss of functional liver mass.


   MATERIALS AND METHODS
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 MATERIALS AND METHODS
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Patients. Twenty-one patients (4 women) without liver dysfunction, renal failure, or metabolic disease undergoing upper GI surgery (17 liver resections, 1 gastrectomy, 1 duodenal resection, and 2 pancreaticoduodenectomies) were studied after an overnight fast (12 h) (Table 1). None of the patients were jaundiced, and none of them had been on chemotherapy, radiotherapy, or other oncological treatment in the last 4 wk preceding the operation. Patients were on their standard oral diets in the prestudy period. One patient used amiloride/hydrochlorothiazide (5/50 mg per day), and one patient used penicillin (500 mg/day) for erysipelas. These drugs may affect renal and intestinal ammonia metabolism, but the data from these patients did not show extreme values in the present study. Patient characteristics are summarized in Table 1. The study was approved by the Medical Ethical Committee, University Hospital Maastricht, and each subject gave written informed consent.


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  		Table 1. Patient characteristics

 
Anesthesia and surgery. All patients were anesthetized according to departmental routines using isoflurane and propofol and epidural catheter analgesia. Central venous and radial artery catheters were placed for monitoring arterial and central venous blood pressure. Urine output was monitored by transurethral catheterization. Body temperature was kept constant using a Bair Hugger system (Arizant Healthcare, Eden Prairie, MN). Blood sampling was performed within 1 h from the start of the operation, before organ transection. In cases requiring liver resection, some additional dissection was required to expose the right renal vein. In cases of peripancreatic dissection, some additional time was spent to expose the suprahepatic veins if necessary.

Assessment of ammonia flux across the gut, liver, and kidney. After exposure of the right renal vein, the portal vein, and a major hepatic vein, before organ transection, intestinal, renal, and hepatic blood flows were measured as described elsewhere (25, 26). Immediately thereafter, 5 ml of blood were drawn from these vessels by direct puncture. Simultaneously, 5 ml of arterial blood were drawn from the radial artery catheter. Net organ fluxes were calculated as arteriovenous concentration difference times organ plasma flow. Splanchnic flux was calculated as hepatic venous – arterial concentration difference times splanchnic flow (portal + hepatic artery flow). Hepatic flux was calculated by subtracting intestinal flux from splanchnic flux. Flux was expressed as µmol·kg body wt–1·h–1 (25, 26).

Duplex flow measurement. Organ blood flow was measured by means of color Doppler ultrasound (Aloka Prosound SSD 5000; Aloka, Tokyo, Japan). Briefly, time-averaged mean velocities of the blood stream and cross-sectional area of the portal vein, hepatic artery, and right renal vein were measured. Blood flow was calculated by multiplying the cross-sectional area of the vessel with the velocity of the blood stream. Portal venous and hepatic arterial blood flows were measured before their hilar bifurcations. Plasma flow (PF) was calculated by correcting blood flow (BF) for hematocrit (Ht) [PF = BF x (1 – Ht)]. Hepatic (and splanchnic) plasma flow was calculated by adding up plasma flow in the portal vein and hepatic artery. Total renal flow was calculated by multiplying the flow through the right kidney by two.

Blood processing and laboratory analyses. After withdrawal, blood was immediately transferred to prechilled heparinized tubes (BD Vacutainer; Becton Dickinson, Franklin Lakes, NJ) and put on ice. Whole blood was centrifuged at 4,000 g, and plasma was deproteinized using sulphosalicylic acid for amino acid analysis and trichloroacetic acid for ammonia analysis as described before (13). pH was measured immediately using an automated analyzer (GEM Premier 3000; Instrumentation Laboratory, Breda, the Netherlands). Amino acids were measured by HPLC, ammonia by a kinetic enzyme assay as detailed before (13, 29).

Effects of major hepatectomy on interorgan ammonia flux. Seven of the twenty-one patients underwent major hepatectomy [resection of 3 or more liver segments ({approx}50% liver volume)]. In these patients, blood sampling was repeated immediately following hepatectomy to study the effects of major hepatectomy on hepatic ammonia clearance and systemic ammonia production.

Statistics. Data are presented as means ± SE. Arteriovenous concentration differences were tested vs. zero using a one-sample t-test with a theoretical mean of zero; correlations were calculated using Pearson's test. A P value of <0.05 was regarded to indicate statistical significance. Statistical calculations were made using Prism 4.0 for Windows (GraphPad Software, San Diego, CA).


   RESULTS
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DISCUSSION
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Patients. At the time of baseline blood sampling (<1 h following laparotomy) blood loss was negligible, urinary output 62.7 ± 8.8 ml/h, and arterial pH 7.38 ± 0.02. Blood flows measured with Doppler ultrasound were 799 ± 130 ml/min (portal), 1,247 ± 156 ml/min (hepatosplanchnic), and 768 ± 99 ml/min (kidneys), which is in agreement with our previous data (18).

Splanchnic ammonia exchange. At baseline steady-state blood sampling, the intestines released ammonia at a similar rate as they consumed glutamine, underlining the stoichiometric relationship between intestinal glutamine and ammonia metabolism (Table 2). Intestinal ammonia release was equaled by hepatic ammonia uptake (Fig. 1), so that at baseline net splanchnic ammonia release was not significantly different from zero (Fig. 2). Consequently, at steady state in humans without portosystemic shunting, the contribution of the splanchnic area, and hence the intestines, to systemic ammonia release appears to be negligible.


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  		Table 2. Arterial levels and organ flux of ammonia and related amino acids

 

Figure 1
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  		Fig. 1. Relation between intestinal ammonia release and hepatic ammonia uptake. The close correlation between intestinal ammonia production and hepatic ammonia uptake evidences that hepatic ammonia clearance prohibits the escape of intestinal-derived ammonia to the systemic circulation.

 

Figure 2
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  		Fig. 2. Splanchnic and renal ammonia flux. Ammonia flux across the splanchnic organs (gut and liver) and kidneys was measured in 21 surgical patients with a normal liver function and without portosystemic shunting. Intestinal ammonia production is equaled by hepatic ammonia uptake, rendering net splanchnic ammonia release insignificant. The kidney significantly adds ammonia to the systemic circulation.

 
Renal ammonia release into the systemic circulation. The kidneys released ammonia into the renal vein and the systemic circulation (Fig. 2). The kidneys consumed glutamine at a rate that was quantitatively comparable with intestinal glutamine utilization. However, in contrast to the 1:1 stoichiometry between glutamine uptake and ammonia release observed in the gut, renal glutamine uptake exceeded systemic ammonia release by the kidneys fivefold.

Effects of major hepatectomy on amino acid metabolism. In the seven patients undergoing major hepatectomy, blood sampling was repeated immediately following removal of the resection specimen. At this time point, systemic plasma concentrations of most amino acids were significantly increased (Table 3). This increase was most outspoken for alanine (average 1.4 times baseline value). Simultaneously, transintestinal (Table 4, Fig. 3A) and transsplanchnic (Table 5, Fig. 3B) arteriovenous concentration gradients for all amino acids were not significantly different from baseline values.


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  		Table 3. Changes in arterial amino acid concentrations after major hepatectomy

 

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  		Table 4. Changes in transintestinal amino acid gradients after major hepatectomy

 

Figure 3
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  		Fig. 3. A: transintestinal concentration gradients before and after major hepatectomy. No significant changes occurred in the gradients of glutamine, alanine, and ammonia. B: transsplanchnic concentration gradients before and after major hepatectomy. No significant changes occurred in the gradients of glutamine, alanine, and ammonia.

 

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  		Table 5. Changes in transsplanchnic amino acid gradients after major hepatectomy

 
Effects of major hepatectomy on splanchnic and renal ammonia exchange. Following major hepatectomy, arterial ammonia concentrations were increased, whereas transintestinal ammonia gradients were not significantly different from baseline values. Despite increased portal ammonia concentrations and reduced liver volume, net transsplanchnic concentration gradients following major hepatectomy remained not significantly different from zero, which implies that the liver removed all ammonia from the portal. The difference between renal venous and arterial ammonia concentration (RV – A) also remained unchanged (33.2 ± 5.7 µmol/l before vs. 30.1 ± 8.9 µmol/l after major hepatectomy, P = 0.67).


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study was designed to study the role of the intestines, liver, and kidney in ammonia homeostasis in humans without portosystemic shunting. Although data on interorgan ammonia metabolism in various animal models as well as in humans with liver disease are already available, such data in humans with a functionally normal liver have been lacking. We were able to obtain these data by sampling blood from the portal, hepatic, and renal veins from patients undergoing upper GI surgery. We also studied the effect of an acute reduction of functional liver mass on remnant metabolic liver function and interorgan ammonia exchange.

In line with previous data, the intestines released ammonia into the portal vein. At steady-state baseline sampling, intestinal ammonia production, however, appeared to be of minor importance for systemic ammonia release in patients with a normal liver since the liver effectively extracted ammonia at a rate that exactly equaled intestinal ammonia production. This led to a zero net balance across the whole splanchnic area at baseline. Also in line with literature data (14, 15, 22, 27), the kidneys were found to release ammonia to the systemic circulation. Since most solid organs, e.g., lungs (2), brain (9), and skeletal muscle (13), are net ammonia consumers, the kidneys appear to be very important for systemic ammonia release in healthy humans and probably play a hitherto underestimated role in the regulation of systemic ammonia concentration.

Renal ammonia is derived from glutamine, and ~40–50% of all glutamine is converted to ammonia by the kidney (22). Subsequently ammonia is either released into the urine or into the renal vein. The balance between renal venous and urinary ammonia excretion is determined by acid-base status, with acidosis stimulating urinary ammonia excretion and alkalosis stimulating renal venous ammonia excretion. Unfortunately, we were unable to assess urinary ammonia excretion for several reasons, including the inaccuracy of the exact assessment of diuresis during a short interval and urease activity of bacteria colonizing urine collection devices.

In seven patients undergoing major liver resection (≥3 liver segments), blood sampling was repeated following liver resection. After major hepatectomy, a marked increase was found in the arterial and portal plasma concentration of most amino acids and ammonia. This was particularly true for the aromatic amino acids, for alanine, the most important aminonitrogen donor for hepatic ureagenesis and for methionine. Arterial plasma concentrations of branched chain amino acids remained unchanged. The resulting amino acid profile resembles the profile that can be found in patients with chronic liver disease (hyperaminoacidemia with an increased ratio between aromatic and branched chain amino acids) (3). In addition, we found decreased arterial glutamine levels after hepatectomy, which is an unexpected finding since these data appear to contrast with previous data showing increased glutamine levels following liver resection (28).

In addition, we found a 21% increase of systemic ammonia levels immediately following major hepatectomy. Such an increase was not found in the aforementioned study (28) where ammonia levels were normalized after liver resection. The major difference between the two studies was the time point at which systemic amino acid and ammonia levels were measured (seconds to minutes after removal of the specimen in the present study vs. hours in the previous one). This suggests that major liver resection disturbs glutamine and ammonia homeostasis temporarily but that a new steady state is established within hours. In this new steady state, ammonia removal by the liver is kept constant despite increased influx of ammonia. The exact cause and nature of the changes in systemic ammonia and glutamine levels immediately following liver resection remain unclear from the present study. Potential explanations include a temporary reduction of hepatic ammonia uptake due to reduced liver mass and temporary disturbance of the hepatic blood flow during liver transection; such changes would facilitate increased release of (intestinal-derived) ammonia to the systemic circulation. This is, however, not supported by changes in splanchnic ammonia release in the present study at the time points measured. It is known that the liver has a tremendous capacity of ureagenesis due to the high Km of the urea cycle enzymes, leading to a rapid increase of hepatic ammonia clearance after an increased portal ammonia load, even in patients with liver disease (7, 12, 30).

Liver surgery is accompanied by manipulation of the liver and its blood supply, leading to disturbances in hepatic perfusion (1, 10, 24) and probably to some portovenous shunting and increased ammonia levels. Alternative explanations for the observations of increased ammonia and decreased glutamine and glutamate levels may be a decreased glutamine synthetase activity in other organs, for example, in skeletal muscle. Along this line of reasoning, hyperaminoacidemia may lead to increased ammonia production elsewhere in the body.

For practical reasons, blood flow measurements could not be repeated following major hepatectomy. However, total portal blood flow is not affected by major hepatectomy in patients with an otherwise normal liver (18). Therefore, concentration gradients are not expected to be influenced by changes in blood flow through the entire hepatosplanchnic bed. Portal blood flow per gram of liver, however, increases following major hepatectomy, proportionate to the resected volume (18). Consequently ammonia and amino acid supply and metabolism per gram of liver increased vastly, immediately following hepatectomy.

The increased metabolic rate per gram of liver is probably crucial to preserve vital functions such as ureagenesis, protein synthesis, and gluconeogenesis. According to simple biochemical principles, reduction of enzyme availability can be overcome by increasing substrate supply to maintain activity rate. This probably also underlies changes following major hepatectomy where total liver function is preserved [unchanged transsplanchnic amino acid concentration gradients and ureagenesis (28)] at the cost of increased substrate supply [increased systemic (and portal) amino acid concentrations and increased blood flow per gram of liver].

The relative increase in glutamine supply may additionally support the adaptation in ureagenesis because hepatic glutaminase, located predominantly in periportal hepatocytes, has the extraordinary characteristic of being activated by its product ammonia (8, 11, 31). Thus, in addition to the ammonia taken up from the portal blood, ammonia generated locally from glutamine breakdown has a feed-forward effect on hepatic urea synthesis (8, 31). Kaiser et al. (11) suggested that this enhanced local ammonia formation may act as a compensatory mechanism for maintenance of a life-compatible urea-cycle flux in a situation of (temporarily) reduced urea synthetic capacity.

In summary, because at metabolic steady state, the liver removes an equal amount of ammonia from the circulation as added by the intestines, the net contribution of the splanchnic area to systemic ammonia release is probably only minor. Other organs, presumably the kidneys, are more important for systemic ammonia release than the intestines. This holds true even after an acute reduction of over 50% of functional liver mass. Such a reduction does not influence transhepatic amino acid concentration gradients and ammonia flux despite an acute increase of the portal nitrogen load per gram of liver. These data provide additional insights in the pathophysiology of hyperammonemia in liver disease. Given the large adaptive capacity of hepatocytes, hepatocellular dysfunction may be of lesser importance in the pathogenesis of hyperammonemia than generally believed. In support of this proposition, it has been shown that hepatic venous ammonia concentrations equal arterial ammonia concentrations in patients with chronic liver disease (13, 16), providing additional evidence for preserved hepatocellular ammonia clearance in the diseased liver. The important role of the kidneys in the regulation of systemic ammonia release may indicate that therapies aimed at reducing systemic ammonia levels should not only be addressed at intestinal ammonia production but also on renal ammonia production and excretion (4, 5, 19).


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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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) and by a National Grant for Clinical Liver Research from the Dutch Hepatology Society.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. H. C. Dejong, Univ. Hospital Maastricht, Dept. of Surgery, PO Box 5800, 6200 AZ Maastricht, the Netherlands (e-mail: chc.dejong{at}mumc.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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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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