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4 Department of Surgery, Nutrition and Toxicology Institute Maastricht, Maastricht University and University Hospital Maastricht, Maastricht 6202 AZ, the Netherlands; and 5 Institute of Hepatology, Royal Free and University College Medical School, University College London, London WC1 6Hx, UK
* To whom correspondence should be addressed. E-mail: chc.dejong{at}ah.unimaas.nl.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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Factors determining plasma AAA levels
The availability of amino acids (and thus also of AAA) for their specific purposes is determined by the rate at which they appear in the plasma and other pools, as well as the rate at which they disappear through conversion to other amino acids, breakdown, excretion, and incorporation into proteins. Although plasma levels of amino acids may provide important information about metabolic processes, the actual flux of amino acids at the whole body level, across organs, and within cells is much more important. Unfortunately, our knowledge about AAA fluxes at the organ level in humans is still limited for a number of reasons. This is predominantly caused by the fact that the in vivo study of hepatic (and intestinal) amino acid uptake and release requires blood sampling from the hepatic veins and from the portal vein and these are difficult to access in humans for obvious technical, but also for ethical, reasons.
As a consequence, human data on this subject are scarce and mainly concern the results of studies in patients with liver disease and a transjugular intrahepatic portasystemic stent shunt (TIPSS) (3,4), through which the portal vein can be accessed via a percutaneous transluminal approach. In patients undergoing resectional liver surgery for treatment of colorectal liver metastases with curative intent, the function and structure of the nontumorous parenchyma is generally well preserved. In addition, the hepatic veins, the portal vein, and, for example, the renal veins are relatively easily accessible during the operation, enabling blood sampling by direct puncture. In this article, we will review the literature on the classical amino acid imbalance theory. With this review as a background, we will discuss some data on AAA obtained in our unit by investigating interorgan amino acid exchange between the gut, the liver, and the kidneys in patients without portosystemic shunting and/or cirrhosis undergoing resectional liver surgery for metastatic cancer as well as data obtained in our recent studies in patients with stable cirrhosis and a TIPSS (4–10).
AAA in liver failure: relation to ammonia
Some 30 y ago, Fischer and colleagues published their "unified hypothesis on the pathogenesis of HE" (11), based on the observation that during hepatic failure, plasma levels of BCAA decreased and the AAA increased (12–14). These changes in plasma levels were thought to be caused by increased BCAA catabolism in muscle and decreased AAA breakdown in the failing liver (13). A reduction in the insulin/glucagon ratio was hypothesized to play a key role in disturbing the balance between anabolism and catabolism. Accumulation of AAA in the circulation in combination with increased breakdown of BCAA, particularly in skeletal muscle, would, according to this hypothesis, give rise to a decrease in the BCAA/AAA ratio, which was called the Fischer-ratio (BCAA/AAA ratio). The increase in plasma AAA in combination with an increased blood brain barrier permeability for neutral amino acids has been suggested to contribute to an increased influx of AAA in the brain, because they compete for the same transporter (large neutral amino acid transporter). This, in turn, would lead to imbalances in neurotransmitter synthesis and accumulation of false neurotransmitters, such as octopamine in the brain, which may contribute to HE (15).
Hyperammonemia in this hypothesis was thought to contribute in an indirect manner in a number of ways. First, ammonia stimulates the secretion of glucagon, leading to hyperglucagonemia. Second, in a situation of hyperammonemia during liver failure, ammonia is detoxified by alternative pathways, the most important of which, although essentially temporary, is the formation of glutamine from ammonia and glutamate (16). This metabolic pathway takes place mainly in brain and muscle, the latter being quantitatively most important (16). In muscle, BCAA transaminate with 
-ketoglutarate in the BCAA transferase reactions (EC 2.6.1.42), yielding glutamate, explaining why hyperammonemia may contribute to low plasma BCAA. Amidation of glutamate subsequently enhances glutamine synthesis. Following coupling of ammonia to glutamate in the glutamine synthetase reaction (EC 6.3.1.2) as an alternative ammonia detoxification route, glutamine is exported from muscle and brain. The increased cerebral release of glutamine in this hypothesis was thought to facilitate the rapid exchange of glutamine for neutral amino acids, notably the AAA, by the large neutral amino acid carrier (11,17). This increased influx of AAA in the brain would raise the availability of precursors for neutrotransmitters. In addition, increased uptake of tryptophan by the brain contributes to accelerated synthesis of the neurotransmitter serotonin, whereas phenylalanine and tyrosine may disturb brain neurotransmission by promoting the synthesis of cerebral catecholamines and the false neurotransmitters phenylethanolamine and octopamine (11,15).
Reversal of the disturbances was anticipated to occur upon restoration of a normal Fischer ratio, e.g. by the administration of supplemental BCAA (13). Likewise, it was suggested that modulation of catecholamine-derived neurotransmission, by administration of L-dihydroxyphenylalanine (DOPA), could be beneficial (11). However, as an illustration of the intricate relation between hyperammonemia and the AAA hypothesis, the beneficial effects of L-DOPA on the levels of consciousness in patients with HE were later suggested to be due to enhanced renal ammonia excretion as a peripheral effect of dopamine (a derivative of L-DOPA) on renal perfusion rather than its central action (18).
Numerous reports have appeared in the literature confirming the amino acid imbalance between AAA and BCAA, leading to a decreased Fischer ratio in both experimental and clinical liver failure (12,19–22). In rats subjected to acute (24-h) (23–25) or more chronic (1–2 wk) portacaval shunting with or without bile duct ligation as a model of mild chronic hepatic failure (26–28), we also confirmed the reduction in Fischer ratio. This is in analogy with results obtained in the carbontetrachloride model of cirrhosis in rats, which probably is a better model for hepatic cirrhosis (29). Despite the tremendous rise in most amino acids, including the BCAA and AAA, the Fischer ratio also decreased in a rat model of acute hepatic ischemia (23–25), suggesting alterations in Fischer ratio may continue to play a pathophysiologic role in this situation. Also, in a study of rats (30) using total hepatectomy, phenylalanine and tyrosine increased, whereas the BCAA decreased, illustrating that it is the failing liver and altered metabolism that play a role rather than the presence of a diseased or dead organ. Equally, a decrease in blood brain barrier permeability for phenylalanine transport from the brain back to the blood was reported to coincide with increased interstitial brain phenylalanine concentrations in humans with HE (31). In dogs and rats, hepatic coma induced a steep increase in brain concentrations of tryptophan, tyrosine, and phenylalanine, with more limited effects on brain BCAA (24,32,33). Less pronounced changes were also observed in portacaval shunt-based rat models of HE (24,28). In this context, it is worthwhile mentioning that BCAA levels are crucially determined by nutritional factors, whereas AAA levels appear to depend much more upon intact hepatic metabolism (which emphasizes the need for pair-feeding in experimental studies focusing on this subject) (20,28). Albumin has a strong tryptophan-binding capacity and therefore plasma free tryptophan levels are inversely correlated with plasma albumin levels (34). It follows that low albumin levels, e.g. during chronic liver failure, may lead to increased brain uptake of tryptophan because of increased availability of free tryptophan. In addition, the interpretation of the importance of plasma tryptophan levels is confounded by the absence of data on albumin and for this reason the present article focuses more on tyrosine and phenylalanine.
In a hypothesis suggesting a role for AAA in the pathogenesis of HE, a pathophysiological insult known to precipitate HE should preferably be accompanied by changes in brain AAA or their metabolites. However, blood ingestion, a metabolic insult known to precipitate encephalopathy, did not lead to any changes in cerebral tryptophan metabolism in rats with a portacaval shunt (35). We previously showed that an upper gastrointestinal bleed in patients with normal liver function leads to a sudden decrease in the plasma concentration of the BCAA isoleucine coinciding with an insidious but temporary increase in plasma valine and leucine as well as phenylalanine and tyrosine, with no change in tryptophan or ammonia (36). Similar changes in plasma BCAA levels were observed in a small series of patients with hepatic cirrhosis during an upper gastrointestinal bleed (36). As expected, these patients developed hyperammonemia during the upper gastrointestinal bleed (36).
Upper gastrointestinal bleeding is an ammoniagenic and catabolic event, probably due to the absence of isoleucine in the hemoglobin molecule (10,37). This makes blood protein, mainly hemoglobin, a protein of low biological value, which subsequently has to be degraded, contributing to uremia and hyperammonemia. Several of the metabolic abnormalities caused by the upper gastrointestinal bleed, including hyperammonemia, can be corrected by simultaneous intravenous administration of isoleucine, which corrects the abnormal BCAA pattern and improves the biological value of the protein (37–39).
The intimate link between hyperammonemia and the amino acid imbalance theory is further illustrated by the fact that ammonia injections in normal animals induce similar decreases in Fischer ratio (11,40,41). Although basal serotonin levels were unchanged in cerebral cortex microdialysates of rats with a portacaval shunt and in thioacetamide-induced fulminant hepatic failure in rats, an ammonia challenge in rats induced an increase in extracellular serotonin, as well as an increase in brain 5-hydroxyindolacetic acid, a metabolite of serotonin (41). This could contribute to an increased inhibitory neurotransmitter activity in the brain contributing to encephalopathy, although no or only limited effects of serotonin receptor antagonists on consciousness levels have been reported (1). The role of the tryptophan metabolite oxindole remains to be clarified (1).
The association between AAA imbalance and ammonia metabolism probably means that therapeutic benefit may be derived from a variety of treatment options aimed at lowering systemic ammonia levels and restoring the Fischer ratio. Until recently, researchers thought this should be achieved mainly by reducing intestinal amino acid and ammonia absorption by cathartics and antibiotics (1). However, it is becoming increasingly clear that this may not be the only approach to lower systemic ammonia levels (42). As we have demonstrated in the past 15 y (4–6,16,25,26,43–45), the kidney plays a crucial role in the regulation of systemic ammonia levels in various situations in experimental animals and humans, including liver failure and simulated gastrointestinal bleeding. In the physiological situation, 70% of all ammonia formed by the kidney is released back into the renal vein and the remaining 30% are excreted in the urine. In situations of severe hyperammonemia, this ratio is reversed, whereby the kidney becomes an organ of net ammonia excretion from the body.
AAA: effects of varying degrees of liver failure in humans
We recently investigated the effects of temporary vascular inflow occlusion of the liver (Pringle maneuver) in patients undergoing hepatic resection for cancer metastases in an otherwise normal liver. The Pringle maneuver consists of temporary and intermittent occlusion of the hepatic artery and portal vein and can be regarded as a model of temporary metabolic failure (it is clearly also a model of ischemia reperfusion injury). This maneuver is frequently used to reduce blood loss during liver surgery in humans. Usually, cycles of 15-min occlusion and 5-min reperfusion are used during transection of the hepatic parenchyma (7). Arterial samples for amino acids were obtained immediately prior to surgery, before liver transection, and before and after each event of the intermittent Pringle maneuver (2 x 15-min ischemia and 5-min reperfusion) in patients with otherwise normal liver function. Hepatic vascular exclusion led to a mild increase in phenylalanine and tyrosine (Fig. 1) as well as all BCAA (not shown), but tryptophan remained unchanged (Fig. 1). In essence, the Fischer ratio remained unchanged in these patients (not shown). Reinstituting hepatic perfusion restored normal amino acid levels (Fig. 1).
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3 segments) or minor liver resection (<3 segments). Surgical procedures were conducted as described previously (46). Throughout the procedure, the stable isotopes 2H5-phenylalanine and 2H2-tyrosine were infused (following 2H4-tyrosine prime) to measure protein breakdown and synthesis as well as phenylalanine hydroxylation employing classical established tracer methods (47). Blood was sampled from the radial artery, right renal vein, the portal vein, and a major hepatic vein by direct puncture. Organ blood flow was measured by means of Doppler ultrasound (48), allowing flux calculation as a measure of net exchange of amino acids across an organ. Systemic plasma concentrations of BCAA remained essentially unchanged following minor and major liver resection (Fig. 2). AAA levels increased after major hepatectomy (Fig. 2). AAA were taken up by the liver, whereas net BCAA flux across the liver did not differ from zero (Fig. 3). There was an inverse correlation between arterial phenylalanine levels and the residual liver volume following major hepatectomy, calculated from the preoperative CT scans (Fig. 4).
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Phenylalanine is hydroxylated to tyrosine by the enzyme phenylalanine hydroxylase (EC 1.14.16.1), which is present in liver and kidney (34,51). This is why tyrosine is not an essential amino acid for humans, but in situations where the liver and/or kidney fail, tyrosine may become essential. The phenylalanine hydroxylase enzyme is deficient in the inborn error of metabolism phenylketonuria. One of the breakdown products of tyrosine is DOPA, which can subsequently be converted to the catecholamines dopamine, noradrenaline, and adrenaline. Dopamine is an important neurotransmitter in the central nervous system.
In our study in patients undergoing liver resections, whole body phenylalanine hydroxylation did not change following liver resection. Because Indocyanine Green clearance before and after liver resection was similar (data not shown), this indicates that hepatic phenylalanine hydroxylation per gram liver, calculated from the CT scan volumes, must have increased considerably following hepatectomy (assuming renal hydroxylation remains unchanged) (Fig. 2).
It has long been assumed that the conversion of phenylalanine to tyrosine is an exclusive function of the liver. Yet, we and others have repeatedly found in experimental animals and humans that the normal kidney takes up phenylalanine and releases tyrosine (26,52–57), pointing to phenylalanine 4-hydroxylase activity in the kidney (58). Recent data suggest that this renal phenylalanine hydroxylation accounts for 
50% of whole body phenylalanine hydroxylation (56,59). It has been estimated, based on classical requirement data (60,61), that the kidneys alone would be capable of producing all the tyrosine needed by the body. The important role of renal phenylalanine hydroxylation is underpinned by the fact that during chronic renal failure, phenylalanine hydroxylation is impaired (62–65), resulting in hypotyrosinemia (62). Tyrosine deficiency may contribute to net protein catabolism and muscle wasting, and for this reason, tyrosine may be a dietary essential amino acid in end stage renal disease (62,66–69). Whether this plays a role in hepatorenal syndrome is presently unknown.
In addition to the previously mentioned studies in patients with otherwise normal liver function undergoing liver surgery, our group also investigated amino acid metabolism in metabolically stable patients with biopsy-proven cirrhosis of the liver and a TIPSS shunt (4) (Table 1). These patients underwent portography to check the patency of their TIPSS, allowing for blood sampling from the portal and hepatic veins. Patient characteristics have been reported in detail elsewhere (4). In addition, patients were studied prior to insertion of a TIPSS shunt as a treatment for upper gastrointestinal bleeding from esophageal varices due to portal hypertension (6) (Table 1). In metabolically stable patients with cirrhosis of the liver (4), we confirmed the expected hyperammonemia and lower Fischer ratio (due to increased aromatic amino acid levels and reduced BCAA) compared with a historical group of healthy control subjects (70). In patients with an upper gastrointestinal bleed with blood still present in the gastrointestinal tract, the ammonia levels were higher and the Fischer ratio was lower than in subjects from whom blood had been evacuated from the intestines [for details, cf. (6)] (Table 1).
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Recent experience with molecular adsorbent recirculating systems (MARS) during liver failure suggests that a low Fischer ratio can be corrected by recirculating albumin dialysis (71). The MARS system utilizes albumin as a molecular adsorbent to remove both water-soluble and protein-bound toxins, particularly albumin-bound compounds such as ammonia, bilirubin, FFA, and AAA (72). Because the system preferentially removes AAA compared with BCAA, the Fischer ratio increased, predominantly by the removal of AAA in several, though small, series of patients (71,73–75). MARS has been shown to be useful in fulminant hepatic failure by attenuating the increase in intracranial pressure, which plays a major role in this situation (72). There may also be an effect on survival and improvement of degree of HE in patients with an exacerbation of their chronic liver failure (74,76). The role of MARS in a more chronic situation of mild HE, when correction of an abnormal Fischer ratio would likely be more important if this were a major pathogenetic factor, is still unknown and deserves further study. It is currently uncertain how hepatic excretory assist devices, such as MARS, compare with bioartificial liver assist devices, which in addition to their excretory functions also have biosynthetic capacity (74).
An alternative way of normalizing the Fischer ratio would be to raise the plasma levels of the BCAA. Intravenous infusion of leucine in healthy subjects led to a 6-fold increase in its arterial concentration, accompanied by a decrease in plasma tyrosine and phenylalanine levels (19). Valine and isoleucine were much less effective with respect to reducing the AAA (19). A mixture of BCAA (70% leucine, 20% valine, and 10% isoleucine) effectively reduced plasma levels of phenylalanine and tyrosine in patients with liver cirrhosis (19). Similar data were obtained following BCAA infusion after total hepatectomy in rats (77). In humans, results with BCAA supplementation have not been uniformly positive and, as pointed out in a recent review, the data are rather difficult to interpret (78). Although there may be an improvement in encephalopathy scores in patients with chronic HE, other outcome measures did not show important differences (78). Oral BCAA supplementation was until recently a problem because of poor palatability, an issue that may be solved in the future by incorporation into granules (78).
Because ammonia and aromatic and BCAA are metabolically interrelated, it may well be that preventing or treating hyperammonemia is equally effective as BCAA supplementation. In this context, promoting renal ammonia excretion may prove to be a novel target for clinical therapies. Similarly, we have demonstrated recently (10) that isoleucine infusion during a simulated upper gastrointestinal bleed restores the imbalance in BCAA profile, coinciding with improved hepatic and muscle protein synthesis. This may diminish the catabolic state with potentially beneficial consequences for AAA metabolism and ammonia and urea levels.
In the past 4 decades, our knowledge regarding the role of AAA in liver failure has further expanded. Phenylalanine, tyrosine, and tryptophan may all be important in the pathogenesis of HE. It is unlikely, however, that these are the sole factors. We should probably regard HE as a syndrome with a multifactorial pathogenesis, where hyperammonemia, amino acid imbalances in AAA and BCAA levels, as well as brain edema, inflammation, and neurotransmitter changes all interact. Novel therapies to normalize AAA levels in patients with (chronic) liver failure (such as MARS) should probably be combined with selective supplementation, e.g. of isoleucine in patients with gastrointestinal bleeding, and enhancing ammonia excretion by the kidneys.
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FOOTNOTES |
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2 Supported by CHCD: Netherlands Organization for Health Research and Development (clinical fellowship 907-00-033); MCGVDP: Netherlands Organization for Health Research and Development (AGIKO 920-03-317); SWMOD: Netherlands Organization for Health Research and Development (clinical fellowship 907-00-177); the Hendrik Casimir Karl Ziegler Fellowship of the Nordrheinwestfälische Akademie für Wissenschaften, and the Royal Dutch Academy of Science (KNAW).
3 Author disclosures: C. H. C. Dejong, travel expenses to meeting were paid by the Ajinomoto Company, Inc. C. H. C. Dejong is a member of the Enhanced Recovery After Surgery (ERAS) group. From 2006, Fresenius Kabi is the main sponsor of this group; M. C. G. van de Poll, no conflicts of interest; P. B. Soeters, no conflicts of interest; R. Jalan, no conflicts of interest; S. W. M. Olde Damink, no conflicts of interest.
6 Abbreviations used: AAA, aromatic amino acids; BCAA, branched chain amino acids; CT, computerized tomography; DOPA, dihydroxyphenylalanine; HE, hepatic encephalopathy; MARS, molecular adsorbent recirculating system; TIPSS, transjugular intrahepatic portasystemic stent shunt.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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