As early as in the 1960s of the last century especially Harper [1••] has investigated the potential effects exerted by amino acid imbalances. Adverse effects have been observed in experimental animals consuming diets containing disproportionate amounts of amino acids. Such effects may also appear in humans when homeostatic mechanisms regulating amino acid concentrations in body fluids are deficient or defective because of liver or kidney damage, malnutrition or a genetic defect of amino acid metabolism. Moreover, also an overload associated with parenteral or enteral supplied amino acids/proteins can lead to amino acid imbalances.
In a recent publication possibly a new leaf in the field of amino acid imbalances was turned over. Grandison et al. [2••] assessed the influence of various diets on fecundity and lifespan in the fruit-fly Drosophila (the genetic pet of molecular biologists). As already shown by others, the group could confirm that similar to other species also in Drosophila dietary restriction extended healthy lifespan [3–5]. However, this extended lifespan was significantly correlated with a lowered fecundity. Adding back vitamins, lipids or carbohydrates to the restricted diet did not affect fecundity or lifespan, indicating that they do not limit fecundity during dietary restriction and that the increased intake of calories per se does not reduce lifespan. In contrast, addition of amino acids increased fecundity and decreased lifespan, as full feeding (Fig. 1). Adding back nonessential amino acids slightly decreases lifespan, with no effect on fecundity. In contrast, adding back essential amino acids increased fecundity as did all 20 amino acids or full feeding and also decreased lifespan. The effects of full feeding can thus be attributed to essential amino acids in the diet, with reallocation of essential amino acids from reproduction to somatic maintenance on dietary restriction (see Fig. 1).
Experiments to identify the type of essential amino acids responsible for the positive effect on fecundity revealed that only the supplementation of methionine during the dietary restriction condition increases fecundity. Unexpectedly, adding back methionine did not decrease lifespan. Instead, the responses of lifespan and fecundity to full feeding were shown to be independently mediated by different amino acids. In summary, this study illustrates that amino acid imbalances have a direct impact on biological parameters independently of carbohydrate and fat supply.
Certainly these data were created in the fruit-fly and cannot be directly transferred to a clinical context. However, these observations call attention to the important regulatory role of amino acids and should stimulate attention for the potential negative effects of long-lasting imbalances in plasma amino acid pattern such as found in patients with kidney and liver diseases and also during prolonged inflammation or septicaemia, should encourage investigations on specially designed amino acid solutions to counteract these imbalances and restore a balanced plasma amino acid pattern. In the following sections, we discuss old and recent data dealing with amino acid imbalances and amino acid signalling in connection with amino acid imbalances.
Experimentally induced amino acid imbalances
In this section we shortly summarize historical experiments providing high amounts of a single amino acid to animals (mostly rats) and humans [1••]. These results have been discussed in an excellent review article by Garlick in 2004 [6••] in which the original references to the following studies are found. Studies using an excessive intake of single amino acid resulting in imbalances of plasma amino acid concentrations mostly have been performed to assess the safety of high amounts of individual amino acid when given in addition to the normal dietary intake of protein [6••]. The investigated amino acids are arranged alphabetically.
It should be stressed at this point of the discussion that modifications of plasma amino acid concentrations are not necessarily mirrored by equivalent alterations of the intracellular amino acid concentrations which are ultimately relevant for biologic actions. Several amino acid transporters at the cell membrane are competing for amino acid transport into the cell. High concentrations of single amino acids can impair uptake of other amino acids, and this type of amino acid antagonism can profoundly affect the intracellular amino acid pattern.
To start with alanine, in adults, no adverse events were reported after intravenous (i.v.) infusions up to 35 g of alanine over 5 min. We have infused 90 mg/kg/h alanine for duration of 8 h (about 50 g in total) to patients after cholecystectomy, which resulted in an increase in plasma glutamine and α-aminobutyrate and an improved nitrogen balance without observing any negative effects .
Infusions of arginine up to 30 g to evaluate pituitary hormone secretion were well tolerated. Also orally administered arginine up to 30 g/day into patients for stimulating wound healing or the immune-state did not induce any adverse effect except nausea and diarrhoea. However, it is in discussion whether increased arginine by augmenting nitric oxide generation may cause negative hemodynamic effects in patients with severe sepsis.
Aspartic acid is of interest because it is component of the sweetener aspartame (a dipeptide of aspartic acid and phenylalanine). Chronic feeding in growing animals on low-protein diets with aspartic acid depresses growth. In humans, the administration of a 10-g bolus dose of aspartic acid did not result in secretion of pituitary hormones and administration of 130 mg/kg/day (about 9 g for 70 kg) as a supplement to an exercise regimen did not induce any adverse effects.
Of the branched-chain amino acids (BCAAs) it was shown in studies on animals fed a low-protein diet that an excess of leucine causes depression of food intake and growth. This effect was not observed during an excess intake of isoleucine or valine. The BCAAs compete with aromatic amino acid for transport into brain and thus, lower neurotransmitter synthesis. Therefore, BCAAs are under discussion as therapeutical means in the treatment of hepatic encephalopathy (see chapter Plauth, this issue). High amounts of leucine stimulate protein synthesis in skeletal muscle and leucine is broadly used during exercise, sport competition and body-building activities [8,9].
The sulphur-containing amino acids (methionine, cysteine, cystine) are regarded being the most toxic of all amino acids tested. In studies on humans, 5–10 g doses of cysteine-induced nausea, light-headedness, and dissociation. In animals low-protein diets that contain high amounts of cysteine reduced weight gain and resulted in an increased mortality.
Methionine especially was termed the most toxic amino acid by Harper [1••]. In female rats fed diets with 5% methionine, there were no successful pregnancies. Eight grams per day of methionine given for 4 days resulted in decreased folate and an increased white cell count. A range of 10–20 g/day of methionine given orally for 2 weeks led to functional psychosis.
Glutamic acid administration in humans is of interest because the monosodium salt of glutamic acid (MSG) is used as a flavour-enhancing agent. Several reports describe adverse symptoms after the consumption of Asian food, a phenomenon generally known as ‘Chinese restaurant syndrome’. This symptom occurs in a subpopulation of participants after the administration of more than 3 g of MSG. This is remarkable because other studies in adults have shown that chronic treatment with 45 g of glutamic acid for 11 months induced no adverse effects. Both of these results clearly demonstrate that individual amino acids may cause different effects when given in various subgroups of healthy participants or of patients.
Infusion of 0.57 g/kg/day of glutamine (equivalent to 40 g/day and 70 kg body weight) to healthy people increased plasma glutamine by 25% above control values . Glutamine infusions were well tolerated and neither ammonia nor glutamic acid increased significantly. However, in cirrhotic patients we could show that enterally but not parenterally supplied glutamine increased plasma ammonia .
Glycine was a key amino acid in the first commercial amino acid solution for i.v. nutrition and was infused in large quantities (up to 15 g/day) in different groups of patients without any observed side-effect. Subsequent studies revealed that glycine has immune-modulating properties and infusions up to 20 g/day to intensive care patients were without any adverse effects. However, experimental studies with i.v. infusion of 1 g/kg/day resulted in neurological symptoms.
A high histidine intake in animals resulted in hypercholesterolemia, hyperlipidemia, enlarged liver, and depression of growth and food intake. These results were confirmed in human studies as 24–64 g/day of histidine caused headache, weakness, drowsiness, nausea, anorexia, mental confusion, and depression. No overt side-effects were seen when up to 4.5 g/day histidine was given as treatment for obesity, rheumatoid arthritis, and chronic uraemia.
Lysine shows little toxicity. In studies in chronic diseases, adults given 40 g/day for 2–5 days or up to 3 g/day for up to 6 months did not develop any negative effects except gastrointestinal discomfort.
Humans with normal phenylalanine metabolism (without phenylketonuria) did not show any adverse effect when fed with a single dose of 10 g phenylalanine or 4 g as a component of aspartame.
In one study, proline supplementation (3–10 g/day) was given to patients with gyrate atrophy (lack of ornithine aminotransferase) with no reports of any deleterious effects. Similar to proline neither for serine (up to 15 g) nor for threonine (up to 22.5 g) any toxicity was reported.
Tryptophan is the least abundant amino acid in our diet. It serves as a precursor amino acid for the synthesis of the neurotransmitter serotonin which affects mood, appetite, and sleep. For sleeplessness, 2 g of tryptophan therapeutically is recommended as a mild sedative. The only critical incident reported during the therapeutic use of tryptophan was an outbreak of eosinophilia–myalgia syndrome which may have resulted from a contaminant in the tryptophan produced by one single manufacturer.
After giving a dose of 14 g of tyrosine in adults no psychological or physical effects were detected. However, children with tyrosinaemia, elevated tyrosine plasma concentrations persisting for more than 45 days were associated with lower scores of intellectual ability.
These findings mainly describe artificially generated imbalances induced by exogeneous administration of an excess of a single amino acid. Regarding the measured endpoints most of the supplied amino acids did not cause any toxic effects in humans even when given in multiple amounts of normal intake. One explanation for this low toxicity of amino acids is that there is a metabolic adaptation to compensate an excess administration that takes time to be fully expressed. In contrast, animal experiments revealed a retarded growth rate when a low-protein intake was combined with an oversupply of a single amino acid. It is to question whether this experimental approach – plasma amino acid elevation caused by excess supply of a single amino acid – is comparable to amino acid imbalances caused by disease processes or organ dysfunction.
The focus of the study in Drosophila discussed above is fundamentally different from this ‘single amino acid approach’, because the investigators in their model have compared a large number of differently composed amino acid solutions – an approach which is surely easier to perform in fruit-flies than in patients [1••]. However, we can learn from this study that amino acids are prominent regulatory effectors which may influence several endpoints different from nitrogen metabolism.
Therefore, the following sections will discuss amino acid imbalances occurring in kidney and liver dysfunctions and recent investigations on the impact on amino acid signalling.
Amino acid imbalances in kidney diseases
The uraemic syndrome is multifactorial and affects most physiologic processes and organ functions. In patients with chronic renal failure (CRF) malnutrition is common and is generally of a mixed type with low body weight, loss of somatic protein (low muscle mass), low plasma levels of serum albumin and other visceral proteins as well as depletion of energy (adipose tissue) stores. In various studies, malnutrition has been observed in 10–70% of haemodialysis patients and in 18–51% in patients treated with continuous ambulatory peritoneal dialysis .
Patients with CRF exhibit several abnormalities in amino acid metabolism due to nutritional inadequacy, endocrine disturbances, uremic toxic effects and consequences of renal replacement therapy [13–15]. Moreover, protein and amino acid metabolism in kidney insufficiency are affected by impairment of multiple metabolic functions of the kidney itself; various amino acids are synthesized or converted by the kidneys and released into the circulation: arginine, tyrosine, cysteine, methionine (from homocysteine) or serine. Thus, loss of renal function can contribute to the altered amino acid pools in renal failure and several amino acids which conventionally are termed nonessential, such as arginine, tyrosine or cysteine might become conditionally indispensable.
One study investigated free amino acid concentrations simultaneously in plasma, erythrocytes (RBC) and muscle of uraemic patients (patients on haemodialysis, continuous ambulatory peritoneal dialysis, and predialysis patients) . Interestingly, amino acid alterations were not in parallel in the three compartments. For a number of nonessential amino acids (alanine, glycine, asparagine, arginine) and for lysine, elevated concentrations were present simultaneously in RBC and in muscle, but not in plasma. On the contrary, low concentrations of some essential amino acids (leucine, valine, phenylalanine, tyrosine) were observed in RBC and plasma, whereas the concentrations in muscle were normal.
These results show that muscle, RBC, and plasma play independent and sometimes opposing roles in amino acid interorgan transport and that differing amino acid abnormalities are found in the three compartments. As already mentioned, plasma amino acid concentrations do not necessarily reflect the intracellular concentrations as the distribution of some amino acids between the extracellular and intracellular compartment can be severely altered in several disease processes.
In acute renal failure (ARF), protein metabolism in many aspects shares similarities with that observed in other acute disease states. ARF presents a hypercatabolic, an inflammatory and pro-oxidative state and it is important to note that in a patient with ARF several mechanisms can aggravate this metabolic response syndrome. Actually, the main characteristic of metabolic alterations in ARF is the augmented activation of protein catabolism with excessive release of amino acids from skeletal muscle and sustained negative nitrogen balance. Muscular protein degradation and amino acid catabolism are activated. Not only is protein breakdown accelerated but there is also defective muscular utilization of amino acids for protein synthesis. Amino acid transport into skeletal muscle is impaired in ARF and this abnormality can be linked both to insulin resistance and to a generalized defect in cellular ion transport in uraemia; both the activity and receptor density of the sodium pump are abnormal in adipose cells and muscle tissue. As a consequence of these metabolic changes, imbalances in amino acid pools in plasma and in the intracellular compartment occur in ARF and a typical plasma amino acid pattern is induced which is characterized by elevated concentrations of cystine, taurine, methionine, and phenylalanine and decreased one of valine and leucine [17,18].
Amino acid imbalances in liver diseases
The liver plays an outstanding role in interorgan metabolism of amino acids. In a catabolic situation amino acids are redistributed from muscle tissue to the liver. An elevated hepatic extraction of amino acids via the portal vein is necessary for an increased hepatic gluconeogenesis and ureagenesis. Moreover, also the hepatic protein synthesis and secretion of acute phase proteins are stimulated. Therefore, it is understandable that hepatic dysfunction has a sustained influence on overall amino acid metabolism.
We compared the plasma and skeletal muscle amino acid pattern of patients with liver cirrhosis before shunt operations, liver malignoma, encephalopathy due to compensated liver disease (PSE) and patients with acute viral hepatitis and hepatic coma (FHF) . A comparison of total plasma and muscle amino acid concentrations in patients with liver diseases and healthy participants showed that the highest increases in amino acid concentrations occurred in FHF (plasma: five-fold to six-fold and muscle: 1.6-fold). The aromatic amino acid tyrosine and phenylalanine were significantly increased in plasma and muscle of all groups. Increased plasma levels of methionine were found in liver cirrhosis, PSE, and FHF. Skeletal muscle methionine was elevated in FHF and PSE. Plasma glutamate levels were lower in liver cirrhosis, liver malignoma, PSE, but higher in FHF, muscle glutamate levels were decreased in all patient groups. Glutamine was significantly increased in plasma and muscle of FHF but decreased in muscle of PSE patients. The plasma levels of the BCAA (valine, leucine, isoleucine) were lower than normal in liver cirrhosis, liver malignoma, and PSE, but higher in FHF. Muscle BCAAs were increased in PSE and FHF. These results indicate that alterations in muscle and plasma amino acid pattern of patients with liver dysfunction are mostly paralleled. This is different to uraemic amino acid pattern (see above) and also to patients with sepsis or inflammation.
A recent study investigated plasma amino acid imbalances in relation to the progression of liver fibrosis . Amino acid imbalances progressed with the evolution of cirrhosis. Imbalances of tyrosine were found in the early stage of liver diseases, whereas BCAAs remain within normal range in the majority of patients with chronic liver diseases during stages F1–F3 and decreases in F4. Moreover, the BCAA to tyrosine ratio decreased significantly as chronic hepatitis progressed to liver cirrhosis. The presence of this amino acid imbalance is associated with a reduction in the serum albumin level 1 year later .
There have been several attempts to use specially composed amino acid solutions and especially those containing increased amounts of BCAAs for the treatment of hepatic encephalopathy. In spite of some successful trials, for the time being administration of amino acid solutions enriched with BCAAs to patients with liver cirrhoses is controversially discussed and not performed regularly (see Mathias Pauth, this issue).
Amino acid imbalances: influence on signalling
As discussed above, a variation of amino acid supply to Drosophila influences lifespan and fecundity [2••]. Therefore, it is of high interest to understand which molecular mechanisms are related to these observations. In the Drosophila experiment it could be demonstrated that an amino acid imbalance leads to transformed insulin/insulin-like growth factor (IGF) signalling (IIS). Similar to the supply of special amino acids, also genetic interventions reducing IIS pathway extend lifespan of worms, flies, and mice [22–24]. Mutations that alter IIS can have pleiotropic effects on growth and metabolic homeostasis but also on fecundity . Interestingly, lowered IIS can indeed improve health at older age . For instance, long-lived mice lacking IRS-1 (insulin receptor substrate) maintain glucose homeostasis better than controls in older age. These knockout mice also show improvements in immune profile and motor performance, as well as lowered incidence of osteoporosis, cataract and ulcerative dermatitis . It is a fascinating vision that amino acid imbalances (lowered essential amino acid) may evoke similar effects.
In mammals, the impact of nutrients on gene expression has become an important area of research [26,27]. Amino acids have multiple and important functions, their homeostasis has to be finely tuned and maintained. In relation to amino acid imbalances investigations in rats revealed that feeding an amino acid-imbalanced diet is resulting in anorexia and a reduced uptake of the imbalanced food [28••]. The decrease in blood concentration of the limiting amino acids becomes apparent as early as a few minutes after feeding an imbalanced diet. A fall of the limiting amino acids in plasma is perceived in the brain. It has been proposed that a specific brain area, the anterior piriform cortex, can sense the variations in amino acid concentrations and lastly mediates an inhibition of food intake.
Low-amino acid uptake as during malnutrition effects the expression of several genes. It is not the scope of this section to describe all the upregulated and downregulated genes affected by amino acid deprivation but among these genes several encode plasma membrane transporters [29,30]. We are on the way to understand that the substrate-binding sites of amino acid transporters are potentially direct sensors of amino acid availability at both faces of the cell surface and may operate as transporter-like sensors (or transceptors) upstream of mTOR . These amino acid transceptors can be regarded as gate keepers of nutrient exchange and regulators of nutrient signalling and form a bridge between cell-transporters (outside) and the mTOR/AMP-activated kinase (AMPK) regulating system (inside) . mTOR plays a key role in determining how nutrients (and also growth factors, oxygen levels) modulate intracellular events critical for the viability and growth of the cell. Nutrients sensing via mTOR are partly regulated via the AMPK pathway (cell starvation) and also by amino acid supply. Studies of our group performed in monocytic cells revealed that glutamine starvation causes a sustained decline of ATP levels followed by an activation of the AMPK . Activation of AMPK downregulates biosynthetic pathways such as fatty acid and cholesterol biosynthesis, yet switches on catabolic pathways that generate ATP, such as fatty acid oxidation, glucose uptake and glycolysis. The AMPK activation also influences mTOR regulation and it is known for many years that amino acids can affect mTOR signalling.
Moreover, amino acids regulate various transcription factors, such as the basic-leucine zipper factors, CCAAT/enhancer-binding protein, as well as specific regulatory sequences, such as amino acid response element and nutrient-sensing response element . Recent investigations revealed that essential amino acids can alter microRNAs expression in skeletal muscle and also growth-related genes which means that amino acids via microRNA switch on or off a series of genes .
We have to learn from basic research that amino acids may exert an enormous significance on regulative elements of cells. In this respect, we should reassess the question about the impact of amino acid imbalances or substitution on regulative cell functions during illness. There are some first experiments investigating the effect of amino acids on regulative cell elements in disease processes. So it was shown that proline and glutamine supplementation increased hepatocyte growth factor gene expression after hepatectomy in malnourished rats . In human liver carcinoma cells (HepG2) glutamine, leucine and proline attenuate IL-8 production, probably through inhibition of NF-κB, and by increasing Akt (a serine/threonine protein kinase) phosphorylation . Glycine pretreatment ameliorates liver injury after partial hepatectomy in the rat and decreased hypoxia-inducible factor-1 (HIF-1) . The administration of BCAAs improves glucose metabolism in cirrhotic patients. BCAA supply accelerated the expression of the glucose-sensing apparatus in HepGs cells and in rat liver . BCAAs stimulated the expression of GLUT2 and L-GK in HepG2 cells and also the expression levels of L-GK, SREBP-1c and LXRα and suppressed the expression levels of G-6-Pase in rat liver. It is amazing that BCAA are closely related to the bioactivity of the glucose-sensing apparatus. These results indicate that amino acids have a potent role in changing cell signalling and it can be assumed that amino acid imbalances act partly via these regulating systems described above.
Approaches for balancing amino acid pattern
The results raise the question of how we could – in a translational approach – merge the experimental observations with the clinical findings of altered amino acid pools in various disease states. One obvious approach is to try to formulate amino acid solutions to avoid or compensate amino acid imbalances. This seems to be difficult because the amino acid patterns vary between different compartments as clearly shown in uraemic patients .
In the past, amino acid solutions have been mainly composed to support optimal growth or improve nitrogen homeostasis, but not to compensate for disease-related amino acid changes (see this issue). Unfortunately, most available amino acid solutions for clinical use are based on the composition of reference proteins of a normal oral diet. Neither do these solutions take into account the fact that i.v. solutions have a completely different metabolic behaviour as oral protein because the hepatic first pass effect is circumvented nor do they take into account the altered amino acid metabolism in various disease states.
For the glutamine deficiency described in catabolic disease states a glutamine supplement (as a glutamine-containing dipeptide) was developed. However, because of the reasons discussed above, it seems to be of interest to develop ‘disease-specific’ amino acid solutions which compensate the whole pattern of amino acid imbalances in various diseases.
Actually, during the late 1970s and 1980s of the last century, there were systematic attempts to define amino acid solutions adapted to the specific metabolic situation in disease processes. In order to achieve this goal, the groups of Bürger, Leweling and us have used a pharmacological approach. During infusion experiments the pharmacokinetic behaviour of each single amino acid was evaluated in patients with various diseases. Using a specific algorithm a disease-specific amino acid pattern was defined according to the pharmacokinetic behaviour of each amino acid. Amino acid having a lower plasma concentration and a higher metabolic clearance rate had a higher concentration in the novel amino acid solution, those with a higher plasma concentration and a lower metabolic clearance rate a lower concentration. Such ‘transfer rate adapted’ amino acid solutions were developed for pediatric use, for liver failure and renal failure according to this concept [39–41].
Our group developed a balanced amino acid solution for patients with ARF (and CRF), actually worldwide the first amino acid solution containing a tyrosine dipeptide to provide tyrosine as conditionally essential amino acid in renal failure. We could demonstrate that in renal failure the elimination of amino acid from the intravascular space is profoundly altered in comparison to healthy participants [42••,43]. Interestingly, the pattern of metabolic aberrations was similar in ARF, CRF, and RDT groups.
In a subsequent study such a pharmacological-adapted amino acid solution was compared with a standard amino acid solution [44••]. Indeed, the novel amino acid solution corrected the deranged plasma concentrations of most of the amino acids in patients with ARF whereas a standard amino acid solution aggravated these imbalances. These results indicate that a pharmacological approach considering the metabolic clearance rates of individual amino acids offers a feasible possibility to overcome amino acid imbalances in disease states and that the conventional concept or ‘standard amino acid solutions’ has to be questioned.
The interest in novel approaches of i.v. amino acid therapy has vanished during the last decades. For the time being special amino acid solutions for specific diseases are rarely recommended and the pharmaceutical industry has stopped all further developments in this field mainly because of commercial reasons. However, it is tempting to hypothesize that the fascinating new findings on the impact of amino acid imbalances on biological variables in the fruit-fly may initiate a new area in the design of amino acid solution adapted for various disease states.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 106).
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This is a classical publication in this field.
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