Norman N. Yoshimura

Plasma amino acids in patients with hepatic encephalopathy. Effects of amino acid infusions.

Abstract Amino acid patterns in a group of patients with severe liver disease and hepatic encephalopathy were studied when patients were taking proteinrestricted diets per os and being infused with two solutions used for total parenteral nutrition. A somewhat constant amino acid pattern was found, with elevated levels of phenylalanine and methionine and decreased levels of the branched chain amino acids isoleucine, leucine, and valine. Patients with severe liver disease are apparently unable to utilize some essential amino acids, creating an amino acid imbalance. The significance of these findings and their possible relation to hepatic encephalopathy are discussed.

Scientific paperPlasma amino acids in patients with hepatic encephalopathy: Effects of amino acid infusions☆☆☆

Abstract Amino acid patterns in a group of patients with severe liver disease and hepatic encephalopathy were studied when patients were taking proteinrestricted diets per os and being infused with two solutions used for total parenteral nutrition. A somewhat constant amino acid pattern was found, with elevated levels of phenylalanine and methionine and decreased levels of the branched chain amino acids isoleucine, leucine, and valine. Patients with severe liver disease are apparently unable to utilize some essential amino acids, creating an amino acid imbalance. The significance of these findings and their possible relation to hepatic encephalopathy are discussed.

Intravenous hyperalimentation with high arginine levels improves wound healing and immune function

The purpose of this study was to evaluate the effect of increased arginine levels in intravenous hyperalimentation (IVH) therapy on wound healing and thymic immune function. Groups of SD rats, 275-325 g, underwent placement of internal jugular catheter, 7-cm dorsal skin wounding, insertion of polyvinyl alcohol sponges subcutaneously, and closure of wounds with stainless-steel sutures. Twenty-four hours later, rats were started on IVH at a rate of 0.8-1 ml/100 g body wt/hr. All IVH solutions contained 20% dextrose, adequate amounts of minerals and vitamins, and two different amino acid mixtures: (A) Fre III (4.05 g ARG/liter) (n = 13); (B) experimental (7.50 g ARG/liter) (n = 11). Solutions were isonitrogenous, and contained similar amounts of essential amino acids. After 7 days of IVH, weight gain did not differ between the two groups; however, cumulative N balance was superior in group A. Wound healing was improved in group B as assessed by fresh wound strip breaking strength, fixed breaking strength, and the amount of reparative collagen deposition as assessed by the hydroxyproline content of the implanted sponges. Group B animals also had improved thymic function as assessed by thymic weight, the total number of thymic lymphocytes/gland and mitogenic reactivity of thymic lymphocytes to PHA and Con A. The experiments indicate that high arginine levels in IVH solutions improve wound healing and thymic immune function following injury.

Infusion of Branched-chain Enriched Amino Acid Solution in: Patients with Hepatic Encephalopathy

Hospitalized patients with hepatic insufficiency often suffer from severe catabolic states and are in urgent need of nutritional support during their acute illness. Protein intolerence, however, remains a significant problem with respect to the provision of adequate nutrition, either enterally or parenterally. The following report is an anecdotal series of 63 consecutive patients in a large urban hospital treated prospectively with nutritional support using a prototype high branched-chain amino acid solution (FO80) given by technique of total parenteral nutrition by the subclavian or internal jugular route with hypertonic dextrose. Sixty-three patients, of which 42 had chronic liver disease (cirrhosis) with acute decompensation and 17 with acute hepatic injury as well as four with hepatorenal syndrome, are the subject of this report. All required intravenous nutritional support and were either intolerant to commercially available parenteral nutrition solutions or were in hepatic encephalopathy at the time they were initially seen. The cirrhotic patients had been hospitalized for a mean of 14.5 +/- 1.9 days before therapy, had a mean bilirubin of 13 mg/100 ml, and had been in coma for 4.8 +/- 0.7 days despite standard therapy. Patients with acute hepatitis had been in the hospital for 16.2 +/- 4.1 days before therapy, had a mean bilirubin of 25 mg/100 ml, and had been in coma 5.2 +/- 1.6 days before therapy. Routine tests of liver function, blood chemistries, amino acids, EEGs, and complex neurological testing including Reitan trailmaking tests were used in the evaluation of these patients. Up to 120 grams of synthetic amino acid solution with hypertonic dextrose was tolerated in these patients with improvement noted in encephalopathy of at least one grade in 87% of the patients with cirrhosis and 75% of the patients with hepatitis. Nitrogen balance was achieved when 75 to 80 grams of synthetic amino acids were administered. Survival was 45% in the cirrhotic group and 47% in the acute hepatitis group. Encephalopathy appeared to correlate with individual amino acids differentially in the various groups and with the ratio between the aromatic and the branched-chain amino acids. Ammonia did not correlate with either the degree of encephalopathy or improvement therefrom. In 24 Patients therapy for hepatic encephalopathy was limited to infusion of the branched-chain enriched amino acid solution only, with wake-up in 66% of this group. The results strongly suggest that in protein intolerant patients requiring nutritional support, infusion with branchedchain enriched amino acid solutions is well tolerated with either no worsening of or improvement in hepatic encephalopathy coincident with the achievement of nitrogen equilibrium and adequate nutritional support.

Brain tryptophan, plasma free tryptophan and distribution of plasma neutral amino acids

Although rat brain tryptophan is strikingly elevated following portacaval shunt, plasma total tryptophan is unchanged and plasma free tryptophan is not elevated to the same degree as brain tryptophan. Investigation of the concentrations of the neutral amino acids (phenylalanine, tyrosine, methionine, threonine, leucine, isoleucine, and valine) revealed that their distribution and the sum of their concentrations were altered following portacaval shunt, and that this pattern was similar to that seen in humans with cirrhosis of the liver. It is suggested that both the elevation in plasma free tryptophan and the decrease in the competing neutral amino acids, act together to increase the transport of tryptophan into brain when portal blood is diverted around the liver. The implications of these findings in therapy of hepatic coma is discussed.

High arginine levels in intravenous hyperalimentation abrogate post-traumatic immune suppression.

Trauma victims often suffer immune system failure. Oral arginine has strong immune-enhancing properties. The metabolic, hormonal, and immune effects of increasing concentrations of arginine as part of post-trauma intravenous hyperalimentation (IVH) were studied. Groups of 11-14 rats, 275-350 g, underwent jugular vein catheterization and bilateral closed femoral fractures under anesthesia. IVH was started immediately postinjury at a rate of 0.8-1 ml/100 g body wt/hr and continued for 5 days. Twenty percent dextrose and three different amino acid mixtures were given as follows: (A) FreII (1.55 g ARG/1); (B) FreIII (4.05 g ARG/1); (C) modified FreIII (7.9 g ARG/1). All rats lost weight over the 5-day postinjury period; however, rats in groups B and C lost significantly less weight than rats in group A (-3.4 +/- 0.8% of initial body weight and -3.6 +/- 0.9% vs -6.1 +/- 1.2%, P less than 0.05). Rats in group A had negative cumulative nitrogen balance, while those in groups B and C were in highly positive balance. No significant difference in body weight change or nitrogen balance was noted between groups B and C. Trauma-induced thymic involution as assessed by thymic weight and lymphocyte content was greatest in group A, which received the lowest amount of arginine, and was linearly abrogated by increasing the amount of arginine administered (A less than B less than C). Thymocyte immune responsiveness increased with the amount of arginine given as assessed by mitogenesis in response to Con A (stimulation index: A--151.3 +/- 28.8 vs B--243.6 +/- 29.2, P less than 0.01 vs C--321.8 +/- 22.3, P less than 0.001 vs A and P less than 0.02 vs B) and PHA (A--65.0 +/- 14.3 vs B--67.7 +/- 15.3, NS, vs C--117 +/- 14.0, P less than 0.005 vs A and B).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma amino acids in dogs with two experimental forms of liver damage

Abstract Mongrel dogs were subjected to two experimental forms of hepatic damage, 2,4-dimethylnitrosamine ingestion, and end-to-side portacaval shunt. Of the two, portacaval shunted animals gave an amino acid pattern much more similar to that found in man. It is suggested that this animal model be used for a study of amino acid patterns in total parenteral nutrition solutions as compared with man.

Glycerol: Its Metabolism and Use as an Intravenous Energy Source

Le glycerol participe a la gluconeogenese insulinogenique a un faible degre anticetogene, compatible cliniquement avec des aminoacides et a une densite calorique plus elevee que le glucose

Optimal Levels of Arginine in Maintenance Intravenous Hyperalimentation

The optimal levels of arginine (Arg) for growth and immunity were studied in mildly depleted, noninjured rats maintained on intravenous hyperalimentation. Three groups of S-D rats (eight/group, weighing 275-300 g) underwent catheter insertion, 1 day of fasting, and then 7 days of intravenous hyperalimentation consisting of 20% dextrose, adequate minerals and vitamins, and three amino acid regimens: (1) FreAmine II (1.55 g Arg/liter); (2) FreAmine III (4.05 g Arg/liter); (3) experimental (7.5 g Arg/liter). The increase in arginine levels was achieved by lowering the glycine levels. There were no differences among the groups in terms of body weight gain (6.9 vs 8.3 vs 10.0 g) or in cumulative N balance (574 vs 660 vs 642 mg). Liver, spleen, and adrenal weights did not differ. Thymus weight was greater in groups B and C: (A) 345 +/- 27 mg vs (B) 445 +/- 34 mg, p less than 0.05, vs (C) 438 +/- 26 mg, p less than 0.05) as were the total number of lymphocytes/thymus (X 10(-9) (A) 0.93 +/- 0.12 vs (B) 1.37 +/- 0.18, p less than 0.05, vs (C) 1.46 +/- 0.15, p less than 0.05). Mitogen-induced thymocyte blastogenesis (cpm) was greatest in group C in response to phytohemagglutinin: (A) 9.558 +/- 3,799 vs (B) 20,088 +/- 5,890, NS, vs (C) 37,234 +/- 6,209, p less than 0.01 vs A and p less than 0.05 vs B) and Concanavalin A: (A) 71,035 +/- 15,228 vs (B) 111,734 +/- 15,021, NS, vs (C) 172,967 +/- 19,861, p less than 0.01 vs A and p less than 0.05 vs B). In the intravenous hyperalimentation-maintained noninjured rat ARG concentrations more than 1.55 g/liter do not enhance N retention or growth. Larger doses of ARG have strong thymic immunostimulatory effects without any toxicity or growth reduction.

The role of alanine in the nitrogen conserving quality of the branched-chain amino acids in the postinjury state

Abstract In a recent study from this laboratory the improved nitrogen-conserving quality of the branched chain amino acids (BCAA) in the post-traumatic state was demonstrated. A number of properties have been ascribed to the BCAA which may be responsible for these effects. In order to elucidate which of these properties ascribed to the BCAA is responsible for this nitrogen-sparing effect, three groups of rats were infused with 8% dextrose, 3% alanine in 5% dextrose, or 3% solution of all the branched-chain amino acids (100% BCAA) in 5% dextrose after undergoing laparotomy and jugular vein cannulation. The groups of animals receiving 100% BCAA showed less negative nitrogen balance and lost less weight than the animals receiving isocaloric 8% dextrose. The group receiving 100% BCAA had a significantly better nitrogen balance than the alanine group. The plasma and muscle amino acid pattern of the 100% BCAA is more nearly normal as compared with the other groups suggesting decreased amino acid efflux from muscle. That the group receiving 100% BCAA showed better nitrogen balance than the alanine group combined with the near normal plasma and muscle amino acid pattern in the 100% BCAA group suggests that the mechanism of the improved nitrogen-conserving quality of the BCAA in the post-traumatic state is not only through increased alanine production and gluconeogenesis by BCAA infusion, but is probably a combination of the BCAA being used as energy substrate in the muscle, serving as a substrate for alanine production and gluconeogenesis and blockage of amino acid efflux from the muscle.