The functional disturbances of the central nervous system in hepatic encephalopathy are due to several coexisting pathogenetic factors: Endogenous neurotoxins, imbalance of amino acids in blood plasma and alterations of the blood-brain barrier. These factors, in turn, effect alterations of neurotransmitters and their receptors. Therapeutic interventions are aimed at the inhibition of ammonia production by protein restriction, lactulose or antibiotics. A new therapeutic concept is the application of branched chain amino acids. Their effect is based on the stimulation of protein synthesis in muscle, enhanced urea synthesis in the liver and increased ammonia detoxification by glutamine synthesis in the brain.
Isolated perfused rat liver is a well-established experimental model for studies on hepatic amino acid and ammonia metabolism. Some aspects and modifications of the liver-perfusion technique are discussed. Perfusion studies with the intact liver have the fundamental advantage that the structural and functional organization of the liver is preserved; however, the experimental system is more complex in view of sub-cellular and intercellular compartmentation and the recently demonstrated metabolic interactions of different cell populations at the acinar level. These problems of complexity by compartmentation can be largely solved by introducing further techniques such as organ spectrophotometry, the retrograde/antegrade perfusion technique, use of micro-oxygen-electrodes, use of selective inhibitors, radiolabeled compounds, different fractionation techniques of the liver tissue. By means of these approaches, intracellular events can be followed up not only indirectly by analyzing the composition of the perfusate before and after a liver passage, but also directly in the different subcellular and subacinar compartments of a structurally and metabolically intact liver.
Twelve patients with chronic renal failure who exhibited a progressive decline in 24-h creatinine clearance despite being given, for 2-10 months, a diet containing 0.3 g of protein/kg ideal weight and 7-9 mg of phosphorus/kg ideal weight supplemented with vitamins, CaCO3, and 10 g per day of essential amino acids, were changed to a supplement containing predominantly keto acids. In 6 patients whose serum creatinine levels were 7.5 mg/dl or greater at changeover, progression continued unabated. In 6 patients with serum creatinine levels at changeover of 6.5-7.4 mg/dl, one was non-compliant with the diet and progressed to dialysis. In the other 5, progression, measured as the rate of change of a bimonthly radioisotope clearance, has been undetectable during the ensuing 1-2 years.
The aim of the study was to use glucose, fructose and xylitol as alternative carbohydrates in hypocaloric parenteral nutrition (HPN) and to investigate their different nutritional effects. Twenty-four patients who had undergone elective gastrointestinal resection were examined in a prospective randomized study. Only metabolically normal patients between 30 and 65 years of age were admitted to the study. No patient with a body weight more than 20% above or below the normal weight of the patients was admitted. The study period extended from the operation day to the fifth postoperative day. The patients were given approximately 1.1 g amino acids and approximately 2.9 g carbohydrates per kg/B.W. and day using either glucose, fructose or xylitol as carbohydrates. The mean plasma glucose concentrations ranged between 6 and 8 mmol/l without insulin being supplied. There were no significant differences between the groups. However, the administration of glucose led to a somewhat larger dispersion range of the values. The labile plasma proteins (transferrin, prealbumin, retinol-binding protein) in the 3 groups revealed almost identical concentration courses. With N-losses between 51 and 57 g/4 days, only slightly negative cumulative N-balances were calculated (-4 to -13 g/4 days). No significant differences were observed between the 3 groups in the level of the urea-N production rates. Advantages which favor a general administration of fructose/sorbitol or xylitol in HPN could not be found in our investigation.
The rate of procedure-related side-effects was evaluated in 11,895 cytaphereses performed with a Haemonetics 30 (H-30) cell processor (2,486 procedures) or with a Haemonetics V-50 (H-50) cell processor (6,813 procedures) or with the Fenwal CS-3000 cell processor (2,596 procedures). The overall rate of side-effects was 7.41% (absolute number 881). There was a significant difference between female and male donors concerning the frequency of hypotension episodes and citrate toxicity related reactions. There were also distinct differences between the single cell separator types concerning the frequency and type of side effects. Hypotension episodes and citrate-related reactions were observed most frequently during cytapheresis with the H-30 (7.65 and 2.96% respectively). Venous access and technical problems appeared more often when the H-50 or the CS-3000 were used. Thus both the H-50 as well as the CS-3000 cell separators allow safe cytapheresis with a low number of side-effects.
Donors risk lymphopenia as a result of thrombocytapheresis as well as leukapheresis. The importance of the removal of lymphocytes is speculative at present. In the study presented, 10 healthy blood donors underwent 5 consecutive, discontinuous flow-leukapheresis procedures in weekly intervals with the effect of a total loss of 2.6 X 10(10) lymphocytes. The number of peripheral lymphocytes decreased steadily from 1,850 +/- 417/microliter to 1,451 +/- 411/microliter over the 5-week period. A significant decrease comprised also OKT3+-, OKT4+- and B-lymphocytes but not OKT8+-cells. Accordingly the OKT4/OKT8 ratio was reduced though not significantly from 1.41 +/- 0.25 to 1.32 +/- 0.27. 6 months after the last apheresis, the total lymphocyte count, OKT3+- and B-lymphocytes were still significantly low. The long-lasting peripheral lymphopenia in cytapheresis donors has to be taken into account as one of the criteria for donor selection. Donors with less than 1,000 lymphocytes/microliter of peripheral blood should be excluded from cytapheresis procedures.
We report the case of a prematurely born, 39-day-old male infant with a history of mechanical ileus and perforated colon in which blood grouping showed group 0 Rh (D)-positive without particularities. Minor tests, however, were distinctly positive in 4 units of blood, whereas all major tests were negative. There is strong evidence that the positive minor cross-reaction was caused by in vivo RBC T-activation with subsequent donor serum anti-T agglutination.
Protein synthesis L-(l-14C) leucine in liver was studied. Normal (n = 40) and operated (n = 40) Sprague-Dawley rats with an initial body weight of 161.18 +/- 12 g were divided into four groups (n = 10), respectively. Each group, subjected to the same conditions of temperature, light, noise and movement received a different commercial formula for human enteral nutrition and water for 8 days (normal rats) and six days (operated rats). All rats received the same caloric and protein intake per ml (l kcal; 6-7.10(-3) g protein), with no statistically significant differences among groups. The differences in diets were merely qualitative. The tolerance to all diets was similar, with rats attaining the expected weight. Losses of protein, alpha aminic nitrogen, total fat and non sterified fatty acid in faeces were negligible. In normal rats, different results in liver protein synthesis were obtained. No mass/synthesis rate correlation was found. Under these conditions it would appear that these results are due to the different diets used. In operated rats, a significantly different liver protein synthesis per gram of body weight was obtained, but not per gram of organ weight. These results suggest that the influence of the qualitative caloric intake, in the stress phase, is less than in the normal state.
Changes in the fatty acid profile of plasma total lipids in patients maintained on TPN were determined in 2 studies. In the first study, 20 newborns, 2-25 days of age, receiving comparable nitrogen, calories and fat were divided into 2 groups of 10 in each. A safflower oil emulsion (Liposyn 20%) containing no alpha-linolenic acid was given to the Group 1 subjects, while a modified emulsion containing 3% of alpha-linolenic acid in safflower oil supplying 5.6% of total calories was given to those of Group 2. Plasma alpha-linolenic acid of the Group 1 infants was 0 throughout. The decrease in EPA and DHA was 85% and 65%, respectively, after 10-15 days of therapy. In the subjects of Group 2, there was an increase in both alpha-linolenic acid and EPA. A similar decrease (63%) in DHA similar to that of Group 1 infants was observed. In the second study, results of 2 representative adult patients are reported. One patient was given a soybean oil emulsion (Intralipid, 10%) that contains 7-8% of alpha-linolenic acid in the oil, furnishing about 11% of total calories. The other patient received a safflower oil emulsion (Liposyn, 10%) that contains no alpha-linolenic acid. Each patient received 500 ml of the respective emulsion daily for 3 weeks. The plasma alpha-linolenic acid of the patient who received the safflower oil emulsion remained 0 throughout. EPA showed a 67% decrease in 21 days. DHA remained at low levels throughout.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this study is to demonstrate the possibility of using the peritoneal route for carrying out periodical dialysis (PPD) together with supplying amino acids (AA's) for nutritional purposes and, at the same time, to determine the influence of the pattern of the mixture of AA's used for this purpose. In order to carry out this study we established three different groups. The PPD technique was the same for all the patients. In the control group PPD was performed without the addition of AA's. In groups 2 and 3 PPD was carried out with the addition of AA's and two different patterns were respectively used for that purpose.
A marked improvement of renal osteodystrophy was achieved after a combined treatment with keto acids and vitamin D in patients with chronic renal failure. Results were checked by histological investigations. The biochemical background of the successful treatment was analysed. A regression of hyperparathyroidism and improvement in vitamin D status are the cause of this phenomenon.
The compliance with the low-protein, supplemented diet is facilitated or hindered by psychological, social and toxic (severe uremia) factors; however, the most important factor which induces good compliance in patients is the fear of dialysis. The early effect of poor compliance is the appearance of intoxication related to renal failure and the consequent appearance of the uremic syndrome. The assessment of compliance with the low-protein intake is done quite easily by measuring urea appearance; however, regular clinical and laboratory controls are mandatory: anthropometric measurements, evaluation of the serum concentrations of proteins (especially those having a rapid turnover), and the evaluation of thyroid function--which is depressed in a state of malnutrition and improves following nutritional therapy--are adequate for detecting a state of malnutrition following poor compliance.
Intravenous bolus kinetics of amino acids and calculation of the kinetic parameters with an 1-compartment model revealed weak spots. Therefore, a new study design with a loading and maintenance dose and description of the plasma concentration time data with a 2-compartment model was created and studied in 9 healthy volunteers. After an over night fast the amino acid mixture Thomaeamin n 10% was infused with a loading dose of 20 mg AA/kg-1 X min-1 for 5 min and a maintenance dose of 5 mg AA/g-1 X min-1 for 55 min. The postinfusion period lasted 120 min. The PAA was determined with a Biotronic LC 6001 and the kinetic parameters were calculated by a Wang 2200 computer with the TOPFIT program package. The results showed mean values (means +/- SE) of the volume distribution between 4.7 +/- 0.6 till 9.4 +/- 1.8 liters, an elimination rate constant of 1.7 +/- 0.5 till 11.0 +/- 2.0 h-1, a total clearance of 186 +/- 37 till 846 +/- 66 ml X min-1 and transfer or endogenous production rate between 12 +/- 0.8 till 135 +/- 16 mumol kg-1 X h-1. The total transfer amounts to 17.6 mmol kg-1 X d-1 (= 2.2 g AA/kg-1 X d-1). It can be concluded that an optimal study design for the investigation of AA kinetics should increase the PAA levels 2-3 fold above basal during the infusion period.(ABSTRACT TRUNCATED AT 250 WORDS)
In a group of 119 patients with advanced chronic renal failure (serum creatinine level 733 +/- 186 mumol/l) the effect of a low-protein diet supplemented with essential amino acids (EAA) or their keto analogues (KA) on uremic metabolism and rehabilitation status was investigated. The protein intake amounted to 0.4 g/kg B.W./day, the phosphorus intake 0.4-0.6 g/day and the energy supply 120-150 kJ/kg B. W./day. In 51 patients there was a substitution with EAA and in 68 patients with their KA. The mean duration of dietary treatment in this study was 19 months (6-64 months). During this time, the serum creatinine increased from 733 +/- 186 to 1,220 +/- 256 mumol/l, whereas the urea nitrogen values remained relatively constant at between 26 and 30 mmol/l. There were no signs of protein malnutrition (nitrogen balance, serum transferrin and serum protein were normal). The hemoglobin concentration remained at greater than 5 mmol/l with creatinine levels of 1,220 +/- 256 mumol/l. During the substitution with KA, there was a significantly greater decrease in serum phosphate (p less than 0.05) and parathyroid hormone (PTH) (p less than 0.01) as compared with the uremics given EAA. In addition, we found a significant increase in testosterone (p less than 0.01) in patients supplemented with KA. Despite advanced chronic renal failure there was a good degree of rehabilitation (full-time work: 21%; part-time work: 66.4%). It can be concluded that a low-protein diet supplemented with EAA or KA can improve the uremic metabolism, rehabilitation status and safely postpone the start of maintenance dialysis.
In this paper we studied the effects of a low-protein, low-phosphorus supplemented diet in 8 type I diabetics with 'overt' diabetic nephropathy and mild or severe renal insufficiency. We examined the following parameters: the rate of decline of creatinine clearance, the urinary protein loss, the total serum protein, the daily insulin requirement, the serum fasting glucose, the pattern of serum lipids (serum total cholesterol, HDL cholesterol and serum triglycerides), the mean blood pressure and body weight. The rate of decline of creatinine clearance decreased monthly from 1.48 +/- 0.20 ml/min during a previous 15.6-month period of unrestricted protein diet (UPD), to 0.13 +/- 0.3 ml/min during the 11.4 months on the supplemented diet (SD). The mean blood pressure did not differ during UPD (130.9 +/- 7.0 mmHg) and during SD (128.1 +/- 1.6 mmHg). Urinary protein loss significantly decreased on SD, and total serum protein increased. The daily insulin requirement and the serum fasting glucose levels significantly decreased on SD. Serum cholesterol was lower during SD than during UPD, while serum HDL cholesterol and serum triglycerides were not significantly modified. In some patients the body weight decreased on SD as a consequence of the disappearance of edema. In conclusion, on the basis of these preliminary observations, the SD slows the progression of renal failure and seems to exert several beneficial and no unwanted side-effects in renal failure of type I diabetics.
Thirty-one patients scheduled for elective surgery for non-malignant abdominal disease were randomized during the first five postoperative days to two different schedules. Group I received water, electrolytes and glucose. Group II received a standard solution containing crystalline amino acids (3.8 g/l), xylitol (25 g/l) and sorbitol (25 g/l), accounting for a total of 900 cal/day. Evaluation was made with clinical, anthropometríc and biochemical parameters. Among others, the following significant differences were observed at the end of the study: retinol bound protein: in group I, 4.25 ± 1.3 and in group II, 5.38 ± 1.53 (p < 0.05); prealbumin: in group I, 18.7 ± 6.24 and in group II, 24.51 ± 7 (p < 0.05). The significantly higher values of short-life plasma proteins observed in group II indicate that with HPPN a higher synthesis of visceral protein is promoted. These data demonstrate that HPPN improves the nutritional state during the postoperative period.
The use of various nonprotein energy sources in parenteral nutrition regimens has been discussed for many years. Besides glucose, glycerol, xylitol, fructose and sorbitol are currently being used as water-soluble parenteral fuels. Despite the increasing frequency with which these glucose substitutes are being used, little information is available regarding the differences they evoke in host responses. All experimental evidence to date has shown glycerol to be equally effective in sparing body nitrogen as glucose when supplied in hypocaloric amounts. Results from studies in injured animals suggest that exogenously administered glycerol is a more potent inhibitor of fatty acid oxidation than glucose. Although results from human volunteers have been variable, glycerol administration after injury appears to markedly reduce fatty acid oxidation and ketogenesis, as well as increase hepatic glycogen. Glycerol toxicity appears to result only from its excessive administration, or when administered intraperitoneally or subcutaneously. Intravenous administration of hypocaloric quantities of glycerol alone or as a component of total parenteral nutrition is safe and effective.
Fat emulsions are essentially composed of triglycerides and phospholipids. Their elimination from the plasma--which is generally rapid--is influenced by the amount and the composition of both these components. During their short stay in the vascular compartment, exogenous particles undergo major compositional changes. They acquire various apolipoproteins--namely C-II, C-III, E and A-IV--by transfer from HDL. They also acquire esterified cholesterol from HDL and LDL and transfer exogenous triglycerides and phospholipids to these endogenous lipoproteins. These exchanges are affected by the type of triglyceride fatty acids and the amount of phospholipids present in fat emulsions, as well as by the infusion rate. Some 10% of emulsions--with a high phospholipid: triglyceride ratio--contain a huge phospholipid excess which can be isolated as a separate fraction from the triglyceride-rich particles. These phospholipids markedly interfere with the metabolism of cholesterol and the plasma lipoprotein profile.
In 12 male 5/6 nephrectomized Sprague-Dawley rats we analyzed the influence of commercially available amino/keto acid supplements on proteinuria. The addition of different supplements to an 8% protein diet resulted in an increase of preexisting proteinuria. Keto acids per se do not seem to cause a remarkable degree of proteinuria/hyperfiltration. Our data underline the importance of the protein content of a low-protein diet and the composition of amino/keto acid supplements, as these factors per se can cause hyperfiltration and might accelerate progression of chronic renal failure.
Due to the metabolic alterations following surgery, glucose is not completely oxidized but is converted into glycogen and lipids. Therefore we analysed 2 groups of 15 patients following surgery. They received parenteral nutrition with identical nitrogen (N = 0.28 g/kg/d) and lipid (1.5 g/kg/d) intake, whereby only the composition of carbohydrates was varied. Group I received exclusively glucose = 0.22 g/kg/h, and group II the combination fructose-glucose-xylitol in a proportion of 2:1:1 at the same infusion rate. The study lasted approximately 10 days. We found decreased exogenous insulin requirements and an increase in the NEFA levels with a maximum on the 3rd and 4th day in group II. There were no significant differences in the levels of either albumin, prealbumin or retinol-binding protein, nor were any hepatic or renal alterations related to the xylitol infusion observed. Xylituria was 6.13 +/- 3% of the amount infused. In our opinion, the partial substitution of glucose in group II led to a better utilisation of the infused energy supply, and to less insulin stimulation, which facilitated the mobilization of endogenous energy sources such as fatty acids, although we did not succeed in increasing the protein synthesis.
