Eggert Holm

Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design

This paper documents dose-dependent effects of ornithine aspartate (OA) on postprandial hyperammonemia and plasma amino acids. Ten patients with cirrhosis were randomized to undergo 1 out of 4 infusion series. Each series consisted of four 8-h infusions (09:00 h-17:00 h), with placebo (NaCl), 5 g, 20 g or 40 g of OA being administered on separate days in varying sequences. This 4-fold crossover design was double-blind. On infusion days, patients received 2 oral protein loads (0.25 g/kg at 09:00 h and 0.5 g/kg at 13:00 h). Venous blood samples were drawn every 2 h and the 24-h urine was collected. In addition to measuring plasma ammonia and amino acids, the urea production rate, serum glucose and serum insulin were analyzed. A significant postprandial rise in the ammonia concentration was noted during the infusions of placebo and 5 g of OA but did not occur with the dosages of 20 g (after the second protein load) and 40 g (after both protein loads). Furthermore, the latter dose, compared with placebo, significantly reduced plasma ammonia after the minor protein load. Urea production rate increased when 20 g or 40 g of OA was administered. Of the amino acids involved in the metabolic pathways of ornithine and/or aspartate, glutamate showed a rise in its plasma level following infusion of 40 g of OA, whereas glutamine did not. Concentrations of methionine, phenylalanine, tyrosine, threonine, serine and glycine declined progressively with increasing doses of OA (5-40 g). The highest dose of the drug caused hyperglycemia and hyperinsulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated venous glutamate levels in (pre)catabolic conditions result at least partly from a decreased glutamate transport activity

Abnormally high postabsorptive venous plasma glutamate levels have been reported for several diseases that are associated with a loss of body cell mass including cancer, human/simian immunodeficiency virus infection, and amyotrophic lateral sklerosis. Studies on exchange rates in well-nourished cancer patients now show that high venous plasma glutamate levels may serve as a bona fide indicator for a decreased uptake of glutamate by the peripheral muscle tissue in the postabsorptive period and may be indicative for a precachectic state. High glutamate levels are also moderately correlated with a decreased uptake of glucose and ketone bodies. Relatively high venous glutamate levels have also been found in non-insulin-dependent diabetes mellitus and to some extent also in the cubital vein of normal elderly subjects, i.e., in conditions commonly associated with a decreased glucose tolerance and progressive loss of body cell mass.

Plasma cystine concentration and redox state in aging and physical exercise.

Because redox-regulated signalling pathways are often modulated by the thiol/disulfide redox state (REDST), changes in plasma REDST may possibly account for pathological processes. We, therefore, investigated the mechanisms that account for changes in the plasma REDST as derived in first approximation from the cystine and acid soluble thiol (mainly cysteine) concentrations. Elderly subjects (studies A) and younger subjects after intensive physical exercise (IPE) (study B) i.e. subjects in conditions typically associated with decreased insulin responsiveness, showed, on the average, an increase in the plasma total free amino acid (TAA) concentration to approximately 3000 microM, including an increase in cystine but no increase in the thiol concentration if compared with controls. The REDST was decreased accordingly. A study on the postabsorptive amino acid exchange rates across the lower extremities (study C) indicated that a TAA level > or =2800 microM supports a balanced net protein synthesis even under conditions of weak insulin stimulation, suggesting that high TAA levels may prevent the release of cysteine into the blood in the postabsorptive state. Collectively, these studies indicate that the age-related oxidative shift in plasma REDST may result from the decrease in amino acid clearance capacity and may be aggravated by excessive physical exercise.

Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma

BACKGROUND/AIMS Exogenous hyperammonemia is known to decrease the plasma levels of branched-chain amino acids (BCAA). To investigate whether changes in intracellular amino acid concentrations of muscle are associated with and may, at least in part, mediate this effect, experiments were carried out on a total of 60 male Wistar rats. METHODS Five groups were formed in a randomized manner. Group A: no treatment; groups B1 and B2: 2-hour and 6-hour continuous central-venous infusions, respectively, of sodium salts; groups C1 and C2: 2-hour and 6-hour infusions of ammonium salts. We obtained venous blood samples and muscle biopsies. Plasma ammonia, whole blood glucose, serum insulin, blood pH, and amino acids in plasma as well as in the intracellular water of muscle were measured. RESULTS As compared with control group A, groups C1 and C2 displayed a 3.3- and a 4-fold increase, respectively, in the plasma ammonium concentration. Regarding insulin, the ammonium-infused rats were similar to group A but not to the sodium-infused B groups, which had significantly lower insulin concentrations. Administering ammonium brought about a decline in BCAA concentrations in plasma after 2 hours and in muscle after 6 hours. The ammonium-induced fall in intracellular BCAA values was preceded by an increase of glutamine as well as by a decrease of glutamate and alanine in both plasma and muscle. CONCLUSIONS It is pointed out that the inter-group differences in serum insulin, although possibly accounting for some of the findings, can by no means explain the entire pattern of amino acid concentrations seen after the ammonium infusions. Instead, our results agree with the hypothesis that hyperammonemia indirectly lowers the plasma levels of BCAA by stimulating glutamine synthesis, thus reducing the intracellular glutamate pool, which is likely to be restored, at least in part, by an intensified BCAA transamination. Clarification is needed as to whether carbon skeletons derived from valine and isoleucine additionally contribute to replenishing the glutamate pool.

Transjugular intrahepatic portosystemic shunting (TIPS) with balloon-expandable and self-expanding stents: Technical and clinical aspects after 3 1/2 years’ experience

PurposeTo evaluate prospectively our experience with transjugular intrahepatic portosystemic shunt (TIPS) using four different metallic stents.MethodsBetween November 1991 and April 1995, 57 patients (41 men and 16 women; age 35–72 years, mean 54 years) underwent the TIPS procedure. Techniques for portal vein localization before and during TIPS were fluoroscopy, computed tomography (CT) studies, wedged hepatic venography, arterial portography, and ultrasound. After predilation we deployed balloon-expandable (n=48) and self-expanding (n=45) metallic stents. Fifteen patients underwent variceal embolization. Initial follow-up angiograms (mean 6.9 months, range 3–24 months) were obtained in 39 of these patients.ResultsFifty-three patients (93%) had successful TIPS placement. The mean decrease in portal pressure was 42.7%. Besides fluoroscopy, the most helpful techniques for portal vein localization were venography and CT. Residual stenosis (n=1) and late shortening (n=4) of Wallstents resulted in shunt dysfunction. The technical problems encountered with the Palmaz stent resulted from its lack of flexibility. We combined balloon-expandable and self-expanding stents in 12 patients. The 30-day and late follow-up (mean 11.9 months) percutaneous reintervention rates were 11.3% and 64.2%, respectively. There were no clinically significant complications related to the TIPS insertions.ConclusionAn ideal stent does not exist for TIPS, and the authors recommend combining a Palmaz stent with a flexible self-expanding stent.

Aminosäurenaufnahme und -abgabe kolorektaler Karzinome des Menschen

Uber den Aminosaurenaustausch menschlicher Tumoren informieren nur wenige Arbeiten. Um diesen Austausch in vivo zu kennzeichnen, wurden 21 Patienten mit resezierbaren kolorektalen Karzinomen wah-rend

Linkage between postabsorptive amino acid release and glutamate uptake in skeletal muscle tissue of healthy young subjects, cancer patients, and the elderly

Abstract Several diseases of varying etiology that are commonly associated with the loss of skeletal muscle mass were found to be associated with a decrease in muscular glutamate and glutathione levels and in glutamate uptake in the postabsorptive state. In view of the Na+ dependency and insulin responsiveness of glutamate transport we studied the postabsorptive glutamate exchange in more detail. Our study demonstrates a linkage between glutamate uptake and the export of other amino acids, suggesting that protein catabolism and the resulting coexport of amino acids plus Na+ substitute for insulin as a driving force for the Na+ gradient in the postabsorptive state. The regression function of the correlation between relative glutamate exchange and cumulative amino acid exchange in cancer patients was lower than that in non-tumor-bearing subjects, suggesting that cancer patients must release more amino acids to achieve the same glutamate uptake. In addition, cancer patients had a lower average cumulative amino acid exchange rate than non-tumor-bearing subjects, suggesting that the abnormally low relative glutamate exchange capacity of cancer patients results mainly from inadequate postabsorptive protein catabolism in the skeletal muscle tissue. Both cancer patients and non-tumor-bearing elderly subjects had higher arterial glutamate levels and alanine release than young subjects, indicative of a substantial glycolytic activity in the skeletal muscle. However, elderly non-tumor-bearing subjects showed, in contrast to cancer patients, in the postabsorptive state a stronger cumulative amino acid release and postabsorptive glutamate uptake than healthy young subjects. These changes are discussed in view of the age-related loss of skeletal muscle mass.

Flux of amino acids and energy substrates across the leg in weight-stable HIV-infected patients with acute opportunistic infections: indication of a slow protein wasting process

Increased whole-body proteolysis with muscle protein net degradation has been suggested as one of the causes of weight loss in patients infected with human immunodeficiency virus (HIV). We studied the exchange rates of amino acids and energy substrates across the lower extremity in 16 HIV patients and 16 age-matched controls with similar body cell mass. The patients had either opportunistic infections or chronic diarrhea but no signs of clinical malnutrition. The following findings were obtained in the HIV patients: an augmented peripheral net release of arginine and lysine; an increase in both the negative arterial-venous difference and the efflux of the nitrogen contained in nonmetabolized amino acids; diminished export of 3-methylhistidine; lowered plasma and erythrocyte amino acid concentrations; reduced output of glycerol and furthermore; and neither a net release nor a net uptake of free fatty acids. The findings concerning nitrogen metabolism support the hypothesis that, in the presence of a reduction in protein breakdown, peripheral protein synthesis is severely depressed, making a slow protein wasting process likely to occur. The balances of glycerol and free fatty acids are due not only to the leg tissues but perhaps also in part to increased net retention of these substrates by skeletal muscle.

Effects of hyperthermia on the peripheral metabolism of ammonia and glutamine.

Although there are a number of physiological states associated with an increase in body temperature, eg, nonseptic and septic fever or exercise, the effects of hyperthermia on intermediary metabolism in vivo have received little attention. The current study was undertaken to examine the peripheral metabolism of ammonia and ammonia-related amino acids using a model of exogenously induced mild hyperthermia in nonfebrile subjects. Arteriovenous levels of metabolites were measured in subjects with known cerebrovascular insufficiency. Peripheral exchange of these metabolites was monitored before, during, and after hyperthermia to an average temperature of 38.5 degrees C. All subjects showed an increase in plasma ammonia and glutamate. There was also an associated peripheral production of ammonia and an uptake of glutamine and alanine by the skeletal muscle tissues. The exchange of glutamate was not affected. These findings indicate that hyperthermia is associated with a nitrogen-sparing effect, the mechanism of which is yet unknown.

Protein- und Aminosäurenstoffwechsel bei Leberinsuffizienz—Infusionstherapeutische und diätetische Folgerungen

Die heutigen Tendenzen und Richtlinien bezuglich der Versorgung leberinsuffizienter Patienten mit Eiweis bzw. Aminosauren ergeben sich uberwiegend aus metabolischen Erkenntnissen und kontrollierten klinischen Studien der letzten 10 Jahre; sie kontrastieren in quantitativer und qualitativer Hinsicht mit alteren Vorstellungen. Subtile Methoden der Beschreibung des Proteinhaushalts und des Ernahrungszustands (Abschnitt 1) haben zusammen mit einer verbesserten Diagnostik fruher Phanomene der hepatischen Enzephalopathie (HE) annahernd zufriedenstellende Effektivitatskriterien nutritiver Masnahmen geliefert. Des weiteren ist die rationale Basis dieser Masnahmen durch neue Einblicke in den Aminosauren— und Ammoniakstoffwechsel (Abschnitt 2) wie auch in die Entstehungsweise der HE (Abschnitt 3) stabiler und breiter geworden. Das hepatologisch konzipierte Aminosaurengemische bei entsprechend gefahrdeten Kranken eine risikofreie und effiziente parenterale Ernahrung ermoglichen, wuste man schon zu Beginn der vergangenen Dekade. Davon zu unterscheiden ist das erst in jungster Zeit ausreichend legitimierte Bestreben, durch Anwendung solcher Aminosaurengemische prakomatose und komatose Zustande nicht nur zu vermeiden, sondern auch adjuvant zu behandeln (Abschnitt 4). Auf dem Sektor der oralen Ernahrung lief die Entwicklung ungefahr parallel, wobei allerdings das Fazit aus den bislang verfugbaren Befunden mehr die Prophylaxe der HE als deren Therapie betrifft (Abschnitt 5).