C. Cangiano

Branched-chain amino acids vs lactulose in the treatment of hepatic coma

A controlled study was carried out in two groups of 20 patients with cirrhosis of the liver and deep coma in order to compare the efficacy of intravenous branched-chain amino acid solutions in 20% glucose (group A) vs lactulose plus glucose in isocaloric amount (group B). There were 3 drop-outs from each group. Plasma amino acids and ammonia were assayed at fixed intervals throughout the 10-day observation period. Routine tests were assayed daily. Complete mental recovery was obtained in 70% of patients in group A and in 47% in group B. The difference was not significant, likely due to the lack of placebo group. With the exception of free tryptophan/all competing amino acids ratio, the modifications in plasma amino acid levels showed no correlation with the clinical course under either treatment. Ammonia, like free tryptophan, decreased significantly upon mental recovery, paralleling the clinical course throughout the study. In conclusion, branched-chain amino acids are at least as effective as lactulose in deep hepatic coma. It is suggested that branched-chain amino acids may reverse coma either by competing with brain entry of the aromatic amino acid or by metabolically decreasing free tryptophan and ammonia.

Plasma amino acids imbalance in patients with liver disease.

The venous plasma amino acid patterns have been determined in 12 normal individuals and in 71 shunted and nonshunted cirrhotics in various grades of hepatic encephalopathy. The free amino acids have been determined by an amino autoanalyzer; the total and free tryptophan have been measured by a spoctrophotofluorimetric method. In 14 instances arterial plasma amino acid patterns have been measured simultaneously. High levels of aromatic and sulfurated amino acids and low levels of branched-chain amino acids have been constantly found in all cirrhotics. Methionine, phenylalanine, valine, leucine, tyrosine, and free tryptophan showed a statistical difference between controls and all other groups. These altered patterns did not correlate either with the grade or the evolution of the coma or with the presence of the surgical anastomosis. No statistical differences were lated with the grade and evolution of the hepatic encephalopathy was free tryptophan. The molar ratios between the amino acids sharing the same transport system across the blood-brain-barrier have been considered. A very good correlation with the grade of the mental disorder was found with the ratios free tryptophan/phenylalanine-tyrosine-methionine-valine-leucine-isoleucine and free tryptophan/branched-chain amino acids.

Glucose intolerance in liver cirrhosis

Abstract Glucose intolerance and hyperinsulinemia frequently occur in patients with chronic liver failure. To investigate the importance of glucose counterregulating factors, an oral glucose tolerance test was performed on 18 patients with compensated liver cirrhosis, matched for liver function tests and degree of portal hypertension, and 10 healthy controls. Blood glucose, immunoreactive insulin, C-peptide, immunoreactive glucagon, glucagon like immunoreactivity, growth hormone, cortisol and free fatty acids were determined in both groups at 30 min intervals for 240 min. Despite the similarity in the severity of liver damage five cirrhotic patients showed normal glucose tolerance, eight impaired glucose tolerance and five overt diabetes. Immunoreactive insulin was significantly higher in cirrhotic patients than in controls both before and during the oral glucose tolerance test. As basal C-peptide values were significantly higher and C-peptide/immunoreactive insulin ratio was significantly lower in cirrhotic patients than in the control subjects, both hyperproduction and hypodegradation seem to be responsible for the high insulin levels. Immunoreactive glucagon and cortisol showed no statistical differences between cirrhotic patients and control subjects whereas high basal growth hormone and free fatty acids values were observed in the cirrhotic group. Basal values and maximum increase or decrease of all the factors examined were tested by a correlation analysis with the blood glucose at 120 min and evaluated by a stepwise linear regression analysis. Only basal blood glucose, basal free fatty acids and immunoreactive insulin increment correlated significantly with blood glucose at 120 min. By the stepwise procedure these factors were found to account for 86% of the variance of the glucose level at 120 min. In chronic liver disease we failed to establish a pathogenetic role of hormones involved in the glucose counterregulating system. Free fatty acids may play an important role in glucose intolerance in chronic liver failure.

Plasma tryptophan and anorexia in human cancer

A correlation between anorexia and brain levels of serotonin and tryptophan (TRP) has been reported in tumor-bearing animals. In the present investigation 45 patients with various types of cancer and 13 control subjects were studied. Prior to the study the patients had received no antineoplastic therapy and were unaware of the malignancy of their disease. Feeding behavior was investigated by means of a questionnaire in which the presence of anorexia (A), aversion to meat (MA), taste (TA) or smell (SA) alterations, nausea and/or vomiting (NV) and early satiety (ES) was assessed. Plasma levels of free TRP, the other neutral amino acids (NAA), albumin and non-esterified fatty acids (NEFA) were assayed. Plasma-free TRP was significantly increased in anorectic cancer patients. The free TRP/competing NAA ratio, which might better predict brain TRP levels, was significantly higher in patients with A, MA, TA, SA, NV and ES than in controls or in non-anorectic (NA) cancer patients. These findings seem to confirm that free TRP may play an important role in human cancer anorexia.

Plasma and Cerebrospinal Fluid Amino Acid Patterns in Hepatic Encephalopathy

Plasma and cerebrospinal fluid amino acid levels were measured in 12 cirrhotic patients in grade 0 hepatic encephalopathy and 17 in grade 3–4 hepatic encephalopathy. In 5 of these patients amino acid determinations were performed during the evolution of the encephalopathy. No correlation was found between the degree of hepatic encephalopathy and the plasma amino acid imbalance. In the CSF of cirrhotic patients without encephalopathy, a significant increase was found in nearly all amino acids, including those known to not easily cross the blood-brain barrier; this suggests the presence of a nonspecific modification of the blood-brain barrier permeability. In patients with severe hepatic encephalopathy, the further increase only in cerebrospinal fluid aromatic amino acids and methionine levels suggests the presence of a selective stimulation of the neutral amino acid transport system across the blood-brain barrier. Finally, the good correlation between glutamine and the sum of neutral amino acids found in the cerebrospinal fluid only in the presence of encephalopathy supports the hypothesis that brain glutamine may stimulate neutral amino acid transport across the blood-brain barrier.

Plasma and CSF tryptophan in cancer anorexia

Eighteen untreated cancer patients and ten sex- and age-matched healthy volunteers were studied. In all patients eating behavior was investigated by means of a specific questionnaire from which the presence of anorexia and anorexia-related symptoms was assessed. To investigate the role of tryptophan in cancer anorexia, fasting plasma and CSF levels of tryptophan and other neutral amino acids were assayed in patients and controls. Cancer patients showed abnormally high plasma free tryptophan levels. In case of patients with cancer anorexia a significant rise of the ratio in plasma between free and tryptophan/large neutral amino acids, competing with tryptophan for its brain entry, was observed. This increase was correlated to a consistent rise of CSF tryptophan levels suggesting a specific role of the serotoninergic system in the pathogenesis of cancer anorexia.

Clinical and metabolic effects of different parenteral nutrition regimens in patients undergoing allogeneic bone marrow transplantation.

BACKGROUND Nutrients may interfere with physiological and pathophysiologic mechanisms. The present study was aimed at evaluating whether the differences in the quality of energy substrates administered with total parenteral nutrition (TPN) after cytoreductive therapy may influence the clinical outcome of patients undergoing bone marrow transplantation (BMT). METHODS Sixty-six consecutive allogeneic BMT patients with hematologic malignancies were randomized to receive either a glucose-based (100% glucose) or a lipid-based (80% lipid, using an omega-6 long-chain triacylglycerol emulsion + 20% glucose) TPN, providing 146.3 kJ/kg body weight, 1.4 g of protein/kg of body weight, administered from day +1 to day +15 after BMT. Time to engraftment (EGT), incidence of sepsis and metabolic complications (hyperglycemia and hypertriglyceridemia), incidence of acute graft-versus-host-disease (A-GVHD) and relapse, survival at 18 months, incidence of deaths for A-GVHD and relapse were evaluated. RESULTS Six patients dropped out before completing the study period. Thirty-one patients in the glucose-based TPN group and 29 patients in the lipid-based TPN group were evaluated. The incidence of hyperglycemia was significantly lower in the lipid-based TPN group than in the glucose-based TPN group (3.4% vs. 32%, respectively; P=0.004). Five patients in the glucose group and none in the lipid group died for A-GVHD (P<0.05). Survival at 18 months tended to be higher in the lipid group than in the glucose group (62% vs. 42%, P=NS). Rate of bone-marrow EGT, time to EGT, incidence of sepsis and fungal infections during TPN, incidence of A-GVHD, and rate of relapse at 18 months were not different in the two groups. CONCLUSIONS The results obtained suggest that the use of lipid-based TPN after allogeneic BMT is associated with lower incidence of lethal A-GVHD and hyperglycemia, without negatively affecting the EGT of infused cells. Intravenously administered lipids might have influenced the severity of A-GVHD likely via modulation of immune response and synthesis of cytokines, prostaglandins, and leukotrienes that participate in the pathogenesis of graft-versus-host disease.

The early cancer anorexia paradigm: changes in plasma free tryptophan and feeding indexes.

Tumor growth is accompanied by an anorexia mediated by humoral factors that appear to influence appetitive mechanisms in the brain. Because tumor resection is followed by resumption of normal food intake, the circulating anorexigenic substance(s) are produced either by the neoplastic tissue or by the host in response to the tumor. Increased levels of plasma free tryptophan and plasma ammonia have been proposed to mediate cancer anorexia. With animal models, it is often difficult to ascertain whether changes in food intake depend upon metabolic changes or the progressively increasing tumor mass per se. The feeding patterns and biochemical changes that occur during tumor growth were evaluated in 96 male Fischer rats that were inoculated with 10(6) methylcholanthrene sarcoma cells or saline (controls). Rats were placed into metabolic cages equipped with an Automated Computerized Rat Eater Meter to continuously determine meal size and meal number. Plasma free tryptophan and ammonia were evaluated 6, 10, 16, 18, 22, and 26 days after tumor inoculation. Anorexia developed by day 17-18, when food intake started to decrease via a decrease in meal size but not meal number and reached 60% of control by day 26. However, long before anorexia developed, free tryptophan was significantly higher 6 days after tumor inoculation, and the greatest increase occurred after 18 days. Ammonia did not differ from control at any time. Data confirm tumor-associated increases in plasma free tryptophan that occurred before the manifestation of anorexia and support a possible role of brain serotonin in cancer anorexia.

Plasma tryptophan levels and anorexia in liver cirrhosis

OBJECTIVE Increased brain tryptophan (TRP) availability for serotonin synthesis may play a role in the pathogenesis of anorexia. Since in chronic liver failure, increased plasma and cerebrospinal fluid TRP concentrations are characteristically reported, we hypothesize that also in liver cirrhosis increased brain TRP availability may constitute the pathogenic mechanism of anorexia. To test this hypothesis, the association between anorexia and plasma TRP was investigated. METHODS Anorexia and plasma amino acid concentrations were evaluated in 16 patients with liver cirrhosis and compared with those obtained in 13 healthy volunteers. RESULTS According to a questionnaire, 11 cirrhotic patients were considered as anorectic. In these patients, brain TRP availability was significantly higher than in nonanorectic patients and controls. DISCUSSION Increased brain TRP availability is also associated with anorexia in liver cirrhosis, and supports the hypothesis that increased serotonergic activity may constitute the common pathogenic mechanism for anorexia associated with different diseases.

Isolated Brain Microvessels as In Vitro Equivalents of the Blood‐Brain Barrier: Selective Removal by Collagenase of the A‐System of Neutral Amino Acid Transport

On treatment with collagenase, brain microvessels, together with several protein components, lose some enzymatic activities such as alkaline phosphatase and γ‐glutamyltranspeptidase, whereas no change occurs in the activities of 5′‐nucleotidase and glutamine synthetase. The energy‐requiring „A‐system” of polar neutral amino acid transport is also severely inactivated, whereas the L‐system for the facilitated exchange of branched chain and aromatic amino acids is preserved. In the collagenase‐digested microvessels, this leads to loss of the transtimulation effect of glutamine on the transport of large neutral amino acids, because such transtimulation is due to a cooperation between the A‐ and L‐systems. By contrast, NH4+ maintains (and even enhances) its ability to stimulate the L‐system of amino acid transport, presumably through glutamine synthesis within the endothelial cells.