Biomedical subjects

H Vilstrup

Publications and source records attributed to H Vilstrup.

At least 91 records · Page 5Linked to original sources

PubMed1993

No net splanchnic release of glutathione in man during N-acetylcysteine infusion.

Glutathione and amino acid concentrations were measured in arterial and hepatic vein plasma in four healthy volunteers and two patients with cirrhosis. There was no significant splanchnic efflux of glutathione (95% confidence limits, -0.501 to 0.405 mumol/min). After infusion of N-acetylcysteine (NAC) in a high dose (150 mg/kg body weight primer plus 15 mg/(h x kg BW), corresponding to treatment of acetaminophen overdose, there was no change in the splanchnic glutathione efflux (95% confidence limits, -0.531 to 0.375 mumol/min). NAC increased hepatic plasma flow rate from 0.90 +/- 0.531 min-1 to 0.97 +/- 0.11 (mean +/- SEM; p < 0.05). The effects of NAC treatment on plasma amino acids corresponded to an increased load on hepatic metabolic N conversion and transamination among nonessential amino acids. Splanchnic uptake of serine, alanine, cystine, isoleucine, and phenylalanine increased after NAC compatible with stimulated hepatic glutathione synthesis. In contrast to the rat, plasma glutathione in man probably originates mainly from extrahepatic tissues.

Acetylcysteine↗

PubMed1993

Passage of amino acids and glucose across the blood-brain barrier in patients with hepatic encephalopathy.

We repeatedly measured blood-brain barrier passage of phenylalanine, leucine, glucose and GABA in nine patients with hepatic encephalopathy using the intravenous double-indicator technique. Controls were four patients without liver disease and two of the patients who had recovered completely from their hepatic encephalopathy. The corrected cerebral venous output curves were fitted by use of a three-compartment model with four parameters. In the patients with hepatic encephalopathy, the permeability-surface area products for phenylalanine and leucine from the blood to the brain and from the brain interstitial fluid to the intracellular compartment, the unidirectional extraction and the brain amino acid influx were similar in the two groups. The permeability from the brain back to blood for phenylalanine was decreased by 72% in patients with hepatic encephalopathy compared with that in the control group (p < 0.05), whereas no difference was seen for leucine. The permeability from the brain back to the blood for phenylalanine decreased with coma grade and normalized in the two patients who recovered. Correspondingly, the calculated brain interstitial fluid concentration of phenylalanine was increased in the patients with hepatic encephalopathy. The transfer variables for blood-brain barrier passage of glucose were similar in the two groups. The permeability from the blood to the brain for GABA was very low in both the patients with hepatic encephalopathy and the control group. We conclude that in hepatic encephalopathy the permeability from brain to blood for phenylalanine decreases with coma grade. The decrease is caused by an increased interstitial fluid concentration of the amino acid. No evidence was found of general or selective blood-brain barrier disturbance in hepatic encephalopathy.

Adult↗

PubMed1992

Effects of an increase in protein intake on hepatic efficacy for urea synthesis in healthy subjects and in patients with cirrhosis.

The efficacy of urea synthesis as measured by functional hepatic nitrogen clearance (i.e., the relation of urea synthesis rate to blood alpha-amino nitrogen concentration) was studied before and after diet protein supplementation in six healthy subjects and five patients with stable cirrhosis (galactose elimination capacity about 60% of control). Daily protein intake was increased for 14 days by a protein-enriched liquid from (mean +/- S.D.) 1.01 +/- 0.32 g/kg body wt. to 1.62 +/- 0.31 g/kg body wt in the control subjects, and from 0.69 +/- 0.21 g/kg body wt. to 1.50 +/- 0.15 g/kg body wt. in the patients with cirrhosis. This increased the hepatic nitrogen clearance from 27 +/- 10 l/h to 39 +/- 15 l/h in the control subjects (p less than 0.05) and from 15 +/- 6 l/h to 21 +/- 7 l/h in the cirrhosis patients (p less than 0.05). There was no effect on the galactose elimination capacity in any group. Compared to the control subjects, the response in hepatic nitrogen clearance relative to the increase in protein intake was reduced by 60% in the patients. Basal glucagon was 75% higher in the patients and increased by 50% during high protein intake (p less than 0.05), but did not parallel the increase in hepatic nitrogen clearance, and it did not change in the control subjects. The study shows that an increase in protein intake selectively increases liver function with regard to disposal of amino nitrogen; the mechanism is qualitatively intact but quantitatively deficient in patients with cirrhosis of the liver, and does not seem to depend on glucagon.

Adult↗

PubMed1992

Effects of epinephrine on urea synthesis in vivo in rats.

Three hours after hysterectomy the rate of urea synthesis doubles in rats. At the same time the increase in catecholamines is at a maximum, suggesting that catecholamines might be of regulatory importance. The effect of exogenous epinephrine on the rate of urea synthesis was studied in rats receiving epinephrine at rates of 2 and 20 micrograms/kg/h. The low dose increased plasma concentration of catecholamines two-fold over control values (p less than 0.01), comparable with the increase seen after surgery, and the high dose of epinephrine increased the concentration five-fold. The high dose increased the rate of urea synthesis by 30% (p less than 0.05), whereas the low dose had no effect. Following a high dose of epinephrine, alanine decreased from 358 +/- 29 to 254 +/- 17 mmol/l (p less than 0.05), indicating that the increase in urea synthesis was due to an effect on the liver rather than on extra-hepatic tissues, in that more aminonitrogen was eliminated from plasma than released into it. In conclusion, epinephrine in physiological concentrations cannot by itself account for the increase of urea synthesis seen in vivo after surgery.

Amino Acids↗

PubMed1992

Glucagon immunoneutralization in diabetic rats normalizes urea synthesis and decreases nitrogen wasting.

To study the effect of glucagon neutralization on urea synthesis in diabetic rats, animals with newly induced (75 mg/kg streptozocin) experimental diabetes mellitus were divided into two groups. One group was given one weekly injection of nonimmune rabbit serum (n = 6), and the other group was given one weekly injection of a specific high-titer antibody against pancreatic glucagon (n = 6). Four weeks later, serum-treated diabetic rats had fasting glucagon concentrations 2-3 times higher than nondiabetic controls given one weekly injection of saline (control). Plasma glucagon binding capacity of diabetic rats given glucagon antibodies was 10-15 times higher than the glucagon concentration. A second group of nondiabetic controls were given nonimmune serum. Blood glucose concentration and urinary glucose output were identical in both groups of diabetic animals. Food intake doubled in both groups of diabetic rats. In control rats, the accumulated nitrogen balance, determined weekly for 4 wk, was positive at 81 +/- 3.1 mmol/96 h; in serum-treated diabetic rats, the accumulated nitrogen balance was negative, -8.3 +/- 2.4 mmol/96 h throughout the 4 wk, whereas it was higher at 4.7 +/- 2.3 mmol/96 h in the glucagon antibody-treated diabetic rats (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

PubMed1992

Hormonal and neural blockade prevents the postoperative increase in amino acid clearance and urea synthesis.

The combined effect of continuous blockade of glucagon and cortisol by somatostatin and etomidate and thoracic epidural analgesia on hepatic conversion of amino nitrogen was studied in eight patients who underwent elective cholecystectomy on day 1 after operation and was compared with 16 patients who underwent operation without blockade. Surgery increased the plasma clearance of total alpha-amino nitrogen from 5.2 +/- 0.3 to 6.6 +/- 0.3 ml/sec (mean +/- sem; p less than 0.05). This increase was due to increased elimination by the liver, because the hepatic effectiveness for amino nitrogen conversion measured by the functional hepatic nitrogen clearance increased from 9 +/- 2 to 16 +/- 4 ml/sec (p less than 0.05). In contrast, during the combined neural and hormonal blockade, surgery decreased the plasma clearance of amino nitrogen from 5.3 +/- 0.3 to 3.9 +/- 0.3 ml/sec (p less than 0.05), and the blockade prevented the postoperative increase in functional hepatic nitrogen clearance. The results suggest that glucagon, cortisol, and afferent neural reflexes are mediators of the hepatic contribution to catabolism after operation.

3-Hydroxybutyric Acid↗

PubMed1992

High volume plasma exchange in fulminant hepatic failure.

We investigated the effect of repeated high volume plasma exchange with fresh donor plasma in 11 patients with fulminant hepatic failure, all initially in stage 3 or 4 encephalopathy. A daily exchange of a volume equal to the extracellular volume (20% of body weight) on three consecutive days was intended. We obtained an average of 2.6 exchanges each with a mean volume equal to 16% of the body weight. Five patients (46%, 95% confidence limits 17%-77%) survived, all with acetaminophen induced liver failure. Four of the 6 non-survivors showed a temporary improvement in cerebral function. Two of the patients woke up completely. The 6 non-survivors maintained a stable condition with a systolic blood pressure > 110 mm Hg for a mean of 6.9 days after initiating plasma exchange. Plasma exchange may be considered in acute liver failure in patients with residual liver function before transplantation is finally decided. In addition, plasmapheresis may be used to keep patients with definite liver failure clinically stable until a transplant can be performed.

Acetaminophen↗

PubMed1991

Increased hepatic capacity of urea synthesis in acute and chronic uraemia in rats.

We studied whole body nitrogen balance in female rats for 28 days after induction of experimental uraemia by 5 6 nephrectomy and at the same time the kinetics of hepatic urea synthesis by means of the in vivo capacity of urea synthesis. The N-balance of 5 uraemic rats kept in metabolic cages was negative on day 2, and positive but only half of control on day 28. In between, it was normal. The uraemic rats lost weight during the first week, and later only slowly regained their initial weight. The capacity for urea synthesis was determined during alanine loading in 5 unoperated controls, in uraemic rats in groups of 5 on days 2, 7, 14, 21, and 28, and correspondingly in sham operated rats. In the control rats the capacity was 8.9 +/- 0.7 micromol/(min 100 g BW) and the same in sham operated rats. In uraemic rats the capacity increased to 17.1 +/- 2.0 micromol/(min 100 g BW) (p < 0.01) 2 days after partial nephrectomy. On day 7, the capacity fell to 5.5 +/- 1.0 (not different from initial values), and thereafter again gradually increased to 16.5 +/- 1.5 micromol/(min 100g BW) on day 28. The early increase in the capacity may be related to glucagon, that nearly doubled on day 2, but not on day 28. The hepatic capacity for urea synthesis doubles biphasically: acutely and after 4 weeks of experimental uraemia. This may play a role in the reduction in N-balance, since an increase in the capacity implies larger hepatic amino-N conversion at any blood amino-acid concentration.

Journal Article↗

PubMed1991

Elective cholecystectomy increases plasma amino-acid clearance and hepatic capacity for urea synthesis for one week.

The importance of the liver in post-operative catabolism was studied in 6 cholecystectomy patients given a mixture of amino-acids as prime-continuous infusionś pre-operatively and on the 1st, 3rd, 6th and 12th post-operative day. The plasma clearance of total alpha-amino-nitrogen and of single amino-acids, the urea-nitrogen synthesis rate, and the functional hepatic nitrogen clearance were calculated. Surgery decreased fasting blood amino-nitrogen concentration by 15% (p < 0.01), and increased the plasma clearance of amino-nitrogen by 30% (P < 0.05) on the 1st, 3rd and 6th post-operative day. Surgery doubled the functional hepatic nitrogen clearance (p < 0.01) on the 1st, 3rd and 6th post-operative day. This indicates that post-operative stress catabolism is partly due to a hepatic condition by which the liver eliminates more amino-nitrogen despite lower amino-acid concentration in the blood, for one week post-operatively.

Journal Article↗

PubMed1991

Elimination of infused branched-chain amino-acids from plasma of patients with non-obese type 2 diabetes mellitus.

Increased plasma levels of branched-chain amino-acids (BCAA) have been demonstrated in poorly controlled diabetes mellitus, and related to absolute or relative insulin deficiency. To study the pathogenesis of this alteration, the elimination of BCAA from plasma was measured in 8 patients with non-obese type 2 diabetes mellitus and in 8 age-matched control subjects during steady-state BCAA concentrations induced by a primed-continuous infusion. Fasting BCAA levels were increased by 40-50% in patients with diabetes. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady-state concentration, were reduced by 20% in diabetics, despite 50% hyperinsulinemia (P < 0.01). Basal BCAA levels and BCAA clearance were negatively correlated (r(2) = 0.46 - 0.56). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were normal in diabetics, and there was no difference in the apparent volumes of distribution of BCAA. The increased basal concentration of BCAA in poorly controlled type 2 diabetics (693 [SD 114; n = 8] mumol/l vs 479 [88; n = 8] in controls (P < 0.005) is attributable to changes in plasma clearances, without any change in the efflux of BCAA into plasma. This may be due to insulin resistance.

Journal Article↗

PubMed1991

Blockade of glucocorticoid receptors prevents the increase in urea synthesis after hysterectomy in rats.

The postoperative increase in hepatic conversion of amino nitrogen to urea nitrogen seems to be a primary cause of post-surgical catabolism. The importance of glucocorticosteroids for the spontaneous urea nitrogen synthesis rate (UNSR) and for the maximally amino acid-stimulated capacity of urea nitrogen synthesis (CUNS) was investigated 3 and 24 h postoperatively, respectively, in hysterectomized rats. Corticosteroid effects were neutralized by glucocorticoid receptor blockade by the pharmacological analogue RU486. Hysterectomy doubled UNSR from 3.16 +/- 0.20 to 6.12 +/- 0.27 mumol (per min per 100 g body weight) after 3 h (P less than 0.01) and increased CUNS by 40% from 7.47 +/- 0.30 to 10.29 +/- 0.41 mumol (per min per 100 g body weight) after 24 h (P less than 0.01). These changes were both normalized by the receptor blockade. Hysterectomy decreased total blood alpha-amino nitrogen concentration by 25% from 3.4 +/- 0.2 to 2.6 +/- 0.2 mmol l-1 (P less than 0.05) 3 h after surgery, which was normalized by glucocorticoid receptor blockade. Hysterectomized rats lost 10 +/- 1 g the first 24 h after surgery. The blockade reduced the weight loss to 6 +/- 1 g body weight (P less than 0.05) without changing food intake. The results indicate that glucocorticoid action plays a major role in the postoperative increase in hepatic amino nitrogen conversion.

Amino Acids↗

PubMed1991

Acute in vivo effects of low ethanol concentration on the capacity of urea synthesis in rats.

We studied the effect of acute exposure, by constant intravenous infusion, to a low blood ethanol concentration (range 8-14 mmol/l) on the in vivo capacity of urea-N synthesis (CUNS), alanine elimination, and the nitrogen retention in fed and fasted rats. Alanine was infused to obtain a constant blood concentration of alpha-amino nitrogen between 7.3 and 11.7 mmol/l, at which concentrations urea synthesis is at maximum. CUNS was calculated after nephrectomy as accumulation of urea in body water, elimination of alanine as alanine infusion rate corrected for accumulation, and nitrogen retention as the difference. In the fed state ethanol decreased CUNS from 7.84 +/- 0.32 mumol N/(min 100 g body weight (BW] (mean +/- SEM) (n = 7) to 6.30 +/- 0.58 (n = 6) (p less than 0.001) and in the fasted state from 8.25 +/- 0.27 mumol N/(min 100 g BW) (n = 10) to 6.90 +/- 0.25 (n = 10) (p less than 0.001). In the fed state ethanol increased the elimination of alanine from 6.49 +/- 0.28 mumol/(min 100 g BW) (n = 7) to 6.95 +/- 0.25 (n = 6) (p less than 0.01), and in the fasted state decreased it from 6.25 +/- 0.12 mumol/(min 100 g BW) (n = 10) to 5.67 +/- 0.20 (n = 10) (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗

PubMed1991

Hepatic amino-nitrogen clearance to urea-nitrogen in control subjects and in patients with cirrhosis: a simplified method.

The functional hepatic nitrogen clearance during amino acid infusion is a measure of liver cell mass. The clinical feasibility of the test has so far been limited by methodological problems. A simplified procedure was used to measure the urea-nitrogen synthesis rate and functional hepatic nitrogen clearance in nine subjects with normal liver function and in nine patients with cirrhosis. The method was based on only four consecutive 2-hr urine collections and five blood samples. Total body water was calculated from a nomogram based on age and anthropometric data, whereas the gut urea hydrolysis was assigned one fixed fraction of synthesis (0.17 in control subjects and 0.26 in patients with cirrhosis). Finally, a solution of a single amino acid, alanine, was infused as substrate for urea synthesis. Urea-nitrogen synthesis rate increased linearly with increasing alpha-amino-nitrogen concentration, and the slope of the regression (functional hepatic nitrogen clearance) was reduced in cirrhosis from 37.5 +/- 7.0 L/hr to 18.4 +/- 6.7 L/hr; p less than 0.005. The hepatic nitrogen clearance was linearly related to the clinical status (Child-Pugh score), to routine liver function tests and to galactose elimination capacity (r = 0.869), a well-established, quantitative, liver function measure. The simplified method makes the measurement of hepatic nitrogen clearance suitable for routine clinical use. The test might prove useful to study the alterations of nitrogen metabolism in cirrhosis, with special reference to hepatic encephalopathy.

Adult↗

PubMed1990

Contradictory effects of uncomplicated versus complicated abdominal surgery on the hepatic capacity for urea synthesis in rats.

Female Wistar rats weighing 217 g were subjected to two types of surgical stress: uncomplicated (hysterectomy) and complicated (spleen and uterus ligated, crushed, and left in situ). Liver function as assessed by amino-N conversion was measured as the capacity for urea-N synthesis preoperatively (control animals) and on Days 1, 3, and 6 postoperatively. Uncomplicated surgery transiently increased the capacity for urea-N synthesis by 30% the first postoperative day (P less than 0.001). Complicated surgery decreased the capacity for urea-N synthesis to 55% throughout the investigation period (P less than 0.001). This was not due to a general change in liver mass since galactose elimination capacity remained constant. The increase in the capacity for urea-N synthesis after uncomplicated surgery is probably due to glucagon since plasma glucagon increased whereas plasma insulin and blood glucose remained unchanged after amino acid loading. The persistent decrease in the capacity for urea-N synthesis in complicated surgery is not due to changes in these regulators: glucagon increased, insulin decreased, and the rats were hypoglycemic. All changes are expected to increase the capacity for urea-N synthesis. The mechanism for the emergence of these two distinct metabolic patterns is not known. The phenomenon is probably important for interpretation of metabolic data on clinical stress.

Amino Acids↗

PubMed1990

Glucagon increases hepatic efficacy for urea synthesis.

The effect of glucagon on the relation between urea synthesis and blood amino acid concentration was studied in seven healthy volunteers. Alanine was given as prime-continuous infusions and, after 1 hr for equilibration, the urea nitrogen synthesis rate was measured in two periods of about 2 hrs as urinary excretion corrected for accumulation and intestinal hydrolysis. During one of the periods, glucagon was infused to obtain a constant concentration of 200-1200 ng/l. The spontaneous urea synthesis during the alanine infusion was 86-141 mmol/hr and linearly related to the alanine concentrations of 1.33-2.99 mmol/l. The hepatic clearance of alanine-nitrogen to urea-nitrogen, assessed by the ratio between the increase in the urea synthesis rate and alanine concentration, was 23 +/- 4 l/hr (mean +/- S.D.). Glucagon increased the rate of urea synthesis by 35 +/- 11 mmol/hr (p less than 0.02) and decreased the alanine concentration by 0.22 +/- 0.06 mmol/l (p less than 0.01). Glucagon increased the hepatic nitrogen clearance to an average of 42 +/- 13 l/hr (p less than 0.01). The difference between infusion of amino-nitrogen and appearance of urea-nitrogen was +15 +/- 10 mmol/hr during alanine infusion alone and -11 +/- 25 mmol/hr during exogenous glucagon. The loss of nitrogen could be accounted for by depletion of non-alanine amino acids from the blood. Glucagon increases the efficacy of urea synthesis, which may be of importance for catabolism by changing the hepatic contribution to nitrogen homeostasis.

Adult↗

PubMed1990

Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis.

We studied the effects of infusion of a branched chain enriched amino acid mixture versus glucose on acute hepatic encephalopathy in patients with cirrhosis. Sixty-five patients were randomly treated with 1 g/kg per day of an amino acid mixture with 40% branched chain contents (32 patients), or isocaloric glucose (33 patients) for a maximum of 16 days. The regimens further included glucose infusion to a total of 26.5 kcal/kg per day and lactulose. The patients took part in the study for 5-6 days. In each group 17 patients woke up. In the amino acid group eleven died and four developed renal failure. In the glucose group ten died, three developed renal and two respiratory failure, and one remained encephalopathic. The coma score worsened in three of the patients who died in the amino acid group, but in all patients who died in the glucose group. The negative nitrogen balance on entry reversed in the amino acid group, but not in the glucose group. Thus, the branched chain enriched amino acid supplement did not change the prognosis for wake-up, but had other effects on the cerebral state and on nitrogen homeostasis.

Adult↗

PubMed1990

Effects of hysterectomy and semi-starvation on amino-acid gradients across liver, muscle and gut in rats.

To study the effects of surgical stress and insufficient food intake on amino-acid exchange of liver, gut, and muscle, blood was sampled in random sequence from the aorta, the inferior caval vein, the portal vein, and the hepatic veins in 3 groups of 20 rats each. Control rats were fed ad libitum, hysterectomised rats were studied on the first and third post-operative day, and semi-starved rats were pair-fed to hysterectomised rats to an intake of 13% of control on the first day. Both groups lost 5-8% of body weight. Surgery increased the concentration gradient (release) of urea across liver by 60%, the glucose gradient (release) by 35%, and doubled the concentration gradients (uptake) across liver of alanine, arginine, glycine, lysine, proline, serine, and threonine, and decreased their plasma concentrations. There was no major change in hepatic amino-acid gradients in semi-starved animals, and there was no appreciable change in gradients of single amino-acids across gut or muscle in animals subjected to surgery or semi-starvation. Post-surgical increases in urea synthesis and hepatic uptake of uragenic and gluconeogenic amino-acids are due to the surgical stress and not to the post-operative semi-starvation.

Journal Article↗

PubMed1990

Indomethacin prevents the increase in urea synthesis capacity and the weight loss after hysterectomy in rats.

Prostaglandins have been suggested to be mediators of post-operative catabolism. Previous studies have shown that stimulation of urea synthesis contributes to post-operative nitrogen loss. The effect of prostaglandins on this hepatic function was assessed in hysterectomized rats on the first post-operative day by measurements of the Capacity of Urea-N Synthesis (CUNS) with and without indomethacin treatment. Hysterectomy increased CUNS by 1 3 and led to a weight loss of 10 g in one day. Indomethacin prevented the increase in CUNS and the post-operative weight loss in operated animals; it also decreased CUNS by 1 3 in control rats. Blood amino-nitrogen concentration of indomethacin treated hysterectomized rats was 1 3 lower than in untreated animals, indicating an even more marked effect of indomethacin on post-operative tissue amino-acid release than on CUNS. Indomethacin exerts a nitrogen sparing effect, possibly depending on normalization of both post-operative hepatic amino-nitrogen conversion and tissue proteolysis. This may be of clinical importance in controlling post-operative catabolism.

Journal Article↗