Functional Hepatic Nitrogen Clearance Research Articles

Non-alcoholic fatty liver disease causes dissociated changes in metabolic liver functions

Non-alcoholic fatty liver disease (NAFLD) is a major health concern affecting 25% of the world's population. It is generally held that a fatty liver does not influence liver function, but quantitative measurements of metabolic liver functions have not been systematically performed. We aimed to study selected hepatocellular metabolic functions in patients with different stages of NAFLD. Twenty-five non-diabetic, biopsy-proven NAFLD patients [12 with simple steatosis; 13 with non-alcoholic steatohepatitis (NASH)] and ten healthy controls were included in a cross-sectional study. Hepatocyte cytosolic function was assessed by the galactose elimination capacity (GEC), mitochondrial-cytosolic metabolic capacity by the functional hepatic nitrogen clearance (FHNC), microsomal function by the aminopyrine breath test, and excretory liver function by indocyanine green (ICG) elimination. GEC was 20% higher in NAFLD than in controls [3.15 mmol/min (2.9-3.41) vs. 2.62 (2.32-2.93); P = 0.02]. FHNC was 30% lower in NAFLD [23.3 L/h (18.7-28.9) vs. 33.1 (28.9-37.9); P = 0.04], more so in simple steatosis [19.1 L/h (13.9-26.2); P = 0.003] and non-significantly in NASH [27.9 L/h (20.6-37.8); P = 0.19]. Aminopyrine metabolism was 25% lower in simple steatosis [8.9% (7.0-10.7)] and 50% lower in NASH [6.0% (4.5-7.5)] than in controls [11.9% (9.3-12.8)] (P < 0.001). ICG elimination was intact. The hepatocellular metabolic functions were altered in a manner that was dissociated both by different effects on different liver functions and by different effects of different stages of NAFLD. Thus, NAFLD has widespread consequences for metabolic liver function, even in simple steatosis.

Time course of compromised urea synthesis in patients with alcoholic hepatitis

Objectives: Alcoholic hepatitis (AH) markedly decreases the urea synthesis capacity. We aimed to investigate the time course of this compromised essential liver function in patients with AH and its relation to treatment and survival.Materials and methods: Thirty patients with AH were included in a prospective cohort study. We measured the substrate-independent urea synthesis capacity, i.e., the functional hepatic nitrogen clearance (FHNC), in the patients at study entry and again at three months (survivors/available: n = 17). Patients with severe disease (Glasgow Alcoholic Hepatitis Score ≥9, n = 17) were randomized to receive either prednisolone or pentoxifylline and were in addition examined after 14 days (n = 9).Results: FHNC (normal range = 25–45 L/h) was markedly decreased at study entry (median = 5.6 (IQR = 3.0–9.6) L/h) and increased by three-fold in survivors at three months (15.1 (12.0–22.9) L/h; p < .001). In patients with severe AH, FHNC was also increased after 14 days of pharmacologic treatment and showed the greatest increase in the patients taking prednisolone (prednisolone 25.4 (20.6–26.2) L/h vs. pentoxifylline 12.3 (8.0–15.3) L/h; p = .05). FHNC at study entry was lower in 90-day non-survivors than in survivors (p = .04).Conclusions: The decrease in the urea synthesis capacity in patients with AH was the most marked in short-term non-survivors and partly recovered in survivors at three months. In patients on pharmacologic treatment, recovery was observed already after 14 days, and it was nearly complete in those on prednisolone. Thus, metabolic liver failure in AH seems to be prognostically important, is potentially reversible, and may recover more rapidly following treatment with prednisolone.

PS-150 - Time course of compromised urea synthesis in patients with alcoholic hepatitis

AbstractObjectives: Alcoholic hepatitis (AH) markedly decreases the urea synthesis capacity. We aimed to investigate the time course of this compromised essential liver function in patients with AH and its relation to treatment and survival.Materials and methods: Thirty patients with AH were included in a prospective cohort study. We measured the substrate-independent urea synthesis capacity, i.e., the functional hepatic nitrogen clearance (FHNC), in the patients at study entry and again at three months (survivors/available: n = 17). Patients with severe disease (Glasgow Alcoholic Hepatitis Score ≥9, n = 17) were randomized to receive either prednisolone or pentoxifylline and were in addition examined after 14 days (n = 9).Results: FHNC (normal range = 25–45 L/h) was markedly decreased at study entry (median = 5.6 (IQR = 3.0–9.6) L/h) and increased by three-fold in survivors at three months (15.1 (12.0–22.9) L/h; p < .001). In patients with severe AH, FHNC was also increased after 14 days of pharmacologic...

Prednisolone but Not Infliximab Aggravates the Upregulated Hepatic Nitrogen Elimination in Patients with Active Inflammatory Bowel Disease

Catabolism and weight loss are serious problems in patients with active inflammatory bowel disease (IBD). The body nitrogen (N) depletion is partly related to increased hepatic capacity for the elimination of N through urea synthesis. This is probably caused by the inflammation per se, and the treatment with prednisolone may aggravate the problem, whereas the effect of biological therapy is unknown. Therefore, we examined the effects of prednisolone or infliximab on the regulation of urea synthesis in patients with active IBD. Urea synthesis was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the urea nitrogen synthesis rate and the blood α-amino nitrogen concentration during alanine infusion. Thirty-seven patients with active IBD treated with either prednisolone or infliximab were examined before and after 7 days of treatment. At baseline, the FHNC was similar in the 2 treatment groups (36 L/h). After 7 days, prednisolone increased the FHNC by 40% (55 L/h) (P = 0.03), whereas infliximab tended to reduce the FHNC by 15% (30 L/h) (P = 0.09). The changes in the FHNC differed significantly between the 2 treatment groups (P < 0.01). Prednisolone treatment further upregulated urea synthesis, which increases the hepatic loss of nitrogen and promotes body catabolism. In contrast, infliximab treatment caused no such aggravation and likely reduced the N loss. These results may argue in favor of infliximab therapy for IBD and add to the pathophysiological understanding of the interplay between inflammation, catabolism, and anti-inflammatory treatment.

Quantitative liver functions in Turner syndrome with and without hormone replacement therapy

Studies have documented elevated levels of liver enzymes in many females with Turner syndrome (TS). Histology has shown a range of changes. Treatment with female hormone replacement therapy (HRT) reduces liver enzymes. To study quantitative liver functions in TS in detail with and without HRT. Randomized crossover study with active treatment (HRT in TS and P-pill in controls) or no treatment. Women with TS (n = 8, age 29.7 +/- 5.6 (mean +/- s.d.) years), verified by karyotype, and age-matched controls (C; n = 8, age 27.3 +/- 4.9 years). We determined liver enzymes in blood, used the galactose elimination capacity to assess hepatocyte cytosol activity, plasma clearance of indocyanine green to assess excretory function, antipyrine clearance to estimate microsomal activity, and the functional hepatic nitrogen clearance (FHNC) to assess mitochondrial-cytosolic metabolic capacity for conversion of amino-nitrogen. Liver enzymes were elevated in untreated TS and reduced by HRT. The hepatic capacities for conversion of galactose, indocyanine green, and antipyrine were normal and did not change by HRT. The FHNC was marginally reduced (untreated TS vs C: 19.4 +/- 5.4 vs 25.2 +/- 7.3 L/h, P = 0.1). FHNC changed slightly with HRT in TS (19.4 +/- 5.4 vs 24.4 +/- 10.2 L/h, P = 0.2). The elevations of liver enzymes in untreated TS are readily suppressed by HRT. Quantitative liver functions in TS are comparable to controls and are not affected by HRT.

Effects of long-term oral misoprostol administration on hepatic amino acid–nitrogen metabolism in patients with cirrhosis

Background: The acute infusion of a Prostaglandin of E series 1 (PGE1) analogue results in nitrogen sparing in cirrhosis. Aims: To test the effects of long-term oral PGE1 on hepatic and whole-body nitrogen metabolism. Patients and methods: Ten patients with advanced cirrhosis were studied in paired experiments, before and 30–50 days after oral misoprostol therapy. α-Amino-nitrogen levels and urea-nitrogen synthesis rate were measured in the post-absorptive state and in response to continuous alanine infusion (2 mmol/kg per hour for 4.5 h). Data were used to compute the functional hepatic nitrogen clearance, i.e. the slope of the regression of α-amino-N levels to urea-N synthesis rate, and the apparent nitrogen exchange. Results: Misoprostol reduced urea-N synthesis rate (during fasting and in response to alanine), resulting in a positive nitrogen exchange. The functional hepatic nitrogen clearance slightly increased, and the regression line was rightwards shifted, indicating a reduced urea synthesis rate at any α-amino-N concentration. Amino acid- and ammonia-N did not accumulate in plasma. No systematic effects on insulin and glucagon were observed. Conclusions: Data are consistent with a nitrogen sparing mechanism of misoprostol, not mediated by hormone levels. These effects may be beneficial in clinical hepatology, and need to be tested in controlled trials.

Urea synthesis in patients with chronic pancreatitis: relation to glucagon secretion and dietary protein intake

Background & Aims: Up-regulation of urea synthesis by amino acids and dietary protein intake may be impaired in patients with chronic pancreatitis (CP) due to the reduced glucagon secretion. Conversely, urea synthesis may be increased as a result of the chronic inflammation. The aims of the study were to determine urea synthesis kinetics in CP patients in relation to glucagon secretion (study I) and during an increase in protein intake (study II).Methods:In study I, urea synthesis rate, calculated as urinary excretion rate corrected for accumulation in total body water and intestinal loss, was measured during infusion of alanine in 7 CP patients and 5 control subjects on spontaneous protein intake. The functional hepatic nitrogen clearance (FHNC), i.e. urea synthesis expressed independent of changes in plasma amino acid concentration, was calculated as the slope of the linear relation between urea synthesis rate and plasma α -amino nitrogen concentration. In study II, 6 of the patients of study I had urea synthesis and FHNC determined before and after a period of 14 days of supplementation with a protein-enriched liquid (dietary sequence randomized).Results: Study I: Alanine infusion increased urea synthesis rate by a factor of 10 in the control subjects, and by a factor of 5 in the CP patients (P<0.01). FHNC was 31.9±2.4 l/h in the control subjects and 16.5±2.0 l/h (P<0.05) in the CP patients. The glucagon response to alanine infusion (AUC) was reduced by 75 % in the CP patients. The reduction in FHNC paralleled the reduced glucagon response (r2=0.55, P<0.01). Study II: The spontaneous protein intake was 0.75±0.14 g/(kg · day) and increased during the high protein period to 1.77±0.12 g/(kg · day). This increased alanine stimulated urea synthesis by a factor of 1.3 (P<0.05), FHNC from 13.5±2.6 l/h to 19.4±3.1 l/h (P<0.01), and the glucagon response to alanine infusion (AUC) by a factor of 1.8 (P<0.05).Conclusions: Urea synthesis rate and FHNC are markedly reduced in CP patients. This is associated with, and probably a result of, impaired glucagon secretion, and predicts a lower than normal postprandial hepatic loss of amino nitrogen. An increase in dietary protein intake increases alanine stimulated urea synthesis and FHNC by a mechanism that involves an increase in glucagon. This indicates that the low FHNC during spontaneous protein intake included an adaptation to the low protein intake, effectuated by a further decrease in glucagon secretion.

Acute effects of moderate dehydration on the hepatic conversion of amino nitrogen into urea nitrogen in healthy men

Intracellular hydration may play a role in the regulation of protein and nitrogen metabolism. The hepatic removal of nitrogen by urea synthesis has a key regulatory role in nitrogen balance. The purpose of the present study was to establish the acute effects of dehydration on the hepatic kinetics of urea synthesis, quantified by functional hepatic nitrogen clearance (FHNC), in healthy volunteers. Seven healthy men were studied twice in random order. On both study days, a primed continuous infusion of alanine was given. On the day of dehydration an intravenous bolus injection of a loop diuretic (furosemide, 1 mg/kg) was superimposed. FHNC was calculated as the ratio between measured synthesis rates of urea nitrogen and blood alanine concentrations. Furosemide induced a weight loss of 1 kg. During dehydration, FHNC decreased by approx. 25% (41+/-11 to 54+/-10 litres/h; P<0.02). On both occasions individual FHNC and glucagon values were positively correlated (r(2)>0.6). In addition, dehydration more than halved the linear slope of the relationship (P<0.05). The FHNC values were correlated with the urinary excretion of both potassium and sodium (r(2)=0.68, P<0.01 and r(2)=0.62, P<0.02 respectively). Changes in the reactivity of urea synthesis to glucagon (i.e. the ratio between FHNC and glucagon concentration) was negatively correlated with an indirectly estimated change in intracellular water (r(2)=0.79, P<0.05). We conclude that acute moderate dehydration down-regulates both total urea synthesis and its sensitivity to glucagon. The latter was related to estimated intracellular water loss. Dehydration may thus have nitrogen-saving consequences with regard to the hepatic contribution to whole-body nitrogen homoeostasis. The mechanism of this effect and the relationship with sodium and potassium fluxes is not known.

Effects of budesonide and prednisolone on hepatic kinetics for urea synthesis

Background/Aims: Glucocorticoids upregulate hepatic urea synthesis and cause protein breakdown to prevail over synthesis, releasing amino acids into the blood stream and increasing the substrate supply for hepatic urea synthesis. Budesonide is a new generation glucocorticoid that may be used for treatment of inflammatory diseases, e.g. Crohn's disease and autoimmune hepatitis. Due to its extensive first-pass metabolism in the liver, it has a potential adverse effect profile superior to that of prednisolone. Little attention has been directed towards differences in nitrogen catabolic properties between budesonide and prednisolone. Methods: Eight normal male subjects (age 20–44 years; BMI 21.6–28.2 kg/m 2) were randomly studied 3 times: 1) At baseline, 2) after 6 days of prednisolone (50 mg/day), and 3) after 6 days of budesonide (9 mg/day). We measured urea nitrogen synthesis rates (UNSR) and blood α-amino-nitrogen (N) levels before, during, and after a 3-h constant infusion of alanine (2 mmol/(kg BW×h)). UNSR was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between UNSR and amino-N concentration represents the hepatic kinetics of conversion of amino- to urea-N, and is denoted the functional hepatic nitrogen clearance (FHNC). Results: Prenisolone, but not budesonide, administration increased basal blood and amino nitrogen concentrations (3.5±0.1 mmol/l (control) vs 3.8±0.1 mmol/l (prednisolone) ( p<0.05) and 3.6±0.1 mmol/l (budesonide) (NS). Basal UNSR values were significantly increased following prednisolone (23.3±6.5 (control) vs 51.2±6.3 (prednisolone) ( p<0.05)), while budesonide had no effect on basal UNSR (33.7±4.2 (budesonide) (NS)). Prednisolone administration increased FHNC (from 24.6±4.7 l/h (control) to 47.3±5.9 l/h (prednisolone) ( p<0.05). Budesonide administration did not significantly increase FHNC (33.7±4.2 l/h (budesonide), ( vs control; p=0.12, vs prednisolone: p<0.05)). Conclusions: Prednisolone administration led to increased levels of amino acids in blood and loss of N as urea, the latter in part due to a specific hepatic mechanism as shown by the increased FHNC. Budesonide led to unaltered levels of amino acids in blood, no changes in loss of N as urea, and unaltered hepatic kinetics for urea synthesis. Thus, oral budesonide administration had very limited effects on the hepatic contribution to nitrogen homeostasis and metabolism via urea synthesis, making treatment with budesonide superior to that of conventional glucocorticoids in this respect.

Acute non-traumatic pain increases the hepatic amino- to urea-N conversion in normal man

Background/Aim: Severe stress results in a catabolic state with nitrogen (N) loss via hepatic urea synthesis, and in most situations a sensation of pain. Our purpose was to establish whether pain per se upregulates liver function as to urea synthesis.Methods: Ten healthy male volunteers were investigated on 3 occasions in a crossover design. Self-controlled electrical pain was applied to the abdominal skin for 30 min to an intensity of 8 on a visual analogue scale from 0 to 10. Next, the electric profile was reproduced during local analgesia (mepivacaine 2.5 mg/kg bw), and the pain was scored to only 0.5. Finally, there was a control experiment with no intervention. Alanine infusion (1 mmol/kg/h) was started 2 h before intervention and continued throughout the investigation. Urea-N synthesis rate (UNSR) was estimated hourly as urinary excretion corrected for accumulation in body water and gut hydrolysis.Results: Pain increased the Functional Hepatic Nitrogen Clearance (FHNC) assessed by the ratio UNSR/AAN (in the 3 h following pain) by 20% (22.7±1.2 vs 19.0±0.7 l/h (control), p<0.05). FHNC during local analgesia was in between (21.1±1.1 l/h) but not significantly different from either of the two other experiments. Mean blood amino-N concentration (AAN) and mean UNSR were comparable in the three situations. There was no difference in serum glucagon among experiments, but pain increased serum cortisol (452±15 vs 233±20 nmol/l (control), p<0.001) and plasma adrenaline (104±16 vs 58±9 pg/ml (control), p<0.05).Conclusion: Acute, severe atraumatic pain induces an increase in the ability of the liver to convert amino- to urea-N, and thus acts as a catabolic stimulus via regulation of liver function. The measurements of known endocrine regulators of urea synthesis do not explain the phenomenon. The present data, however, suggest the hypothesis that the effects of pain were attenuated by local analgesia. If this is confirmed by further experiments, it would indicate a signal transmission to the liver which has not been previously described.

Hepatic amino- to urea-N clearance and forearm amino-N exchange during hypoglycemic and euglycemic hyperinsulinemia in normal man

Background/Aims: Hypoglycemia has well-described effects on glucose metabolism, whereas the possible effects on hepatic amino nitrogen conversion in relation to muscle amino nitrogen flux are more uncertain. Methods: We studied six healthy young male subjects three times, i.e. for 6 h in the basal state, during a 6-h euglycemic hyperinsulinemic (1.5 mU/kg/min) clamp and during a 6-h hypoglycemic (plasma glucose below 2.8 mmol/l) clamp. Alanine (2 mmol/kg body weight/h) was infused for 3 h to describe the relationship between blood amino nitrogen concentrations and hepatic ureagenesis estimated from urea urine excretion and accumulation in body water. The slope of this relationship is denoted functional hepatic nitrogen clearance (FHNC) and quantifies substrate-independent alterations in hepatic amino nitrogen degradation. In parallel, amino nitrogen balances across muscles were estimated by the forearm flux method. Results: Euglycemia decreased circulating glucagon values (100±25 ng/l vs. 160±30 ng/l), whereas hypoglycemia doubled glucagon (350±45 ng/l, p<0.05). Hepatic nitrogen clearance (FHNC) decreased during hyperinsulinemic euglycemia (19.5±3.4 1/h vs. 30.6±5.7 l/h, p<0.01), whereas forearm net uptake of amino nitrogen increased (130±40 nmol/100 ml7times;min vs. control: −10±4 nmol/100 ml7times;min). During hypoglycemia there was a 3-fold increase in hepatic nitrogen clearance up to 83.0±16.8 l/h ( p<0.01) and increased release of amino nitrogen from the forearm (−100±30 nmol/100 ml7times;min, p<0.01). Conclusion: Hypoglycemia in man induces a marked increase in hepatic amino- to urea-N clearance. This catabolic response to hypoglycemia in the liver may be of primary importance for muscle amino acid release. Our data are compatible with the notion that liver and muscle together are responsible for catabolism during hypoglycemia, and that glucagon may be the primary mediator via its effect on liver metabolism.

Effects of xylitol on urea synthesis in patients with cirrhosis of the liver.

In individuals with cirrhosis the normal inhibiting effect of glucose on urea synthesis is lost, probably because of very high concentrations of glucagon. In agreement, glucose does not prevent the inducing effect of glucagon on urea synthesis in normal humans. In contrast, the sugar alcohol, xylitol, prevents the increasing effect of glucagon in normal humans. We, therefore, examined the effect of xylitol on urea synthesis in individuals with cirrhosis and hyperglucagonemia. Urea synthesis, calculated as urinary excretion rate corrected for accumulation in total body water and intestinal loss, was measured during infusion of alanine (2 mmol/[h x kg body wt]) and during infusion of alanine superimposed on infusion of xylitol (0.12 g/[h x kg body wt]) in 8 individuals with biopsy-proven alcoholic cirrhosis. The functional hepatic nitrogen clearance (FHNC), ie, urea synthesis expressed independent of changes in plasma amino acid concentration, was calculated as the slope of the linear relation between the urea synthesis rate and the plasma amino acid concentration. All individuals had elevated basal plasma glucagon concentration (261 +/- 61 ng/L; mean +/- SEM) and a markedly increased response to alanine infusion (1037 +/- 226 ng/L). This was not changed by xylitol. Neither the basal urea synthesis rate (13.2 +/- 2.5 mmol/h) nor the alanine-stimulated urea synthesis rate (76.8 +/- 3.64 mmol/h) was changed by xylitol. FHNC during the infusion of alanine alone was 10.5 +/- 0.9 L/h and did not change during the concomitant infusion of xylitol (10.1 +/- 1.1 L/h). Xylitol reduces neither urea synthesis nor FHNC. The data do not support an important role of xylitol as a nitrogen-sparing agent in cirrhosis.

Growth hormone prevents prednisolone-induced increase in functional hepatic nitrogen clearance in normal man

Background/Aims: Glucocorticoid treatment increases urea excretion and leads to negative nitrogen balance. This effect is presumed mainly to reflect actions on tissue protein metabolism, but has been shown in rats to involve an hepatic element in the form of upregulation of the kinetics of ureagenesis. Likewise, the anabolic action of growth hormone administration has been shown to involve an hepatic element, just as growth hormone administration has been shown to prevent the protein catabolic side effects of prednisolone. Whether glucocorticoids increase the ability of the liver to convert amino-N to urea-N in man, and whether growth hormone counteracts any possible effect of glucocorticoid has not been studied. Methods: We measured urea nitrogen synthesis rates and blood a-amino-N levels before, during and after a 4-h constant i.v. infusion of alanine (2 mmol · kg BW −1 · h −1. The urea nitrogen synthesis rate was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between urea nitrogen synthesis rate and amino-N concentration represents the hepatic kinetics of conversion of amino- to urea-N, and is denoted the functional hepatic nitrogen clearance. Eight normal male subjects (aged 22–28 years; BMI 21.6–26.3 kg/m 2) were randomly studied four times: i) after 4 days of s.c. saline injections, ii) after 4 days of s.c. growth hormone injections (0.1 IU · kg −1 · day −1), iii) after 4 days of glucocorticoid administration (50 mg/d) and iv) after 4 days of growth hormone and glucocorticoid administration. All injections were given at 20 00 hours and 25 mg prednisolone was given morning and evening. Results: Growth hormone decreased functional hepatic nitrogen clearance (l/h) by 21% (from 38.8±1.8 l/h (control) to 30.5±2.7 l/h (4 d growth hormone) (mean±SE) (ANOVA; p<0.05)). Glucocorticoid increased functional hepatic nitrogen clearance by 23% (47.7±3.3 l/h, p<0.05), while growth hormone plus glucocorticoid offset any effect on functional hepatic nitrogen clearance (36.2±3.3 l/h, p=0.83). Conclusions: Glucocorticoid administration leads to loss of nitrogen as urea, in part due to a specific hepatic mechanism, as shown by the increased functional hepatic nitrogen clearance. Growth hormone has the opposite effect, and also neutralises the glucocorticoid effect when given together with prednisolone. This adds to the understanding of the development and treatment possibilities of steroid catabolism.

Increased hepatic urea synthesis in patients with active inflammatory bowel disease

Background/Methods: Patients with active inflammatory bowel disease are often reported to be in negative nitrogen balance. Therefore, we examined basal and amino acid stimulated urea synthesis in 11 patients with active inflammatory bowel disease (six with Crohn's disease and five with ulcerative colitis) and in 10 patients with non-active disease (six with Crohn's disease and four with ulcerative colitis). A primed continuous infusion of an amino acid mixture was given from t=1 h to t=5 h; during the first and the last 2 h no amino acid infusion was given. Urea nitrogen synthesis rate was calculated in hourly intervals for 7 consecutive hours. Urea nitrogen synthesis rate was quantified independent of changes in blood amino acid concentration by means of the functional hepatic nitrogen clearance, i.e. the linear slope of the regression of urea nitrogen synthesis rate on blood amino acid concentration. Results: Basal urea nitrogen synthesis rate was 24.5±2.9 mmol/h in the patients with no disease activity and 43.8±2.2 mmol/h in patients with active disease ( p<0.01). During amino acid infusion urea nitrogen synthesis rate was elevated two-fold in the patients with active disease. Functional hepatic nitrogen clearance was 28.2±1.5 l/h in patients with no disease activity and 56.1±4.1 l/h in patients with active disease ( p<0.01). No differences between the two groups were observed as regards basal or stimulated plasma glucagon and cortisol and serum levels of interleukin-1α, interleukin-1β, tumor necrosis factor plasma and interleukin-6. Conclusions: The results show that the liver function related to conversion of amino-nitrogen to urea is increased in patients with active inflammatory bowel disease. No differences among known and possible regulators of urea synthesis were found between the two groups. The accelerated hepatic amino-nitrogen conversion contributes to the less efficient nitrogen economy in patients with active inflammatory bowel disease.

Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis

Zinc deficiency is common in cirrhosis and has been involved in the altered nitrogen metabolism. In this study, we measured the effects of zinc supplementation on the dynamics of amino acid-derived urea synthesis in cirrhosis with mild or latent encephalopathy. The hepatic conversion of amino acids into urea was studied in eight patients with advanced cirrhosis under controlled conditions of substrate availability (continuous alanine infusion), before and after 3-month oral zinc sulfate supplementation (600 mg/d). Eight more patients, matched for hepatocellular failure and encephalopathy, served as controls. Plasma zinc levels were reduced in all patients and returned to normal after oral zinc. The alanine-stimulated urea nitrogen synthesis rate in relation to alpha-amino-N concentration–the functional hepatic nitrogen clearance–increased by 25% after zinc supplementation, i.e., more urea was produced at any alpha-amino-N concentration. Basal and alanine-induced glucagon decreased by 50%, and the ammonia response to alanine decreased by 30%. Psychometric tests improved, as did routine and dynamic liver function tests and the Child- Pugh score. Also, the plasma concentration of lipid peroxides was reduced by zinc. No significant changes were observed in the control group. Our data indicate that long-term oral zinc speeds up the kinetics of urea formation from amino acids and ammonia. Changes in the hormonal drive and/or the antioxidant activity of zinc might be involved in the general improvement in liver function, whereas the beneficial effects on encephalopathy might stem from decreased ammonia. (Hepatology 1996 May;23(5):1084-92)

Effects of long-term growth hormone (GH) and triiodothyronine (T 3) administration on functional hepatic nitrogen clearance in normal man

Background/Aims: A decline in urea excretion is seen following long-term growth hormone administration, reflecting overall protein anabolism. Conversely, hyperthyroidism is characterized by increased urea synthesis and negative nitrogen metabolism. The seemingly opposite effects are presumed to reflect different actions on peripheral protein metabolism. The extent to which these hormonal systems have different direct effects on hepatic urea genesis has not been fully characterized. methods: We measured urea nitrogen synthesis rates and blood alanine levels concomitantly before, during, and after a 4-h constant intravenous infusion of alanine (2 mmol · kg bw −1 · h −1). Urea nitrogen synthesis rate was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between urea nitrogen synthesis rate and alanine concentration represents the liver function as to conversion of amino-N, and is denoted the functional hepatic nitrogen clearance. Eight normal male subjects (age 21–27 years; body mass index 22.4–27.0 kg/m 2) were randomly studied four times: 1) After 10 days of subcutaneous saline injections, 2) after 10 days of subcutaneous growth hormone injections (0.1 IU/kg per day), 3) after 10 days of triiodothyronine administration (40 μg on even dates, 20 μg on uneven dates) and 4) after 10 days given 2)+3). All injections were given at 20 00 h. Results: Growth hormone decreased functional hepatic nitrogen clearance (l/h) by 30% (from 33.8±3.2 l/h (control) to 23.8±1.5 l/h (10 days growth hormone) (mean±SE) (ANOVA; p<0.01)). Triiodothyronine did not change functional hepatic nitrogen clearance (36.7±3.2 l/h), but triiodothyronine given together with growth hormone abolished the effect of growth hormone functional hepatic nitrogen clearance (38.8±4.8 l/h). Conclusions: The results show that long-term growth hormone administration acts on liver by decreasing functional hepatic nitrogen clearance, thereby retaining amino-N in the body. Triiodothyronine has no effect on functional hepatic nitrogen clearance, but given together with growth hormone, it abolishes the effect of growth hormone on functional hepatic nitrogen clearance. A possible mechanism is the known effect of thyroid hormones in reducing the bioavailability of insulin-like growth factor-I. Thus, the effects of growth hormone and triiodothyronine on amino-N homeostasis are interdependent and to some extent exerted via interplay in their regulation of liver function as to amino-N conversion.

Effects of xylitol on urea synthesis in normal humans: relation to glucagon.

Xylitol exerts a nitrogen-sparing effect in stress catabolic states with hyperglucagonemia, but the mechanism(s) is unknown. We examined the effects of xylitol on urea synthesis during physiologic glucagon concentrations and during hyperglucagonemia. Urea synthesis was measured independently of blood amino acid concentration by means of functional hepatic nitrogen clearance (FHNC) (ie, the linear slope of the relation between urea synthesis rate and blood alpha-amino nitrogen concentration during infusion of alanine). FHNC was measured on four separate occasions in each of seven healthy subjects: during constant infusion of alanine alone, alanine superimposed on a constant infusion of xylitol (blood xylitol 1 mmol/L), alanine superimposed on infusion of glucagon, and alanine superimposed on infusions of xylitol and glucagon. During alanine infusion alone, plasma glucagon rose to -170 ng/L, and FHNC was (mean +/- sem) 27.9 +/- 1.3 L/h. Xylitol did not affect plasma glucagon and only moderately reduced FHNC to 24.3 +/- 1.0 L/h (p < .05). Glucagon infusion increased plasma glucagon to -450 ng/L and FHNC twofold to 50.9 +/- 6.2 L/h; this increase was totally prevented by the addition of xylitol that reduced FHNC to 27.4 +/- 2.6 L/h (p < .01). The results show that xylitol only inhibited FHNC minimally during spontaneous glucagon levels. In contrast, xylitol completely inhibits the increase in FHNC by glucagon. This suggests that the mechanism whereby xylitol reduces nitrogen loss in stress catabolic conditions with hyperglucagonemia involves an effect on liver metabolism. The mechanism is unknown but may be related to depletion of hepatocyte adenine nucleotides.

Effects of beta-blockade on hepatic conversion of amino acid nitrogen and on urea synthesis in cirrhosis

β-Blockers are widely used to prevent gastrointestinal hemorrhage in cirrhosis. The metabolic effects of treatment are scarcely studied: hepatic function reportedly does not change significantly, but β-adrenoceptors have been reported to regulate protein and amino acid metabolism. We studied hepatic nitrogen metabolism in response to constant alanine infusion in seven patients with cirrhosis before and 7 to 10 days after treatment with oral propranolol (60 to 100 mg/d). Beta-blockade was effective: it decreased heart rate by 25%, abolished orthostatic tachycardia, and reduced portal blood flow by 20%. Alanine-stimulated urea nitrogen synthesis rate (UNSR) was higher in patients with propranolol treatment, without any difference in aminonitrogen concentration. The kinetics of hepatic conversion of amino acid nitrogen into urea—ie, functional hepatic nitrogen clearance (FHNC)—increased by 30%, from (mean ± SD) 17.0 ± 4.1 to 22.0 ± 6.6 L/h ( P < .01). Increased urea production during alanine infusion resulted in negative nitrogen exchange even at the peak of α-aminonitrogen concentration. Basal insulin level was only slightly reduced during propranolol treatment, whereas the insulin response to alanine was significantly blunted. No differences in glucagon and cortisol were demonstrated. Epinephrine and norepinephrine levels were high-normal and did not vary after treatment. Increased urea production and stimulation of hepatic nitrogen clearance during beta-blockade may be mediated by relative hypoinsulinemia or by direct involvement of β-adrenoceptors in the control of nitrogen metabolism, possibly by regulation of amino acid uptake and release in peripheral tissues.

Elective Laparoscopic Cholecystectomy Nearly Abolishes the Postoperative Hepatic Catabolic Stress Response

Surgery results in a catabolic state of postoperative stress, where the efficiency of the liver to convert amino acids to urea is increased. This study measured the metabolic consequences of the less traumatic laparoscopic surgery in elective cholecystectomy compared with traditional open surgery technique. The authors previously have shown that open cholecystectomy doubles the urea synthesis measured by the means of the functional hepatic nitrogen clearance. Glucagon and cortisol increased by 50% (p < 0.05) and 75% (p < 0.05), respectively, after open cholecystectomy. Patients undergoing uncomplicated elective laparoscopic cholecystectomies were included. Preoperatively and on the first postoperative day, blood and urine samples were drawn every hour under basal conditions and during amino acid infusion. The urea synthesis rate was calculated from the urea excreted in urine and accumulated in total body water. Functional hepatic nitrogen clearance was quantified as the slope of the linear relation between blood amino-N concentration and the urea synthesis rate. The results were compared with an historic matched group of patients who underwent open cholecystectomies and were studied by the same protocol. The laparoscopic cholecystectomy increased the functional hepatic nitrogen clearance by only 25% (from 8.7 +/- 0.9 to 11.1 +/- 1.5 mL/sec [mean +/- SEM; p < 0.05]), compared with a doubling after open cholecystectomy (from 9.4 +/- 0.9 to 17.6 +/- 3.3 mL/sec [p < 0.05]). The difference between the groups was significant (p < 0.05). Neither glucagon nor cortisol increased significantly after laparoscopic cholecystectomy. The laparoscopic technique results in a much smaller postoperative hepatic catabolic stress response and probably reduced tissue loss of amino-N. This may be important for the more rapid convalescence and reduced postoperative fatigue.

Kinetics of hepatic amino-nitrogen conversion in ageing man.

Previous studies have shown that hepatic function, quantitatively measured by dynamic liver function tests, progressively declines with ageing. Urea synthesis is a specific process taking place in the liver; a reduced urea synthesis in response to a protein-rich metal has previously been demonstrated in the elderly, but the process has never been standardized in relation to amino acid supply. We measured the hepatic conversion of alpha-amino nitrogen into urea nitrogen in response to alanine infusion in 32 subjects, with normal routine liver and renal function tests and without evidence of previous hepatic disorders, belonging to three different age-groups (< or = 55 years, 56-70, > or = 71). The functional hepatic nitrogen clearance was reduced on average by 20% in subjects aged 56-70 years, and by 30% in subjects over 70 years old in comparison to the age-group under 55 years (ANOVA: P = 0.0001), and significantly correlated with age (r = -0.684). No sex differences were observed on the effects of age on hepatic clearance. Also, liver volume, measured by ultrasonography, was reduced with advancing age, but the age-related decrease in hepatic nitrogen conversion was not primarily dependent on decreased liver volume. The measurement of functional hepatic nitrogen clearance has already been validated as a quantitative liver function test in clinical hepatology. In keeping with previous studies, the age-related decline in hepatic nitrogen conversion points to a decreased functional capacity of the ageing hepatic parenchyma.