Fasting Venous Ammonia Research Articles

Diagnostic value of blood variables following attenuation of congenital extrahepatic portosystemic shunt in dogs

BackgroundThe aims of this study were to determine if extrahepatic portosystemic shunt (EHPSS) postoperative closure could be predicted based on preoperative blood analyses and to determine the accuracy of blood...

L-ornithine L-aspartate in bouts of overt hepatic encephalopathy.

High-quality data on the efficacy of L-ornithine L-aspartate (LOLA) in patients with cirrhosis and bouts of overt hepatic encephalopathy (OHE) are missing. We evaluated the efficacy of intravenous LOLA in the reversal of bouts of OHE in patients with cirrhosis. In this prospective, double-blind, randomized, placebo-controlled trial conducted at two tertiary care institutes in India, 370 patients with cirrhosis and bouts of OHE were screened. After exclusion, 193 (52.16%) patients were randomized to receive either intravenous infusions of LOLA (n = 98), 30 g daily, or placebo (n = 95) for 5 days. Standard of care treatment (including lactulose and ceftriaxone) was given in both groups. Randomization was done centrally (http://www.sealedenvelope.com/). All study personnel were blinded to the treatment assignment. Fasting venous ammonia levels were estimated daily from 0 to 5 days. Serum tumor necrosis factor-alpha, interleukins, hemogram, and liver and renal function tests were performed at days 0 and 5. Primary outcome was mental state grade at day 5 of treatment. The grade of OHE was significantly lower in the LOLA group (compared to placebo) on days 1-4 but not on day 5. The mean time taken for recovery was lower in the LOLA group compared to the placebo group (1.92 ± 0.93 versus 2.50 ± 1.03 days, P = 0.002; 95% confidence interval -0.852 to -0.202). Venous ammonia at day 5 and length of hospital stay were significantly lower in the LOLA group. No significant difference in interleukins was seen between the groups. Conclusion: In patients with bouts of OHE, intravenous LOLA (as an add-on therapy to lactulose and ceftriaxone) significantly improves the grade of OHE over days 1-4, but not on day 5, and decreases venous ammonia, time of recovery, and length of hospital stay. (Hepatology 2018;67:700-710).

L-Ornithine L-Aspartate In Acute Overt Hepatic Encephalopathy

Introduction: Good quality data on effectiveness of L-Ornithine L-Aspartate (LOLA) in cirrhotic patients with acute overt hepatic encephalopathy (HE) is absent. We aimed to evaluate efficacy of intravenous LOLA in reversal of acute overt HE in cirrhotic patients. Methods: A prospective double-blind, randomized placebo controlled trial was conducted at Gastroenterology department of two tertiary care institutes in India. Three hundred and seventy cirrhotic patients with acute overt HE were screened. After exclusion, 196 (52.97%) patients were randomized to receive either intravenous infusions of LOLA (n=98), 30 grams daily or Placebo (n=98) for 5 days. Standard of care treatment (including Lactulose) was given in both groups. Fasting venous ammonia levels were estimated daily from 0-5 days. Serum concentration of, Interleukin 1β, Interleukin 6, Interleukin 10, Tumor Necrosis Factor α, Hemogram, liver, renal function tests were performed at day 0 and 5. Primary outcome was mental state grade at day 5 of treatment. Results: On completion of 5 days of treatment, 75.5% patients in LOLA group and 74.5% patients in placebo group had resolution of overt HE. Mean time taken for recovery was 1.92±0.93 days in LOLA group & 2.45±1.06 days in placebo group, p=0.002 (95% CI -0.852 to - 0.202). Length of hospital stay and Venous ammonia at day 5 were significantly lower in LOLA group. No significant change was seen in Interleukins and Tumor Necrosis Factor α in both the groups. Conclusion: In patients suffering from acute overt HE, intravenous LOLA decreases the time of recovery from HE, shortens the length of hospital stay and decreases the venous ammonia.Table: Table. Results from a linear regression analysis on venous ammonia and interleukins at day 5 adjusted for baseline and center.Figure: Percentage of patients with resolution of Hepatic encephalopathy from day 1 to day 5.

L-Ornithine l-Aspartate in Acute Overt Hepatic Encephalopathy

Background and Aim: High quality data on efficacy of l-ornithine l-aspartate (LOLA) in cirrhotics with acute overt hepatic encephalopathy (HE) is missing. We aimed to evaluate the efficacy of intravenous LOLA in reversal of acute overt HE in cirrhotics. This prospective double-blind randomized placebo controlled trial was conducted at Gastroenterology department of two tertiary care institutes in India. Methods: Three hundred and seventy cirrhotics with acute overt HE were screened. After exclusion, 196 (52.97%) patients were randomized to receive either intravenous infusions of LOLA (n = 98), 30 grams daily or placebo (n = 98) for 5 days. Standard of care treatment (including lactulose) was given in both groups. Fasting venous ammonia levels were estimated daily from 0 to 5 days. Serum concentration of tumor necrosis factor α, interleukin 1β, interleukin 6, interleukin10, hemogram, liver, renal function tests were performed at day 0 and 5. Primary outcome was mental state grade at day 5 of treatment. Results: After 5 days of treatment there was no significant difference in mental state grade between LOLA and placebo groups. However the mean time taken for recovery was 1.92 ± 0.93 days in LOLA group and 2.45 ± 1.06 days in placebo group, P = 0.002 (95% CI −0.852 to −0.202). Venous ammonia at day 5 and length of hospital stay were significantly lower in LOLA group. No significant change was seen in interleukins and tumor necrosis factor α in both the groups. Conclusion: In patients with acute overt HE, intravenous LOLA decreases venous ammonia, decrease the time of recovery and shortens the length of hospital stay (Table 1).Table 1Results From a Linear Regression Analysis on Venous Ammonia and Interleukins at Day 5 Adjusted for Baseline and Center.LOLA (mean ± SD)Placebo (mean ± SD)Adjusted difference (95% confidence interval)aLOLA–placebo. #: Number of patients tested.P-valueAmmonia (μg/dL) # (L = 81, P = 81)40.3 ± 33.860.7 ± 35.120.9 (10.4–31.3)0.0001Interleukin 1β (pg/ml) # (L = 85, P = 78)3.1 ± 19.52.4 ± 5.30.9 (−0.4 to 2.3)0.15Interleukin6 (pg/ml) # (L = 83, P = 79)37.8 ± 46.545.8 ± 54.43.3 (−8.8 to 15.4)0.59Interleukin10 (pg/ml) # (L = 84, P = 79)12.5 ± 32.019.1 ± 21.46.7 (−0.2 to 12.7)0.06TNF alpha (pg/ml) # (L = 84, P = 78)11.33 ± 50.07.97 ± 13.1−1.30 (−8.67 to 6.1)0.73a LOLA–placebo.#: Number of patients tested. Open table in a new tab The authors have none to declare.

A low-cost, user-friendly electroencephalographic recording system for the assessment of hepatic encephalopathy.

Electroencephalography (EEG) is useful to objectively diagnose/grade hepatic encephalopathy (HE) across its spectrum of severity. However, it requires expensive equipment, and hepatogastroenterologists are generally unfamiliar with its acquisition/interpretation. Recent technological advances have led to the development of low-cost, user-friendly EEG systems, allowing EEG acquisition also in settings with limited neurophysiological experience. The aim of this study was to assess the relationship between EEG parameters obtained from a standard-EEG system and from a commercial, low-cost wireless headset (light-EEG) in patients with cirrhosis and varying degrees of HE. Seventy-two patients (58 males, 61 ± 9 years) underwent clinical evaluation, the Psychometric Hepatic Encephalopathy Score (PHES), and EEG recording with both systems. Automated EEG parameters were calculated on two derivations. Strong correlations were observed between automated parameters obtained from the two EEG systems. Bland and Altman analysis indicated that the two systems provided comparable automated parameters, and agreement between classifications (normal versus abnormal EEG) based on standard-EEG and light-EEG was good (0.6 < κ < 0.8). Automated parameters such as the mean dominant frequency obtained from the light-EEG correlated significantly with the Model for End-Stage Liver Disease score (r = -0.39, P < 0.05), fasting venous ammonia levels (r = -0.41, P < 0.01), and PHES (r = -0.49, P < 0.001). Finally, significant differences in light-EEG parameters were observed in patients with varying degrees of HE. Reliable EEG parameters for HE diagnosing/grading can be obtained from a cheap, commercial, wireless headset; this may lead to more widespread use of this patient-independent tool both in routine liver practice and in the research setting. (

Transient Hyperammonemia Due to Urea Cycle Enzyme Deficiency in Irish Wolfhounds

Background:Irish Wolfhounds frequently have a congenital portosystemic shunt, but a considerable proportion of the 6‐to 8‐wk‐old pups has hyperammonemia in the absence of portosystemic shunting. This hyperammonemia causes no signs and is transient, normalizing at the age of 3–4 months.Hypothesis:Transient hyperammonemia has a metabolic basis in Irish Wolfhounds.Animals:Two related (same sire) litters of Irish Wolfhounds (17 pups) and their parents were studied.Methods:Integrity of the portal circulation was examined by ultrasonography and scintigraphy. Absence of parenchymal liver disease was verified by liver biopsy. Amino acid profiles were measured in 4 pups and repeated in 2 of these pups when ammonia concentrations had normalized. The amino acid profiles were compared with those of healthy Irish Wolfhound pups.Results:Fasting venous ammonia concentrations were high (113–622 μg/dL, 65–345 μmol/L) in all pups, whereas bile acids were within reference range in all but 1. The ammonia and bile acid concentrations from all parents were within reference range. Portosystemic shunting was excluded in all but 1 pup. Liver biopsy excluded significant lesions in all 10 pups examined. Hypercitrullinemia was found and persisted even when ammonia had normalized, at the expense of an increase in glutamine and asparagine.Conclusions and Clinical Importance: Citrulline concentrations are controlled by the urea cycle enzymes argininosuccinase and argininosuccinate synthetase, and a defect in either of these enzymes may be responsible for the transient hyperammonemia in Irish Wolfhounds. Resolution of the hyperammonemia is associated with increased activity of alternative metabolic pathways forming glutamine and asparagine. Confirmation requires measurement of enzyme activities in liver tissue.

Oral glutamine challenge in cirrhotics pre- and post-liver transplantation: a psychometric and analyzed EEG study.

Latent or sub-clinical hepatic encephalopathy is a recognized complication of cirrhosis and is thought to represent one end of the spectrum of neuropsychiatric impairment, which occurrs as a result of portal-systemic shunting. We studied the psychometric, analyzed electroencephalography (EEG), and venous blood ammonia responses to an oral glutamine challenge in 17 patients with cirrhosis and in 4 normal controls. The cirrhotics were attending for liver transplant assessment and had no clinical evidence of hepatic encephalopathy. The oral glutamine challenge was repeated following liver transplantation. Five of sixteen patients (31%) showed impaired performance on at least one of the baseline psychometric tests. There was a correlation between fasting venous ammonia and choice reaction time (r = .7, P < .01). Following glutamine challenge there was a significant increase in blood ammonia from a mean fasting value ranging between 58 micromol/L to 120 micromol/L (P < .01), between significant prolongation of reaction times of 387 ms to 428 ms (P < .01), and an increase in mean EEG amplitude between 68.5 microV to 78.6 microV (P < .001). Four normal controls who were challenged with glutamine and 6 cirrhotic patients who were challenged with water showed no change in any of these parameters. Following orthotopic liver transplantation (OLT) the eight patients studied had normal baseline psychomotor performance with significant improvements in digit symbol, digit span, information processing, number connection tests (P < .05), and reaction time (P < .005). Posttransplantation, there were no significant changes in blood ammonia, analyzed EEG, or choice reaction time in response to oral glutamine challenge (six patients). We conclude that short lived changes in blood ammonia (in cirrhotics) can cause significant impairment of sensitive tests of brain function and that psychometric performance is improved following OLT.

Oral glutamine challenge in cirrhotics pre- and post-liver transplantation: A psychometric and analyzed EEG study

Latent or sub-clinical hepatic encephalopathy is a recognized complication of cirrhosis and is thought to represent one end of the spectrum of neuropsychiatric impairment, which occurrs as a result of portal-systemic shunting. We studied the psychometric, analyzed electroencephalography (EEG), and venous blood ammonia responses to an oral glutamine challenge in 17 patients with cirrhosis and in 4 normal controls. The cirrhotics were attending for liver transplant assessment and had no clinical evidence of hepatic encephalopathy. The oral glutamine challenge was repeated following liver transplantation. Five of sixteen patients (31%) showed impaired performance on at least one of the baseline psychometric tests. There was a correlation between fasting venous ammonia and choice reaction time (r = .7, P < .01). Following glutamine challenge there was a significant increase in blood ammonia from a mean fasting value ranging between 58 micromol/L to 120 micromol/L (P < .01), between significant prolongation of reaction times of 387 ms to 428 ms (P < .01), and an increase in mean EEG amplitude between 68.5 microV to 78.6 microV (P < .001). Four normal controls who were challenged with glutamine and 6 cirrhotic patients who were challenged with water showed no change in any of these parameters. Following orthotopic liver transplantation (OLT) the eight patients studied had normal baseline psychomotor performance with significant improvements in digit symbol, digit span, information processing, number connection tests (P < .05), and reaction time (P < .005). Posttransplantation, there were no significant changes in blood ammonia, analyzed EEG, or choice reaction time in response to oral glutamine challenge (six patients). We conclude that short lived changes in blood ammonia (in cirrhotics) can cause significant impairment of sensitive tests of brain function and that psychometric performance is improved following OLT. (Hepatology 1997 Oct;26(4):870-6)

Transient metabolic hyperammonaemia in young Irish wolfhounds.

Inherited portosystemic shunts occur in 2 to 3 per cent of Irish wolfhounds and are associated with high venous ammonia concentrations and signs of hepatic encephalopathy. Moreover, the vast majority of Irish wolfhound pups without signs of hepatic encephalopathy have moderate hyperammonaemia. The aim of this study was to investigate whether the increased ammonia levels in these clinically healthy dogs are caused by low-grade portosystemic shunting, and whether the hyperammonaemia persists in adulthood. The fasting venous ammonia concentration and the fraction of portal blood by-passing the liver, expressed as the shunt index (SI) were measured in 42 Irish wolfhound pups, and the dogs with high SI values were examined post mortem. The ammonia concentration was also measured in 25 adult Irish wolfhounds in which it had been measured when they were seven to eight weeks old. Eleven of the 42 pups had a portosystemic shunt, as evidenced by a high SI (mean 0.82, range 0.12 to 1.00, normal range 0.01 to 0.05) and by post mortem examination. Their mean ammonia concentration was 249 mumol/litre (range 121 to 350). The 31 pups with a normal SI (mean 0.025, range 0.00 to 0.05) had a mean ammonia concentration of 93 mumol/litre (range 51 to 125). In the 25 dogs in which the ammonia concentration was measured twice, the mean concentration at seven to eight weeks of age was 77 mumol/litre (range 47 to 115) and in the adults it was 17 mumol/litre (range 6 to 27) at a mean age of 3.1 years (range 1.0 to 8.9). These results show that Irish wolfhounds with ammonia concentrations > 125 mumol/litre had a portosystemic shunt, whereas the hyperammonaemia in dogs with ammonia concentrations < 120 mumol/litre was transient and of metabolic origin.

Metabolism of 15N-ammonia in patients with cirrhosis: a three-compartmental analysis.

Urinary 15N-ammonia and 15N-urea were measured by gas chromatography-mass spectrometry after the intravenous administration of 15N-ammonia (0.2 mumol/kg/hr) to 6 volunteers and 11 patients with cirrhosis. Urinary 15N-nitrogen excretion as ammonia and urea was measured during the 210-min infusion period, and urea synthesis and ammonia conversion to amino acids were analyzed with a three-compartment model using the nonlinear least-squares method. The rate of urea synthesis in control subjects was 14.1 +/- 1.2 mg/kg/hr (mean +/- S.E.M.), and in cirrhotic patients it was 11.0 +/- 3.2 mg/kg/hr. The cirrhotic group was divided into those with compensated cirrhosis (Child class A patients) and those with decompensated cirrhosis (Child classes B and C patients), and the rates of urea synthesis for these groups were 14.5 +/- 1.5 and 8.9 +/- 1.6 mg/kg/hr, respectively. The difference between decompensated cirrhotic patients and control subjects was statistically significant (p less than 0.001). The percentage of ammonia reutilization of a given dose of 15N-ammonia was 75.9% +/- 2.4% in compensated cirrhotic patients and 82.9% +/- 3.6% in decompensated cirrhotic patients (p less than 0.05). Fasting venous ammonia levels correlated inversely with urea synthesis (p less than 0.001) and correlated positively with ammonia reutilization (p less than 0.05). These results are consistent with a decreased capacity to synthesize urea and an increased capacity to convert ammonia to amino acids in chronic liver failure.

Arterial and venous ammonia concentrations in the diagnosis of canine hepato-encephalopathy

Fasting venous ammonia concentrations were measured in 105 dogs with liver disease. In 69 of these patients and in 38 normal dogs simultaneous arterial and venous ammonia concentrations were measured. In patients with liver disease ammonia values were significantly higher in arterial blood than in venous blood, therefore arterial measurements are preferable for clinical diagnosis. A significant positive correlation was demonstrated between arterial or venous concentrations and the degree of hepato-encephalopathy. In an individual patient, however, the fasting ammonia concentration is an unreliable indicator of the degree of encephalopathy. Elevated ammonia values confirm the diagnosis of hepato-encephalopathy, but normal levels do not exclude it. A strong correlation was found between the existence of encephalopathy and the presence of portosystemic collateral circulation.

Subclinical hepatic encephalopathy: Detection, prevalence, and relationship to nitrogen metabolism

Neuropsychological status, hepatic function, and nitrogen metabolism were quantitatively assessed in 30 cirrhotic patients 1 to 5 years after portal-systemic shunt surgery to determine the frequency of behavioral deficits and their relationship to existing metabolic abnormalities. Evaluation consisted of three measures of liver function (Child's score, galactose elimination capacity, and antipyrine clearance), three tests of nitrogen metabolism (fasting venous ammonia (NH3), ammonia tolerance test, and maximal rate of urea synthesis), neurological examination, EEG, and 11 psychometric indices. Control values for the tests of hepatic function, nitrogen metabolism, and psychometric performance were established in a group of 14 normals matched to the cirrhotics for age, sex, and education. All patients were normal by conventional neurological and mental status examinations. Ten patients (33%) had EEG's compatible with hepatic encephalopathy; 18 patients (60%) showed impaired performance on one of the psychometric tests (Reitan Trail B). NH3 was inversely correlated with four psychometric tests and maximal rate of urea synthesis was directly related to five tests. In contrast, ammonia tolerance score was not significantly associated with any of the neuropsychological variables and the three quantitative measures of hepatic function together only correlated with five tests. Five cirrhotic patients with hyperammonemia and impaired psychometric tests were treated for 7 days with a protein-free diet. In all subjects, hyperammonemia and neuropsychological abnormalities improved or disappeared. Average values for the psychometric tests in 15 alcoholic subjects without liver disease did not differ significantly (P > 0.05) from the normal group. We conclude that the majority of cirrhotic patients after portal-systemic shunt operations have demonstrable neuropsychological deficits. The severity of impairment appears to be related more to status of nitrogen metabolism than to level of over-all hepatic function.

Some effects of induction of urease immunity in patients with hepatic insufficiency

Eight patients with far advanced liver disease have been immunized with crystalline jackbean urease. Six had surgically produced portacaval shunts. Four units of urease activity subcutaneously injected as a primary immunizing dose produced detectable levels of antiurease without toxic or anaphylactoid reactions. Secondary doses of 8 to 10 units were tolerated by all patients without evidence of ammonia intoxication. The persistence of detectable antibody was four to six weeks. Although there was variation between persons, all patients responded with antibody production to secondary challenges of the injected crystalline enzyme given at three to four week intervals. Six of the eight patients increased their daily intake of dietary protein from 80 to 300 per cent without evidence of increased fasting venous ammonia levels. Six of the eight patients showed marked clinical improvement with fewer episodes of confusion, somnolence and signs of hepatic failure. Five have shown increases in serum albumin levels, and six have had marked decreases in fluid retention. Two patients with severely depressed liver function receiving 20 units of jackbean urease as a secondary immunologic challenge demonstrated signs of ammonia intoxication three to four days after injection. These corresponded to the time of antigen disappearance and antibody depression.