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PubMed1992

[Serum and tissue lysosomal enzymes and liver dysfunction after an experimental acute lower limbs ischemia in the rats].

Adult male Wistar rats were divided in 3 groups. In the first group, infrarenal abdominal aorta was occluded for 6 hours and reperfused thereafter. In the second group, the reperfusion was not made, and the third group underwent a sham operation. Lysosomal enzymatic activities were assessed in serum tissues. Lysosomal membrane fragilities were estimated also in these tissues. Finally, 14C-aminopyrine breath test (ABT) was studied to define the possible liver dysfunction caused by limb ischemia. As a result, release of lysosomal enzymes from ischemic muscle was confirmed in vitro experiments, and the increase in the serum was statistically significant in the first and second groups as compared to the third group. Particularly prominent was a marked elevation of cathepsin-D in the first group which was observed immediately after the release of occlusion. Results of liver lysosomal enzymes and ABT revealed significant cellular damages and depression of microsomal function of the liver both in the first and second groups. These studies suggest that lysosomal enzymes derived from ischemic muscle exert a possible toxicity on the liver, and liver damage thus resulted may play a roll on the pathogenesis of whole body injury associated with acute and critical lower limb ischemia.

Acid Phosphatase↗
PubMed2003

Influence of ischemia and surgery times on development of primary dysfunction liver transplant in patients.

OBJECTIVE: (1) To determine the incidences of primary failure and primary dysfunction of liver transplants performed at our center. (2) To evaluate the effects of mean cold and warm ischemia times as well as the length of five stages of surgery on the development of primary dysfunction. PATIENTS AND METHODS: We reviewed 248 liver transplants consecutively performed in 206 patients at the Hospital Ramón y Cajal, Madrid over 79 months. Six cases were excluded because the patients died within 24 hours of transplant, it was therefore not possible to establish the postoperative liver function. Recipients were classified according to their posttransplant liver function as showing normal primary function (NP) or primary dysfunction (PD), which included patients with primary failure (PF) and inadequate primary function (IPF). The NP and IPF groups were defined in terms of transaminase levels and prothrombin activity from posttransplant days 2 to 7. The following factors were analyzed: graft cold (CIT) and warm (WIT) ischemia times; graft arterial (AIT) and venous (VIT) ischemia times; and times of surgery (ST), arterial anastomosis (AAT), and anhepatic phase (APT). RESULTS: Twenty-three (9.3%) patients were classified as showing PD, 12 (4.8%) of whom suffered an episode of PF. The mean values (and standard deviations) of the times (in minutes) were ST = 308.19 +/- 109.78; CIT = 411.08 +/- 140.62; WIT = 46.51 +/- 37.70; AIT = 510.95 +/- 165.95; VIT = 458.68 +/- 151.98; AAT = 54.12 +/- 31.84; and APT = 58.53 +/- 90.07. No significant differences were detected in the mean times of patients showing NP or PD. Neither were any differences observed between the two patient groups according to the variables CIT longer than 10 hours and WIT longer than 60 minutes. CONCLUSIONS: Our times of surgery and cold ischemia are shorter than those reported by other transplant teams, mostly North American surgeons who quote figures of around 7 and 12 hours, respectively. These relatively low values may account for the lack of effect shown by the times of ischemia or surgery stages on the appearance of primary dysfunction in patients undergoing liver transplant.

Anastomosis, Surgical↗
PubMed1994

Effect of glycyrrhizin in children with liver dysfunction associated with cytomegalovirus infection.

Glycyrrhizin (GL) has an inhibitory effect on several viruses including human immunodeficiency virus type 1 (HIV-1) and varicella-zoster virus (VZV). In addition, some therapeutic and prophylactic effects on chronic active viral hepatitis have been claimed for GL. In this study, 0.2% GL dissolved in saline (2 mg/ml GL), supplemented with 2% glycine and 0.1% cysteine (Stronger Neo-Minophagen C, SNMC) was administered intravenously in a dose of 50 ml/day for a period of more than one week to three infants with cytomegalovirus (CMV) infection who exhibited abnormal liver function or hepatomegaly. Liver function had become normal at the end of the course of SNMC. These findings suggest that GL might have therapeutic effects on liver dysfunction associated with CMV infections.

Antibodies, Viral↗
PubMed1993

False elevations of alpha-fetoprotein associated with liver dysfunction in germ cell tumors.

BACKGROUND: Determination of serum concentration human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) is crucial in diagnosis, prognosis, treatment, and follow-up of patients with germ cell tumors. Elevation of these markers almost indicates progression or recurrence of the germ cell tumor. However, an increase in these tumor markers can be produced by several benign causes. METHODS: The authors report nine cases of gonadal germ cell tumors that had increased serum levels of AFP without tumoral progression, recurrence, or residual tumor. RESULTS: The AFP elevations were attributed to liver damage secondary to drugs (chemotherapy, anesthetics, or antiepileptics), virus, or alcoholism. No clinical evidence (or in some cases surgical evidence) of malignant tumor activity was found in any of the patients. CONCLUSIONS: The elevation of serum levels of AFP in patients with germ cell tumors can be produced by liver dysfunction. These elevations must be interpreted with caution to avoid unnecessary treatments.

Adolescent↗
PubMed1994

A patient with chronic hepatitis C who simultaneously developed interstitial pneumonia, hemolytic anemia and cholestatic liver dysfunction after alpha-interferon administration.

Following a three-week administration of alpha-interferon (IFN-alpha), a 62-year-old woman with chronic hepatitis C manifested fever and dyspnea and showed diffuse infiltrative opacities on chest roentgenograms. Her laboratory data included results of anemia with reticulocytosis, a decreased complement level and hepatitis with elevated ALP, LDH and gamma-GTP. Because laboratory data also revealed a positive lymphocyte stimulation test for IFN-alpha, this cytokine was considered to be responsible for the development of interstitial pneumonia, hemolytic anemia and cholestatic liver dysfunction due to its immunomodulatory effects. Although these three disorders have been reported to develop singly after IFN-alpha therapy, this is the first report of a patient in whom these disorders occurred simultaneously.

Anemia, Hemolytic, Autoimmune↗
PubMed1991

Low angiotensinogen levels are related to the severity and liver dysfunction of congestive heart failure: implications for renin measurements.

PURPOSE: To compare the determination of plasma renin activity (PRA) and the direct measurement of active renin by immunoradiometric assay (IRMA) as methods of assessing the renin system in patients with congestive heart failure. PATIENTS AND METHODS: The status of the renin-angiotensin system in congestive heart failure was assessed by measuring the plasma renin substrate concentration, PRA, and plasma concentration of active renin in 37 patients with mild to severe congestive heart failure. Natremia and plasma levels of atrial natriuretic factor (ANF) were determined as biologic indexes of the severity of heart failure, and concentrations of prealbumin and retinol-binding protein were used as indexes of liver dysfunction. RESULTS: The PRA and the concentrations of active renin and ANF were markedly higher in patients with New York Heart Association class IV heart failure than in patients with class II to III heart failure, while natremia and the concentrations of renin substrate, prealbumin, and retinol-binding protein were markedly lower in the class IV patients than in the class II to III patients. Plasma renin substrate concentration was negatively correlated with active renin concentration (n = 37, r = -0.45, p = 0.005), and positively related to natremia (r = 0.56, p less than 0.0005), prealbumin (r = 0.54, p less than 0.001), and retinol-binding protein (r = 0.60, p less than 0.0001). CONCLUSIONS: Low levels of plasma renin substrate can be considered as an indirect index of the severity of heart failure that reflects both the high level of circulating active renin and the decrease in hepatic protein output. In patients with class IV heart failure, low levels of renin substrate led to a marked underestimation of active renin concentration from measurements of PRA. In contrast, direct IRMA of active renin measures the true plasma active renin concentration, independent of plasma renin substrate, and closely reflects renin secretion.

Adult↗
PubMed1999

Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction.

BACKGROUND & AIMS: Manganese (Mn) deposition could be responsible for the T(1)-weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction. METHODS: Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side portacaval anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats. RESULTS: Mn content was significantly increased in frontal cortex (by 38%), occipital cortex (by 55%), pallidum (by 186%), putamen (by 66%), and caudate (by 54%) of cirrhotic patients compared with controls. Brain Mn content did not correlate with patient age, etiology of cirrhosis, or history of chronic hepatic encephalopathy. In cirrhotic and portacaval-shunted rats, Mn content was increased in pallidum (by 27% and 57%, respectively) and in caudate/putamen (by 57% and 67%, respectively) compared with control groups. Mn concentration in pallidum was significantly higher in portacaval-shunted rats than in cirrhotic rats. No significant changes in brain Mn concentrations were observed in rats with acute liver failure. CONCLUSIONS: These findings suggest that brain Mn deposition results both from portal-systemic shunting and from liver dysfunction.

Animals↗
PubMed2002

Increased nitric oxide production in hepatocytes is involved in liver dysfunction following obstructive jaundice.

BACKGROUND: Obstructive jaundice damages critical functions in the liver. However, the mechanisms involved in hepatic dysfunction are obscure. Nitric oxide is implicated in liver injury under various pathological conditions. We previously reported that proinflammatory cytokine interleukin-1beta (IL-1beta) stimulated the production of nitric oxide in hepatocytes, which was associated with mitochondrial dysfunction. Studies were performed to examine whether obstructive jaundice influences the production of nitric oxide in hepatocytes and alters hepatic energy metabolism. MATERIAL AND METHODS: Hepatocytes were isolated and cultured from a rat model of obstructive jaundice or sham control. Nitric oxide production, ATP content, and ketone body ratio (acetoacetate/beta-hydroxybutyrate; KBR) were compared between the two groups in the presence of IL-1beta. RESULTS: Hepatocytes obtained from obstructive jaundice rats markedly increased the levels of nitric oxide production stimulated by IL-1beta compared with those from sham control. Western blot analysis revealed that the enhancement of nitric oxide production was a posttranslational event, since protein levels of inducible nitric oxide synthase (NOS) were unchanged between the two groups. IL-1beta decreased cellular ATP content in obstructive jaundice but not in sham control. Further, the KBR, which is a marker of mitochondrial redox state, was lower in obstructive jaundice than in sham control. Addition of N(G)-monomethyl-L-arginine, an inhibitor of NOS, abolished the decreases in ATP content and KBR as well as the nitric oxide production. CONCLUSIONS: These results indicate that a priming of nitric oxide production following obstructive jaundice is associated with the alteration of hepatic energy metabolism in part through mitochondrial dysfunction. Regulation of nitric oxide production may be a useful therapy for preventing liver dysfunction in obstructive jaundice.

Adenosine Triphosphate↗
PubMed2004

Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status.

AIM: To study the pharmacokinetic and metabolism profiles of a single dose of acetaminophen in patients with cirrhosis. METHODS: Oral acetaminophen (1000 mg) was administered to seven healthy subjects and 14 patients with cirrhosis (nine Child-Pugh A or B and five Child-Pugh C grade), being five without and nine with oesophageal varices. Plasma levels of acetaminophen and its metabolites were determined by HPLC. RESULTS: Patients showed a higher mean area under the curve concentration-time (67.4 +/- 22.4 mg h/L vs. 38.8 +/- 4.3 mg h/L; P = 0.01), a lower clearance (166.7 +/- 85.0 mL/min vs. 367.8 +/- 62.5 mL/min; P = 0.01) and higher elimination half-life (3.8 +/- 1.1 h vs. 2.0 +/- 0.4 h; P = 0.01) of acetaminophen than healthy volunteers. The appearance in blood and the urinary excretion of metabolites in patients did not differ from healthy subjects. Absorption profile was faster in patients. Patients with lower mean and systolic arterial pressure had lower AUC of acetaminophen, independently of liver dysfunction stage. CONCLUSIONS: Patients with cirrhosis had a higher AUC and lower clearance of acetaminophen. Acetaminophen attained earlier therapeutic concentrations in patients with oesophageal varices. Mean and systolic arterial pressures were significantly associated with AUC suggesting the importance of the haemodynamic function on the pharmacokinetics of acetaminophen in patients with cirrhosis.

Acetaminophen↗
PubMed2000

Effects of lactate-buffered and lactate-free dialysate in CAVHD patients with and without liver dysfunction.

BACKGROUND: Continuous modalities of renal replacement deplete patients of bicarbonate, which is traditionally replaced indirectly by lactate in dialysate or replacement fluids. We have compared a new lactate-free dialysate (unbuffered dialysate with separate bicarbonate replacement of dialytic bicarbonate loss) with standard lactate-buffered dialysate in terms of acid-base control, lactate accumulation, and hemodynamic stability in patients undergoing continuous renal replacement therapy in an intensive care unit. METHODS: A nonrandomized crossover cohort study involving 54 patients with multi-organ failure (of whom 19 had significant hepatic dysfunction) was performed. All patients completed 24-hour continuous hemodiafiltration against both lactate-buffered and lactate-free dialysate. Arterial pH, blood gases, bicarbonate, and lactate, venous sodium, blood pressure, and inotrope requirements were measured before and at six hourly intervals during the first 24 hours of dialysis against each dialysate. RESULTS: Lactate-free dialysate provided more rapid control of acidosis than lactate buffered with less total administration of buffer than that given during the lactate-buffered period (total mmol bicarbonate vs. total mmol lactate + bicarbonate). Lactate accumulation was slight in both periods, but was higher during lactate-buffered continuous venovenous hemodiafiltration (CVVHD). The mean arterial pressure rose during lactate-free dialysis with decreased inotrope doses and fell during lactate-buffered dialysis with increased inotrope requirement. Results in patients with liver dysfunction were not significantly different from those without it. CONCLUSIONS: Over the time scale of 24 hours, lactate derived from continuous dialysis circuits is efficiently cleared from the blood of most patients with multi-organ failure, but with less effect on systemic acidosis than is produced by equivalent amounts of bicarbonate.

APACHE↗
PubMed2000

Renal clearance of N(1)-methylnicotinamide: a sensitive marker of the severity of liver dysfunction in cirrhosis.

BACKGROUND/AIMS: Data have appeared suggesting that an impairment of renal tubular secretion is present in liver cirrhosis, even in the absence of a clinically evident renal dysfunction. To address this question, we evaluated the renal clearance of N(1)-methylnicotinamide (NMN), a marker of the renal secretory function, in healthy subjects and patients with liver cirrhosis of increasing severity, but with a normal glomerular filtration rate. METHODS: The renal clearances of endogenous NMN, inulin, and creatinine were measured in 14 normal subjects and in two groups of age-matched cirrhotic patients (10 Child A and 10 Child C). In 6 subjects, 2 per group, the concentration dependence of the NMN clearance was also studied, following an oral nicotinamide load. RESULTS: Contrary to expectations, the renal NMN clearance increased in cirrhotic patients, in relation to the severity of liver disease (r = 0.83 with Pugh's score; p < 0.001). The NMN-to-inulin clearance ratio increased from a control value of 2.2 +/- (SD) 0.4 to 3.1 +/- 0.2 and 5.2 +/- 0.9 in Child A and Child C cirrhotics, respectively (p < 0.001 for all comparisons), indicating that NMN was completely cleared from plasma in the latter patients. Consistently, the analysis of the concentration dependence of the renal NMN clearance revealed the presence of a carrier-mediated reabsorption which apparently was no longer operating in the decompensated patients. Discriminant analysis showed that renal NMN clearance, and NMN-to-creatinine and NMN-to-inulin clearance ratios could all distinguish between the three study groups, with sensitivities and specificities equal or greater than 90%. CONCLUSIONS: Contrary to previous proposals, NMN is not a probe of general validity for renal tubular secretion. In particular, due to an imbalance between secretion and reabsorption, its renal clearance in liver cirrhosis cannot be used to determine the degree of tubular secretion of which an individual is capable. However, renal NMN clearance appears to be a very sensitive marker of the severity of liver dysfunction in cirrhosis. The potentialities of this renal parameter as a diagnostic and prognostic test in liver cirrhosis deserve further study.

Adult↗
PubMed2000

The acid-labile subunit of the ternary insulin-like growth factor complex in cirrhosis: relation to liver dysfunction.

BACKGROUND/AIMS: In the circulation, insulin-like growth factor-I (IGF-I) is bound in a trimeric complex of 150 kDa with IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). Whereas circulating IGF-I and IGFBP-3 are reported to be low in patients with chronic liver failure, the level of ALS has not been described in relation to hepatic dysfunction. The aim of the present study was therefore to measure circulating and hepatic venous concentrations of ALS in relation to hepatic function and the IGF axis. METHODS: Twenty-five patients with cirrhosis (Child class A/B/C:5/10/10) and 30 controls with normal liver function were studied. During a haemodynamic investigation, blood samples were collected from the hepatic vein and femoral artery, and the plasma concentrations of ALS, IGF-I and IGFBP-3 were determined. RESULTS: Hepatic venous and arterial concentrations of ALS were significantly decreased in the cirrhotic patients compared with the controls (-69% and -68%, respectively, both p<0.001). IGF-I and IGFBP-3 were similarly decreased in the cirrhotic patients (-51%,p<0.001). A significant hepatic extraction of ALS was found in the controls (6%, p<0.01) and in the cirrhotic patients (8%, p=0.08). ALS correlated significantly with indicators of liver dysfunction, including the Child-Turcotte score (r=-0.69, p<0.0001), IGF-I (r=0.82, p<0.0001) and IGFBP-3 (r=0.74, p<0.0001). CONCLUSIONS: Circulating and hepatic venous ALS are decreased in patients with cirrhosis with significant relations to liver dysfunction and other components of the IGF complex. A small hepatic extraction was found in controls, which suggests extrahepatic production of ALS. Future studies should focus on organ-specific removal of ALS.

Adult↗
PubMed1997

Inhibition of nitric oxide synthesis improves detoxication in inflammatory liver dysfunction in vivo.

Inflammatory stimulation of the liver induces nitric oxide (NO) biosynthesis and suppression of detoxication. In this study the effect of NO biosynthesis on cytochrome P-450 (CYP) enzyme activity was investigated by comparing in vivo and in vitro assays. To establish liver inflammation, CD rats were injected with Corynebacterium parvum (C. parvum) suspension. After 5 days NO biosynthesis was highly induced as indicated by increased NO2- plus NO3- serum concentrations. At the same time the aminopyrine breath test (ABT), measuring CYP activity in vivo, was reduced to 42% and the in vitro assay of aminopyrine turnover was suppressed to 12% of NaCl- injected controls. When C. parvum-injected animals were treated with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), CYP activities significantly improved with an ABT of 76% and an in vitro aminopyrine turnover of 47% of controls. Neither C. parvum injections nor L-NMMA treatment resulted in a significant change of CYP protein concentrations. These data indicate that suppression of xenobiotic metabolism can be attenuated by inhibition of NO biosynthesis during an ongoing process of inflammation.

Animals↗
PubMed1989

Cyclosporin A pharmacokinetics in liver transplant recipients in relation to biliary T-tube clamping and liver dysfunction.

Cyclosporin A pharmacokinetics were studied after oral (4-14 mg/kg body weight) and intravenous dosing (1.5-3.5 mg/kg) in 13 orthotopic liver transplant recipients before and after permanent clamping of the biliary T-tube. After T-tube clamping, cyclosporin A absorption was faster and more complete with the mean time of peak concentration, tmax, reduced to around three hours from around six hours and mean bioavailability rising from only 16.6% (n = 13) to 30% in the entire group (n = 11 after clamping) or to 35% after excluding two patients who developed severe cholestasis after the preclamping study. Bioavailability in these two patients fell below 8% and to around 1% in a further patient with severe graft dysfunction. Clamping reduced the metabolic clearance of cyclosporin A by only 25% from a mean before clamping of 2.9 ml/min/kg to 2.3 ml/min/kg (n = 11). Oral cyclosporin A becomes a reliable means of maintaining therapeutic drug concentrations only after bioavailability increases in association with T-tube clamping and in the absence of severe liver dysfunction or cholestasis.

Absorption↗
PubMed1991

Diurnal fluctuations of arterial ketone body ratio in normal subjects and patients with liver dysfunction.

To explore the metabolic aspects of chronic liver disease, diurnal changes of arterial ketone body ratio (acetoacetate/3-hydroxybutyrate), reflecting hepatic mitochondrial redox potential, were investigated in normal subjects, patients with chronic liver disease (Child's class A or B), and patients with hepatic failure (Child's class C). Ketone body ratio in normal subjects increased after breakfast from 0.96 to 2.00, after lunch from 2.17 to 2.38, and after dinner from 1.23 to 2.55 with blood glucose level ranging from 103 to 141 mg/dL (5.7 to 7.8 mmol/L). By contrast, the ketone body ratio in the Child A or B group changed little and remained within a range of 0.70-1.35 despite a large change in blood glucose level from 102 to 176 mg/dL (5.7 to 9.8 mmol/L). Ketone body ratio in Child's class C remained near or below 0.4 with no response to glucose administration, despite a marked elevation in blood glucose level. These results indicate that hepatic mitochondrial redox potential undergoes diurnal changes in sharp response to meals in normal liver function but that these fluctuations are absent in patients with liver damage (Child's class A, B, and C). Furthermore, it remains at low levels in severe liver failure (Child's class C). It is also suggested that hepatic mitochondrial redox potential plays an important role in the regulation of blood glucose levels.

Acetoacetates↗