Could serum nitrate and nitrite levels possibly predict hepatorenal syndrome in hepatitis C virus-related liver cirrhosis?

Purpose

This study aimed to determine whether serum levels of nitric oxide metabolites (nitrates and nitrites) correlate with renal dysfunction in patients with liver cirrhosis and, moreover, to assess nitric oxide metabolite (NOx) power for predicting hepatorenal syndrome (HRS) in such patients.

Methods

Among patients admitted to the Tropical Medicine Department, Ain Shams University Hospital, a total of 60 patients with chronic hepatitis C-related liver cirrhosis were included in this study. Patients were divided into three groups. Group I included 20 patients with compensated liver cirrhosis (CLC). Group II included 20 patients with decompensated liver cirrhosis (DLC). Group III included 20 patients with decompensated liver cirrhosis and HRS. Twenty healthy subjects with no clinical or laboratory evidence of liver disease were enrolled as a control group (group IV).

Results

Patients with HRS had a higher mean nitrite levels followed by DLC, then CLC, and then controls. The sensitivity and specificity of NO metabolites (nitrites) were 100 % and 93.3 %, respectively, with accuracy of 95 % at cutoff value of 387 μmol/L for diagnosing patients with HRS. There was a highly significant statistical difference between patients positive and negative for nitrites as regards renal profile (p?=?0.000).

Conclusion

A strong relation between nitrite cutoff value and renal dysfunction in liver cirrhosis has been found. Also, patients with HRS had higher mean serum nitrite levels than decompensated liver cirrhosis or compensated liver cirrhosis, raising the possibility of using nitrate and nitrite levels as a predictor for HRS in HCV-related liver cirrhosis.     

Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome

Hepatorenal syndrome (HRS) is a functional renal disorder complicating decompensated cirrhosis. Treatments to date, except liver transplantation, have been able to improve but not normalize renal function. The aim of this study was to determine the efficacy of transjugular intrahepatic portosystemic stent shunt (TIPS) as a treatment for type 1 HRS in ascitic cirrhotic patients, following improvement in systemic hemodynamics with a combination of midodrine, octreotide, and albumin (medical treatment). Fourteen ascitic cirrhotic patients with type 1 HRS received medical therapy until their serum creatinine reached below 135 micromol/L for at least 3 days, followed by a TIPS if there were no contraindications. Patients were assessed before and after medical treatment, as well as at 1 week and 1, 3, 6, and 12 months post-TIPS with measurements of renal function, sodium handling, systemic hemodynamics, central blood volume, and hormonal markers. Medical therapy for 14 +/- 3 days improved renal function (serum creatinine: 233 +/- 29 micromol/L vs. 112 +/- 8 micromol/L, P =.001) and renal sodium excretion (5 +/- 2 mmol/d vs. 9 +/- 2 mmol/d, P =.002) in 10 of the 14 patients. TIPS insertion in five of the responders further improved renal function and sodium excretion, so that by 12 months post-TIPS, glomerular filtration rate (96 +/- 20 mL/min, P <.01 vs. pre-TIPS) and urinary sodium excretion (119 +/- 15 mmol/d, P <.01 vs. pre-TIPS) were normal, associated with normalization of plasma renin and aldosterone levels and elimination of ascites. In conclusion, TIPS is an effective treatment for type 1 HRS in suitable patients with cirrhosis and ascites, following the improvement of renal function with combination therapy of midodrine, octreotide, and albumin.     

Increased plasma levels of neuropeptide Y in hepatorenal syndrome

BACKGROUND/AIMS: To investigate the relationship between neuropeptide Y (NPY), a potent renal vasoconstrictor peptide released upon marked stimulations of sympathetic nervous system (SNS), and renal and circulatory function in cirrhosis. METHODS: Plasma levels of NPY (radioimmunoassay) and norepinephrine and renal function parameters were determined in 17 healthy controls, nine patients with cirrhosis without ascites, and 37 patients with cirrhosis and ascites, of whom 12 had hepatorenal syndrome (HRS). RESULTS: Patients with ascites showed circulating levels of NPY similar to those of patients without ascites and controls (73+/-4, +/-4 and 68+/-4 pmol/l, respectively; NS). However, patients with HRS had significantly increased levels of NPY with respect to the other groups (110+/-6 pmol/l; P<0.001). NPY levels correlated inversely with renal plasma flow and glomerular filtration rate and directly with norepinephrine. In patients with HRS (n=6) treatment with terlipressin and albumin was associated with a marked improvement in circulatory and renal function and marked suppression of NPY and norepinephrine levels. CONCLUSIONS: Patients with HRS have increased levels of NPY which are related to circulatory dysfunction and SNS activation and may contribute to renal vasoconstriction.     

Value of the extracellular water ratio for assessment of cirrhotic patients with and without ascites

Aims:  Ascites, which often complicates liver cirrhosis, is reported to be a factor that worsens the outcome. The aims of this study were to quantify body water compartment changes in cirrhotic patients, with and without ascites, and to elucidate the value of body water analysis for predicting the development of ascites.
Methods:  A total of 109 cirrhotic patients, with and without ascites, and 65 controls were studied. Intra- and extracellular water (ECW) in the whole body and in the arm, leg and trunk were measured using the recently developed 8-electrodes multiple-frequency bioelectrical impedance analyzer. Furthermore, patients without ascites were followed to an episode of ascites or death.
Results:  Patients with liver cirrhosis had significantly higher ECW ratios than controls. ECW ratios were increased in cirrhotic patients with moderate and severe disease. The ECW ratio of the trunk showed highly significant changes in cirrhotic patients with ascites. The ECW ratio correlated with age, serum albumin, and prothrombin time. A relative expansion of ECW and low albumin were predictive of further episodes of ascites (log-rank 6.94, P  < 0.01). In multivariate analysis, the ECW ratio was independently associated with the development of ascites.
Conclusion:  Liver cirrhosis was characterized by a redistribution of body water. The ECW ratio is a reliable tool for quantification of redistribution of body water and can predict the development of ascites.     

Effects of "body compression" on parameters related to ascites formation: therapeutic trial in cirrhotic patients

Decreased effective circulating blood volume is an important factor in ascites formation in liver cirrhosis. We designed a "body compression" apparatus as a means to restore effective blood volume and investigated its effectiveness in reducing ascites formation in cirrhotics in terms of its effect on parameters of ascites formation noted below. The subjects, eight cirrhotics with ascites and eight cirrhotics without ascites were given spironolactone (50–75 mg/day) and furosemide (40–80 mg/day) while they received a diet containing 85 mEq of sodium per day. All four limbs and the lower abdomen were compressed with constant pressure [height (cm) divided by 13.6 mmHg] once, for 3 h, using stroke rehabilitation splints, while patients lay supine. In cirrhotics both with and without ascites, urine volume, urinary sodium excretion, and creatinine clearance during the body compression were greater than values during control (non-compression) periods (urine volume, means 285 vs 169 ml/3 h; P < 0.001, urinary sodium excretion 15.8 vs 9.5mEq/3h; p < 0.001, creatinine clearance 74 vs 59 ml/min, P < 0.001, respectively). The increased basal plasma renin activity, angiotensin II, aldosterone, and norepinephrine levels in all cirrhotics were significantly decreased by the body compression. In another group of six cirrhotics who received no diuretics or albumin, repeat body compression alleviated ascites in three with well preserved renal function, but was ineffective in three with markedly impaired renal function. These results suggest that the improvement in renal function brought about by the body compression is attributable to an increase in effective circulating blood volume. This maneuver may be a useful complementary therapy in patients with cirrhotic ascites with well preserved renal function. (Received Jan. 12, 1998; accepted June 26, 1998)     

Incidence and characteristics of type 2 hepatorenal syndrome in patients with cirrhosis and refractory ascites

BACKGROUND AND AIM: Type 2 hepatorenal syndrome (HRS) is a well described progressive impairment of renal function in patients with cirrhosis but its natural history, especially in patients with refractory ascites, is not well known. The aim of this study was to assess the incidence, predictive factors and outcome of type 2 HRS in patients with cirrhosis and refractory ascites. PATIENTS AND METHODS: Thirty patients with refractory ascites were followed-up for 17.5 +/- 26.3 months. The clinical characteristics, biological findings and outcome were analysed. The occurrence of renal dysfunction, and type 2 HRS in particular, was systematically analysed. RESULTS: Twenty-five patients (83.3%) developed renal dysfunction. Type 2 HRS was diagnosed in 16 patients (53.3%). Patients with type 2 HRS were older than patients without (64.8 +/- 9.1 yr vs 52.8 +/- 9.0 yr ; p < 0.001). All the others studied variables were similar between type 2 HRS and non-type 2 HRS patients. There was no significant difference in the overall probability of survival between these 2 groups. CONCLUSIONS: In patients with cirrhosis and refractory ascites, the development of type 2 HRS is frequent but does not occur in more severe liver disease and does not affect prognosis.     

Atrial natriuretic peptide in liver cirrhosis with mild ascites

To clarify the involvement of atrial natriuretic peptide (ANP) in the pathogenesis of liver cirrhosis, we measured plasma ANP in patients with various stages of cirrhosis and in age-matched normal subjects. Urinary cyclic guanosine monophosphate (cGMP) was also measured as a marker of active biological ANP. In addition, effects of exogenous synthetic human ANP (0.5 Μg/kg) on renal functions were examined in normal subjects and in cirrhotics without ascites or with mild ascites. Plasma ANP levels were not significantly different among these 3 groups. Urinary cGMP concentrations were significantly higher in both cirrhotics without ascites and cirrhotics with mild ascites, (340 pmol/ml, P<0.05 and 496 pmol/ml, P<0.01 respectively) than normal subjects (95 pmol/ml). In normal subjects, marked increases in urinary volume (UV), sodium excretion (UNaV), fraction excretion of sodium (FENa) and free water clearance (CH₂O) were induced after ANP infusion, and significant recoveries were subsequently observed in these parameters. However, in cirrhotics, the responses to ANP infusion of UV, FENa and CH₂O were far less dramatic. The response of UV, UNaV and FENa in cirrhotics with mild ascites was delayed compared to cirrhotics without ascites. These results suggest that the blunted natriuretic responsiveness to ANP is contributory to the pathogenesis of initial sodium retention in cirrhotics. This study was presented in part in the 25th annual meeting of the Japanese Association for the Study of the Liver, June, 1, 1989 Kanazawa, Japan.     

Renal functional reserve is well maintained in patients with advanced liver cirrhosis and ascites

BACKGROUND: Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in healthy humans can be induced by amino acid stimulation. The rise in GFR from baseline to maximum is referred to as the renal functional reserve (RFR). Recently, we showed that the RFR is preserved in patients with compensated cirrhosis despite impaired renal function. In the present study, we evaluated RFR in decompensated cirrhotics with ascites. METHODS: Steady-state inulin- and para-aminohippurate (PAH) clearances were performed at rest and during amino acid infusion in 22 patients with decompensated liver cirrhosis and ascites. RESULTS: Baseline GFR and ERPF (means +95% confidence intervals) were: GFR 25.2 (21.1-29.2) ml min(-1), ERPF 266.6 (229.7-303.5). Amino acid infusion significantly increased GFR by 67% (38.3-95.8) to 34.6 (29.2-40.0) ml min(-1) (means + (95% confidence intervals), P < 0.001) and ERPF by 29% (11.9-46.3) to 326.3 (274.1-378.5) ml min(-1) (P = 0.002). Renal vascular resistance dropped by 13.4% (3.3-23.5) from 29.4 (24.8-33.9) mmHg ml(-1) min(-1) to 26.4 (22.0-30.7) mmHg ml(-1) min(-1) (P = 0.036). The improved kidney function was accompanied by a decrease in systemic aldosterone levels (P < 0.05). CONCLUSION: In patients with liver cirrhosis and ascites, amino acid infusion improves kidney function. Trials are warranted to test the long-term effects of amino acid infusions in patients with hepatorenal syndrome.     

Vasodilatory State of Decompensated Cirrhosis: Relation to Hepatic Dysfunction, Ascites, and Vasoactive Substances

The objective of this study was to determine the relations between the hallmark circulatory finding of decompensated cirrhosis, a reduced systemic vascular resistance (SVR), and the indices of hepatic decompensation, the accumulation of ascites, and the concentrations of various vasoactive substances. At a university-affiliated teaching hospital, eighteen hospitalized patients with cirrhosis and 18 age- and sex-matched healthy subjects were used. This was a case-control study. Measurements included cardiac dimensions and indices derived from echocardiograms and Doppler studies, abdominal ultrasound estimates of ascites, indices of hepatic function, and various serum (S) and urinary (U) substances. Results showed that cirrhotics had increased left atrial and left ventricular dimensions, left ventricular mass, heart rate, cardiac output (CO), transvalvular velocities, and a decreased SVR. SVR was related to hepatic dysfunction, as reflected by an abnormal prothrombin time ratio (r= -0.64, p= 0.006), and also related to overall severity of liver disease as estimated by the Child-Pugh score (r= -0.53, p = 0.044). Although cirrhotics with ascites generally had a reduced SVR, estimates of ascites were directly related to SVR (r = 0.57, p = 0.03) and inversely related to CO (r= -0.53, p= 0.04). Concentrations of S and U digoxin-like immunoreactive substance (DLIS) were also increased, but the concentrations of S glucagon and estradiol were not elevated. The accumulations of S and U DLIS, S glucagon, and S estradiol were all related to hepatic dysfunction. S estradiol was also related to SVR (r = -0.55, p= 0.04), but this was only evident with S estradiol expressed as a logarithm and did not emerge as significant on a multivariate analysis. The reduced SVR observed in decompensated cirrhosis is related to various indices of hepatic dysfunction. Certain substances that accumulate in cirrhosis (such as DLIS, glucagon, and estradiol) do not explain the vasodilatation observed. Although ascites in decompensated cirrhosis generally signifies a vasodilated state, a reduced SVR may be found even before ascites is clinically evident, and tense ascites may actually obscure this finding.     

RIFLE classification as predictive factor of mortality in patients with cirrhosis admitted to intensive care unit

Background and Aim:  To evaluate the association of the Risk, Injury, Failure, Loss and End-stage renal failure (RIFLE) score on mortality in patients with decompensated cirrhosis admitted to intensive care unit (ICU).
Methods:  A cohort of 412 patients with cirrhosis consecutively admitted to ICU was classified according to the RIFLE score. Multivariable logistic regression analysis was used to evaluate the factors associated with mortality. Liver-specific, Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA) and RIFLE scores on admission, were compared by receiver–operator characteristic curves.
Results:  The overall mortality during ICU stay or within 6 weeks after discharge from ICU was 61.2%, but decreased over time (76% during first interval, 1989–1992 vs 50% during the last, 2005–2006, P  < 0.001). Multivariate analysis showed that RIFLE score (odds ratio: 2.1, P  < 0.001) was an independent factor significantly associated with mortality. Although SOFA had the best discrimination (area under receiver–operator characteristic curve = 0.84), and the APACHE II had the best calibration, the RIFLE score had the best sensitivity (90%) to predict death in patients during follow up.
Conclusions:  RIFLE score was significantly associated with mortality, confirming the importance of renal failure in this large cohort of patients with cirrhosis admitted to ICU, but it is less useful than other scores.     

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

Aim:  This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT).
Methods:  We reviewed "blindly" allograft biopsy specimens of women who underwent transplantation for PBC ( n  = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV ) ( n  = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients.
Results:  Granulomatous destructive cholangitis was found in five biopsies from four PBC patients ( P  = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis ( P  = 0.0002), lobular necroinflammatory activity ( P  < 0.0001), steatosis ( P  < 0.0001) and fibrosis ( P  < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis ( n  = 2) or cirrhosis ( n  = 2). No other PBC patient had evidence of cirrhosis after OLT.
Conclusions:  Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients.     

Nitrite and nitrate levels in patients with cirrhosis of the liver: influence of kidney function and fasting state

BACKGROUND: Increased serum nitrite/nitrate (NOx) levels, the stable metabolites of nitric oxide (NO), have been reported in patients with cirrhosis. NOx levels, however, are influenced not only by endogenous NO synthesis but also by urinary NOx excretion and dietary intake. We attempted to elucidate factors that influence NOx levels independently of endogenous NO production and to determine the conditions under which NOx levels reflect endogenous production in patients with cirrhosis and healthy controls. METHODS: NOx serum concentrations and urinary NOx excretion were determined by means of the Griess reaction in relation to Child-Pugh score, kidney function, fasting state, and after exposure to tap water. RESULTS: Multifactor regression analysis showed inulin clearance (P = 0.0074) and Child-Pugh score (P = 0.0001) to be independent factors predicting NOx levels in patients with cirrhosis. NOx serum levels correlated negatively with the inulin clearance (P < 0.0001), which deteriorated with progressive loss of liver function. NOx levels decreased by about 30% within a 24-h fasting period. After 24 h fasting urinary NOx excretion was not significantly increased in patients with advanced cirrhosis. CONCLUSION: NOx serum levels, taken as a surrogate for endogenous NO formation, have to be viewed with caution in patients with cirrhosis because they often have impaired kidney function. However, in steady-state conditions after an adequate fasting period NOx levels might be good prognostic markers in patients with cirrhosis since they reflect two possible sequelae of liver insufficiency-namely, increased NO formation and impaired kidney function.     

Renal Functional Reserve is Well Maintained in Patients with Advanced Liver Cirrhosis and Ascites

Background: Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in healthy humans can be induced by amino acid stimulation. The rise in GFR from baseline to maximum is referred to as the renal functional reserve (RFR). Recently, we showed that the RFR is preserved in patients with compensated cirrhosis despite impaired renal function. In the present study, we evaluated RFR in decompensated cirrhotics with ascites. Methods: Steady-state inulin- and para-aminohippurate (PAH) clearances were performed at rest and during amino acid infusion in 22 patients with decompensated liver cirrhosis and ascites. Results: Baseline GFR and ERPF (means +95% confidence intervals) were: GFR 25.2 (21.1-29.2) ml min -1, ERPF 266.6 (229.7-303.5). Amino acid infusion significantly increased GFR by 67% (38.3-95.8) to 34.6 (29.2-40.0) ml min -1 (means + (95% confidence intervals), P < 0.001) and ERPF by 29% (11.9-46.3) to 326.3 (274.1-378.5) ml min -1 ( P = 0.002). Renal vascular resistance dropped by 13.4% (3.3-23.5) from 29.4 (24.8-33.9) mmHg ml -1 min -1 to 26.4 (22.0-30.7) mmHg ml -1 min -1 ( P = 0.036). The improved kidney function was accompanied by a decrease in systemic aldosterone levels ( P < 0.05). Conclusion: In patients with liver cirrhosis and ascites, amino acid infusion improves kidney function. Trials are warranted to test the long-term effects of amino acid infusions in patients with hepatorenal syndrome.     

Serum levels of soluble Fas, nitric oxide and cytokines in acute decompensated cirrhotic patients

AIM： To evaluate plasma levels of nitrite/nitrate （NOx）, soluble Pas （spas） antigen, tumor necrosis factor alpha （TNF-α） and interleukin-6 （IL-6） in patients with compensated and acute decompensated cirrhosis and to evaluate mediators causing acute decompensation in liver cirrhosis,
METHODS： This prospective study was conducted in the medical intensive care unit of an academic tertiary center, Fifty-five patients with acute decompensation （gastrointestinal hemorrhage, encephalopathy, hydropic decompensation） and twenty-five patients with compensated liver drrhosis were included, Blood samples were taken for analyses of spas, Nox, IL-6, TNF-α, Liver enzymes and kidney functions were also tested,
RESULTS： In patients with acute decompensation, plasma spas levels were higher than in non-decompensated patients （15305 ± 4646 vs 12458± 4322 pg/mL, P 〈 0.05）. This was also true for the subgroup of patients with alcoholic liver cirrhosis （P 〈 0.05）. The other mediators were not different and none of the parameters predicted survival, except for ALT （alanine-aminotransferase）. In patients with portal-hypertension-induced acute hemorrhage, NOx levels were significantly lower than in patients with other forms of decompensation （70.8 ± 48.3 vs 112.9 ± 74.9 pg/mL, P 〈 0.05）. When NOx levels were normalized to creatinine levels, the difference disappeared. IL-6, TNF-α and spas were not different between bleeders and non-bleeders. In decompensated patients spas, IL-6 and NOx levels correlated positively with creatinine levels, while IL-6 levels were dependent on Child class.
CONCLUSION： In acute decompensated cirrhotic patients sPas is increased, suggesting a role of apoptosis in this process and patients with acute bleeding have lower NOx levels, However, in this acute complex clinical situation, kidney function seems to have a predominant influence on mediator levels,     

Ⅰ型肝肾综合征患者前列腺素I2和血栓素A2水平分析

目的 通过分析肝硬化腹水伴Ⅰ型肝肾综合征(HRS)患者的临床资料、实验室指标、前列腺素I2(PGI2)和血栓素A2(TXA2),探讨花生四烯酸代谢与Ⅰ型HRS发生的关系.方法 纳入肝硬化腹水伴Ⅰ型HRS患者38例(HRS组)及肝硬化腹水且肾功能正常患者50例(非HRS组),收集两组患者的一般资料和血液,分析肝肾功能、电解质、PGI2和TXA2水平.结果 HRS组和非HRS组的PGI2、TXA2、PGI2/TXA2水平分别为(32517±6023) pg/ml、(7432±2186) pg/ml、4.79 ±1.58和(29 597±3343) pg/ml、(5032 ±2104)pg/ml、7.50±2.38,HRS组TXA2水平高于非HRS组(t=2.385,P=0.027),而PGI2/ TXA2水平低于非HRS组(t=2.29,P=0.035),两组PGI2水平差异无统计学意义(t=1.233,P=0.23).结论 Ⅰ型肝肾综合征患者PGI2/TXA2比例失调,花生四烯酸代谢异常可能和Ⅰ型HRS发生有关.     

Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis

BACKGROUND/AIMS: The liver plays a prominent role in the metabolism of asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. This study was designed to determine whether plasma levels of ADMA and NO production are altered in patients with compensated and decompensated alcoholic cirrhosis. METHODS: Plasma levels of l-arginine, ADMA, symmetric dimethylarginine (SDMA) and NO (nitrite plus nitrate, NOx) were measured in nine patients with compensated alcoholic cirrhosis (Child-Pugh A) and 11 patients with advanced cirrhosis (Child-Pugh B-C). Seven healthy volunteers served as controls. RESULTS: ADMA and NOx concentrations in decompensated cirrhosis were higher than in the compensated group and control group (ADMA: 1.12+/-0.08 vs. 0.58+/-0.05 and 0.58+/-0.07micromol/l, respectively; P<0.05; NOx 97.90+/-10.27 vs. 37.42+/-3.91 and 40.43+/-5.30micromol/l, respectively; P<0.05). There was a positive correlation between the clinical score of the patients and concentrations of ADMA (r(2)=0.547, P<0.01) and NOx (r(2)=0.689, P<0.01). SDMA and l-arginine levels were not significantly different between the three groups. CONCLUSIONS: The results suggest that hepatocellular damage is a main determinant of elevated ADMA concentration in advanced alcoholic cirrhosis. By inhibiting NO release from vascular endothelium, ADMA might oppose the peripheral vasodilation caused by excessive NO production in severe cirrhosis.     

Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty-three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (C(Na)), lithium clearance (C(Li)), osmolal clearance (C(Osm)), and urine sodium concentration (U(Na)) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 +/- 19 versus 92 +/- 25 mL/min, P < 0.005) and in the R group (31 +/- 19 versus 41 +/- 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in C(Na) (0.89 +/- 0.21 versus 1.52 +/- 1.45 mL/min, P < 0.05), C(Li) (17.3 +/- 8.9 versus 21.5 +/- 11.6 mL/min, P < 0.05), and C(Osm) (2.10 +/- 0.81 versus 3.06 +/- 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in C(Na) (0.11 +/- 0.18 versus 0.35 +/- 0.40 mL/min, P < 0.05) and C(Li) (5.5 +/- 4.2 versus 9.5 +/- 8.55 mL/min, P < 0.05). U(Na) increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. Conclusion: The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients.     

Levels of circulating endothelin-1 and nitrates/nitrites in patients with virus-related hepatocellular carcinoma

A balance between endothelins (ET) and nitric oxide (NO) might interfere with liver haemodynamics and disease progression in various liver diseases. Increased levels of endothelin 1 (ET-1) and nitrites and nitrates (NOx, the end products of NO metabolism) have been reported in hepatocellular carcinoma (HCC), but the balance has not been studied. The purpose of this study was to assess the ratio of NOx to ET-1 in patients with virus-related hepatocellular carcinoma and to investigate its correlation with the extent of the disease. Eighteen patients with virus-related HCC (six Okuda stage I, six Okuda stage II and six Okuda stage III) were included in the study and were compared with 22 patients with viral cirrhosis (14 decompensated, eight compensated) and seven normal controls. ET-1 was measured with an ELISA assay and NOx with a modification of the Griess reaction. Patients with virus-related HCC had the highest levels of circulating ET-1 and NOx (13.24 +/- 0.82 pg/ml and 112.28 +/- 18.56 micromol/l) compared to compensated cirrhosis (9.47 +/- 0.50 pg/ml, P < 0.004 and 54.47 +/- 2.36 micromol/l, P < 0.01), decompensated cirrhosis (9.57 +/- 0.32 pg/ml, P < 0.001 and 90.20 +/- 11.23 micromol/l, NS) and normal controls (8.84 +/- 0.61 pg/ml, P < 0.001 and 51.17 +/- 6.18 micromol/l, P < 0.01). There was a significant increase of ET-1 and NOx at HCC stage III compared to HCC stages I and II, cirhotics and controls. HCC stage III patients also had a NOx/ET-1 ratio that was higher than HCC stages I and II patients, normal controls and patients with compensated cirrhosis. Virus-related HCC patients have high levels of circulating ET-1, compared to compensated or decompensated cirrhosis. Highest levels of ET-1 are produced in Okuda III tumours. NOx are also increased but only in Okuda stage III tumours. The NOx/ET-1 ratio is increased in virus-related HCC and DC. This increase may account for the known increase in tumour blood flow.     

Clinical efficacy of tolvaptan for treatment of refractory ascites in liver cirrhosis patients

AIM: To evaluate the efficacy and safety of tolvaptan to treat refractory ascites in decompensated liver cirrhosis patients with or without further complications, such as hepatorenal syndrome and/or hepatocellular carcinoma.METHODS: Thirty-nine patients (mean age 55 years, males: 32) with decompensated liver cirrhosis and refractory ascites were enrolled. All patients received a combination of tolvaptan (15 mg/d for 5-14 d) and diuretics (40-80 mg/d of furosemide and 80-160 mg/d of spironolactone). The etiology of cirrhosis included hepatitis B (69.2%), hepatitis C (7.7%) and alcohol-induced (23.1%). Changes in the urine excretion volume, abdominal circumference and edema were assessed. The serum sodium levels were also measured, and adverse events were recorded. A follow-up assessment was conducted 1 mo after treatment with tolvaptan.RESULTS: Tolvaptan increased the mean urine excretion volume (1969.2 ± 355.55 mL vs 3410.3 ± 974.1 mL, P < 0.001), and 89.7% of patients showed improvements in their ascites, 46.2% of whom showed significant improvements. The overall efficacy of tolvaptan in all patients was 89.7%; the efficacies in patients with hepatocellular carcinoma and hepatorenal syndrome were 84.2% and 77.8%, respectively. The incidence of hyponatremia was 53.8%. In patients with hyponatremia, the serum sodium levels increased after tolvaptan treatment (from 128.1 ± 4.22 mEq/L vs 133.1 ± 3.8 mEq/L, P < 0.001). Only mild drug-related adverse events, including thirst and dry mouth, were observed.CONCLUSION: Tolvaptan is a promising aquaretic for the treatment of refractory ascites in patients with decompensated liver cirrhosis.