Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort.

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.

Capnography is superior to pulse oximetry for the detection of respiratory depression during colonoscopy.

BACKGROUND: Pulse oximetry is a widely accepted procedure for ventilatory monitoring during gastrointestinal endoscopy, but this method provides an indirect measurement of the respiratory function. In addition, detection of abnormal ventilatory activity can be delayed, especially if supplemental oxygen is provided. Capnography offers continuous real-time measurement of expiratory carbon dioxide. OBJECTIVE: We aimed at prospectively examining the advantages of capnography over the standard pulse oximetry monitoring during sedated colonoscopies. PATIENTS AND METHODS: Fifty patients undergoing colonoscopy were simultaneously monitored with pulse oximetry and capnography by using two different devices in each patient. Several sedation regimens were administered. Episodes of apnea or hypoventilation detected by capnography were compared with the occurrence of hypoxemia. RESULTS: Twenty-nine episodes of disordered respiration occurred in 16 patients (mean duration 54.4 seconds). Only 38% of apnea or hypoventilation episodes were detected by pulse oximetry. A mean delay of 38.6 seconds was observed in the events detected by pulse oximetry (two episodes of disturbed ventilation were simultaneously detected by capnography and pulse oximetry). CONCLUSIONS: Apnea or hypoventilation commonly occurs during colonoscopy with sedation. Capnography is more reliable than pulse oximetry in early detection of respiratory depression in this setting.

Epidemiologic study on the current incidence of inflammatory bowel disease in Madrid.

INTRODUCTION: The incidence of inflammatory bowel disease (IBD) varies widely according to geographical area and has been reported to have increased in the last few years. No data are available on the current incidence of this disease in Madrid (Spain). AIM: to determine the incidence of inflammatory bowel disease in the area of influence of University Hospital Fundación Alcorcón (Madrid), and to compare our results with those from other Spanish and European series. PATIENTS AND METHODS: A prospective, population-based study was performed to determine the incidence of IBD in the area of University Hospital Fundación Alcorcón in Madrid between 2003 and 2005. Total population: 213,587 inhabitants (177,490 older than 14 years). Crude rates and age- and sex-specific rates adjusted to the European standard population were calculated. A retrospective study (1998-2003) was also performed. RESULTS: A total of 69 cases were diagnosed -Crohn s disease (CD): 35, ulcerative colitis (UC): 33, indeterminate colitis: 1- in the prospective period. Crude rates of CD and UC were 7.92 and 7.47 cases/100,000 inhabitants/year, respectively (the population aged 0-14 years). Specific rates were 8.0 (95% CI, 7.03-8.97) and 7.47 (95% CI, 6.5-8.4), respectively. Mean age at diagnosis was 31.02+/- 10.76 and 39.91+/-16.19 years for CD and UC, respectively. Incidence in the retrospective study was 7.13 and 6.22 cases/100,000 inhabitants/year, respectively for CD and UC. CONCLUSIONS: The incidence of CD and UC in Madrid has increased in the last decades, with rates close to those in northern European countries for CD, higher than those recently published in Spanish prospective studies and similar to those previously described in Spain and southern countries for UC. Rates were higher in the prospective period than in the retrospective one.

[Effect of pentoxifylline on survival, cardiac function and both portal and systemic hemodynamics in advanced alcoholic cirrhosis--a randomized double-blind placebo-controlled trial]. / Effecto de la pentoxifilina en la supervivencia, la función cardiaca y en la hemodinámica portal y sistémica de la cirrosis alcohólica avanzada.

OBJECTIVE: To assess the effect of pentoxiphylline (a potent inhibitor of tumor necrosis factor alpha) on survival, on systemic and portal hemodynamics, and on cardiac function in patients with alcoholic cirrhosis. DESIGN: A randomized double-blind placebo-controlled trial. SETTING: A single center using parallel groups of patients to compare pentoxiphylline with placebo. PATIENTS: We recruited 24 patients with alcoholic cirrhosis (8 Child-Pugh B and 16 Child-Pugh C). INTERVENTIONS: Patients were randomly assigned to receive pentoxiphylline (400 mg tid; n = 12) or placebo (n = 12) over a 4-week period. OUTCOME MEASURES: The primary outcome was to extend short-term and long-term survival. Secondary outcomes included hemodynamic benefits (improvement in cardiac function and/or systemic vascular resistance index, or decrease in portal pressure). RESULTS: Portal pressure and cardiac function remained unchanged and there were no significant differences in short-term or long-term survival between treatment and placebo groups. The group on pentoxiphylline increased systemic vascular resistance and decreased cardiac indices (from 1,721 +/- 567 to 2,082 +/- 622 dyn.sec(-1) cm(-5) m(-2) and from 4.17 +/- 1.4 to 3.4 +/- 0.9 l.m(-2), p = 0.05). CONCLUSIONS: Although pentoxiphylline seems to provide some short-term hemodynamic benefits in patients with advanced alcoholic cirrhosis, this drug has no effect on survival or portal pressure in these patients.

Long-term reversal of hypocholesterolaemia in patients with chronic hepatitis C is related to sustained viral response and viral genotype.

BACKGROUND: Genotype-3 of hepatitis C virus (HCV) has been associated with serum lipid changes (reversible with sustained viral response) and liver steatosis. AIM: To characterize the relationships among hepatic steatosis, cholesterol and sustained viral response in these patients. METHODS: Patients (n = 215) with chronic hepatitis C (157 with genotype-1 of HCV) had age, body mass index, gender, alcohol intake, glycaemia, serum lipids, transaminases, grade and stage (METAVIR and Scheuer), degree of liver steatosis, sustained viral response, insulinaemia, leptinaemia, beta-hydroxybutyrate and glycerol measured, and were compared with 32 hepatitis B virus (HBV)-infected subjects. RESULTS: Genotype-3 of HCV patients had age-adjusted hypocholesterolaemia and more frequent hepatic steatosis (P < 0.001). Steatosis was inversely correlated with serum cholesterol (P < 0.01) and directly with viral load (P < 0.03). In patients with genotype-3 of HCV and sustained viral response, serum cholesterol increased from 138 (95% CI: 120-151) to 180 mg/dL (95% CI: 171-199) 12 months after treatment conclusion (P < 0.0001). By contrast, cholesterol values were unchanged in genotype-3 of HCV non-responders and in patients with genotype-1 of HCV regardless of response. Rising cholesterol in sustained viral response did not parallel the changes in beta-hydroxybutyrate. CONCLUSIONS: Besides causing hepatic steatosis, genotype-3 specifically decreases serum cholesterol. This interference with the metabolic lipid pathway is related to viral load, is reversed with sustained viral response, and seems unrelated to mitochondrial dysfunction.

Altered expression and activation of signal transducers and activators of transcription (STATs) in hepatitis C virus infection: in vivo and in vitro studies.

BACKGROUND: Signal transducers and activators of transcription (STATs) play a critical role in antiviral defence. STAT3 is also important in cell protection against inflammatory damage. STAT proteins are activated by interferons and by hepatoprotective cytokines of the interleukin 6 superfamily, including cardiotrophin 1. METHODS: We analysed the status of STATs in hepatitis C virus (HCV) infected livers and the relationship between expression and activation of STATs and HCV replication in Huh7 cells transfected with HCV genomic replicon. RESULTS: STAT3alpha expression was reduced in HCV infected livers showing an inverse correlation with serum alanine aminotransferase. In patients with HCV infection, nuclear staining for phosphorylated STAT3 was faint in parenchymal cells (although conspicuous in infiltrating leucocytes), in contrast with strong nuclear staining in hepatocytes from control livers. Expression and activation of STAT1 (a factor activated by both interferon (IFN)-alpha and IFN-gamma) were increased in HCV infected livers, particularly in those with high inflammatory activity. Conversely, phosphorylated STAT2 (a factor selectively activated by IFN-alpha) was undetectable in livers with HCV infection, a finding that was associated with marked downregulation of the two functional subunits of the IFN-alpha receptor. HCV replication in Huh7 cells caused STAT3alpha downregulation and blocked STAT3 phosphorylation by either IFN-alpha or cardiotrophin 1. HCV replication in Huh7 cells also inhibited STAT1 and STAT2 activation by IFN-alpha while there was no impairment of STAT1 phosphorylation by the proinflammatory cytokine IFN-gamma. CONCLUSIONS: STAT3 is downregulated in HCV infected livers and in Huh7 cells bearing the full length HCV replicon. HCV replication is associated with impaired Jak-STAT signalling by antiviral and cytoprotective cytokines. These effects may favour viral replication while facilitating the progression of liver disease.

Diagnostic and therapeutic approach to cholestatic liver disease.

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some specific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hyperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a middle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, alpha1-antitrypsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.

The effect of liver transplantation on circulating levels of estradiol and progesterone in male patients: parallelism with hepatopulmonary syndrome and systemic hyperdynamic circulation improvement.

The correction of hepatopulmonary syndrome (HPS) after liver transplantation (LT) remains controversial. The aims of our study were to: 1) analyze whether LT reverses HPS; 2) note any relationship between HPS and the systemic hemodynamic disturbance; and 3) note changes in circulating sex hormones and the possible association with pulmonary and systemic hemodynamic changes. Systemic hemodynamic parameters, cardiac output and systemic vascular resistance (SVR), sex hormones, and intrapulmonary vasodilatation assessed by contrast transesophageal echocardiography, and gas exchange abnormalities were investigated in 19 patients with advanced cirrhosis prior to and 6 months (176.8+/-30 days) after LT. LT was followed by a marked reduction in cardiac output (6.6+/-1.7 vs 3.5+/-0.5 l/min; p<0.001) and SVR (1039+/-460 vs 1978+/-294 dyn x sec x cm(-5); p<0.005). Before LT, circulating estradiol and progesterone levels were invariably elevated (66+/-22 pg/ml and 1.8+/-1.1 ng/ml, respectively, normal values <31 pg/ml and 0.35 ng/ml, respectively), and dropped after LT (28+/-12 pg/ml p<0.001 and 0.38+/-0.2 ng/ml; p<0.001, respectively). Seventeen of 19 patients had intrapulmonary vasodilatation and increased alveolar-arterial oxygen difference, thereby fulfilling diagnostic criteria for HPS. Patients with HPS presented higher cardiac output (p<0.05), lower SVR (p<0.01), and higher progesterone and estradiol levels than patients without HPS (p<0.05). LT produced normalization of intrapulmonary vasodilatation in all patients. LT normalized hyperdynamic circulation and is a useful therapeutic option in patients with HPS. Normalization of sex hormone levels after LT suggests that they could play a pathogenic role in the development of HPS.

Disturbed synthesis of insulinlike growth factor I and its binding proteins may influence renal function changes in liver cirrhosis.

Insulinlike growth factor-1 (IGF-1) is an anabolic hormone synthesized by the liver upon stimulation by growth hormone (GH). IGF-1 exerts important effects on renal hemodynamics and renal sodium handling. The bioactivity of this hormone is influenced by its binding proteins (BP) of which IGF-BP3 favors retention in the capillary lumen while IGF-BP1 facilitates the transport to the target tissues. IGF-BP1 modulates the actions of IGF-1 on target cells including renal tubules. Although a number of reports have dealt with disturbances of the IGF-1/IGF-BP system in cirrhosis, no studies have yet addressed the relationship between alterations in this system and renal function changes in cirrhosis. In the present study we have included 20 patients with cirrhosis and 10 healthy subjects (control group). As compared with the controls, patients showed lower circulating levels of IGF-1 and IGF-BP3, higher IGF-BP1 levels, and a tendency to higher insulinemia and GH values. The index IGF-1 x IGF-BP1/IGF-BP3 (IGF-1-IGF-BP index, reflecting the accessibility of circulating IGF-1 to target cells) was higher in patients with ascites. IGF-1 directly correlated with renal blood flow (P < 0.05), with IGF-BP3 (P < 0.001) and inversely with the Pugh's score (P < 0.02). A negative correlation was found between IGF-1-IGF-BP index and fractional sodium excretion (P < 0.01) and between IGF-BP1 and urinary sodium excretion (P < 0.02). Our findings support the hypothesis that the disturbance of the IGF-1/IGF-BP axis may be related to the degree of renal vasodilation and renal sodium retention in cirrhotic patients.

Circulating adrenomedullin in cirrhosis: relationship to hyperdynamic circulation.

BACKGROUND/AIMS: Peripheral arterial vasodilation may be the key factor in the sodium and water retention of cirrhosis. The mechanism responsible for this vasodilation remains to be fully elucidated. Adrenomedullin is a novel peptide, highly expressed in cardiovascular tissues, with potent and long-lasting vasodilating activity. METHODS: The possible implication of adrenomedullin in the hemodynamic changes of cirrhosis has been investigated. We measured the plasma concentration of adrenomedullin in 20 cirrhotic patients and 11 healthy subjects. In addition, systemic, portal and renal hemodynamics, hormonal factors and renal function parameters were evaluated in the same patients. RESULTS: Circulating adrenomedullin was significantly higher in the group of patients with cirrhosis (72.1; 46-100 vs 21.6; 11-34 fmol/dl, respectively; p<0.02) and was directly correlated with the Pugh score (r: 0.6; p: 0.01), inversely correlated with the creatinine clearance (r: -0.6; p<0.01) and tended to inversely correlate with systemic vascular resistance index (r: -0.46; p: 0.07). There were no portal-peripheral differences in adrenomedullin levels. Transjugular intrahepatic portosystemic shunt insertion did not induce changes in the peripheral concentration of adrenomedullin, but baseline values of this hormone predicted the degree of hyperdynamic circulation after TIPS. CONCLUSIONS: Circulating adrenomedullin is increased in cirrhosis. These levels increase with the severity of the disease, especially in patients with hepatorenal syndrome. This peptide may contribute to vasodilation of cirrhosis.

[Serum levels of soluble interleukin-2 receptor in alcoholic patients]. / Concentración sérica del receptor soluble de interleucina-2 en pacientes alcohólicos.

OBJECTIVES: Contribution of cellular immunity to the onset and perpetuation of alcohol-induced liver damage remains controversial. The aim of this work was to know whether T-cells participate in the pathogenesis of alcoholic liver injury by measuring the serum levels of sIL-2R in alcoholic patients with different degree of hepatic damage. PATIENTS AND METHODS: Fifty two patients and eighteen healthy subjects (Control group) were included. All patients were active drinkers of at least 100 grams/day of ethanol over a ten-years period. Serum sIL-2R was determined by ELISA. Liver biopsy was performed in all patients and liver function tests, serum immunoglobulins and complement proteins C3 and C4 were measured in all participants. The relationship between the sIL-2R and the severity of liver disease was studied. RESULTS: Circulating sIL-2R was higher in the group of patients than in the control (2.388 +/- 275.7 U/ml vs. 795.7 +/- 48.7 IU/mL; p < 0.001). There were not increased circulating sIL2R in those patients with alcoholic hepatitis. However, patients with cirrhosis showed increased serum sIL-2R regardless of the presence of alcoholic hepatitis. Furthermore, serum levels of sIL-2R inversely correlated with hepatic function test (r = -0.69; p < 0.001 for serum albumin; and r = -0.73; p < 0.001 for the prothrombin time) and were highest in those patients of the Child-Turcotte's class C. CONCLUSIONS: Circulating sIL-2R increases in alcoholic cirrhosis. However, our data do not support a contributory role of the cellular immunity, as assessed by circulating sIL-2R levels to the alcoholic liver damage. The increased serum sIL-2R in cirrhosis may result from defective heptic clearance of this molecule.

[Idiopathic ductopenia in adults as a cause of cryptogenic cirrhosis and complications of portal hypertension]. / Ductopenia idiopática del adulto como causa de cirrosis criptogenética y complicaciones de la hipertensión portal.

We describe a 56 years old male patient with long-term chronic liver disease of unknown etiology presenting with esophageal varices rupture. Prophylaxis of re-bleeding with propranolol and endoscopic sclerotherapy failed to prevent further haemorrhagic events and the placement of a transjugular intrahepatic portosystemic shunt (TIPS) was needed. The portal hemodynamic data revealed sinusoidal portal hypertension and the liver biopsy displayed ductopenic cholestasis. The patient met all criteria of idiopathic ductopenia. Subsequently, the jaundice worsened and the patient required liver transplantation.

Enhanced urinary excretion of cGMP in liver cirrhosis. Relationship to hemodynamic changes, neurohormonal activation, and urinary sodium excretion.

Cyclic guanosine monophosphate (cGMP) has been proposed to mediate peripheral arterial vasodilation in liver cirrhosis. Nitric oxide and natriuretic peptides are the main signals for cGMP generation. Variation in urinary cGMP excretion parallels changes in plasma cGMP levels. Our aim was to determine urinary excretion of cGMP (UcGMPV) and to investigate its relationship to systemic hemodynamics, neurohumoral activity and renal sodium excretion in cirrhosis. Urinary excretion of cGMP was measured in 19 healthy subjects and 20 patients with alcoholic cirrhosis. Systemic hemodynamic parameters, blood volume (BV), plasma atrial natriuretic factor (ANF), and the endothelium-dependent vasodilator substance P (SP) were determined in all patients and in five healthy subjects. Urinary cGMPV was higher in the group of patients (736 pg/min; 50-3229 pg/min) than in controls (126 pg/min; 0-1657 pg/min) (P < 0.01). In addition, UcGMPV inversely correlated with the systemic vascular resistance and directly with cardiac output, blood volume, SP, ANF, and Pugh's score. By Cox regression analysis, only systemic vascular resistance remained inversely associated with UcGMPV. In conclusion, urinary cGMP excretion is increased in cirrhosis. It is suggested that increased cGMP generation may be related to the hyperkinetic circulation in human cirrhosis.

Serum angiotensin converting enzyme and C4 protein of complement as a combined diagnostic index in alcoholic liver disease.

Diagnosis of liver cirrhosis relies on hepatic biopsy. So far, attempts have failed to achieve a serologic test that differentiates cirrhosis from other hepatic conditions. The aim of this work was to assess the diagnostic value of the ratio of serum angiotensin converting enzyme activity (SACE) and the levels of protein C4 of serum complement (SACE/C4) in differentiating cirrhotic from noncirrhotic alcoholic liver diseases. In this study, 68 active alcoholic patients (17 with fatty liver or minimal changes, 11 with acute alcoholic hepatitis and 40 with cirrhosis) were included. Twenty healthy subjects were studied as a control group. Liver biopsy was performed in all patients. SACE levels were significantly higher in the group with cirrhosis when compared with the group of patients without cirrhosis and the control. On the other hand, serum C4 level decreased as liver damage progressed. SACE values above 25 IU/l had a sensitivity of 92.5 percent (95 percent confidence interval, 87.5 to 97.5) and a specificity of 79 percent (95% percent confidence interval, 70.5 to 87.5), in detecting those patients with liver cirrhosis. The sensitivity further increased to 95 percent (95 percent confidence interval, 90.5 to 99.5) and the specificity to 100 percent when the SACE/C4 ratio was used and a cutoff point of 145 was chosen. To conclude, in alcoholics SACE is specifically elevated in patients with cirrhosis, and the SACE/C4 ratio is a excellent biochemical index for the diagnosis of cirrhosis in alcoholic patients.

[Sympathetic nervous activity in cirrhosis: the relationship between peripheral hemodynamics and renal function changes]. / Actividad nerviosa simpática en la cirrosis: relación con la hemodinámica periférica y cambios en la función renal.

The relationship between the activity of the sympathetic nervous system and the systemic and peripheral hemodynamic and renal function changes and the antinatriuretic activity in a group of 30 cirrhotic patients and 8 healthy subjects (control group) was investigated. Plasma catecholamines (noradrenaline, adrenaline and dopamine), plasma renin activity, plasma aldosterone concentrations, mean arterial pressure, cardiac output, blood volume, right femoral arterial flow (RFAF) and renal function parameters were determined in all the participants. Cyclic GMP urinary excretion (cV-UGMP) was used as an indirect index of systemic nitric oxide production. The plasma concentration of noradrenaline was greater in the patients than in the control group and was directly correlated with other vasopressor and antinatriuretic systems, RFAF, cV-UGMP, the degree of hepatic failure studied by the Pugh score and was inversely correlated with creatinine clearance and urinary sodium excretion. On Cox regression analysis, only the RFAF, creatinine clearance and plasma adrenaline concentration remained independently associated with plasma noradrenaline levels. Furthermore, plasma noradrenaline was significantly higher in patients with greater hyperdynamic circulation. These results indicate that extrasplanchnic vasodilatation substantially contributes to sympathetic nervous hyperactivity which may significantly influence in the renal function changes observed in these patients.

Plasma levels of substance P in liver cirrhosis: relationship to the activation of vasopressor systems and urinary sodium excretion.

The mediators of the hyperdynamic circulation of liver cirrhosis are not well characterized. Substance P is a potent vasodilatory peptide produced by the enteric nervous system and partly cleared by the liver. In this work we have investigated the plasma levels of substance P and their relationship to the hemodynamic, neurohormonal, and renal function changes occurring in patients with cirrhosis. Seven healthy subjects (control group), 7 cirrhotic patients without ascites (group I), and 24 cirrhotic patients with ascites (group II) were studied. Cardiac output (CO), femoral blood flow (FBF), blood volume (BV), femoral arteriovenous difference of oxygen content (Ca-v O2), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma norepinephrine (NE) were determined. Five patients underwent trans-jugular intrahepatic porto-systemic stent shunt (TIPSS) because of refractory ascites. Immunoreactive substance P (irSP) was measured by radioimmunoassay after plasma extraction. irSP was higher in ascitic patients than in healthy controls (P < .01) and directly correlated with PRA, PAC, plasma NE, and Pugh's score and was inversely correlated with urinary sodium excretion, glomerular filtration rate, and Ca-v O2. No differences were observed between portal and peripheral vein irSP concentration. TIPSS placement induced a decrease in portal pressure and an increase in CO but circulating irSP remained unchanged. Our data show that circulating irSP is increased in decompensated cirrhotic patients and may be involved in the pathogenesis of the hemodynamic changes of cirrhosis. Alleviation of portal hypertension did not result in decreased plasma levels of this vasodilatory substance.

Arteriovenous shunting, hemodynamic changes, and renal sodium retention in liver cirrhosis.

BACKGROUND: Arterial vasodilation has been postulated to initiate sodium retention in cirrhosis. This work was designed to analyze whether arteriovenous shunting underlies vasodilation and influences renal function in cirrhosis. METHODS: The femoral arteriovenous difference in oxygen content (Ca-VO2) was measured in 10 healthy subjects (control group) and 31 cirrhotic patients: 9 without ascites (group 1), 10 with ascites and a urinary sodium excretion rate (UNaV) of > 10 mEq/24 h (group 2), and 12 with ascites and UNaV of < or = 10 mEq/24 h (group 3). In 8 subjects from each group, femoral blood flow and the cardiac output were determined by duplex-Doppler ultrasonography. In 9 cases arteriovenous shunting in the femoral territory was estimated using 30 +/- 5-microns radiolabeled microspheres. RESULTS: Ca-VO2 was lower in group 3 than in controls or group 1. Ca-VO2 correlated inversely with femoral blood flow, plasma renin activity, plasma aldosterone concentration, and degree of shunting measured by microspheres. Ca-VO2 correlated directly with systemic vascular resistance and prothrombin index. CONCLUSIONS: In decompensated cirrhotic patients, there is an increased arteriovenous shunt for oxygen in the lower extremities that is associated with increased arterial blood flow, decreased systemic vascular resistance, and worsening of liver function. This shunt is due partly to opening of arteriovenous precapillary connections.