Diagnostic performance of Baveno IV criteria in cirrhotic patients with upper gastrointestinal bleeding: analysis of the F7 liver-1288 study population.

BACKGROUND & AIMS: The definition of failure to control bleeding agreed upon at the Baveno IV consensus meeting, included the Adjusted Blood Requirement Index [ABRI: number of blood units/(final-initial hematocrit+0.01)]. ABRI ≥0.75 denotes failure. However, timing for hematocrit measurements was not defined. The aims of this study were: (1) to assess the Baveno IV criteria performance to classify treatment success or failure to control bleeding at 5 days, (2) to determine the appropriate timing for hematocrit. METHODS: Two hundred and forty-two cirrhotic patients with gastrointestinal bleeding were independently classified by three clinical experts according to the Baveno IV criteria, by analysis of the database of a randomized trial. ABRI was calculated by using the closest hematocrit to the 5 day time point from the first trial product administration (ABRI-1) or after the latest transfusion within the 5-day period (ABRI-2). The gold standard for success/failure for 5-day control of bleeding was the clinical judgment of the three independent observers based on all the clinical and follow-up data. RESULTS: Inter-observer agreement for the final outcome assessment was 0.82 and a final consensus was obtained in 236/242 patients. Inter-observer agreement on patient classification with Baveno IV criteria was 0.70 with ABRI-1 and 0.84 with ABRI-2. c-statistics for correct patients classification were 0.86 for ABRI-1, 0.84 for ABRI-2, and 0.88 for Baveno IV criteria without ABRI. ABRI-1 caused misclassification of 27 patients and ABRI-2 of 39. CONCLUSIONS: Baveno IV criteria are accurate to assess outcome of patients with variceal bleeding. There is a substantial observer variability linked to timing of hematocrits for ABRI calculation. With the current definition ABRI does not add to the performance of the other criteria.

Cirrhosis ameliorates monocrotaline-induced pulmonary hypertension in rats.

Common bile duct ligation (CBDL) induces biliary cirrhosis and pulmonary vasodilatation. We tested whether CBDL ameliorates monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. Five groups of rats were studied: controls; rats dosed with MCT (60 mg.kg(-1) subcutaneously); CBDL; rats dosed with MCT followed by CBDL on day 7; and rats dosed with MCT followed by CBDL (day 7) and L-NAME therapy between days 24 and 28. 28-day survival was 26% in the MCT group and 72% in the MCT+CBDL group. Pulmonary vascular resistance measured on days 21 and 28 increased in the MCT and MCT+CBDL+L-NAME groups, but returned to normal in the MCT+CBDL group on day 28. Pulmonary artery (PA) medial hypertrophy persisted in MCT+CBDL rats. PA inflammation increased in MCT+CBDL rats, with accumulation of both intra- and perivascular macrophages. Exhaled nitric oxide (NO) levels decreased in the MCT group and increased in the MCT+CBDL group, which showed upregulation of inducible NO synthase and normal endothelial NO synthase. Blood endothelin (ET)-1 increased in CBDL, MCT, and MCT+CBDL rats. Levels of ET(B) receptors increased and ET(A) receptors decreased in the MCT+CBDL group, whereas the opposite changes occurred in the MCT group. Biliary cirrhosis induces pulmonary vasodilation that ameliorates MCT-induced PH and improves survival. Upregulation of inducible NO synthase and ET(B) receptor and downregulation of ET(A) receptor may be involved.

[Progress in portal hypertension]. / Hypertension portale: avancées et perspectives.

In patients with portal hypertension due to cirrhosis, the mechanisms responsible for circulatory modifications are well-known. An elevation in intrahepatic vascular resistance related to a hepatic endothelin hyperproduction and an arterial nitric oxide (NO) hyperproduction. The presence and the degree of portal hypertension might be determined by the measurement of the hepatic venous pressure gradient but non-invasive technique as FibroTest or FibroScan might be useful to estimate the presence of severe portal hypertension. Numerous substances decrease portal pressure either by reducing hepatic vascular resistance or by reducing portal tributary blood flow. The combination of both types of substances is probably the best pharmacological treatment of portal hypertension but further hemodynamic and clinical studies are needed.

Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis.

BACKGROUND: Two algorithms based on sequential measurements of liver and spleen stiffness using two-dimensional shearwave elastography (2D-SWE) have been recently proposed to estimate clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mm Hg) in patients with cirrhosis, with excellent diagnostic accuracy. AIM: To validate externally these algorithms in a large cohort of patients with cirrhosis. METHODS: One hundred and ninety-one patients with stable cirrhosis (Child-Pugh class A 39%, B 29% and C 31%) who underwent liver and spleen stiffness measurements using 2D-SWE at the time of HVPG measurement were included. Diagnostic accuracy of the 2 algorithms was assessed by calculating sensitivity, specificity, positive and negative predictive values. RESULTS: The first algorithm, using liver stiffness <16.0 kilopascals (kPa) and then spleen stiffness <26.6 kPa, was used to rule-out HVPG ≥10 mm Hg. In our population, its sensitivity and negative predictive value were 95% and 63% respectively. The second algorithm, using liver stiffness >38.0 kPa, or liver stiffness ≤38.0 kPa but spleen stiffness >27.9 kPa, was used to rule-in HVPG ≥10 mm Hg. In our population, its specificity and positive predictive value were 52% and 83% respectively. Restricting the analyses to the 74 patients without any history of decompensation of cirrhosis or to the 65 patients with highly reliable liver stiffness measurement did not improve the results. CONCLUSION: In our population, diagnostic accuracies of non-invasive algorithms based on sequential measurements of liver and spleen stiffness using 2D-SWE were acceptable, but not good enough to replace HVPG measurement or to base clinical decisions.

Relationship between the Fibrotest and portal hypertension in patients with liver disease.

BACKGROUND: The best technique to estimate portal hypertension (PHT) is to measure the hepatic venous pressure gradient (HVPG), which is an invasive method. AIM: To assess the relationship between the Fibrotest (Biopredictive, Paris, France) and the presence and degree of PHT in patients with liver disease, and to determine if the Fibrotest can diagnose severe PHT, defined by HVPG >or= 12 mmHg, in cirrhotic patients. METHODS: Patients who underwent a transjugular liver biopsy were prospectively included. HVPG was measured, and classification of histological lesions assessed. The same day, blood samples for Fibrotest were performed. RESULTS: A total of 130 patients were included (no or minimal fibrosis: 12%, moderate fibrosis 17%, cirrhosis 71%). There was a significant correlation between Fibrotest and HVPG (Pearson correlation coefficient = 0.58, P < 0.0001), also weaker in cirrhotic patients (Pearson correlation coefficient = 0.24, P = 0.02). In cirrhotic patients, Fibrotest was significantly higher when there was a severe PHT (0.87 +/- 0.15 vs. 0.73 +/- 0.14, respectively, P = 0.02). The areas under the receiver operating characteristic curves for the diagnosis of severe PHT was 0.79 +/- 0.07, not different from that of platelets and Child-Pugh score. CONCLUSION: In patients with liver disease or cirrhosis, Fibrotest is correlated with the presence and degree of PHT. Other studies are needed to confirm these results, especially in non-decompensated cirrhotic patients.

Lack of clinical or haemodynamic rebound after abrupt interruption of beta-blockers in patients with cirrhosis.

BACKGROUND: Beta-blockers may have to be interrupted in patients with cirrhosis. The concept of a rebound after interruption of beta-blockers is based on an animal study and on isolated case reports of variceal bleeding. AIM: To determine if a rebound occurs in patients with cirrhosis following abrupt interruption of beta-blockers. METHODS: We prospectively included all consecutive patients with cirrhosis undergoing right heart and hepatic vein catheterisation. Four groups were defined: 'no beta-blockers' including patients not receiving beta-blockers; '≤1 day', '2-3 days' and '≥4 days' classified according to the time patients had interrupted beta-blockers before catheterisation. Results were expressed as median (interquartile range). RESULTS: A total of 150 patients were included. Among the 25 patients in the groups '2-3 days' and '≥4 days', median duration of beta-blockers interruption was 4 (3-6) days. No gastrointestinal bleeding occurred during that period, nor during the following month. Hepatic venous pressure gradient was not different among patients in usually treated with beta-blockers. After adjustment, beta-blockers interruption was not associated with hepatic venous pressure gradient. Cardiac index was higher in the '≥4 days' group [4.6 L/min/m(2) (3.5-5.1)] than in the '≤1 day' group [3.4 (2.6-4.0); P = 0.001] or in the '2-3 days' group [3.1 (2.7-3.7); P = 0.007], but not different from the 'no beta-blockers' group. CONCLUSIONS: Abrupt interruption of beta-blockers is associated neither with an apparent increase in the risk of variceal bleeding nor with a haemodynamic rebound. Thus, interruption of beta-blockers in patients with cirrhosis may not require particular dosing or surveillance.

Pharmacological treatment of portal hypertension: hemodynamic effects and prevention of bleeding.

In the past 10 years, it has been clearly shown that vasoactive substances reduce portal pressure in patients or animals with portal hypertension. Some of these substances act by inducing splanchnic vasoconstriction, while others reduce hepatic and porto-systemic collateral vascular resistance and, thus, induce a portal hypotensive effect. Still others induce arterial hypotension, which causes a vasoconstrictive effect in the splanchnic territory. Since these drugs act on different vascular receptors, their combination should have a more marked effect on portal hypertension. Up to now, only nonselective beta-blockers have been used in the prevention of first gastrointestinal bleeding in patients with portal hypertension and esophageal varices and in the prevention of recurrent gastrointestinal bleeding. These trials have shown that propranolol or nadolol significantly reduce either a first episode of bleeding or recurrent bleeding. This pharmacological treatment also improves the survival rate in these patients. All of these studies have helped us to understand, in part, why gastrointestinal hemorrhage occurs in certain patients. Additional studies of beta-blockers or other substances are, nevertheless, necessary to select patients who will respond to this type of treatment. Finally, it is possible that the pharmacological treatment of portal hypertension may also be used before esophageal varices occur.

Hemodynamic effects of dobutamine in patients with alcoholic cirrhosis.

The effects of dobutamine infusion on cardiac output, hepatic blood flow, and the gradient between wedged and free hepatic venous pressures were studied in 14 patients with alcoholic cirrhosis. Cardiac output rose from 5.8 +/- 1.2 l/min (mean +/- SD) to 7.1 +/- 1.5 l/min. Hepatic blood flow and the gradient between wedged and free hepatic venous pressures did not change significantly during the dobutamine infusion (1.360 +/- 0.510 l/min to 1.446 +/- 0.502 l/min and 17.7 +/- 4.9 mm Hg to 17.9 +/- 3.7 mm Hg). We conclude that in alcoholic cirrhotic patients, dobutamine increased cardiac output as a result of increased heart rate and that there were no significant changes in percentage of cardiac output distributed to the liver.

Effect of propranolol on hepatic blood flow in patients with cirrhosis.

The effect of propranolol on systemic and hepatic hemodynamics was studied in patients with cirrhosis. One hour after 40 mg propranolol by mouth as well as during continuous oral dosing at doses that reduced heart rate 25%, cardiac output and the hepatic venous pressure gradient fell significantly, whereas arterial pressure and hepatic blood flow did not change significantly. In six patients with cirrhosis and surgical end-to-side portacaval shunts, cardiac output and the hepatic venous pressure gradient also decreased 15 minutes after intravenous propranolol (5 mg), whereas hepatic blood flow did not change significantly. In the patients with surgical shunts, systemic vascular resistance rose significantly but hepatic arterial vascular resistance fell. Our data show that in patients with cirrhosis, propranolol induces an increase in the fraction of cardiac output reaching the liver.

Possible deleterious hemodynamic effect of nifedipine on portal hypertension in patients with cirrhosis.

The acute effects of nifedipine, 10 mg administered sublingually, were studied in 10 patients with alcoholic cirrhosis. Nifedipine significantly increased cardiac output and reduced systemic vascular resistance. Nifedipine also increased the hepatic venous pressure gradient by 15% (P less than 0.01). Hepatic blood flow and azygos blood flow did not change significantly. It is suggested that nifedipine increases portal pressure and thus may be deleterious to patients with portal hypertension.

Pharmacokinetics of lomefloxacin in patients with cirrhosis.

The effect of liver failure on the pharmacokinetics of lomefloxacin was studied in 12 patients with cirrhosis. Patients received a single oral dose of 400 mg lomefloxacin, and blood and urine samples were collected at intervals over the next 48 hours. The concentrations of lomefloxacin in all samples were measured using high-pressure liquid chromatography (HPLC). The mean (+/- standard deviation) maximum plasma concentration (Cmax) in these patients was 3.9 +/- 1.20 micrograms/mL. The mean time to maximum serum concentration (Tmax) was 2.1 +/- 2.6 hours, and the mean elimination half-life (t1/2) was 9.16 +/- 1.93 hours. Mean renal clearance was 88.9 +/- 38.0 mL/min/1.73 m2, and the mean nonrenal clearance was 61.6 +/- 19.0 mL/min/1.73 m2, which corresponded to 41% of the total body clearance. No correlations were observed between nonrenal clearance and hepatic insufficiency (Pugh score) or nonrenal clearance and plasma bilirubin. These results show that liver failure does not per se affect lomefloxacin kinetics. Thus, no adjustments in lomefloxacin dosages appear to be necessary for patients with impaired liver function tests.

Orthotopic liver transplantation with hepatic artery anastomoses. Hemodynamics and response to hemorrhage in conscious rats.

Orthotopic liver isotransplantation was performed in one group of Lewis rats using cuffs for the portal vein and the infrahepatic vena cava, stents for the hepatic artery and the bile duct. Three other groups were also investigated: group A, normal rats; group B, sham-transplanted rats (clamping of the vessels, washing of the liver, placing cuffs around the portal vein); and group C, sham-transplanted rats with ligature section of the hepatic artery. Blood-flow measurements were performed, 1 week after the surgical procedure, with the radioactive microsphere method in conscious animals. Transplanted rats exhibited significant (ANOVA, P less than 0.05) increase in cardiac index and decrease in mean arterial pressure and systemic vascular resistance. Blood flows of the portal territory and to the kidneys were not significantly modified. Arterial liver blood flow and arterial liver vascular resistance in rats with liver transplantation were not significantly different between normal and sham-transplanted rats but were significantly different from rats with ligature of the hepatic artery. These results confirm the validity of the method used for vascular anastomoses. Hypotensive hemorrhage (2 ml/100 g bw) induced marked hemodynamic changes, but rats with liver transplantation when compared with normal and sham-transplanted rats exhibited the following: (a) significantly lower percentage of decrease in cardiac index and in mean arterial pressure; and (b) significantly higher renal and portal tributary blood flows. Plasma catecholamine concentrations and plasma volume were higher in rats with liver transplantation than in normal rats but were not significantly different from sham-operated rats. Histologic examination of the liver revealed slight portal edema in sham-operated rats and small necrotic areas in the liver, probably corresponding to the reperfusion injury, in rats with liver transplantation. In conclusion, the method described for the four vascular anastomoses allows functional perfusion of the transplanted liver. Rats with liver transplantation exhibited a hyperkinetic circulatory syndrome and an improved tolerance to hemorrhage. Changes in plasma catecholamine concentrations and in plasma volume did not account for the hemodynamic changes.

Studies of portal hemodynamics and hepatic oxygen consumption during acute liver allograft rejection.

Hemodynamics and oxygen variables, plasma cytokines, and histological features of a liver tissue sample obtained by transvenous biopsy were evaluated during 65 episodes of acute rejection. The hepatic venous pressure gradient was significantly higher in patients with acute rejection than in those without (5.1+/-0.3 vs. 3.1+/-0.2 mmHg, P<0.01). The increase in pressure gradient was related to the severity of rejection lesions. Hepatic blood flow was significantly lower in patients with than in those without acute graft rejection (1.28+/-0.11 vs. 1.75+/-0.13 L/min, P<0.05). Plasma interleukin-6 levels were significantly increased in patients with acute rejection and positively correlated with pressure gradient values. In patients with acute rejection, a significant decrease in hepatic venous oxygen content (-16%) was associated with a significant increase in hepatic oxygen consumption (+24%), whereas hepatic oxygen transport did not change significantly. In treated patients with a favorable response, the pressure gradient decreased significantly by 46%, but it remained elevated in patients who later developed chronic graft rejection. In conclusion, this study confirms that acute graft rejection may induce an increase in portal pressure, which is related to the severity of rejection lesions. It also shows that acute rejection decreases hepatic blood flow and increases hepatic oxygen consumption. In addition, it suggests that the hepatic venous pressure gradient might be useful to determine the outcome of rejection.

Pharmacokinetics of ketanserin in patients with cirrhosis.

The pharmacokinetics of ketanserin, a new serotonin S2 (5HT2) antagonist, were studied in 26 patients with cirrhosis. Patients were randomised to receive either a single oral dose of ketanserin 20mg (n = 14) or 40mg (n = 8) or an intravenous dose of ketanserin 5mg (n = 4). The plasma kinetics of ketanserin and its metabolite ketanserinol were determined over 48 hours, by high pressure liquid chromatography with a fluorometric detector. Pharmacokinetic parameters were calculated using noncompartmental analysis based on a statistical moment theory. The first-pass effect of ketanserin was markedly decreased after oral administration compared with results previously obtained in healthy subjects. The peak concentration was not higher in cirrhotic patients than in controls. This result could be due to an increase in the initial volume of distribution. The production of ketanserinol was reduced in cirrhotics. A decreased mean ketanserin elimination half-life (t1/2 = 12 +/- 4 and 10 +/- 3h vs 16 +/- 3 and 18 +/- 4h in healthy controls after oral ketanserin 40mg and intravenous ketanserin 5mg, respectively) contrasted with a substantial increase in t1/2 for ketanserinol (33 +/- 13 vs 19 +/- 4h). The volumes of distribution were also markedly reduced in patients with cirrhosis. These results suggest either a reduction in the oral dosage of ketanserin or an increase in the interval between doses in patients with cirrhosis.

Effects of glibenclamide on systemic and splanchnic haemodynamics in conscious rats.

1. The effects of the sulphonylurea, glibenclamide (20 mg kg-1, i.v.), at a dose that blocks vascular potassium channels, on systemic and splanchnic haemodynamics (radioactive microspheres) were studied in conscious rats. 2. Glibenclamide significantly decreased cardiac index and hepatic artery blood flow while it significantly increased vascular resistance in systemic, portal and hepatic arterial territories. 3. In rats with suppressed cardiovascular reflexes, glibenclamide induced vasoconstriction in systemic, portal and hepatic arterial territories. 4. Intracerebroventricular administration of glibenclamide did not alter systemic or regional vascular tone. 5. Glibenclamide blunted the vasodilator effect of the potassium channel opener, diazoxide but not that of the L-type calcium channel blocker, nicardipine. 6. Another sulphonylurea, glipizide (20 mg kg-1, i.v.), induced significant systemic and splanchnic vasoconstriction. 7. Thus, the glibenclamide-induced blockade of vascular potassium channels caused a vasoconstriction in the systemic and splanchnic vascular beds. In these territories, therefore, the opening of glibenclamide-sensitive potassium channels might be responsible for a basal vasodilator tone.

Noncirrhotic portal hypertension.

This article reviews the different conditions leading to noncirrhotic intrahepatic portal hypertension, describes the related vascular lesions, and provides a review of the clinical characteristics, diagnosis, and treatment options available. Diseases associated with noncirrhotic portal hypertension are also specifically discussed.

A randomised controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis.

74 cirrhotic patients with a history of variceal or gastric bleeding were randomly assigned to treatment with propranolol (40 to 360 mg/day) or placebo. The patients were all in good condition and doses of propranolol were titrated until a 25% reduction in heart rate was achieved. After 2 years, the cumulative percentage of patients free from rebleeding was significantly greater among the patients receiving propranolol (79%) than in the placebo group (32%; p less than 0.0001). Similarly, the percentage of surviving patients was significantly greater with propranolol (90%) than with placebo (57%; p less than 0.02) after 2 years. It was concluded that in cirrhotic patients in good condition, propranolol reduced both the risk of recurrent gastrointestinal haemorrhage and the mortality rate during a 2-year period of continuous administration of the drug.

Granulomonocytic colony forming cells in myelofibrosis: concentrations within hepatic blood and peripheral blood.

Hepatic and peripheral blood GM-CFC concentrations were compared in 8 cases of myelofibrosis. Hepatic blood concentrations were significantly higher (p less than 0.05). The density-distribution profile for hepatic blood GM-CFCs shifted to the left as compared to peripheral blood in 4 cases out of 5. The maximal blood transit time for circulating GM-CFCs was about 1 min. These results suggest that spleen and liver are a production site of blood GM-CFCs in myelofibrosis. In particular, they would be responsible for the presence in blood of the lightest GM-CFCs (less than 1.060 g cm-3). Increased GM-CFC inflow from bone marrow and/or liver and spleen to blood is the single explanation for the increased value of the circulating GM-CFCs.

Review article: future indications for terlipressin therapy.

Vasoconstrictor agents such as terlipressin (Glypressin) have been shown to have beneficial effects in the treatment of hepatorenal syndrome (HRS), in terms of improving renal function and subsequent survival rates. Patients with HRS have also been shown to have improved survival after liver transplantation if they receive terlipressin treatment prior to transplantation. In addition, studies show that terlipressin may have beneficial effects in treating other indications, including paracentesis-induced circulatory dysfunction and endotoxic shock. A positive effect has also been demonstrated with vasopressin in cardiopulmonary resuscitation.

Review article: hepatorenal syndrome--definitions and diagnosis.

Hepatorenal syndrome (HRS) is a severe complication of cirrhosis that develops in the final phase of the disease. Two types of HRS exist. Type 1 is defined by a rapid reduction of renal function and in type 2 HRS the reduction of renal function is slowly progressive. Type 1 HRS is diagnosed when the serum creatinine level increases by more than 50% of the baseline value to above 133 micromol/L. According to the International Ascites Club, HRS is defined by the presence of five criteria: (1) severe cirrhosis; (2) glomerular hypofiltration; (3) no other functional or organic causes; (4) failure of plasma volume expansion; (5) no proteinuria. Additional diagnostic criteria may be present. The diagnosis of HRS may be difficult in patients with severe cirrhosis. Other types of acute renal failure may occur. For example, ischaemic or toxic tubular necrosis or sepsis may cause renal failure in these patients. Furthermore, uncontrolled HRS may lead to ischaemic tubular necrosis; thus, these patients must be managed as soon as possible in an intensive care unit.