Changes In Portal Blood Flow Research Articles

Comparison of portal vein hemodynamics with ultrasound-based elastography for the prediction of liver fibrosis in patients with chronic liver disease

Chronic liver disease includes nonalcoholic fatty liver disease, progresses from steatosis and hepatitis to fibrosis and cirrhosis, with hemodynamic changes in portal blood flow. This study aimed to compare portal vein hemodynamics with liver stiffness (LS) and steatosis and included 28 subjects with chronic liver disease, in whom LS and steatosis were evaluated in the same image employing two elastography techniques: transient elastography (TE) with controlled attenuation parameter (CAP) using a FibroScan and two-dimensional shear-wave elastography (2D-SWE) with attenuation imaging (ATI). Additionally, peak maximum velocity (Vmax) of the right portal vein and spleen stiffness with 2D-SWE were evaluated. A strong positive correlation was present between LS values obtained with TE and 2D-SWE and between the attenuation coefficients of steatosis obtained with CAP and ATI. Additionally, a negative correlation was present between LS values and the Vmax of the right portal vein (r = 0.415, p = 0.031). The optimal Vmax cutoff value for discriminating liver fibrosis with an LS value of > 5 kPa was < 17 cm/s; the ability of Vmax to predict fibrosis was comparable to that of the FIB4-index. Low Vmax of the right portal vein was useful for identifying liver fibrosis in patients with chronic liver disease.

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte-Mediated Paracrine Mechanism.

In cirrhosis, liver microvascular dysfunction is a key factor increasing hepatic vascular resistance to portal blood flow, which leads to portal hypertension. De‐regulated inflammatory and pro‐apoptotic processes due to chronic injury play important roles in the dysfunction of liver sinusoidal cells. The present study aimed at characterizing the effects of the pan‐caspase inhibitor emricasan on systemic and hepatic hemodynamics, hepatic cells phenotype, and underlying mechanisms in preclinical models of advanced chronic liver disease. We investigated the effects of 7‐day emricasan on hepatic and systemic hemodynamics, liver function, hepatic microcirculatory function, inflammation, fibrosis, hepatic cells phenotype, and paracrine interactions in rats with advanced cirrhosis due to chronic CCl4 administration. The hepato‐protective effects of emricasan were additionally investigated in cells isolated from human cirrhotic livers. Cirrhotic rats receiving emricasan showed significantly lower portal pressure than vehicle‐treated animals with no changes in portal blood flow, indicating improved vascular resistance. Hemodynamic improvement was associated with significantly better liver function, reduced hepatic inflammation, improved phenotype of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells and macrophages, and reduced fibrosis. In vitro experiments demonstrated that emricasan exerted its benefits directly improving hepatocytes’ expression of specific markers and synthetic capacity, and ameliorated nonparenchymal cells through a paracrine mechanism mediated by small extracellular vesicles released by hepatocytes. Conclusion: This study demonstrates that emricasan improves liver sinusoidal microvascular dysfunction in cirrhosis, which leads to marked amelioration in fibrosis, portal hypertension and liver function, and therefore encourages its clinical evaluation in the treatment of advanced chronic liver disease.

Changes in portal blood flow in acute alcoholic pancreatitis

The paper presents the results of a clinical study in 25 patients with the established diagnosis of acute pancreatitis, who were in inpatient treatment at the State Budgetary Healthcare Institution “Republican Clinical Hospital No. 4” divided into groups depending on the sex and the acute pancreatitis form. In the course of the study, it was established that liver damage and microcirculation disturbances were observed against the background of pancreas damage and fermentation. It is manifested by changes in the blood flow in the hepatic veins and significant hemodynamics disorders in the portal vein. The degree of changes manifestation depends on the aetiological factor and the intensity of the inflammation in the pancreas. The changes are less significant in the edematic form of acute pancreatitis, and they return to normal rather quickly. In acute pancreatitis of alcoholic genesis, the changes in hemodynamics in the portal system are more persistent and profound, which persist throughout the observation period. It has also been established that ultrasonic dopplerography is a safe, rapid and relatively simple noninvasive and sufficiently informative method for detecting hemodynamic disturbances in the portal vein system and hepatic veins in acute pancreatitis.

The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells.

RVXB decreases PP in two rat models of cirrhosis. This effect is mostly associated with decreased IHVR, enhanced NO bioavailability, HSC deactivation, and reduced intrahepatic microthrombosis. Our findings suggest that RVXB deserves further evaluation as a potential treatment for cirrhotic PH. (Hepatology 2017;65:2031-2044).

Prediction of portal and hepatic blood flow from intake level data in cattle.

Interest is growing in developing integrated postabsorptive metabolism models for dairy cattle. An integral part of linking a multi-organ postabsorptive model is the prediction of nutrient fluxes between organs, and thus blood flow. The purpose of this paper was to use a multivariate meta-analysis approach to model portal blood flow (PORBF) and hepatic venous blood flow (HEPBF) simultaneously, with evaluation of hepatic arterial blood flow (ARTBF; ARTBF=HEPBF - PORBF) and PORBF/HEPBF (%) as calculated values. The database used to develop equations consisted of 296 individual animal observations (lactating and dry dairy cows and beef cattle) and 55 treatments from 17 studies, and a separate evaluation database consisted of 34 treatment means (lactating dairy cows and beef cattle) from 9 studies obtained from the literature. Both databases had information on dry matter intake (DMI), metabolizable energy intake (MEI), body weight, and a basic description of the diet including crude protein intake and forage proportion of the diet (FP; %). Blood flow (L/h or L/kg of BW0.75/h) and either DMI or MEI (g or MJ/d or g or MJ/kg of BW0.75/d) were examined with linear and quadratic fits. Equations were developed using cow within experiment and experiment as random effects, and blood flow location as a repeated effect. Upon evaluation with the evaluation database, equations based on DMI typically resulted in lower root mean square prediction errors, expressed as a % of the observed mean (rMSPE%) and higher concordance correlation coefficient (CCC) values than equations based on MEI. Quadratic equation terms were frequently nonsignificant, and the quadratic equations did not outperform their linear counterparts. The best performing blood flow equations were PORBF (L/h)=202 (±45.6) + 83.6 (±3.11) × DMI (kg/d) and HEPBF (L/h)=186 (±45.4) + 103.8 (±3.10) × DMI (kg/d), with rMSPE% values of 17.5 and 16.6 and CCC values of 0.93 and 0.94, respectively. The residuals (predicted - observed) for PORBF/HEPBF were significantly related to the forage % of the diet, and thus equations for PORBF and HEPBF based on forage and concentrate DMI were developed: PORBF (L/h)=210 (±51.0) + 82.9 (±6.43) × forage (kg of DM/d) + 82.9 (±6.04) × concentrate (kg of DM/d), and HEPBF (L/h)=184 (±50.6) + 92.6 (±6.28) × forage (kg of DM/d) + 114.2 (±5.88) × concentrate (kg of DM/d), where rMSPE% values were 17.5 and 17.6 and CCC values were 0.93 and 0.94, respectively. Division of DMI into forage and concentrate fractions improved the joint Bayesian information criterion value for PORBF and HEPBF (Bayesian information criterion=6,512 vs. 7,303), as well as slightly improved the rMSPE and CCC for ARTBF and PORBF/HEPBF. This was despite minimal changes in PORBF and HEPBF predictions. Developed equations predicted blood flow well and can easily be used within a postabsorptive model of nutrient metabolism. Results also suggest different sensitivity of PORBF and HEPBF to the composition of DMI, and accounting for this difference resulted in improved ARTBF predictions.

Changes in portal blood flow and liver functions in cirrhotics during Ramadan fasting in the summer; a pilot study.

Assessment of short term changes in portal blood flow and long term changes in liver functions in cirrhotic patients who chose to fast during the month of Ramadan in summer. During Ramadan, healthy Muslims obligated to fast from predawn to sunset. Forty cirrhotic patients intended to fast during the month of Ramadan in the year 2014, were examined by Congestion index (CI) as a non-invasive indicator of short term changes in the portal blood flow, while liver function tests were determined as an indicator of long term changes in liver functions. A total of 38 patients completed the whole month fasting and two patients discontinued fasting due to variceal bleeding. The complicated patients were 7. CI showed a statistically significant increase from fasting to postprandial status (P<0.001), with statistically significant increases from fasting to postprandial status in Child class A (P<0.001), and B (P<0.001). We did not find a statistical significance between patients with complications and those without complications (P=0.6). There was a statistically significant rise in the serum bilirubin after Ramadan. Deterioration noticed as advanced Child classes, development of lower limb edema, increasing ascites, increasing jaundice and overt encephalopathy. Cirrhotic patients showed significant short-term changes in the portal blood flow. However, these changes are not linked to complications or deterioration of liver functions and accommodated especially in patients with Child class A and B. Child class C patients should not fast.

Effect of sevoflurane anaesthesia on hepatic blood flow in infants with obstructive hepatobiliary disease.

Currently most studies on anaesthetic effects on hepatic blood flow of cirrhotic patients have been performed on adults or experimental animals. We performed this study to evaluate the effect of sevoflurane anaesthesia on hepatic blood flow in infants with obstructive jaundice by Doppler ultrasound. Forty-four infants with biliary atresia (1-3 months of age) scheduled for a Kasai procedure were enrolled. Hepatic blood flow was calculated by Doppler ultrasound measurements before induction, and after inhalation of 2% and 3% sevoflurane. Infants were allocated to three groups according to baseline portal blood flow/hepatic artery blood flow: group A (portal blood flow/hepatic artery blood flow < 1), group B (1 ≤ portal blood flow/hepatic artery blood flow < 2) and group C (portal blood flow/hepatic artery blood flow ≥ 2). Changes in portal blood flow, hepatic artery blood flow and hepatic blood flow were compared among groups. In group A (n = 9), the median (IQR) hepatic blood flow increased after inhalation of 2% sevoflurane compared to that before induction (from 49.7 (32.0-89.0) to 116.1 (40.4-159.1) ml/min; P = 0.035). Whereas in groups B and C in whom the ratio of portal blood flow and hepatic artery blood flow was normal or mildly changed, the increases in hepatic blood flow after sevoflurane anaesthesia were not significant. For infants with obstructive jaundice that had reduced portal blood flow and compensatory increase in hepatic artery blood flow, sevoflurane may produce a protective effect on hepatic blood flow.

Assessment of splanchnic hemodynamics in patients with cirrhosis after separating operations in comparison with non-operated patients with compensated and decompensated clinical course

Separating operations are recommended for treatment and prophylaxis of bleeding from varicose veins of gullet as a result of portocaval (azygoportal) shunting at cirrhosis and directed to its elimination using azygoportal separation. At the same time the frequency of relapse of bleeding after operations remains rather high. And the formation of new varicose nodi as a result of disorder of hepatic and splanchnic hemodynamics that inevitably appears at different dates after operation is considered as the main cause of it. At the same time an assessment of hemodynamic changes after azygoportal separation is interpreted in different ways by different authors.Aim of research. To assess an influence of separating surgical interventions on the character of changes of splanchnic hemodynamics in patients with cirrhosis in comparison with non-operated patients with compensated and decompensated clinical course.Material and methods. There were examined 190 patients with cirrhosis: in 133 took place gastrointestinal bleeding from varicose veins of gullet, in 57 – diuretic resistant ascites. 16 patients underwent separating operations. 20 patients underwent endoscopic sclerotherapy of gullet veins. 84 patients died during observation (7 after surgical treatment). Duration of observation was from 2-3 weeks to 2,5-3 years. All patients underwent the repeated ultrasound of abdominal cavity. There were assessed diameter of hepatic and splenic vessels; quantitative and qualitative characteristics of blood flow in hepatic and splenic arteries, portal and splenic veins.Results of research. At assessment of splanchnic hemodynamics the changes of portal blood flow in first months after operation characterized with moderate dilation of portal vein and decrease of linear speed in it. At the same time the volumetric blood flow did not essentially change. It was noticed the decrease of volumetric blood flow in splenic vein at the expense of constriction of its lumen and decrease of linear speed in it. Arterial blood flow characterized with decrease of inflow to liver through hepatic artery and increase of blood flow through splenic artery. At later dates the character of changes of splanchnic hemodynamics after azygoportal separation was analogous on all indicators to non-operated patients at transfer from compensated to decompensated course of cirrhosis – decrease of blood flow through the portal vein and hepatic artery at relative increase of splenic blood flow. An increase of index of stagnation in the portal vein and splenic-hepatic portal index that took place in all operated patients and non-operated ones at the stage of decompensation was an unfavorable prognostic indication.Conclusion. The character of changes of splanchnic hemodynamics after gastroesophageal separation is analogous to non-operated patients at transfer from compensated course of cirrhosis to decompensated one. Decrease of the portal blood inflow through the splenic vein is a compensatory mechanism that must decrease the portal pressure. The quality of life in postsurgical period is determined by duration of compensation of hemodynamic disorders

Assessment of splanchnic hemodynamics in patients with cirrhosis after portocaval shunting in comparison with no-operated patients with the compensated and decompensated course of disease

Portocaval shunting is recommended for decrease of the portal pressure and regression of the varicose veins in patients with cirrhosis. But the shunting surgery at cirrhosis is limited by the high risk of development of hepatic encephalopathy and the hepatocellular insufficiency in post-surgical period. And the disorder of the hepatic and splanchnic hemodynamics that inevitably appears at different dates after surgery is considered as the main cause of these states.Aim of research. To assess an influence of the shunting surgical interventions on the character of changes of splanchnic hemodynamics in patients with cirrhosis in comparison with no-operated patients with compensated and decompensated course of disease.Material and methods. 190 patients with cirrhosis were examined: 133 had gastrointestinal bleeding, 57 – diuretic-resistant ascites. 18 patients underwent surgery – portocaval shunting. 84 patients died during observation (10 after surgery). The duration of observation was from 2-3 weeks to 2,5-3 years.All patients underwent the repeated ultrasound examination of abdominal cavity. There were defined the diameter of hepatic and splenic vessels; quantitative and qualitative characteristics of the blood flow in hepatic and splenic arteries, in portal and splenic veins. Results of research. At assessment of splanchnic hemodynamics we noticed the differences of parameters depending on time that passed after surgery. The changes of portal blood flow in first 3-6 month were characterized by the moderate widening of portal and splenic veins at little decrease of its mean linear and volume speed so an inflow of the portal blood still stable. Arterial blood flow in hepatic artery was forced at the expense of both widening of diameter and increase of the mean speed of blood flow. The splenic arterial blood flow practically was not changed. The reliable decrease of the volume blood flow in portal vein at the expense of decrease of its linear speed was observed in all patients at later dates. An unfavorable sign was an increase of an index of haemostasia in portal vein and of splenic and hepatic portal index in dynamics that took place in all operated patients and in no-operated ones at the stage of decompensation.Conclusions. The character of changes of splanchnic hemodynamics after portocaval shunting is analogous to the one in no-operated patients at transition from the compensated course of cirrhosis to decompensated one. The compensatory mechanism that preserves the volume of the portal inflow to liver is the widening of the portal vein and preservation of the splenic blood flow. The quality of life in post-surgical period is determined by the duration of compensation of hemodynamic disorders

Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.

Increased hepatic vascular resistance is the primary factor in the development of portal hypertension. Metformin ameliorates vascular cells function in several vascular beds. Our study was aimed at evaluating the effects, and the underlying mechanisms, of metformin on hepatic and systemic hemodynamics in cirrhotic rats and its possible interaction with the effects of propranolol (Prop), the current standard treatment for portal hypertension. CCl4-cirrhotic rats received by gavage metformin 300 mg/kg or its vehicle once a day for 1 wk, before mean arterial pressure (MAP), portal pressure (PP), portal blood flow (PBF), hepatic vascular resistance, and putative molecular/cellular mechanisms were measured. In a subgroup of cirrhotic rats, the hemodynamic response to acute Prop (5 mg/kg iv) was assessed. Effects of metformin ± Prop on PP and MAP were validated in common bile duct ligated-cirrhotic rats. Metformin-treated CCl4-cirrhotic rats had lower PP and hepatic vascular resistance than vehicle-treated rats, without significant changes in MAP or PBF. Metformin caused a significant reduction in liver fibrosis (Sirius red), hepatic stellate cell activation (α-smooth muscle actin, platelet-derived growth factor receptor β polypeptide, transforming growth factor-βR1, and Rho kinase), hepatic inflammation (CD68 and CD163), superoxide (dihydroethidium staining), and nitric oxide scavenging (protein nitrotyrosination). Prop, by decreasing PBF, further reduced PP. Similar findings were observed in common bile duct ligated-cirrhotic rats. Metformin administration reduces PP by decreasing the structural and functional components of the elevated hepatic resistance of cirrhosis. This effect is additive to that of Prop. The potential impact of this pharmacological combination, otherwise commonly used in patients with cirrhosis and diabetes, needs clinical evaluation.

Regarding “liver stiffness is influenced by a standardized meal in patients with chronic hepatitis C virus at different stages of fibrotic evolution”

We congratulate Arena et al.1 for their interesting article regarding the confounding effect of a meal on the accuracy of liver stiffness (LS) measurements for the prediction of fibrosis stage in patients with chronic hepatitis C virus (HCV) hepatitis. In that study the most prominent postprandial increase in LS was observed in patients with cirrhosis. Hemodynamic parameters were not measured, but it is suggested that the postprandial changes in LS are likely consequent to the adaptation of the hepatic microcirculation to increased portal blood flow (PBF) and to the postprandial increase in portal pressure. We recently published a study2 involving 19 patients with cirrhosis and portal hypertension in whom LS and hepatic hemodynamics were measured by Doppler-ultrasonography at baseline and 30 minutes after the ingestion of a standardized meal similar to that used by Arena et al. In a subgroup of 10 patients, the baseline and postprandial hepatic venous pressure gradient (HVPG) were also measured. In agreement to what was described by Arena et al.,1 showing that most patients irrespective of the stage of fibrosis had a peak increase of LS 30 minutes after the meal, in our series postprandial hyperemia (confirmed by a marked increase in PBF, +33 ± 31%, P < 0.0001 versus baseline) was accompanied by a marked increase in LS (+27 ± 33%; P < 0.0001). However, we observed that postprandial changes in LS did not correlate with the changes in PBF. Similarly, in patients in whom HVPG was measured, LS changes did not mirror the HVPG increase after the standardized meal. In contrast, postprandial changes in LS were directly correlated with changes in hepatic artery blood flow (r = 0.658; P = 0.002), so that in patients showing the expected postprandial decrease in hepatic artery blood flow (reflecting the “buffer response” to increased PBF after a meal) the LS increase was significantly attenuated as compared with patients lacking this adaptive mechanism (+12 ± 21% versus +62 ± 29%, P < 0.0001). Altogether, our results suggest that the postprandial increase in LS in cirrhosis cannot be explained by the increase in PBF and portal pressure, while it seems at least in part dependent on changes in the arterial component of hepatic blood flow. Since extensive formation of collaterals in advanced portal hypertension leads to increased dependence of the hepatic blood flow on its arterial component, and since hepatic artery buffer response is reduced in cirrhosis,3 a greater postprandial increase in LS should be anticipated in overt cirrhosis. Annalisa Berzigotti, M.D. Juan G. Abraldes, M.D. Jaume Bosch, M.D. Hepatic Hemodynamic Laboratory, Liver Unit, IDIBAPS and CIBERehd, Hospital Clinic, Barcelona, Spain

Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats

Increased production of vasoconstrictive prostanoids, such as thromboxane A2 (TXA2 ), contributes to endothelial dysfunction and increased hepatic vascular tone in cirrhosis. TXA2 induces vasoconstriction by way of activation of the thromboxane-A2 /prostaglandin-endoperoxide (TP) receptor. This study investigated whether terutroban, a specific TP receptor blocker, decreases hepatic vascular tone and portal pressure in rats with cirrhosis due to carbon tetrachloride (CCl4 ) or bile duct ligation (BDL). Hepatic and systemic hemodynamics, endothelial dysfunction, liver fibrosis, hepatic Rho-kinase activity (a marker of hepatic stellate cell contraction), and the endothelial nitric oxide synthase (eNOS) signaling pathway were measured in CCl4 and BDL cirrhotic rats treated with terutroban (30 mg/kg/day) or its vehicle for 2 weeks. Terutroban reduced portal pressure in both models without producing significant changes in portal blood flow, suggesting a reduction in hepatic vascular resistance. Terutroban did not significantly change arterial pressure in CCl4 -cirrhotic rats but decreased it significantly in BDL-cirrhotic rats. In livers from CCl4 and BDL-cirrhotic terutroban-treated rats, endothelial dysfunction was improved and Rho-kinase activity was significantly reduced. In CCl4 -cirrhotic rats, terutroban reduced liver fibrosis and decreased alpha smooth muscle actin (α-SMA), collagen-I, and transforming growth factor beta messenger RNA (mRNA) expression without significant changes in the eNOS pathway. In contrast, no change in liver fibrosis was observed in BDL-cirrhotic rats but an increase in the eNOS pathway. Our data indicate that TP-receptor blockade with terutroban decreases portal pressure in cirrhosis. This effect is due to decreased hepatic resistance, which in CCl4 -cirrhotic rats was linked to decreased hepatic fibrosis, but not in BDL rats, in which the main mediator appeared to be an enhanced eNOS-dependent vasodilatation, which was not liver-selective, as it was associated with decreased arterial pressure. The potential use of terutroban for portal hypertension requires further investigation.

Effect of Meal Ingestion on Liver Stiffness in Patients with Cirrhosis and Portal Hypertension

Background and AimsLiver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population.MethodsIn 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured.ResultsPost-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes.ConclusionsLiver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.

Effect of etonogestrel contraceptive implant (Implanon®) on portal blood flow and liver functions

Background This study was conducted to evaluate changes in portal blood flow and liver functions among women using Implanon® for 2 years. Study Design Fifty healthy Implanon® users were enrolled in this longitudinal study and followed up for 24 months. Portal blood flow, assessed by color Doppler; prothrombin time and concentration; serum albumin; bilirubin; gamma-glutamyl transferase (GGT); alanine aminotransferase (ALT); and aspartate aminotransferase (AST) were measured before and 24 months after insertion. Results After 24 months of Implanon® insertion, there were no significant changes in portal blood flow, serum albumin, prothrombin time or concentration. However, there was a significant increase in serum levels of total and unconjugated bilirubin and GGT and a significant decrease in ALT and AST levels. All levels, however, remained within the normal range of values. Conclusions Implanon® use for 2 years does not seem to influence portal hemodynamics. Changes in serum levels of bilirubin, GGT, ALT and AST are unlikely to be of clinical significance.

Portal vein pulsatility index is a more important indicator than congestion index in the clinical evaluation of right heart function

To study the changes of portal blood flow in congestive heart failure. We studied the congestion index (CI) and portal vein pulsatility index (PI) in patients with varied degrees of congestive heart failure using ultrasonic Doppler. Ten patients with (mean) right atrial pressure (RA) < 10 mmHg were classified as group 1 and the remaining 10 patients with RA > or = 10 mmHg as group 2. There were no difference on cardiac index (HI, P=0.28), aortic pressure (AO, P=0.78), left ventricular end-diastolic pressure (LVED, P=0.06), (max)imum portal blood velocity (Vmax, P=0.17), (mean) portal blood velocity (Vmean, P=0.15) and portal blood flow volume (PBF, P=0.95) between the two groups. Group 2 patients had higher pulmonary wedge pressure (PW, 29.9+/-9.3 mmHg vs 14.6+/-7.3 mmHg, P=0.002), pulmonary arterial pressure (PA, 46.3+/-13.2 mmHg vs 25.0+/-8.2 mmHg, P=0.004), RA (17.5+/-5.7 mmHg vs 4.7+/-2.4 mmHg, P<0.001), right ventricular end-diastolic pressure (RVED, 18.3+/-5.6 mmHg vs 6.4+/-2.7 mmHg, P<0.001), CI (8.7+/-2.4 vs 5.8+/-1.2, P=0.03), and PI (87.8+/-32.3% vs 27.0+/-7.4%, P<0.001) than Group 1. CI was correlated with PI (P<0.001), PW (P<0.001), PA (P<0.001), RA (P=0.043), RVED (P=0.005), HI (P<0.001), AO (P<0.001), CO (P<0.001), LVED (P<0.001), Vmax (P<0.001), Vmean (P<0.001), cross-sectional area of the main portal vein (P<0.001) and PBF (P<0.001). CI could be as high as 8.3 in patients with RA < 10 mmHg and as low as 5.9 in those with RA > or = 10 mmHg. Our data show that RI is a more significant indicator than CI in the clinical evaluation of high RA > or = 10 mmHg, whereas CI is better than PI in the assessment of left heart function.

Understanding the splenic contribution to portal flow: The role of splenic artery ligation as inflow modification in living donor liver transplantation

Understanding the splenic contribution to portal flow: The role of splenic artery ligation as inflow modification in living donor liver transplantation

Cytochrome P450 enzyme-mediated drug metabolism at exposure to acute hypoxia (corresponding to an altitude of 4,500�m)

To investigate the effect of acute hypoxia and concomitant changes in portal blood flow on the disposition of drugs mainly metabolized by the cytochrome P(450) enzymes (CYP) 3A4 (verapamil) and CYP1A2 (theophylline). Twenty healthy male participants were studied on two 14-h study days in a normobaric hypoxic chamber and were allocated randomly to one of two groups receiving short infusions of either theophylline (6 mg kg (-1) body weight) or verapamil (5 mg) intravenously. According to a randomized, cross-over design, participants were once exposed to normoxia and once to hypoxia (12% oxygen corresponding to the ambient( P)O(2) at an altitude of 4,500 m above sea level). The concentrations of theophylline, 1,3-dimethyluric acid, verapamil, and norverapamil were determined in serial blood samples by means of liquid chromatography-mass spectrometry (LC/MS/MS). Portal blood flow was assessed by transabdominal duplex ultrasonography. Acute hypoxia did not alter the pharmacokinetics of theophylline [half-life+/-SD: 9.29+/-1.77 versus 9.39+/-1.40 (hypoxia)], 1,3-dimethyluric acid (12.9+/-4.72 versus 15.1+/-8.59), verapamil (2.00+/-0.98 versus 1.79+/-0.58), or norverapamil (7.98+/-2.94 versus 9.91+/-6.40). Individual changes of elimination half-life and changes in capillary oxygen saturation,( P)O(2), or portal vein flow were not correlated. Portal vein flow was unaffected by hypoxia. Acute hypoxia corresponding to hypoxia at altitudes of 4,500 m does not impair the metabolism mediated by CYP1A2 or CYP3A4. At rapid ascent to and short-term stay at altitudes up to 4,500 m, the doses of drugs metabolized by these CYPs do therefore not require dose modification, and major changes in the disposition of already administered drugs are not to be expected.

CLINICAL OUTCOME IN SPLANCHNIC HEMODYNAMICS AFTER LIVING DONOR LIVER TRANSPLANTATION.

O22 Aims: To study the outcome of splanchnic and systemic hemodynamics early after living donor liver transplantation. Methods: The influence of hemodynamic changes on liver function was determined as well. Portal vein velocity and diameter were measured prospectively using Doppler-ultrasound in 23 consecutive recipients with cirrhosis, before and 1, 7, 14 and 30 days after living related right lobe liver transplantation. Portal blood flow (PBF) was calculated. Liver function tests were obtained at the same time-periods. Hepatic venous pressure gradient (HVPG) was determined at day 7 and a transyugular liver biopsy was performed. Hemodynamic results were compared with those preoperatively obtained in donors. Results: The mean graft/recipient weight ratio (GRWR) was 1.01±0.23. Fourteen patients were Child B and 9 were Child C. The mean right PBF in recipients at day 1 was significantly higher than in donors (1.55±0.34 vs 0.89±0.26 L/min, p<0.01). The main determinant of elevated PBF in recipients was the increase in right portal vein velocity (86±21 vs 48±13 cm/sec, p<0.01). GRWR did not differ between Child B and C patients. However, PBF was significantly higher in Child C patients (1.61±0.33 vs 1.38±0.35 L/min, p<0.05). PBF decreased significantly at 1 month but did not achieve normal values. When PBF was analyzed in relation to right lobe volume (PBF/RLV), the mean value of this ratio at day 1 significantly correlated with bilirubin value at day 7 (r = 0.78; p<0.01). HVPG at day 7 was increased (8.5±2.7 mmHg) and correlated closely with PBF/RLV at day 1 (r= 0.70; p<0.01). Histological findings were not related to hemodynamic or biochemical changes. Cardiac output was increased at all time-points but did not correlate with PBF or biochemical changes. Conclusions: Portal blood flow markedly increases early after living related right lobe liver transplantation. Changes in splanchnic hemodynamics may influence the outcome of liver function. Doppler ultrasound is a useful tool for the early detection of hemodynamic changes in these patients.

P0227 REPEATED LIVER CELL TRANSPLANTATION VIA PORTH A CATH SYSTEM IN A CHILD

Introduction: Liver cell transplantation is a novel experimental approach for the treatment of inborn errors of liver metabolism. We report a repeated cell infusion approach via a Porth A Cath system for the treatment of an eight year’s old girl with Crigler Najjar Syndrome. Methods: Hepatocytes were isolated from the left liver segment of one female and two male identical donors using the classical two step collagenase perfusion method. Cell recovery accounted for 3.8, 2.1, and 2.15 billions respectively, and viability ranged between 81 & 87 % (Trypan Blue exclusion method). A Porth A Cath system was inserted into a jejunal vein, and the access chamber placed subcutaneously in the left hypochondrion. 1.9 billion fresh isolated hepatocytes were first infused over two hours. The child received then five separate infusions for a total of 4.18 billion hepatocytes. The fourth first infusions used fresh liver cells, whereas cryopreserved cells were infused for the subsequent 5 infusions. The procedure was well tolerated, without any change in portal blood flow and portal pressure following the infusions. She received triple immunosuppression including anti IL2r antibodies (Simulect, Novartis, Bâle, Sw), tacrolimus (Fujisawa, Berlin, G) and steroids. Results: Transplantation efficiency was evaluated by measuring total Bilirubin levels, under identical phototherapy program. Mean bilirubin level during the five years before transplantation were 17.5±0.49 mg/dL. The level dropped to 16.16±0.31 mg/dL after the first infusions * p<0.05 and to 15.08±0.27 mg/dL after the second infusions. Six months after the first infusion, and the total of nine infusions, bilirubin levels had decreased progressively (13.6±0.42 mg/dL *** p<0.001) to reach the lowest value of 11.4 mg/dL. The effect of LCT was however not persistent, and bilirubin returned thereafter to pre- transplant values from month 6 post-LCT. The reason for the loss of metabolic effect could be rejection or apoptosis of transplanted cells. Conclusion: We conclude that liver cell transplantation can be done safely and repeatedly via a permanent portal access system, using a Porth A Cath. Metabolic effect in this case was temporary, which means that repopulation did not occur despite original efficient engraftment.

585 Major changes in portal blood flow and low grade steatosis as new pronostic factors in corticosteroid treated patients with alcoholic hepatitis

585 Major changes in portal blood flow and low grade steatosis as new pronostic factors in corticosteroid treated patients with alcoholic hepatitis