Hepatic Venous Blood Research Articles

Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors.

Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT® delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan-Meier estimation. 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n=11; colorectal carcinoma n=2; pancreatic adenocarcinoma n=2; periampular carcinoma n=2; breast and endometrial cancer each n=1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema. Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS-PHP.

Should Low Central Venous Pressure Be Maintained during Liver Transplantation?

Low central venous pressure, which indirectly reflects free hepatic venous pressure, is maintained during hepatic resection surgery to reduce intraoperative blood loss by facilitating hepatic venous outflow. However, whether the low central venous pressure protocol established for non-transplant hepatobiliary surgery should be generalized to liver transplantation is controversial because patients with cirrhosis have decreased portal and hepatic venous blood flow and vulnerability to renal failure. However, consistent with observations from hepatic resection surgeries, lowering central venous pressure during the preanhepatic phase significantly reduces blood loss and transfusion volume. Conversely, inherent study limitations and different study designs have yielded different results in terms of renal dysfunction. Although hepatic venous outflow promoted by lowering blood volume seems to facilitate a liver graft to accommodate portal blood flow increased by portal hypertension-induced splanchnic vasodilatation, the association between low central venous pressure and reduced incidence of portal hyperperfusion injury has not been demonstrated. Stroke volume variation predicts fluid responsiveness better than central venous pressure, but it has not been associated with a greater clinical benefit than central venous pressure to date. Therefore, the safety of maintaining low central venous pressure during liver transplantation has not been verified, and further randomized controlled studies are warranted to establish a fluid management protocol for each phase of liver transplantation to reduce intraoperative blood loss and transfusion rate, thereby maintaining liver graft viability. In conclusion, low central venous pressure reduces intraoperative blood loss but does not guarantee renoprotection or graft protection.

Safety and efficacy of chemosaturation in patients with primary and secondary liver tumours: A single-centre experience after 54 treatments.

e15625 Background: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT Delivery System; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumours while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyse the safety and efficacy of the second generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Methods: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Results: A total of 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors (ocular melanoma [OM] n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1) and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumours had durable disease stabilisation (40%). Median OS, PFS and hPFS were 261, 117 and 135 days, respectively. Tumour volume negatively correlated with OS. Complications and toxicites included thrombopenia, cardiovascular events, ulcerous bleeding and edema. Conclusions: Second generation CS-PHP seems to be effective and tolerable. Patient selection based on tumour volume end entity is of importance. Particularly patients with OM and hepatobiliary tumours represent promising candidates for CS-PHP.

Physiologic Reduction of Hepatic Venous Blood Flow by the Valsalva Maneuver Decreases Liver Stiffness.

Liver stiffness increases after intake of food or water, suggesting that hepatic venous blood flow affects the results of elastographic measurements. This study investigated the correlation between in vivo liver stiffness and hepatic blood flow using the Valsalva maneuver for reducing intrahepatic venous blood flow. Intrahepatic changes in venous blood flow were assessed by sonography based on the pulsed wave Doppler velocity, vessel diameter assessment, and blood flow volume measurements in the portal vein and right hepatic vein. Time-harmonic elastography at 7 harmonic driving frequencies (30-60 Hz) was used to measure liver stiffness in the right liver lobe of 15 healthy volunteers. The right hepatic vein diameter, flow volume, and peak pulsed wave velocity decreased during the Valsalva maneuver from mean ± SD values of 8.64 ± 1.85 to 6.55 ± 1.84 mm (P = .002), 0.53 ± 0.23 to 0.37 ± 0.26 L/min (P = .037), and 22.14 ± 4.87 to 17.38 ± 5.41 cm/s (P = .01), respectively. This maneuver decreased liver stiffness in all volunteers by a mean of approximately 13% from 1.71 ± 0.22 to 1.48 ± 0.22 m/s (P = .00006). Our results demonstrate that liver stiffness is sensitive to altered venous blood flow, which is of clinical importance when using elastography for evaluation of portal hypertension. Furthermore, our results indicate that accurate measurement of liver stiffness requires standardized breathing conditions to rule out effects of changes in hepatic blood flow on elastographic findings.

Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography

Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) and positron emission tomography (PET). Nine healthy participants and eight patients with varying degrees of cholestasis were examined with 11C-CSar PET and measurement of arterial and hepatic venous blood concentrations of 11C-CSar. Results are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion of 11C-CSar from hepatocytes to bile was 0.36 (0.30-0.62)min-1, 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005-0.07min-1). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min-1, 2.3times higher than the rate constant for backflux to blood (0.05, 0.04-0.09). The increased backflux did not fully normalize exposure of the hepatocyte to bile acids as mean hepatocyte residence time of 11C-CSar was 2.5 (1.6-3.1)min in healthy participants and 6.4 (3.1-23.7)min in patients. The rate constant for transport of 11C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023-0.11)min-1 in healthy participants and only slightly reduced in patients 0.039 (0.017-0.066). This first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease. Positron emission tomography (PET) using the radiolabelled bile acid (11C-CSar) enabled quantification of the individual steps of the hepatic transport of bile acids from blood to bile in man. Cholestasis reduced uptake and secretion and increased backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support therapeutic decisions. The trial is registered at ClinicalTrials.gov (NCT01879735).

Central hemodynamic and splanchnic circulation in children with meningococcal septic shock

Meningococcal infection is caused by the bacterium Neisseria meningitidis (also termed meningococcus). Invasive meningococcal disease remains a rare infectious disease not only with high mortality but also with important morbidity and remains as a leading cause of sepsis and septic shock. The pathogenic mechanisms of microcirculatory disorders in meningococcal septic shock have been subject to controversy. This article presents the results of a study of 11 paediatric patients’ (4 boys and 7 girls) with meningococcal septic shock (Group I) who were hospitalized at the Regional Children's Infectious Hospital from 2009 to 2011. The average age of the patients was 37.4 ± 8.4 mo. Septic shock was diagnosed according to International Pediatric Sepsis Consensus Conference: definitions of criteria for sepsis and organ dysfunction in paediatrics. Heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, average blood pressure, SpO2 were monitored. The cardiac output, ejection fraction, fraction shortening, stroke volume were measured by ultrasound in M-mode by Teichholz method. Blood circulation in the a. mesenterica, a. hepatica, a. lienalis, a. renal sinister, v. porta, v. lienalis, v. renal sinister was determined by impulse Doppler’s wave. Acid-base and electrolytes level in serum, nitric oxide (NO), endothelin I, creatinine, C-reactivity protein and lactate blood level were measured. The control group consisted of 21 healthy children (9 boys and 12 girls), aged 37.5 ± 5.4 mo. in average (Group II). We used t-criteria (Student’s) and correlation with R-criteria (Spearmen) for statistical analysis. The data showed a statistically significant lower fraction of ejection, fraction of shortening, stroke volume in Group I. Moreover, our data showed a statistically high level of mesenterial and portal blood flow rate and high pulse index in v. renal sinister compared to healthy children. The blood level of NO was increased in Group I as well as in Group II. Direct correlations were determined between the level of NO and mesenteric, hepatic arterial and venous blood flow rate. Statistically significant inverse correlations between the level of NO and pulse resistive index in splanchnic vessels were discovered as well as inverse correlations between the NO level and the indicator of the severity of condition on PRISM scale (r = –0.952). At the same time, we have found no correlation between splanchnic circulation value and cardiac output. Based on the results of this study, we consider that NO has organ protective effects in children with meningococcal sepsis. Future research should aim to introduce new strategies of intensive care for patients with meningococcal septic shock with early use of inotrope and NO-donor therapy in fluid restriction combination.

Neutrophil gelatinase-associated lipocalin and cystatin C in cirrhosis and portal hypertension: Relations to organ extraction and dysfunction.

Early detection of renal dysfunction in cirrhosis is important, and several renal biomarkers have been put forward. Neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C are markers of renal dysfunction, but relations to splanchnic and systemic hemodynamics and kinetics are sparsely studied in cirrhosis. In patients with cirrhosis and portal hypertension, we studied plasma levels and renal, hepatic, and peripheral extraction of NGAL and cystatin C and relations to patients characteristics, liver dysfunction, and hemodynamics. Forty-five cirrhotic patients (Child class A/B/C:15/15/15) and 15 controls were evaluated with a full clinical, biochemical, and hemodynamic assessment. Urine and regional plasma concentrations of NGAL and cystatin C were measured. There was no significant difference in circulating or hepatic NGAL or cystatin C between all patients and controls but a trend towards increased levels with increasing Child class. In addition, there was a significant renal but no hepatic or systemic extraction of both NGAL and cystatin C (P < 0.001). Plasma NGAL correlated with glomerular filtration rate (r = -0.56, P < 0.0001), and hepatic venous pressure gradient (r = 0.34,P = 0.02) and urinary NGAL correlated with heart rate (r = 0.58, P= 0.007), blood pressure (r = -0.46, P < 0.05), cardiac output (r = 0.45, P < 0.05), and systemic vascular resistance (SVR) (r = -0.48, p < 0.05). Plasma cystatin C correlated with hepatic venous pressure gradient (r = 0.45, P < 0.005), blood pressure (-0.40, P < 0.01), and glomerular filtration rate (r = 0.98, P < 0.000). Extractions of NGAL and cystatin C levels seem largely unaffected by the severity of liver disease in cirrhosis with a renal extraction. These biomarkers therefore have the potential of being both valuable in diagnosing renal failure and reflecting the degree of portal hypertension and systemic haemodynamic changes.

Lipopolysaccharide-Induced Neutrophil Dysfunction Following Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS) Insertion is Associated with Organ Failure and Mortality

Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised. The objective of this study was to characterise neutrophil function, LPS and cytokine concentrations within the splanchnic circulation of alcoholic cirrhotic patients undergoing TIPSS insertion for variceal haemorrhage and correlate this with outcome. 26 patients with alcoholic cirrhosis and variceal haemorrhage were studied prior to and 1-hour after TIPSS insertion. Neutrophil function, LPS and cytokine concentrations were determined in arterial, hepatic venous (HV) and portal venous blood (PV). Significantly higher LPS concentrations and neutrophil reactive oxidant species (ROS) production were observed in PV vs HV blood. Cross-incubation of HV plasma with PV neutrophils resulted in reduced ROS production. Insertion of TIPSS was associated with a significant increase in arterial LPS concentrations and deterioration in neutrophil phagocytosis. Number of organ failures and arterial IL-6 concentrations at presentation were associated with increased mortality. The portal circulation has a distinct immunological milieu characterised by a pathological neutrophil phenotype and an anti-inflammatory cytokine profile associated with heightened LPS levels. TIPSS insertion renders this neutrophil functional defect systemic, associated with an increase in arterial LPS and a susceptibility to sepsis.

Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans

Animal studies indicated that systemic ophthalmic acid (OPH) is a biomarker for hepatic glutathione (GSH) homeostasis, an important determinant of liver function. We aimed to clarify whether OPH levels can be used as a read-out for hepatic GSH homeostasis after paracetamol (APAP) challenges during pylorus-preserving pancreaticoduodenectomy (PPPD) or partial hepatectomy (PH). Nineteen patients undergoing PPPD (n=7, control group) or PH (n=12) were included. APAP (1000 mg) was administered intravenously before resection (first challenge), and six and twelve hours later, with sequential blood sampling during this period. Arterial, hepatic and portal venous blood samples and liver biopsies were taken on three occasions during the first APAP challenge. Plasma and hepatic OPH and GSH levels were quantified, and venous-arterial differences were calculated to study hepatic release. Systemic GSH levels decreased during the course of the APAP challenge in both surgical groups, without notable change in OPH levels. Hepatic GSH and OPH content was not affected within ˜3 hours after administration of the first APAP dose in patients undergoing PPPD or PH. In this period, net release of OPH by the liver was observed only in patients undergoing PPPD. The drop in circulating GSH levels following APAP administrations, did not result in an increase in plasma OPH in both patients with an intact liver and in those undergoing liver resection. Hepatic content of GSH and OPH was not affected during the first APAP dose. It is uncertain whether hepatic GSH homeostasis was sufficiently challenged in the present study. In the present study, plasma OPH seemed not useful as a marker for GSH depletion because APAP administration during liver surgery did not lead to (immediate) GSH depletion or increased OPH levels. Based on stable levels of hepatic GSH, OPH and thiyl radicals during surgery, standard APAP administration seems to be safe in a postoperative care program with regards to GSH homeostasis in this specific population. However, no general statements can be made on the basis of the current experiment, since GSH homeostasis and susceptibility to xenobiotic toxicity are influenced by several metabolic and genetic factors.

The influence of PEEP and positioning on central venous pressure and venous hepatic hemodynamics in patients undergoing liver resection.

In order to assess the occurrence of blood congestion in the liver during liver resection, we aimed to evaluate the influence of a positive-end-expiratory-pressure (PEEP) and positioning of patients on central venous pressure (CVP) and venous hepatic blood flow parameters. We further analyzed correlations between CVP and venous hepatic blood flow parameters. In 20 patients scheduled for elective liver resection we measured CVP and quantified venous hepatic hemodynamics by ultrasound assessment of flow-velocity and diameter of the right hepatic vein and the portal vein after equilibration following these maneuvers: M1: 0° supine position, PEEP 0cmH2O; M2: 0° supine position, PEEP 10cmH2O; M3: 20° reverse-trendelenburg position; PEEP 10cmH2O; M4: 20° reverse-trendelenburg position, PEEP 0cmH2O. Changing from supine to reverse-trendelenburg position led to a significant decrease in CVP (M3 5.95 ± 2.06 vs. M1 7.35 ± 2.18mmHg and M2 8.55 ± 1.79mmHg). A PEEP of 10cmH2O and reverse-trendelenburg position led to significant reduction of systolic (VsHV) and diastolic (VdHV) flow-velocities of the right hepatic vein (VsHV M3 19.96 ± 6.47 vs. M1 27.81 ± 11.03cm s-1;VdHV M3 14.94 ± 6.22 vs. M1 20.15 ± 10.34cm s-1 and M2 20.19 ± 13.19cm s-1) whereas no significant changes of flow-velocity occurred in the portal vein. No correlations between CVP and diameters or flow-velocities of the right hepatic and the portal vein were found. Changes of central venous pressure due to changes of PEEP and positioning were not correlated with changes of venous hepatic blood flow parameters as measured after equilibration. Strategies aiming for low central venous pressure cannot be supported by these results. However, before ruling out low-CVP-strategies during liver resections these results should be confirmed by further studies.

The portal‐drained viscera release fibroblast growth factor 19 in humans

Fibroblast growth factor 19 (FGF19) is an ileum‐derived endrocrine factor that is produced in response to transepithelial bile salt flux. FGF19 represses bile salt synthesis in the liver. Despite the general assumption that FGF19 signals to the liver via portal blood, no human data are available to support this notion. The aim was to study portal FGF19 levels, and determined bile salt and FGF19 fluxes across visceral organs in humans. Bile salt and FGF19 levels were assessed in arterial, portal, and hepatic venous blood collected from fasted patients who underwent partial liver resection for colorectal liver metastases (n = 30). Fluxes across the portal‐drained viscera (PDV), liver, and splanchnic area were calculated. Portal bile salt levels (7.8 [5.0–12.4] μmol/L) were higher than levels in arterial (2.7 [1.7–5.5] μmol/L, P < 0.0001) and hepatic venous blood (3.4 [2.5–6.5] μmol/L, P < 0.0001). Bile salts released by the PDV (+1.2 [+0.7–+2.0] mmol kg−1 h−1, P < 0.0001) were largely taken up by the liver (−1.0 [−1.8 to −0.4] mmol kg−1 h−1, P < 0.0001). Portal levels of FGF19 (161 ± 78 pg/mL) were higher than arterial levels (135 ± 65 pg/mL, P = 0.046). A net release of FGF19 by the PDV (+4.0 [+2.1 to +9.9] ng kg−1 h−1, P < 0.0001) was calculated. There was no significant flux of FGF19 across the liver (−0.2 [−3.7 to +7.4] ng kg−1 h−1, P = 0.93). In conclusion, FGF19 levels in human portal blood are higher than in arterial blood. FGF19 is released by the portal‐drained viscera under fasted steady state conditions.

What Is Causing This Patientʼs Acute Liver Failure

Introduction: Acute liver failure remains one of the most difficult challenges in ever day medicine. This case describes an acute and unusual presentation of a rare cause of acute liver failure. Case presentation: A 61 year old male presented with 3 weeks complain of worsening lower extremities edema and right upper quadrant (RUQ) pain. Past medical history consists of chronic back pain and hypertension. He is a previous heavy smoker with 45 pack year. He does not abuse alcohol. Initial vital signs were within normal range. Physical examination showed jaundice, hepatomegaly, RUQ tenderness and bilateral pretibial edema. Liver function tests were significant for rapid deterioration over the course of 12 days of hospitalization. T.bilirubin raises from 2.3 to 8.9 (direct up to 7.4), progressive rise of ALT up to 350 IU/l, AST up to 207 IU/l, ALP at 368 IU/l and ammonia of 137 mcg/dl. PT/INR and acetaminophen level were normal. Viral and autoimmune serologies were negative. Ferritin was high at 1915 mcg/L along with high ferritin saturation at 63%. CT chest revealed 2 nonspecific ground glass opacities in the left upper lobe, the largest was 2.2cm. CT abdomen revealed hepatomegaly without any intrahepatic nodular lesions. Abdominal US with Doppler showed 7 mm gall bladder wall thickness and normal hepatic and portal venous blood flow. MRCP was unremarkable. Transcutaneous liver biopsy was performed for further evaluation of worsening LFTs and revealed metastatic small cell carcinoma. Patient subsequently deteriorated with further worsening of liver function test and development of hepatic encephalopathy. Family decided on comfort measures and patient died 12 days after hospitalization. Discussion Fulminant hepatic failure (FHF) is characterized by the development of severe liver injury with impaired synthetic capacity and encephalopathy in patients with previous normal liver. Most common causes are viral hepatitis, drug toxicity, ischemia or vascular thrombosis. Malignancy causing acute hepatic failure is rare but must be considered to avoid inappropriate referral for transplantation. There have been reported cases of Small Cell lung Carcinoma presenting as FHF. In some of them the diagnosis of metastasis to liver were made histologically after death with no nodular lesions visible in the liver using a contrast-enhanced CT scan. However, there have been reported cases of Extra Pulmonary Small Cell Cancer which could be the case in this patient.

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.

Circulating lipocalin 2 is neither related to liver steatosis in patients with non-alcoholic fatty liver disease nor to residual liver function in cirrhosis

Lipocalin 2 (LCN2) is induced in the injured liver and associated with inflammation. Aim of the present study was to evaluate whether serum LCN2 is a non-invasive marker to assess hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD) or residual liver function in patients with liver cirrhosis. Therefore, LCN2 was measured by ELISA in serum of 32 randomly selected patients without fatty liver (controls), 24 patients with ultrasound diagnosed NAFLD and 42 patients with liver cirrhosis mainly due to alcohol. Systemic LCN2 was comparable in patients with liver steatosis, those with liver cirrhosis and controls. LCN2 negatively correlated with bilirubin in both cohorts. In cirrhosis, LCN2 was not associated with more advanced liver injury defined by the CHILD-PUGH score and model for end-stage liver disease score. Resistin but not C-reactive protein or chemerin positively correlated with LCN2. LCN2 levels were not increased in patients with ascites or patients with esophageal varices. Consequently, reduction of portal pressure by transjugular intrahepatic portosystemic shunt did not affect LCN2 levels. Hepatic venous blood (HVS), portal venous blood and systemic venous blood levels of LCN2 were similar. HVS LCN2 was unchanged in patients with end-stage liver cirrhosis compared to those with well-compensated disease arguing against increased hepatic release. Current data exclude that serum LCN2 is of any value as steatosis marker in patients with NAFLD and indicator of liver function in patients with alcoholic liver cirrhosis.

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C-Cholylsarcosine PET.

The aim of this study was to develop a method for the quantification of hepatobiliary uptake and secretion of conjugated bile acids with PET and the (11)C-labeled conjugated bile acid analog [N-methyl-(11)C]cholylsarcosine ((11)C-CSar). Six pigs (13 experiments) underwent dynamic (11)C-CSar PET of the liver with simultaneous measurements of hepatic blood perfusion and (11)C-CSar concentrations in arterial, portal, and hepatic venous blood. In 3 pigs (7 experiments), bile was collected from a catheter in the common hepatic duct. PET data were analyzed with a 2-tissue compartmental model with calculation of rate constants for the transport of (11)C-CSar among blood, hepatocytes, and intra- and extrahepatic bile ducts. PET results were validated against invasive blood and bile measurements. The directly measured rate of secretion of (11)C-CSar into bile was equal to the rate of removal from blood at steady state. Accordingly, hepatocytes did not accumulate bile acids but simply facilitated the transport of bile acids from blood to bile against a measured concentration gradient of 4,000. The rate constant for the secretion of (11)C-CSar from hepatocytes into bile in experiments with a catheter in the common hepatic duct was 25% of that in experiments without a catheter (P < 0.05); we interpreted this result to be mild cholestasis caused by the catheter. The catheter caused an increased backflux of (11)C-CSar from hepatocytes to blood, and hepatic blood flow was 25% higher than in experiments without the catheter. The capacity for the overall transport of (11)C-CSar from blood to bile, as quantified by intrinsic clearance, was significantly lower in experiments with the catheter than in those without the catheter (P < 0.001). PET and blood measurements correlated significantly (P < 0.05). The in vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic (11)C-CSar PET.

Environmental Factors Responsible for Variability of Hepatic Vein Flow: A Doppler Assessment in Healthy Twins.

Doppler interrogation studies of the liver blood flow indicate altered hepatic vein waveforms in association with impaired hepatocellular function. However, little is known about the mechanisms responsible for variations of these parameters in the absence of disease. We aimed to investigate the contribution of heritable and environmental factors to the physiological variability of hepatic vein flow in a twin cohort. Two hundred twenty-eight healthy adult Hungarian twins (69 monozygotic, 45 same-sex dizygotic pairs) underwent Doppler sonography of the hepatic vein. Age- and sex-adjusted heritability of the highest velocity (amplitude of S wave) of hepatic vein flow was negligible. Shared environment contributed to 33% (95% CI, 16%-51%), and unshared environment was responsible for the largest portion (67%; 95% CI, 49%-84%) of the variance. Duration of sports activities was significantly (P < 0.05) related to the magnitude of hepatic vein flow, while other risk factors and lifestyle characteristics had no significant influence. The data suggest that genetic factors have little impact on the parameters of hepatic venous blood flow. The variability observed in healthy twins by the Doppler interrogation can be explained by the effect of unshared environmental components primarily related to regular physical activity. These findings underscore the importance of unique environments in physiological variations of hepatic venous blood flow.

Metastatic Spread Emerging From Liver Metastases of Colorectal Cancer: Does the Seed Leave the Soil Again?

To investigate whether liver metastases contribute to metastatic spread of colorectal cancer (CRC) by shedding intact tumor cells. Metastases represent the primary cause of death in CRC. Understanding the metastatic activity of metastases and which patients are at high risk for tumor cell dissemination may, therefore, have significant influence on cancer care in the future. Circulating tumor cells (CTCs) were detected in the hepatic inflow (portal venous blood [PVB]) and outflow compartment (hepatic venous blood [HVB]) of a training (n = 55) and validation (n = 50) set using the CellSearch system. Isolated CTC from the HVB were subjected to gene expression analyses by quantitative polymerase chain reaction. CTC detection rate (37.2% vs 19.6%; P = 0.04) and count (mean: 12.7, SEM: ± 5.9 vs 1.9; ± 1.2; P = 0.01) were significantly higher in HVB compared to PVB. The increased CTC detection rate (54% vs 11.4%; P < 0.001) and CTC count (14.7 ± 5.1 vs 1.1 ± 0.6; P < 0.001) in the HVB compared to the PVB compartment was confirmed in the validation cohort. Expression of epithelial markers and genes involved in cell-to-cell and cell-to-matrix adhesion was reduced in CTC compared to tumor cells in liver metastases. Metastasis size greater than 5 cm was associated with CTC shedding from established liver metastases in the training and validation cohorts. Colorectal liver metastases shed intact tumor cells with an invasive phenotype. Metastasis size serves as a surrogate marker for metastatic activity of colorectal liver metastases.

Peripheral and Hepatic Vein Cytokine Levels in Correlation with Non-Alcoholic Fatty Liver Disease (NAFLD)-Related Metabolic, Histological, and Haemodynamic Features.

BackgroundHaemodynamic impairment, inflammatory mediators and glucose metabolism disturbances have been implicated in the pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD).AimTo investigate the cytokine profile in NAFLD patients in peripheral (P) and hepatic venous (HV) blood and to compare with histology, haemodynamic and metabolic parameters.Methods40 obese patients with an indication for a transjugular liver biopsy were enrolled. Besides an extended liver and metabolic work-up, interleukin (IL) 1B, IL4, IL6, IL10, IL23, tumour necrosis factor (TNF) α and interferon (INF) γ were measured in plasma obtained from P and HV blood by means of multiplex immunoassay. The T helper (Th)1/Th2, the macrophage M1/M2 and the IL10/IL17a ratios were calculated.ResultsA decrease of the P-IL10/IL17-ratio and an increase of the P-M1/M2-ratio (p<0.05) were observed in NASH versus no-NASH patients. A P-M1/M2-ratio increase was detected also in patients with portal hypertension in comparison with patients without it (p<0.05). Moreover diabetic patients showed an increase of the P-Th1/Th2-ratio in comparison with non-diabetic ones (p<0.05). The P-M1/M2 ratio positively correlated with steatosis grade (r = 0.39, p = 0.02) and insulin (r = 0.47, p = 0.003). The HV-M1/M2 ratio positively correlated with fasting insulin and Hepatic Venous Pressure Gradient (r = 0.47, p = 0.003). IL6 correlated with the visceral fat amount (r = 0.36, p = 0.02). The P- and HV-IL10/IL17 ratios negatively correlated with fasting insulin (respectively r = -0.4, p = 0.005 and r = 0.4, p = 0.01).ConclusionsA proinflammatory cytokine state is associated with more disturbed metabolic, histological, and haemodynamic features in NAFLD obese patients. An increase of the M1/M2 ratio and a decrease of the IL10/IL17 ratio play a key role in this process.

Endothelin 1 and transforming growth factor-β1 correlate with liver function and portal pressure in cirrhotic patients

ObjectiveThe invasive measurement of hepatic venous pressure gradient is the recommended method for the assessment of portal hypertension. We assessed if the mediators that regulate portal hypertension may be used as noninvasive markers of portal hypertension and liver insufficiency. Materials and methodsWe explored in prospective, observational study the concentration of endothelin-1, nitric oxide, and transforming growth factor-β1/2 in peripheral and hepatic venous blood; their relationship with the values of portal hypertension and liver insufficiency; and their level changes 4–6months after non-selective beta-blocker therapy in cirrhotic patients with non-bleeding esophageal varices. Results(1) Cirrhotics have significantly increased peripheral endothelin 1 and decreased transforming growth factor-β1 levels; (2) peripheral levels of all factors correlated significantly with their hepatic levels; (3) after therapy, peripheral endothelin-1 levels significantly increased, but transforming growth factor-β2 levels decreased and were lower in patients with pressure gradient value normalization; (4) before and after therapy, peripheral and hepatic endothelin-1, transforming growth factor-β1/2 levels correlated significantly with liver failure indicators (laboratory parameters, Child-Pough and MELD scores) and pressure gradient values. ConclusionsPeripheral endothelin-1 and transforming growth factor-β1 levels, which strongly correlate with their hepatic levels, reflect the stage of portal hypertension and liver insufficiency in cirrhosis.

Primary malignant hepatic paraganglioma mimicking liver tumor: A case report.

An extra-adrenal pheochromocytoma is also known as a paraganglioma. The present study reported the case of a 47-year-old female patient with an extremely rare primary nonfunctioning hepatic paraganglioma without any clinical signs and symptoms. A computed tomography scan of the entire abdomen region revealed a hyper-enhanced, well-marginated round mass located in segment 3 of the liver. A preoperative diagnosis of hepatocellular carcinoma was established and a left lateral hepatic lobectomy was performed. During the removal of the mass, the patient experienced extreme fluctuations in blood pressure. Analysis of hepatic and peripheral venous blood test results confirmed the increase of noradrenaline secretion. Postoperatively, the patient's blood pressure and catecholamine level returned to the normal range. However, three years after surgery, a plasma catecholamine examination revealed a high noradrenaline level. Abdominal magnetic resonance imaging scans revealed two metastases, located in the spleen and below the right posterior lobe of the liver, which were identified as malignant paragangliomas. Therefore, the patient was diagnosed with primary malignant hepatic paraganglioma recurrence three years after hepatic resection.