Hepatic Hemodynamics Research Articles

The effects of proton pump inhibitor on hepatic vascular responsiveness and hemodynamics in cirrhotic rats

BackgroundLiver cirrhosis is associated with increased intrahepatic resistance due to hepatic fibrosis and exaggerated vasoconstriction. Recent studies have indicated that proton pump inhibitors (PPIs), in addition to acid suppression, modulate vasoactive substances and vasoresponsiveness. PPIs are frequently prescribed in patients with cirrhosis due to a higher prevalence of peptic ulcers, however other impacts are unknown. MethodsLiver cirrhosis was induced in Sprague–Dawley rats with common bile duct ligation (BDL). On the 29th day after BDL and after hemodynamic measurements, the intrahepatic vascular responsiveness to high concentrations of endothelin-1 (ET-1) was evaluated after preincubation with (1) Krebs solution (vehicle), (2) esomeprazole (30 μM), or (3) esomeprazole plus Nω-nitro l-arginine (NNA, a non-selective NO synthase (NOS) inhibitor, 10−4 M). After perfusion, the hepatic protein expressions of endothelial NOS (eNOS), inducible NOS (iNOS), cyclooxygenase (COX)-1, COX-2, endothelin-1, DDAH-1 (dimethylarginine dimethylaminohydrolase-1, ADMA inhibitor), DDAH-2, ADMA (asymmetrical dimethyl arginine, NOS inhibitor) were evaluated. In the chronic model, the BDL rats received (1) vehicle; or (2) esomeprazole (3.6 mg/kg/day, oral gavage) from the 1st to 28th day after BDL. On the 29th day and after hemodynamic measurements, plasma liver biochemistry and liver fibrosis were evaluated. ResultsEsomeprazole did not affect hepatic ET-1 vasoresponsiveness. The hepatic protein expressions of the aforementioned factors were not significantly different among the groups. There were no significant differences in hemodynamics, liver biochemistry and hepatic fibrosis after chronic esomeprazole administration. ConclusionPPIs did not affect hepatic vasoresponsiveness or the release of vasoactive substances. Furthermore, they did not influence hemodynamics, liver biochemistry or severity of hepatic fibrosis in the cirrhotic rats.

Intra-operative portal hemodynamics in pediatric LDLT: Doppler ultrasound surveillance.

Doppler ultrasonography is useful in monitoring intra-operative PV flow in LDLT. A retrospective cohort study included 550 pediatric recipients (<18years) who underwent LDLT from October 2006 to August 2016 in our hospital. A total of 33 recipients (incidence 6%) were found to have insufficient intra-operative PV flow after PV reperfusion. The treatments included intra-operative stent placement (n=25), anticoagulation (n=3), thrombectomy and re-anastomosis (n=2), graft repositioning (n=1), collateral ligation (n=1), and replaced PV (n=1). The peak PV velocity, HAPSV, HARI, and HV velocity before and after the interventions were significantly improved 0(0,5.5) cm/s vs. 37.36±15.30cm/s, 38.68±8.92cm/s vs. 62.30±16.97cm/s, 0.55±0.08 vs. 0.76±0.10, and 32.37±10.33cm/s vs. 40.94±15.01cm/s, respectively (P<.01). Insufficient PV flow and decreased HARI are two significant criteria indicating need for intra-operative PV management. Dramatic changes in the hepatic hemodynamics were detected after proper treatment. Immediate resolution of PV flow is feasible in pediatric LDLT.

Numerical zero-dimensional hepatic artery hemodynamics model for balloon-occluded transarterial chemoembolization.

Balloon-occluded transarterial chemoembolization (B-TACE) is a valuable treatment option for patients with inoperable malignant tumors in the liver. Balloon-occluded transarterial chemoembolization consists of the transcatheter infusion of an anticancer drug mixture and embolic agents. Contrary to conventional TACE, B-TACE is performed via an artery-occluding microballoon catheter, which makes the blood flow to redistribute due to the intra- and extrahepatic arterial collateral circulation. Several recent studies have stressed the importance of the redistribution of blood flow in enhancing the treatment outcome. In the present study, the geometries of a representative hepatic artery and the communicating arcades (CAs) are modeled. An in silico zero-dimensional hemodynamic model is created by characterizing the geometry and the boundary conditions and then is validated in vitro. The role of CAs is assessed by combining 2 cancer scenarios and 2 catheter locations. The importance of the diameter of the CAs is also studied. Results show that occluding a main artery leads to collateral circulation and CAs start to play a role in blood-flow redistribution. In summary, numerical zero-dimensional simulations permit a fast and reliable approach for exploring the blood-flow redistribution caused by the occlusion of a main artery, and this approach could be used during B-TACE planning.

Compartment model analysis of intravenous contrast-enhanced dynamic computed tomography in hepatic hemodynamics: A validation study using intra-arterial contrast-enhanced computed tomography.

To verify the utility of the 2-in-1-out-compartment model analysis (CMA) of intravenous contrast-enhanced dynamic computed tomography (IV-CT) for evaluating hepatic arterial and portal venous flow using intra-arterial contrast-enhanced CT (IA-CT). We retrospectively evaluated 49 consecutive patients who underwent IV-CT and were radiologically or histologically diagnosed as having hepatic malignant lesion (51 classical hepatocellular carcinomas [HCC], 4 early HCC, 3 cholangiolocellular carcinomas, 1 mixed HCC, 3 cholangiocellular carcinomas). As a gold standard for hepatic arterial and portal blood flows, we defined the normalized enhancement in CT values on CTAP (nCTAP) and CTHA (nCTHA). The hepatic arterial (k1a ) and portal venous inflow velocity (k1p ) constants in hepatic lesions and surrounding liver parenchyma were obtained from the CMA of IV-CT with various outflow velocity constant (k2 ) limits using the nonlinear least square method. The correlation coefficient between the normalized enhancement in IA-CT and CMA of IV-CT was statistically evaluated according to various k2 limits. The highest mean correlation coefficient between k1a and nCTHA (r = 0.65, P < 0.0001) was observed when k2 ≦0.035. The highest mean correlation coefficient between k1p and nCTAP (r = 0.69, P < 0.0001) was observed when k2 ≦0.045. The decrease in correlation coefficient was significant when the upper k2 limit was lower than 0.03 or higher than 0.07 compared to the best mean correlation coefficient (P < 0.05). Hepatic arterial and portal venous flows can be evaluated quantitatively to some extent with appropriate outflow velocity constant limits using the CMA of IV-CT.

Vasopressin and nitroglycerin decrease portal and hepatic venous pressure and hepato-splanchnic blood flow.

Various methods are used to reduce venous blood pressure in the hepato-splanchnic circulation, and hence minimise blood loss during liver surgery. Previous studies show that combination of vasopressin and nitroglycerin reduces portal pressure and flow in patients with portal hypertension, and in this study we investigated this combination in patients with normal portal pressure. In all, 13 patients were studied. Measurements were made twice to confirm baseline (C1 and BL), during vasopressin infusion 4.8 U/h (V), and during vasopressin infusion combined with nitroglycerin infusion (V + N). Portal venous pressure (PVP), hepatic venous pressure (HVP), central haemodynamics and arterial and venous blood gases were obtained at each measuring point, and portal (splanchnic) and hepato-splanchnic blood flow changes were calculated. Vasopressin alone did not affect PVP, whereas HVP increased slightly. In combination with nitroglycerin, PVP decreased from 10.1 ± 1.6 to 8.9 ± 1.3 mmHg (P < 0.0001), and HVP decreased from 7.9 ± 1.9 to 6.2 ± 1.3 mmHg (P = 0.001). Vasopressin reduced portal blood flow by 47 ± 19% and hepatic venous flow by 11 ± 18%, respectively. Addition of nitroglycerin further reduced portal- and hepatic flow by 55 ± 13% and 30 ± 13%, respectively. Vasopressin alone had minor effects on central haemodynamics, whereas addition of nitroglycerin reduced cardiac index (3.2 ± 0.7 to 2.7 ± 0.5; P < 0.0001). The arterial-portal vein lactate gradient was unaffected. The combination of vasopressin and nitroglycerin decreases portal pressure and hepato-splanchnic blood flow, and could be a potential treatment to reduce bleeding in liver resection surgery.

Closed-Loop Lumped Parameter Modeling of Hemodynamics During Cirrhogenesis in Rats.

Cirrhosis is the common end stage of any given chronic liver disease, developing after persistent destruction and regeneration of parenchymal liver cells. The associated architectural distortion increases the intrahepatic vascular resistance, leading to portal hypertension and systemic circulatory disorders. This study investigates the impact of the changing vascular resistances on the hepatic and global circulation hemodynamics during cirrhogenesis. Cirrhogenesis was revisited using the thioacetamide rat model (N = 20). Rats were sacrificed at weeks 0, 6, 12, and 18. For each time-point, three-dimensional vascular geometries were created by combining hepatic vascular corrosion casting with μCT imaging. Morphological quantification of the trees branching topology provided the input for a lobe-specific lumped parameter model of the liver that was coupled to a closed-loop model of the entire circulation of the rat. Hemodynamics was simulated in physiological and pathological circumstances. The simulations showed the effect of the liver vascular resistances (driven by the hepatic venous resistance increase) on liver hemodynamics with portal hypertension observed after 12 weeks. The closed-loop model was further adapted to account for systemic circulatory compensation mechanisms and disorders frequently observed in cirrhosis and simulated their impact on the hepatic, systemic, and pulmonary hemodynamics. The simulations explain how vascular changes due to cirrhosis severely disrupt both hepatic and global hemodynamics. This study is a priori the first to model the rat's entire blood circulation during cirrhogenesis. Since it is able to simulate cirrhosis main characteristics, the model may be translated to humans for the assessment of liver interventions.

Liver and systemic hemodynamics in children with cirrhosis: Impact on the surgical management in pediatric living donor liver transplantation.

Cirrhosis in adults is associated with modifications of systemic and liver hemodynamics, whereas little is known about the pediatric population. The aim of this work was to investigate whether alterations of hepatic and systemic hemodynamics were correlated with cirrhosis severity in children. The impact of hemodynamic findings on surgical management in pediatric living donor liver transplantation (LT) was evaluated. Liver and systemic hemodynamics were studied prospectively in 52 children (median age, 1 year; 33 with biliary atresia [BA]). The hemodynamics of native liver were studied preoperatively by Doppler ultrasound and intraoperatively using invasive flowmetry. Portosystemic gradient was invasively measured. Systemic hemodynamics were studied preoperatively by Doppler transthoracic echocardiography and intraoperatively by using transpulmonary thermodilution. Hemodynamic parameters were correlated with Pediatric End-Stage Liver Disease (PELD) score and the histological degree of fibrosis (collagen proportionate area [CPA]). Cirrhosis was associated with a 60% reduction of pretransplant total liver flow (n = 46; median, 36 mL/minute/100 g of liver) compared with noncirrhotic livers (n = 6; median, 86 mL/minute/100 g; P = 0.002). Total blood flow into the native liver was negatively correlated with PELD (P < 0.001) and liver CPA (P = 0.005). Median portosystemic gradient was 14.5 mm Hg in children with cirrhosis and positively correlated with PELD (P < 0.001). Portal vein (PV) hypoplasia was observed mainly in children with BA (P = 0.02). Systemic hemodynamics were not altered in our children with cirrhosis. Twenty-one children met the intraoperative criteria for PV reconstruction using a portoplasty technique during the LT procedure and had a smaller PV diameter at pretransplant Doppler ultrasound (median = 3.4 mm; P < 0.001). Cirrhosis in children appears also as a hemodynamic disease of the liver, correlated with cirrhosis severity. Surgical technique for PV reconstruction during LT was adapted accordingly. Liver Transplantation 23 1440-1450 2017 AASLD.

A computational model of the hepatic circulation applied to analyze the sensitivity of hepatic venous pressure gradient (HVPG) in liver cirrhosis

Measurement of hepatic venous pressure gradient (HVPG) is currently widely adopted to provide an estimate of portal pressure gradient (PPG) in the diagnosis and treatment of portal hypertension associated with liver cirrhosis. Despite the well-documented clinical utility of HVPG, it remains poorly understood how the relationship between HVPG and PPG is affected by factors involved in the pathogenesis and progression of cirrhosis. In the study, a computational model of the hepatic circulation calibrated to in vivo data was developed to simulate the procedure of HVPG measurement and quantitatively investigate the error of HVPG relative to PPG under various pathophysiological conditions. Obtained results confirmed the clinical consensus that HVPG is applicable to the assessment of portal hypertension caused by increased vascular resistance located primarily at the sinusoidal and postsinusoidal sites rather than at the presinusoidal site. On the other hand, our study demonstrated that the accuracy of HVPG measurement was influenced by many factors related to hepatic hemodynamics even in the case of sinusoidal portal hypertension. For instance, varying presinusoidal portal vascular resistance significantly altered the difference between HVPG and PPG, while an enhancement in portosystemic collateral flow tended to improve the accuracy of HVPG measurement. Moreover, it was found that presinusoidal and postsinusoidal vascular resistances interfered with each other with respect to their influence on HVPG measurement. These findings suggest that one should take into account patient-specific pathological conditions in order to achieve a better understanding and utilization of HVPG in the clinical practice.

Hepatic Hemodynamics and Portal Flow Modulation: The A2ALL Experience.

A principal aim of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study was to study hepatic blood flow and effect of portal flow modulation on graft outcomes in the setting of increasing use of smaller and left lobe grafts. Recipients of 274 living donor liver transplant were enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, including 233 (85.0%) right lobes, 40 (14.6%) left lobes, and 1 (0.5%) left lateral section. Hepatic hemodynamics were recorded after reperfusion. A total of 57 portal flow modulations were performed on 52 subjects. Modulation lowered portal pressure in 68% of subjects with inconsistent effects on hepatic arterial and portal flow. A higher rate of graft dysfunction was observed in modulated vs. unmodulated subjects (31% vs. 18%; P = 0.03); however, graft survival in modulated subjects was not different from unmodulated subjects at 3 years. These results suggest the need for a study using a prespecified portal flow modulation protocol with defined indications to better define the effects of these interventions.

Mycosis Fungoides of the Liver

The following case describes a patient with hepatic mycosis fungoides with lack of concurrent cutaneous involvement. A 66-year-old woman presented to an outpatient clinic with an unintentional thirty-pound weight loss over a six-month period. Past medical history was most notable for cutaneous mycosis fungoides treated with total body light therapy over ten years prior with complete remission of symptoms. EGD and colonoscopy were performed given the weight loss and these displayed large gastric and esophageal varices. A CT abdomen/pelvis showed a nodular liver contour, esophageal, paraesophageal, and omental varices with a dilated portal vein. The patient underwent a transjugular liver biopsy with hepatic hemodynamics showing a hepatic portal venous gas of 8-10 mmHg and pathology revealing a clonal population of T-cell rearrangement infiltrate. The patient was referred to hematology for possible hepatic T-cell lymphoma, however liver biopsy staining, bone marrow biopsy, and a PET scan demonstrated findings most consistent with mycosis fungoides of the liver. Mycosis fungoides is an uncommon variant of non-Hodgkin lymphoma of T cell origin with unknown etiology. Though it is most commonly characterized by cutaneous manifestations, it can ultimately involve the blood, lymph nodes, and visceral organs. Lymph nodes are the most commonly affected extracutaneous site, but hepatic, splenic and renal involvement has been documented in the literature. While extracutaneous disease typically correlates with extent of skin lesions, there may be lack of concurrent cutaneous and visceral involvement, as with our patient. With hepatic mycosis fungoides, there are often no overt clinical signs of liver dysfunction, so clinicians must be aware of the patient's past medical history in order to facilitate an early, accurate diagnosis.

THE COMPARATIVE ANALYSIS OF THE CLINICAL AND LABORATORY INDICATORS AND RHEOHEPATHOGRAPHY IN PATIENTS WITH MECHANICAL JAUNDICE, LIVER CIRRHOSIS, AND MULTIPLE ORGAN DYSFUNCTION SYNDROME

Objective: to identify changes of indicators of tetrapolar rheohepathography (RHG) in patients with mechanical jaundice, liver cirrhosis, and multiple organ dysfunction syndrome (MODS) taking into account the comparative assessment of their clinical and laboratory indicators. Material and methods . The clinical and laboratory parameters and results of RHG were analyzed in 73 patients undergoing treatment from December 2015 to June 2017. Four groups were singled out: 1-st (control) - 27 patients with limb fractures, somatically practically healthy; 2-nd - 11 patients with mechanical jaundice; 3-rd - 14 patients with liver cirrhosis; 4-th - 21 patients with MODS. Results. It has been established that the parameters of RHG come back to normal within the first 24 hours after the surgical intervention to eliminate mechanical jaundice, despite the presence of an increased level of general bilirubin and cytolysis syndrome. The greatest degradation of the RHG parameters was diagnosed in the patients of the groups with liver cirrhosis and MODS. Conclusion. The parameters of RHG in patients with mechanical jaundice, liver cirrhosis, and MODS differ, which indicates different pathogenesis of the development of hepatic hemodynamics disorders in these conditions.

A sonographic Doppler study of the hepatic vein, portal vein and hepatic artery in liver cirrhosis: Correlation of hepatic hemodynamics with clinical Child Pugh score in Singapore.

Liver cirrhosis has been a rising complication of chronic liver disease in Singapore. Ultrasound has been widely accepted as a non-invasive imaging modality for the evaluation of hepatic haemodynamics. This study aims to correlate the Doppler ultrasound values with the progression of liver cirrhosis to allow further understanding and possible prediction of clinical events for timely intervention. Study sample of 56 eligible patients with liver cirrhosis was divided according to their Child-Pugh clinical score into Child's A (n = 29 patients), B (n = 19 patients) and C (n = 8 patients). The maximum portal vein velocity, maximum hepatic vein velocity, maximum hepatic artery velocity and hepatic artery resistive index were assessed by Doppler ultrasound. The incidence of ascites increases with the severity of cirrhosis. Flattening of the hepatic vein waveforms was dependant on degree of liver cirrhosis. Maximum hepatic vein velocity was higher in cirrhotic patients (where p = 0.05). Maximum portal vein velocity was found to be lower in cirrhosis (where p < 0.001) and mean maximum portal vein velocity decreases as severity of cirrhosis worsens. Hepatic artery resistive index was significantly higher in cirrhosis (where p < 0.001). Significant association was found between maximum hepatic vein velocity and maximum hepatic artery velocity and significant negative correlation was observed with the maximum portal vein velocity and hepatic artery resistive index. The study demonstrated that these parameters can supplement the evaluation of liver cirrhosis and will be able to distinguish the different grades of liver cirrhosis using Doppler ultrasound.

Effects of All-Oral Anti-Viral Therapy on HVPG and Systemic Hemodynamics in Patients With Hepatitis C Virus-Associated Cirrhosis

Patients with hepatitis C virus-associated cirrhosis and clinical significant portal hypertension (CSPH, hepatic venous pressure gradient [HVPG] 10 mmHg or greater), despite achieving sustained virological response (SVR) to therapy, remain at risk of liver decompensation. We investigated hemodynamic changes following SVR in patients with CSPH and whether liver stiffness measurements (LSMs) can rule out the presence of CSPH. We performed a multicenter prospective study of 226 patients with hepatitis C virus-associated cirrhosis and CSPH who had SVR to interferon-free therapy at 6 Liver Units in Spain. The portal pressure gradient was determined based on HVPG at baseline and 24 weeks after therapy; patients also underwent right-heart catheterization and LSM at these time points. Primary outcomes were effects of SVR on the hepatic, pulmonary, and systemic hemodynamics; factors related to HVPG ≥10% reduction and to CSPH persistence; and whether LSMs can rule out the presence of CSPH after SVR. Most patients (75%) had esophageal varices, 21% were Child-B, and 29% had at least 1 previous episode of liver decompensation. Overall, HVPG decreased from 15 (IQR: 12-18) before treatment to 13 (10-16) mmHg after SVR (reduction of 2.1 ± 3.2 mmHg; P<.01). However, CSPH persisted in 78% of patients. HVPG decreased by 10% or more from baseline in 140 patients (62%). Baseline level of albumin below 3.5 g/dL was the only negative factor associated with an HVPG reduction of 10% or more. LSM decreased from 27 (20-37) kPa before treatment to 18 (14-28) kPa after SVR (P < .05). One third of patients with a reduction in LSM to below 13.6 kPa after SVR still had CSPH. A higher baseline HVPG and a lower decrease in LSM after treatment were associated with persistence of CSPH after SVR. Systemic hemodynamics improved after SVR. Interestingly, pulmonary hypertension was present in 13 patients at baseline and 25 after SVR, although only 3 patients had increased pulmonary resistance. In a multicenter prospective study of patients with hepatitis C virus-associated cirrhosis, an SVR to all-oral therapy significantly reduced HVPG, compared with before treatment. Nevertheless, CSPH persists in most patients despite SVR, indicating persistent risk of decompensation. In this population, changes in LSM do not correlate with HVPG and cut-off values are not reliable in ruling out CSPH after SVR.

Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis

Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis.

Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction

BackgroundFocal hepatic venous outflow obstruction frequently occurs after extended liver resection and leads to a portal hypertension, arterial hypoperfusion and parenchymal necrosis.In this study, we investigated the pharmacological modulation of liver perfusion and hepatic damage in a surgical model of hepatic outflow obstruction after extended liver resection by administration of 5 different drugs in comparison to an operative intervention, splenectomy.MethodsMale inbred Lewis rats (Lew/Crl) were subjected to right median hepatic vein ligation + 70% partial hepatectomy. Treatment consisted of a splenectomy or the application of saline, carvedilol or isosorbide-5-mononitrate (ISMN) (5 mg · kg−1 respectively 7,2 mg · kg−1 per gavage 12 h−1). The splenectomy was performed during operation. The effect of the treatments on hepatic hemodynamics were measured in non-operated animals, immediately after operation (n = 4/group) and 24 h after operation (n = 5/group). Assessment of hepatic damage (liver enzymes, histology) and liver cell proliferation (BrdU-immunohistochemistry) was performed 24 h after operation. Furthermore sildenafil (10 μg · kg−1 i.p. 12h−1), terlipressin (0.05 mg · kg−1 i.v. 12 h−1) and octreotide (10 μg · kg−1 s.c. 12 h−1) were investigated regarding their effect on hepatic hemodynamics and hepatic damage 24 h after operation (n = 4/group).ResultsCarvedilol and ISMN significantly decreased the portal pressure in normal non-operated rats from 11,1 ± 1,1 mmHg (normal rats) to 8,4 ± 0,3 mmHg (carvedilol) respectively 7,4 ± 1,8 mmHg (ISMN). ISMN substantially reduced surgery-induced portal hypertension from 15,4 ± 4,4 mmHg to 9,6 ± 2,3 mmHg. Only splenectomy reduced the portal flow immediately after operation by approximately 25%. No treatment had an immediate effect on the hepatic arterial perfusion. In all treatment groups, portal flow increased by approximately 3-fold within 24 h after operation, whereas hepatic arterial flow decreased substantially. Neither treatment reduced hepatic damage as assessed 24 h after operation. The distribution of proliferating cells appeared very similar in all drug treated groups and the splenectomy group.ConclusionTransient relative reduction of portal pressure did not result in a reduction of hepatic damage. This might be explained by the development of portal hyperperfusion which was accompanied by arterial hypoperfusion.

Impact of higher-order heme degradation products on hepatic function and hemodynamics

Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions. Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia. Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton. Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia. Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.

Phase-contrast MR flow imaging: A tool to determine hepatic hemodynamics in rats with a healthy, fibrotic, or cirrhotic liver.

To test a magnetic resonance (MR) scanning protocol as a noninvasive tool to determine hepatic hemodynamics and to assess the degree of liver fibrosis in an animal model of liver fibrosis and cirrhosis. Fifty-four male Wistar rats were studied. Thirty-nine received thioacetamide (TAA) in their drinking water for either 12 or 16 weeks. MR measurements were performed using flow-sensitive 2D phase-contrast MRI and a 9.4T preclinical scanner. The following hemodynamic parameters were investigated: portal cross-sectional area, mean portal flow velocity, and portal and aortic flow volume rate. Therefore, rats (n = 46) were divided into three groups: CON (control, n = 13), FIB (fibrosis, n = 25), and CIR (cirrhosis, n = 8). Furthermore, the degree of liver fibrosis was assessed by a self-established MR score and verified by a standardized histological score (n = 48). Portal and aortic flow parameters could be reliably detected. A significant decrease in portal flow velocity was found in FIB (FIB vs. CON: -21%, P = 0.006 and CIR vs. CON: -17%, P = 0.105) and in portal flow volume rate in FIB and CIR (FIB vs. CON: -20%, P = 0.009 and CIR vs. CON: -25%, P = 0.024). If the histological score is taken as standard, the self-established MR score enabled discrimination between healthy and diseased livers (sensitivity to identify diseased livers: 89% and specificity to identify healthy livers: 100%). This MR scanning protocol presents a noninvasive tool to determine hepatic hemodynamics in healthy and diseased rats. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1526-1534.

Molecular Bases Underlying the Hepatoprotective Effects of Coffee.

Coffee is the most consumed beverage worldwide. Epidemiological studies with prospective cohorts showed that coffee intake is associated with reduced cardiovascular and all-cause mortality independently of caffeine content. Cohort and case-control studies reported an inverse association between coffee consumption and the degree of liver fibrosis as well as the development of liver cancer. Furthermore, the beneficial effects of coffee have been recently confirmed by large meta-analyses. In the last two decades, various in vitro and in vivo studies evaluated the molecular determinants for the hepatoprotective effects of coffee. In the present article, we aimed to critically review experimental evidence regarding the active components and the molecular bases underlying the beneficial role of coffee against chronic liver diseases. Almost all studies highlighted the beneficial effects of this beverage against liver fibrosis with the most solid results indicating a pivot role for both caffeine and chlorogenic acids. In particular, in experimental models of fibrosis, caffeine was shown to inhibit hepatic stellate cell activation by blocking adenosine receptors, and emerging evidence indicated that caffeine may also favorably impact angiogenesis and hepatic hemodynamics. On the other side, chlorogenic acids, potent phenolic antioxidants, suppress liver fibrogenesis and carcinogenesis by reducing oxidative stress and counteract steatogenesis through the modulation of glucose and lipid homeostasis in the liver. Overall, these molecular insights may have translational significance and suggest that coffee components need clinical evaluation.

Preconditioning by portal vein embolization modulates hepatic hemodynamics and improves liver function in pigs with extended hepatectomy

Portal vein embolization is performed weeks before extended hepatic resections to increase the future liver remnant and prevent posthepatectomy liver failure. Portal vein embolization performed closer to the operation also could be protective, but worsening of portal hyper-perfusion is a major concern. We determined the hepatic hemodynamic effects of a portal vein embolization performed 24hours prior to hepatic operation. An extended (90%) hepatectomy was performed in swine undergoing (portal vein embolization) or not undergoing (control) a portal vein embolization 24hours earlier (n=10/group). Blood tests, hepatic and systemic hemodynamics, hepatic function (plasma disappearance rate of indocyanine green), liver histology, and volumetry (computed tomographic scanning) were assessed before and after the hepatectomy. Hepatocyte proliferating cell nuclear antigen expression and hepatic gene expression also were evaluated. Swine in the control and portal vein embolization groups maintained stable systemic hemodynamics and developed similar increases of portal blood flow (302 ±72% vs 486 ±92%, P=.13). Portal pressure drastically increased in Controls (from 9.4±1.3mm Hg to 20.9±1.4mm Hg, P<.001), while being markedly attenuated in the portal vein embolization group (from 11.4±1.5mm Hg to 16.1±1.3mm Hg, P=.061). The procedure also improved the preservation of the hepatic artery blood flow, liver function, and periportal edema. These effects occurred in the absence of hepatocyte proliferation or hepatic growth and were associated with the induction of the vasoprotective gene Klf2. Portal vein embolization preconditioning represents a potential hepato-protective strategy for extended hepatic resections. Further preclinical studies should assess its medium-term effects, including survival. Our study also supports the relevance of hepatic hemodynamics as the main pathogenetic factor of post-hepatectomy liver failure.

In vivo imaging of hepatic hemodynamics and light scattering property during ischemia-reperfusion in rats based on spectrocolorimetry.

A red-green-blue camera-based imaging method is proposed for estimating spatial maps of concentrations of oxyhemoglobin (CHbO), deoxyhemoglobin (CHbR), total hemoglobin (CHbT), tissue oxygen saturation (StO2), and scattering power (b) in liver tissue. Hemodynamic responses to hepatic ischemia-reperfusion of in vivo rat liver tissues induced by portal triad occlusion were evaluated. Upon portal triad occlusion, this method yielded images of decreased CHbO, CHbT, StO2, and b, and increased CHbR followed by a progressive increase in CHbO and StO2 during reperfusion. Time courses of the changes in CHbO, CHbR, CHbT, and StO2 over different regions of interest (ROIs) revealed that ischemia results in an abrupt significant (P<0.05) reduction in CHbO, CHbT, and StO2 with a simultaneous increase in CHbR compared to the baseline level, indicative of the hemodynamic responses during hepatic ischemia-reperfusion. Upon reperfusion, there was a gradual increase in CHbO and StO2, and decrease in CHbR. The change in average scattering power b implies the presence of morphological alterations in the cellular and subcellular structures induced by ischemia or anoxia. This study shows the potential of monitoring spatiotemporal changes in hemodynamic parameters and morphological changes in studies of hepatic pathophysiology.