Effects of systemic arterial hypoperfusion on splanchnic hemodynamics and hepatic arterial buffer response in pigs

The hepatic arterial buffer response (HABR) tends to maintain liver blood flow under conditions of low mesenteric perfusion. We hypothesized that systemic hypoperfusion impairs the HABR. In 12 pigs, aortic blood flow was reduced by cardiac tamponade to 50 ml. kg(-1). min(-1) for 1 h (short-term tamponade) and further to 30 ml. kg(-1). min(-1) for another hour (prolonged tamponade). Twelve pigs without tamponade served as controls. Portal venous blood flow decreased from 17 +/- 3 (baseline) to 6 +/- 4 ml. kg(-1). min(-1) (prolonged tamponade; P = 0.012) and did not change in controls, whereas hepatic arterial blood flow decreased from 2 +/- 1 (baseline) to 1 +/- 1 ml. kg(-1). min(-1) (prolonged tamponade; P = 0.050) and increased from 2 +/- 1 to 4 +/- 2 ml. kg(-1). min(-1) in controls (P = 0.002). The change in hepatic arterial conductance (DeltaC(ha)) during acute portal vein occlusion decreased from 0.1 +/- 0.05 (baseline) to 0 +/- 0.01 ml. kg(-1). min(-1). mmHg(-1) (prolonged tamponade; P = 0.043). In controls, DeltaC(ha) did not change. Hepatic lactate extraction decreased, but hepatic release of glutathione S-transferase A did not change during cardiac tamponade. In conclusion, during low systemic perfusion, the HABR is exhausted and hepatic function is impaired without signs of cellular damage.     

Role of hepatic arterial embolisation in the carcinoid syndrome.

Eighteen patients with severe symptoms of the carcinoid syndrome were assessed for hepatic embolisation. Four were too ill, and one had mild symptoms; thus 13 received a periembolisation regimen of cyproheptadine, fenclonine, aprotinin, methylprednisolone, tobramycin, flucloxacillin, and metronidazole. Embolisation was not performed in one patient with an occluded portal vein and was unsatisfactory in two others, in one because she was moribund and in the other because the hepatic artery had been ligated. Dramatic improvement in symptoms occurred in the nine patients in whom embolisation was successfully carried out, with abolition of flushing, severe abdominal pain, and wheeze and reduction in diarrhoea from 10.5 (SD 7.6) to 1.6 (0.9) stools/day. Urinary excretion of 5-hydroxyindole acetic acid fell from 1048 (716) to 289 (184) mumol/24 h (200 (137) to 55 (35) mg/24 h). Complications included one death from septicaemia, a hepatic abscess requiring surgical drainage, abdominal pain in three patients, pleural effusion in two, and transient encephalopathy in one. Relief of symptoms lasted for one to 24 months, and second embolisation in two patients produced further remissions of four to six months. Five patients died, one to 40 months after embolisation, in four cases because of metastases or heart failure. Hepatic embolisation is the treatment of choice for symptoms of the carcinoid syndrome resistant to medical treatment.     

Prediction of early death after therapeutic hepatic arterial embolisation.

A consecutive series of 14 patients with hepatic malignant disease treated by palliative hepatic arterial embolisation was reviewed. Twelve patients had hepatic pain from their tumour and two were suffering from the carcinoid syndrome. Six patients died within four weeks of the procedure (group 1) and eight survived for at least 10 weeks (group 2). Factors were sought that might permit prediction of a high risk of early death (group 1). The pre-embolisation angiograms reviewed by a "blind" observer showed no differences in vascularity or tumour size between the groups and no difference in the extent of arterial occlusion after embolisation. The portal vein was patent in all patients. No significant difference was seen between the groups in the pre-embolisation biochemical values, with the exception of lower serum albumin concentrations and higher alkaline phosphatase activities in group 1. All those who died early had serum alkaline phosphatase activities of 45 KAU or above, while six of the eight who survived longer had activities below this value (p less than 0.02). These findings suggest that serum alkaline phosphatase activity of 45 KAU or more (normal range 3-13) might alone be a useful predictor of early death. Stepwise discriminant analysis using a weighted combination of serum alkaline phosphatase activity and albumin concentration predicted the outcome in all but one of the patients studied (p less than 0.002).     

Maintenance of hepatic arterial blood flow during hemorrhage is mediated by adenosine

The effect of hemorrhage (1.91 mL/min, 10 mL/kg) on splanchnic blood flow was determined in cats anesthetized with pentobarbital. The hepatic artery (HA) is relatively protected during hemorrhage and does not constrict, whereas the superior mesenteric artery (SMA) undergoes significant vasoconstriction. Adenosine receptor antagonism with 8-phenyltheophylline blocks the dilator response to infused adenosine selectively (does not block responses to isoproterenol). The dilator response to reduced portal blood flow (the HA buffer response) is also antagonized and adenosine receptor blockade converts the HA response to hemorrhage to one similar to that of the SMA. Thus, the protective dilation of the HA during hemorrhage is mediated by adenosine. In contrast, the vasodilation of the HA seen with reinfusion of the shed blood is not altered by adenosine receptor antagonism.     

Bizarre atypia in gastric brushings associated with hepatic arterial infusion chemotherapy

Hepatic arterial infusion chemotherapy (HAIC) for unresectable hepatic neoplasms has been associated with gastric ulcers and epithelial atypia that may be misinterpreted as carcinoma. Gastric brushings were reviewed from six patients who developed gastric ulcers with histologically proven atypia following HAIC. Marked cytologic atypia, reminiscent of a pronounced radiation effect, was present in gastric epithelial cells in five patients. The atypical cells occurred singly or in small sheets. They were markedly enlarged but a low nuclear-cytoplasmic ratio was preserved. The abundant cytoplasm was vacuolated or foamy. Binucleation and multinucleation were common, and massive nucleoli were characteristic. The brushings also contained the reparative, inflammatory and necrotic changes associated with usual benign gastric ulcers. The bizarre atypia associated with HAIC can be a source of misdiagnosis of cancer in cytologic as well as in histologic specimens.     

Congruence between the courses of the biliary ductal and the hepatic arterial systems

The development of diagnostic methods and new surgical techniques means it is increasingly important to have accurate knowledge of the anatomy of the hepatic arterial and biliary systems, including their variations, at extrahepatic and intrahepatic levels. The aim of this study was to determine how often the biliary and arterial systems run together and branch in the same pattern. Fifty corrosion casts of the liver were used to analyse the origin and branching patterns of arteries and the confluences of bile ducts. In addition, both systems were analysed to determine the frequency of normal arrangements and variations. The congruence of the course of both systems was analysed at the porta hepatis and in the left and right hemilivers down to the segmental level. A congruent course of the arterial and the biliary systems was identified in 38% of cases at the porta hepatis, in 32% of cases in the left hemiliver and in 30% of the right hemiliver. The congruence of both systems at the porta hepatis and in the left hemiliver was identified only if both systems were normal. In the right hemiliver, however, the congruence of both systems was identified even when both systems were variable, but only in 10% of cases. The results of the study show that, on the basis of knowledge of the course and branching of one system, the other system cannot be predicted.     

The role of hepatic arterial flow on portal venous and hepatic venous wedged pressure in the isolated perfused CCl4-cirrhotic liver

In cirrhosis, hepatic venous pressure gradient is used to measure portal venous and sinusoidal pressures, as well as drug-induced decreases of elevated pressures. The aim of this study was to investigate the influence of hepatic arterial flow (HAF) changes on portal venous perfusion (PVPP) and wedged hepatic venous pressure (WHVP). Normal and CCl4-cirrhotic rats were subjected to a bivascular liver perfusion with continuous measurements of PVPP, WHVP, and hepatic arterial perfusion pressure. Flow-pressure curves were performed with the use of different flows either through the portal vein (PVF: 20-32 ml/min) or HAF (5-15 ml/min). Increases in HAF lead to significant absolute and relative increases in PVPP (P = 0.002) and WHVP (P < 0.001). Absolute changes in HAF correlated to absolute changes in PVPP (cirrhosis: r = 0.64, P < 0.001; control: r = 0.67, P < 0.001) and WHVP (cirrhosis: r = 0.71, P < 0.001; control: r = 0.82, P < 0.001). Changes in PVPP correlated to changes in WHVP due to changes in PVF only in cirrhosis (r = 0.75, P < 0.001), whereas changes in HAF correlated in both cirrhosis (r = 0.92, P < 0.001) and control (r = 0.77, P < 0.001). In conclusion, increases and decreases in HAF lead to respective changes in PVPP and WHVP. This suggests a direct influence of HAF on PVPP and WHVP most likely due to changes in sinusoidal perfusion.     

Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response

The hepatic arterial buffer response (HABR) effectively controls total blood perfusion in normal livers, but little is known about blood flow regulation in cirrhosis. We therefore studied the impact of HABR on blood perfusion of cirrhotic livers in vivo. After 8-wk CCl(4) treatment to induce cirrhosis, 18 anesthetized rats (and 18 noncirrhotic controls) were used to simultaneously assess portal venous and hepatic arterial inflow with miniaturized ultrasonic flow probes. Stepwise hepatic arterial blood flow (HAF) or portal venous blood flow (PVF) reduction was performed. Cirrhotic livers revealed a significantly reduced total hepatic blood flow (12.3 +/- 0.9 ml/min) due to markedly diminished PVF (7.3 +/- 0.8 ml/min) but slightly increased HAF (5.0 +/- 0.6 ml/min) compared with noncirrhotic controls (19.0 +/- 1.6, 15.2 +/- 1.3, and 3.8 +/- 0.4 ml/min). PVF reduction caused a significant HABR, i.e., increase of HAF, in both normal and cirrhotic livers; however, buffer capacity of cirrhotic livers exceeded that of normal livers (P < 0.05) by 1. 7- to 4.5-fold (PVF 80% and 20% of baseline). Persistent PVF reduction for 1, 2, and 6 h demonstrated constant HABR in both groups. Furthermore, HABR could be repetitively provoked, as analyzed by intermittent PVF reduction. HAF reduction did not induce changes of portal flow in either group. Because PVF is reduced in cirrhosis, the maintenance of HAF and the preserved HABR must be considered as a protective effect on overall hepatic circulation, counteracting impaired nutritive blood supply via the portal vein.     

Importance of the hepatic arterial glucose level in generation of the portal signal in conscious dogs

The aim of this study was to determine whether the elimination of the hepatic arterial-portal (A-P) venous glucose gradient would alter the effects of portal glucose delivery on hepatic or peripheral glucose uptake. Three groups of 42-h-fasted conscious dogs (n = 7/group) were studied. After a 40-min basal period, somatostatin was infused peripherally along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)). In test period 1 (90 min), glucose was infused into a peripheral vein to double the hepatic glucose load (HGL) in all groups. In test period 2 (90 min) of the control group (CONT), saline was infused intraportally; in the other two groups, glucose was infused intraportally (22.2 micromol x kg(-1) x min(-1)). In the second group (PD), saline was simultaneously infused into the hepatic artery; in the third group (PD+HAD), glucose was infused into the hepatic artery to eliminate the negative hepatic A-P glucose gradient. HGL was twofold basal in each test period. Net hepatic glucose uptake (NHGU) was 10.1 +/- 2.2 and 12.8 +/- 2.1 vs. 11.5 +/- 1.6 and 23.8 +/- 3.3* vs. 9.0 +/- 2.4 and 13.8 +/- 4.2 micromol x kg(-1) x min(-1) in the two periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). NHGU was 28.9 +/- 1.2 and 39.5 +/- 4.3 vs. 26.3 +/- 3.7 and 24.5 +/- 3.7* vs. 36.1 +/- 3.8 and 53.3 +/- 8.5 micromol x kg(-1) x min(-1) in the first and second periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). Thus the increment in NHGU and decrement in extrahepatic glucose uptake caused by the portal signal were significantly reduced by hepatic arterial glucose infusion. These results suggest that the hepatic arterial glucose level plays an important role in generation of the effect of portal glucose delivery on glucose uptake by liver and muscle.     

H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of K(ATP) channels

Hepatic blood supply is uniquely regulated by the hepatic arterial buffer response (HABR), counteracting alterations of portal venous blood flow by flow changes of the hepatic artery. Hydrogen sulfide (H(2)S) has been recognized as a novel signaling molecule with vasoactive properties. However, the contribution of H(2)S in mediating the HABR is not yet studied. In pentobarbital-anesthetized and laparotomized rats, flow probes around the portal vein and hepatic artery allowed for assessment of the portal venous (PVBF) and hepatic arterial blood flow (HABF) under baseline conditions and stepwise reduction of PVBF for induction of HABR. Animals received either the H(2)S donor Na(2)S, DL-propargylglycine as inhibitor of the H(2)S synthesizing enzyme cystathionine-gamma-lyase (CSE), or saline alone. Additionally, animals were treated with Na(2)S and the ATP-sensitive potassium channel (K(ATP)) inhibitor glibenclamide or with glibenclamide alone. Na(2)S markedly increased the buffer capacity to 27.4 +/- 3.0% (P < 0.05 vs. controls: 15.5 +/- 1.7%), whereas blockade of H(2)S formation by DL-propargylglycine significantly reduced the buffer capacity (8.5 +/- 1.4%). Glibenclamide completely reversed the H(2)S-induced increase of buffer capacity to the control level. By means of RT-PCR, Western blot analysis, and immunohistochemistry, we observed the expression of both H(2)S synthesizing enzymes (CSE and cystathionine-beta-synthase) in aorta, vena cava, hepatic artery, and portal vein, as well as in hepatic parenchymal tissue. Terminal branches of the hepatic afferent vessels expressed only CSE. We show for the first time that CSE-derived H(2)S contributes to HABR and partly mediates vasorelaxation of the hepatic artery via activation of K(ATP) channels.     

Changes in acetoacetate/beta-hydroxybutyrate ratio in arterial blood following hepatic artery embolization in man

Acetoacetate/beta-hydroxybutyrate ratio in the hepatic venous blood was compared to the ratios in arterial blood and peripheral venous blood in hypoxic state following right hepatic artery embolization in 5 patients with liver cancer. Ketone body ratios in right hepatic venous blood were positively correlated with those in arterial blood (r = 0.960, p less than 0.001), but not with those in peripheral venous blood. The free NAD+/NADH ratio of the liver mitochondria, which is reflected by the ketone body ration in hepatic venous blood, can be evaluated by the ketone body ratio in the arterial blood.     

Patterns of arterial supply of the human fetal liver. The significance of the accessory hepatic artery

One or two aberrant hepatic arteries were found in 30% of human fetal livers. The liver received a triple or double arterial supply. The aberrant artery arises from the left gastric or superior mesenteric arteries and supplies an entire lobe or more without joining the branches of the usual hepatic artery in 38.5%. The artery has an important significance for the arterial supply of the fetal liver.     

Histologic analysis of liver tissue following hepatic arterial infusion of ferromagnetic particles in a rabbit tumour model

It is possible to arterially embolize liver tumours in small animal models with ferromagnetic particles that generate hysteretic heating on exposure to an alternating magnetic field. The aim of this study was to determine the response of hepatic tissue to arterial infusion of ferromagnetic particles. Eight rabbits containing hepatic VX2 carcinomas received a hepatic arterial infusion of ferromagnetic particles suspended in lipiodol. Four rabbits were sacrificed after 60 min to determine the acute tissue response, and the other four rabbits were sacrificed after 14 days to determine the longer-term tissue response. The tumour, normal hepatic parenchyma (NHP), lungs and gallbladder of each subject were examined using light microscopy, and chemically analysed for iron concentration. Large aggregates of particles embolized within the tumour vasculature. There was only a sparse distribution of particles in the NHP, with no acute tissue response. The tumour to NHP iron concentration ratio was 4.9. Particles also lodged in blood vessels of the gallbladder wall. Two weeks after infusion there were isolated foci of necrosis in the NHP, and macrophages were associated with particle aggregates, which were also observed within multinucleated giant cells. There was no evidence that particles embolized in the lungs. Hepatic arterial infusion of ferromagnetic particles suspended in lipiodol resulted in excellent tumour targeting with no acute tissue reaction in the NHP, and no evidence of pulmonary embolization. After 14 days there was evidence of phagocytosis of the particles in NHP, but not in the tumour tissue. However, the suspension caused multiple foci of infarction in NHP, probably due to occlusion of larger arteries.