Total Hepatic Blood Flow Research Articles

Splanchnic arterial blood flow in rats with portacaval shunts.

With indirect methods, it was shown in rats with portacaval shunts (PCS) that total hepatic blood flow (THBF) remained constant when expressed per gram of liver. These results implied an absolute increase in hepatic arterial blood flow (HABF). The aim of this study was to investigate HABF and splanchnic nonhepatic arterial blood flow (SNHABF) with a direct method (57Co microspheres) in PCS rats. One month after surgery, the following results were obtained in PCS rats compared with pair-fed, sham-operated rats: 1) liver mass atrophy was 42.3 +/- 10.9%, 2) HABF (ml X min-1 X g liver-1) was increased by a factor of 2.7, 3) SNHABF (ml X min-1 X 100 g body wt-1) was higher (9.8 +/- 3.3 vs. 5.6 +/- 2.7) (P less than 0.05) and 4) THBF (ml X min-1 X g liver-1) was decreased (1.36 +/- 0.34 vs. 1.85 +/- 0.86) but not significantly. Increases in HABF and SNHABF were not the direct consequence of an increase in cardiac output as attested by a normal cerebral blood flow (ml X min-1 X g organ-1) in PCS rats. In PCS rats, an increase in HABF may prevent the further spread of liver necrosis. The cause and the reason for an increase in SNHABF remain unknown.

Intraoperative hemodynamic investigations during portacaval shunt.

We studied the hemodynamics of hepatic blood flow before and after creation of portacaval shunts in 28 patients. Electromagnetic flow recordings were used to measure hepatic arterial flow (HAF) and portal venous flow (PVF) with respect to total hepatic blood flow (THBF). No correlation between PVF and portal pressure was found, but PVF was directly related to liver function. The concept that patients with low PVF tolerate shunts better (with respect to postoperative course and encephalopathy) than those with high PVF was not supported. Our investigations suggest the existence of a compensatory mechanism that tends to maintain THBF by increasing HAF following creation of a shunt. This compensatory increase occurs only in those patients with good liver function and normal or enlarged livers.

A new method to measure portal and hepatic blood flow using taurocholate in the rat.

Hepatic artery and portal vein blood flows were assessed separately in anesthetized rats using radiolabeled taurocholate. The ratio of portal vein blood flow to total hepatic blood flow was calculated from measurements of taurocholate concentrations of portal vein, hepatic artery and hepatic vein, and of taurocholate hepatic extraction ratio. Animals were administered [14C]taurocholate intraperitoneally as a label of the taurocholate pool 24 hr before the experiments. In steady-state conditions, serum [14C]taurocholate activities were used as an index of taurocholate relative concentration and the hepatic extraction ratio of taurocholate was estimated using [3H]taurocholate infused into the systemic blood stream. Total hepatic blood flow was estimated by the Fick's principle using indocyanine green. The mean hepatic blood flow was 13.9 ml X min-1 (S.E. 1.9), and the mean ratio of portal blood flow to hepatic blood flow was 72.2% (S.E. 6.7). It is concluded that taurocholate may be used to assess separately portal venous and hepatic arterial blood flow in the rat.

Hepatic oxygen and glucose metabolism in the fetal lamb. Response to hypoxia.

Although the fetal liver is an active metabolic organ, its oxygen and glucose requirements have not previously been described. We measured hepatic blood flows and the oxygen and glucose differences across the liver in 12 late gestation fetal lambs in utero. Four animals were studied at least 1 wk postsurgically and again 2-5 d later to assess daily variations in hepatic blood flow and metabolism (group I). A second group of eight animals was studied 3-5 d postsurgically during a control period and during acute fetal hypoxia (group II). Under control conditions total hepatic blood flow averaged 400 ml/min per 100 g in both groups, and 75-80% was of umbilical origin. Liver blood flow and oxygen consumption were usually similar during repeated measurements, but in one animal varied considerably. During periods of normoxia, oxygen consumption for both the right and left lobes of liver was 4 ml/min per 100 g. Oxygen consumption of the whole liver accounted for 20% of total fetal oxygen consumption. This was achieved with oxygen extraction of 10-15%, so that hepatic venous blood was well oxygenated and provided an important source of oxygen for other fetal tissues. Under control conditions we could demonstrate no net hepatic uptake or release of glucose suggesting that the liver ultimately utilizes another carbon source to support its oxidative metabolism. During acute hypoxia total liver blood flow and its umbilical venous contribution both fell by 20%. Blood flow to the right lobe of the liver fell twice as much as that to the left lobe. Hepatic oxygen consumption was linearly related to oxygen delivery during the control and hypoxic periods. Consequently, right hepatic oxygen uptake fell by 45% whereas left hepatic oxygen uptake was unchanged, suggesting a functional difference between the lobes. During hypoxia glucose was released from both liver lobes; 6 mg/min per 100 g for the right lobe and 9 mg/min per 100 g for the left lobe. Total hepatic release of glucose was estimated to nearly equal umbilical uptake, so that 45% of the glucose available to fetal tissues was of hepatic origin. We conclude that the fetal liver responds to acute hypoxia by reducing its own oxygen consumption and releasing glucose to facilitate anaerobic metabolism.

Hepatic blood flow after canine portasystemic shunting.

Effects of portasystemic shunting on total hepatic blood flow (THBF) were evaluated in mongrel dogs with 35 and 50micro radioactive microspheres. THBF was measured prior to shunting and 1 hour and 3 weeks after surgery. Using systemic and pulmonary artery catheters, pertinent hemodynamic variables were also measured. In sham-operated dogs (n = 5), there were no significant changes in the hemodynamic parameters or the components of THBF during the experiment. After end-to-side shunting (n = 7), animals experienced a significant, permanent fall in hepatopetal portal blood flow (HABF). In contrast, dogs with side-to-side shunts (n = 7) exhibited a transient, significant increase in HABF 1 hour after surgery. Although the shunt eliminated HPBF, the rise in HABF prevented a significant, immediate fall in THBF. Three weeks after surgery, however, HABF had returned to the baseline range, and THBF was significantly lower than the preshunt value. Dogs with H-graft mesocaval shunts (n = 5) also exhibited a transient, significant rise in HABF 1 hour after surgery. Since HPBF did not fall substantially, THBF at this time was significantly higher than the baseline value. Three weeks after surgery, HABF had fallen to the baseline range, but THBF was not significantly different from the preshunt level. In animals with distal splenorenal shunts (n = 11), there was no significant change in HABF after shunting. Both HPBF and THBF were transiently, significantly reduced immediately after surgery, but three weeks later neither parameter was significantly lower than the preshunt values. There were no significant, persistent changes in the systemic perfusion pressures or flows in the shunted groups. These experiments demonstrate that the reported increase in HABF following portasystemic shunting is dependent on the type of shunt and, if it occurs, is a transient phenomenon. Hence, immediate postoperative changes in hemodynamic variables or hepatic blood flows do not necessarily reflect long-term patterns. In the normal dog, total portasystemic shunting produces a permanent, significant decrease in THBF, whereas selective shunting maintains THBF in the near-normal range.

Angiographic, hemodynamic, and histologic evaluation of portal hypertension and periportal fibrosis induced in the dog by intraportal polyvinyl alcohol injections.

Intrahepatic periportal fibrosis and portal hypertension were produced in the dog by repeated intraportal injection of a polyvinyl alcohol suspension over a two- to six-month period. Progressive hepatic fibrosis originating in the portal triads around occluded portal vein radicles occurred during the first year. Porto-systemic venous collaterals developed at the earliest three to four weeks after initial embolization. Angiographic changes included an increase in number and diameters of opacified hepatic arterial branches and a more dense arterial hepatogram than on the baseline studies, but these were only evident in advanced hepatic fibrosis. Decreases in portal and total hepatic blood flow of 53 +/- 15% and 17 +/- 7%, respectively, were observed after development of periportal fibrosis and stable portal hypertension, while the compensatory increase in hepatic arterial flow was a slowly evolving process resulting in an increase of 135 +/- 51% in the fibrotic stage. Animals with advanced hepatic fibrosis and portal hypertension remained in good general health, allowing extensive follow-up examinations at regular intervals over a prolonged period of time.

Temporary beneficial effect of arterialization of the liver in cirrhotic dogs with a portacaval shunt. A preliminary report.

The effect of arterialization of the portal vein was investigated in cirrhotic dogs with a portacaval shunt. In dogs receiving a portacaval shunt only (PCS), the pressure in the intrahepatic portal vein fell to about 10% of the preshunt value, while the total hepatic blood flow was reduced by 63.9%. By contrast, in dogs with arterialization in addition to a portacaval shunt (PCS + A), the pressure in the portal vein was almost restored to preshunt levels, and the decrease in total hepatic blood flow was only 35.7%; this difference in the reduction of hepatic perfusion is significant (p less than 0.01). 2 weeks after the operation, PCS + A dogs had lower plasma levels of bilirubin and alkaline phosphatase, and a higher antipyrine clearance than PCS dogs (p less than 0.05). This improvement, however, was of short duration. The results of the ammonia tolerance test were not affected by the arterialization procedure.

Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants.

Liver blood flow and indices of hepatic drug metabolism (antipyrine elimination rate and cytochrome P-450 concentration in liver biopsy specimens) were studied in 19 epileptics on long-term anticonvulsant treatment, and in 18 controls. The size of the liver and the total estimated liver blood flow were greater inthe epileptics than in the controls, whereas the relative liver blood flow (per unit weight of the liver) was not significantly different. The epileptics had higher cytochrome P-450 levels and they eliminated antipyrine faster than the controls. It was concluded that long-term ingestion of enzyme-inducing anticonvulsants is associated with an increase in the total hepatic blood flow in parallel with the increase in liver size, and not as an independent phenomenon. Since the relative perfusion rate of the hepatocytes was unchanged, the enhanced activity of drug metabolizing enzymes is presumed to be mainly responsible for the increased drug clearance observed in epileptic subjects.

Hepatic gluconeogenesis during halothane anaesthesia in man.

It is known that hepatic gluconeogenesis from lactate and aminoacids is inhibited by halothane in in vitro studies on isolated, perfused livers. In the present work, the effect of halothane anaesthesia on hepatic gluconeogenesis was studied in three volunteers during a constant amino-acid infusion and compared with three control subjects who did not receive any halothane during the amino-acid infusion. Prior to the investigation, all the subjects were on a carbohydrate-poor diet in order to deplete hepatic glucogen stores. During the investigation, hepatic gluconeogenesis was stimulated by a constant amino-acid infusion which caused a slight rise in total hepatic blood flow (THBF), a marked increase in splanchnic oxygen consumption and oxygen extraction, elevation in blood glucose and urea levels and in splanchnic glucose and urea releases. Halothane anaesthesia administered during continued amino-acid infusion caused a reduction in THBF to sub-control values, while the increased oxygen consumption was only slightly reduced, thereby further increasing splanchnic oxygen extraction. Blood glucose and urea levels of the anaesthetized subjects were consistent with those of the control subjects. Splanchnic release of glucose was reduced almost to control values during halothane. However, the release of urea was only slightly reduced. It is concluded that the stimulating effect on hepatic gluconeogenesis caused by the amino-acid infusion was inhibited during halothane anaesthesia, while metabolization of the amino-acids, other than through gluconeogenesis, proceeded without any major changes.

Radionuclide angiography of the liver and spleen: Noninvasive method for assessing the ratio of portal venous to total hepatic blood flow and portasystemic shunt patency

Radioactivity versus time curves were generated for the first pass of technetium-99m pertechnetate through the left ventricle, kidneys, spleen and liver, after a 20 mCi peripheral intravenous bolus injection. The rate of change of radioactivity in these organs before recirculation is proportional to blood flow through the organ. The hepatic perfusion index, defined as the ratio of portal flow to total hepatic blood flow, was correlated with the angiographic grade of portal perfusion. The hepatic perfusion index in seven normal subjects was 66.0 ± 3.4 percent (mean ± standard error of the mean), and in 22 cirrhotic patients with decreasing angiographic perfusion of grades 1 to 4 the index was 54 ± 4.6, 37 ± 2.6, 17 ± 4.7 and 3 ± 1.1 percent, respectively. The correlation between the calculated perfusion index and the angiographic grade of portal flow was highly significant (p < 0.001). The passage of radionuclide through the spleen differed before and after shunt surgery in patients with portal hypertension. The slope to height ratio, based on the downslope of the splenic curve, was significantly greater (p < 0.01) in the shunted patients and provided a simple index for assessing shunt patency.

A noninvasive method for measuring portal venous/total hepatic blood flow by hepatosplenic radionuclide angiography.

Radionuclide angiography was used to generate first-pass radioactivity vs. time curves for the left heart, right hepatic lobe, right lung, spleen, and both kidneys following rapid intravenous injection of 20 mCi (740 MBq) of 99mTc-pertechnetate. Seven normal subjects were examined as well as 57 cirrhotic patients, who also underwent angiographic grading of portal venous perfusion. For analysis, two time points were identified: (a) t0, when 99mTc first entered the liver (the initial rise of either curve); and (b)tc, when 99mTc was maximal in abdominal organs (the renal peak). Analysis was based on the slopes of the two phases of the hepatic curves t0 + 7 seconds and Tc + 7 seconds; this time selection permitted analysis of all curves. The hepatic perfusion index (HPI) = slope (tc + 7 secs)/slope (t0 + 7 secs) + slope (tc + 7 secs). The mean HPI for the normal subjects was 66% +/- 7; for the cirrhotic patients with angiographic Grades I, II, III, and IV, the HPI was 52% +/- 9, 37% +/- 6, 15% +/- 7, and 3% +/- 4, respectively. Correlation between HPI and angiography was significant (p less than 0.001). This method offers a readily available, rapid, relatively inexpensive, and quantitative method of grading the ratio of portal venous to total hepatic blood flow.

Participation of the arterial and portal drainage in the calculation of total hepatic blood flow in guinea pigs

Experiments were performed on partly isolated livers of guinea pigs. The hepatic outflow (HOF) was measured by an electromagnetic flowmeter placed on the inferior vena cava. Nutritive hepatic blood flow (HBF) was measured with 133Xe bolus technique with the tracer injected into the portal vein or hepatic artery. Under unchanged perfusion conditions, three exponents could be demonstrated irrespective of the site of injection. Two of them observed during the first 5 min represent the intrahepatic, the third (slowest one) the extrahepatic blood flow. Occlusion of either the portal vein or the hepatic artery results in a monoexponential decrease during the first 5 min. Calculation of the HBF was based on an equation including both components of the washout curves obtained after arterial and portal application. The calculated HBF was equal to the value of the directly measured total outflow but overestimated HBF f calculated from the first exponent of the washout curve obtained after intraportal tracer application.

Control of hepatic arterial blood flow: independence from liver metabolic activity.

This investigation tested the hypothesis that hepatic arterial blood flow is not dependent on hepatic metabolism, but rather is controlled in a manner that tends to maintain total hepatic blood flow constant. Cats anesthetized with pentobarbital sodium received SKF 525 A or 2,4-dinitrophenol (DNP), respectively, to inhibit or stimulate metabolism. Blood flows and oxygen uptake of the liver and gut were determined by use of a hepatic venous long circuit and noncannulating electromagnetic recording of hepatic arterial blood flow. In both sets of experiments the hepatic arterial blood flow. In both sets of experiments the hepatic artery constricted sufficiently to offset elevated portal venous blood flow, thereby maintaining total hepatic blood flow constant. The reduced hepatic arterial conductance occurred with DNP despite elevated metabolic rate and reduced oxygen in the portal and hepatic veins. Altered gut metabolism correlated with altered vascular conductance in the gut; hepatic arterial conductance changes did not correlate with changes in liver metabolic activity. The data confirmed the hypothesis. It is suggested that for hormonal homeostatis it is essential that total hepatic blood flow be regulated because hepatic clearance is flow dependent.

Active and passive control of hepatic blood volume responses to hemorrhage at normal and raised hepatic venous pressure in cats.

Hepatic blood volume decreases in response to a rapid hemorrhage (15.3 mL/min) were measured in cats anesthetized with pentobarbital or ketamine-chloralose, by use of in vivo plethysmography alone or in combination with various surgical procedures and vascular circuits. The hepatic blood volume contracts during hemorrhage to compensate for a constant proportion (26 +/- 6%) of the blood loss regardless of the extent of the actual blood loss. Following denervation of the liver and alpha adrenoreceptor blockade (3 mg phentolamine, intraportal) the liver compensation was unaltered. After denervation, nephrectomy, hypophysectomy, and adrenalectomy the liver was still able to compensate for 20 +/- 7.4% of the hemorrhage. Decreases in liver volume were linearly related to decreases in total hepatic blood flow that ensued whether the decreased blood flow was induced by hemorrhage or by clamping of the arteries supplying the splanchnic organs (superior mesenteric artery, celiac artery). The hepatic volume response to hemorrhage could be predicted accurately (97 +/- 6.6%) simply from the linear passive relationship between flow and volume for a particular animal. However when hepatic venous pressure was experimentally elevated, the volume response to passive flow decrease was markedly reduced whereas the response to hemorrhage and noradrenaline infusion was unimpaired suggesting that active control factors were required to produce normal hepatic volume responses to hemorrhage at raised venous pressure. Phentolamine reduced the response at raised venous pressure but was without effect at normal venous pressure in the same animal, indicating that the hepatic nerves and (or) adrenal catecholamines are of paramount importance in control of the response at raised venous pressure when the passive flow influence is much reduced.

Effects of portacaval shunt and transposition on fatty acid and cholesterol biosynthesis in rat liver.

Male rats underwent either portacaval shunt or portacaval transposition; in both cases, sham-operated pair-fed rats served as controls. Three weeks after a portacaval shunt, fasting serum values of glucose (-35%) and cholesterol (-24%) were lower, and fasting plasma glucagon was higher (+65%). The wet weight of the liver and its total content in DNA, RNA, and protein decreased by 43, 40, 43, and 48%, respectively. The supernatant of liver obtained after centrifugation at 700 g incorporated less [1-14C]acetate (-56%) into fatty acids and less [1-14C]acetate (-94%) and [2-14C]mevalonate (-37%) into cholesterol. The activity of acetyl CoA carboxylase was reduced by 56%. The in vivo incorporation of [3H]H2O into liver fatty acids was 83% lower and that into liver cholesterol was 39% lower than in pair-fed controls. Several of the preceding parameters, including in vitro and in vivo labeling of hepatic fatty acids and cholesterol, were found to be mostly normal in rats with portacaval transposition. These data suggest that the reduction of fatty acid and cholesterol biosynthesis in the liver of rats with portacaval shunt was due to the reduction of total hepatic blood flow rather than to the diversion of portal blood constituents.

Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat.

1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls. 4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.

The effect of norepinephrine on blood flow through the fetal liver and ductus venosus

Experiments were conducted with 11 chronically catheterized fetal sheep to determine the effects of norepinephrine on the distribution of umbilical venous blood through the ductus venosus, and within the fetal liver. An intraumbilical infusion of 1.1 μg/kg/min of norepinephrine increased placental blood flow but did not alter the proportion of this flow that was diverted through the ductus venosus. Under control conditions the umbilical flow to the fetal liver was preferentially distributed to the left side and accounted for 80% of the total hepatic blood flow. Flow through the hepatic artery was negligible. Norepinephrine reduced portal flow but also reduced the asymmetric distribution of hepatic umbilical blood flow by greatly increasing the perfusion of the right side of the fetal liver.

Hemodynamic Patterns in Human Hepatic Cirrhosis A Prospective Randomized Study of the Hemodynamic Sequelae of Distal Splenorenal (Warren) and Mesocaval Shunts

Increasingly successful operative management of gastroesophageal variceal hemorrhage has been achieved by newer techniques of portal venous reconstruction. Although it is postulated that the clinical success may be due to more selectivity in portal venous shunting, direct determination of the effect of portasystemic shunt on portal vein blood flow has not been possible. Direct determinations of portal vein blood flow were performed preoperative on unanesthetized, hemodynamically stable cirrhotic patients by observation of radiopaque water-insoluble droplets. Patients were then randomized into elective distal splenorenal (Warren) or mesocaval shunt and determinations were performed postoperatively under similar conditions when clinically possible. Although portal vein blood flow was not significantly different before (929 +/- 147 ml/min) or after 899 +/- 271 ml/min) distal splenorenal shunt, there was a large change in portal vein blood flow after mesocaval shunt, decreasing from 772 +/- 177 ml/min (hepatopetal) to -1021 +/- 310 ml/min (hepatofugal) p < 0.01). After either procedure total hepatic blood flow (as determined by cardiac green clearance) was not significantly changed, nor was renal blood flow; however, cardiac output was significantly increased after mesocaval shunt. Thus the theoretical hemodynamic goals of the selective distal splenorenal shunt, i.e., preservation of the hepatopetal flow within the portal vein, is achieved as determined in the early postoperative period. The correlation between these changes and the eventual clinical outcome remains to be determined.

Noninvasive kinetic approach to the estimation of total hepatic blood flow and shunting in chronic liver disease--a hypothesis.

The intact hepatocyte theory of chronic liver disease suggests a relationship between the degree of shunting of total liver blood flow around the functional liver cell mass and the fraction of functional liver cell mass. By defining this relationship we have developed pharmacokinetic equations to permit the estimation of both total hepatic blood flow and the extent to which this blood flow is shunted. The method requires the determination of the systemic (hepatic) clearances of a high (e.g., indocyanine green [ICG]) and a low (e.g., antipyrine [AP]) extraction ratio drug in the same patient. Applying these equations to literature data obtained from patients with moderate or severe chronic liver disease and from patients with a surgical portacaval shunt, we find: (1) a modest decrease in total hepatic blood flow (16%) and a significant degree of shunting (27%) in patients with moderate chronic liver disease; (2) a substantially reduced total hepatic blood (52%) and extensive shunting (72%) in patients with severe chronic liver disease, and (3) a degree of shunting comparable to that estimated in patients with moderate chronic liver disease but a seriously compromised total hepatic blood flow (a reduction of 55% compared to normal) in patients with surgical portacaval shunts.

Portal pressure reduction induced by partial mechanical obstruction of the superior mesenteric artery in the anesthetized dog

In an effort to avoid the potentially dangerous side effects of vasopressin infusions, we attempted to reproduce mechanically the splanchnic hemodynamic changes induced by vasopressin without its systemic effects. Superior mesenteric arterial pressure was reduced to 50 to 70 mm Hg for 30 to 60 min in 10 normal dogs by partial balloon obstruction of the superior mesenteric artery. Balloon inflation caused a decrease in portal venous pressure (5.6 ± 0.6 versus 2.8 ± 0.7 mm Hg), hepatic vein wedge pressure (4.8 ± 0.4 versus 2.3 ± 0.5 mm Hg), and portal vein flow (424 ± 53 versus 275 ± 52 ml per min), and an increase in hepatic arterial blood flow (172 ± 19 versus 217 ± 29 ml per min). Total hepatic blood flow and oxygen delivery to the liver were unchanged. Partial balloon obstruction caused an increase in cardiac output (1950 ± 203 versus 2317 ± 376 ml per min) and mean arterial pressure (138 ± 6 versus 151 ± 7 mm Hg), whereas heart rate did not change. Partial balloon obstruction of the superior mesenteric artery caused similar changes in splanchnic hemodynamics to those of vasopressin infusions into the superior mesenteric artery, but without the potential deleterious effects of vasopressin on systemic hemodynamics.