Intrahepatic vascular resistance (IHVR) seems to be located at the level of the portal venules (presinusoidal) or sinusoids (Sherman et al, 1996; Shibayama & Nakata, 1985; Zhang et al, 1994, 1995). Knisley suggested the presence of sphincter-like structures at the entrance and exit of sinusoids that maintain tremendous portal venous pressure gradients, but these may be species dependent (Knisley et al, 1957). In dogs and cats, IHVR is located at the level of hepatic venules (postsinusoidal) under resting conditions (Lautt et al, 1986, 1987), whereas it may be shifted to presinusoidal sites during neural stimulation (Greenway & Lautt, 1970; Legare & Lautt, 1987). Sinusoidal contraction in response to the vasoconstrictor endothelin (ET) 1 has been observed despite the lack of smooth muscle (Bauer et al, 1994, 1995; Okumura et al, 1994; Zhang et al, 1994, 1995). This contractility is mainly attributed to hepatic stellate cells—also called Ito cells, lipocytes, and fat-storing cells—which are distinguished by autofluorescence derived from their intracellular vitamin A (Suematsu et al, 1995; Zhang et al, 1994). ET-1 causes reversible and graded contraction of isolated stellate cells in tissue culture and results in narrowing of sinusoidal lumens in perfused livers (Pinzani et al, 1992; Rockey & Weisiger, 1996; Rockey et al, 1992; Zhang et al, 1994). Hepatic stellate cells have been compared to pericytes, because they contain smooth muscle–specific intermediate desmin-like and actin-like filaments that encircle neighboring sinusoids (Greenwel et al, 1991; Martinez-Hernandez, 1985; Martinez-Hernandez & Amenta, 1993; see Chapter 6).

Studies using intravital fluorescent microscopy showed that the sites of sinusoidal dilation and constriction is colocalized with that of an autofluorescent vitamin A substance (Suematsu et al, 1995, 1996; Zhang et al, 1994, 1995). Hepatic stellate cells acting as liver-specific pericytes (Friedman, 1997; Martinez-Hernandez, 1985; Martinez-Hernandez & Amenta, 1993) may play a crucial role in modulating IHVR and blood flow, especially at the sinusoidal level (Bauer et al, 1994; Okumura et al, 1994; Pannen et al, 1996; Zhang et al, 1994, 1995). Endothelium-derived nitric oxide (NO) in the hepatic sinusoids may modulate portal resistance under physiologic circumstances (Bauer et al, 1997; Shah et al, 1997). Electron microscopy studies have also demonstrated the presence of smooth muscle cells in the sublobar veins (Aharinejad et al, 1997), as well as terminal hepatic venules (Sasse et al, 1976), which may contribute to IHVR.

Relationship between Hepatic Artery and Portal Vein Blood Flow

Individual control of the hepatic arterial and portal venous circulations is complicated by the existence of a complex interaction between the two systems within the liver. Studies have shown an increase in hepatic arterial blood flow following reduction of portal blood flow (Kock et al, 1972; Mathie et al, 1980a; Schenk et al, 1962); however, a compensatory increase in portal flow following decreased arterial perfusion has rarely been observed (Mathie, 1997). Intraoperative measurements of hepatic artery and portal vein flow in anesthetized patients demonstrated a significant increase in hepatic arterial flow, up to 30% of baseline, with temporary occlusion of the portal vein and no effect on portal flow on occlusion of the hepatic artery (Jakab et al, 1995).

The ability of the hepatic artery to respond acutely to changes in portal flow is referred to as the hepatic arterial buffer response (Lautt, 1981). Highlighting its early embryonic origin, in experiments measuring fetal hepatic arterial blood flow, it has been shown that this regulatory process is even present prenatally (Ebbing et al, 2008). Experimental studies support the view that adenosine, accumulating in the liver as a result of reduced hepatic outflow or released from the walls of blood vessels in response to partial tissue hypoxia, has a significant role in the regulation of the buffer response (Lautt & Legare, 1985; Mathie & Alexander, 1990). This adenosine washout hypothesis is supported by the fact that portal infusion of adenosine increases hepatic arterial blood flow by one half to one third the amount of direct arterial instillation (Lautt et al, 1987). The demonstration of receptors mediating dilation to adenosine in the hepatic arterial vascular bed reinforces this view (Mathie et al, 1991; Fig. 4.1).

FIGURE 4.1 Diagrammatic representation of the microvascular bed of the liver, showing the anatomic association between hepatic arterioles, portal venules, and bile ductules. The probable site of action of vasoactive agents on the hepatic arterial circulation is indicated.

Metabolism

Hepatic arterial blood flow has not been traditionally linked to liver metabolism (Lautt, 1983; Mathie & Blumgart, 1983a). It has been shown that neither altered oxygen supply nor bile secretion causes a dependent change in arterial flow (Lautt, 1983); instead, the physiologic role of the buffer system is to maintain hepatic clearance in the face of reduced portal flow and to maintain adequate tissue oxygenation. This is despite the fact that the liver receives more oxygen than it requires and can therefore extract more by hepatocyte metabolism if needed. Therefore arterial flow is independent of oxygenation and is secondary to the nutrient and hormonal needs of the liver.

Blood Gas Tensions

Experimental studies have attempted to clarify the role of arterial blood gas tensions and pH on the hepatic circulation. Hypercarbia (Paco₂ > 70 mm Hg) increases portal venous flow and decreases hepatic arterial flow in dogs (Hughes et al, 1979a), whereas hypocarbia (Paco₂ < 30 mm Hg) decreases both (Hughes et al, 1979b). Systemic hypoxia (Pao₂ < 70 mm Hg) causes a decrease in arterial flow but has no effect on the contribution from the portal vein (Hughes et al, 1979c). The response to metabolic acidosis is similar to that induced by hypercarbia, whereas metabolic alkalosis has essentially no significant effect (Hughes et al, 1980b). The sympathetic nervous system is thought to be responsible for the hepatic arterial vasoconstriction observed in hypercarbia and hypoxia (Mathie & Blumgart, 1983b).

Sympathetic Nervous System

Denervation experiments have shown that the sympathetic nervous system is not involved in basal arterial tone in the liver (Mathie & Blumgart, 1983b). Hepatic sympathetic nervous stimulation causes hepatic arterial vasoconstriction and reduced blood flow, but this is secondary to the autoregulatory response (Greenway & Stark, 1971). Sensory denervated rats and pigs have a diminished arterial buffer response on partial occlusion of the portal vein (Ishikawa, 1995). Portal pressure increases as a result of an increase in portal venous resistance, but portal flow does not decrease, unless there is a decrease in intestinal or splenic blood flow caused by simultaneous sympathetic stimulation of these vascular beds. The liver is a significant blood reservoir, and 50% of its blood volume may be mobilized by nerve stimulation (Greenway & Lautt, 1989).

Although the hepatic artery contains both α-adrenergic and β-adrenergic receptors, the portal venous system is believed to contain only α-receptors (Richardson & Withrington, 1981). At low doses, epinephrine causes hepatic and mesenteric arterial vasodilation, whereas at high doses, vasoconstriction occurs in the hepatic arterial and portal venous vascular beds and in the mesenteric circulation (Greenway & Stark, 1971; Richardson & Withrington, 1981).

Other Endogenous Vasoactive Agents

Hepatic blood flow is profoundly increased by glucagon as a consequence of its strong vasodilatory action on the mesenteric vasculature, but insulin has little hemodynamic effect on the hepatic circulation. Histamine causes hepatic arterial dilation and, in the dog only, hepatic venous constriction. Bradykinin is a potent hepatic arterial vasodilator that has little effect on the portal venous system. The hepatic arterial vascular bed is dilated by most prostaglandins; however, prostacyclin does not affect hepatic arterial flow but increases portal blood flow through a vasodilator effect on the prehepatic vascular bed. NO causes vasodilation in the hepatic arterial and mesenteric vascular beds as discussed earlier. Each of the gut hormones—gastrin, secretin, cholecystokinin, and vasoactive intestinal peptide—causes vasodilation of the hepatic artery. In addition, antagonists of calcitonin gene–related peptide and neurokinin significantly reduce hepatic arterial blood flow, suggesting the presence of their receptors on the arterial vasculature (Biernat et al, 2005).

Angiotensin decreases hepatic arterial and portal blood flow and is one of the few substances to produce a significant vasoconstrictor effect on the hepatic artery. However, the ETs that can exert a powerful and prolonged generalized systemic constriction (Miller et al, 1989; Zhang et al, 1994) also have a direct effect on the hepatic blood flow. ETs reduce hepatic perfusion (Kurihara et al, 1992), increase portal pressure (Bauer et al, 1994; Isales et al, 1993; Tanaka et al, 1994; Tran-Thi et al, 1993), and reduce sinusoidal diameter (Bauer et al, 1994; Okumura et al, 1994; Zhang et al, 1994). Vasopressin decreases portal flow and pressure by mesenteric arterial vasoconstriction but has variable effects on the hepatic artery. Serotonin is believed to mediate vasoconstriction of portal radicles and has been targeted as a substance involved in the maintenance of portal hypertension, which will be discussed later. In contrast, hydrogen sulfide either endogenously or exogenously can reverse the norepinephrine-induced vasoconstriction in an NO-independent fashion (Fiorucci et al, 2005). Intraportal administration of exogenous vasoactive agents affects hepatic arterial resistance (Lautt et al, 1984); the mechanisms underlying this intrahepatic transvascular effect are not understood, but it is likely that the close anatomic association between arterioles and venules (see Fig. 4.1) could permit this and may be a means by which hepatic arterial blood flow is finely controlled by endogenous agents such as gut hormones.

Anesthetic Agents

Hepatic arterial and portal venous blood flow decreases passively in parallel with cardiac output during halothane inhalation, with little change in vascular resistance (Hughes et al, 1980a; Thulin et al, 1975). Hepatic oxygen consumption is not diminished by halothane because of a marked increase in the oxygen extraction rate from the reduced blood supply (Andreen et al, 1975). Enflurane has been found to have similar effects to those of halothane, although there is a decrease in hepatic arterial vascular resistance as part of a generalized decrease in peripheral vascular resistance (Hughes et al, 1980a). Cyclopropane and methoxyflurane reduce LBF, mainly by increasing the mesenteric vascular resistance (Batchelder & Cooperman, 1975). NO in concentrations of 30% to 70% reduces hepatic artery and portal vein flow, possibly as a result of a generalized stimulatory action on α-adrenergic receptors (Thomson et al, 1982). Isoflurane seems to have minimal effects on hepatic arterial and portal venous flows, and the intravenous agent fentanyl may have little effect on prehepatic splanchnic blood flow (Nagano et al, 1988); thiopentone in low doses vasoconstricts the hepatic arterial and mesenteric vascular beds (Thomson et al, 1986).

Measurement of Liver Blood Flow

The earliest methods of measuring LBF involved direct invasive techniques, such as intravascular devices or venous outflow collection (Burton-Opitz, 1910, 1911; MacLeod & Pearce, 1914). Indirect determination of blood flow by the use of a variety of indicator-clearance techniques were subsequently developed but were confounded by the presence of liver disease. The available methods are discussed under three broad headings: 1) flow in single blood vessels, 2) total LBF, and 3) hepatic tissue perfusion. The techniques currently employed for experimental and clinical investigations are listed in Table 4.1.

Table 4.1 Summary of Methods Currently Used for Measuring Liver Blood Flow

Flow in Single Vessels

Electromagnetic flowmeter

Doppler ultrasound

Total Liver Blood Flow Hepatic Tissue Perfusion

Laser Doppler flowmetry

Flow in Single Vessels

Noninvasive

In experiments performed on anesthetized dogs, good correlation was found between portal venous flow measured by a transcutaneous Doppler duplex system and electromagnetic flow probes fitted to the portal vein (Dauzat & Layrargues, 1989). However, the clinical application of transcutaneous Doppler ultrasound to obtain quantitative hepatic blood flow measurements in the portal vein have been more difficult (Burns et al, 1987). This technique has been utilized to assess postoperative hemodynamic consequences of portosystemic shunt procedures, such as transjugular intrahepatic portosystemic stent shunt (TIPS) (see Chapter 96; Fung et al, 1998), and for diagnosis of cirrhosis and portal hypertension (Iwao et al, 1997). In normal subjects, portal blood flow of 600 to 900 mL/min was reported (Brown et al, 1989; Moriyasu et al, 1986), whereas blood flow in the common hepatic artery was reported to be approximately 250 mL/min (Nakamura et al, 1989). The use of color Doppler has improved the suitability of the Doppler method for routine clinical use (Rosemurgy et al, 1997). The availability of ultrasound echo-enhancing materials, such as the galactose-based microbubble agent Levovist (Ernst et al, 1996), may further improve the precision of hepatic blood flow measurement and imaging using the Doppler technique.

Total Liver Blood Flow

Clearance Techniques

The rate of disappearance from the bloodstream of an indicator substance exclusively cleared by the liver is proportional to LBF. First applied to humans by Bradley and colleagues in 1945, indirect clearance methods of LBF measurement rely on the Fick equation. The flow measurement obtained by Bradley’s group depended on the fact that intravenously injected bromosulfophthalein is removed from the bloodstream and into the bile entirely by hepatocytes. They derived a value for the rate of hepatic bromosulfophthalein removal indirectly by determining the rate of intravenous infusion of dye that maintained the arterial concentration at a constant level, and by measuring the arteriovenous concentration difference of bromosulfophthalein, they were able to calculate total hepatic blood flow. The mean value obtained in a group of normal subjects was 1.5 L/min.

Other substances dependent on hepatocyte extraction into bile have also been applied, such as indocyanine green (Caesar et al, 1961). None of these substances achieve complete hepatic removal, and hepatic vein cannulation is necessary to allow calculation of the true extraction efficiency. Many investigators now use a simplified version of the original method, in which indocyanine green is administered as a bolus, instead of as an infusion, and hepatic extraction efficiency is determined from an analysis of the clearance curve derived from blood samples taken from a peripheral vein, instead of from the hepatic vein (Grainger et al, 1983). Limitations of this technique include extrahepatic shunting, which is common in liver disease and results in an underestimation of blood flow. Other hepatic clearance techniques have been used, such as colloidal clearance by the hepatic Kupffer cells (Dobson & Jones, 1952) and hepatocyte removal of galactose (Keiding, 1988), sorbitol (Zeeh et al, 1988), rose bengal (Combes, 1960), or propranolol (George, 1979). The more complete hepatic extraction of these substances overcomes the need to cannulate a hepatic vein in patients with normal liver function.

A modification of the colloid extraction method developed in the 1980s allows the derivation of the ratio of hepatic arterial to total LBF, termed the hepatic perfusion index. The basis of the technique is the ability to determine by dynamic scintigraphy the temporal separation of accumulating hepatic activity from the arterial and portal supplies after the intravenous administration of a bolus of technetium-99m–sulfur colloid (Fleming et al, 1981; Parkin et al, 1983).

Indicator Dilution

The indicator dilution method relies on the application of the Stewart-Hamilton principle, also derived from the Fick equation (Stewart, 1897). In principle, the hepatic blood flow is proportional to the amount of hepatic blood that has diluted an introduced indicator. This method involves the injection into the hepatic artery and portal vein of a labeled substance that is not removed by the liver; changes in hepatic vein concentration are measured by blood sampling or by monitoring the hepatic isotope activity with an external detector. Such a method is therefore independent of hepatocellular function and reliable, provided the indicator remains in the vascular space and is not excreted prior to sampling. In addition, sampling must not be done in such a manner that affects hepatic circulation, or not more than 30 mL/min in dogs (Cohn et al, 1969).

Portal vein flow may be determined separately using a modification of this technique by sampling portal blood after splenic vein or superior mesenteric artery injection (Chiandussi et al, 1968; Huet et al, 1973). Hepatic artery flow may be calculated as the difference between total hepatic flow and portal flow. In addition, a modified thermal dilution technique has been used to measure portal blood flow in humans (Biber et al, 1983). Indicator dilution methods overestimate true blood flow to hepatic tissue when intrahepatic or extrahepatic shunts are present, although it is possible to measure azygos blood flow by thermal dilution in patients with cirrhosis (Bosch & Groszmann, 1984).

Indicator Fractionation

The measurement of regional blood flow by fractional distribution of cardiac output was first described by Sapirstein in 1956. Briefly, a known amount of radioactive microspheres is injected into the left ventricle, and a reference sample is withdrawn from a peripheral artery at a known rate. The microspheres are then extracted from the various vascular beds, where they have lodged in proportion to the cardiac output. The hepatic arterial blood flow is determined directly by this method, but the portal flow contribution is found indirectly by addition of the flow values in the prehepatic splanchnic organs. Examination of the intrahepatic distribution of microspheres provides a means of assessing the pattern of arterial flow in different regions of the liver (Greenway & Oshiro, 1972). Because the microsphere method requires the postmortem removal of the organs of interest for radioactivity or colorimetric measurement, the additional determination of tissue weight enables flow per gram (i.e., tissue perfusion) to be calculated. Microspheres may be employed to determine the extent of portosystemic shunts: the fractional distribution in the liver may be measured with respect to systemic (lung) activity after portal vein injection, or it may be estimated by injecting a second radioactive microsphere directly into the splenic or mesenteric venous system (Groszmann et al, 1982).

Hepatic Tissue Perfusion

Inert Gas Clearance

By exploiting the fact that radioactive gases such as krypton (⁸⁵Kr) and xenon (¹³³Xe) distribute equally between tissue and blood according to a specific partition coefficient, the rate of clearance of such gases can be measured after their injection into the hepatic blood supply. After injection and rapid diffusion throughout the liver, the gas clears from the tissue into the blood and is almost completely eliminated from the body after a single passage through the lungs. The clearance rate is proportional to hepatic tissue perfusion, which may be calculated using a standard formula (Leiberman et al, 1978). Beta-emissions of ⁸⁵Kr are recorded by a Geiger-Müller tube or semiconductor (silicon) detector placed on or immediately above the exposed liver surface, while the γ-emissions of ¹³³Xe are monitored transcutaneously by a single scintillation crystal or a γ-camera; the latter device allows simultaneous measurement of hepatic tissue perfusion in many regions of interest.

Inert gas techniques involve minimal trauma to the patient, and their accuracy is not markedly affected by the presence of hepatic cellular disease or nonperfusion shunts; however, some variability does occur, even within the same subject, when multiple studies are performed. The first to use the inert gas method in the hepatic circulation were Aronsen and colleagues (1966), who recorded the γ-emissions of ¹³³Xe after the injection of a saline solution of the isotope into the portal vein.

Laser Doppler Flowmetry

Laser Doppler flowmetry (LDF) is a more recent but established technique for the real-time measurement of microvascular red blood cell perfusion in the liver. By illuminating the tissue with low-power laser light and capturing the backscattered light with independent photodetectors, the Doppler shift of moving cells can be transmitted as an electrical signal. Linearity of the LDF signal from the liver with total organ perfusion has been shown (Almond & Wheatley, 1992; Shepherd et al, 1983, 1987), and the technique has been shown to be sensitive to rapid changes in organ flow (Almond & Wheatley, 1992). In a rat model, the technique provided a good measure of hepatic perfusion in vivo (Wheatley et al, 1993a; Fig. 4.3). LDF has also been used successfully to assess LBF during shock and resuscitation (Wang et al, 1995) and during drug-induced changes in LBF in the rat (Kurihara et al, 1992), and the technique has been applied successfully to measure LBF during liver transplantation in humans (Seifalian et al, 1997). A major drawback of the technique is that, owing to the small volume of tissue interrogated by the laser, the LDF signal can only be used to measure arbitrary, instead of absolute, blood perfusion in a single area. The development of laser Doppler perfusion imaging devices that estimate tissue perfusion by scanning an area of tissue using a laser may overcome the problem of signal calibration (Wardell et al, 1993).

FIGURE 4.3 LDF measurements during a single liver transplantation in the rat. The arrow shows the point at which the hepatic artery was opened. HA, hepatic artery; IVC, inferior vena cava; LDF, laser Doppler flowmetry; OLT, orthotopic liver transplantation; PV, portal vein.

(From Wheatley AM, Zhao D, 1993: Intraoperative assessment by laser Doppler flowmetry of hepatic perfusion during orthotopic liver transplantation in the rat. Transplantation 56:1315-1318.)

In Vivo Fluorescent Microscopy

Intravital microscopy was first described in the microvessels of the frog tongue by Waller in 1846. Using this technique, individual sinusoids and terminal venules can be visualized, and changes in their diameters and the velocities with which erythrocytes pass through them can be seen (Menger & Messmer, 1991; Fig. 4.4). The introduction of fluorescent dyes has broadened the spectrum of in vivo microscopy in the liver from morphologic analysis to the study of pathologic events. However, from a hemodynamic point of view, intravital fluorescent microscopy has problems of interpretation (Sherman et al, 1990). In perfused liver, a 2.5-fold increase in portal venous blood flow has been found to be associated with only a 22% increase in sinusoidal red blood cell velocity, suggesting that changes in portal venous blood flow have only a minor effect on the capillary transit time (Sherman et al, 1996). In the regenerating liver; however, a 50% increase in portal venous blood flow resulted in a similar (66%) increase in sinusoidal red blood cell velocity (Wheatley et al, 1996; Zhang et al, 1997).

FIGURE 4.4 Hepatic hemodynamic and cellular alterations observed in cirrhotic livers with intravital fluorescent microscopy. Note the characteristic alterations in cirrhotic livers with regard to distension of the central veins (A, control vs. B, cirrhotic), reduction in number of sinusoids feeding directly into the central veins (C, control vs. D, cirrhotic), and movement of hepatic stellate cells (as measured by their vitamin A autofluorescence) from a homogeneous distribution in control livers (E) to a heterogeneous distribution focused around and along fibrous bands connecting the central veins (F).

Near-Infrared Spectroscopy

Near-infrared spectroscopy is a new noninvasive technique that utilizes light transmission and absorption to measure hemoglobin and mitochondrial oxygenation. In contrast to visible light, which can only penetrate a few millimeters, near-infrared light (700 to 1000 nm) can be detected through up to 80 mm of tissue. The application of this technology to monitor liver oxygenation has been validated in models of endotoxic shock in pigs (Nadhum, 2006) and by intraoperative quantification of congestion and mitochondrial redox during hepatic vein occlusion in living-donor transplantation (Ohdan, 2003).

New and Future Developments

Orthogonal polarized spectral imaging has been used to obtain images of the liver microcirculation comparable to those of fluorescence microscopy but without the need for fluorescent dyes (Langer, 2001). This system relies on the absorbance of hemoglobin and can discriminate a single red blood cell in an individual capillary with a diameter of 5 microns. Studies with hand-held devices using this technology have been applied to healthy living donors to obtain sinusoidal red blood cell velocity and columetric blood flow (Puhl et al, 2003). A recent successor to spectral imaging is sidestream dark field imaging, whereby a light guide surrounded by diodes can detect both red and white blood cells in the microcirculation without the surface reflections (Czerny et al, 2009). Portal venous blood flow measured by noninvasive magnetic resonance imaging (MRI) has been found to correlate well with flow measured by Doppler ultrasound flow probes (Pelc et al, 1992); subsequently, the technique has been used to measure portal venous blood flow in human liver transplantation candidates (Kuo et al, 1995). Further methodology improvements in MRI (e.g., dynamic contrast enhancement) and in other techniques, such as positron emission tomography, may lead to their increasing use in the study of hepatic hemodynamics in humans (Chow et al, 2003).

Clinical Relevance

Hemorrhagic Shock, Hypoperfusion, and Ischemia-Reperfusion Injury

Total LBF decreases approximately in relation to the degree of the hemorrhage, and portal venous blood flow decreases in parallel to cardiac output; but similar to the coronary, pulmonary, and cerebral circulations, hepatic arterial flow does not decrease until extremely low blood pressures are reached. As a result, the hepatic oxygen supply tends to be maintained, although oxygen extraction greatly increases to preserve normal total oxygen consumption (Smith et al, 1979). Hepatic blood volume can increase significantly in cardiac failure and can compensate up to 25% of hemorrhage from its large capacitance vessels (Lautt, 2007).

The clinical entity known as shock liver has long been recognized, typically related to cardiogenic or hemorrhagic shock (Birgens et al, 1978; Bynum et al, 1979). Hepatic dysfunction caused by hypoperfusion is manifested pathologically by centrilobular necrosis and clinically by abdominal pain, cholestatic jaundice, and marked elevation of serum transaminases. Three phases of liver injury attributed to ischemia were proposed by Champion, whereby the initial hepatic dysfunction would resolve as long as no additional insults (e.g., sepsis) were incurred (Champion et al, 1976). Gottlieb and colleagues (1983) showed that hepatic dysfunction in humans after trauma was related to a reduced hepatic blood flow rate up to 70% of resting levels. Hepatic blood flow was markedly reduced after injury, and although total splanchnic oxygen delivery was decreased, oxygen consumption remained normal as a result of increased hepatic extraction.

In the ischemic state, upregulation of acute-phase proteins (C-reactive protein, fibrinogen, ceruloplasmin, haptoglobin) is prioritized over production of other hepatic proteins such as albumin and transferrin (Sganga et al, 1985).

More recently, hemorrhagic shock has been recognized to result in generalized vascular endothelial dysfunction and impaired endothelial biosynthesis of NO. Endothelial NO that continues to be expressed by the liver during ischemia is believed to protect against the initial hepatic injury arising from severe hemorrhage. By contrast, more prolonged hemorrhagic shock (>6 hours’ duration) induces greatly increased production of NO owing to activation of an inducible NO synthase enzyme in hepatocytes and Kupffer cells (Peitzman et al, 1995).

Survival has been demonstrated after portal vein ligation to control hemorrhage after traumatic injury (Pachter et al, 1979) or after temporary portal occlusion during difficult biliary tract surgery. Similarly, survival after hepatic artery ligation for trauma, aneurysm, hemobilia, or neoplasms has been described (Rappaport & Schneiderman, 1976). In the transplantation era, the consequences of ischemia and reperfusion for the liver have been increasingly investigated and understood. The damage to the hepatic endothelium and parenchyma that results from postischemic reperfusion is caused by numerous interrelated phenomena, including the action of locally liberated oxygen-derived free radicals and excess formation of vasoconstrictor agents (Wendon, 1999). Endogenous NO tends to protect the liver in the early reperfusion period after hepatic ischemia (Shimamura et al, 1996; Wang et al, 1995). Ischemia is also the primary signal for heat-shock protein production in liver tissue. Experimental studies of heat-shock protein preconditioning through intermittent portal clamping demonstrated attenuated transaminase elevations and improved bile production after ischemia (Terajima et al, 1999).

Liver Atrophy

Liver atrophy results from a significant reduction of LBF containing hepatotrophic substances (see Chapter 5). The degree of atrophy depends on the degree of blood flow deprivation and may be distributed according to the source of deprivation, including portal venous or hepatic artery blood flow or their combination.

Atrophy and fatty degeneration of the canine liver after total portal diversion through an Eck fistula initially was reported more than a century ago (Hahn et al, 1893). Partial or complete diversion of portal vein blood flow from the liver results in atrophy. Complete portal venous flow diversion with interruption of all portal venous collaterals results in more profound liver atrophy than the partial deviation of portal venous flow resulting from side-to-side portacaval anastomoses (Bollman, 1961). A precise relationship between the degree of liver atrophy and the reduction of portal venous blood flow is still to be determined, primarily because of the relative composition and contribution of portal flow and resultant compensatory hepatic arterial flow.

Liver atrophy after portal diversion is not believed to be the result of a decrease in absolute volume flow but instead is due to the effective loss of hepatotrophic substances in the portal blood. Rats subjected to portal flow diversion with portacaval transposition had a decrease in relative liver weight (Guest et al, 1977) despite the effective preservation of portal perfusion from the inferior vena cava (Ryan et al, 1978). Dogs with “partial portacaval transposition” (Marchioro et al, 1967) or “splanchnic flow division” (Starzl et al, 1973, 1975) with diversion of pancreaticogastroduodenosplenic blood had atrophy in liver lobes, although normal tissue perfusion was shown in all regions of the liver (Mathie et al, 1979). Starzl hypothesized that insulin was the factor responsible for preventing atrophy.

The fate of the liver after ligation of the hepatic artery depends largely on the extent of a functional collateral arterial circulation (Rappaport & Schneiderman, 1976). If limited collaterals are present, liver infarction and necrosis may occur after hepatic artery ligation, resulting in death. However, hepatic artery ligation results only in transient ischemic changes in the periphery of the hepatic acinus (zone 3) in the presence of adequate collaterals. Atrophy after hepatic artery ligation can occur in liver segments that have compensatory collateral supply to prevent necrosis. The effects of hepatic artery flow absence are magnified by the presence of low portal venous blood flow, limited oxygen saturation, and superimposed infection (Rappaport & Schneiderman, 1976). Histologically, arterial obstruction results in ischemic changes such as mitochondrial swelling, cell membrane disruption, platelet aggregation, and widening of the spaces of Disse (Mallet-Guy et al, 1972).

Liver Resection and Regeneration

As exemplified in Greek mythology by the myth of Prometheus, the adult liver exhibits a remarkable potential to restore its cellular mass in response to injury through hepatocyte hyperplasia. After the removal of two thirds of liver mass in the rat by partial hepatectomy, liver mass and function are fully recovered by 2 to 3 weeks. In the early stages of regeneration, as a consequence of hepatocyte division, clusters of hepatocytes develop with a reduced distribution of sinusoids (Martinez-Hernandez & Amenta, 1995). Hepatic regeneration of the normal liver remnant proceeds rapidly after partial hepatic resection (see Chapters 4 and 80; Aronsen et al, 1970; Blumgart et al, 1971).

Major resection is associated with a significant and persistent increase in portal pressure (Lee et al, 1987; Morsiani et al, 1995; Wu et al, 1993). Partial liver resection without devascularization normally would be expected to produce little change in total blood flow to the liver. This occurs because the major contributor to total flow, the portal vein, is affected less by events occurring within the liver than by control mechanisms in the arterial resistance vessels of the prehepatic splanchnic bed. On the other hand, the failure of the liver to directly control its portal venous flow may have the result of portal hyperperfusion of a reduced parenchymal mass. Because essentially the same total blood flow is redistributed to a smaller mass of liver tissue, a corresponding increase in tissue perfusion (mL/min per unit tissue weight) would be anticipated in the in situ remnant. Experimental studies support these expectations; an increase in hepatic tissue perfusion was observed in rats immediately after two-thirds hepatectomy (Rice et al, 1977; Wheatley et al, 1993b; Wu et al, 1993). This increase in hepatic perfusion is due primarily to portal venous inflow (Wu et al, 1993), because hepatic arterial blood flow is low, and hepatic arterial resistance is high even 24 hours after partial hepatectomy in rats (Wheatley et al, 1996). Similar studies in patients showed an immediate increase in tissue perfusion of approximately 120% in the remnant (Mathie & Blumgart, 1982). Recent experimental evidence has suggested that intrahepatic shear stress from increased portal flow is a regulator of liver regeneration (Schoen et al, 2001). The significance of blood flow in relation to liver regeneration has been debated frequently in the years since Mann (1944) suggested that regenerative hyperplasia of the liver after partial resection was a function of portal blood flow, and that the process could be prevented by portal flow diversion. However, regenerative hyperplasia normally occurs after partial liver resection in portacavally transposed animals, in which there is no direct supply of portal blood nor the usual posthepatectomy increase in hepatic tissue perfusion. A similar response is seen during portal vein embolization for preoperative expansion of the liver remnant (see Chapter 93A, Chapter 93B ).

Blood Flow in Hepatic Tumors

It has been demonstrated that tumors of the liver, whether primary or secondary, are perfused almost exclusively with arterial blood (Breedis & Young, 1954). Several investigators have attempted to achieve differential diagnosis of patients by measuring the proportion of the hepatic arterial contribution to total flow, adopting the hepatic perfusion index obtained by scintigraphy (Leveson et al, 1985) or the Doppler perfusion index obtained by ultrasound (Leen et al, 1991a). Such measurements have shown an increased hepatic arterial contribution in patients with confirmed liver metastases compared with normal subjects. Patients who have colorectal cancer with no observed liver metastases were found to have altered hemodynamics that overlapped those of the other groups, suggesting the presence of occult hepatic disease (Leen et al, 1991b). The Doppler perfusion index has been shown to be more sensitive than computed tomography, conventional ultrasound, or laparotomy alone in the detection of colorectal liver metastases (Leen et al, 1995).

Taking advantage of this phenomenon, the application of the vasoconstrictors epinephrine, phenylephrine, or angiotensin has improved cytotoxic drug delivery to tumor-bearing areas in human and animal models (Bloom et al, 1987; Goldberg et al, 1991; Hemingway et al, 1991). This approach is feasible because the neovasculature of tumor tissue lacks smooth muscle and therefore does not respond to vasoconstrictor agents, enabling increased delivery of chemotherapeutic drugs. Biodegradable microspheres also have been used for enhancing targeted therapy; they cause temporary blood flow interruption, resulting in improved uptake of chemotherapeutic agents in tumor tissue and consequent reduced systemic toxicity (Ball, 1991). Multiple drugs have been utilized in the palliative setting for percutaneous intrarterial instillation, and these can be loaded into the two current commercially available microsphere systems, DC Bead and QuadraSphere (Liapi et al, 2010).

Bile Duct Obstruction

Bile duct obstruction can affect hepatic hemodynamics significantly (see Chapter 7). In general, LBF is reduced in the presence of chronic biliary obstruction, leading to hepatic dysfunction. Conversely, acute increases in bile duct pressure from early obstruction result in a reflexive increase in LBF, which attempts to maintain adequate flow in the face of an increased pressure gradient opposing secretion and excretion of bile. Most evidence suggests that the hemodynamic response of the liver to biliary obstruction is related, directly or indirectly, to changes in bile duct pressure. Given the limited space of Mall in the portal triad, it is conceivable that increased biliary pressures may compress the portal capacitance vessels, leading to increased arterial flow (Kanda et al, 1996). Nagorney and colleagues (1982) showed that acute serial increases in bile duct pressure in dogs with complete bile duct obstruction increased hepatic arterial blood flow by 250% but did not affect portal venous blood flow.

Chronic bile duct obstruction is associated with a decrease in total LBF. In addition, dilation of the sinusoids and elevation of portal pressure in dogs was noted after 4 weeks of complete bile duct obstruction (Ohlsson et al, 1970). Relief of long-term obstruction does not result in the return of normal hemodynamics, suggesting irreversible intrahepatic vascular damage (Aronsen et al, 1969). Furthermore a 23% reduction in effective LBF persisted for 1 to 5 years after operative decompression in patients with choledocholithiasis and jaundice for more than 2 weeks preoperatively (Aronsen, 1968). Hunt (1979) serially measured LBF daily for 1 week after bile duct ligation in rats, using the ¹³³Xe clearance technique to document the early hemodynamic response. Total LBF decreased steadily after the first postoperative day to a plateau level of approximately 50% of the preoperative value 5 days after operation. Mathie and colleagues (1988) confirmed the decrease in total LBF after bile duct ligation by measuring the individual portal venous and hepatic arterial components of LBF. Using electromagnetic flowmeters in dogs with complete bile duct ligation, hepatic arterial and portal venous blood flow were observed to decrease by 36% and 44%, respectively; they also showed a 200% increase in intrahepatic portal resistance but a lesser increase in hepatic arterial resistance. Similarly, Bosch and others (1983) showed that dogs with chronic bile duct ligation had decreased portal venous flow and had developed sinusoidal portal hypertension and extensive portosystemic shunting.

The precise mechanism for reduction in LBF after chronic bile duct obstruction is unknown. Although increased portal vascular resistance is the accepted underlying cause, the primary site of this resistance change has been considered to be presinusoidal (Reuter & Chuang, 1976), sinusoidal (Bosch et al, 1983), or postsinusoidal (Tamakuma et al, 1975). Bosch and colleagues (1983) also showed the development of significant portosystemic shunting with an inverse correlation between shunting and portal venous blood flow, suggesting that the site of shunting is predominantly extrahepatic (Ohlsson, 1972).

Chronic biliary obstruction results in two hemodynamic consequences: portal hypertension associated with secondary biliary fibrosis and shock after biliary tract decompression. Approximately 20% of patients with prolonged biliary obstruction develop clinically significant portal hypertension (Adson & Wychulis, 1968; Blumgart et al, 1984; Sedgwick et al, 1966). The operative risk of biliary decompression in these patients is significant. Technical difficulties of stricture repair—dense fibrous adhesions, hilar ductal involvement, and infection—are complicated by the risk of hemorrhage from subhepatic and periductal varices and potential postoperative liver failure. Portosystemic shunts may be performed before biliary decompression in patients with bleeding esophageal varices or previous intraoperative hemorrhage that precluded successful stricture repair (Adson & Wychulis, 1968; Sedgwick et al, 1966).

In addition to the hemodynamic consequences of chronic bile duct obstruction, sudden decompression of the obstructed biliary tree also may have profound hemodynamic effects. Tamakuma and colleagues (1975) studied the significance of clinical shock after biliary decompression and noted that hypotension and shock could develop in the immediate postoperative period. They showed that biliary decompression resulted in an abrupt decrease in wedged hepatic vein pressure, portal vein pressure, and arterial pressure within 30 minutes of decompression. Similarly, Steer and colleagues (1968) reported that rapid needle decompression of an obstructed biliary tree in jaundiced dogs induced a decreased arterial pressure, central venous pressure, and portal venous pressure within 1 hour; they concluded that sudden decompression of chronic biliary obstruction leads to sequestration of fluid within the liver, resulting in a decrease in the effective circulating plasma volume and subsequent hypotension.

Portal Hypertension (See Chapter 70A, Chapter 70B, Chapter 74 )

Hemodynamics

Portal hypertension is a state of sustained increase in the intraluminal pressure of the portal vein and its collaterals. A mean pressure greater than 12 mm Hg is the accepted target, as variceal bleeding does not occur at lower pressures than this (Garcia-Tsao et al, 1985). Hemodynamic factors that influence portal hypertension are best understood by application of the flow-resistance principle that applies to the portal venous system. Portal pressure depends on two basic components: portal blood flow and hepatic portal vascular resistance. Portal hypertension may result from a significant increase in hepatic portal inflow from the prehepatic splanchnic vasculature, an increase in intrahepatic portal resistance, or both. Although simple in concept, multiple factors may influence both the components of the system and the pathophysiology of portal hypertension.

Increased portal pressure, diminished hepatic portal blood flow, and an extensive extrahepatic collateral venous network supplied by a hyperdynamic splanchnic and systemic circulation characterize the hemodynamics of portal hypertension (e.g., in cirrhosis). The traditional view of the source of increased portal pressure is fibrotic encroachment around portal radicles, leading to increased intrahepatic portal resistance. In cirrhotic patients, extrahepatic shunts may account for at least 50% of the portal flow, whereas 80% of portal flow actually reaching the liver has been observed to bypass the sinusoidal vascular bed via intrahepatic shunts (Okuda et al, 1977). The magnitude of extrahepatic shunt flow in patients with cirrhosis was measured directly by thermal dilution assessment of azygos blood flow; a value 300 mL/min greater than in patients without portal hypertension was noted (Bosch & Groszmann, 1984). The hepatic artery probably provides a greater relative contribution to the total LBF in patients with cirrhosis than in normal subjects, although it also was shown that 33% of the arterial blood may flow through intrahepatic shunts to the systemic venous circulation (Groszmann et al, 1977).

The direction of portal blood flow has been proposed as a contributor to the pathophysiology of portal hypertension. The progression of intrahepatic disease and increasing sinusoidal pressure has been postulated as contributing to reversal of flow in the portal vein, which further aggravates the injury by depriving the liver of nutrients (Warren & Muller, 1959). However, reversed, or hepatofugal, portal vein flow has rarely been documented. Hemodynamic information from 273 cirrhotic patients collected from the literature in the 1970s revealed no case of spontaneous flow reversal (Moreno et al, 1975), and Gaiani and colleagues (1991) reported an incidence of only 3.1% in a sample of 228 patients.

The hypothesis that the low peripheral vascular resistance in portal hypertension may be caused by the stimulated production of NO induced by endotoxemia was proposed by Vallance and Moncada in 1991. The initial experimental evidence was provided by Pizcueta and others (1992), who showed an increase in systemic and splanchnic vascular resistance in cirrhotic rats after the administration of an NO inhibitor. Although endotoxemia is likely responsible for the decompensation in end-stage cirrhosis, the hemodynamic alterations are due to NO (Lee et al, 1995; Niederberger et al, 1995). Constitutive NO synthase seems to be upregulated in discrete anatomic locations, such as in the endothelium of the mesenteric artery and in the esophageal, gastric, and jejunal mucosa (Mathie, 1999).

Intrahepatic Vascular Resistance in Liver Cirrhosis

Liver cirrhosis occurs in response to chronic liver injury and is characterized primarily by a disruption of hepatic architecture, with the development of fibrous septa and abnormal nodules and circulation, leading to a sustained increase in portal vascular resistance and portal pressure. In addition, afferent (portal venules and hepatic arterioles) and efferent vessels (hepatic venules) can be found within the fibrous septa (Kelty et al, 1950). The pathogenesis of cirrhosis involves initial hepatocyte necrosis and inflammation with subsequent transformation of hepatic stellate cells into myofibroblasts (see Chapter 6). Microscopically, excessive accumulation of collagen leads to the collagenization of the space of Disse and to Ito cell activation (Greenwel et al, 1991; Martinez-Hernandez, 1985; Martinez-Hernandez & Amenta, 1993). Capillarization of sinusoidal endothelial cells occurs by defenestration or loss of endothelial cell pores and the appearance of a basement membrane (Varin & Huet, 1985). In the cirrhotic liver, the sites of vascular resistance are still unclear; however, because portal and hepatic venules can be found within the fibrous septa, constriction or distortion of portal venules, hepatic venules, or both may be involved (Kelty et al, 1950). As portal venous blood flow progressively decreases in cirrhosis, arterial resistance may decrease through an increase in arterial flow, suggesting an intact buffer response. Studies in cirrhotic rats have demonstrated higher hepatic arterial flows compared with normal controls under baseline conditions (Richter et al, 2000). This finding was confirmed using intraoperative measurements in patients with end-stage cirrhosis undergoing living-donor liver transplantation (Aoki et al, 2005).

Until recently, it was thought that the elevated IHVR in cirrhosis was irreversible. Evidence now suggests that it can be reduced pharmacologically with vasodilators (Bhathal & Grossman, 1985; Reichen & Le, 1986). IHVR can be marginally reduced by prostaglandin E₂ (Ballet, 1991) and isoprenaline and more substantially by nitroprusside, papaverine, and verapamil (Ballet, 1991; Bhathal & Grossman, 1985; Reichen & Le, 1986). Groszmann (1990) reported that intravenous nitroglycerin caused a 24% decrease in IHVR in cirrhotic patients.

In alcoholic patients, a significant correlation is seen between the extent of hepatic stellate cell activation and the level of portal vascular resistance (Rockey & Chung, 1995). Several factors have been implicated in stellate cell activation such as inflammatory mediators, cytokines, and growth factors (Friedman, 1993, 1997; Gandhi et al, 1994; Greenwel et al, 1991) and ET (Pinzani et al, 1996; Rockey & Weisiger, 1996; Rockey et al, 1998). ET-induced contractility of isolated hepatic stellate cells increases in proportion to the degree of hepatic stellate cell activation (Rockey & Weisiger, 1996). Overexpression of ET-1 has been found in patients with cirrhosis (Housset et al, 1993; Rockey & Weisiger, 1996), which probably contributes to the elevated IHVR, probably by increased hepatic stellate cell contraction (Housset et al, 1993; Rockey & Weisiger, 1996). Microscopically, ET-1 receptors (ET_a and ET_b) are detected on all cell types in rat liver, especially Ito cells, as well as in cirrhotic human subjects (Leivas et al, 1995; Pinzani et al, 1996; Rockey et al, 1998). ET-1-induced hepatic sinusoidal contractility is enhanced in ethanol-induced fatty liver but not in cirrhotic liver, indicating that ET-1 may be involved in the regulation of sinusoidal flow in the early stage of liver cirrhosis in rats (Bauer et al, 1995).

Decreased endothelial NO synthesis and release by the liver (Gupta et al, 1998; Rockey & Chung, 1998) coupled with an associated increase in portal vascular resistance may potentiate by the effect of increased ET-1 expression by hepatic endothelial and hepatic stellate cells (Pinzani et al, 1996). The interplay between NO, ET, and other local regulatory mechanisms controlling sinusoidal hemodynamics is depicted in Figure 4.5. Groszmann (1990) suggested that the increased mesenteric blood flow in the hyperdynamic stage of portal hypertension may be relatively less important than the elevated intrahepatic portal resistance in maintaining increased portal pressure. Clinically, the vasodilaton of the splanchnic circulation likely serves to increase flow in the extrahepatic collateral circulation, leading to variceal hemorrhage.

FIGURE 4.5 Local regulatory mechanisms of hepatic sinusoidal microcirculation. [Ca⁺⁺], concentration of intracytoplasmic free calcium ion; cGMP, cyclic guanosine monophosphate; DAG, diacylglycerol; ET, endothelin; ET_aR, endothelin-α receptor; ET_bR, endothelin-β receptor; H, hepatocyte; IFγ, interferon-γ; IP₃, inositol triphosphate; LPS, lipopolysaccharide; PKC, protein kinase C; SEF, sinusoidal endothelial fenestrae; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α.

Treatment (See Chapter 70A, Chapter 70B, Chapter 74 )

Medical and surgical management strategies for portal hypertension strive to improve patient survival by the reduction of pressure and flow in extrahepatic variceal vessels, mainly esophageal and gastric vessels, while preserving adequate portal flow to the liver. Portosystemic shunting and pharmacologic reduction of portal flow can provide effective decompression, but both deprive the liver of portal flow. Surgical treatment of portal hypertension may be performed by one of the many portosystemic shunt procedures (see Chapter 76B); the initial clinical application of the portacaval shunt was reported 50 years after its description by Eck (Whipple, 1945). The hemodynamic consequences of shunt surgery depend on the particular shunt performed, the nature and severity of the disease, and the hemodynamic condition of the patient. End-to-side portacaval shunts divert all portal blood flow away from the liver, whereas less complete diversions reduce portal flow in proportion to the degree to which the shunt reduces portal pressure. The hepatic artery flow may increase by 100%, but even a maximal flow increase can usually only partly compensate for loss of portal flow (Mathie & Blumgart, 1983a). Hepatic oxygen consumption tends to be maintained by increased oxygen extraction from the available arterial supply.

Total portacaval shunts are very effective in reducing portal pressure and preventing bleeding from esophageal varices. However, because of bypass of the hepatic circulation, liver failure and encephalopathy are common complications of the operation (see Chapter 76A). Therefore, partial shunts—such as the side-to-side (see Chapter 76B), mesocaval (see Chapter 76D), and proximal or distal splenorenal shunts (see Chapter 76C)—have gained popularity. Transjugular intrahepatic portosystemic shunting (TIPS), first reported by Rössle and colleagues (1989), is currently the treatment of choice for recurrent variceal bleeding in patients who are refractory to conservative medical management (see Chapters 75A and 76E; Iannitti & Henderson, 1997).

Pharmacologic reduction of portal hypertension (see Chapter 75B) initially was based largely on an attempt to diminish hepatic portal inflow from the mesenteric vascular bed by the use of vasoconstrictor agents. At a dose that decreases the heart rate by 25%, the β-adrenoceptor antagonist propranolol significantly reduced the risk of rebleeding in cirrhotic patients who were otherwise in good condition (Lebrec et al, 1981). Propranolol exerts its action by two mechanisms: decreased cardiac output as a result of β₁-adrenergic cardiac receptor blockade and antagonism of β₂-adrenoceptors in the splanchnic vasculature that leaves the vasoconstrictive influence of α-adrenergic receptors unopposed, resulting in a decrease portal flow and pressure. Vasopressin causes generalized peripheral vasoconstriction (Bosch et al, 1988), whereas the effect of somatostatin is specific to the splanchnic vascular bed (Kravetz et al, 1984) and is the result of an inhibition of glucagon release and direct vasoconstriction. Somatostatin is at least as effective as vasopressin in controlling bleeding, and with fewer side effects; it may be the agent of choice in acute management of variceal hemorrhage. Serotonin may play a significant role in maintaining increased portal pressure, and smooth muscle serotonin-receptor antagonists have been shown to lower the pressure in cirrhosis (Hadengue et al, 1987; Mastaï et al, 1989).

The nitrovasodilators isosorbide dinitrate and isosorbide mononitrate were observed to lower the portal pressure in portal hypertensive animals (Blei & Gottstein, 1986) and to increase hepatic (but not azygos) blood flow in cirrhotic patients (Navasa et al, 1989), suggesting that they may act by reducing intrahepatic portal vascular resistance. Application of nitroglycerin by transdermal tape to cirrhotic patients resulted in a reduction in portal pressure without affecting hepatic blood flow (Iwao et al, 1991).

These experiments support the previous discussion of NO and ET-1 control of hepatic sinusoidal tone. An ET receptor antagonist was reported to reduce portal pressure in cirrhotic rats by nearly 30% (Reichen et al, 1998). The combined effects of the long-acting nitrovasodilator molsidomine plus propranolol have been found by some (Hori et al, 1996) but not others (Garcia-Pagán et al, 1996) to be a more effective portal hypotensive regimen than propanolol alone.

Hemodynamic Studies and Human Liver Transplantation

Orthotopic liver transplantation (OLT) (see Chapter 97A, Chapter 97B, Chapter 97C, Chapter 97D, Chapter 97E, Chapter 98A, Chapter 98B, Chapter 98C ) of a normal donor organ does not normalize the splanchnic and systemic hemodynamic alterations of end-stage liver disease (Henderson, 1993). In fact, total hepatic blood flow remains elevated 6 months after OLT (Hadengue et al, 1993; Henderson et al, 1989; Navasa et al, 1993) mainly because of portal venous blood flow (Henderson et al, 1992a, 1992b; Henderson, 1993; Paulsen & Klintmalm, 1992). Azygos flow also remains elevated, and other portosystemic shunts have been documented up to 4 years after OLT (Navasa et al, 1993). Ligation of these portosystemic collateral pathways has been shown to increase portal venous blood flow (Fujimoto et al, 1995). Cardiac output data have been conflicting, with one group reporting persistently elevated values (Hadengue et al, 1993) and others showing decreases 2 weeks and 2 months after OLT (Navasa et al, 1993). Gadano and colleagues (1995) emphasized that factors such as anemia and sepsis may account for the deranged hemodynamics after OLT.

Effect of Liver Transplantation on Liver Blood Flow

Henderson and others (1989) demonstrated that LBF remains elevated for a prolonged period after liver transplantation, suggesting that baseline LBF may be under direct sympathetic control, which is lost after OLT, leading to an unopposed rise. The hemodynamic consequences of OLT in human patients are difficult to interpret for several reasons: 1) the causes of liver failure in end-stage transplant candidates are diverse; 2) immunosuppressive drugs are used, such as cyclosporine, which causes arterial hypertension; and 3) to control systemic hypertension after OLT, patients may also be given vasodilators such as hydralazine, which can cause persistently increased cardiac output.

The hepatic artery buffer reponse is conserved following OLT despite denervation. This was demonstrated in a series of experiments by Payen and colleagues (1990), who serially clamped the portal vein every 12 hours for 7 days following OLT and reported reciprocal increases in hepatic arterial flow.

The advent of living-donor partial liver transplantation has introduced the phenomenon of small-for-size syndrome, whereby the pressure of the full portal flow traveling through a small liver remnant leads to decreased arterial flow, presumably through an intact hepatic arterial buffer response (Michalopoulos, 2010). The reduced hepatic arterial flow is hypothesized to be diverted to the splenic and gastroduodenal circulation. Prospective studies have demonstrated that ligation or embolization of the splenic artery leads to improved hepatic arterial inflow and improved graft function (Lo et al, 2003; Umeda et al, 2007).

Effect of Laparoscopy on Liver Blood Flow

The use of a carbon dioxide pneumoperitoneum in laparoscopic donor surgery has been demonstrated to substantially reduce portal venous flow in parallel with the intraperitoneal pressure (Schilling et al, 1997; Jakimowicz et al, 1998). The hepatic artery buffer response is usually preserved during laparoscopy, however, conflicting data exist in support of the maintenance of this effect in high-pressure pneumoperitoneum. Rat models using fluorescent microspheres supported preserved hepatic arterial flow during decreased portal venous flow (Yokoyama et al, 2002), but this was not supported by others (Richter et al, 2001), who saw a parallel decrease in arterial and portal venous flows during laparoscopy. Some groups have suggested the avoidance of head-up positioning and pressures greater than 15 mm Hg during laparoscopy to preserve LBF (Junghans et al, 1997; Klopfenstein et al, 1998).