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Lautt WW. Hepatic Circulation: Physiology and Pathophysiology. San Rafael (CA): Morgan & Claypool Life Sciences; 2009.
The liver receives 25% of the cardiac output, although it constitutes only 2.5% of body weight. The hepatic parenchymal cells are the most richly perfused of any of the organs, and each parenchymal cell on the average is in contact with perfusate on two sides of the cell. Of the total hepatic blood flow (100–130 ml/min per 100 g of liver, 30 ml/min per kilogram of body weight), one fifth to one third is supplied by the hepatic artery. About two thirds of the hepatic blood supply is portal venous blood. The gross vascular supply of the liver is conceptually described in Figures 2.1 and 2.2.

FIGURE 2.1
The branches of the portal vein form a system of a rather constant pattern that is symbolized as a white trellis. The branches of the hepatic artery and the tributaries of the hepatic bile duct become coordinated with the portal venous branches (risers (more...)

FIGURE 2.2
The hepatic veins (dark), like the spokes of a wheel, are radially arranged around an axle (the inferior vena cava). The portal venous branches wind between them. Reproduced from Elias H, Sherrick JC. Morphology of the Liver. Academic Press, New York, (more...)
The high pressure, well-oxygenated arterial blood mixes completely with the low-pressure, less well-oxygenated, but nutrient-rich, portal venous blood within the hepatic sinusoids. Uptake of compounds by the parenchymal cells and exchange between parenchymal cells and plasma are affected by several unique characteristics of the hepatic microvascular circulation. The characteristics of uptake and exchange by the liver (Chapter 3) have major impact on lipoprotein metabolism, endocrine homeostasis, and therapeutic procedures (drug clearance). While the flow rate of blood through the liver is high, the volume of blood contained within the liver is similarly high and plays a central role in the maintenance of cardiovascular homeostasis (Chapter 4). The liver represents a major blood reservoir in the body; it has a crucial role in the response to blood loss or expanded fluid volume and has a recognized role in determining the response to pressor, antihypertensive, and afterload-reducing agents. Intrahepatic and portal venous pressures are regulated primarily by hepatic venous sphincters, and in the basal resting state, portal pressure is insignificantly different from sinusoidal pressure (Chapter 6). The hepatic circulation has multiple interacting factors that attempt to regulate hepatic blood flow as constant as possible in response to acute and chronic conditions (Chapter 16). The hepatic circulation directly influences renal function through a reflex control, with the afferent sensory limb detecting blood flow-dependent changes in intrahepatic adenosine content and the efferent role acting through sympathetic nerves in the kidney (Chapter 13). This mechanism offers a mechanistic explanation of the hepatorenal syndrome and a therapeutic approach for prevention and treatment of fluid retention.
The constant ratio of blood flow to liver cell mass is regulated in part by adjusting blood flow through the hepatic arterial buffer response (Chapter 5). The flow/mass ratio is also regulated powerfully by flow. Liver blood flow determines liver parenchymal cell volume by a mechanism that is based on the effect of hepatic blood flow to generate shear stress on hepatic endothelium, with the result being nitric oxide generation and triggering of the hepatic regeneration cascade (Chapter 15).
2.1. MICROCIRCULATION
The microvascular unit of the liver is the hepatic acinus (Figure 2.3). The acinus represents a cluster of parenchymal cells approximately 2 mm in diameter. The parenchymal cells are grouped around terminal branches of the hepatic arteriole and portal venule [305,309]. The acini have been likened to clusters of berries suspended on a vascular stalk. This analogy is particularly appropriate because the vascular stalk enters the center of the acinus where the hepatic arterial blood and portal venous blood are well mixed within the sinusoidal periportal zone (Rappaport’s zone 1). Flow in adjacent sinusoids is concurrent; all entrances to the acinus occur in the periportal region, whereas all exits occur at the periphery, thus producing strong gradients for oxygen and other substances that are added to or removed from the blood as it passes through the acinus. The central zone has the highest degree of oxygenation and the highest activity of respiratory enzymes [100,361]. Zone 3 lies on the outer limits of the acinus and is supplied by blood that has already passed the parenchymal cells of zones 1 and 2. Zone 3 is supplied by the least oxygenated blood and is rich in microsomal enzymes. This unique one-way flow arrangement precludes substances diffusing from the hepatic venous blood to the hepatic arterial resistance vessels. Therefore, even if the hepatic parenchymal cells release large quantities of vasoactive metabolites, such as adenosine [237], the parenchymal cells are not capable of regulating the hepatic artery according to their metabolic requirements.

FIGURE 2.3
The acinus is the functional unit of the liver. There are approximately 100,000 acini per human liver; each is approximately 2 mm in diameter. Acini cluster like grapes at the end of vascular stalks comprising the terminal branches of portal veins, hepatic (more...)
Despite my personal preference for the acinus model, it should be emphasized that the classic lobule is more readily seen in the pig, where the lobule is bordered by connective tissue to form a distinct visual unit. This is not seen in humans or most other mammals (reviewed by Jungermann and Katz [157]).
2.2. HEPATIC MICROVASCULAR ZONES
All hepatocytes are not geared to perform identical functions. At any given time, metabolic events occurring in a single cell need not correspond with events in any other hepatocyte. When reports of gross analysis in the liver of a fed animal indicate that glycogen accounts for 5% and fat 4% of total cell volume, the impression is that every hepatocyte reflects these percentages. However, hepatocytes do not have the same percentage of stored fuels and the enzymes that control the rate of synthesis and utilization are not uniform among cells. The location and temporal differentiation of functions among the cells is called “metabolic zonation.” Metabolic zonation can occur as a result of the oxygen gradient across the acinus or the gradient of hormones and nutrients that are extracted as the blood passes through the acinus, or due to chemicals added progressively to the blood before exiting the acinus. The partial pressure of oxygen in rat livers has been estimated at approximately 65 mmHg in the periportal zone (zone 1) with pO2 in the perivenous zone (zone 3) of approximately 30–35 mmHg [360,379]. Oxidative energy metabolism is also predominant in zone 1. Enzymes of the tricarboxcylic acid cycle and respiratory chain are mainly located in hepatocytes in the periportal zone. Enzymes of glycolysis are relatively more active in the perivenous zone where oxygen tension is lower. The hepatocytes in the periportal zone are more devoted to gluconeogenesis than are those in the perivenous zone. The role of oxygen in determining these gradients is shown in studies on isolated hepatocytes and on livers of rats that were perfused in a retrograde fashion, with the result that the metabolic zonation could be reversed in vivo [258].
Acute changes in hepatic circulation can lead to rapid changes in hepatocyte enzyme activity. The activity of γ-glutamyl transpeptidase is usually limited to the highly arterialized zone 1 in rat livers. Arterialization of the liver, by diverting portal blood, distributes the activity of the enzyme over all zones of the acinus [283]. How rapidly the changes occur is debatable but may suggest an additional potential role or effect of the hepatic arterial buffer response (Chapter 5). Figure 2.4 shows enzymatic activities that are predominant in each of the microcirculatory zones of the acinus.

FIGURE 2.4
Metabolic areas in the acini. The central region (zone 1) is in the center of the acinus where oxygen content is the highest (white periportal area) and decreases progressively to zone 3 (shaded area). PV, portal vein; ThV, terminal hepatic venule; BD, (more...)
The metabolic consequences of zonation have been reviewed and are beyond the purview of this monograph [100,128,158,309,361].
Cytotoxic injury is also subject to zonal differences [302]. Zonal necrosis is found most frequently in zone 3. The zonality appears to be related to the mechanism of injury, with zone 3 necrosis being induced by carbon tetrachloride, bromobenzene, and acetaminophen and has been attributed to the zonal concentration of the enzyme system responsible for the conversions of the agents to hepatotoxic metabolites. The necrosis in zone 1, produced by allyl formate, has been attributed to the location in that zone of the enzyme system that converts the compound to its toxic metabolite. Midzone (zone 2) necrosis produced by ngaione is attributed to the midzonal accumulation of its toxic metabolite. The necrosis due to idiosyncrasy-dependent hepatic injury in most instances is not zonal [387]. As fibrosis forms in livers subject to zone 3 damage, the histological pattern becomes easily recognizable as a starfish-like pattern surrounding the hepatic venule with each arm of the pattern representing the abutment of the perivenous zones from adjacent acini. The impact of zonation on hepatic toxicology is discussed in Chapter 12.
2.3. INTRAHEPATIC FLOW DISTRIBUTION
Blood flow within the liver appears to be quite uniformly distributed, as indicated by the even distribution of microspheres injected into either the hepatic artery or the portal vein [119]. The surface 2 mm of the liver directly beneath Glisson’s capsule is more richly supplied by arterial blood [232].
Intraportal and intra-arterial infusions of norepinephrine result in Rmax and ED50 estimates of blood volume responses that are not significantly different. Norepinephrine administered by either route has equal access to the hepatic capacitance vessels [231]. The use of radioactively tagged microsphere distribution throughout core samples taken from top to bottom of liver lobes administered at several different time points demonstrated a dynamically changing vascular perfusion. The heterogeneity of flow distribution decreased in response to norepinephrine in contrast to the increase in heterogeneity seen in response to norepinephrine in isolated liver preparations [232].
Substances reaching the liver via the hepatic artery or portal vein are equally well extracted, suggesting that both vascular inlets perfuse the hepatic parenchymal cells equally [221]. Bile salts produce equal stimulation of bile flow, despite producing quite different direct vascular effects, when infused via the two vascular channels [209]. As an approximation, the hepatic arterial and portal venous flows meld in equal proportions throughout the liver. Elevation in venous pressure, reduction of portal venous flow, and stimulation of hepatic nerves or norepinephrine infusion do not result in flow redistribution within the liver [59,120,128]. We found no gravity effect on the ratio of arterial to portal blood flow within the cat liver [232].
In the normal liver, it seems likely that one function of the hepatic arterial buffer response (Chapter 5) is to maintain homogeneity of liver perfusion. If local portal venous stasis occurs, the hepatic artery supplying that acinus should dilate to increase the higher pressure arterial input, thereby flushing the sinusoids and restoring sinusoidal blood flow.
Blood and solutes enter the sinusoidal microcirculation via the terminal portal venules or terminal hepatic arterioles in the central or zone 1 of the liver acinus [307]. Sinusoids distribute the blood sequentially through acinar zones 1, 2, and 3, passing approximately 16–20 hepatocytes before terminating in hepatic venules at the acinar periphery. Red blood cells remain restricted within the sinusoidal space defined by the endothelial cells, which have large fenestrations and permit molecules as large as albumin to pass through the fenestrations and enter the small space of Disse before making contact with the microvilli of the hepatocytes. The volume of the sinusoids in zone 1 is less than zone 3 but the surface area per unit volume is higher in zone 1, thereby facilitating uptake of compounds from the space of Disse [268].
The hepatic sinusoids are arranged in a syncytium of interconnected spaces referred to as hepatic lacunae. The lacunae are the interconnected channels between the sinusoids with all but the parenchymal cells removed (Figure 2.5). The lacunar space consists of the plasma compartment and the space of Disse, separated and defined by a sinusoidal endothelial cell layer. Within the lacunar space lays a continuous layer of endothelial cells with large fenestrations (Figure 2.6). When Starling elevated the hepatic venous pressure and noted a protein-rich effluent in the hepatic lymph, he deduced the characteristics of the sieve as being much more porous than similar endothelial cells in tissues such as muscle. Chronic liver disease is frequently associated with capillarization of the hepatic endothelial cells with reduced fenestrations and, subsequently, reduced freedom of movement between hepatocytes and plasma. The space of Disse is a small space, equivalent to the interstitial fluid of other vascular beds.

FIGURE 2.5
Hepatocytes are connected as a syncytium of cell plates of one cell thick. The syncytium is tunneled through with lacunae that are defined by the space between hepatocyte plates and contain the space of Disse (equivalent to extracellular space in other (more...)

FIGURE 2.6
The sinusoidal endothelial cells form a tube within the hepatic lacunae. The large fenestrations permit passage of large molecules between the space of Disse and the plasma. The pores are much smaller in muscle and absent in brain. Reproduced from by (more...)
2.4. KUPFFER CELLS
Kupffer cells are liver-specific macrophages that reside in the sinusoidal lumen where they are exposed to the systemic circulation via the hepatic artery and to the splanchnic circulation via the portal vein. They constitute approximately 80% of the total population of macrophages in the body [291]. Because of their phagocytic capacity, they participate in the host defense system to clear circulating endotoxin from the blood [22,376]. Kupffer cells are also capable of secreting mediators involved in the host responses to inflammation, such as cytokines, endothelins, prostanoids, and nitric oxide [53,323].
Kupffer cells activate inducible nitric oxide synthase, producing large amounts of nitric oxide [348]. This enzyme is not present in resting cells and, after stimulation, requires a period of mRNA expression and new protein synthesis to detect enzyme activity [23,348]. Different stimuli such as cytokines, interferon-γ, lipopolysaccharide, tumor necrosis factor, and interleukin-1 are able to induce the synthesis and to release nitric oxide from Kupffer cells [66,177].
Kupffer cells not only play an important role in the body’s defense system but may also contribute to liver damage [376]. Extensive nitric oxide production by Kupffer cells causes cytotoxicity. Nitric oxide damaging effects might be due to a cooperative action with superoxide, yielding the peroxynitrite anion (ONNO–). Peroxynitrite, known to oxidize sulfhydryls and to generate products indicative of hydroxyl radical reaction with deoxyribose and dimethyl sulfoxide, induces lipid peroxidation [18,304]. Nitric oxide cytotoxic effects are dependent on the concentration of superoxide radical [328]. In chronic alcoholic rats, production of both superoxide radical and nitric oxide in isolated Kupffer cells seems to be at the same rate [13,370]. Similarly, the superoxide radical from mitrochrondria and microsomal enzymes increases as nitric oxide concentrations increase in hepatocytes from alcoholic LPS-treated rats [28,173,370].
Nitric oxide by itself might have a protective effect by regulating the production of specific inflammatory mediators by Kupffer cells during sepsis [350]. In the septic liver, nitric oxide has a profound inhibitory effect on the production of prostaglandin E2 (PGE2), thromboxane B2, and interleukin-6 [350]. In this case, nitric oxide might be an autoregulator of inflammatory reactions. Nitric oxide and superoxide radicals are used as weapons by the Kupffer cells to kill engulfed microorganisms. Macrophage use of these weapons is not unique to the liver. Macrophages, including Kupffer cells, attack, engulf, and kill invading organisms.
Kupffer cells can have an influence on microvascular flow by protruding their pseudopods toward the vascular space in response to endotoxin administration in vivo [260,289]. Moreover, the nitric oxide produced by Kupffer cells may affect microvascular flow because of the strong vasorelaxant properties acting on other cells (Chapter 9). Indirectly, nitric oxide, by suppressing Kupffer cell eicosanoid synthesis, may also have an impact on vascular tone. However, keep in mind the anatomy of the acinus. Vasoactive substances released from Kupffer cells cannot diffuse upstream to act on the resistance vessels of the terminal branches of the hepatic artery and portal vein.
Kupffer cells straddle inside the sinusoidal space like a spider in ambush for particulate substances passing through the hepatic circulation. Kupffer cells account for approximately 15% of the liver cell population. They are attached by their pseudopodia to the endothelial cells and some of these processes penetrate through the fenestrae and reach out to the parenchymal liver cells [377]. Although Kupffer cells are generally considered to be fixed macrophages, in vivo microscopy shows that they can independently move at a speed of 4.6 μm/min [253]. Kupffer cells are more abundant in zone 1 of the acinus (43% of total) and those cells are larger and more active in phagocytosis. Zone 2 contains 32% and zone 3, 25% of total Kupffer cells [174] with the smaller perivenous Kupffer cells appearing to be more active in cytokine production and to have a higher cytotoxic capacity [174].
Twenty-five percent of the cardiac output passes through the liver, thereby allowing an efficient filtration role for the macrophage activities of the Kupffer cell. No direct vascular role has been suggested for the Kupffer cell (see Chapter 9 for vascular role of nitric oxide and Chapter 15 for role of nitric oxide in the regulation of hepatocyte proliferation).
2.5. STELLATE CELLS
Stellate cells, also known as fat-storing cells, Ito cells, or hepatic perisinusoidal lipocytes, are mesenchymal cells that reside in the perisinusoidal space of Disse and can undergo reversible contraction [160,320]. Intrahepatic resistance and portal pressure are affected by stellate cells [160,162]. They express smooth muscle-specific intermediate filament desmin, which allows these cells to contract [319]. Stellate cells generally form around the exterior of the endothelial cells like fingers that are capable of compressing the sinusoidal diameter by squeezing the endothelial cells [383].
Studies on isolated stellate cells showed that vasoconstrictors, such as angiotensin II, thrombin, and endothelin-1, increase intracellular free calcium, which is coupled with cell contraction [301]. Kawada et al. [161] quantified constriction and relaxation of stellate cells by culturing the cells on a flexible silicone rubber membrane to measure tension. Constriction of the stellate cells was elicited by a thromboxane A2 analogue, prostaglandin F2α, and endothelin-1, whereas prostacyclin (prostaglandin I2) analogues and PGE2 induced cell relaxation [160,161]. Sinusoidal constriction induced by endothelin-1 may be mediated by stellate cells; this effect was inhibited by nitric oxide donors [383]. It is suggested that a balance between dilators and constrictors becomes disrupted in conditions of reperfusion injury or endotoxin shock, and that the balance favors stellate cell constriction, thus leading to sinusoidal regional blood flow heterogeneity [54].
Sinusoidal blood pressure and vascular resistance are so low that a pressure gradient across the liver from the portal venous inflow to the hepatic venous outflow is only approximately 5 mmHg. The low pressure gradient is remarkable considering that 30% of the inflow to the liver sinusoids is provided by the hepatic artery under arterial pressure. With such a low sinusoidal perfusion pressure, small imbalances in microscopic sinusoidal flow could lead to stagnation at many sites. The hepatic arterial buffer response works at the acinar level. The regulation of flow within the acinus may also be actively controlled by regional regulators at a single-cell level. The stellate cells likely play such a role, although this does not seem to have been shown. It would seem that the stellate cell would have to detect zero flow and then dilate to pull outward on the endothelial cells and enlarge the sinusoidal space.
2.6. SINUSOIDAL ENDOTHELIAL CELLS
Injury of sinusoidal microvasculature is one of the first events in the sequel of developing hepatic failure during severe sepsis, endotoxemia, or reperfusion injury [136]. The inducible nitric oxide synthase is activated in the liver in inflammatory conditions [320,349]. The affected sinusoidal endothelial cells might lead to alterations in nitric oxide levels. Increased release of nitric oxide by Kupffer cells could be anticipated to have an impact on sinusoidal blood flow by directly relaxing stellate cells or smooth muscle [321]. However, nitric oxide released by hepatic sinusoidal cells is unlikely to influence the arterial or portal resistance site upstream. Nitric oxide produced by the endothelium of the inlet vessels does, however, play a significant vascular role (Chapters 5 and 9).
A role of sinusoidal endothelial nitric oxide may be minor for the vasculature, but a key role for regulating hepatocyte proliferation is described in Chapter 15. A role for vascular endothelium in both the hepatic artery and the portal vein is described in Chapter 5.
Nitric oxide also plays a major regulatory role in glucose homeostasis. Dysfunction of hepatic parasympathetic nerve-induced stimulation of nitric oxide synthase results in insulin resistance in skeletal muscle and is suggested as the initiating metabolic defect in the prediabetic state that leads progressively to obesity, syndrome X, and type 2 diabetes. This science is discussed elsewhere (for a review, see reference [202]).
2.7. THE SPACE OF MALL
The space of Mall, variously known as the portal duct or portal triad, represents the service conduit that supplies the center of each acinus with portal and arterial blood, collects bile and lymph, and through which passes a rich array of sensory and efferent nerves. The terminal branches of the hepatic artery are in intimate contact with the terminal branches of the portal vein. Direct arterial branches have been shown to enter the terminal portal venules before entry into the sinusoids. An additional vascular circuit exists within the space of Mall, the peribiliary plexus (Figure 2.7). The hepatic artery sends off small branches that form a dense mesh-like plexus surrounding the bile duct. A significant proportion of the hepatic arterial flow passes through the peribiliary plexus before it drains into the portal vein at or near where the portal vein and hepatic artery merge at the origin of sinusoids. The function of the peribiliary plexus is not known, although substances such as adenosine, when back-perfused through the bile duct, reach the hepatic arterial resistance vessels and cause dilation.

FIGURE 2.7
A cast of the portal vein (P), hepatic artery (A), and peribiliary arterial plexus (PP) of a rat, showing a connection between a small artery and the plexus (arrow). The peribiliary plexus forms a dense sheath around the bile duct, suggesting function (more...)
The fluid in the space of Mall is also proposed to serve as a medium for signals between hepatic blood vessels (Chapter 5) and sensory nerves (Chapter 13).
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