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Lautt WW. Hepatic Circulation: Physiology and Pathophysiology. San Rafael (CA): Morgan & Claypool Life Sciences; 2009.

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Hepatic Circulation: Physiology and Pathophysiology.

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Chapter 1Historical Perspectives

In science, the development of knowledge is largely dependent on the technological status of the science, which determines the chronology of discoveries. Cardiovascular functions have been the subject of speculation since the first caveman consciously considered the significance of blood loss. The description of the circulation of the blood by William Harvey in 1628 allowed, for the first time, the development of accurate knowledge about the hepatic circulation. Glisson, for whom the hepatic capsule was named in the mid-1600s, advanced the knowledge of the gross anatomy of the hepatic vascular bed and demonstrated that portal blood flowed through the liver. Wepfer in 1664 was apparently the first to notice the glandular appearance of hepatic acini beneath Glisson’s capsule. Twenty-one years later, in 1685, Malpighi confirmed the existence of similar microvascular units that he redefined as hexagonal lobules. To this day, there is no complete consensus on whether the microvascular unit of the liver should be referred to as a lobule, centering on a hepatic vein, or an acinus, centering on a “portal triad” consisting of a terminal branch of the hepatic artery, portal vein, and bile duct, encased within a limiting plate of cells defining the space of Mall. Although anatomical examinations were pursued, function remained largely unknown. In 1890, the space of Disse was identified and named, but the significance of this narrow space between the liver cell and the vascular endothelial cells was unknown. Claude Bernard and Ernest Starling, in the late 19th century, established the liver as an organ of major endocrine, metabolic, and vascular importance.

The development of microscopy was aided by transillumination of the liver, which allowed for greater visibility of the blood flow and structures immediately beneath Glisson’s capsule. The advent of the motion picture allowed investigation in the fourth dimension—time.

In 1954 Child [52] enthused “Today a new chapter in hepatic physiology is being written, not through the study of fixed and stained sections of the liver, not through indirect evidence based upon gross physiological observations, but upon actual observation of living tissue. From the dynamic picture presented by the transillumination technique, Knisely, Mann, Seneviratne, and others have been able to verify many of the complex vascular mechanisms postulated by the microscopic anatomists of the past. For instance, Knisely has identified an inlet sphincter at the junction of the portal venule and the portal vein. Furthermore, he has seen an outlet sphincter located at the junction of the sinusoid with the central vein.”

Rappaport [308], describing historical development and the impact of the motion picture recording of transilluminated hepatic vascular beds enthused, “though only morphological information was initially gathered, it enabled a continuous record of events in space and time that one could study and restudy until all information on the living vessels and their ever moving content was extracted.”

Rappaport became a strong advocate of the acinus as the functional unit of the liver. The unique microcirculatory anatomy of the acinus allows for blood to flow from the center of the acinus and exit into hepatic venules after passing only 16–20 hepatocytes. He also showed movies of red blood cells spinning around clusters of hepatocytes for several rotations before racing out into the terminal hepatic venules.

Whereas the transilluminated moving view of the hepatic circulation provided views of hemodynamic interactions on the surface of the liver, the advent of scanning electron microscopy of vascular casts allowed visualization of static detailed three-dimensional vascular structures with a great depth of field and access to the entire liver mass [124]. The authors acknowledged that all of the existing connections had previously been demonstrated by other techniques; however, the richness of the image of the three-dimensional SEM photographs added depth to the knowledge. Casts produced by infusing latex through the hepatic artery or portal vein show tufts of sinusoids grouped around the terminal conducting vessels, appearing like crowns of flowers on vascular stalks (Figure 1.1).

FIGURE 1.1. A cast of the hepatic microvessels of the rat made by perfusing casting medium through the aorta until all hepatic vessels were filled.


A cast of the hepatic microvessels of the rat made by perfusing casting medium through the aorta until all hepatic vessels were filled. Both subcapsular sinusoids (CAPS) and deeper vessels are focused. Tufts of sinusoids surround terminal limbs of afferent (more...)

In the 1960s, a group of Swedish scientists led by Bjorn Folkow revolutionized the concept of the functions and methods to study peripheral vascular beds by separately considering resistance, capacitance, and fluid exchange functions. They directly applied the principles identified by Starling in 1896 who demonstrated that raising the venous pressure in different vascular beds resulted in lymph formation of dramatically different characteristics, that coming from the liver being high in volume and of a protein content similar to plasma. The counteracting “Starling forces” of hydrostatic pressure and colloid osmotic pressure gradients acting across the endothelial vascular wall explained extracellular fluid exchange dynamics. These concepts were pivotal for the approach developed by the Swedes.

In 1960, Mellander, a senior scientist of the Swedish group, described a technique for the simultaneous measurement of resistance, capacitance, and fluid exchange responses in the vascular bed of skeletal muscle. A plethysmograph containing the intact vascular bed, for example, the hind-limb, was key to the studies. This technique was later extended to the intestinal vascular bed [81] and the spleen [118]. These early conceptual breakthroughs were reviewed by Mellander and Johansson [264].

The first use of a crude plethysmograph to measure changes in hepatic volume in vivo was carried out by Francois-Franck and Hallion [83] in 1896 who demonstrated a decrease in liver volume after hemorrhage. Greenway adapted the plethysmograph models of the Swedes to encase the liver in a fluid-filled space without interfering with the vascular inlet or outlet, bile or lymph flow, or hepatic innervation. In addition to assembling a three-piece Plexiglas plethysmograph around the liver and plugging the outlet with an inert gel, plastibase, the research team of Clive Greenway, his postdoctoral fellow Ron Stark, and myself as a graduate student added vascular circuitry to the plethysmograph preparation. This preparation has been fully described [103].

The hepatic venous long-circuit represented a powerful new tool (Chapter 4). The circuit was established by cannulating the inferior vena cava in the thorax to direct lower vena caval blood to an exterior reservoir. The blood was warmed and pumped back to the heart through catheters in the jugular veins. To separate hepatic venous blood from other vena caval blood, the inferior vena cava was ligated proximal to the hepatic venous entrance to the vena cava. Blood from the vena cava below the occlusion was drained in a retrograde manner through venous catheters in the femoral veins, which emptied the blood into the same extracorporeal reservoir. Finally, an electromagnetic flow probe was placed on the hepatic artery. Although this preparation was surgically very complex, the information it provided was unprecedented. Hepatic venous pressure could be accurately monitored and manipulated. Hepatic venous pressure could be increased by elevating the hepatic venous outflow catheter so that pressure, volume, and fluid exchange studies could be readily carried out. Pure mixed hepatic venous blood samples were available for chemical or blood gas sampling. Total hepatic blood flow could be accurately quantified and calibrated, simply by timing the outflow into a calibrated cylinder. Portal venous flow was calculated by subtracting the hepatic arterial flow from total hepatic blood flow. The nerves could be electrically stimulated in this preparation and catheters in the portal vein and hepatic arterial branch could determine blood pressures and administer drugs.

Although in 1896, Starling made initial forays into studies of fluid exchange in the liver, quantification of fluid exchange awaited the plethysmograph just as quantification of solute exchange across intrahepatic vascular compartments awaited the use of multiple tracer dilution technology as carried out by Goresky [97]. Individual tracer compounds or a cocktail of compounds were injected into the portal vein and the efflux of the tracer from a continuously sampled hepatic venous outflow provided novel and readily quantifiable information regarding the passage of substances from the blood into the different hepatic spaces. Red blood cells produced sharp outflow curves as the blood went directly through the liver. Albumin showed greater access to hepatic space followed by sucrose, sodium, and heavy water. This technique gained use for several years to explore normal and diseased livers. Many of the research tools described made a large impact on advancement of knowledge and then, for a variety of reasons, have become valued for the historical development of knowledge and are no longer used or required.

I recommend two books in particular for a historical perspective. The first is a classic, The Hepatic Circulation and Portal Hypertension by Child [52]. Child heavily references historical data and reports extensively on morphology. The knowledge of the hepatic and portal circulation in health and disease up to the mid-1900s was detailed in a most scholarly manner.

The second book is one that I had the privilege of editing in 1981. The book was a collection from authors who met at a symposium on Hepatic Circulation in Health and Disease in Saskatoon, Saskatchewan, Canada, in 1980. The authors presented orally and contributed chapters covering a comprehensive range of hepatic vasculature knowledge. The full transcripts of the lively discussions add spice. By that time, most of the modern techniques required to evaluate and quantitate hepatic vascular function had been developed. Full knowledge, however, had not yet been extracted.

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53076
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