The Liver: Introduction and Index
The liver is the largest gland in the body and performs an astonishingly large number of tasks that impact all body systems. One consequence of this complexity is that hepatic disease has widespread effects on virtually all other organ systems. At the risk of losing sight of the forest by focusing on the trees, we will focus on three fundamental roles of the liver:
Vascular functions, including formation of lymph and the hepatic phagocytic system.
Metabolic achievements in control of synthesis and utilization of carbohydrates, lipids and proteins.
Secretory and excretory functions, particularly with respect to the synthesis of secretion of bile.
The latter is the only one of the three that directly affects digestion - the liver, through its biliary tract, secretes bile acids into the small intestine where they assume a critical role in the digestion and absorption of dietary lipids. However, understanding the vascular and metabolic functions of the liver is critical to appreciating the gland as a whole. Architecture of the Liver and Biliary Tract
The liver lies in the abdominal cavity, in contact with diaphragm. Its mass is divided into several lobes, the number and size of which vary among species. In most mammals, a greenish sac - the gallbladder - is seen attached to the liver and careful examination will reveal the common bile duct, which delivers bile from the liver and gallbladder into the duodenum. The image below is of a liver from a dog, and illustrates these concepts. The panel on the left shows that aspect of the liver that faces the contents of the abdominal cavity. The right panel shows the flatter face of the liver which is in contact with the diaphragm.
Understanding function and dysfunction of the liver, more than most other organs, depends on understanding its structure. The major aspects of hepatic structure that require detailed attention include:
The hepatic vascular system, which has several unique characteristics relative to other organs
The biliary tree, which is a system of ducts that transports bile out of the liver into the small intestine
The three dimensional arrangements of the liver cells, or hepatocytes and their association with the vascular and biliary systems.
The Hepatic Vascular System
The circulatory system of the liver is unlike that seen in any other organ. Of great importance is the fact that a majority of the liver's blood supply is venous blood. The pattern of blood flow in the liver can be summarized as follows:
Roughly 75% of the blood entering the liver is venous blood from the portal vein. Importantly, all of the venous blood returning from the small intestine, stomach, pancreas and spleen converges into the portal vein. One consequence of this is that the liver gets "first pickings" of everything absorbed in the small intestine, which, as we will see, is where virtually all nutrients are absorbed.
The remaining 25% of the blood supply to the liver is arterial blood from the hepatic artery.
Terminal branches of the hepatic portal vein and hepatic artery empty together and mix as they enter sinusoids in the liver. Sinusoids are distensible vascular channels lined with highly fenestrated or "holey" endothelial cells and bounded circumferentially by hepatocytes. As blood flows through the sinusoids, a considerable amount of plasma is filtered into the space between endothelium and hepatocytes (the "space of Disse"), providing a major fraction of the body's lymph.
Blood flows through the sinusoids and empties into the central vein of each lobule.
Central veins coalesce into hepatic veins, which leave the liver and empty into the vena cava.
The Biliary System
The biliary system is a series of channels and ducts that conveys bile - a secretory and excretory product of hepatocytes - from the liver into the lumen of the small intestine. Hepatocytes are arranged in "plates" with their apical surfaces facing and surrounding the sinusoids. The basal faces of adjoining hepatocytes are welded together by junctional complexes to form canaliculi, the first channel in the biliary system. A bile canaliculus is not a duct, but rather, the dilated intercellular space between adjacent hepatocytes.
Hepatocytes secrete bile into the canaliculi, and those secretions flow parallel to the sinusoids, but in the opposite direction that blood flows. At the ends of the canaliculi, bile flows into bile ducts, which are true ducts lined with epithelial cells. Bile ducts thus begin in very close proximity to the terminal branches of the portal vein and hepatic artery, and this group of structures is an easily recognized and important landmark seen in histologic sections of liver - the grouping of bile duct, hepatic arteriole and portal venule is called a portal triad.
The gall bladder is another important structure in the biliary system of many species. This is a sac-like structure adhering to the liver which has a duct (cystic duct) that leads directly into the common bile duct. During periods of time when bile is not flowing into the intestine, it is diverted into the gall bladder, where it is dehydrated and stored until needed.
Architecture of Hepatic Tissue
The liver is covered with a connective tissue capsule that branches and extends throughout the substance of the liver as septae. This connective tissue tree provides a scaffolding of support and the highway which along which afferent blood vessels, lymphatic vessels and bile ducts traverse the liver. Additionally, the sheets of connective tissue divide the parenchyma of the liver into very small units called lobules.
The hepatic lobule is the structural unit of the liver. It consists of a roughly hexagonal arrangement of plates of hepatocytes radiating outward from a central vein in the center. At the vertices of the lobule are regularly distributed portal triads, containing a bile duct and a terminal branch of the hepatic artery and portal vein. Lobules are particularly easy to see in pig liver because in that species they are well deliniated by connective tissue septae that invaginate from the capsule. Physiology of the Hepatic Vascular System
Hepatic Blood Volume and Reservoir Function
The liver receives approximately 30% of resting cardiac output and is therefore a very vascular organ. The hepatic vascular system is dynamic, meaning that it has considerable ability to both store and release blood - it functions as a reservoir within the general circulation.
In the normal situation, 10-15% of the total blood volume is in the liver, with roughly 60% of that in the sinusoids. When blood is lost, the liver dynamically adjusts its blood volume and can eject enough blood to compensate for a moderate amount of hemorrhage. Conversely, when vascular volume is acutely increased, as when fluids are rapidly infused, the hepatic blood volume expands, providing a buffer against acute increases in systemic blood volume.
Formation of Lymph in the Liver
Approximately half of the lymph formed in the body is formed in the liver. Due to the large pores or fenestrations in sinusoidal endothelial cells, fluid and proteins in blood flow freely into the space between the endothelium and hepatocytes (the "space of Disse"), forming lymph. Lymph flows through the space of Disse to collect in small lymphatic capillaries associated with portal triads (the reason they are not called portal tetrads is because these lymphatic vessels are virtually impossible to identify in standard histologic sections), and from there in the systemic lymphatic system.
As you might expect, if pressure in the sinusoids increases much above normal, there is a corresponding increase in the rate of lymph production. In severe cases the liver literally sweats lymph, which accumulates in the abdominal cavity as ascitic fluid. What lesions can you envision that would raise blood pressure in sinusoids, resulting in production of ascites ?
The Hepatic Phagocytic System
The liver is host to a very important part of the phagocytic system. Lurking in the sinusoids are large numbers of a type of tissue macrophage known as the Kupffer cell. Kupffer cells are actively phagocytic and represent the main cellular system for removal of particulate materials and microbes from the circulation. The image below is a lightly stained section of liver from a mouse that was injected intravenously with a very small quantity of India ink - Kupffer cells are clearly visible throughout the section because they have phagocytosed the ink particles and appear dark black.
Their location just downstream from the portal vein allows Kupffer cells to efficiently scavenge bacteria that get into portal venous blood through breaks in the intestinal epithelium, thus preventing invasion of the systemic circulation. Metabolic Functions of the Liver
Hepatocytes are metabolic superachievers in the body. They play critical roles in synthesizing molecules that are utilized elsewhere to support homeostasis, in converting molecules of one type to another, and in regulating energy balances. If you have taken a course in biochemistry, you probably spent most of that class studying metabolic pathways of the liver. At the risk of damning by faint praise, the major metabolic functions of the liver can be summarized into several major categories: Carbohydrate Metabolism
It is critical for all animals to maintain concentrations of glucose in blood within a narrow, normal range. Maintainance of normal blood glucose levels over both short (hours) and long (days to weeks) periods of time is one particularly important function of the liver.
Hepatocytes house many different metabolic pathways and employ dozens of enzymes that are alternatively turned on or off depending on whether blood levels of glucose are rising or falling out of the normal range. Two important examples of these abilities are:
Excess glucose entering the blood after a meal is rapidly taken up by the liver and sequestered as the large polymer, glycogen (a process called glycogenesis). Later, when blood concentrations of glucose begin to decline, the liver activates other pathways which lead to depolymerization of glycogen (glycogenolysis) and export of glucose back into the blood for transport to all other tissues.
When hepatic glycogen reserves become exhaused, as occurs when an animal has not eaten for several hours, do the hepatocytes give up? No! They recognize the problem and activate additional groups of enzymes that begin synthesizing glucose out of such things as amino acids and non-hexose carbohydrates (gluconeogenesis). The ability of the liver to synthesize this "new" glucose is of monumental importance to carnivores, which, at least in the wild, have diets virtually devoid of starch. Fat Metabolism
Few aspects of lipid metabolism are unique to the liver, but many are carried out predominantly by the liver. Major examples of the role of the liver in fat metabolism include:
The liver is extremely active in oxidizing triglycerides to produce energy. The liver breaks down many more fatty acids that the hepatocytes need, and exports large quantities of acetoacetate into blood where it can be picked up and readily metabolized by other tissues.
A bulk of the lipoproteins are synthesized in the liver.
The liver is the major site for converting excess carbohydrates and proteins into fatty acids and triglyceride, which are then exported and stored in adipose tissue.
The liver synthesizes large quantities of cholesterol and phospholipids. Some of this is packaged with lipoproteins and made available to the rest of the body. The remainder is excreted in bile as cholesterol or after conversion to bile acids. Protein Metabolism
The most critical aspects of protein metabolism that occur in the liver are:
Deamination and transamination of amino acids, followed by conversion of the non-nitrogenous part of those molecules to glucose or lipids. Several of the enzymes used in these pathways (for example, alanine and aspartate aminotransferases) are commonly assayed in serum to assess liver damage.
Removal of ammonia from the body by synthesis of urea. Ammonia is very toxic and if not rapidly and efficiently removed from the circulation, will result in central nervous system disease. A frequent cause of such hepatic encephalopathy in dogs and cats are malformations of the blood supply to the liver called portosystemic shunts.
Synthesis of non-essential amino acids.
Hepatocytes are responsible for synthesis of most of the plasma proteins. Albumin, the major plasma protein, is synthesized almost exclusively by the liver. Also, the liver synthesizes many of the clotting factors necessary for blood coagulation Biliary Excretion of Waste Products: Elimination of Bilirubin
The liver is well known to metabolize and excrete into bile many compounds and toxins, thus eliminating them (usually) from the body. Examples can be found among both endogenous molecules (steroid hormones, calcium) and exogenous compounds (many antibiotics and metabolities of drugs). A substantial number of these compounds are reabsorbed in the small intestine and ultimately eliminated by the kidney.
One of the most important and clinically relevant examples of waste elimination via bile is that of bilirubin. Additionally, the mechanisms involved in elimination of bilirubin are similar to those used for elimination of many drugs and toxins.
Bilirubin is a useless and toxic breakdown product of hemoglobin, which also means that it is generated in large quantities. In the time it takes you to read this sentence aloud, roughly 20 million of your red blood cells have died and roughly 5 quintillion (5 x 1015) molecules of hemoglobin are in need of disposal.
Dead, damaged and senescent red blood cells are picked up by phagocytic cells throughout the body (including Kuppfer cells in the liver) and digested. The iron is precious and is efficiently recycled. The globin chains are protein and are catabolized and their components reused. However, hemoglobin also contains a porphyrin called heme that cannot be recycled and must be eliminated. Elimination of heme is accomplished in a series of steps:
Within the phagocytic cells, heme is converted through a series of steps into free bilirubin, which is released into plasma where it is carried around bound to albumin, itself a secretory product of the liver.
Free bilirubin is stripped off albumin and absorbed by - you guessed it - hepatocytes. Within hepatocytes, free bilirubin is conjugated to either glucuronic acid or sulfate - it is then called conjugated bilirubin.
Conjugated bilirubin is secreted into the bile canaliculus as part of bile and thus delivered to the small intestine. Bacteria in the intestinal lumen metabolize bilirubin to a series of other compounds which are ultimately eliminated either in feces or, after reabsortion, in urine. The major metabolite of bilirubin in feces is sterobilin, which gives feces their characteristic brown color.
If excessive quantities of either free or conjugated bilirubin accumulate in extracellular fluid, a yellow discoloration of the skin, sclera and mucous membranes is observed - this condition is called icterus or jaundice. Determining whether the excessive bilirubin is free or conjugated can aid in diagnosing the cause of the problem. http://www.vivo.colostate.edu/hbooks...ver/index.html