Guyton and Hall Physiology Chapter 71 - The Liver

• The liver carries out various interconnected functions, which become particularly noticeable when liver abnormalities arise.
• The liver's major functions include blood filtration and storage, metabolism of essential compounds, bile formation, vitamin and iron storage, and coagulation factor formation.

Physiologic Anatomy of the Liver

• The liver constitutes about 2% of total body weight, approximately 1.5 kg in an average adult.
• The basic functional unit is the liver lobule, a cylindrical structure millimeters in length and 0.8 to 2 mm in diameter.
• The human liver contains 50,000 to 100,000 individual lobules.
• The liver lobule is structured around a central vein that drains into the hepatic veins and then into the vena cava.
• It is composed of liver cellular plates radiating from the central vein, with small bile canaliculi between adjacent cells emptying into bile ducts.
• Small portal venules in the septa receive blood from the gastrointestinal tract via the portal vein, flowing into hepatic sinusoids between the hepatic plates and then into the central vein.
• The hepatic cells are exposed continuously to portal venous blood.
• Hepatic arterioles are present in the interlobular septa, supplying arterial blood to the septal tissues, with some arterioles emptying directly into the hepatic sinusoids.
• Most hepatic arterioles empty one third of the distance from the interlobular septa.
• The venous sinusoids are lined by endothelial cells and large Kupffer cells, also called reticuloendothelial cells, which are resident macrophages capable of phagocytizing bacteria and foreign matter in the hepatic sinus blood.
• The lining of the sinusoids features extremely large pores, approximately 1 micrometer in diameter.
• Tissue spaces called the spaces of Disse, also known as the perisinusoidal spaces lie beneath this lining, between the endothelial cells and the hepatic cells.
• The millions of spaces of Disse connect to lymphatic vessels in the interlobular septa, allowing excess fluid to be removed through the lymphatics.
• Substances in the plasma can move freely into the spaces of Disse because of the large pores in the endothelium.
• Large portions of the plasma proteins diffuse freely into these spaces.

Hepatic Vascular and Lymph Systems

• The hepatic vascular system involves blood flow from the portal vein and hepatic artery.
• About 1050 ml/min of blood flows from the portal vein into the liver sinusoids, and 300 ml/min flows from the hepatic artery, averaging 1350 ml/min, or 27% of the resting cardiac output.
• The pressure in the portal vein averages 9 mm Hg, while the pressure in the hepatic vein averages 0 mm Hg, indicating low resistance to blood flow through the hepatic sinusoids.
• Cirrhosis of the liver increases resistance to blood flow as destroyed liver parenchymal cells are replaced with fibrous tissue that contracts around the blood vessels.
• Cirrhosis commonly results from chronic alcoholism or excess fat accumulation, known as nonalcoholic steatohepatitis (NASH).
• Nonalcoholic fatty liver disease (NAFLD) is a less severe form of fat accumulation and inflammation in the liver, associated with obesity and type 2 diabetes.
• The liver's high lymph flow is due to the permeable hepatic sinusoids, allowing fluid and proteins to pass into the spaces of Disse.
• Lymph draining from the liver has a protein concentration of about 6 g/dl, slightly less than plasma.
• About half of all the lymph formed in the body under resting conditions arises in the liver.
• High hepatic vascular pressures can cause fluid transudation into the abdominal cavity, leading to ascites.
• When hepatic vein pressure rises 3 to 7 mm Hg above normal, fluid transudes into the lymph and leaks into the abdominal cavity.
• This fluid is almost pure plasma, containing 80% to 90% as much protein as normal plasma.
• At vena caval pressures of 10 to 15 mm Hg, hepatic lymph flow increases to as much as 20 times normal
• "Sweating" from the liver surface causes large amounts of free fluid in the abdominal cavity
• Blockage of portal flow causes high capillary pressures in the gastrointestinal tract, resulting in edema of the gut wall and transudation of fluid into the abdominal cavity, also causing ascites.
• Cirrhosis can also follow ingestion of poisons such as carbon tetrachloride, viral diseases such as infectious hepatitis, obstruction of the bile ducts, and infectious processes in the bile ducts.
• The portal system is also occasionally blocked by a large clot that develops in the portal vein or its major branches.
• When the portal system is suddenly blocked, the return of blood from the intestines and spleen through the liver portal blood flow system to the systemic circulation is impeded.
• This impedance results in portal hypertension, with the capillary pressure in the intestinal wall increasing to 15 to 20 mm Hg above normal.
• The patient may die within a few hours because of excessive loss of fluid from the capillaries into the lumens and walls of the intestines if the obstruction is not relieved.
• The liver functions as a blood reservoir because it is an expandable organ and can store large quantities of blood in its blood vessels.
• The liver's normal blood volume is about 450 ml, or almost 10% of the body's total blood volume.
• When high pressure in the right atrium causes back-pressure in the liver, the liver expands and the hepatic veins and sinuses may store 0.5 to 1 liter extra blood.
• This storage of extra blood occurs especially in cases of cardiac failure with peripheral congestion.
• The liver, in effect, functions as a large, expandable, venous organ capable of acting as a valuable blood reservoir capable of supplying extra blood in times of diminished blood volume.

Regulation of Liver Mass-Regeneration

• The liver can restore itself after significant tissue loss, unless the injury is complicated by viral infection or inflammation.
• Partial hepatectomy, removing up to 70% of the liver, causes the remaining lobes to enlarge and restore the liver to its original size.
• The liver regeneration is remarkably rapid and requires only 5 to 7 days in rats.
• During liver regeneration, hepatocytes are estimated to replicate once or twice, and after the original size and volume of the liver are achieved, the hepatocytes revert to their usual quiescent state.
• Hepatocyte growth factor (HGF) is important in causing liver cell division and growth, with blood levels rising more than 20-fold after partial hepatectomy.
• HGF is produced by mesenchymal cells in the liver and in other tissues, but not by hepatocytes.
• Mitogenic responses are usually found only in the liver after these operations, suggesting that HGF may be activated only in the affected organ.
• Other growth factors and cytokines may also be involved in stimulating liver regeneration.
• Transforming growth factor-β, a cytokine secreted by hepatic cells, inhibits liver cell proliferation and terminates liver regeneration.
• Physiological experiments indicate that liver growth is closely regulated to body size, so an optimal liver to body weight ratio is maintained for optimal metabolic function.
• The regenerative process of the liver is severely impaired and liver function deteriorates in liver diseases associated with fibrosis, inflammation, or viral infections

The Hepatic Macrophage System Serves a Blood-Cleansing Function

• Blood flowing through the intestinal capillaries picks up many bacteria from the intestines.
• Kupffer cells, the large phagocytic macrophages lining the hepatic venous sinuses, efficiently cleanse blood, trapping and digesting bacteria in less than 0.01 second.
• Probably less than 1% of the bacteria entering the portal blood from the intestines succeeds in passing through the liver into the systemic circulation.

Metabolic Functions of the Liver

• The liver shares substrates and energy, processes and synthesizes multiple substances, and performs many other metabolic functions.
• The liver stores large amounts of glycogen, converts galactose and fructose to glucose, performs gluconeogenesis and forms many chemical compounds from intermediate products of carbohydrate metabolism.
• The liver allows remove excess glucose from the blood, stores it, and then return it to the blood when the blood glucose concentration begins to fall too low, which is called the glucose buffer function of the liver.
• In a person with poor liver function, blood glucose concentration after a meal rich in carbohydrates may rise two to three times as much as in a person with normal liver function.
• Gluconeogenesis occurs only when the glucose concentration falls below normal.
• Large amounts of amino acids and glycerol from triglycerides are then converted into glucose, thereby helping to maintain a relatively normal blood glucose concentration.

Fat Metabolism

• Liver oxidation of fatty acids supplies energy.
• Liver synthesis of cholesterol, phospholipids, and lipoproteins.
• Liver synthesis of fat from proteins and carbohydrates.
• To derive energy from neutral fats, the fat is first split into glycerol and fatty acids.
• The fatty acids are then split by beta-oxidation into two-carbon acetyl radicals that form acetyl coenzyme A (acetyl-CoA).
• 80% of the cholesterol synthesized in the liver turns into bile salts and is secreted into the bile.
• The remainder is transported in the lipoproteins and carried by the blood to the tissue cells of the body.
• Phospholipids are likewise synthesized in the liver and transported principally in the lipoproteins.
• Both cholesterol and phospholipids are used by the cells to form membranes, intracellular structures, and multiple chemical substances that are important to cellular function.
• Almost all the fat synthesis in the body from carbohydrates and proteins also occurs in the liver.
• After fat is synthesized in the liver, it is transported in the lipoproteins to the adipose tissue to be stored.

Protein Metabolism

• The most important functions of the liver in protein metabolism are deamination of amino acids, formation of urea for removal of ammonia from the body fluids, formation of plasma proteins, interconversions of the various amino acids and synthesis of other compounds from amino acids
• Deamination of amino acids is required before they can be used for energy or converted into carbohydrates or fats.
• A small amount of deamination can occur in the other tissues of the body, especially in the kidneys, but it is much less important than the deamination of amino acids by the liver.
• Liver formation of urea removes ammonia from the body fluids.
• Large amounts of ammonia are formed by the deamination process, and additional amounts are continually formed in the gut by bacteria and then absorbed into the blood.
• If the liver does not form urea, the plasma ammonia concentration rises rapidly and results in hepatic coma and death.
• Even greatly decreased blood flow through the liver—as occurs occasionally when a shunt develops between the portal vein and the vena cava—can cause excessive ammonia in the blood, an extremely toxic condition.
• Essentially all the plasma proteins, with the exception of part of the gamma globulins, are formed by the hepatic cells, accounting for about 90% of all the plasma proteins.
• The remaining gamma globulins are the antibodies formed mainly by plasma cells in the lymph tissue of the body.
• The liver can form plasma proteins at a maximum rate of 15 to 50 g/day.
• Plasma protein depletion causes rapid mitosis of the hepatic cells and growth of the liver to a larger size.
• Effects of plasma protein depletion coupled with rapid output of plasma proteins until the plasma concentration returns to normal.
• With chronic liver disease, plasma proteins, such as albumin, may fall to very low levels, causing generalized edema and ascites.
• Among the most important functions of the liver is its ability to synthesize certain amino acids and other important chemical compounds from amino acids.
• The nonessential amino acids can all be synthesized in the liver.
• To perform this function, a keto acid having the same chemical composition (except at the keto oxygen) as that of the amino acid to be formed is synthesized.
• An amino radical is then transferred through several stages of transamination from an available amino acid to the keto acid to take the place of the keto oxygen

Other Metabolic Functions of the Liver

• The liver is a storage site for vitamins A, D, and B12.
• The liver stores iron as ferritin. When iron is available in the body fluids in extra quantities, it combines with apoferritin to form ferritin and is stored in this form in the hepatic cells until needed elsewhere.
• The liver forms substances used in blood coagulation, including fibrinogen, prothrombin, accelerator globulin, factor VII
• The liver removes or excretes drugs, hormones, and other substances.
• The liver is well known for its ability to detoxify or excrete many drugs into the bile, including sulfonamides, penicillin, ampicillin, and erythromycin.
• Several of the hormones secreted by the endocrine glands are also either chemically altered or excreted by the liver, including thyroxine and essentially all the steroid hormones, such as estrogen, cortisol, and aldosterone.
• Liver damage can lead to excess accumulation of one or more of these hormones in the body fluids and therefore cause overactivity of the hormonal systems.
• Excretion by the liver in the bile is one of the major routes for excreting calcium from the body

Measurement of Bilirubin in the Bile as a Clinical Diagnostic Tool

• Bilirubin provides an exceedingly valuable tool for diagnosing both hemolytic blood diseases and various types of liver diseases.
• Red blood cells rupture, and the released hemoglobin is phagocytized
• The hemoglobin is first split into globin and heme.
• The heme ring is opened to give (1) free iron, which is transported in the blood by transferrin, and (2) a straight chain of four pyrrole nuclei, which is the substrate from which bilirubin will eventually be formed.
• Biliverdin is rapidly reduced to free bilirubin.
• Free bilirubin combines strongly with plasma albumin and is transported.
• The unconjugated bilirubin is absorbed through the hepatic cell membrane.
• It is released from the plasma albumin and soon thereafter conjugated about 80% with glucuronic acid to form bilirubin glucuronide, about 10% with sulfate to form bilirubin sulfate, and about 10% with a multitude of other substances.
• Excretion by the liver in the bile is one of the major routes for excreting calcium from the body

Jaundice—Excess Bilirubin in the Extracellular Fluid

• Jaundice refers to a yellowish tint to the body tissues.
• The usual cause of jaundice is large quantities of bilirubin in the extracellular fluids
• The skin usually begins to appear jaundiced when the concentration rises to is, above 1.5 mg/dl.
• The common causes of jaundice are (1) increased destruction of red blood cells and (2) obstruction of the bile ducts or damage to the liver cells
• These two types of jaundice are called hemolytic jaundice and obstructive jaundice.
• In hemolytic jaundice, the excretory function of the liver is not impaired, but red blood cells are hemolyzed so rapidly that the hepatic cells simply cannot excrete the bilirubin as quickly as it is formed.
• In obstructive jaundice, the rate of bilirubin formation is normal, but the bilirubin formed cannot pass from the blood into the intestines.
• In obstructive jaundice tests for urobilinogen in the urine are completely negative, and stools become clay-colored.
• In severe obstructive jaundice, significant quantities of conjugated bilirubin appear in the urine.
• In hemolytic jaundice, almost all the bilirubin is in the "unconjugated" form; in obstructive jaundice, it is mainly in the "conjugated" form.