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Chapter

70 Liver as an Organ Physiologic Anatomy of the Liver -Liver is the largest organ in the body at about 2% body weight in the adult -Basic functional unit is the liver lobule Constructed around a central veinempties into the hepatic veins then the vena cava Lobule composed of liver cellular platesradiate out like spokesusually two cells thickin b/w adjacent cells lie bile cannuliculithese empty into bile ducts Portal venules in the septaget their blood from portal veinfrom here blood flows into hepatic sinusoidslie b/w hepatic plates and central veinso hepatic cells are exposed to portal venous blood Hepatic arterioles are also in the septa -Venous sinusoids are line by endothelial cells and Kupffer cells Kupffer cells are resident macrophages Endothelial lining is porousspace of Disse lie underneathconnect with lymphatic vesselsexcess fluid is removed by the lymphaticsplasma substance (plasma proteins for ex.) can move freely into the spaces -Little pressure in the hepatic vein to the vena cavaso resistance to blood flow through the hepatic sinusoids is normally very low Cirrhosis -Liver parenchymal cells are destroyedreplaced with fibrous tissue -This fibrous tissue contracts around blood vesselsimpedes portal blood flow -Commonly a result of chronic alcoholism -Fat accumulation in the liver can also be a causesubsequent liver inflammation named nonalcoholic steatohepatitis (NASH) -Less severe form of this is nonalcoholic fatty liver disease (NAFLD) Most common cause of liver disease in many industrialized countries (including US) Usually associated with type II diabetes

-Cirrhosis can also be a result of: 1) Poisons (ex. CCl4) 2) Viral diseases (ex. infectious hepatitis) 3) Bile duct obstruction 4) Infection of the bile ducts Portal Hypertension -Sudden blockage of portal system -Impediment of returning blood flow from the intestines and spleen back into the systemic circulation -Increases capillary pressure in the intestinal wall to 15-20 mmHg above normal -Death can occur in hours from the excessive loss of fluid from the capillaries into the lumens and walls of the intestines Liver -an expandable organ -stores large amounts of blood -normal450mL stored10% of bodys total blood -Increased pressure in the right atrium (usually low)venous backup (since venous blood flows into right atrium)causes backpressure in the liver and it expands to hold .5-1 L of bloodthis situation is frequently seen with CHF -Very permeable pores in the hepatic sinusoidsallow ready passage of fluid and proteins into the space of Disse So the lymph draining the liver has a slightly lower protein conc. than that of plasma Large quantities of the lymph forms because of this permeabilityliver gives rise to about the lymph in the body Transudate and Ascites -excess fluid transudes to the lymph with hepatic vein pressure 3-7 mmHg above normal Fluid is almost pure plasma Only 80-90% as much of the protein found in normal plasma -With pressure of 10-15 mmHg above normal in the vena cava Hepatic lymph flow is up to 20x above normal Release of fluid from the surface of the liver

Leads to large amounts of free fluid in the peritoneal cavityAscites -Another cause of ascites: Portal flow blockagehigh capillary pressure in the GI portal systemresults in edema of the gut wallfluid transudes through the serosa of the gut into the abdominal cavity Liver Regeneration -Regeneration after partial hepatectomy or acute liver injuryas long as theres no viral infection, inflammation, or fibrosis -Hepatocytes replicate once or twice to regain the original size and volume of the liver -Hepatocyte growth factor (HGF) and other growth factors play an important role in the cell division and growth -TGF- is suggested to terminate regeneration -Pre liver portal bloodlots of bacteria -This is because of the specialized macrophages (Kupffer cells) that line the hepatic venous sinuses -Prevents colon bacilli from entering systemic circulation (<1%) Summarized carbohydrate metabolism functions of the liver 1) Storage of large amounts of glycogen 2) Conversion of galactose and fructose to glucose 3) Gluconeogenesis 4) Formation of many chemical compounds from intermediate products of carbohydrate metabolism

Summarized fat metabolism functions in the liver 1) Oxidation of fatty acids to supply energy for other body functions 2) Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins 3) Synthesis of fat from proteins and carbohydrates -Derivation of energy from neutral fats (one glycerol and three FA chains) 1. Fat split into glycerol and FAs 2. FAs are split by beta oxidationends up forming acetyl-CoA)these can enter the CA cycle-oxidation can happen in all cells of the body, but happens especially rapid in the liver 3. Liver cannot use all of the acetyl-CoA2 molecules of it is converted into acetoacetic acid 4. Acetoacetic acid is highly solubletransported via the ECF throughout the body 5. Tissues reconvert the acetoacetic acid back to acetyl-CoA -80% of cholesterol synthesized in the liverconverted to bile saltssecreted in the bile -Rest is transported in the lipoproteinscarried in the blood to tissues in body -Phospholipids are synthesized in the livertransmitted by the lipoproteins -Almost all the fat synthesis in the body from carbs and proteins also occurs in the liverafter fat is synthesized in the livertransported by the lipoproteins to the adipose tissue to be stored

Summarized protein metabolism functions in the liver 1) Deamination of amino acids 2) Formation of urea for removal of ammonia from the body fluids 3) Formation of plasma proteins 4) Interconversions of the various amino acids and synthesis of other compounds from amino acids -Death occurs in a few days w/o protein metabolism from the liver -Deamination of amino acids Required before AAs can be used for energy or converted into carbs or fats Greatest amount of deamination in the liver (also sizable in the kidney) -Urea formation Removes ammonia from the body fluids This ammonia is largely a result from deamination (also some from gut bacteria) If urea not formed in liverplasma NH3 risesresults in hepatic coma and death Greatly decreased blood flowcan also result in increased ammonia in the blood (Hyperammonemia) -All plasma proteins (except some gamma globulins) are made in the liver Accounts for 90% of all plasma proteins Formed by liver at a max rate of 15-50g/dayso can be replenished fairly quickly Plasma protein depletioncauses mitosis of hepatic cells and rapid growth of liver sizerapid production of plasma proteins until levels return to normal If there is a chronic liver diseasevery low plasma protein levels, such as with albumin)leads to edema and ascites (fluid leaks out of the vasculature to the tissue because of the pressure gradient)

-Liver can synthesize certain amino acidsalso certain chemical compounds from amino acids Ex. : Nonessential amino acids can all be synthesized in the liver (nonessential meaning they can be synthesized in the body and dont have to come from the diet) 1) Keto acid with the same chemical composition of the amino acid (except at the keto oxygen) to be form is synthesized 2) Next an amino radical is transferred, through several stages of transanimation, from an available amino acid over to the keto acid to take the place of the keto oxygen -Liver is a storage site of vitamins Greatest quantity is vitamin Astorage for up to 10 months w/o deficiency Also seen are vitamins D and B12D for 3-4 months, B12 for at least 1 year up to several -Greatest proportion of iron storage in the body is in the liver (except for the hemoglobin in blood) Stored in the form of ferritin Hepatic cells contain apoferritincapable of combining reversibly with iron With excess iron apoferritin combines with the iron to form ferritin Ferritin stored until low iron levels in body fluidferritin releases iron System works as a blood iron buffer as well as an iron storage system -Liver forms the blood substances used in coagulation which include: 1) Fibrinogen 2) Prothrombin 3) Accelerator globulin 4) Factor VII Vitamin K is needed in the liver for their formationespecially with prothrombin and factors VII,I X, and X W/O vitamin K. their cocnc. decreases almost preventing coagulation

Bilirubin -Excreted in the bile and eliminated in the feces -Greenish-yellow pigment -Major end product of degradation -Valuable tool in diagnosing hemolytic blood disease and various liver diseases -Explanation: RBCs rupture at the end of their lifespan when they become too fragile (on average 120 days) Hemoglobin is released and then phagocytized by tissue macrophages (of the RES) Hemoglobin is split into first 1) Globin and 2) Heme Heme ring is opened (by heme oxygenase) to give 1) Free irontransported in blood by transferrin 2) A straight chain of four pyrrole nucleisubstrate for which bilirubin will be formed For the first substance formed from this is biliverdin Biliverdin is rapidly reduced to form unconjugated (AKA free) bilirubin Unconjugated bilirubin is released from the macrophages into the plasma where it combines with albumin Plasma albumin bound unconjugated bilirubin is transported throughout the blood and interstitial fluids This is then sent to the liver where the bilirubin is absorbed by hepatocytes and released from the plasma albumin o 80% is conjugated with glucuronic acidforms bilirubin glucuronide o 10% is conjugated with sulfateforms bilirubin sulfate o 10% with multiple other substances In its conjugated form its excreted from the hepatocytes by active transport and into the bile canaliculi and then into the intestines

-Once in the intestines About is converted by bacteria to urobilinogen -Urobiligen Highly soluble Some is reabsorbed through the intestinal mucosa back into the blood- o Most of this is re-excreted by the liver back into the gut o About 5% though is excreted by the kidneys into the urinewhen exposed to air its oxidized to form urobilin o In the feces it becomes oxidized to form stercobilin Jaundice -Usual cause is large quantities of bilirubin (either unconjugated or not) in the ECF -Normal plasma conc. is 0.5mg/dl of plasmaalmost entirely unconjugated -With abnormal conditionscan rise to as much as 40mg/dl much can become the conjugated type -Skin usually appears yellow tinted at about 3x normal (1.5mg/dl) -Common causes of jaundice: 1) Hemolytic Jaundice Excretory function is normal RBCs rapidly hemolyzed leading to bilirubin formationhepatic cells cant excrete bilirubin fast enough Unconjugated bilirubin levels rise Also increased urobilinogen levels 2) Obstructive jaundice Bilirubin formation rate is normal Bilirubin cannot pass into the intestines This is because of either obstruction of the bile ducts (gallstone or cancer blocking the CBD) or from damage to the hepatic cells (seen with hepatitis) Conjugation still occurs in the normal way Conjugate bilirubin is then returned to the blood (so its not excreted in bile, urine, or waste, but rather stays in the body via blood)

Function Test Pre-Hepatic Jaundice (Hemolytic) Total Bilirubin Normal/ Increased Conjugated Normal Bilirubin Unconjugated Normal/ Bilirubin Increased Urobilinogen Normal/ Increased Urine Color Normal

Hepatic Jaundice (Cirrhosis, Hepatitis for ex.) Increased Increased Increased Decreased

Post-Hepatic Jaundice (obstructive of some variety) Increased Increased Normal Decreased/Negative

Stool Color Normal Alkaline Normal Phosphotase Levels AST/ALT Normal Increased Increased Conjugated Not present Present Present Bilirubin in Urine Splenomegaly Present Present Absent -In hemolytic jaundice: almost all of the bilirubin is unconjugated -In obstructive jaundice: almost all of the bilirubin is conjugated with total obstruction no bilirubin can make it to the intestinesmeans no conversion to urobilinogen by bacteria so no urobilinogen is reabsorbed into the bloodnone excreted by kideneys tests are completely negative for urobilinogen stools are clay colored (no stercobilin) conjugated bilirubin is excreted in the urine because it can pass through the kidneys while albumin bound unconjugated bilirubin cannot

Dark (Urobilinogen+ Dark (Conjugated Bilirubin) Conjugated Bilirubin Normal/Pale Pale Increased Increased

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