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© Jim Swan
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Functions of the Liver
Manufacture •blood proteins - albumin, clotting proteins •urea - nitrogenous waste from amino acid metabolism •bile - excretory for the bile pigments, emulsification of fats by bile salts Storage •glycogen - carbohydrate fuel Two additional Two additional •iron - as hemosiderin and ferritin functions, protein functions, protein •fat soluble vitamins A, D, E, K metabolism and metabolism and glycemic Detoxification glycemic regulation will be regulation will be •alcohol considered considered •drugs and medicines shortly. shortly. •environmental toxins
Central vein of lobule
From hepatic artery
Leads to hepatic vein
Kupffer cells Portal triad: Portal arteriole portal venule bile ductule
From hepatic portal vein
Hepatocytes Hepatocytes perform all the perform all the functions of the functions of the liver, dividing up liver, dividing up the task the task according to according to demands. demands.
Sinusoids Sinusoids are Sinusoids are Hepatocytes formed of formed of
To bile duct fenestrated fenestrated endothelium. endothelium.
Structure of the liver - The liver is composed mostly of cells known as hepatocytes which perform the functions listed above. They have the ability to shift functions so their efforts can be directed at what is most needed. They can also divide to repair and replace tissue. Cirrhosis is a condition which can occur in the liver and other organs in which the cells are damaged as a result of toxins, pathogenic organisms, etc. Cirrhosis causes thickening and fibrosis and can progressively damage the liver to the point it can no longer recover by replacing its cells. Other functions also suffer as more hepatocytes become committed to detoxification. The liver is organized into lobes and lobules. Each lobule is served by a branch from the portal vein, the hepatic artery and a bile duct. Blood from the artery and vein mixes in sinusoids passing through the lobule. Hepatocytes line the sinusoids and withdraw digestive endproducts, toxins, etc. from the blood. Into the blood the put urea, glucose, and other substances. Into the bile ductule they put bile to be taken to the gallbladder and common bile duct. Kupffer cells are found inside the sinusoids to phagocytize debris, rbc, and pathogens.
Inf. Vena cava Hepatic vein Hepatic portal system Superior mesenteric vein
Hepatic Portal System
Hepatic portal vein Splenic vein Spleen Inferior mesenteric vein
Large intestine Small intestine The hepatic portal system functions to take blood from the The hepatic portal system functions to take blood from the spleen, stomach, small and large intestines to the liver spleen, stomach, small and large intestines to the liver before it enters the general circulation. before it enters the general circulation.
The hepatic portal system functions to take blood from the spleen, stomach, small and large intestines to the liver before it enters the general circulation. This allows wastes, toxins, and digestive end-products to be processed by the liver.
Diaphragm Left lobe Right lobe
The Normal Liver
A normal liver is about 1200 to 1600 grams, the largest parenchymal organ.
Cirrhosis of the liver: chronic inflammation and loss of normal liver tissue with fibrosis and nodular regeneration, due to disease or toxins.
Audio mp3 file for hi slide
Note the venous drainage from both the rectal veins and lower esophageal veins. When cirrhosis occurs in the liver it produces portal vein hypertension. This causes inertia of blood flow in the rectal and esophageal veins, which can lead to varicies in these veins, including inflammation and bleeding.
Functions of the Liver (contd.)
Transamination - removing the amine from one amino acid and using it to produce a different amino acid. The body can produce all but the essential amino acids, which must be included in the diet. Deamination - removal of the amine group in order to catabolize the remaining keto acid. The amine group enters the blood as urea which is excreted through the kidneys.
Amino Acid Structure
R H2N C COOH
Ingested amino acid
Keto acid from metabolism
New keto acid
New amino acid
e.g. glutamic acid e.g. α ketoglutaric acid The amine group from the ingested amino acid is added to the keto acid to produce a new amino acid.
Ingested or manufactured amino acid Keto acid Amine CO2 NH3 (ammonia) O Urea H2N C NH2 Catabolized for energy Ammonia is toxic and must be converted to urea
Functions of the Liver (contd.)
Glycemic Regulation - the management of blood glucose. •glycogenesis - the conversion of glucose into glycogen. •glycogenolysis - the breakdown of glycogen into glucose. •gluconeogenesis - the manufacture of glucose from non carbohydrate sources, mostly protein.
The Phases of Glycemic Regulation
Absorptive Phase - in this phase digestive endproducts are being absorbed from the gut and sent to storage. The processes occurring during this phase are: 1) Glycogenesis - glucose from the blood plasma is moved into the liver for storage as glycogen. The hormone which governs this is insulin. 2) Protein manufacture - amino acids absorbed from the blood are transaminated and made into proteins. (insulin) 3) Fat synthesis (Insulin)
(Islets of Langerhans) Exocrine acini
Exocrine refers to substances secreted via ducts. The acini are the circular arrangements of secretory cells.
Endocrine cells: Glucagon-secreting alpha cells stain red insulin-secreting beta cells stain blue capillaries
Endocrine cells release their secretions into the bloodstream.
Effects of Insulin:
1) Lowers blood glucose.
2) Stimulates glycogenesis and other storage Insulin stimulates glucose transporters functions.
on muscle and other cells
3) Stimulates uptake of glucose by body cells, especially muscle and fat cells.
Glucose used for energy (catabolism) Glucose used for fat synthesis
Summary of Insulin Action
Stimulus: plasma glucose β cells of islets of Langerhans Insulin Glucose uptake
Amino acid uptake and protein synthesis
Fat glycogenesis synthesis
insulin - (See Figure 25.18) produced by the beta cells of the Islets of Langerhans, these cells are part of the endocrine portion of the pancreas which consists of islands surrounded by pancreatic exocrine cells. Insulin lowers blood glucose by triggering glycogenesis and its uptake by other cells for metabolism. The stimulus for insulin release is rising blood glucose during the absorptive phase which acts directly on the beta cells. In Type I (insulin dependent) diabetes mellitus the pancreas does not secrete enough insulin and insulin injections or oral administration are used to compensate. The amount of insulin taken must match the amount of carbohydrates consumed.
The Post-Absorptive Phase
In this phase glucose is moved back into the blood to replace what is used in metabolism.
1) Glycogenolysis - the first source of glucose is the breakdown of glycogen. The primary hormone for this is glucagon, which comes from the α islet cells. Epinephrine also causes release of glucose into the blood when the sympathetic nervous system is activated. Epinephrine comes from the adrenal medulla. Adrenal gland Kidney
1) glycogenolysis - the first source of glucose is the breakdown of glycogen. The primary hormone for this is glucagon. Epinephrine also causes release of glucose into the blood when the sympathetic nervous system is activated.
2) lipolysis - fat is broken down into glycerol and fatty acids. Fat Glycerol + Fatty Acids “Glucose sparing” Glycolysis & glucogenesis Aerobic metabolism
Glucagon and epinephrine trigger lipolysis. Lipolysis begins when glycogen reserves fall to about 1/3 of maximum.
2) lipolysis - fat is broken down into glycerol and fatty acids. Glycerol is used to make glucose or in glycolysis. Fatty acids can be catabolized by many cells, especially aerobic muscle fibers. This is said to be "glucose sparing" because it leaves glucose available for those cells, e.g. neurons, which rely on glucose exclusively. Glucagon and epinephrine also trigger lipolysis. Lipolysis begins when glycogen reserves fall to about 1/3 of maximum. Glycerol is used to make glucose or in glycolysis. Fatty acids can be catabolized by many cells, especially aerobic muscle fibers. This is said to be "glucose sparing" because it leaves glucose available for those cells, e.g. neurons, which rely on glucose exclusively.
3) Gluconeogenesis - Amino acids are made into glucose under two conditions: a) When they are in abundance as in a high protein, low carbohydrate diet, an action mediated by glucagon; b) When other fuel reserves are low or when severe stress causes release of cortisol. Cortisol causes proteins from muscles and connective tissue to be broken down into amino acids to make glucose.
NOTE: gluconeogenesis due to epinephrine is minor.
3) gluconeogenesis - Amino acids are made into glucose under two conditions: a) when they are in abundance as in a high protein, low carbohydrate diet, an action mediated by glucagon; and b) when other fuel reserves are low or when severe stress causes release of cortisol. Cortisol causes proteins from muscles and connective tissue to be broken down into amino acids to make glucose. Fats are not made into glucose under normal circumstances (except for the glycerol, as above), but in high fat diets or when carbohydrate fuel is unavailable the body shifts to utilizing fat to make glucose.
Summary of Glucagon Action
Stimulus: This also stimulates β cells to release some insulin. plasma glucose
α cells of Islets of Langerhans Glucagon
Glycogenolysis and gluconeogenesis levels of plasma glucose Glucose sparing
glucagon - (See Figure 25.20) Is produced by the alpha cells of the Islets of Langerhans. Glucagon release is triggered by lowering blood glucose levels which occurs during the post-absorptive phase when glucose is withdrawn from the blood for metabolism. Glucagon causes glycogenolysis and lipolysis to yield more glucose and fatty acids for fuel. As blood glucose rises it will stimulate the release of insulin by the beta cells. This is a confusing yet important response. Insulin is necessary for uptake of the glucose for cellular metabolism. And by this mechanisms of two antagonistic hormones glucose levels can be precisely controlled under normal circumstances. We will more thoroughly discuss hyper- and hypoglycemia and diabetes mellitus at a later time.
Epinephrine: Stress Response
Stresses: Hunger, exercise, “fight or flight” Sympathetic N.S. Hypothalamus
Adrenal medulla Epinephrine
epinephrine - (See Figure 25.21) Epinephrine is released by the adrenal medulla into the blood and directly from sympathetic stimulation when the sympathetic nervous system is activated. It causes glycogenolysis and lipolysis which releases fuel for "fight or flight", exercise, and other stressors. NOTE: glycogenolysis in muscles releases glucose for muscle contraction, and does not directly contribute to blood glucose. However this effect is also "glucose sparing" in that plasma glucose is then available for other uses.
Cortisone is released from the adrenal cortex during periods of extreme physical stress. Called a glucocorticoid, this hormone makes fuel available for metabolism, repair and replacement of tissue. This fuel comes mostly from the breakdown of proteins in muscle and connective tissue. Cortisol also has anti-immune and anti-inflammatory effects which are utilized clinically when injury occurs and to suppress the immune response. Administered over a period of time this also results in tissue damage from the hormone's catabolic effects.
GI T ract: Fat A mino A cids G lucose
ABSORPTIVE PHASE POST-ABSORPTIVE PHASE
insulin catabolism of muscle and connective tissue
Liver: amino acids glycogenesis BLOOD insulin pyruvate GLUCOSE glygogenlactate olysis GLYCOGEN glucagon glycerol epinephrine
cortisol gluconeogenesis glucagon
muscle and fat cells
Fat synthesis from glucose
Glycerol is fed into glycolysis as G-3-P and can be metabolized or made into glucose.
Keto acids are easily metabolized and do not accumulate to cause acidosis.
Ketone bodies accumulate when β oxidation occurs in excess, and cause acidosis.
The concepts illustrated here should be a review of material previously studied, and our discussion is intended only to refresh your memory and to relate the metabolic pathways to the overall discussion of nutrition. Metabolism of Fats: Fats are lipolyzed into glycerol and fatty acids. The glycerol is converted to G-3-P and can be reconverted to glucose, or continue in glycolysis. The fatty acids are long chain hydrocarbons with a carboxyl group at one end. They are cleaved into acetyl groups in the process known as beta oxidation. The acetyl groups are then processed aerobically. Not all cells can perform beta oxidation, but your red muscle fibers are responsible for most of it normally. The process also yields reduced electron acceptors. The carboxyl groups are known as "ketone bodies" and are slower to be metabolized. When they accumulate, as they do in a Type I diabetic with insufficient insulin, they can cause acidosis. Also called ketoacidosis, it is a life-threatening complication for insulindependent (Type I) diabetes. Fats yield between 8 and 9 kcal/gram. Protein metabolism - as noted earlier, amino acids are first deaminized to produce a keto acid. The keto acids can be plugged into the aerobic pathway at many points depending on their particular structure. They are therefore readily metabolized and do not accumulate and do not, despite their name, contribute to ketoacidosis in diabetics.
Type I - a.k.a. insulin dependent diabetes mellitus IDDM
usually childhood onset (< 30 yrs. old.) β cells unable to secrete insulin due to damage: congenital, damage due to toxins or radiation, autoimmunity, secondary to other disorders. Managed with insulin injections, oral insulin. Damage to tissues caused by hyperglycemia. Life threatening acidosis when unmanaged.
Diabetes, its causes and types, may be covered in the Endocrine unit.
Type II – non insulin dependent diabetes mellitus - NIDDM “adult onset” – usually over 30 yrs old Due to insulin resistance of receptors on target cells. Insulin secretion may be normal or excessive. Many early Type II diabetics hypersecrete insulin. May have abnormal insulin, presence of insulin antagonists, receptor defects. Often associated with hight carb and fat diet, obesity and lack of exercise. Also genetic components. Hyperglycemia is the most damaging effect.
Treatment of Type II - NIDDM
Insulin analogs – stimulate receptors better than insulin Drugs which increase insulin binding and glucose utilization in muscles. Coordinate with diet (reduced carbohydrates) and exercise (significantly improves effectiveness).
Effects of Hyperglycemia
Increases blood osmolarity – interferes with electrolyte and water transport. Causes hypoxia to cells and ischemia in tissues by damaging blood vessels.
Causes of Hypoglycemia
Hyposecretion by the α cells. Reactive hypoglycemia – exaggerated response by the β cells. Often a precursor or warning of Diabetes type II.
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