Digestive Liver Function PDF

Liver function PHYSIOLOGICAL ANATOMY - - - - The liver is the largest organ in the body (composes 2% of body weight). The anatomical unit of the liver is the hepatic lobule. The functional unit is the acinus The space in between the fenestrated endothelium of sinusoids and hepatocytes is known as Di...

Liver function PHYSIOLOGICAL ANATOMY - - - - The liver is the largest organ in the body (composes 2% of body weight). The anatomical unit of the liver is the hepatic lobule. The functional unit is the acinus The space in between the fenestrated endothelium of sinusoids and hepatocytes is known as Disse space, where other types of cells reside: Kupffer cells (liver’s own immune cells) and Stellate cells (vitamin A) This space has lymphatic drainage. Very important as if there’s fibrosis, we’ll have collection of lymph in the abdomen, high pressure, accumulation of liquid and ascites. Basic zones of liver acinus: ○ Portal triad (hepatic artery + bile duct + portal vein) ○ Central vein In the liver, there’s Zonation: we find peripheral (1), intermediate (2), and pericentral (3) zones Hepatic sinusoids and Disse space - The hepatic sinusoid is unique: the endothelial lining of the sinusoids is fenestrated (like a window), it resembles the renal glomerular fenestrated endothelium, but has no basement membrane - The size of these fenestrations is large, but dynamic (changes rapidly with alcohol consumption, fasting,...) - Function = to allow macromolecules to pass directly for absorption by hepatocytes - These “windows” are used by macrophages (Kupffer cells) and other immune cells to enter the Disse space - Disse space contains: - Hepatic stellate cells. They contain specific types of droplets which are full of vitamin A. They get activated upon damage, lose all their droplets and start generating fiber in order to replace hepatocytes and repair the damage. This is what gives place to liver fibrosis - Kupffer cells HEPATIC VASCULAR SYSTEM Blood arriving at the liver: ⅔ coming from the portal system, ⅓ coming from the hepatic artery. The total is almost ⅓ of the total cardiac output (5L), in other words, 27%. All this is drained through the central veins into the peripheral venous system: through the suprahepatic veins and into the IVC. Hepatic pressure gradient - If the liver is healthy, the pressure gradient between the portal and suprahepatic veins will be 5-9 mmHg (5-9 mmHg in portal vein, 0mmHg in suprahepatics). This is the max value this gradient, known as infrahepatic gradient, can reach. - If there is cirrhosis, the liver is stiffer. The pressure exerted in the portal vein in order for blood to enter the liver will need to be much higher, giving place to an important portal hypertension (when infrahepatic gradient > 10 mm Hg). Portal hypertension Caused by increases in liver stiffness (cirrhosis): the gradient increases along with increase in liver stiffness, which causes resistance to portal hepatic flow. 1. The blood flow from the stomach and intestines will seek a path of lesser resistance, trying to reach the central venous system. It will reach the collateral venous system, causing varices. The most risky varices are those at the level of the esophagus, which can rupture. If they start to bleed, it can cause the death of the patient. This collateral system bypasses the liver, as it offers lesser resistance when the liver is cirrhotic and unhealthy. 2. In some cases of cirrhosis, due to the high pressure, the liquid in the blood will seep out to the interstitium, giving place to ascites. There’s an outflow of fluid due to hydrostatic pressure into the abdominal cavity (this is the 2nd consequence of having high portal pressure). 3. Lastly, other consequences are: - Splenomegaly (as cells start accumulating in the spleen due to slow flow) = sequestering of platelets and other cells (hypersplenism) - Platelets are depleted and therefore, clotting is compromised = risk of bleeding out LIVER REGENERATION The liver regenerates in a unique way when a part of it is resected (partial hepatectomy). The main cells responsible for regeneration are mature hepatocytes, which after being stimulated, enter the cell cycle and begin to divide. After resection, the liver regenerates to the size necessary for the individual’s hepatic functions (“hepatostat”). This also happens in the case of transplant, when there is chronic damage to the whole liver of the individual and a new piece of liver needs to be transplanted from a donor. Once again, when the necessary size is reached, hepatocytes return to a quiescent state. There are 3 phases of regeneration: i. Priming phase: inflammatory cytokines (TNFalpha, IL-6) ii. Proliferation phase: growth factors (EGF, HGF) iii. Termination phase: transforming growth factor beta (TGFb) When the liver is diseased (accumulation of fat, inflammation or fibrosis), regeneration is highly impaired. PROTECTION and INTESTINAL BLOOD PURIFICATION Kupffer cells (red): found transiting throughout the liver, protecting it from bacterial products arriving through the portal system. They enter the space of Disse through the fenestrae of hepatic sinusoids, in response to chemokines and damage signals. As soon as they become in contact with bacteria, Kupffer cells phagocyte them in a very short time (0.01 s). Immediately eliminated. Portal blood may carry some bacteria that have penetrated through the intestinal barrier. Hepatic venous blood (after passage through the liver) is sterile. Hepatic Stellate cells (green) (vitamin A reservoirs) Liver sinusoidal endothelial cells (blue) (LSEC) METABOLIC FUNCTIONS of the LIVER Carbohydrate metabolism The liver is responsible for - Storing carbohydrates in the form of glycogen. The liver stores other simple carbohydrates (fructose, galactose) other than glucose by transforming them into glucose and then glycogen. - Gluconeogenesis: synthesis of glucose from amino acids, lactate or glycerol - Glycogenolysis: break down glycogen to obtain glucose which’ll enter glycolysis - Diversion of intermediate metabolites of Glucose for the synthesis of other products. It can use this glucose for the synthesis of other products such as glycoproteins, nucleotides,... Lipid metabolism - - - Uses the 𝛽-oxidation of fatty acids to obtain energy for other functions (the acetyl-CoAs obtained from beta oxidation are transformed to aceto-acetic acid and carried to other tissues, where it’s reconverted into Acetyl-CoA to obtain energy) Synthesizes large amounts of cholesterol and phospholipids Much of this cholesterol is then used for the synthesis of bile salts Synthesizes practically all of the lipoproteins in the body. Cholesterol and phospholipids travel in the form of lipoproteins to tissues, for membrane synthesis De novo lipogenesis: Hepatocytes can also synthesize lipids de novo by using glucose and amino acids. If not needed, these lipids travel in the form of lipoproteins to adipose tissue for storage Protein metabolism - - Deamination of amino acids (to be recycled and used in other metabolic processes) Formation of urea, which is used to remove ammonia from the body, byproduct of deamination Synthesis of plasma proteins: transporters, proteins of the clotting system (coagulation cascade), inflammatory proteins,... 90% of plasma proteins are synthesized by the liver Interconversion of the different amino acids (transamination): when we need one more than the others, they can easily be interchanged at the liver Synthesis of different compounds from amino acids OTHER LIVER FUNCTIONS Vitamin storage - Vitamin A, which is stored in hepatic stellate cells Vitamin D and Vitamin B12 stored in hepatocytes Iron deposit Hepatocytes contain large amounts of apo-ferritin, which when combined with iron, allow its storage in the form of ferritin (iron+apo-ferritin) Protein production. Coagulation cascade - Fibrinogen (gives rise to fibrin), Prothrombin, Factor V (the most important), VitK dependent factors Some proteins of the coagulation cascade are Vitamin K dependent for their synthesis: FII, FVII, FIX and FX (1-9-7-2, vitamin K dependent) Detoxification - - Drugs and toxins (through cytochromes P450, a superfamily of enzymes which oxidize steroids, fatty acids, xenobiotics, and are important for the clearance of various compounds. Present in the walls of the sarcoplasmic reticulum of hepatocytes) Hormones: thyroxine, steroids,... transformed and modified in the liver, and excreted through the bile Concept of Liver zonation We have some hepatocytes fulfilling some functions, while others are found fulfilling others. Some functions are more important in the peripheral zone (zone 1) and others in the pericentral zone (zone 3) ○ Hepatocytes in zone 1 have more oxygen so they can perform more gluconeogenesis ○ Hepatocytes in zone 3 have less oxygen, so they’ll perform more glycolysis + xenobiotic metabolism (xeno = things that are not human, such as drugs etc), and not so much respiration JAUNDICE Jaundice is a condition which involves yellowish coloration of skin and mucous membranes. The liver is very important in the excretion of bile, which contains, amongst other substances, bilirubin destined to be excreted. When the liver isn’t functioning well, there is high bilirubin in blood and we adopt a yellowish tone. Heme metabolism - Heme groups are produced as by-products of the degradation of erythrocytes. Macrophages and other phagocytic cells destroy fragile RBCs. - The same macrophages oxidize the pyrrole groups of heme and produce biliverdin, which is reduced into indirect or unconjugated bilirubin - This unconjugated bilirubin is absorbed by the liver, which conjugates it (ex: with glucuronate or others) formin direct bilirubin - Direct or conjugated bilirubin is excreted into the bile duct along with the rest of bile components, and reaches the intestines - Intestinal microbiome transforms the conjugated bilirubin into urobilinogen. At this point, urobilinogen follows different pathways: - Most is converted into stercobilinogen, which is oxidized to stercobilin and excreted through the feces. Responsible for the brown colour of feces. - A part of urobilinogen is quickly reabsorbed through the intestinal walls - A portion of this reabsorbed urobilinogen reaches the kidneys, where it gets converted to urobilin and excreted through the urine. Gives urine its characteristic yellow colour. Too much bilirubin (for ex, due to increased erythrocyte lysis) = yellow colour. - A small part of that absorbed urobilinogen returns to the liver, being recycled and secreted once again in bile In case of jaundice, there may be: - A defect in the excretion of conjugated bilirubin (liver-biliary diseases) - An excess production of unconjugated bilirubin (abnormally high destruction of RBCs; increased hemolysis). The amount exceeds the liver and body’s function of processing bilirubin, giving place to jaundice. * Liver O2 supply: liver receives 50% of its oxygen supply through the portal vein. The other 50% from the proper hepatic arteries (left and right)