L.11 Physiology of the Liver and the Pancreas.pdf

Physiology of the pancreas and liver MUHAMMAD ALBAHADILI 2022-2023 objectives At the end of lecture we able to Describe the exocrine functions of pancreas List the functions of liver define the toxic material excreted by liver Describe...

Physiology of the pancreas and liver MUHAMMAD ALBAHADILI 2022-2023 objectives At the end of lecture we able to Describe the exocrine functions of pancreas List the functions of liver define the toxic material excreted by liver Describe the function of gallbladder  Acidity corrected by Conditioning of chyme HCO3- secreted from pancreas, liver and duodenal mucosa The stomach empties chyme into the duodenum, which is Acidic Hypertonic Partly digested  Hypertonicity corrected by Osmotic movement of water across duodenal wall Digestion completed by Enzymes from pancreas and small intestinal mucosa Bile acids (salts) from liver ?!  pancreas Exocrine gland (in part) with acini & ducts Acini secrete enzymes Ducts secrete alkaline juice Endocrine hormons The endocrine pancreas The islets of Langerhans form the primary component of the endocrine pancreas. These clusters of endocrine cells can be found throughout the pancreas but are most prevalent in the tail. Pancreatic islet cells can be differentiated from exocrine cells as they are smaller and paler. There is an extensive network of blood vessels surrounding the islets – each islet has its own capillary network which is in contact with every cell in that islet – into which the hormones insulin, glucagon, and somatostatin are secreted. insulin Produced β (or B) cells, which constitute 70% of pancreatic endocrine cells. It acts on all cells in the body to increase the uptake of glucose from the blood into the cells. glucagon Produced α(orA)cells(20%) and it acts mainly on the liver. It increases glycogenolysis and gluconeogenesis to raise blood glucose concentration Somatostatin Secreted from δ (or D) cells (5–10%). It acts locally as a paracrine agent, inhibiting the production of insulin and glucagon. It also inhibits the gut peptides secretin, cholecystokinin (CCK), gastrin, and motilin. Pancreatic Produced by PP or F cells (1–2%). polypeptide It self-regulates the pancreas secretion activities, both exocrine and endocrine. Pancreatic exocrine the pancreas secretes about 1.5 L of fluid a day. This fluid contains cations, anions, albumin, globulin and digestive enzymes by: The duct (the bulk of the fluid) is the sodium- and bicarbonate-rich juice secreted which neutralizes acid from the stomach. The acinar cells (a small volume) of fluid rich in digestive enzymes, which break down carbohydrates, fats, proteins and nucleic acids Most of these enzymes are secreted in an inactive form to protect the pancreas from autodigestion and are activated in the duodenum Bicarbonate secretion The pancreas secretes a fluid rich in bicarbonate, which, together with secretions from the gallbladder and the intestinal juices, neutralizes gastric acid in the duodenum, raising the pH to 6 or 7. Enzyme secretion There are three major types of enzymes secreted by the pancreas: Proteolytic enzymes (trypsin, chymotrypsin, proelastase & carboxypeptidase) Amylase Lipase. Additionally, the pancreas also secretes ribonuclease and deoxyribonuclease. Proteolytic enzymes Proteolytic enzymes play an important role in protein digestion. Enterokinase (enteropeptidase) in the brush border of the duodenum secreted in response to cholecystokinin, converts trypsinogen to trypsin. Trypsinogen is therefore not activated until it reaches the duodenum where it is needed.  Trypsin then activates the other proteolytic pro-enzymes, including its own proenzyme trypsinogen, resulting in an autocatalytic chain reaction. To protect the pancreas from the chain reaction and autodigestion (that would result from even a small amount of trypsin in the pancreas), the pancreas contains a trypsin inhibitor called the kazal inhibitor. This forms a complex with trypsin and prevents it from acting. In acute pancreatitis, phospholipase A2 is activated by trypsin in the pancreatic duct. It then acts on lecithin (a normal constituent of bile) to form lysolecithin, which damages cell membranes and causes disruption of pancreatic tissue and necrosis of surrounding fat.  Amylase Like salivary amylase, pancreatic amylase hydrolyses polysaccharides into disaccharides, It is secreted in its active form Lipase This is the most important enzyme in terms of fat digestion. It hydrolyses triglycerides into glycerol and fatty acids, therefore in pancreatic insufficiency where enzyme secretion is deficient, fats cannot be digested, and a malabsorption syndrome occurs. Colipase is a protein co-enzyme required for optimal enzyme activity of pancreatic lipase. It is secreted by the pancreas in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. (Colipase links bile acids & lipases to spread them over the surface of fat) control of pancreatic secretion Pancreatic exocrine secretion is controlled by neuro-endocrine signals, which are hormones and substances released from nerve terminals Cephalic phase Gastrin is released from the mucosa of the antrum in response to vagal stimulation. This causes the release of a small amount of pancreatic juice with a high protein content. Gastric phase Vago-vagal reflexes elicited by distension of the fundus or antrum cause the release of small amounts of pancreatic juice with a high enzyme Intestinal phase The most important phase. It involves the secretion of two hormones, secretin, and cholecystokinin Secretin is released from the duodenal and upper jejunal mucosal cells in response to acid in the lumen. Secretin acts on the pancreatic ducts to stimulate the secretion of a large volume of HCO3-rich fluid (but with low levels of pancreatic enzymes). It also stimulates bile production in the liver, Inhibits the gastric acid secretion Cholecystokinin (CCK, also called pancreozymin) is secreted from duodenal and upper jejunal mucosal cells in response to peptides, amino acids, and fatty acids in the lumen. It has two actions: It acts on pancreatic acinar cells to stimulate enzyme synthesis and release. It acts on the gallbladder by stimulating its contraction and the relaxation of the sphincter of Oddi. Also, inhibit the appetite & gastric acidity Vagotomy & somatostatin inhibit the intestinal phase Felicitate secretin release The liver main functions of the liver are the metabolism of protein, fat, and carbohydrate; bile production; storage of vitamins, minerals, and glycogen; biotransformation; and detoxification and protection Carbohydrate metabolism The liver plays an important role in glucose homeostasis. keep levels within the range of 3.5–5.5 mmol/L. The liver contains approximately 80 g of glycogen. This is enough to keep blood glucose levels within the normal range for approximately 24 hours at rest. insulin and glucagon, control the levels of plasma glucose. Insulin promotes the synthesis of glycogen, protein, and fat while inhibiting gluconeogenesis and lipolysis. Glucagon up-regulates gluconeogenesis and ketogenesis.  Maintain the glucose level in the normal range Regulation of glucose in blood by: glycogenesis, the formation of glycogen from glucose. glycogenolysis, the breakdown of glycogen into glucose. The liver is also responsible for gluconeogenesis, from amino acids, lactate, or glycerol Convert galactose &fructose to glucose Lipid metabolism Lipids are insoluble in water, and they are assembled into lipoproteins (complexes of lipids and protein) in the liver, for transport in the blood. Cholesterol is needed for the manufacture of steroid hormones and bile acids and can be synthesized in the liver. Protein metabolism The liver synthesizes all the plasma proteins except g-globulins. Amino acids from the intestines and muscles enter the liver and by controlling their metabolism (especially via transamination and gluconeogenesis) the plasma protein concentrations can be regulated. The protein concentration of plasma is 60–80 g/L and is made up of mainly albumin, globulin, and fibrinogen. Liver synthesis: Glycogen coagulation factors I (fibrinogen), II (prothrombin), V, VII, VIII, IX, X, XI, XIII, as well as protein C, protein S, antithrombin, and fibrinolytic system cholesterol, lipogenesis, the production of triglycerides, and a bulk of the body's lipoproteins are synthesized in the liver from carbohydrates and fat. Convert cholesterol to bile salt Albumin Convert CHO & protein to ketone body. Haematopoiesis In embryonic life, the liver is the main site of haematopoiesis. This occurs from the 2nd to 7th months but ceases before birth. By 5 months of gestation, the bone marrow is supplementing the liver in this function. Defence The portal blood supply to the liver allows for toxins and microorganisms to be filtered out before the blood returns to systemic circulation. This protects the rest of the body from any harmful substances that may have breached the gut defence mechanisms. Kupffer cells in the sinusoids facilitate this via phagocytosis. Urea metabolism Amino acids are transaminated and deaminated via oxidative pathways in the liver to form ammonia, which is converted to urea via the urea (ornithine) cycle. In liver failure, there is decreased synthesis of urea and increased levels of ammonia—a toxic product. Ammonia can depress cerebral blood flow and cerebral oxygen consumption. Vitamin metabolism The liver is the main store of the fat-soluble vitamins (A, D, E and K). Vitamin B12 folate and converts it to its active form, tetrahydrofolate. Storage The liver acts as a store for, among others, glycogen, fat, and fat-soluble vitamins, folate, iron, and copper. This storage function is important as it enables the body to withstand periods of insufficient intake of stored nutrients. Some stores are large enough to sustain the body’s needs for a few years, e.g. stores of vitamin B12 are sufficient for about 3 years; folate stores can last a few months. Drug and hormone metabolism The liver metabolizes drugs and hormones via biotransformation in three stages: Phase I (oxidation) Phase II (conjugation) Phase III (elimination). These processes are useful, in conjunction with the filtering action of the portal blood supply in allowing the body to detoxify or degrade toxins or waste products. Phase I reactions often produce more active metabolites, e.g. they can change prodrugs into active drugs. Phase II reactions make the substrate more water soluble to facilitate phase III. Phase III occurs via ATPase pumps. Bile production and function Bile is an aqueous, alkaline, greenish-yellow liquid produced by the liver to: Eliminate endogenous and exogenous substances from the liver Emulsify fats in the small intestine and facilitate their digestion and absorption. Bile consists of bile acids, cholesterol, phospholipids, bile pigments (bilirubin), electrolytes (Na, K, Ca, Cl, HCO3) and water. Waste products found in bile include cholesterol and the bile pigments, which give bile its colour. Bile passes out of the liver through the bile ducts, and it is concentrated and stored in the gall bladder. During and after a meal, it is excreted from the gall bladder by contraction and passes into the duodenum through the common bile duct. Most of the bile acids are reabsorbed from the terminal ileum and recycled by the liver. Bile pigments are normally excreted in the faeces, which colour dark brown. Bile acids Bile acids (also called bile salts) are detergents that emulsify lipids. They have a hydrophobic and a hydrophilic end, and they form micelles in aqueous solutions. Bile acids are synthesized in hepatocytes from cholesterol and excreted into the bile. The principal primary bile acids are cholic acid and chenodeoxycholic acid. They are made more soluble by conjugation with taurine or glycine. Of the bile acids excreted into the intestine, 95% are reabsorbed (mostly in the terminal ileum) and recycled by the liver.  Micelles Polar groups of bile acids on outside Hydrophobic fatty acids within Vehicle to carry hydrophobic molecules through aqueous luminal contents into ‘unstirred layer’ next to epithelial cells Fatty acids released slowly and enter cells by diffusion  This is termed enterohepatic recycling. The total pool of bile acids is recirculated six to eight times a day. Reabsorption through enterohepatic recirculation means we only need a small pool of bile acids. Normally about 250–500 mg of bile acids are produced a day, which replaces the amount excreted in the faeces. The main functions of bile acids are: Triglyceride assimilation – bile acids emulsify lipids with the aid of lecithin (found in high concentrations in bile) and break them down to 1-mm-diameter droplets. This provides a large surface area for digestive enzymes to act on Lipid transport – bile acids form mixed micelles with the products of lipid digestion and facilitate transport to the brush border, where they are absorbed Bile flow induction – bile acids stimulate the flow of bile by osmotically attracting water and electrolytes as they are secreted. It is also thought that some bile acids are secreted in an unconjugated form. They are absorbed without water and electrolytes from the bile ducts to be quickly carried back to the liver for re-secretion Regulation of bile acid synthesis – normal reabsorption of bile acids from the intestines inhibits hepatic synthesis of bile acids. Water and electrolyte secretion – if bile acids are present in the colon, they Bilirubin This yellow pigment, which gives bile its colour. Knowledge of bilirubin metabolism is essential to understanding the pathophysiology behind jaundice. Most bilirubin (biliverdin) is formed by the breakdown of hemoglobin from worn-out red cells, but about 15% results from the breakdown of other proteins such as myoglobin, cytochromes, and catalases. Bilirubin is insoluble and is transported to the liver in the plasma, bound to albumin. In the liver is conjugated with glucuronic acid to form bilirubin diglucuronide  Bilirubin diglucuronide is water soluble, unlike bilirubin, and is actively transported against its concentration gradient into the bile canaliculi. A small amount escapes into the blood, where it is transported bound to albumin, and then excreted in the urine. The intestinal mucosa is permeable to unconjugated bilirubin and to urobilinogen (a colourless derivative of bilirubin produced by intestinal flora); some of the bile pigments urobilinogen is reabsorbed from the gut into the portal circulation. The intestinal mucosa is relatively impermeable to conjugated bilirubin. Some of the reabsorbed substances are excreted again by the liver, but small amounts of urobilinogen enter the general circulation and are excreted in the urine. and then to stercobilinogen, which is excreted in the faeces (brown colour). Gallbladder  Gallbladder Storing and Concentrating Bile. in the fasting state, the sphincter of Oddi is contracted. However, in response to stimulation during and after meals it relaxes, allowing the gallbladder to release its contents. The maximum volume that the gallbladder can hold is only 30 to 60 milliliters. Bile is normally concentrated in this way about 5-fold, but it can be concentrated up to a maximum of 20-fold. Gallbladder contraction Gallbladder emptying begins several minutes after the start of a meal. cephalic phase, the taste and smell of food, and the presence of food in the mouth and pharynx cause impulses in branches of the vagus nerve that increase the emptying of the gallbladder. intestinal phase The highest rate of emptying of the gallbladder occurs, mostly in response to cholecystokinin released from the duodenal mucosa as a result of the presence of the products of fat digestion and essential amino acids in the duodenum. Cause contractions of the gallbladder and relaxation of the sphincter of Oddi.  Steatorrhoea If bile acids or pancreatic enzymes are not secreted in adequate amounts Fat appears in faeces Pale Floating Foul smelling  Prehepatic: Jaundice Unconjugated bilirubin remains in the circulation only when the liver is unable to conjugate all the bilirubin that is delivered to it. Clinical jaundice (icterus) is However, increased haemolysis, (whatever caused by plasma levels of the cause), may cause an excess of bilirubin, bilirubin exceeding 50 mmol/L, and this can overcome the liver’s capacity to and it presents as a yellow conjugate it. Therefore, haemolytic jaundice pigmentation of skin, sclera and results in raised levels of unconjugated mucosa. The colour of the sclera bilirubin. This is particularly dangerous in is the best indicator, but it must neonates, as the unconjugated bilirubin can be examined in good white light. cross the blood–brain barrier and cause brain damage (kernicterus). Prehepatic Because unconjugated bilirubin is not Hepatic soluble, it does not pass into the urine, so Post-hepatic. this type of jaundice is often called ‘acholuric jaundice’. The urinary urobilinogen is elevated due to increased resorption from the gut, as the total bilirubin load is raised  Hepatic Post-hepatic Congenital enzyme deficiency in posthepatic jaundice, the Transport inside the liver passage of conjugated bilirubin Hepatitis through the biliary tree is blocked, Conjugated or mixed and it leaks into the circulation instead. It is soluble and excreted in the urine, making it dark. However, the faeces are deprived of their stercobilinogen and are pale. bile salts, along with conjugated bilirubin, escape into the circulation, and this causes itching (pruritus) Signs of liver dysfunction