BIOL1XX8 2024 The Liver (PDF)

The Liver Dr Tim Lee School of Life and Environmental Sciences [email protected] https://thebiomedicalscientist.net/news/3d-model-human-liver The Liver – An astonishing, multi-functional organ ‘Hepatic’ – Pertaining to the liver ‘Ferrous’ – relating to iron Maintains blood glucose levels...

The Liver Dr Tim Lee School of Life and Environmental Sciences [email protected] https://thebiomedicalscientist.net/news/3d-model-human-liver The Liver – An astonishing, multi-functional organ ‘Hepatic’ – Pertaining to the liver ‘Ferrous’ – relating to iron Maintains blood glucose levels Produces ketone bodies, amino acids & other nutrients Distributes cholesterol and triglycerides Manufactures plasma proteins (albumin) and most coagulation factors Acid-base balance (H+, bicarbonate) Removes waste products (bilirubin, several drugs) https://openclipart.org/detail/129409/swiss-army-knife The Liver – An astonishing, multi-functional organ ‘Hepatic’ – relating to the liver ‘Ferrous’ – relating to iron Inactivates some neurotransmitters and hormones (oestrogen) Involved in iron balance and copper metabolism Filters/inactivates bacteria and viruses from the gut Makes bile (digestion and waste) and synthesises bile salts https://openclipart.org/detail/129409/swiss-army-knife The Liver – Learning Objectives Describe the external and microscopic anatomy of the liver, including the portal vein and hepatic arteries, the bile ducts, liver lobules, and portal triads. Describe the liver’s role in maintaining blood cholesterol levels Describe how albumin helps to maintain blood volume Describe the control of iron balance in the body, including the role of transferrin, ferroportin and hepcidin The Liver – Location Under ribcage, mainly on right side of the body LIVER https://upload.wikimedia.org/wikipedia/commons/4/43/Gray1224.png The Liver – Blood Supply Hepatic Vein Low O2, consistent nutrients :(:) Hepatic Artery (25%) High O2, consistent nutrients High O2, medium nutrients Hepatic Portal Vein (75%) Low O2, variable nutrients The liver is so large, and so much blood flows through it, that about 12% of our blood at any one time is in the liver. The Liver – Internal Anatomy Portal Triad Central vein https://commons.wikimedia.org/wiki/File:Animal_liver.jpg Reytan: Courtesy: Department of Histology, Jagiellonian University Medical College [http://www.histologia.cm-uj.krakow.pl/index.html ] {{GFDL}}penStax College [CC BY SA 3.0 https://creativecommons.org/licenses/by-sa/3.0/deed.en )] The main cells of the liver are the Hepatocytes. They are responsible for most of the functions of the liver, 80% of cells by number and mass in the liver are hepatocytes. The Liver – Internal Anatomy https://commons.wikimedia.org/wiki/File:Liver_lobules_MHCII-GFP_mouse.jpg By Vojtech.dostal [CC BY-SA 3.0 (https://creativecommons.org/licenses/bysa/3.0)] This image is unaltered from the original. The Liver – Internal Anatomy Portal Triad } Liver Lobule Hepatic artery Hepatic duct Hepatic portal vein Central vein The Liver – Glucose Homeostasis Covered elsewhere in the unit Remember glucagon and insulin Glucagon causes the liver to release glucose Insulin causes the liver to store glucose as glycogen The Liver – Cholesterol Balance Cholesterol – Cell membranes, hormones (progesterone and testosterone) Too much builds up in blood vessels High density/Low density lipoprotein Some triglycerides converted into cholesterol in the liver Excess cholesterol removed via bile https://commons.wikimedia.org/wiki/File:Cycle_du_cholest%C3%A9rol.pdf The Liver – Albumin and maintaining water in the blood Albumin- blood protein mainly responsible for maintaining blood osmolarity High osmolarity mean high solute concentration in the solution, low osmolarity means low solute concentration High osmolarity Low osmolarity The Liver – Albumin and maintaining water in the blood High osmolarity Low osmolarity The Liver – Albumin and maintaining water in the blood Albumin proteinincreases the osmolarity of the blood, preventing water loss into the interstitial fluid The Liver – Iron Balance Iron is important in the body Mainly for helping red blood cells to carry oxygen Red blood cells are made in the bone marrow, so there needs to be a method to deliver iron there Free iron is toxic, but it can be carried in the blood stream in transferrin, a glycoprotein that can carry 2 atoms of iron at a time. Image author: Schlenk, under licence Creative Commons Attribution-Share Alike 4.0 International, no changes made The Liver – Iron Balance Where does iron in the circulation come from and go to? Things that can increase amount of iron in circulation: Absorption from gut (diet) Recycling of old red blood cells Release from storage in the liver (stored in ferritin) Things that can decrease amount of iron in circulation: Making red blood cells Blood loss (injury, menstruation) Cells lost from the skin and lining of the gut We have no mechanism for getting rid of excess iron https://commons.wikimedia.org/wiki/File:Ferritin.png The Liver – Iron Balance How does iron get into and out of cells? Getting IN- transferrin just binds to a receptor on the cell surface, then moves inside and releases its iron. Getting OUT- can only leave cells through a transmembrane iron transporter called ferroportin. The Liver – Iron Balance Where do we find ferroportin? 3 places: Gut cells- they absorb iron from the food we eat, and then release that iron into the circulation through ferroportin. White blood cells- they eat (phagocytose) old red blood cells (100-120 days), and then release the iron from them into the circulation through ferroportin (usually in the spleen) Liver- released stored iron through ferroportin transporters. The Liver – Iron Balance How are iron levels in the circulation/blood stream controlled? Through a negative feedback loop Normal levels of transferrin in the blood are ~250 – 300 mg/dL (ie, 300 mg in 1/10 of a Litre). The controller of this is the hormone hepcidin. Ferroportin acts like a tap, releasing iron into the bloodstream. Hepcidin turns the taps off, it binds to ferroportin, removing it from the membrane and breaking it down, preventing the release of iron from cells into the bloodstream. The Liver – Iron Balance When is hepcidin released? Hepcidin is made by the liver. It is released in moderate levels under normal conditions When the cells of the liver detect that the iron content in the blood stream is too high, release of hepcidin increases. It then acts on liver cells, gut cells, and white blood cells to prevent those cells from releasing their stored iron (it ‘turns off the tap’). As iron is used up over time, circulating iron levels decrease, and eventually production goes down too as balance is restored. The reverse is also true- if iron in the circulation is too low, then hepcidin release declines. The Liver – Iron Balance Stimulus: Large iron intake in food Variable: Increased iron levels in the blood Ferroportin deactivated, iron not released into bloodstream Receptor: Transferrin Receptor 2 (on hepatocyte cell surface) Effectors: Liver Gut Spleen Control Centre: Hepatocytes Hepcidin Released Old RBCs are recycled in the spleen General scenario Hepcidin regulates iron release through ferroportin Fp Liver releases iron Liver stores iron Iron from Fp recycled RBCs released into circulation Iron in the circulation (bound to transferrin) RBCs transport oxygen in circulation Fp Iron absorbed from diet released to circulation Iron lost (skin or gut cells, injury, menstruation) Bone marrow uses iron to make red blood cells (RBCs) Old RBCs are recycled in the spleen Elevated blood iron levels Hepcidin regulates iron release through ferroportin Fp Liver releases iron Liver stores iron Iron from Fp recycled RBCs released into circulation RBCs transport oxygen in circulation Iron in the circulation (bound to transferrin) Fp Iron absorbed from diet released to circulation Iron lost (skin or gut cells, injury, menstruation) Bone marrow uses iron to make red blood cells (RBCs) Old RBCs are recycled in the spleen Blood iron levels go back down Increase in hepcidin released from liver Fp Liver releases less iron Liver stores iron Less iron from recycled RBCs released into circulation Fp Iron in the circulation (bound to transferrin) RBCs transport oxygen in circulation Fp Less iron absorbed from diet released to circulation Iron lost (skin or gut cells, injury, menstruation) Bone marrow uses iron to make red blood cells (RBCs) Old RBCs are recycled in the spleen Low blood iron levels Hepcidin regulates iron release through ferroportin Fp Liver releases iron Liver stores iron Iron from Fp recycled RBCs released into circulation RBCs transport oxygen in circulation Iron in the circulation (bound to transferrin) Fp Iron absorbed from diet released to circulation More iron lost (skin or gut cells, injury, menstruation) Bone marrow uses iron to make red blood cells (RBCs) Old RBCs are recycled in the spleen Blood iron levels go back up Decrease in hepcidin release from liver Fp Liver releases more iron Liver stores iron Iron from Fp recycled RBCs released into circulation Iron in the circulation (bound to transferrin) RBCs transport oxygen in circulation Fp More iron absorbed from diet released to circulation Iron lost (skin or gut cells, injury, menstruation) Bone marrow uses iron to make red blood cells (RBCs) The Liver – Iron Balance Whole picture is a bit more complex Iron content of the blood is not the only thing that determines amount of hepcidin released, there are two other things: Erythroferrone, hormone released when red blood cells are being made, lowers hepcidin release (shouting “we are making red blood cells, please release iron for us to use in reb blood cell production!”) Interleukin 6 (or IL-6) is a cytokine, a cell signalling molecule a bit like a hormone. This is released as part of an inflammation response and increases hepcidin release (maybe because it is shouting “the body is being invaded by bacteria- we need to deny that bacteria access to iron that can help it grow!”) The Liver – Iron Balance Iron levels in the bloos (mg/dL) Scenario: A patient has their blood iron levels (transferrin) monitored continuously over several days. At the 10 hour time point, they were given an iron-rich supplement to eat. A graph of their iron levels over the study period is displayed on the right. 380 75 360 70 340 65 320 60 300 A 55 280 50 260 45 C 40 240 220 The patient’s hepcidin levels were also monitored. Which of the following lines (A, B, C, D) is most likely to reflect the patient’s hepcidin levels over the study period? 80 B 200 D 35 0 5 10 15 Time (hr) 20 Iron levels in blood (mg/dL) Line A Line B Line C Line D 25 30 Hepcidin concentration in the blood (ng/mL) 400 The Liver – Iron Balance The science of iron homeostasis is relatively new: Ferroportin was discovered in 2000 Hepcidin was discovered in 1998 and its functions were described in the early 2000s An important researcher in this field is Nancy C. Andrews, working at Harvard Medical School, who had a leading role in determining the function of hepcidin Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100:3776–3781. Photo by Syrgal, licensed under the Creative Commons Attribution-Share Alike 4.0 International license The Liver – Learning Objectives Describe the external and microscopic anatomy of the liver, including the portal vein and hepatic arteries, the bile ducts, liver lobules, and portal triads. Describe the liver’s role in maintaining blood cholesterol levels Describe how albumin helps to maintain blood volume Describe the control of iron balance in the body, including the role of transferrin, ferroportin and hepcidin