Physiology Sheet 29 PDF

29 Jawad Al Shkirat Hana Masarweh Rand Abu-Azab Ebaa Alzayadneh  BLOOD To continue talking about erythropoietin (EPO). Anephric (non-functioning kidney) individuals have severe anemia (why?) Due to the Lack of EPO, the main site for producing it is the kidney an...

29 Jawad Al Shkirat Hana Masarweh Rand Abu-Azab Ebaa Alzayadneh  BLOOD To continue talking about erythropoietin (EPO). Anephric (non-functioning kidney) individuals have severe anemia (why?) Due to the Lack of EPO, the main site for producing it is the kidney and a very small amount of it will be produced in the liver. So, in anephric individuals, 10% residual EPO (mainly from the liver), supports 30-50% needed RBC Production. Of course in these individuals their hematocrit (packed cell volume) cannot reach the normal level, it can reach half of the normal level➔ ~23-25% (depending only on liver EPO), so they need a replacement of EPO (from an external source). Remember that: the normal hematocrit (“packed cell volume”) is 40-45%. Response to Hypoxia The EPO level increases within minutes to hours in response to hypoxia, however, RBC production doesn’t occur that fast, it requires more time (days, weeks, months) depending on the loss that happened or the cause or the demands. The effect of EPO on the bone marrow: 1. Drives the production of proerythroblasts from HSCs (hematopoietic stem cells) 2. Accelerates their maturation into RBCs. EPO can increase RBC production up to 10-fold (so this surely required time) Erythropoietin remains high until normal tissue oxygenation is restored. The EPO is regulated by negative feedback mechanism, so once the O2 level is normal this will inhibit the releasing of EPO because we only require the optimal amount of RBC’s (more RBC count isn’t beneficial because it will affect our hemodynamic circulation).  ‫يعني هون القصد انه نفس العامل الي هو تركيز االكسجين بحفز تصنيع ال و هو نفسه بثبط تصنيعه لما‬ ‫نوصل الى التركيز الطبيعي (عدد الخاليا المطلوب مهي المسؤوله عن تركيز االكسجين) طيب ليش بثبط‬ ‫التصنيع؟‬.‫النه الجسم ما بحتاج خاليا دم زياده عن اللزوم النه هذا بأثر عليه بسلبيات معينه رح ندرسها لقدام‬ The requirements for normal erythropoiesis: 1. Vitamin B12 2. Folic acid 3. Iron 4. Amino acid (coming from good nutrition) These are the most important factors after EPO. Rapid, large-scale cellular proliferation requires optimal nutrition. Vitamin B12 and folate (folic acid) both are needed to make thymidine triphosphate (thus, building DNA) we need this for the proliferation process of the cells. ‫مهم فهم هاي النقطه الزم يكون في كميه الماده الوراثيه كافيه عشان تكون عمليه االنقسام و تكاثر‬ ‫ب‬12 ‫الخاليا طبيعيه و كميه الماده الوراثيه عشان تكون كافيه الزم تتضاعف هون بيجي دور الفيتامين‬ ‫و حمض الفوليك انهم بدخلوا بعمليه تضاعف الماده الوراثيه و بالتالي اذا صار عليهم خلل يعني رح‬ ‫(يعني سبب التلف في الخليه‬.‫يصير خلل في تضاعف الماده الوراثيه و بالتالي خلل في خاليا الدم الحمراء‬.‫ ب و حمض الفوليك)عشان هيك خليك متنبه‬12 ‫اصله بكون في الفيتامين‬ Abnormal DNA replication causes failure of nuclear maturation and cell division, so if there is a maturation failure the RBC size ➔ large RBC shape ➔ irregular (weird looking) and RBCs will be fragile (macrocytes) When the RBCs are fragile it means that they will undergo fast hemolysis (destruction) due to no flexibility (causes anemia). ‫الن بدنا نتكلم عن اذا صار في نقص العوامل الي فوق شو عي االنيميا الي ممكن تصير‬ Pernicious Anemia Pernicious anemia (Megaloblastic anemia): is considered to be a type of megaloblastic anemia, which is characterized by the production of large, bizzare, immature red blood cells by the bone marrow. Causes; failure to absorb vitamin B12 and failure to produce intrinsic factor Failure to produce intrinsic factor➔ because of atrophic gastric mucosa (that lines the stomach) Intrinsic factor binds to vitamin B12 o Protects it from digestion o Binds to receptors in the ileum o Mediates transport by pinocytosis When Vitamin B12 is absorbed it will be stored in the liver and released as needed. Usual stores: 1 – 3 mg Daily needs: 1 – 3 μg Thus normal stores are adequate for 3 – 4 years The benefits here lie when someone gets Atrophic gastric mucosa and has (Failure to absorb vitamin B12) the B12 level will not drop suddenly because we have a large store. Until the appearance of the symptoms of failure to absorb vitamin B12 appear. Folic Acid Deficiency Folic acid is present in green vegetables, some fruits, and meats. Destroyed easily during cooking (so it’s very common to have a deficiency in it) (Subject to dietary deficiencies) It may also be deficient in cases of intestinal malabsorption (for folic acid and vitamin B12) so this is more dangerous since it affects both..‫لو كانت المشكله في االمعاء بتكون أخطر النها بتأثر على كليهما‬ ‫يعني في اسباب خاصه لكل عامل و في اسباب بتأثر عليهم الثنين زي امراض في االمعاء‬ Maturation failure may reflect combined B12 and folate deficiency (can lead anemia). Ether vitamin B12 or folic acid deficiency or both can lead to anemia. Hemoglobin It’s very important for the main function of RBCs (transport oxygen). Hgb consist of peptide attach to iron atom (main factor of transport oxygen).‫يعني الحديد من اهم مكونات الهيموغلوبين النه هو الي بربط مع االكسجين‬ Formation of Hemoglobin The formation of Hgb start before RBCs comes out of the bone marrow since it still has a nucleus (the engine that’s responsible for synthesizing everything in cell) and the other organelles that are required for the synthesizing process. Occurs from proerythroblast through reticulocyte stage. Reticulocytes retain a small amount of endoplasmic reticulum and mRNA supporting continued hemoglobin synthesis. After maturation (leaving the bone marrow) the formation process stops and the RBC cells will have a sufficient amount of Hgb for their entire life cycle (120 days). ‫مش مطلوب‬ ‫لكن ألقي نظره عليه‬ Most important Each of the iron atoms can bind loosely with one molecule (2 atoms) of oxygen (nonionic bond because if its bound by an ionic bond, it will be very difficult to leave the cell) Types of Globin Chains Several types of globin chains resulting from gene duplication – α, β, γ, average MW ~ 16,000. Predominant form in adults is Hemoglobin A with 2 α and 2 β chains; MW 64,458. Each globin chain is associated with one heme group containing one atom of iron. Each of the four iron atoms can bind loosely with one molecule (2 atoms) of oxygen. Thus each hemoglobin molecule can transport 8 oxygen atoms. Variation in Globin Chains Modest differences in O2 binding affinities, so each isoform of Hgb has a different affinity to bind with O2. Some of these isoforms are a result of mutation like Sickle hemoglobin: Glutamic acid➔ Valine at amino acid 6 (substitution). Sickle hemoglobin affects the structure of Hgb when there is a hypoxia, so the hemoglobin of homozygous individuals (“SS”) forms elongated crystals when exposed to low O2. This leads to hemolysis of RBCs and vascular occlusion (by thrombus) since it lost it’s flexibility. This is sickle cell anemia and the body cannot compensate for the RBC lost.  Oxygen Binding to Hemoglobin Must be loosely bound - binding in settings of higher O2 concentration (in lungs), releasing in settings of lower concentration (in tissue) and this happens in smooth easy way because of the loose bonds. The affinity difference between low O2 pressure and high O2 pressure depends on O2 saturation and CO2 level. Binds loosely with one of the coordination bonds of iron. Carried as molecular oxygen (not as ionic oxygen) Fetal hemoglobin After the birth of baby its main Hgb is fetal hemoglobin which has higher affinity to O2 than adult Hgb, this property allows the baby to get enough O2 in the utero, from the circulation of the mother. Later on, it will be replaced gradually by adult Hgb (Hemoglobin A). Iron Metabolism Iron is a key component of hemoglobin myoglobin, and multiple enzymes (cytochromes cytochrome oxidase, peroxidase, and catalase) Thus iron stores are critically regulated. Total body iron ~ 4 – 5 g %65in hemoglobin (majority). 4% in myoglobin (mainly in muscles). 1% in intracellular heme compounds (like cytochrome in mitochondria). 0.1% associated with circulating transferrin (since iron cannot be found freely in the body it must bind to transporter protein (transferrin)). 15 – 30% stored mainly as ferritin in mainly in liver and reticuloendothelial system (RES) like spleen. Transferrin is a glycoprotein found in vertebrates that binds and consequently mediates the transport of iron (Fe) through blood plasma. They are produced in the liver. Transferrin and ferritin relationship Serum ferritin level indicates total iron stores, while transferrin saturation value reflects iron transportation, which decreases before anemia develops. Hemosiderin: Insoluble iron in the cells of tissues or cells of the liver, considered as excess, unused iron. Iron from our diet, which is exceeds our needs and is unbound to the transferrin(unabsorbed), is going to be excreted via feces/ stool. Blood loss is also related to menstruation in females. Large amounts of excess iron can cause diseases, it is mainly caused from disorders in the metabolism of iron (malfunction of an enzyme, genetic disorder). Whatever is packed within the RBCs is enough for the whole life cycle. Enzymes with RBCs can’t be repaired or fixed and they have a life span, that’s why the life span of RBCs is limited RBCs pass through capillaries around the spleen, liver, and red bone marrow. Aged, nonflexible RBCs will rupture, and the phagocytosed by the macrophages that reside in those areas. Most of the RBC components will be recycled: Globin will be broken down into amino acids and then released into the blood, so it can be used as building blocks for other proteins. Heme: Iron from the Heme will be extracted, bound to transferrin to be transported out of the macrophage, then can bound to ferritin to be stored in the liver, and then may bound again to transferrin and transported to other areas for RBCs formation (like bone marrow). The heme in macrophages will be digested into biliverdin, then converted to bilirubin. Bilirubin: a yellow-colored dye, transported through the blood plasma to the liver (must end in the liver no matter where the macrophages are), where it is collected and then flowed through ducts to the gall bladder where it should be stored. When stimulation occurs, it flows through the bile duct to the duodenum of the small intestine, where it’s modified by the bacteria to urobilinogen and then to brownish stercobilin, excreted via feces. Some of the urobilinogen will be taken up through the blood to the kidney, where it is converted to yellowish urobilin and removed via urine. Anemia can be due to: -Decreased number of RBCs, or decreased amount of the components needed for RBCs or hemoglobin production. -From acute or chronic blood loss, when the blood loss rate is greater than the blood formation rate (the ability to replenish the RBCs) The body goes through acute correction and long-term correction of the volume to correct or return the pressure to the neutral range. Those methods can fix the pressure but can't fix the oxygen-carrying capacity. The oxygen-carrying capacity can be fixed through the return of the RBC concentration to its normal range (through erythropoiesis). Iron deficiency: microcytic anemia, not enough hemoglobin, RBCs will be hypochromic as the concentration of hemoglobin is low. (Microcytic= small in size) ‫تمت كتابة هذا الشيت صدقة جارية عن روح والدة زميلنا عمرو رائد من دفعة تيجان‬ ‫دعواتكم لها بالرحمة والمغفرة‬ Thank you