Moath Darwish. Waseem Alhaj. Tareq Adely

Transcription

1 4 Moath Darwish Waseem Alhaj Tareq Adely

2 Please refer to the slides for pictures. Iron deficiency anemia 1. Iron absorption and regulation a. only 10% of ingested iron are absorbed b. absorption of iron occurs in duodenum c. Iron from plants is a nonheme, and poorly absorbed ( vegetabeles are not good source for iron) d. Iron from meat is a heme and directly absorbed in the duodenum e. The amount of iron absorbed is regulated. (1) Hepcidin is the master iron regulatory hormone and determines whether iron is absorbed or not absorbed in the duodenum and whether iron is released from macrophages or not released. (2) A decreased level of iron stores in the body leads to reduced hepcidin synthesis in the liver. This upregulates ferroportin, causing more iron to be reabsorbed in the duodenum to bind to transferrin and more iron to be released from bone marrow macrophages to bind to transferrin for erythropoiesis. (3) An increased level of iron stores In the body leads to increased hepcidin synthesis in the liver. This downregulates ferroportin, causing iron accumulation in enterocytes, which are eventually shed into the bowel. A reduced level of ferroportin also causes iron blockade in bone marrow macrophages, so less is released for binding to transferrin.

3 2. Epidemiology a. Most common overall anemia b. Most common nutritional deficiency worldwide c. People at increased risk of anemia are: (1) infants aged 1 to 2 years Due to inadequate intake of iron (infant's milk is poor in iron) (2) elderly because they can't digest meat well (3) teenagers Restricted diets with very little meat intake; decreased intake of heme iron. (4) low socioeconomic class. 3. Pathogenesis: Decreased synthesis of heme (iron + protoporphyrin) leads to a decreased synthesis of Hb- microcytic hypochromic anemia. 4.causes classification causes discussion Decreased intake vegetarians Non heme iron in vegetables is poorly absorbed. Not sufficient to body demand

4 Increased utilization Blood loss 1)Pregnancy/lactation 2)Infants/adolescence Gastrointestinal loss 1)daily requirement for iron on lactation and pregnancy increases. 2) Iron is required for tissue growth and expansion of blood volume in the developing fetus Decreased absorption Celiac, Crohn's Absence of the villous surface in the duodenum decreases absorption of iron 5. Clinical findings a. symptoms due to anemia include headache, pallor, fatigue. b. symptoms specific to iron deficiency: (1)glossitis and inflammation in the mouth (2)hair loss (3)CNS manifestation (depression, insomnia, and pica); there is a theory that some brain s enzymes contains iron. Pica: a tendency or craving or craving to eat to substances eat substances other other than than normal normal food (such food as (such clay, plaster, clay, orplaster, ashes or ashes Pica: (4)spoon nails 6.labratory findings A. Decreased serum iron and iron saturation B. Decreased serum ferritin C. Microcytic and hypochromic are present with increased central area of pallor D. Although erythropoietin is high, low iron stores in bone marrow blunt its effectiveness, so there is no much increase in erythroid cells. E. Thrombocytosis -the doctor said that the exact mechanism is unknown, but some theories say that erythropoietin, which increases in case of anemia, cross react to activate megakaryocytes too. - but according to textbooks, thrombocytosis occurs as a reactive phenomenon to

5 increase blood viscosity and prevent high-output heart failure. The stages of iron deficiency in sequence are as follows: absent iron stores; decreased serum ferritin; decreased serum iron, then microcytic hypochromic anemia appears. In peripheral blood smears: 1)Anisopoikilocytosis: anisocytosis RBCs of varying sizes, poikilocytosis RBCs of varying shapes 2)Target cells: appears in abnormal hemoglobinization( thalassemia, sickle cell anemia, iron deficiency anemia) Iron stains blue(left); compare it to iron absence(right) Megaloblastic Anemia vitamin B12 overview 1. Water-soluble vitamin present in meat and eggs 2. Vitamin B12 stores in the liver is sufficient to supply the body for years, so it's deficiency due to loss of storage is rare. 3. Intrinsic factor which is released from parietal cells of the stomach is important to absorb vitamin B12 in the ileum 4. Important in myelination of nerves. 5. It's an important Coenzyme in thymidine synthesis a. causes of vitamin B12 deficiency classification causes discussion

6 Decreased intake Impaired absorption Pure vegan diet Malnutrition Intrinsic factor Terminal ileum absorption Vitamin B12 is absent in vegetables -Autoimmune destruction of parietal cells: this occurs in pernicious. -gastrectomy decrease intrinsic factor -Crohn disease, celiac disease interfere with the vitamin absorption. C. Folic acid overview 1. Water soluble vitamin that is found in vegetables and meat 2. The liver contains small amount of folic acid, so deficiency due to loss of storage is quick. 3. It's coenzyme important in thymidine synthesis b. causes of folic acid deficiency classification causes discussion Decreased intake Malabsorption Drug inhibition Increased demand Malnutrition Celiac disease 1)Methotrexate 2) anti-convulsant, Oral contraceptives, alcohol Pregnancy Low vegetables intake In celiac disease, villi in the jejunum may be destroyed, leading to folic acid deficiency. 1)This drug inhibits thymidine synthesis in the cell. 2)inhibits uptake of folic acid from the intestine There is increased utilization of folic acid in DNA synthesis 1)folic acid could be lost from serum in renal failure and dialysis which lead to it's deficiency 2) methotrexate and vitamin b12 deficiency impair utilization of folic acid synthesis.

7 pathogensis of megaloblastic anemia 1. Impaired DNA synthesis delays nuclear maturation. this Causes a block in cell division in all rapidly dividing cells, leading to large, immature, hematopoietic cells with a pale inactive chromatin 2. Ineffective hematopoiesis a. Megaloblastic precursors outside the bone marrow sinusoids are phagocytosed and destroyed by bone marrow macrophages. b. Megaloblastic precursors undergo apoptosis, causing pancytopenia (anemia, neutropenia, and thrombocytopenia). Clinical findings in vitamin B12 deficiency 1. Pernicious anemia (PA) there is Abnormal autoreactive T-cell response initiates direct gastric mucosal injury also triggers formation of autoantibodies include : A)Type 1 antibody: antibodies block Vit B12 from binding to intrinsic factor B) Type 2 antibody: Antibodies that prevent the binding of vitamin B12 intrinsic factor complexes to ileal receptors C)type 3 antibody: Antibodies directed against the proton pump in parietal cells( to understand this point read the extra box below) 2. Neurologic disease associated with demyelination (A) Peripheral neuropathy with sensorimotor dysfunction (B) weakness in the muscle that is supplied by the nerve. Laboratory findings in vitamin B12 deficiency

8 1)peripheral blood findings include A. Pancytopenia b. Oval (egg-shaped) macrocytes C. Hypersegmented neutrophils Hypersegmented neutrophils have more than five nuclear lobes D. giant metamyelocyte E. large,hyper lobulated Megakaryocytes: 2) 4. Bone marrow findings in vitamin B12 deficiency Megaloblastic immature nucleated cells are present with a pale inactive chromatin pattern as a result of increased erythropoietic level, bone marrow cellularity initially increase, but because impaired DNA synthesis in the cells, they undergo apoptosis and Bone marrow cellularity will decrease too Clinical findings in folic acid deficiency Similar to vitamin B12 deficiency with the exception of neurologic disease Laboratory findings in folic acid deficiency Peripheral blood and bone marrow findings similar to vitamin B12 deficiency Anemia of chronic diseases: -overview this condition is associated with chronic diseases with persistent inflammation like tuberculosis, HIV infection, rheumatologic diseases and malignancies NOTE :malignancies are associated with chronic inflammation because malignant cell activate the immune system when they go necrosis Pathogenesis : interlukin -6,that is released during persistent inflammation, activate hepcidin, leading to decrease iron transfer from stores and from macrophage to erythroid cells.

9 Laboratory findings: 1)serum ferritin is increased 2) Iron stores in BM are markedly increased 3) Initially, normochromic normocytic anemia, with time it becomes hypochromic microcytic anemia. How to differentiate between iron deficiency anemia and anemia of chronic diseases? In anemia of chronic diseases, serum ferritin and iron stores in bone marrow are high, unlike in case of iron deficiency anemia. Treatment : unlike iron deficiency anemia, we don't give iron supplement, instead, we treat the underlying cause. Aplastic Anemia: 1)causes classificiation Idiopathic Inflammation Idiosyncratic reaction to drugs discussion and example Most cases Rheumatoid arthritis and viral infection Like chloramphenicol and gold idiosyncratic reaction: drug reactions that occur rarely and unpredictably amongst the population 2)pathogenesis A) due to Immunologic alterations occur in the myeloid stem (progenitor) cells, causing T-cell activation and release of cytokines that suppress or destroy the myeloid stem cells. B) or due to acquired or genetic mutation that overlap with PNH.( to understand how read the below extra box) 3)laboratory findings a. Pancytopenia This is due to Mutations in TERT, the gene for the RNA component of telomerase, cause short telomerases in congenital aplastic anemia

10 b. Reticulocytopenia c. Hypocellular bone marrow (bone marrow is filled with fat) D.no splenomegaly Myelophthisic anemia: overview: it's an infiltrative disease that cause secondary bone marrow failure causes: 1) most commonly due to bone marrow cancer like leukemia. 2)also, it could less commonly be caused due to granuloma, which is an aggregation of macrophages that could destroy normal bone marrow cells. laboratory findings 1)pancytopenia 2)no splenomegaly : chronic renal failure pathogenesis Low erythropoietin level decreases erythropoiesis Uremia impairs platelet function, leading to bleeding labtratory findings :1) normochromic normocytic anemia 2) echinocytes, a condition in which RBC's have small cytoplasmic projection (spines) Hypothyroidism: since Thyroxin is essential for cell metabolism, it's deficiency causes bone marrow's cells maturation to decrease, leading to macrocytic anemia

11 chronic liver diseases laboratory findings : A)since clotting factors are synthesized in the liver, it's diseases leads to bleeding B)since liver is the major organ where lipids are synthesized, it's diseases causes impairment in lipid synthesis, which lead to abnormal RBC's with long projection (acanthocytes) Myelodysplastic syndrome are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells. [ pathogenesis : exposure to an agent known to cause DNA damage and mutations. laboratory findings : 1)megaloblastic immature erythroid, myeloid and megakaryocyte. 2)hyper cellular bone marrow, with low peripheral blood count, since these cells have defective in their function they become unable to exit from bone marrow 3) Aggregates of iron in the nucleus, this condition called ring sideroblasts; ring because they are found around the nucleus. Polycythemia: It s an increase in the mass of RBCs, which is full of hemoglobin. Erythrocytosis is an increase in the number of RBCs.

12 Polycythemia vera: (aka primary polycythemia and rubra vera) Neoplastic disease of erythroid cells Pathogenesis: JAK-2 mutation, which is erythropoietin receptor, become very sensitive to erythropoietin. Also there are other mutations. Splenomegaly a result of extramedullary erythropoiesis on it. Panmyelosis an increased erythropoiesis, granulopoiesis and megakaryopoiesis ( because there precursor cells also contains JAK-2) By negative-feedback there will be a decrease in erythropoietin level. Clinical symptoms: Plethora, cyanosis and itching( plethora is a red skin / itching occurs due to increased WBCs numbers and increased histamine and other cytokines) Sluggish circulation predisposes to thrombosis Bleeding can also occur because platelets aren t functioning well Hypertension Gout occurs when RBCs die they release uric acid which forms crystals Lab findings: High HB, Hct, RBC count reticulocytes count. High WBCs and platelets (panmyelosis) Secondary polycythemia: An adaptive change with no mutations Causes:

13 a.chronic hypoxia, the body respond by increasing erythropoietin, examples include : chronic lung and heart diseases, alcoholism, smoking and high altitude.( alcohol suppresses normal respiration, also it increases urination with subsequent high blood concentration) b.renal cell carcinoma: cells secrete erythropoietin c.surreptitious: when athletes take certain drugs to increase there performance Secondary polycythemia is reversible and characterized with high erythropoietin with no splenomegaly