L1-Anemia.pdf

Anemia GNT Block color index: Main text Dr. Notes Male’s text Femal’s text Important Extra Editing file: Objectives To understand the normal control of erythropoiesis To understand the pathophysiology of anemia To recognize the general features of anemia To understand the basis of anemia cl...

Anemia GNT Block color index: Main text Dr. Notes Male’s text Femal’s text Important Extra Editing file: Objectives To understand the normal control of erythropoiesis To understand the pathophysiology of anemia To recognize the general features of anemia To understand the basis of anemia classification To understand iron metabolism, how iron deficiency and anemia of chronic disease may arise and how to manage it Click on PATHOMA for a revision and more info! Our YouTube’s playlist for this lecture! This lecture was given by: Dr. Mansour Al jabry and prof. Fatma Al Qahtani *No objectives was found in new male slides Quick reminder of Hematopoiesis Introduction to anemia EXTRA Introduction Hemoglobin Function ● ● Structure Hemoglobin main important molecule in anemia is the protein molecule in RBC. that carries O2 from the lungs to the body's tissues and returns carbon CO2 from the tissues back to the lungs. Other function,Hemoglobin maintains the shape of RBCs It also maintains the blood pH. (Buffering effect) ● ● There are many types of hemoglobin. HbA is the major hemoglobin found in Adults. HbA is made up of two alpha (α) and two beta (β) subunits. Will be discussed in biochemistry lecture:) Hemoglobin structure Heme (Non protein) Iron binding O2 (Ferrous state, Fe2+) porphyrin ring Important for RBCs Globin chain (protein) 2 α chains 2 β chains Quick recap - discussed in next slides… What is the difference between hematopoiesis and erythropoiesis? Hematopoiesis is the formation of mature blood cells whereas erythropoiesis is the formation of mature erythrocytes (red blood cells) Introduction Hematopoiesis Hematopoietic Stem Cells (HSCs): Characterized by: Any abnormalities of hematopoietic stem cells will give many diseases. ↑ results in cancer, ↓results in anemia. 1. Ability of self renewal 2. Cell differentiation HSCs: They’re stem cells that give rise to other blood cells (WBCs and RBCs). #Extra Regulation of Hematopoiesis Regulation of hematopoiesis is mediated by Transcriptional Factors Which includes: Transcriptional Factors: proteins that are capable of controlling gene expression, regulating the stem cell functions and differentiation Transcriptional Factors The controlling factors/triggering factors Erythropoietin from kidney ● ● ● ● ● GATA1 Hematopoiesis started by HSC HSC will be divided to lymphoid lineages and myeloid stem cell Myeloid SC divided to other myeloid lineages which give WBCs (discussed later) and Erythroid Precursors are found in the bone marrow which give mature RBCs Exists and goes to the circulation, results in 4^6 cells. All process must be normal to give normal RBCs in function, size and shape Introduction Erythropoiesis Formation of RBCs The bone marrow is the major site of erythropoiesis it can occur in many site but this is the main site ,with the need of : 1. 2. 3. 4. 5. Folic acid Erythropoietin Iron (Fe2+) Ferrous form Vit B12 Amino acid minerals and other regulatory factors Formation of RBCs started from Erythroblast Hb synthesis begins at erythroblast and stops at reticulocyte, but it is highly active at normoblasts especially intermediate normoblast. It occurs at all stages of RBC synthesis except in mature erythrocyte, and it’s anucleated because the Hb can take place inside the all process must be normal to give normal RBCs in function , size and shape cells. Erythroblast Basophilic Normoblast Intermediate Normoblast Late Normoblast Reticulocyte Erythrocyte The only form which will go to circulation Cell Hb Synthesis + ++ +++ ++ + Bone marrow Location Normal CBC ranges Important to know Hb values Hemoglobin (g/dL) male Dr: important, especially MCV Red Cell Count (×10¹²) Male 13.5 - 17.5 40 - 52 4.5 - 6.5 Female 11.5 - 15.5 36 - 48 3.9 - 5.6 Mean Cell Volume (MCV) (pg= picograms) pigment ratio in RBCs 80 - 95 30 - 35 Normocytic Microcytic Test color of Hb Difference between male and female due to menstrual cycle Mean Cell Hemoglobin (MCH) (fL= femtoliters) size of RBCs Macrocytic “Buffy coat” - Circulation Hematocrit (PCV) (%) ↑ Hb = Polycythemia, ↓ Hb = Anemia No Hb synthesis here less than 80 (micro) above than 95 (macro) Normochromic white and red areas equal Hypochromic white area higher Pale in colour Anemia Definition ● ● An (without) -aemia (blood): It is reduction of Hb concentration below the normal range for the age and gender. (disorder in Hemoglobin conc.) Leading to decreased O2 carrying capacity of blood and thus O2 availability to tissues (hypoxia) Clinical features: Presence or absence of clinical feature depends on: 1 Speed of onset: Rapidly progressive anemia causes more symptoms than 2 Severity: Mild anemia → no symptoms usually . 3 Age: Elderly tolerate anemia less than young patients slow onset anemia due to lack of compensatory mechanisms: cardiovascular system, bone marrow (BM) and O2 dissociation curve. Hb is less than 9g/dL → Symptoms appear Because they have risk of developing heart failure, and their compensatory mechanism is weaker Clinical Features: Related to Anemia Related to Compensatory Mechanisms Weakness & Headache Palpitation (tachycardia) Pallor Angina Dizziness & Lethargy Cardiac failure Especially with preexisting coronary artery disease Due to the fear of HF we must not overlook mild anemia in elderly How does our body detect anemia? Our body detects it by hypoxia, and not through measuring the Hb concentration. When hypoxia is detected, compensatory mechanisms start and a message is sent by erythropoietin to the bone marrow signalling the need for generating more RBCs and hemoglobin. MCQ Classification of Anemia Classification Mechanism Based on morphology Hypochromic Microcytic Anemia Disruption or reduction of Hemoglobin components Low MCH small size Low hemoglobin Etiology Anemia Cause Sideroblastic anemia(vampire disease) Reduction in Porphyrin Iron def. Anemia decreased levels of iron Thalassemia Reduction in globin chain Blood loss most Acute bleeding common cause Reduction in RBC count Normocytic Normochromic Anaemia Hemolysis RBCs broken in circulation Low hemoglobin Normal MCV, MCH Disruption of RBCs production: Macrocytic Anemia High MCV Disruption of DNA synthesis Bone marrow failure ● ● ● ● ● Autoimmune Enzymopathy Membranopathy Mechanical artificial valve Sickle cell anemia ● ● Chemotherapy Aplastic anemia shut down of bone marrow ● Malignancy Anemia of chronic disease Megaloblastic anemia most common cause: ● Deficiency of vitamin B12 and Folate ● MDS (Myelodysplastic syndrome) Sideroblastic anemia Causes:1- genetic (eg, X-linked defect in ALA synthase gene), 2-acquired (myelodysplastic syndromes), and reversible (alcohol is most common; also lead poisoning, vitamin B 6 deficiency, copper deficiency, drugs [eg, isoniazid, linezolid]) Treatment: pyridoxine (B6 , cofactor for ALA synthase). → → Thalassemia is of 2 types: 1-α-thalassemia: α-globin gene deletions on chromosome 16 →  α-globin synthesis. Normal is αα/αα. Often  RBC count, in contrast to iron deficiency anemia 2-β-thalassemia:Point β-thalassemias mutation in splice sites or Kozak consensus sequence (promoter) on chromosome 11→ Ž  β-globin synthesis (β+) or absent β-globin synthesis (β0). → Iron Deficiency Anemia Iron Deficiency Anemia (IDA) IDA affects mental activity in children common cause of anemia ● The most common disorder (24%) ● Iron is among the abundant minerals on earth (6%) Cause: ● excess loss due to hemorrhage period in female ● Iron has limited absorption ability: ○ Only 5-10% of taken iron will be absorbed ○ Inorganic iron can not be absorbed easily. Team 436: Why can so little of iron be absorbed? Because iron itself is very toxic for the body, and its accumulation due to increased iron absorption for example may lead to hemochromatosis (iron overload disease) which may lead to deficiency of many glands and leads to disease like diabetes. Causes 1-Chronic blood loss - Major cause (most common) (80% of cases) ● ● ● GIT bleeding: peptic ulcer, esophageal varice, hookworm & cancer Uterine bleeding most common cause in female Hematuria 2-Increased demands ● ● ● ● Immaturity. because it’s very toxic Growth Pregnancy EPO Erythropoietin therapy neonates and infants need to be fed with iron containing milk 3-Malabsorption ● ● Enteropathy Gastrectomy 4-Poor diet ● Rare as the only cause (rule out other causes) → iron due to chronic bleeding (eg, GI loss, heavy menstrual bleeding), malnutrition, absorption disorders, GI surgery (eg, gastrectomy), or  demand (eg, pregnancy) Ž→ final step in heme synthesis. → Iron Deficiency Anemia Iron Cycle & Storage: Check the video(iron absorption )in the playlist for good understanding :) Numbers aren’t important ● ● ● ● ● ● ● Iron site of absorption(1mg): Duodenum then will take the iron by Iron carrier protein: transferrin in plasma (4mg) then will take it in bone marrow (factory,need) which is the site of production of RBCs to the normoblasts (150mg) then mature RBCs will go to the circulation with the iron RBCs can be lost by period in female, from circulation it can go to reticuloendothelial system after half life of RBCs (120 day) will store in macrophage (store area of iron) storge form: Ferritin , haemosiderin when we need the iron it can be broken from the storage form and return to circulation some of iron go to the liver store especially in muscle myoglobin Can also loss in urine , faeces , nails , hair , skin Most important iron transporter Extra, Figure interpretation: - Greatest amount of iron in the body is found in the circulation (1.7 - 2.4 g), and it is reutilized for hemoglobin synthesis when RBCs die. Iron is transferred from macrophages to plasma transferrin and then to bone marrow for erythropoiesis. - Iron absorption is normally just sufficient to make up for iron loss. Daily iron absorption (1mg) = Daily iron loss (1mg) Hepcidin Role in Iron Cycle & Storage: Iron absorption occur in duodenum in 2 areas: DMT-1 (gate control absorption ) , ferroportin. these areas control by key molecule Hepcidin (keymaster hormone secreted by the liver, control iron status in the body). iron in food in Fe3+ must convert to Fe2+ and the will enter to the duodenum area. can be stored in ferritin form or enter to circulation transfer by transferrin in the portal plasma to the bone marrow hepcidin can also control in the store area (macrophage) in RES inhibit or secrete depend on the demand What is the mechanism behind the positive feedback effect of IL-6? It is a protective mechanism formed by the body during inflammation (IL-6 is an inflammatory cytokine) to prevent microorganisms from utilizing iron in their pathogenesis . Hypoxia IL-6 TFR2 + ve feedback - ve + ve - ve feedback - ve Hepcidin - ve Duodenum (Parietal cell) Iron for erythropoiesis BM macrophage Hypoxia → ↓ Hepcidin release → ↑ Iron absorption IL-6 or TFR2 → ↑ Hepcidin release → ↓ Iron absorption Extra, Figure interpretation (Duodenum): - Iron enters the body in the ferric form (Fe3+). For iron to enter the duodenum cells it must be converted to the ferrous form(Fe2+) by the enzyme ferrireductase. When the iron is released to the circulation it is released in the ferric form by the enzyme ferroxidase so, it can be carried in circulation by transferrin. - Ferric ion (Fe3+) = non-absorbable form - Ferrous ion (Fe2+) = absorbable form Iron Deficiency Anemia Iron Absorption Body iron status Increased demands → Low iron stores → High absorption (iron deficiency, pregnancy...) Iron overload → Full iron stores → Low absorption Content and form of dietary iron ● ● ● More iron Heme iron Ferrous iron All lead to more absorption Enhancers Balance between dietary enhancers & inhibitors Inhibitors ● Meat (Heme iron) ● Dairy food (calcium) ● Fruit (Vit C) ● High fibers food (phytate) ● Sugar (solubilizing ● Coffee/tea (polyphenols) agent) ● Anti -acids ● Acids Factors favoring absorption 1. 2. 3. 4. 5. 6. 7. Heme iron Ferrous Iron (Fe2+) Acid Iron deficiency Pregnancy Hemochromatosis Solubilizing agent (sugar) Factors reducing absorption 1. 2. 3. 4. 5. 6. 7. Inorganic iron Ferric iron (Fe3+) Alkalines Iron overload Tea ‫❌ ﺷﺎھﻲ ﺑﻌﺪ اﻻﻛﻞ‬ Increased hepcidin due infection Precipitating agent (phenol) Iron Deficiency Anemia Development of IDA Signs of Anemia Normal Pre-latent Latent Iron def. anemia Stores Normal Low Low Low MCV/MCH Normal Normal Low Low Hemoglobin Normal Normal Normal Low Signs and symptoms of iron def. anemia will not appear until three parameters are affected (Stores, MCV/MCH, Hemoglobin).in the last stage Signs and Symptoms of IDA Beside symptoms and signs of anemia (mentioned previously), +/- bleeding patients present with: Koilonychia (spoon-shaped nails) Most specific sign ● ● ● ● Angular stomatitis and/or glottitis Fissures around the mouth specific sign Dysphagia due to pharyngeal web in esophagus (Plummer-Vinson syndrome) more sever Angular stomatitis: Inflammatory condition causing red, swollen patches in the corners of the mouth Glossitis (swollen and inflamed tongue) Plummer-Vinson syndrome (PVS) which is a rare condition characterized by a triad of IDA, dysphagia, and esophageal webs Pharyngeal web: Protrusion of normal esophageal tissue into the esophagus causing dysphagia Iron Deficiency Anemia Investigations first investigation after CBC (Blood film) 1- Perl’s stain Prussian blue Important to know stain’s name BM iron stain detecting presence of iron, gold standard but invasive procedure Normal IDA Perl’s stain in IDA: Reduced or absent iron stores (hemosiderin) Absent blue dots in Erythroids since there’s no iron ● ● blue color Normal bone marrow. Stain should be blue with blue dots in erythroids. no blue color 2- Morphology of IDA Normal IDA microcytic hypochromic anemia with: When IDA is classified based on morphology, it appears as microcytic hypochromic anemia ● Normal microscopy of blood 1-RBC are pale →less Hb (remember Hb is responsible for the red colour of the RBC) 2-Reduction in RBC count ● Anisocytosis (variation in size) Poikilocytosis (variation in shape) 3- Iron studies iron profile Blood tests used to evaluate body iron stores or the iron level in blood serum. TIBC (Total iron binding capacity of transferrin) Serum iron Iron Deficiency Anemia Thalassemia ↑ ↓ ↓ ↑ Serum ferritin (iron store) ↓ ↑ Transferrin saturation ↓ ↑ 3 4 1 4 Iron Deficiency Anemia Treatment Always start with oral therapy 1- Treat the underlying cause ● ● 2- Iron replacement therapy if the underlying cause not clear Oral: ferrous sulfate OD(once daily) for 6 months. IV: ferric sucrose OD for 6 months If there was no response (If the patient’s oral treatment didn’t respond, IV should be given) we also give fibers to prevent constipation 3-Blood transfusion: In severe cases to improve signs and symptoms Response to treatment: Hb should rise 2g/dL every 3 weeks (good response). ● ● Good response: Rise in Hb level after treatment No response: No rise in Hb level after treatment Prevention 1-Dietary modification: Red Meat is better source than vegetables. 2-Iron supplementation: For high risk groups (Pregnant women & Children) 3-Food fortification (with ferrous sulfate): It causes GIT disturbances, staining of teeth and metallic taste. (So It’s not a preferable preventative measure). If there is no response, it could be due to three reasons: 1- You don’t treat the underlying cause or diagnose the patient properly 2- Unreported or unnoticeable bleeding (rectal bleeding in colon cancer) 3- The patient is not compliant with the treatment Anemia of Chronic Disease Anemia of Chronic Disease ● Usually characterized by normochromic normocytic anemia Caused by decreased release of iron from iron stores due to raised serum Hepcidin 1. Malignancy (Most common) 2. Chronic inflammations 3. Chronic infections including HIV, malaria, TB 4. Tissue necrosis Overview associated with: Common cause after iron IL-6 IL-1 TNF - Tuberculosis - SLE - Carcinoma - Lymphoma + ve - ve Pathophysiology Hepcidin - ve no Iron for erythropoiesis BM macrophage (same channel) Work-up and treatment Management Team 438 Explanation Chronic diseases like TB, SLE, carcinoma and lymphoma releases a lot of IL-6, IL-1 and TNF these are responsible of the high hepcidin levels which is in turn prevents the release of iron from the stores, so there is NO iron for erythropoiesis. ● Normocytic normochromic in general or mildly microcytic anaemia ● Low serum iron and TIBC ● Normal or high serum ferritin (acute phase reactant) ● High hemosiderin in macrophages but low in normoblasts 1. 2. Treat the underlying cause Iron replacement +/- Erythropoietin (EPO) Summary Hemoglobin Hematopoiesis EXTRA ● HbA is composed of Heme (Iron binding O2 Fe2+, protoporphyrin ring) and globin chains (α & β) and it’s the major type of Hb in Adults. ● ● Regulation of hematopoiesis is mediated by Transcriptional Factors which includes: Erythropoietin & GATA1. Hematopoietic Stem Cells (HSCs) characterized by: Ability of self renewal & cell differentiation ● ● It’s major site is the bone marrow Regulatory factors needed for erythropoiesis: Folic Acid, Vit.12, Ferrous form iron (Fe+2), erythropoietin, amino acids, minerals and others Stages of erythropoiesis Erythropoiesis Cell Erythroblast Basophilic Normoblast Intermediate Normoblast Late Normoblast Reticulocyte Hb Synthesis + ++ +++ ++ + Erythrocyte (RBC) The only form which will go to circulation - Anemia It is the reduction of Hb concentration below the normal range for the age and gender. typical value would be: less than 13.5 g/dL in adult male, less than 11.5 g/dL in adult female, less than 14 g/dL in newborn infant. MCV: (80-95), MCH: (30-35) Hypochromic Microcytic (Disruption of Hb) Classification of anemias -Sideroblastic anemia -Iron def. Anemia - Thalassemia Normocytic Normochromic (Reduction in RBCs) Macrocytic (Disruption of DNA synthesis) Reduction in RBCs count: -Blood loss: acute bleeding -Hemolysis: Sickle cell anemia Distribution of RBCs production: - Bone marrow failure -Anemia of chronic disease -Megaloblastic anemia -MDS (Myelodysplastic syndrome) Iron Deficiency Anemia Major cause is chronic blood loss. eg: GIT bleeding Iron is carried by transferrin and stored as ferritin and hemosiderin. Ferroportin is the gate of iron from cell to circulation. Absorption of iron occurs in the duodenum and its controlled by hepcidin through negative feedback of ferroportin: ● Hypoxia → ↓ Hepcidin release → ↑ Iron absorption ● IL-6 or TFR2 → ↑ Hepcidin release → ↓ Iron absorption Iron metabolism and absorption Features Investigations Factors Favoring Absorption Heme iron Ferrous Iron (Fe2+) Pregnancy Acid Iron deficiency Factors Reducing Absorption Inorganic iron Ferric iron (Fe3+) Increased hepcidin Alkaline Iron overload Angular stomatitis, koilonychia, dysphagia ● ● Presence of iron in Perl’s stain Microcytic hypochromic anemia on morphology Anemia of Chronic Disease ● ● ● ● Characterized by normochromic normocytic anemia, low serum iron and TIBC, high serum ferritin ( acute phase reactant) (main thing to differentiate between IDA and Anemia of Chronic Disease is Ferritin serum) Caused by decreased release of iron from iron stores due to raised serum Hepcidin Mostly associated with Malignancy Managed by Treat the underlying cause MCQs Q1. Which of the following is the gold standard for iron deficiency anemia investigation? A.TIBC B. Serum iron C. Perl’s stain D. Serum iron Q2. A 31 years old patient came to the clinic with extreme fatigue, dizziness, weakness, fast heartbeat. Investigation showed low serum iron, low serum ferritin. He is diagnosed with iron deficiency anemia, which of the following signs is the most specific sign in iron deficiency anemia patients? A. Koilonychia B. Angular stomatitis C. Dysphagia D. glottitis C. Hb more than 9 g/dl D. Hb less than 9 g/dl Q3. Severe symptoms of anemia appear at: A. Hb is 13 g/dl B. Hb is 20 g/dl Q4. Which of the following is a trigger or controlling factor of erythropoiesis? A. GATA1 B. Erythropoietin C. GABA1 D. A,B Q5. Which of the following will cause a breakdown of RBC leading to a normocytic normochromic anemia? A. Sickle cell anemia B. Aplastic anemia C. Chemotherapy D. Folate deficiency Q6. Patient was found to have vitamin B12 deficiency, which of the following type of anemia is most likely to be found? A. Microcytic hypochromic anemia B. macrocytic anemia C. Normocytic normochromic anemia D. Sideroblastic anemia A1. C A2. A A3. D A4. D A5. A A6. B How was the lecture? Members board Team Leaders: Aleen AlKulyah Remaz Almahmoud Sultan albaqami Team Members: ● Milaf alotaibi ● ● Reuf Alahmari Ryan alghizzi ● ● Deema almadi Feras Mazen ● ● huda bin jadaan Mishal Aldakhail ● ● Elaf moatabi Abdullah Alzamil ● ● Aseel Alsaif Khalid Alanezi ● ● Razan alsoteehi Mohammed Manee ● ● Maryam Alghannam Ziad Alhabardi ● ● Raghad Alqhatani Zeyad Alotaibi ● ● Lama Alotaibi Omar Alamri ● ● AlJoharah Alwohaibi Moath Alhudaif ● ● Aroub Almahmoud Faris Alzahrani ● ● Dana Almuhaisen Abdullah Alkodari Special thanks to 442 team [email protected]