L2. Megaloblastic anemia.pdf

Megaloblastic anemia GNT Block color index: Main text Dr. Notes Male’s text Femal’s text Important Extra Editing file: Objectives To understand the mechanisms by which macrocytic anaemia may arise To appreciate the signs and symptoms of macrocytic anaemia To understand how macrocytic anaemia...

Megaloblastic anemia GNT Block color index: Main text Dr. Notes Male’s text Femal’s text Important Extra Editing file: Objectives To understand the mechanisms by which macrocytic anaemia may arise To appreciate the signs and symptoms of macrocytic anaemia To understand how macrocytic anaemia can be classified To be able to know the causes of macrocytic anaemia To understand the normal metabolism of vitamin B12 and folic acid, and to appreciate how megaloblastic anaemia may arise To suggest some normoblastic causes of macrocytosis Click on PATHOMA for a revision and more info! Our YouTube’s playlist for this lecture! This lecture was given by: Dr.Osama khojah and prof. Fatma Al Qahtani *No objectives was found in new male slides EXTRA Overview Definition In macrocytic anaemia the red cells are abnormally large (MCV >100 fL). There are several causes but they can be broadly subdivided into megaloblastic and non‐megaloblastic, based on the appearance of developing erythroblasts in the bone marrow.x Macrocytosis Hypersegmented neutrophils term used to describe red blood cells that are larger than normal ● ● Neutrophils with more than 5 (normal is 3 - 5 lobes) The presence of hypersegmented neutrophils is an important diagnostic feature of megaloblastic anemias. Macrocytic Anemia Type Megaloblastic Macrocytic Non-Megaloblastic (Normoblastic) Macrocytic DNA synthesis Large RBC’s as a result of impaired DNA synthesis Which causes inability of cell replication. RNA and protein synthesis is not affected, so the cell will continue to grow and increase in size. Large RBC’s with no impairment of DNA synthesis. The exact mechanisms creating large red cells in each of these conditions is not clear. Etiology Most commonly as a result of Folate and Vitamin B12 deficiency Many possible causes like alcoholism, liver disease, and aplastic anemia hypersegmented neutrophils present absent Information Not only RBC’s are affected but also leukocytes, megakaryocytes, and the intestinal epithelium Normoblastic macrocytic EXTRA Suggested mechanism of how normoblastic macrocytic anemia is caused: Liver disease ● ● Chronic liver disease, such as cirrhosis, can lead to impaired synthesis of proteins, including those involved in the production and maintenance of red blood cells. The liver plays a role in processing and storing vitamin B12 and folate, essential for normal red blood cell production. Liver dysfunction can disrupt these processes, contributing to macrocytic anemia. Alcoholism ● ● ● ● ● ● ● Chronic alcohol use can have multiple effects on the hematologic system, including macrocytosis. Alcohol can directly suppress the bone marrow, affecting the normal production of red blood cells. Additionally, alcohol can lead to nutritional deficiencies, particularly of vitamin B12 and folate, which are essential for proper red blood cell formation. Aplastic anemia Aplastic anemia is characterized by a reduction in the number of blood cells produced in the bone marrow. In some cases, this can lead to macrocytic anemia. The bone marrow failure in aplastic anemia affects the normal production of red blood cells, leading to larger and fewer red blood cells (macrocytosis). remember aplastic anemia is mainly one of the causes of normocytic-normochromic anemia with some macrocytosis of remaining RBC. Introduction -Values are not important, you just have to know that: The the first three are different in male than female And the last four are same in both -WBC values are not important as well Normal Adult Red Cell Values Male Female Haemoglobin (g/L) 135-175 115-155 Haematocrit (PCV) (%) 40-52 36-48 Red cell count (x10 12/L) 4.5-6.5 3.9-5.6 Mean cell haemoglobin(pg) 27-34 Mean cell volume (FL) 80-95 Mean cell haemoglobin concentration (g/L) 300-350 Reticulocyte count (x109/L) 25-125(1.0-2%) In children normal haemoglobin values (g/L) are: ● Newborn: 150 – 210 ● 3 months: 95 – 125 ● 1 year to puberty: 110 – 135 * PCV, Packed cell volume. Normal WBC Count in Adults Characteristic Value X 109/L Total 4.0 - 11.0 Neutrophils 2.5 - 7.5 Lymphocytes 1.5 - 3.5 Monocytes 0.2 - 0.8 Eosinophiles 0.04 - 0.44 Basophiles 0.01 - 0.1 Platelets 150-450 Children normally have higher lymphocytes count Classification of Anemia Chick here for the original diagram from male slides Microcytic Hypochromic Anemia Normocytic Normochromic Anemia <80 fL 80-(95-100) fL < 27 pg >26 pg MCV MCH 1. 2. 3. 4. 5. Iron def. Anemia Thalassemia Anemia of chronic disease(some cases) Lead poisoning Sideroblastic anemia (some cases) 1. 2. 3. 4. 5. 6. Etiology 7. 8. 9. 10. 11. Many haemolytic anaemias Anemia of chronic disease (some cases) After acute blood loss Renal disease(insufficiency) Mixed deficiencies Bone marrow failure, e.g. post-chemotherapy, infiltration by carcinoma, etc. Chronic disease infection inflammation malignancy sickle cell disease Macrocytic Anemia Characterized by: increased MCV Increased MCV: >100 fL >34 pg If serum B12 and folate normal: 1. alcoholism 2. bone marrow disorders 3. hypothyroidism 4. liver disease 5. medication (chemotherapy, antivirals) If 1-serum B12 and folate is low 2- elevated homocysteine : A-with Elevated methylmalonic acid : Vit B12 deficiency B-with normal methylmalonic acid: Folate deficiency Important points Will be discussed in next slide Microcytic Anemia Male Slides Test blood levels: Etiology 1. 1. 2. 3. Serum iron decreased Serum ferritin decreased TIBC elevated iron deficiency anemia 2. 3. 4. Serum iron normal or elevated Serum ferritin normal or elevated TIBC normal Hgb Electrophoresis: A-normal in α B-abnormal in β thalassemias 1. 2. 3. 4. Serum iron normal or decreased Serum ferritin normal or elevated TIBC normal or decreased Hgb electrophoresis normal chronic disease Macrocytic anemia Macrocytic anemias can be divided into those showing: Pictures are not important Megaloblastic erythropoiesis ● ● Normoblastic erythropoiesis Describes abnormal red cell development characterized by a lack of synchrony between the maturation of the red cell nucleus and its cytoplasm. It arises as a consequence of disordered DNA synthesis and results in a macrocytic anemia. ● multiple deficiencies Describes the normal appearance of red cell maturation, but may still be associated with macrocytosis in the peripheral blood. Normoblastic Conditions in which Macrocytosis or hypersegmented neutrophils may occur in the absence of megaloblastic anemia Female Macrocytosis Female dr: focus on the bold and the rest is for reading ● ● ● ● ● ● ● ● ● ● ● ● Alcohol Liver disease (especially alcoholic) Reticulocytosis (hemolysis or haemorrhage) Aplastic anaemia or red cell aplasia* Hypothyroidism Myelodysplasia including acquired Sideroblastic anaemia Myeloma and macroglobulinaemia Leukoerythroblastic anemia Myeloproliferative disease Chronic respiratory failure Pregnancy Newborn Slides Macrocytosis with Normoblastic Female dr: focus on the bold and the rest is for reading ● ● ● ● ● ● ● ● ● ● ● Normal neonates (Physiological) Chronic alcoholism Myelodysplastic syndromes Chronic liver disease Hypothyroidism Normal pregnancy Therapy with anticonvulsant drugs Haemolytic anaemia Chronic lung disease (with hypoxia) Hypoplastic and aplastic anaemia Myeloma Hypersegmented neutrophils ● ● ● Congenital (familial) abnormality Iron deficiency Renal failure Note:- High MCV recorded when cold agglutinins or paraproteins are present. Causes of Megaloblastic Anemia The Cause Details B12 related Cobalamin (B12) deficiency or abnormalities of cobalamin metabolism Folate related Folate deficiency or abnormalities of folate metabolism Therapy with antifolate drugs e.g. methotrexate Independent of either cobalamin or folate deficiency and refractory to cobalamin and folate therapy. a. Some cases of acute myeloid leukaemia, myelodysplasia. b. Orotic aciduria (responds to uridine) c. Therapy with drugs interfering with synthesis of DNA (e.g. cytosine arabinoside, hydroxyurea, 6-mercaptopurine, azidothymidine (AZT). d. Thiamine responsive Female dr: important Female dr: important Female dr: for reading Female dr: for reading Suggested but poorly documented causes of megaloblastic anaemia not due to cobalamin or folate deficiency or metabolic abnormality: (Rare) a. Vitamin E deficiency b. Lesch-Nyhan syndrome (?responds to adenine) Female dr: for reading Other causes of megaloblasts Female dr: for reading a. b. c. d. e. f. Abnormalities of nucleic acid synthesis Orotic aciduria Drug therapy : 1-Antipurines (mercaptopurine,azathioprine), 2-Antipyrimidines (fluorouracil, zidovudine (AZT)), 3-Others (hydroxyurea) Myelodysplastic syndromes, erythroleukaemia Some congenital dyserythropoietic anaemias Uncertain aetiology IMP Vitamin B12 & folate Dietary source Vitamin B12 Folate Only food of animal origin, especially liver Most foods, especially liver, green vegetable and yeast; destroyed by cooking 7 - 30 μg 200-250 μg 1-3 μg 100-200 μg Average daily intake In adults Team442: dr’s notes: you won't be asked the exact numbers so just understand the concept Minimum daily requirement In adults Team442: dr’s notes: you won't be asked the exact Higher during pregnancy and lactation numbers so just understand the concept Body stores In adults 3-5 mg, mainly in the liver 8-20 mg, mainly in the liver Time to develop deficiency in the absence of intake or absorption Anemia in 2-10 years (It takes time) (years) Macrocytosis in 5 months (Months) Intrinsic factor secreted by gastric parietal cells Conversion of polyglutamates to monoglutamate by intestinal folate conjugase (this enzyme should be Terminal ileum Duodenum and jejunum In adults Requirements for absorption Team442: due to large hepatic stores of Vit B12 Site of absorption normal for the ability to absorb) Team442: because body stores are minimal Structure (Not important) ● ● Forms ● ● Methylcobalamin: mostly found in blood circulation Adenosylcobalamin: main form in tissue Hydroxocobalamin: supplement, main form of treatment cyanocobalamin: supplement ● ● Tetrahydrofolic acid (THF): active form Methyl THF: primary form found in blood This pictures will be explained later Causes Vitamin B12 & folate deficiency ● ● ● ● ● Vitamin B12 deficiency Female’s dr: focus on red Folate deficiency Female’s dr: focus on red Malabsorption Malabsorption Intestinal causes: ○ Crohn’s disease ○ Ileal resection ○ Chronic tropical sprue ○ Multiple jejunal diverticula ○ Abnormal intestinal bacterial flora ○ Small intestinal strictures Gastric causes: ○ Total or partial gastrectomy ○ Gastritis Vagotomy Pernicious anaemia Inadequate secretion of intrinsic factor ● ● ● Increased requirement: (People who need more folate) ● ● ● ● ● Nutritional Inadequate intake of meat Veganism (vegans) Diphyllobothrium latum acid-suppressing drugs alcohol abuse Congenital intrinsic factor deficiency (rare) Long-term dialysis congestive heart failure acute liver disease Nutritional ● Others ● ● ● ● Pregnancy Premature infants Chronic haemolytic anaemias Myelofibrosis Various malignant diseases Increased loss ● ● ● ● ● Coeliac disease Jejunal resection Tropical sprue Inadequate dietary intake Complex mechanisms ● ● Anticonvulsant therapy ethanol abuse (only some cases with macrocytosis are folate deficient) Certain anticonvulsant medications, specifically some older generation drugs, have been associated with causing folate deficiency by the following mechanisms: 1. Impaired Absorption: Some anticonvulsants, such as phenytoin and phenobarbital, can interfere with the absorption of folate in the gastrointestinal tract. This may result in reduced levels of folate available for the body to use. 2. Increased Metabolism: Anticonvulsants can induce hepatic enzymes, which may accelerate the breakdown of folate in the liver. This increased metabolism can lead to a decrease in the circulating levels of folate. 3. Altered Folate Metabolism: Anticonvulsants may affect the metabolism of folate within cells. For example, they can interfere with the conversion of folate to its active forms that are essential for various cellular processes. B12 & folate deficiency EXTRA B12 & folate deficiency Manifestation Neurological Hematological Neural tube defect Neuropathy (NTD) Megaloblastic anemia Severe Megaloblastic anemia Pernicious anemia Neuropathy due to Vit B12 and folate deficiency Neuropathy is mostly due vit B12 deficiency, causes: Progressive neuropathy, affecting: ○ The peripheral sensory nerves. ○ Posterior and lateral columns of the spinal cord (subacute combined ● ● degeneration of the cord). ○ Optic atrophy. Psychiatric symptoms Cause: ○ The neuropathy is likely due to accumulation of S-adenosyl homocysteine* and reduced level of S-adenosyl methionine in nervous tissue resulting in defective methylation of myelin and other substrates. ● ● Also caused by ↑ Methylmalonic acid, How? ● ● ● Vitamin B12 a cofactor for the conversion of methylmalonic acid to succinyl CoA (important in fatty resulting in defective acid metabolism). Vitamin B12 deficiency results in increased levels of methylmalonic acid, which impairs spinal cord myelinization. Damage results in a condition known as subacute combined degeneration of spinal cord Neural tube defect (NTD) Female’s dr: you just have to know that folate and vitamin B12 deficiency leads to spina bifida, the rest is for reading only ● ● ● ● Folate or Vit B12 deficiency in the mother predisposes the fetus to neural tube defect (anencephaly, spina bifida or encephalocoele) . This result in build-up of homocysteine and S-adenosyl homocysteine in the fetus which impair methylation of various proteins and lipids. Polymorphism in the enzyme 5,10 methylene tetrahydrofolate reductase (5,10-MTHFR). This mutation (677 C→T) in the MTHFR gene results in low serum and red cell folate and high serum homocysteine in the parents and fetus with NTD. Cleft palate in children and hair lip Pictures are from the main slides, but skipped by female’s doctor B12 & folate absorption Explanation is EXTRA Absorption and metabolism of Folic acid ● ● ● ● Dietary folate is converted to methyl tetrahydrofolate form which circulates in plasma. After entering cells vitamin B12 is needed to convert: ○ Methyl THF to THF (the active form of folate) ○ Homocysteine to methionine (by transferring a methyl group). THF becomes THF polyglutamate, then becomes 5,10methylene THF polyglutamate which is essential for the formation of DNA building blocks (dTMP: dThymine-Monophospate). Once it forms DNA precursor, 5,10- methylene THF polyglutamate becomes DHF polyglutamate ○ which can be reconverted to THF polyglutamate again though the enzyme: dihydrofolate reductase (inhibited by methotrexate which is useful in the treatment of malignant diseases) Summary: Dietary folate → methyl tetrahydrofolate “circulates in plasma” → THF “in cell by help of B12” → THF polyglutamate → 5,10- methylene THF polyglutamate “ essential for DNA synthesis” → DHF polyglutamate Absorption and metabolism of B12 ● ● ● B12 from the food is combined with the intrinsic factor (IF) which is secreted from the stomach by the parietal cells. IF–B12 complex reaches terminal ileum 1+2, Vitamin B12 is absorbed into portal blood where it becomes attached to the plasma‐binding protein transcobalamin (TC, also called transcobalamin II)3 Vitamin B12 is a coenzyme for these biochemical reactions: 1. Conversion of methyl THF to the active form THF (By taking the methyl group), forming the main form of circulating B12 which is (methylcobalamin) 2. Conversion of Homocysteine (harmful) to methionine (By giving the methyl group). 3. Conversion of methylmalonyl coA to succinyl coA (By acting as a coenzyme (in the form Adenosylcobalamin, which is the main form in tissues) EXTRA Vitamin B12 This summary was done by Rafan Alhazzani Reaction Substrate Form of B12 Enzyme Final product Conversation of propionyl-CoA to succinyl-CoA propionyl-CoA Deoxy-adenosyl-cobalamine Methylmalonyl CoA Mutase Succinyl-CoA Conversion of homocysteine to methionine homocysteine Methylcobalamin Methionine Synthase Methionine, N5-methyl-TH4 TH4 Pernicious anemia Pernicious Anemia (PA) Definition Etiology Severe megaloblastic anemia ● ● Due Autoimmune attack of the gastric mucosa leading to atrophy. Helicobacter pylori infection may be the cause which present in: ○ Younger age as iron deficiency anaemia ○ Elderly as pernicious anaemia Genetic Epidemiology Tends to be in families Age & Gender More common in elderly female patients than males (1.6:1) at the age of 60 and above (rare in children) Location More common in Northern Europeans (Denmark, Sweden, Norway etc) ● ● The mucosa become thin with plasma cells and lymphoid infiltration of the lamina propria. Intestinal metaplasia may occur, Increased incidence of gastric carcinoma in (2-3% of pernicious anaemia patients). (Very common as a complication) ● Pathophysiology ● It may be associated with autoimmune diseases including the autoimmune polyendocrine syndrome. Achlorhydria is present and absent secretion of intrinsic factor (IF) Pernicious anemia is not caused by a problem in the uptake (not a cubilin receptor problem) of vitamin B12, it’s caused by a problem in the secretion of Intrinsic factor. Q: Is pernicious anemia caused by a defective problem in the uptake of vitamin b12? A: no. It’s a problem in secretion of intrinsic factor Findings 1. 2. 3. Absent serum vitamin B12 level or almost absent level (main finding) Raised serum gastrin levels* Progressive neuropathy is common feature *How is the gastrin levels is elevated in pernicious anemia? The autoimmune response in pernicious anemia often targets the gastric parietal cells, leading to their destruction. As a result: 1.Intrinsic Factor Decrease: With the loss of parietal cells, there is a reduction in the production of intrinsic factor, a protein required for the absorption of vitamin B12 in the small intestine. 2.Decreased B12 Absorption: The diminished intrinsic factor results in impaired absorption of vitamin B12, leading to the characteristic B12 deficiency seen in pernicious anemia. 3.Feedback Loop with Gastrin: Gastrin is a hormone that stimulates the secretion of gastric acid. In response to the decreased gastric acid production due to the loss of parietal cells, there is a feedback mechanism that increases the secretion of gastrin. 4.Elevated Gastrin Levels: The increased gastrin levels aim to stimulate the remaining parietal cells, promoting the production of gastric acid. However, since the primary defect is the destruction of parietal cells, this feedback loop results in persistently elevated gastrin levels. The elevated gastrin levels can be observed in blood tests and may contribute to other symptoms or conditions, such as an increased risk of gastric carcinoid tumors or gastric cancer. Monitoring and managing gastrin levels are important aspects of the overall care for individuals with pernicious anemia Megaloblastic Anaemia Hematological findings Tissue Findings 1. Peripheral blood 2. 3. 4. 1. 2. 3. Bone marrow 4. 5. 6. 7. 1. 2. Other laboratory abnormalities 3. 4. 5. 6. 7. 8. Microscope Macrocytic anaemia, oval macrocytes, anisocytosis, poikilocytosis, high MCV. Pallor Glossitis Dimorphic anemia when it is associated with iron deficiency or with thalassaemia trait. Hypersegmented neutrophils angular cheilitis Leukopenia and thrombocytopenia Hypercellular marrow with M:E ratio in normal or reduced Accumulation of primitive cells due to selective death of more mature cells. Megaloblast (large erythroblast which has a nucleus of open, fine,lacy chromatin). Dissociation between the nuclear and cytoplasmic development in the erythroblasts. Mitosis and dying cells are more frequent than normal (due to ineffective hematopoiesis) Giant and abnormally shaped, metamyelocytes, polypoid megakaryocytes. Increased stainable iron in the macrophage and in the erythroblasts. Chromosomal abnormalities Ineffective hematopoiesis (intramedullary cell death by apoptosis) associated with increased serum indirect bilirubin. ↑urobillinogen and faecal stercobillinogen ↑LDH, ↑serum iron, ↑blood carbon monoxide (↑LDH,= lactate dehydrogenase is an abundant enzyme is in red blood cells and functions as a marker for hemolysis (or turn-over of cells)) ↑serum lysozyme ↓ haptoglobins (large amounts bind to free hemoglobin causing reduced serum level (marker of hemolysis)) Positive schumm’s test Positive urine hemosiderin Histopathological findings Left: Normal Gastric mucosa Right: Gastric atrophy in patients with pernicious Anemia Heavy infiltration of lamina propria with plasma cells and lymphocytes in patients with pernicious Anemia Left: Normal small intestinal mucosa Right: Histopathology of small intestinal mucosa in malabsorption syndrome ‫ة‬ Megaloblastic Anaemia Clinical Features Progressive symptoms and signs of anaemia ● ● ● ● Weakness, anorexia, weight loss, diarrhoea or constipation, tiredness, shortness of breath, angina of effort, heart failure Mild jaundice, glossitis, stomatitis, angular cheilitis. Purpura, melanin pigmentations. Infections angular cheilitis (Fissures) Pallor Glossitis (Tongue swelling) Treatment In case of Vitamin B12 deficiency Folate deficiency Compound Hydroxocobalamin Folic acid Route Intramuscular Oral Dose 1000μg 5 mg Initial dose 6X1000 μg over 2-3 weeks Daily for 4 months 1000μg every 3 months Depends on underlying disease; life-long therapy may be needed in chronic inherited hemolytic anemia, renal dialysis, myelofibrosis Maintenance Prophylactic - Total gastrectomy - Ileal resection - Pregnancy - severe hemolytic anemias - dialysis - prematurity Pictures of the Lecture Dr. Fatma didn’t mention or explain these pics, so we are adding them here if you want to take a look ;) EXTRA Pics are from the slides Summary Thanks to hematology team 439 ● ● ● Megaloblastic erythropoiesis describes abnormal red cell development characterized by a lack of synchrony between the maturation of the red cell nucleus and its cytoplasm. It arises as a consequence of disordered DNA synthesis and results in a macrocytic megaloblastic anemia. It can be caused by vitamin B12 or folate deficiency or antifolate drugs (ex. methotrexate) Clinical features include: jaundice, glottitis, angular cheilosis, purpura Vitamin B12 Deficiency Folate Deficiency Found in Only food of animal origin green vegetable and yeast Time to develop deficiency in the absence of intake or absorption Anemia in 2-10 years Macrocytosis in 5 months. Absorption Requires intrinsic factor secreted by gastric parietal cells, Cubilin, transcobalamin II Conversion of polyglutamates to monoglutamates by intestinal folate conjugase Site of absorption Terminal ileum Duodenum and jejunum Cause of deficiency Manifestation of deficiency (Malabsorption) ● Total or partial gastrectomy ● Inadequate secretion of intrinsic factor ● Pernicious anaemia (Nutritional ) ● Veganism (Others) ● Alcohol abuse ● ● ● ● ● Pregnancy Infants Inadequate dietary intake Malabsorption Increased requirement Neuropathy can manifest due to vit B12 or folate deficiency. Cause of the neuropathy as a result of B12 deficiency is likely to be related to Accumulation of S-adenosyl homocysteine and reduced levels of S-adenosyl methionine in nervous tissue. Hematological findings in peripheral blood ● ● Macrocytic anemia, oval macrocytes, anisocytosis,Poikilocytosis Hypersegmented neutrophils, leukopenia, and thrombocytopenia Hematological findings in bone marrow ● ● ● ● ● Giant and abnormally shaped, metamyelocytes, polyploid megakaryocytes Megaloblast (large erythroblast which has a nucleus of open, fine, lacy chromatin). Increased stainable iron in the macrophage and in the erythroblasts. Hypercellular marrow with M:E ratio in normal or reduced. Accumulation of primitive cells due to selective death of more mature cells. Treatment Pernicious Anemia Hydroxocobalamin, IM ● ● ● ● Folic acid, oral It’s a problem in secretion of intrinsic factor Severe megaloblastic anaemia due to autoimmune attack on the gastric mucosa leading to atrophy and absence of intrinsic factor (IF) secretion Absent serum vitamin B12 Raised serum Gastrin MCQs Q1. Absorption of Vitamin B12 occurs at: A. Stomach B. Duodenum C. Jejunum D. Terminal ileum C. Both A and B D. None C. Jejunum D. Both B and C C. Young Male D. Elderly Male C. Intramuscular D. Rectal C. Intramuscular D. Rectal Q2. Macrocytic Anemia is caused by: A. Vitamin B12 deficiency B. Folate deficiency Q3. Folate absorption occurs at: A. Stomach B. Duodenum Q4. Pernicious Anemia most common in: A. Young female B. Elderly Female Q5. What is the route of administration of Vitamin B12? A. Oral B. Intravenously Q6. What is the route of administration of Folate? A. Oral B. Intravenously A1. D A2. C A3. D A4. B A5. C A6. A 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]