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151 Cards in this Set
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What is the precursor for erthyrocytes?
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Erythroblasts.
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What is another name for erythroblasts?
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Normoblasts.
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What happens to the color of the cells as hematopoiesis takes place?
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The cells become more and more red.
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What happens in magaloblastic erythropoiesis?
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The cells appear larger...their nucleus/cytoplasm ratio is much larger than normoblasts.
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Does the nucleus disappear in megaloblastic erythropoiesis?
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Eventually it does yes.
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What is the problem with this kind of erythropoiesis?
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It is ineffective because many of these cells die in the bone marrow.
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What do you see in the white blood cells?
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You see a huge horseshoe type kind of nucleus in the cells. There are also an abnormal number of segments--> they are hypersegmented.
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What are some of the characteristics of megaloblastosis?
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7....
Anemia may be present, it may be severe or Hb may be normal... MCV is raised or normal is there is thalassemia or iron defiency. MHC is raised. MCHC is normal. RBC is low. Neutropenia. Thrombocytopenia. |
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What leads to an elevation of the MCV?
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There are large red cells and this may lead to an elevation of the MCV.
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What are the causes of macrocytosis?
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There are 12 causes;
1) Megaloblastosis 2) Reticulocytosis 3) Alcohol 4) Hypothyroidism 5) Liver disease 6) Aplastic anemia. 7) Marrow infiltration 8) Myelodysplasia 9) Pregnancy 10) Newborn 11) Chronic lung disease 12) Postspleenectomy. |
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What does macrocytosis cause in terms of RBC's?
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It is only one of the conditions that causes large RBC's in the blood.
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What does the blood film look like in magablastosis?
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Red cells- oval macrocytosis, poikilocytosis, anisocytosis.
Neutrophils- Hypersegmentation. |
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What are poikilocytes?
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Cells that are different in shape.
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What are anisocytes?
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Cells that are different in size.
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What else do you see in megablastosis in terms of erythropoiesis?
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The erythropoiesis is ineffective and the survival of red cells of macrocytes is reduced so there is hemolysis and as a result the LDH and indirect bilirubin are raised.
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What happens to normal RBC's in capillaries and how does this compare to what happens to macrocytes?
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RBC's have a biconcave shape and they are able to squeeze through the capillaries. Macrocytes don't have that luxury. When they get stuck they breakdown.
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What is their breakdown manifested as?
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Raised LDH and indirect bilirubin. These are biomarkers that can be used in any hemolysis.
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What are the causes of megablastosis?
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There are 4 causes:
1) Folate deficiency 2) Vit. B12 deficiency 3) Drugs 4) Inborn errors of metabolism. |
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What does dietary folate have that folic acid doesn't?
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It has 3 things:
1) Additional H atoms. 2) Additional formyl groups. 3) Additional glutamates. |
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What is folic acid used for? What is it's purpose?
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It is used to synthesize precursors for DNA synthesis...namely for thymidilate synthesis.
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What does dihydrofolate reductase do?
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It is constantly converting FH4 to FH2 so that we can build up DNA.
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What happens if you have a deficiency in tetrahydrofolate or are taking a drug that inhibits the enzyme?
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The pathology is that you can't make DNA.
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What is an example of a drug that inhibits dihydrofolate reductase?
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Methotrexate.
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What occurs in Vit B12 deficiency?
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High levels of homocystein are present.
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What is the requirement for folate?
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You need to be taking 100 microgram per day.
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How much folate does the body store?
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It stores about 10 mg which can last us about 4 months.
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What foods have the highest concentration of folate?
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Liver, yeast, spinach, greens, nuts.
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Is it easily destroyed?
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Yes, it is easily destroyed by boiling. So in order for you to get folate from eating vegetables you can't boil your vegetables.
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Where does folate absorption occur?
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Duodenum and proximal jejunum.
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What are the 3 reactions before folate is absorbed?
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1) Deconjugation
2) Reduction 3) Methylation to methyl tetrahydrofolate. |
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What is meant by deconjugation?
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deconjugation of polyglutamates to monoglutamates by folate conjugase of small bowel.
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What is being reduced?
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Folate...by tetrahydrofolate reductase in the mucosal cell.
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Where does methyl tetrahydrofolate appear?
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It appears in the portal blood.
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What are the causes of folate deficiency?
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There are 4 causes:
1) Poor nutrition. 2) Malabsorption. 3) Increased folate requirement. 4) Antifolate drugs. |
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What can contribute to poor nutrition?
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Old age, poverty, invalidism (the condition of being an invalid), psychiatrically disturbed, infancy, alcoholism*, excess food boiling.
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What can contribute to the malabsorption?
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Adult celiac disease.
childhood celiac disease tropical sprue dermatitis herpetiformans specific malabsorption of folate mild deficiency in : crohn’s disease, jejunal resection chronic heart failure |
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What do you see in gluten hypersensitivity?
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You will see atrophy of the villi. The villi will be falttened. It can occur in an adult and they might not be aware of this.
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What are the conditions that require an increase in folate requirement?
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Preganacy, prematurity, hemolytic anemia, myelofibrosis, sideroblastic anemia, leukemia, myeloma, lymphoma, carcinoma, inflammatory conditions, rheumatoid arthritis, Psoriasis, TB.
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What is a result of Vit. B12 deficiency in woman?
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She can't get pregnant.
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What is the importance of folate?
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It is needed for the closure of the neural tube.
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What are anti-folate drugs?
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Anticonvulsants: diphenylhydantoin
Primidone, Barbiturates, alcohol |
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What are some other drugs that are considered anti-folate?
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The inhibitors of DHFR...Methotrexate, pyrimethamine, aminopterine, septrin, AZT.
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What are the results of folate deficiency?
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Megablastosis, glossitis, mouth ulceration, neural tube defects.
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What do they have mouth ulcerations?
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Because the cells in the mucus membranes have a high turnover so they get mouth ulcers as a result of folate deficiency. Remember that folate is required to synthesize DNA precursors.
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What is the serum folate level affected by?
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It is affected markedly by the recent diet.
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What are the causes of a high serum folate level?
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Vitamin B12 deficiency
Blind loop syndrome Folic acid therapy Hydrolysed sample Infected blood sample |
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What is a more accurate reflection of folate status?
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The amount of folate that is present in red cells.
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When would the Red cell folate be low?
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In folate deficiency and in Vitamin B12 deficiency.
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Why is the red cell folate more representative of your folate level?
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Because it lasts 3 months (120 days) and so it is more accurate as a long term marker than serum folate which fluctuates based on your diet.
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What is another name for Vitamin B12?
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Cobalamin --> it has a cobalt atom in the middle.
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What are the two biochemical reactions that involve B12?
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1) Methyl B12 Conversion of homocysteine to methionine with methyltetrahydrofolate and methionine synthetase.
2) Deoxyadenosyl B12 Isomerization of methylmalonyl CoA to succinyl CoA. |
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What happens in Vitamin B12 deficiency?
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You will have deficiency in folate.
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What can you give patients with magablastosis?
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You can give them excess folate and correct the megablastosis.
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Will it correct the neurological defect?
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No, but you will reduce the anemia. The neurological effects of vitamin B12 are serious and irreversible but teh anemia is reversible.
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So what is important here?
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To figure out if it is a folate deficiency or a vitamin B12 deficiency.
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What is lacking in thymidine defiency and megaloblastic change?
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5, 10 methylene tetrahydrofolate
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Why?
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Because with a lack of cobalamine, methyl FH4 gets trapped within the serum and doesn't get into the RBC's.
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WHAT IS THE PATHWAY?
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Lack of cobalamin --> methyl FH4
trapped in serum --> lack of cellular methylene FH4 --> reduced thymidine synthesis --> Lack of DNA. |
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What is the second reaction?
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It is the isomerization of methamalonyl CoA to Succinyl CoA.
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What do you measure if you want to measure vitamin B12 deficiency?
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You measure the methyl malonic acid.
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What else do you have to check for?
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You also have to check for homocystein.
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What will the results be if there is vitamin B12 deficiency?
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Both of these values, methyl malonic acid and homocystein, will be high.
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What is the enzyme that isomerizes methamalonym CoA to succinyl CoA?
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Adenosyl cobalamin.
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Where is vitamin B12 found?
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Only in the animal products so vegans are kind of fucked. Liver, meat, diary products. In eggs and milk there is vitamin B12.
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How much vitamin does a normal Western diet contain?
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3-30 microgram and of this 1-5 microgram is absorbed.
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What is the daily requirement for vitamin B12?
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1-2 micrograms/day.
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Where are vitamin B12 stores in the body and how much is it?
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The liver...it is about 3-5 mg and it lasts somewhere between 3-5 years.
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How is vitamin B12 absorbed?
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Intrinsic factor in the stomach attached itself to the intrinsic vitamin B12 and it is absorbed in the small intestine (duodenum) by attaching to a certain receptor.
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What is the name of the receptor that vitamin B12+intrinsic factor bind to in order to be absorbed?
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Cubilin.
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What happens after it binds?
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Vitamin B12 gets into the portal vein and in the blood it attaches to transcobalamin II.
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What is the name of the receptor that vitamin B12+intrinsic factor bind to in order to be absorbed?
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Cubilin.
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What happens after it binds?
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Vitamin B12 gets into the portal vein and in the blood it attaches to transcobalamin II.
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Name a Vitamin B12 binding protein?
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Transcobalamin I or Haptocorrin.
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How does it act?
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most B12 in serum bound to this is released slowly to tissues.
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What happens if one is deficient in this?
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Causes low vitamin B12 levels but no tissue deficiency.
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What is another vitamin B12 binding protein?
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Transcobalamin II...It is only 2% saturated with vitamin B12.
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What is it involved in?
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In transport of vitamin B12 from gut to tissues.
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What happens if you are deficient in it?
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It causes megaloblastic anemia from a few weeks of age w/o serum vitamin B12 levels.
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What is more abundant; Transcobalamin I or II in blood?
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Transcobalamin I.
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Which one is more important?
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Transcobalamin II.
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Why?
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Because II is the one that is responsible for transport to tissue. So you may have low TC I levels but if your TC II is OK your B12 levels may be normal.
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What happens if you have TC II deficiency?
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Your B12 stores may not be reduced but because you don't have transport to tissue what you end up with is megaloblastic anemia.
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What are the three causes of vitamin B12 deficiency?
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1) Inadequate uptake
2) Malabsorption of vitamin B12 3) Defective transport |
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what type of person would have an inadequate intake of vitamin B12?
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A strict vegan.
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What are the causes of malabsorption of vitamin B12?
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A) Lack of intrinsic factor (IF)
B) Diversion of vitamin B12 C) Disease of the terminal ileum |
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What are the causes of lack of IF?
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I) adult pernicious anemia
II) Congenital IF deficiency III) Gasterectomy |
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What can cause diversion of vitamin B12?
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I) Fish tapeworm
2) Blind loop syndrome (stagnation of intestinal contents with bacterial overgrowth producing substances that interfere with absorption of fat, vitamins, and other nutrients, usually occurs in a portion of small intestine that has been excluded from the flow of chyme.) |
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What are some diseases of the terminal ileum that result in malabsorption of vitamin B12?
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Resection, Crohn's, Celiac, tropical sprue, pancreatic disease, Zollinger Ellison disease, Immerslund's disease (A rare familial disease characterized by megaloblastic anemia and persistent proteinuria.)
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What are the causes of defective transport of vitamin B12?
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Transcobalamin I or II deficiency.
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What causes adult pernicious anemia?
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Severe malabsorption of vitamin B12 with lack of IF due to autoimmune atrophic gastritis.
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What is the most common cause of vitamin B12 deficiency?
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adult pernicious anemia.
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What is the mean age of the patients with this disorder? What is the ratio of men to women who suffer from this disorder?
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60 years of age; men: women...7:10 so slightly more prevalent in women than in men.
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Which patients have a higher incidence? What are the symptoms?
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Patients with blood group A. Symptoms include light colored eyes, early greying...it is familial.
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Why are patients with pernicious anemia slightly yellow?
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Because they have slight hemolysis and so they have a slightly higher bilirubin level.
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Describe the gastric pathology in pernicious anemia type A?
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It is an autoimmune gastritis. There are antibodies to parietal cells and IF.
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What are the symptoms of PA type A?
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achlorhydria (Absence of hydrochloric acid from the gastric juice.)
hypergastrinaemia due to hyperplasia of gastrin producing cells gastrin carcinoids |
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What secretes acid and intrinsic factor in the stomach?
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Parietal cells.
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What produces gastrin?
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Antral cells...because of the hypertrophy of the antral cells you have high levels of gastrin.
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What do zymogen cells secrete?
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Pepsinogen
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What are the two conditions that result from Vitamin B12 deficiency? What happens if you don't treat the patient?
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Megaloblastic anemia, neurological disease. The patient will eventually die. The neurological disease is irreversible.
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What is meant by the neurological disease seen in vitamin B12 deficiency?
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1) Peripheral neuropathy
2) Subacute combined degeneration 3) Retrobulbar neuritis- Optic Atrophy 4) Mental Changes |
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What is meant by peripheral neuropathy?
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Vibrant sense in the peripheral nerve is diminished.
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What is meant by combined degeneration?
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This can affect the spinal cord as well and so you get not only sensory but also motor effects.
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What is meant by the mental changes?
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Some patients actually go mad! It is called megaloblastic madness.
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What happens morphologically to the spinal cord in subacute combined degeneration?
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There is demyelination of the dorsal and dorsolateral columns.
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What is the biochemical basis of this neuropathy?
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The exact reason is still unknown. Here is what is known: There is undermyelination and demyelination as well as lack of methionine and SAM synthesis. There is also a lack of betaine in the brain which exacerbates the condition.
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In pernicious anemia what are the antibodies that are present? What are the percentages? Which one is specific which one is not?
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1) Parietal cell antibodies 95% Not specific.
2) Intrinsic factor antibodies 55% Specific |
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What do these antibodies do?
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2 things...
1) They block the attachment of B12 to IF 2) They bind to IF and prevent ileal attachment. |
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How do you diagnose PA?
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Serum B12 assay, Schilling test
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How do you differentiate between B12 and folate deficiency?
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In folate deficiency your serum folate will be lower. In B12 deficiency your serum folate will be normal but your red cell folate will be lower.
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Who cares? Why does this matter?
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Because folate deficiency is very serious and needs to be treated aggressively...
* NOT SO SURE ABOUT THIS SO MAKE SURE THAT THIS IS RIGHT! |
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How do you treat pernicious anemia?
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It is a life long condition and they have to be continuously treated. They are initially treated with a 5 day course of Hydroxocobalamin or Cyanocobalamin. After that they are given these every 2 months for life.
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Is there a need to measure the vitamin B12 levels in these patients?
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No.
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What is tricky here?
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2 things...
1) Giving folate may cause a hematologic remission but exacerbate the neurological symptoms. 2) It is tricky for the patient: they will ask you "I feel fine, why do I need to get these shots?" But they do and you should give it to them. |
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What are the diseases associated with Pernicious anemia?
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There are 5:
1) Thyroid thyrotoxicosis or myxoedema 2) Addison's disease 3) Hypoparathyroidism 4) Diabetes Mellitus 5) Gastric carcinoma...if there is adenocarcinoma there is a 3X chance of PA while if there is a carcinoid tumor the chances are increased to 13X!! |
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What are some of the other effects of vitamin B12 deficiency?
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There is mucous membrane atrophy (sore tongue-->glossitis) and infertility.
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What does glossitis look like?
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Smooth tongue that is tender like red meat.
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What else do you see in these patients?
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You see redness at the sides (angles) of the mouth called angular stomatitis.
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What can cause the infertility in B12 deficiency?
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3 things:
1) Failure of ovulation 2) Lack of development of fertilized ovum 3) Unsuccessful implantation |
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What else can you see in these patients?
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Recurrent early fetal loss caused by:
Thrombophilic states and Hyperhomocysteinemia which leads to a hypercoagulable state. |
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What is a true deficiency of vitamin B12? What are the LEVELS?
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Less than 100pg/ml
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What happens between 100-200pg/ml?
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You may or may not have a true deficiency...50% true deficiency; 50% not true deficiency.
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What is holo-transcobalamin?
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It is B12 attached to TC II (transcobalamin II).
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What is it's importance?
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It may be a more sensitive marker of deficiency.
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Which drugs induce megaloblastic anemia?
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Antifolates, purine analogs, pyrimidine analogs, Ribonucleotide inhibitors, anticonvulsants, oral contraceptives, NO, PAS (p-aminosalicylic acid)
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What is an example of an anti folate drug?
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methotrexate
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What is an example of purine analog?
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6MP
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What is an example of pyrimidine analog?
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Flourouracil
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What is an example of ribonucleotide inhibitor?
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Hydroxyurea, cytosar
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What is an example of anticonvulsant?
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Phenytoin
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Why does NO considered a drug that percipitates megaloblastic anemia?
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Because it inactivates methyl transferase
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Why is PAS (p-aminosalicylic acid) included in this list?
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Because it leads to cobalamin malabsorption.
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What is cobalamin A and B disease?
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It is a disease caused by defective synthesis of adenosyl-cobalamin in mitochondria which is an essential cofactor for the enzyme methylmalonyl-CoA mutase.
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What are the findings?
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You get methylmalonic acid in large amounts in the urine, there is ketoacidosis in the first few weeks of life.
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Is the disease megaloblastic?
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Not usually
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How do you treat it?
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It responds to systemic cobalamin therapy.
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What happens if you have a deficiency in mutase?
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The effects are the same but it doesn't respond to cobalamin therapy.
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What does Deficiency of adenosyl-cobalamin cause?
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Methylmalonic aciduria.
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What does Deficiency of methylcobalamin cause?
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homocysteinaemia, hypomethioninaemia with megaloblastic anaemia and neurological
defects - mental deficiency, spasticity, delirium etc |
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What are the serum B12 and folate like here?
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They may be high!
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What is the genetics of the disease?
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It is AR.
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How do you treat this?
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With parenteral hydroxycobalamin biweekly and oral betaine.
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What do cobalamine E and G disease cause?
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They cause methylcobalamin deficiency leading to homocysteinaemia and hypomethioninemia.
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How can you reverse megaloblastic anemia?
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It is reversed by frequent parenteral hydroxycobalamin therapy.
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What are the neurological lesions seen in cobalamine E and G diseasE?
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Mental retardation, cerebral atrophy,ataxia,blindness.
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Can these be reversed by B12 therapy?
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It is very difficult...
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What is the genetics of cobalamine E and G disease?
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It is AR.
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What happens if there is a deficiency of the enzyme methionine synthase?
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You get similar effects that do not respond to vitamin B12.
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What are the inborn errors of folate metabolism?
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There are 4 entries here:
1) Congenital folate malabsorption. 2) Dihydrofolate reductase deficiency 3) Methyl transferase deficiency 4) Forimino glutamate transferase deficiency |
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What does congenital folate malabsorption cause?
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Severe megaloblastic anemia, seizures, mental retardation.
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What are some other errors of metabolism?
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Orotic aciduria, Lesch Nyhan syndrome, Thiamine responsive megaloblastic anemia.
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