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79 Cards in this Set
- Front
- Back
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two vitamins are necessary for the formation of thymidine
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B12 and Folate
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Without a sufficient supply of vitamin B12 and folate, what happens?
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DNA synthesis is impaired and megaloblastic anemia occurs
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Why does B12 and folate deficiency cause of megaloblastic anemia?
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DNA synthesis is impaired, but RNA and protein synthesis are not affected. Thus a nuclear to cytoplasmic asynchrony develops, resulting in <b>large precursor cells that have mature cytoplasm, but immature nuclei.</b>
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What is intrinsic factor?
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Protein produced by parietal cells of the stomach that binds to B12 and is endocytosed in a complex and absorbed.
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Where is intrinsic factor made?
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Parietal cells of stomach
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What is the Schilling test and how does it work?
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a method formerly used to ID the cause of B12 deficiency.
1) Patient ingests radioactive B12 and is given an IV dose of non-radioactive B12. 2) 24 hr urine collected. If patient excretes over a certain percentage of radioactive B12 in the urine, then absorption of B12 is adequate, and lack of intake is the cause. 3) If patient does NOT excrete the expected amount in urine (indicating the B12 is NOT getting into the blood), the problem is with absorption, not intake. 4) The patient ingests B12 along with intrinsic factor. If patient excretes the expected level now, it is due to the patient lacking intrinsic factor. If not, other causes of deficiency are investigated. |
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What is elevated in B12 deficient states?
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Homocysteine; Methylmalonic Acid
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Which of these are elevated in folate deficiency:
Homocysteine Methylmalonic acid |
Homocysteine
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Neurologic sx of B12 deficiency
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Subacute combined degeneration of spinal cord. Symptoms may include numbness, tingling, loss of vibratory sensation, loss of proprioception, spastic weakness. Complete paraplegia is remains untreated.
Due to buildup of methylmalonic acid. (Usually methylmalonic acid --> succinyl CoA via B12) |
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Why is it bad to treat B12 deficiency with just folate?
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While this will correct the megaloblastic anemia, it does NOT to alleviate neurological damage (because B12, NOT folate, is involved in converting methylmalonic acid to succinyl coA). MUST rule out B12 deficiency before starting folate therapy.
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Most common cause of vitamin B12 deficiency
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Pernicious anemia
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Pernicious anemia - what happens?
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Immunologic destruction of the gastric mucosa, resulting in parietal cell loss and therefore lack of intrinsic factor.
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What is the circulating form of folate in the body?
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5-methyl tetrahydrofolate (5-methyl FH4)
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What do you see in peripheral blood smears in folate deficiency?
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normochromic, macrocytic anemia, with variation in cell size. Low reticulocyte count, and hypersegmented neutrophils. May see a pancytopenia due to generally ineffective hematopoeisis
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What do you see in bone marrow in folate deficiency?
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See megaloblastic changes with red cell precursors that have more immature nuclei than the cytoplasm (open and rope-like nuclei). May also see large myeloid precursors.
HYPERCELLULAR bone marrow due to ineffective hematopoiesis - precursors are getting made but not getting released into the blood. |
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Treatment of patients with B12 deficiency
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Parenteral B12 injections (because the problem is usually with absorption, not intake)
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Anything that interferes with folate metabolism or inhibits DNA synthesis will lead to ______
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megaloblastic anemia
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the ineffective erythropoeisis seen in megaloblastic anemia leads to an elevation in what 3 things in serum?
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serum iron, serum bilirubin, and serum lactate dehydrogenase
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Why is there an elevation in serum iron, serum bilirubin, and serum lactate dehydrogenase in megaloblastic anemia?
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These are contents of RBC precursors that leak out into the blood as the precursors are destroyed
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Other causes of macrocytosis (instead of just megaloblastic anemia)
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liver disease
reticulocytosis hypothyroidism myelofibrosis |
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Vitamin B12 is absorbed in the
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ileum
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Most ingested iron is in form of ____
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heme (Fe2+)
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Fe Absorption occurs in ____
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proximal small bowel
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T/F Non-heme (Fe3+) iron is reduced to Fe2+ by low pH in stomach
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T
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What cell type controls iron absorption?
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Intestinal mucosal cell
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What is hepcidin?
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Protein made by liver. Increased levels decrease intestinal iron absorption, Decreased levels INCREASE intestinal iron absorption.
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Decreased iron stores
Anemia Increased erythropoiesis Decreased pO2 Lack of inflammation All of these are what? |
Stimuli for increased iron absorption, the opposite of which will DECREASE iron absorption.
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Iron in circulation is transported by _____
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transferrin
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Transferrin binds to ___ on RBC precursors (and other cells) and enters cell by pinocytosis
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TfR1
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Iron is incorporated into heme or stored as _____
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ferritin
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What is ferritin?
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ubiquitous intracellular protein that stores iron and releases it in a controlled fashion
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a RBC precursor containing ferritin
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sideroblast
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What happens after senescent RBCs die (after ~120 days)?
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They're engulfed by macrophages in spleen, where heme is freed from globin.
Most of this iron is released to plasma transferrin while rest is stored as ferritin in macrophages. Some ferritin is degraded to hemosiderin (aggregates of protein shells of ferritin). Not readily available for use. |
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most commonly found in macrophages and is especially abundant in situations following hemorrhage, suggesting that its formation may be related to phagocytosis of red blood cells and hemoglobin
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hemosiderin
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hypoferremia
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decreased serum iron levels (can be caused by increased hepcidin)
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When is there increased need for iron?
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Early childhood, adolescence, pregnancy, lactation.
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Most common pathologic cause of iron deficiency
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GI bleeding
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T/F IRON DEFICIENCY IN A MALE ALWAYS NEEDS TO BE WORKED UP!!!
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T
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3 stages of iron deficiency anemia
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1) Iron depletion
2) Iron deficient erythropoiesis 3) Iron deficient anemia |
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What happens in iron depletion, 1st stage of iron deficiency anemia?
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Negative iron balance (loss of iron is > than intake)
Iron is mobilized from stores Serum ferritin decreases Iron absorption increases Serum transferrin increases Asymptomatic |
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What happens in iron deficient erythropoiesis, 2nd stage of iron deficiency anemia?
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Serum iron decreases
Iron saturation (Fe/transferrin) <15% Percentage of sideroblasts decrease in marrow Increase in RBC protoporphyrin |
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lead poisoning: good test
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Increases in RBC protoporphyrin
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What happens in last stage of iron deficiency anemia?
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Normochromic/ Normocytic at start
Marrow then produces microcytic cells Hypochromic/ Microcytic anemia Symptomatic |
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Characteristics and Clinical features of the type of anemia caused by iron deficiency
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Hypochromic, microcytic. Poikilocytosis if severe (abnormally shaped red blood cells)
Low reticulocyte count. Other counts may drop if severe. Decrease in neutrophil function if severe. PICA Epithelial changes |
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Why do epithelial changes occur in iron deficiency anemia?
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Depletion of iron-containing enzymes.
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What color does iron stain with Prussian Blue?
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Blue
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Treatment for iron deficiency
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First find and treat cause.
Give iron orally - will see reticulocyte count increase in 5-10 days. |
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disease in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells
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sideroblastic anemia
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atypical, abnormal nucleated erythroblasts (precursors to mature red blood cells) seen in bone marrow with granules of iron accumulated in perinuclear mitochondria.
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sideroblasts
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primary pathophysiology of sideroblastic anemia
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failure to completely form heme molecules, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell.
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How is sideroblastic anemia acquired?
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Can be genetic, can be acquired (anti-TB drugs, lead poisoning, ethanol, myelodysplastic syndrome)
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4 differential diagnoses of microcytic / hypochromic anemia
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Iron deficiency
Anemia of chronic disease Sideroblastic Thalassemia |
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microcytic / hypochromic anemias in which iron will be normal to high
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Sideroblastic
Thalassemia |
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microcytic / hypochromic anemias in which ferritin will be normal to high
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Anemia of chronic disease
Sideroblastic (high) Thalassemia |
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Causes of acquired (non-heriditary) hemochromatosis
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Increased iron intake (Bantu siderosis)
Ineffective erythropoiesis Chronic liver disease Neonatal hemochromatosis (congenital, but not inherited) |
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What is hepatic iron index ?
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A screening test for hereditary hemachromatosis.The theoretical basis for the HII is that iron accumulation increases steadily with age in patients with HH resulting in a correlation between age and hepatic iron content in patients with HH but not in patients who have secondary iron overload .
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Symptoms in Fe poisoning
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Generally GI symptoms, but major overdoses can result in cardiovascular collapse, coma, hepatic necrosis
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Symptoms of hemachromatosis
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Unexplained fatigue, arthralgias, hepatomegaly.
With biochemical markers of Fe overload (transferrin saturation and serum ferritin) |
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Subunit composition of the following:
A) Hb F B) Hb A C) Hb A2 |
A) α2γ2
B) α2β2 C) α2δ2 |
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Temporal changes in globin chain production.
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Embryonic Hb, Then Fetal, Then Adult
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At birth, 10-30% is Hb___ while 70-90% is Hb ___
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F; A
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As an adult, <1% is Hb___ while 95-97% is Hb ___
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F; A
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characterized by decreased synthesis of globin chains, resulting in an imbalance in the production of globin chains
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Thalassemia
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How are thalassemias named?
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For the type of chain that isn't being produced correctly
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What do the following mean?
β<sup>0</sup> β<sup>+</sup> |
No β globin production; Reduced β globin production
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_____ thalassemias are seen predominantly in people of Mediterranean European, Southeast Asian or African descent
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Beta
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Clinical features of Beta Thalassemia Major
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Onset during first year of life (switch from fetal -> adult Hb)
Growth failure Systolic flow murmer/ cardiac failure Increased iron absorption Erythroid hyperplasia bone pain “hair on end” skull x-ray Extramedullary hematopoieis in spleen and liver |
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T/F Thalassemia can be cured by bone marrow transplantation
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T
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What happens in Beta Thalassemia intermedia?
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At least one of the genes is β+. But both are defective.
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How many α thalassemia genes?
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2 α genes on each chromosome 16
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What is the genotype and anemia of
A) the carrier state? B) Trait C) HbH - hemoglobin H D) Hydrops (lethal in utero) |
A) -α/αα (normal)
B) --/αα OR -α/-α (mild or normal) C) --/-α (severe) D) --/-- |
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What is hemoglobin H disease?
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Presence of two unstable hemoglobins in the blood - Hemoglobin barts (γ4) and Hemoglobin H (β4). Result in poor Oxygen delivery to tissues.
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What is hemoglobin Barts?
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four γ chains
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What is Hemoglobin H?
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four β chains
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Alpha-thalassemia trait is similar to _______ in phenotype
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Beta-thalassemia trait
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What is Hereditary Persistence of Fetal Hemoglobin? (HPFH)
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Failure of switch from γ to β chains. Can be protective if there are other hemoglobin-opathies present, for example in sickle cell anemia.
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What do the following have in common?
Hemoglobin Lepore Hemoglobin Constant Spring Hemoglobin E |
Abnormal Globin Chains Resulting in Thalassemia-like Phenotype
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2nd most common abnormal globin (after S)
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Hemoglobin E
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Epidemiology of HbE
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Seen in SE Asian population
Homozygous (EE)- mild anemia, microcytosis, and target cells Heterozygous (AE)- only microcytosis |
