DSA 3c

what is the difference bt the left and right image

Left image: normal normoblast. Right image: megaloblastic normoblast.

what is the difference bt the left and right image

Left image: normal normoblast; microscopic appearance of nuclear-cytoplasmic synchrony between cytoplasmic and nuclear maturation Right image: megaloblastic normoblast; microscopic appearance of nuclear-cytoplasmic asynchrony (or dissociation); the nucleus lags behind the maturation in the cytoplasm

In contrast to a normal population of cells, the majority of megaloblastic cells are not resting but rather are ___; as a result, an increased percentage of these cells have DNA values between 2N and 4N because of ___.

vainly engaged in attempting to double their DNA, with frequent arrest in the S phase and lesser arrest in other phases of the cell cycle; delayed cell division

If folate deficiency is suspected, always exclude the possibility of

vitamin B12 deficiency!

•A strict vegetarian male for the past 5 years, presented with paresthesias involving the lower limbs more than the upper limbs and a positive Romberg's sign. MRI showed posterior column involvement. The serum B12 level (68 pg/ml) was found to be low. The body stores 3 to 6 years worth of B12. based on presentation and diet - w/u shows?

•Based on his presentation and diet history, his workup confirmed decreased cobalamin, the only water-soluble vitamin stored in the body.

•A serious vitamin B12 deficiency can be corrected two ways:

•weekly shots of vitamin B12 or •daily high-dose B12 pills.

•__ provides information about folate status over the lifetime of RBCs. •In patents with normal or low-normal folate levels in whom folate deficiency is clinically suspected (based on risk factors such as malabsorption or other findings, including megaloblastic anemia), it is more common to use ancillary testing of ______, to confirm folate deficiency. •In folate deficiency, the plasma homocysteine level is __ and MMA is ___.

RBC folate; methylmalonic acid (MMA) and homocysteine, rather than RBC folate analysis; elevated but MMA is normal, whereas both plasma homocysteine and MMA are elevated in vitamin-B12 deficiency.

Explain folate trap

a deficiency of vitamin B12 produces megaloblastic anemia because of its role in folate metabolism. During the many transformations of folate from one form to another, a proportion gets accidentally converted to N5-methyl-THF, an inactive metabolite. This is called the "folate trap," since there is no way for active N5,N10-THF to be regenerated except through a reaction for which a form of vitamin B12, methyl-B12, is a cofactor. Deficiency of B12 then produces a situation where more and more folate is trapped in an inactive form with no biochemical means of escape. The end result is failure to synthesize adequate DNA.

Products of ____ constitute the primary source of vitamin B12. ____ are advised to use vitamin B12 fortified foods and supplements to meet their needs.

animal origin; Older individuals and vegans;

The derangement in DNA synthesis causes most bone marrow precursors to undergo ____ and leads to pancytopenia. The ineffective erythropoiesis leads to anemia; the anemia is further exacerbated by a mild degree of ____ of uncertain etiology (not enough to be labeled a hemolytic anemia, but may have elevated LDH).

apoptosis in the marrow (ineffective hematopoiesis); red cell hemolysis

Pernicious anemia is a specific form of megaloblastic anemia caused by ____ that leads to vitamin B12 def. These changes are secondary to the presence of __.

atrophic gastritis and an attendant failure of intrinsic factor production; autoantibodies

Cobalamin deficiency: common causes are malabsorption due to ___. Dietary deficiency is rare.

atrophic gastritis, gastric bypass (or sx in which part of stomach or si are removed) or tapeworm infection

Macrocytosis due to excess RBC membrane occurs in patients with ___ when?... Macrocytosis with an MCV of about 100 to 105 fL/cell can occur with ___ use in the absence of folate deficiency. Mild macrocytosis can occur in ___, especially as recovery occurs. Macrocytosis is also common in ___. Others: reticuocytosis (polychromasia), newborn

chronic liver disease when cholesterol esterification is defective; chronic alcohol; aplastic anemia; myelodysplasia

The most common cause of a macrocytic anemia is megaloblastic anemia, which is the result of impaired DNA synthesis. Although DNA synthesis is impaired, RNA synthesis is unaffected, leading to a buildup of ___. This results in a larger-than-normal cell. The nuclear chromatin of these cells also has an altered appearance.

cytoplasmic components in a slowly dividing cell;

Most folic acid deficiency is caused by __. Some is caused by __.

dietary deficiency; disease of the small intestine, such as celiac disease, or drugs, but occasionally no cause can be discovered

Megaloblastic anemia, the maturation defect is not restricted to the ___; the bone marrow biopsy specimen demonstrates a ___typical of megaloblastic hematopoiesis. The ___ is due to the marrow response to peripheral cytopenias. The bone marrow appropriately make more cells but the cells are ___. Morphologic differences include a ___.

erythroid lineage; hypercellular marrow; hypercellularity; abnormal; larger cell, larger nucleus, and finer chromatin in red cells, megakaryocytes, and granulocytes

Megaloblastic Maturation: This increased DNA content in megaloblastic cells is morphologically expressed as larger than normal "immature" nuclei with ___ chromatin, whereas the relatively unimpaired RNA and protein synthesis results in large cells with ___ cytoplasm and cell volume. Megaloblastic anemia (image is a bone marrow aspirate). The granulocytic precursors are also __ and have ___ chromatin.

finely particulate; greater "mature"; on the picture: Megaloblasts in various stages of differentiation. Note that the orthochromatic megaloblast (B) is hemoglobinized (as revealed by cytoplasmic color), but in contrast to normal orthochromatic normoblasts, the nucleus is not pyknotic. large and have abnormally immature (granulocytic cells)

clinical vitamin B12 deficiency has two main manifestations:

hematological and neuropsychiatric disorders.

____ lobes, typify megaloblastic anemia.

hypersegmented neutrophils - six or more lobes Right: Neutrophils are also larger than normal and hypersegmented, having five or more nuclear lobules instead of the normal three to four. Hypersegmentation (>5% of neutrophils with > 5 lobes or 1% with > 6 lobes) of polymorphonuclear cells may occur without anemia. *

Megaloblastic Maturation: ____ nuclei with ___ chromatin, whereas the relatively unimpaired RNA and protein synthesis results in large cells with greater "mature" cytoplasm and cell volume. As the name implies, erythroid precursors and red cells are abnormally large due to _____.

larger than normal "immature"; finely particulate defective cell maturation and division

A peripheral smear may reveal macroovalocytes, a characteristic of megaloblastosis. They should be distinguished from other macrocytes (some are not even oval) that can occur in

liver disease; hypothyroidism; and polychromatophilic macrocytes (reticulocytes) seen in hemolytic anemia and disorders associated with increased RBC production.

Macrocytes are enlarged RBCs (ie, MCV > 100 fL/cell). Macrocytic RBCs occur in a variety of clinical circumstances, many unrelated to the megaloblastosis and the resultant anemia. Right Upper Image: This image shows

non-nutritional macrocytic anemia that is not drug-induced. Round morphology of the RBCs, as opposed to oval macrocytosis, suggests liver disease; target cells are also evident. Right Lower: Polychromasia

The defect in DNA synthesis, with lesser alterations in RNA and protein synthesis, leads to a state of unbalanced cell growth and impaired cell division is called?

nuclear-cytoplasmic asynchronism/nuclear-cytoplasmic dissociation, specifically for megaloblastic maturation.

best sources of b12

organs, beef, chicken, pork, fish, diary products, seafood, nutritional yeast, fortified cereals and soy products

•Abnormally low vitamin B-12 levels: Test for ____ by measuring available autoantibodies such as

pernicious anemia; •Anti-parietal cell antibodies are present in 90% of PA cases. In patients older than 70 years, 10% have false-positive abnormal Anti-parietal cell antibody levels. •Intrinsic Factor (IF) antibodies are present in 60% of patients. These are more specific but less sensitive. •If either antibody is positive, the diagnosis of PA is confirmed and further testing is not required.

B12 synthesized by ____ humans don't ___ and must obtain it through dietary sources. b12 found in ___ of animals in intestines

plants and animals - make it ; bacteria

dx algorithm for microcytic anemia:

r/o meds or alcohol check vit B12 and folate lvls decreased folate and normal Vit b12? folate def decreased/normal vit b12 and normal folate? check MMA lvl increased MMA? consider a b12 def normal vit b12 and folate? consider primary bone marrow disorder, chronic liver dz or hypothyroidism

•Laboratory parameters after administration of vitamin B-12 to deficient anemic patients- basically how do you know if you intervention is working?

•Reticulocytosis starts in 3-4 days and peaks at 1 week. •Hemoglobin concentration rises in 10 days and returns to the reference range in 8 weeks. •LDH falls within 2 days. •Hypersegmented neutrophils disappear in 1-2 weeks.

Vitb12 w/u initial test?

•Serum cobalamin levels are the initial test.

•Circulating folate levels are strongly influenced by The plasma folate level can be restored to normal with Principal food sources of folate are

-recent intake and are an unreliable index of tissue stores. - one folate-rich meal. -liver, spinach, legumes, and orange juice, although in countries that fortify cereal with folic acid, this is often the major source.

Megaloblastic Anemia is not the same as

Macrocytic Anemia

•In folate deficiency, MMA is __ and HC is _

WNL; elevated

megaloblastic microcytic anemia: Large red cells: which can be described as? Thrombocytopenia? The megaloblastic changes are noted in ... Serum indirect bilirubin and lactate dehydrogenase (LDH) may be ...

-macrocytic, macro-ovalocytosis, anisocytosis, and poikilocytosis, as well as Howell-Jolly bodies. -is also not uncommon. platelets often have bizarre size and shape. -all three lines, i.e. red cells, white cells, and platelet precursors within the marrow. -elevated because can have a insignificant hemolytic component.

liver stores b12 for ___. Daily losses are ____ mcg/day, the body usu has sufficient stores so that vit b12 def develops more than ___ years after absorption ceases.

3 years supply - 2000-5000 mcg stored; 3 years

•Subacute combined degeneration is a term that specifically denotes the

B12 deficiency as the etiologic cause of the spinal cord involvement. If remained untreated, it leads to irreversible neurological deficits. Thus, early diagnosis and treatment are of utmost importance.

__, rather than ___, can explain most cases of vitamin B12 deficiency. Absorption of vitamin B12 from food requires normal function of the ____

Intestinal malabsorption rather than inadequate diet intake; stomach, pancreas, and small intestine.

vitb12 w/u: •Borderline vitamin B-12 level and clinical features of vitamin B-12 deficiency:

Measure methylmalonic acid (MMA) and homocysteine(HC).Both folate and vitamin B-12 deficiency can lead to metabolite elevation. •In vitamin B-12 deficiency, MMA and HC are elevated. MMA is more sensitive than HC. Work up: Another biochemical parameter that can be used to determine a vitamin B12 deficiency is the concentration of methylmalonic acid (MMA) which increases in the serum and in the urine when there is a deficiency of vitamin B12. An increase in the homocysteineconcentration in serum is another indicator for vitamin B12, vitamin B6 and/or folic acid deficiency. However, since is an increase in the serum concentration in the case of a vitamin B12 deficiency as well as in the case of a folic acid deficiency, this parameter alone is not sufficient to specifically determine the deficiency which is present.

A 56-year-old woman presented with a four-month history of progressive cognitive decline, weakness, incoordination, and gait disturbance. She had a score of 12 of 28 on the Mini-Mental State Examination, moderate weakness, and severe ataxia; reflexes, vibratory sensation, and the sense of position were absent throughout her arms and legs. Cobalamin is important in the maintenance of normal myelin, and its deficiency results in subacute combined degeneration (SCD) of the spinal cord. Cobalamin deficiency may also cause perivascular degeneration of myelinated fibers in the cerebrum (Panel A, arrow), and these brain lesions probably account for dementia.Because cobalamin deficiency may produce dementia that is easily correctable with treatment, vitamin B12 screening is routine in the evaluation of dementia. MRI of the spine showed by degeneration of myelin and axonal loss (subacute combined degeneration). Laboratory tests revealed macrocytic anemia, hypersegmented neutrophils, a low serum vitamin B12 concentration (34 pg per milliliter), anti-intrinsic-factor antibodies, and abnormal results on the first stage of the Schilling test. Vitamin B12 injections rapidly improved cognitive function, and strength and walking also improved. Vitamin B12 deficiency causes a typical pattern of degeneration of the white matter in the central nervous system that can be manifested clinically as encephalopathy, myelopathy, peripheral neuropathy, and optic neuropathy.

Neurological signs and symptoms due to myelin degeneration in both the sensory and motor pathways in B12 depletion

•A mild B12 deficiency can be corrected with

a standard multivitamin. •In many people, a vitamin B12 deficiency can be prevented. If a strict vegetarian or vegan, it's important to eat breads, cereals, or other grains that have been fortified with vitamin B12, or take a daily supplement. A standard multivitamin delivers 6 micrograms, more than enough to cover the average body's daily need. •If over age 50, the Institute of Medicine recommends that you get extra B12 from a supplement, since you may not be able to absorb enough of the vitamin through foods. A standard multivitamin should do the trick. •Remember to always consider absorption issues

explain the steps of B12 absorption

diet b12 - parietal cells produce IF. B12 is bound to r binder which is cleaved by pancreatic enzymes; then bind to IF in the duodenum and jejunum. then absorbed int he ileum with transcobalamin II to the liver through portal blood then with TcI and TCII bound to b12 in the systemic blood eventually

Folic acid is found in ___. folate can be easily destroyed by

fresh leafy and other vegetables, especially spinach, kale, Brussels sprouts and asparagus;\ Folate is found naturally in foods such as fruits and dark leafy vegetables, but can be easily destroyed by cooking or processing. Folic acid is susceptible to being destroyed with boiling, poaching, and simmering.

Megaloblastic anemias, whether due to vitamin B12 deficiency or folic acid deficiency, present with____ morphologic blood and bone marrow changes. Anemia is ____ Presence of___ is considered quite characteristic of megaloblastic anemia. The reticulocyte count is usually ___.

identical; macrocytic - MCV sometimes reaching as high as 150 cubic microns (μ3). macro-ovalocytes decreased despite marked anemia

Folic acid is absorbed from the -. There are ___ (lots/some/no) body stores of folic acid.

proximal small intestine; no body stores

Folic acid is needed by the body to

synthesize and break down amino acids, and to synthesize DNA/RNA.

how do folate def and vit b12 PBS compare?

they are the same

•Macrocytic high reticulocyte production:

•Any anemia with polychromasia •***Large circulating erythrocytes are not always associated with a pathologic process or condition. In fact, RBCs of newborns and infants tend to be larger (mean MCV = 108 fl) than normal adult.

•Macrocytic, low reticulocyte production

•Megaloblastic Anemias: •Anemia of Vitamin B12 Deficiency •Anemia of Folate Deficiency •Non-megaloblastic macrocytic anemias: •Alcoholism •Hypothyroidism •Chronic liver disease

•A 70-year-old woman was brought to neurology clinic with complaints of walking inability, sleeplessness and frequent urination. As a lonely living woman without significant health problems, 7 months earlier she experienced difficulty in handling utensils because of tingling sensorial feelings. She noticed weakness in her hands. Subsequently, gait imbalance and decreased strength of the lower limbs, especially on the right side has begun. She had "trouble in "controlling her legs", and stumbled frequently. In the following months the clinical picture progressed steadily until the patient was bedridden. •On presentation, she was oriented to person and place but not to time. Neurological examination disclosed normal findings of cranial nerves. She could not walk even with assistance and the motor strength of the upper limbs were 4/5 and the lower limbs were 2/5. Bilateral limb, and truncal ataxia was noted. Deep tendon reflexes were 2+ in the lower extremities and reduced in the upper extremities. Joint position sense was impaired in all extremities. There was loss of vibration sense in the lower extremities and paresthesia on the palmar site of both hands. •Hemoglobin level was low at 10.3 g/dL; mean corpuscular volume was elevated at 106 fL; white blood cell count was low normal at 4.6x103 /uL; and platelet count normal at 576x103 /uL. Bone marrow was megaloblastic. Serum vitamin B12 level was 10 pg/mL (normal range, 200-950 pg/mL) and folic acid level greater than 20 ng/mL (normal range, 3-17 ng/mL). Free T3, T4, and TSH levels were normal. Anti-parietal cell, and anti-intrinsic factor antibody screening tests were positive. Biopsy of the gastric mucosa disclosed a massive chronic atrophic gastritis with marked loss of parietal cells and prominent infiltrates of lymphocytes and plasma cells.

•Neurologic complications of pernicious anemia and vitamin B12 deficiency was diagnosed and treatment with cobalamin was started. A daily dose of 1000 µg cobalamin was administered intramuscularly for ten days and thereafter this dose was repeated weekly for a month and then monthly. Clinical improvement was noted within 2 weeks of initiation of the treatment; paresthesias in hands resolved substantially and the muscle strength of the lower limbs increased (3/5). At the end of the third week after treatment, the mental state returned to normal. After 1 month, limb and truncal ataxia resolved substantially. The result of bone marrow biopsy showed normal morphology of the cells. Furthermore, joint position sense in all extremities, vibration sense in the lower extremities, improved considerably at the end of the second month of the therapy.