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HEME II > Anemias of Diminished Erythroposeisis > Flashcards

Anemias of Diminished Erythroposeisis Flashcards

1
Q

most common and important anemias associated with RBC underproduction

A

nutritional deficiencies then renal failure then chronic inflammation

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2
Q

pernicious anemia cause

A

B12 (cobalamin) deficiency; autoimmune gastritis, failure of intrinsic factor production

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3
Q

what are B12 and folic acid required for

A

coenzymes for synthesis of thymidine (one of 4 bases found in DNA)

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4
Q

characteristics of megablastic anemias

A

macrocytic and oval; ample hemoglobin; lack central pallor, but MCHC not elevated; anisocytosis and poikilocytosis; reticulocyte count low; occasional nucleated RBC if severe in circulation; neutrophils larger than normal and hypersegmented; marrow hypercellular

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5
Q

what secretes intrinsic factor

A

parietal cells of fundic mucosa

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6
Q

what frees B12 from binding proteins in food

A

pepsin in stomch and binds to salivary proteins called cabalophilins or R-binders

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7
Q

what occurs to bound B12 in duodenum

A

released by pancreatic proteases and associates with intrinsic factor

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8
Q

where is the intrinsic factor/B12 absorbed

A

ilial enterocytes, where B12 associates eith transcobalamin II and secreted into plasma

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9
Q

2 rxns that require B12

A

1) methycobalamin serves as essential cofactor in conversion of homocysteine to methionine by methionine synthase (yields FH4) 2) isomerization of methylmalonyl coA to succinyl coA

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10
Q

what builds up in urine and plasma with B12 deficiency

A

methylmalonic acid and propionate

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11
Q

neural effects may be caused by what due to B12 deficiency

A

formation and incorporation of abnormal fatty acids into neuronal lipids = predisposes to myelin breakdown

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12
Q

What is FH4 crucial for

A

conversion of dUMP to dTMP (deoxyuridine monophosphate to deoxythymidine), immediate precursor of DNA

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13
Q

autoantibodies in pernicious anemia

A

75% type I-blocks binding of vit B12 to intrinsic factor; Type II-prevent binding og intrinsic factor-vit B12 complex to ileal receptor; Type III in 85-90%-recognize the alpha and beta subunits of the gastric proton pump

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14
Q

where is the gastric proton pump normally localized

A

microvilli of canalicular system of gastric parietal cell

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15
Q

primary cause of gastric pathology in pernicious anemia

A

NOT auto antibodies; autoreactive T-cell response initiates gastric mucosal injury and triggers formation of autoantibodies

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16
Q

achlorhydria and loss of pepsin secretion

A

B12 not readily released from proteins in food and can cause anemia

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17
Q

exocrine pancreas fxn and B12

A

with loss, can’t release B12 from R-binder-B12 complexes

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18
Q

anemia due to B12 with normal absorption causes

A

pregnancy, tapeworms, hyperthyroidism, disseminated cancer, chronic infection

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19
Q

atrophic glossitis

A

tongue shiny, glazed, and ‘beefy’; seen in B12 deficiency

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20
Q

CNS and B12 deficiency findings

A

demyelination of dorsal and lateral tracts, sometimes followed by loss of axons

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21
Q

diagnosis of pernicious anemia

A

1) moderate/severe megaloblastic anemia
2) leukopenia with hypersegmented granulocytes
3) low serum B12
4) elevated homocysteine and methylmalonic acid in serum

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22
Q

elevated homocysteine levels risk factors

A

increase artherosclerosis and thrombosis

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23
Q

FH4 fxn

A

serves as acceptor of 1-carbon fragments from cmpds such as serine and formimonoglutamic acid, then donates these 1-carbon units to various rxns

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24
Q

most important metabolic processes involving FH4

A

1) purine synthesis
2) conversion of homocysteine to methionine
3) deoxythmidylate monophosphate synthesis

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25
Q

3 major causes of folic acid deficiency

A

1) decreased intake
2) increased requirement
3) impaired utilization

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26
Q

normal transport form of folate

A

5-methyltetrahydrofolate

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27
Q

how quickly can a defiency of folic acid appear

A

reserves modest; can arise within weeks-months if intake is inadequate

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28
Q

alcoholics and low folate

A

low intake (intestinal absorption), trapping within liver, excessive urinary loss, disordered metabolism

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29
Q

drugs that interfere with folate absorption

A

anticonvulsant phenytoin and oral contraceptives

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30
Q

folic acid antagonists

A

methotrexate-inhibit dihydrofolate reductase and lead to deficiency of FH4

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31
Q

diagnosis of folate deficiency

A

decreased folate levels in serum or red cells; serum homocysteine levels increased, but methylmalonate concentrations normal; neurologic changes do NOT occur

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32
Q

why should B12 deficiency be excluded b4 treating for folate deficiency

A

folate therapy with B12 deficiency doesn’t effect or can exacerbate neurological deficits of B12 deficiency states

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33
Q

whom is iron deficiency common in the US

A

toddlers, adolescent girls, and women of childbearing age

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34
Q

heme iron vs nonheme iron absorption

A

20% heme and 1-2% nonheme

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35
Q

fxnal storage compartments for iron

A

80% in hemoglobin; myoglobin and iron-containing enzymes like catalase and cytochromes contain the rest

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36
Q

storage pool of iron

A

hemosiderin and ferritin=make up ~15-20% total body iron

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37
Q

transferrin

A

transports iron in plasma; synthesized in liver; usually 1/3 saturated with iron (120 ug/dL in men and 100 ug/dL in women)

38
Q

ferritin

A

ubiquitous protein-iron complex that is found at highest concentrations in liver, spleen, bone marrow, and skeletal muscles

39
Q

where is ferritin in liver

A

stored within parenchymal cells (from transferritin)

40
Q

where is ferritin found in other tissues like spleen and bone marrow

A

mainly in macrophages (from breakdown of RBCs)

41
Q

where is intracellular ferritin located

A

cytosol and lysosomes

42
Q

basis of prussian blue stain to see hemosiderin

A

potassium ferrocyanide

43
Q

what do blood ferritin levels correlate with

A

body iron stores since this is where it is derived; below 12 ul/L in iron deficiency, can be up to 5000 ug/L

44
Q

where is iron absorbed

A

proximal duodenum; no regulated pathway for iron excretion (1-2 mg/day lost in shedding of skin and mucosal cells)

45
Q

nonheme iron absorption

A

1) most in Fe3+/ferric state and must be reduced to Fe2+/ferrous by ferrireductases like cytochromes and STEAP3 in lumin
2) Fe2+ transported across apical membrane by divalent metal transporter 1 (DMT1)

46
Q

2 pathways for iron that enters duodenal cells

A

1) transport to the blood

2) storage as mucosal iron

47
Q

how does Fe2+ enter circulation

A

1) transported from cytoplasm across the basolateral enterocyte membrane by ferriportin
2) newly absorbed Fe3+ binds rapidly to transferrin

48
Q

what is ferriportin transport coupled to

A

oxidation of Fe2+ to Fe3+ via iron oxidases hephaestin and ceruloplasmin

49
Q

what regulates iron absorption and how

A

hepcidin, made in liver; inhibits iron transfer from the enterocyte to plasma by binding to ferriportin and casuing it to be endocytosed and degraded; iron is then lost as cells are sloughed

50
Q

what other fxn does hepcidin do

A

suppresses iron release from macrophages-important in anemia of chronic disease

51
Q

TMPRSS6

A

hepatic transmembrane serine protease that normally suppresses hepcidin production when iron levels low; rare mutations cause microcytic anemia

52
Q

hemochromatosis

A

systemic iron overload-low hepcidin

53
Q

secondary hemochromatosis causes

A

diseases associated with ineffective erythropoiesis like B-thalassemia major and myelodysplastic syndromes

54
Q

causes of iron deficiency

A

1) dietary lack
2) impaired absorption
3) increased requirement
4) chronic blood loss

55
Q

daily iron requirement (accounting for absorption percentage)

A

~7-10 mg for men and 7-20 for women

56
Q

what is absorption of inorganic iron enhanced by

A

asorbic acid, citric acid, aas, sugars in diet

57
Q

what is absorption of inorganic iron inhibited by

A

tannates (in tea), carbonates, oxalates, and phosphates

58
Q

impaired absorption causes

A

sprue, fat malabsorption (steatorrhea), chronic diarrhea

59
Q

most common cause of iron deficiency anemia in Western world

A

chronic blood loss

60
Q

what type of anemia does iron deficiency cause

A

hypochromatic microcytic anemia

61
Q

progressive loss of iron

A

first lowers serum iron and transferrin saturation levels without producing anemia

62
Q

best way to see depletion of iron in bone marrow macrophages

A

Prussian blue stains on smears of aspirated marrow

63
Q

central pallor of RBCs

A

normally 1/3 of RBC diameter

64
Q

Plummer-Vinson syndrome

A

esophageal webs along with microcytic hypochromatic anemia and atrophic glossitis

65
Q

CBC specs in iron deficiency

A

serum iron and ferritic low, TIBC high (elevated transferrin); transferrin saturation below 15%; low hepcidin levels; hgb and HCT low

66
Q

3 groups of chronic diseases that cause iron deficiency

A

1) chronic microbial infections (osteomyelitis, bacterial endocarditis, lung abscess)
2) chronic immune diseases (RA, regional enteritis)
3) neoplasms (carcinomas of breast and lung, Hodgkin lymphoma)

67
Q

CBC specs in chronic disease iron deficiency

A

low serum iron, reduced TIBC, abundant stored iron in macrophages; (also low erythropoietin)

68
Q

IL-6

A

stimulates increase in hepatic production of hepcidin in chronic inflammation; inflammatory mediator

69
Q

red cells in chronic iron deficiency anemia

A

normo or hypochromatic; and microcytic

70
Q

what can rule out iron deficiency as cause of anemia

A

increased iron in marrow macrophages, high serum ferritin, reduced TIBC

71
Q

most cases of known etiology of aplastic anemia

A

follow exposure to chemicals and drugs

72
Q

Fanconi anemia

A

rare autosomal recessive disorder caused by defects in multiprotein complex that is required for DNA repair; marrow hypofunction early in lifealong with multiple congenital anomalies (hypoplasia of kidney and spleen, bone anomalies of thumbs or radii)

73
Q

inherited defects in telomerase

A

found in 5-10% of adult-onset aplastic anemia; either short telomeres (more common) or telomerase mutations

74
Q

65% aplastic anemias

A

idiopathic-no known cause

75
Q

two major etiologies of aplastic anemias

A

1) extrinsic, immune-mediated suppression of marrow progenitors (T-cells)
2) intrinsic abnormality of stem cells

76
Q

expression analysis of remaining marrow stem cells in aplastic anemia reveal

A

apotosis and death pathway genes up-regulated

77
Q

what finding should seriously question diagnosis of aplastic anemia

A

spenomegaly

78
Q

RBCs in aplastic anemia

A

usually slightly macrocytic and normochromatic; reticulocytopenia is the rule

79
Q

marrow in aplastic anemia

A

hypocellular

80
Q

myeloid neoplam marrow

A

hypercellular marrows filled with neoplastic progenitors

81
Q

what is pure RBC aplasia associated with

A

neoplasms (thymoma, large grandular lymphocytic leukemia), drug exposures, autoimmune disorders, parvovirus infection

82
Q

parvovirus B19

A

preferentially infects and destroys RBC progenitors; normally cleared 1-2 weeks and aplasia is transient; crisis in moderate/severe hemolytic anemias

83
Q

myelophthisic anemia

A

marrow failure in which space-occupying lesions replace normal marrow elements (metastatic cancer, granulomatous disease, myeloproliferative diseases-spent phase)

84
Q

fibrotic marrow causes appearance of what in peripheral smear

A

nucleated erythroid precursors, immature granulocytic forms (leukoerythroblastosis), teardrop-shaped RBCs (due to tortuous escape)

85
Q

chronic renal failure anemia is proportional to

A

severity of uremia

86
Q

kidney failure anemia causes

A

reduced erythropoietin, reduced RBC lifespan, iron deficiency due to platelet dysfxn, and increased bleeding

87
Q

hepatocellular liver disease anemia cause

A

decreased marrow fxn; slightly macrocytic due to lipid abnormalities

88
Q

hypothyroid anemia

A

mild normochromatic, normocytic anemia

89
Q

relative polycythemia results from

A

dehydration; stress polycythemia or Gaisbock syndrome

90
Q

seconary polycythemia

A

reponse to increased erythropoietin

91
Q

polycythemia vera

A

myeloproliferative disorder associated with mutations that lead to erythropoietin-independent growth of RBC progenitors

92
Q

HIF-1alpha

A

hypoxia-induced factor that stimulates transcription of erythropoietin gene

HEME II (5 decks)

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