Path 14 Other Anemias

Front 1

most common and important anemias associated with RBC underproduction

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nutritional deficiencies then renal failure then chronic inflammation

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pernicious anemia cause

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

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what are B12 and folic acid required for

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

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anisocytosis

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variation in size

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poikilocytosis

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variation in shape

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characteristics of megablastic anemias

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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

Front 7

what secretes intrinsic factor

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parietal cells of fundic mucosa

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what frees B12 from binding proteins in food

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

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what occurs to bound B12 in duodenum

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released by pancreatic proteases and associates with intrinsic factor

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where is the intrinsic factor/B12 absorbed

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

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2 rxns that require B12

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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

Front 12

what builds up in urine and plasma with B12 deficiency

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methylmalonic acid and propionate

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neural effects may be caused by what due to B12 deficiency

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

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What is FH4 crucial for

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

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autoantibodies in pernicious anemia

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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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where is the gastric proton pump normally localized

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microvilli of canalicular system of gastric parietal cell

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primary cause of gastric pathology in pernicious anemia

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

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achlorhydria and loss of pepsin secretion

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

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exocrine pancreas fxn and B12

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

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anemia due to B12 with normal absorption causes

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pregnancy, tapeworms, hyperthyroidism, disseminated cancer, chronic infection

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atrophic glossitis

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tongue shiny, glazed, and 'beefy'; seen in B12 deficiency

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CNS and B12 deficiency findings

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

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diagnosis of pernicious anemia

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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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elevated homocysteine levels risk factors

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increase artherosclerosis and thrombosis

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FH4 fxn

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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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most important metabolic processes involveing FH4

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

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3 major causes of folic acid deficiency

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

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daily required intake of folic acid

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50-200 ug; green veggies-lettuce, spinach, asparagus, broccoli; certain fruits, and animal sources (liver)

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cooking and folic acid

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destroys 95%+

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normal transport form of folate

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5-methyltetrahydrofolate

Front 31

how quickly can a defiency of folic acid appear

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

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alcoholics and low folate

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

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drugs that interfere with folate absorption

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anticonvulsant phenytoin and oral contraceptives

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folic acid antagonists

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methotrexate-inhibit dihydrofolate reductase and lead to deficiency of FH4

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diagnosis of folate deficiency

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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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why should B12 deficiency be excluded b4 treating for folate deficiency

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

Front 37

whom is iron deficiency common in the US

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toddlers, adolescent girls, and women of childbearing age

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heme iron vs nonheme iron absorption

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20% heme and 1-2% nonheme

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fxnal storage compartments for iron

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

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storage pool of iron

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

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transferrin

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

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free iron

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highly toxic

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ferritin

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

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where is ferritin in liver

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stored within parenchymal cells (from transferritin)

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

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mainly in macrophages (from breakdown of RBCs)

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where is intracellular ferritin located

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cytosol and lysosomes

Front 47

basis of prussian blue stain to see hemosiderin

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potassium ferrocyanide

Front 48

what do blood ferritin levels correlate with

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

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where is iron absorbed

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

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nonheme iron absorption

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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)

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2 pathways for iron that enters duodenal cells

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1) transport to the blood 2) storage as mucosal iron

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how does Fe2+ enter circulation

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

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what is ferriportin transport coupled to

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

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what regulates iron absorption and how

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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

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what other fxn dies hepcidin do

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

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TMPRSS6

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

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hemochromatosis

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systemic iron overload-low hepcidin

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secondary hemochromatosis causes

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

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causes of iron deficiency

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

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daily iron requirement (accounting for absorption percentage)

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

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what is absorption of inorganic iron enhanced by

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asorbic acid, citric acid, aas, sugars in diet

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what is absorption of inorganic iron inhibited by

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

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human breast milk vs cow iron

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breast milk ~.3mg/L; cow milk contains twice as much, but less bioavailability

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impaired absorption causes

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sprue, fat malabsorption (steatorrhea), chronic diarrhea

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most common cause of iron deficiency anemia in Western world

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chronic blood loss

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what type of anemia does iron deficiency cause

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hypochromatic microcytic anemia

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progressive loss of iron

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first lowers serum iron and transferrin saturation levels without producing anemia

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best way to see depletion of iron in bone marrow macrophages

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Prussian blue stains on smears of aspirated marrow

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central pallor of RBCs

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normally 1/3 of RBC diameter

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poikilocytosis

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small, elongated RBCs (pencil cells)

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Plummer-Vinson syndrome

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esophageal webs along with microcytic hypochromatic anemia and atrophic glossitis

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CBC specs in iron deficiency

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

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3 groups of chronic diseases that cause iron deficiency

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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)

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CBC specs in chronic disease iron deficiency

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

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IL-6

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

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red cells in chronic iron deficiency anemia

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normo or hypochromatic; and microcytic

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what can rule out iron deficiency as cause of anemia

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

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most cases of known etiology of aplastic anemia

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follow exposure to chemicals and drugs

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Fanconi anemia

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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)

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inherited defects in telomerase

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

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65% aplastic anemias

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idiopathic-no known cause

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two major etiologies of aplastic anemias

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

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expression analysis of remaining marrow stem cells in aplastic anemia reveal

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apotosis and death pathway genes up-regulated

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what finding should seriously question diagnosis of aplastic anemia

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spenomegaly

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RBCs in aplastic anemia

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usually slightly macrocytic and normochromatic; reticulocytopenia is the rule

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marroe in aplastic anemia

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hypocellular

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myeloid neoplam marrow

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hypercellular marrows filled with neoplastic progenitors

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what is pure RBC aplasia associated with

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

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parvovirus B19

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

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myelophthisic anemia

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

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fibrotic marrow causes appearance of what in peripheral smear

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

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chronic renal failure anemia is proportional to

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severity of uremia

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kidney failure anemia causes

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

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hepatocellular liver disease anemia cause

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decreased marrow fxn; slightly macrocytic due to lipid abnormalities

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hypothyroid anemia

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mild normochromatic, normocytic anemia

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relative polycythemia results from

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dehydration; stress polycythemia or Gaisbock syndrome

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seconary polycythemia

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reponse to increased erythropoietin

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polycythemia vera

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

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HIF-1alpha

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hypoxia-induced factor that stimulates transcription of erythropoietin gene