Intro to Anemia and Nutritional Anemias Flashcards
Definition of anemia and classifications
Anemia: Reduction of the total circulating RBC mass below normal limits - reduces the O2 carrying capacity of the blood and can lead to tissue hypoxia
- diagnosed based on decreased hematocrit and hgb concentrations of blood
Classifications:
- blood loss = acute or chronic
–> acute = results in hypovolemia and decreased tissue perfusion
–> chronic = results in constant blood volume with decreased RBC mass + increased plasma volume
- increased RBC destruction = hemolytic anemias:
–> inherited genetic defects (sickle cell disease)
–> AB mediated destruction
–> mechanical trauma
- decreased RBC production:
–> iron deficiency anemias
–> folate/B12 deficiency
–> renal failure
–> malignancy
–> hematopoeitic stem cell disorders
Clinical features of anemia
- pallor –> paleness of skin and mucous membranes
- weakness/fatigue
- tachycardia
- dyspnea on exertion –> decreased O2 content of blood
- fatty change in liver, myocardium and kidney in long standing cases
Signs/symptoms of hypoxia
Occurs in severe anemia
- CNS –> headache + faintness
- cardiovascular –> angina due to ischemic cardiac muscle
- skeletal muscle –> claudication due to ischemia skeletal muscle
- with acute blood loss –> shock and renal hypoperfusion may results in oliguria/anuria
Factors determining the clinical severity of anemia
- degree of anemia
- rapidity of onset
- effectiveness of compensatory mechanisms
- O2 requirements of patient
Compensatory mechanisms in anemia
- heart = increased CO = increased SV + HR
- -> tachycardia
- -> patients with underlying heart disease may develop CHF
- increased 2,3-DPG = decreased affinity of Hgb for O2 to increase delivery of O2 to tissues
- -> can compensate for anemia down to ~30% hct
- -> first compensatory mechanism to a slowly developing anemia
- lungs = increased respiratory rate
- kidneys = release EPO –> stimulates bone marrow RBC production by targeting RBC progenitor cell = CFU-erythroid –> takes several weeks to effect hct measurements
- redistribution of blood flow away from organs with lower O2 demands to organs with greater O2 demands (heart, brain, muscle)
- decreased O2 consumption –> easy fatiguability, sleep more than usual, decreased physical activity
- over time, the body may tolerate decreased O2 saturation by unknown mechanisms = cellular acclimitization
Important considerations in the diagnosis of anemia
- anemia vs. increased extracellular volume: excessive IV fluids temporarily decreases the hct
- -> transfusion of large amounts of plasma and albumin draws water from the interstitial compartment and increases the ECV = decreased hct and hgb until redistribution occurs
- reticulocyte count: is the bone marrow producing more RBCs in response to the anemia?
- -> reticulocyte = non-nucleated RBC precursor that still contains ribosomal RNA - can be visualized by staining methods; should be increased in anemia
- peripheral smear: is RBC production increased?
- -> schistocytes
- specific cause of anemia: detect underlying disease process –> etiology determines tx
Effects of acute blood loss
Effects are mainly due to decreased intravascular volume
Clinical features depend on the rate of blood loss and whether bleeding is internal or external
Anemia does not occur initially with acute blood loss –> develops as blood volume is restored either physiologically with intravascular shift of water from interstitial fluid compartment or by administration of fluids
Clinical effects of hypovolemia and decreased tissue perfusion: tachycardia, hypotension and decreased urine output
- if massive loss = cardiovascular collapse, shock and death
Treatment of acute blood loss
Restore intracellular fluid volume with acellular fluids –> electrolyte solutions +/- RBCs and other blood components depending on magnitude of blood loss
Massive transfusion protocols: dilutional coagulopathy results from dilution of coagulation factors and platelets after administration of large volume of fluids to increase intravascular volume and O2 delivery
- transfusion of packed RBCs, platelets and plasma in similar proportions to whole blood may minimize this effect
Red cell transfusion: performed using concentrated RBCs = packed cells
- performed in acute blood loss in order to maintain tissue oxygentation
- in chronic anemia –> only transfuse/treat when the patient is symptomatic or at risk
Treatment of chronic anemia
Treat the root of the cause –> treat the patient not the lab value
EPO analogs: used to treat patients with chronic renal failure, patients on chemo and prophylactically in patients undergoing elective surgery to decrease the need for allogenic transfusion
- many formulations = epogen/procrit –> epoetin alpha + aranesp –> darbepoeitin alpha
Other effects of EPO:
- EPO receptors are also present on non-erythroid cells including some neoplastic cells
- inhibits apoptosis
- stimulates vascular endothelial cell proliferation
- promotes angiogenesis
EPO response is limited by abailability of iron for hgb synthesis –> most patients need iron supplements during treatment
Adverse effects of EPO
- hypertension - seen more in patients with renal failure; probably due to increased hct = vasoconstriction + increased viscosity
- -> managed medically with anti hypertensive drugs
- thrombic events - increased risk in patients with higher hgb targets = chronic renal failure, malignancy, critical illness
- cancer progression - increased tumor progression/recurrence + decreased survival when EPO dosed to increase hgb > 12 g/dL
Iron deficiency anemia
Hgb structure
Other functional iron containing compounds
Iron deficiency anemia - effects hgb synthesis
Hgb = heme + 4 globin chains
–> heme = Fe2+ + protoporphyrin
Other iron containing compounds = myoglobin, enzymes and cytochrones
–> myoglobin: keeps a reserve supply of O2 for muscle cells to use
Iron cycle
Iron balance is maintained mainly by regulating absorption of Fe in the proximal duodenum
- absorbed Fe is bound to transferrin in the plasma and transported to bone marrow –> delivered to developing RBCs and incorporated into hgb
- RBC precursors in the marrow possess receptors for transferring –> mediate iron transport via receptor mediated endocytosis
- mature RBCs are released into circulation
- after ~120 days RBCs are ingested by macrophages in the spleen, liver and marrow
- Fe is extracted from hgb and recycled to plasma transferrin –> synthesized in the liver
- ferritin = storage iron –> soluble iron-protein complex
- hemosiderin = large, heterogeneous water insoluble aggregates of ferric iron and protein
Dietary iron
Absorbed in the duodenum and proximal jejunum
- inorganic iron = from veggies –> approx 1-5% is absorbable; absorption depends on Fe stores
- heme iron = from animal products –> ~20-25% absorbable; absorption does not depend on Fe stores
RDA:
- men and post menopausal women ~1 mg/day
- premenopausal women ~1.5 mg/day
- pregnant women ~ 3 mg/day
- growth increases daily requirement
- absorption is increased by tissue hypoxia and by increased RBC production in the marrow
Regulation of iron absorption
Regulated by hepcidin –> synthesized and released by the liver in response to increased intrahepatic Fe levels; hepcidin is high when there are normal iron stores in the body
- hepcidin downregulates ferroportin = decreased trapping of absorbed iron
- when iron stores are decreased and/or erythropoeisis is increased = hepcidin is decreased and ferroportin is increased –> greater amount of iron is absorbed via ferroportin and transferred to transferrin
- non-heme iron is mostly in Fe3+ (ferric) state - reduced to Fe2+ (ferrous) state by brush border enzyme ferrireductase prior to absorption
- Fe2+ is transported across luminal membrane by divalent metal transport protein (DMT1)
Causes of iron deficiency anemia
- dietary lack of iron - vegans
- impaired absorption - celiac sprue, chronic diarrhea, fat malabsorption, gastrectomy (decreased HCl and less transit time through the duodenum)
- increased iron requirements - growing children and pregnant women
- chronic blood loss - GI blood loss until proven otherwise
- at risk groups:
1. women of childbearing age
2. pregnant women
3. teenage girls
4. preterm and low birth weight babies
5. GI disease/malabsorption
6. frequent blood donors
7. people with renal failure, especially on dialysis - decreased EPO production, blood loss during dialysis and GI bleeds
Iron deficiency stages and corresponding labs
- Iron depletion = reduced iron stores = decreased ferritin
- Iron deficiency without anemia = synthesis of functional iron containing compounds begins to be affected
- increased TIBC = increased serum transferrin
- decreased serum iron = decreased transferrin bound iron
- decreased transferrin saturation = serum iron/TIBC x 100%
- increased soluble transferrin receptor
- increased erythrocyte protoporphorin –> intracellular iron depletion increases the amount of ALA synthetase = enzyme that mediates first step of synthesis of erythrocyte protoporphorin –> in absence of iron, heme can’t be formed and protoporphorin accumulates
Clinical manifestations of iron deficiency anemia
- RBCs gradually become microcytic (decreased MCV) and hypochromic (decreased MCHC) as anemia progresses
- General signs/symptoms of anemia
- Pica
- Epithelial changes - angular stomatitis + koilonychia
- Children –> retarded growth and impaired cognitive development
- Pregnant women –> increased risk of preterm birth and low birthweight
Tx of iron deficiency anemia
Oral iron salts - 150-200 mg/day of elemental iron in 3 divided doses
- adverse effects = GI irritation
- hematopoeitic response
–> increased reticulocytes after 3-4 days, peaks at 5-10 days
–> increased hgb after 2 weeks, peaks at 2-3 months
Continue tx after anemia is corrected to replenish iron stores for weeks-months –> monitor serum ferritin
Parenteral iron - given to certain patients, mainly those with dialysis depndant renal failure treated with EPO
- adverse effect = rarely anaphylactic shock
Differential diagnosis for iron deficiency anemia
Other anemias with decreased hgb synthesis
- inflammation = decreased iron release + hepcidin modification
- thalassemias = decreased globin synthesis
- decreased heme synthesis
All tend to have normal/small RBCs, sometimes with decreased intracellular hgb concentration
Anemia of chronic disease
Decreased proliferation of erythroid precursors and impaired iron utilization rather than deficiency
Clinical settings:
- infections –> osteomyelitis
- malignancy
- chronic immune disorders –> rheumatoid arthritis
Pathophysiology: IL-6 mediated induction of hepcidin –> decreased iron absorption, decreased release of macrophage iron, NOT responsive to iron supplementation
- cytokine mediated inhibition of erythropoeisis
Iron deficiency anemia vs. anemia of chronic disease
Factors that support anemia of chronic disease:
- presence of increased storage iron in marrow macrophages
- high serum ferritin level
- decreased TIBC
Acute inflammation decreases the synthesis of transferrin
Megaloblastic anemia
Not all macrocytic anemias are megaloblastic –> megaloblastic cells have a characteristic nuclear maturation defect; other conditions can cause macrocytic cells that aren’t megaloblastic
- Folate + B12 are necessary for thymine production - necessary for DNA but not RNA synthesis –> deficiency results in a nuclear but not cytoplasmic maturation defect
- folate deficiency = developmental neurologic injuries
- B12 deficiency = acquired central and long tract neurological deficiency
Biochemistry of folate
Involved in 1 carbon transfers to methionine, purines and pyrimidines
Biochemistry of B12
1 carbon transfers in all cells: homocysteine –> methionine
- catalyzed by methionine synthetase
- Folate and B12 are cofactors
1 carbon transmutation in nerve cells: methyl malonyl coA –> succinyl coA
- catalyzed by MMCoA mutase
- B12 is a cofactor
- MMA = an excitatory neurotoxin causing epilepsy and depleting neurons of ATP –> B12 deficiency causes MMA buildup and neuron death
Changes in megaloblastic anemia
- Large oval RBCs + PMNs > 5 lobes = hallmarks
- MCHC not elevated
- reticulocyte count is decreased
huge variation in size/shapes of RBCs - megaloblastic changes are seen in the bone marrow in all stages of erythrocyte development
- large polychromatophilic normoblasts with poorly condensed chromatin
- nuclear-cytoplasmic dissynchrony
- giant bands –> delayed nucleus devt in granulocyte lineage
- hematopoeisis becomes inefficient –> some cells fail to mature at all and undergo apoptosis = pancytopenia –> decrease in all 3 blood cell lines
Folate homeostasis and causes of deficiency
RDA = 400 mcg –> increased requirements in pregnancy, lactation, chronic hemolysis and psoriasis
Absorbed in jejunum and proximal ileum
Body stores last 1-3 months
Causes of deficiency:
- dietary –> malnutrtition and alcoholics
–> >80 g/day has a direct toxic effect on bone marrow
–> subacute chronic effects of alcohol
Non-hematologic problems associated with folate deficiency
- neural tube defects - damage occurs in the first gestational month
- intestinal dysplasia - exacerbates decreased absorption
- hypercoagulable state
- reproductive failure - infertility, fetal loss, birth defects
Clinical presentation of folate deficiency
- GI - malabsorption, weight loss, diarrhea, abdominal pain, glossitis
- hematologic - macrocytic anemia, pancytopenia
- fever - from hypermetabolism
- reproductive failure
B12 homeostasis and causes of deficiency
RDA = 5 mcg
Body stores last 3 years
Ultimate source is from bacteria
Causes of deficiency:
- dietary insufficiency - rare, vegans
- IF deficiency - congenital deficiency, gastric resection, destruction by autoantibodies (pernicious anemia)
- competitive utilization - bacterial overgrowth (diabetics) and fish tapeworm (diphyllobothrium latum)
- ileal disease - tropical sprud, resection, crohns
Absorption and metabolism of B12
- saliva contains R binders - released from food in stomach and binds R binders
- binds intrinsic factor in duodenum - absorbed per cubilin in ileum
- carried by transcobalamins I-III in bloodstream –> TC II required for transfer to tissues
- excess excreted in urine
Symptoms of B12 deficiency
- anemia
- GI - weight loss, diarrhea, abdominal pain, glossitis
- reproductive - infertility, fetal loss
- beefy red tongue + angular stomatitis
- vitiligo - associated with pernicious anemia and other autoimmune diseases
- neurological
- -> peripheral neuropathy = parasthesias + hyporeflexias
- -> spinal cord degeneration = weakness, hyperreflexia, decreased vibration and position sense
- -> demyelination followed by long tract loss - motor and sensory tracts involved in patchy distribution
- -> memory loss, disorientation, depression
Pernicious anemia
Familial autoimmune disease with decreased intrinsic factor - associated with other autoimmune disorders (Hashimotos)
- Type A gastritis –> parietal cells destroyed
- 90% have anti-parietal canalicular antibodies
- Type I anti-IF antibodies –> block IF binding
- Type II anti-IF antibodies –> block IF absorption
- Antibodies found in serum and gastric juice
- Antibodies are not completely specific for pernicious anemia
Other causes of megaloblastic anemia
- nitrous oxide exposure - N2O destroys B12 + blocks homocysteine methyltransferase
- inborn errors of metabolism
- -> enzyme deficiencies = dihydrofolate reductase + homocysteine methyltransferase
- -> receptor deficiencies = IF deficiency + ileal receptor deficiency (imerslund graesbeck syndrome)
- DNA synthesis inhibitors
- -> chemo drugs = antimetabolites + methotrexate
- -> zidovudine (AZT)
- -> antimicrobials –> trimethoprim + pyrimethamine
- small bowel bacterial overgrowth syndrome with villous atrophy
- tuberculosis ileitis –> malabsorption causing decreased B12 + brain atrophy
- disordered blood cell production in leukemia –> large RBCs from skipped divisions
Clinical lab findings in folate deficiency
- RBC folate is average of values over time RBCs are in circulation –> more accurate than serum folate
- serum homocysteine is increased in tissue deficiency
Clinical lab findings in B12 deficiency
- serum B12 is not the best marker because there is a broad range of normal values
- methylmalonic acid is increased
Prevention and tx of megaloblastic anemia
- folate supplementation for all patients at risk –> chronic hemolysis, psoriasis and pregnancy
- IM B12 in pernicious anemia –> confirm response to tx by measuring the reticulocyte count after 7-10 days
