Underproduction Anemia

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    Anemia of Chronic DiseaseEdit section

    • New Term "Inflammatory Anemia"
    • Caused by chronic inflammation or infection.
      • Some due to infection (TB, osteomyelitis, endocarditis)
      • Malignancies, collagen vascular disorders.
      • Epo production is inhibited during inflammatory states.
        • Also rise in IL-6, TNF-alpha, etc.. that cause decreased Epo responsiveness.
        • IL-6 causes synthesis of hepatic peptide hepcidin, which decreases iron absorption in GI tract and decreases iron release by macrophages.  --> proteolysis of ferroportin.
      • Hepcidin analogues/inhibitors being developed are being developed. 
    • Labs:
      • Microcytic or Normocytic
      • Hb typically 80-100. (typically >80)
      • Blood film:
        • Can be normal, or over time can get microcytic hypochromatic erythrocytes.
      • Reticulocytes low (despite degree of anemia).
      • Iron level initially normal, but over time low.
      • TIBC low
      • Ferritin elevated.
        • (NOTE: contrast to iron deficiency, where iron is low, ferritin low, but TIBC high)
      • Bone Marrow (not always necessary): see ample iron staining.
    • Notes:
      • If no cause is found on quick history, not recommended to search for infectious and inflammatory causes!
      • Leading cause of consultation to hematology.
      • Diabetes and CHF can increase cytokine levels causing inflammatory anemia.
    • Treatment:
      • Does not require therapy.  No need to give iron.
      • ESA (aka EPO) can improve anemia, but use with extreme caution due to risks of hypertension and thrombosis.

    Iron Deficiency AnemiaEdit section

    • Pathogenesis notes:
      • Exacerbated by increased iron use syndromes (i.e. pregnancy, lactation).
      • Iron also essential to DNA synthesis, cellular respiration, and oxygen transport.
      • Most iron is stored in RBC mass, each cc of pRBC has 1mg of elemental iron
        • Giving someone 1 unit of blood (250ccs) = 250mg of elemental iron.
      • Iron does not leave the body easily, must be CAREFULLY controlled.
      • Iron absorption is negatively regulated by hepcidin (small peptide synthesized in the liver).
        • Levels go up in inflamation --> causes decreased iron absorption in enterocytes and decreased secretion by macrophages.
        • Causes internalization and proteolysis of ferroportin that allows iron absorption.
        • i.e. anemia of chronic disease = anemia of hepcidin excess.
        • i.e. hemochromatosis = hepcidin deficiency
          • (both are a spectrum of hepcidin activity)
      • Dietary sources:
        • Heme-iron found in: Red meat, fish, poultry
        • Non-Heme Iron: Vegetables, Lentils, beans, leafy vegetables, peas, spinach.  (in vegetables iron often chelated by phytates and oxalates that may limit avialability).
      • However, we do not have a good way to get rid of iron.  A few mg through the GI tract and premenopausal women.  Hence absorption is carefully regulated.  (hecidin is a good thing).
      • Absorbed in proximal small bowel, hence malabsorption can happen in:
        • Celiac disease, IBD, Surgical resection.
          • Some malabsorption syndromes such as celiac do not have diarrhea, steatorrhea, and weight loss. (asymptomatic, need serologic/biopsy testing).
    • Symptoms:
      • Mild: Fatigue, lack of well being, irritability, decreased exercise tolerance, headache ("end of the week symptoms").
        • Also rarely glossitis, stomatitis (inflammation of mouth+lips)
      • Advanced: iron deficiency: tendency to eat ice, clay, starch, paper, crunchy materials (called "pica").
        • Unknown why pica occurs, patients often embarrassed. 
    • Physical:
      • Conjunctival pallor (seen first)
      • Glostitis, smotatitis
      • Severe iron deficiency: Spooning of the nails (called Koilonychia).
    • Labs:
      • Low serum iron
      • Low ferritin (acute phase reactant, but iron deficiency seldom have ferritins > 150).
      • Increased TIBC (Total Iron Binding Capacity) and decreased transferrin saturation.
        • NOTE: SerumIron / TIBC = transferrin saturation.
        • (In anemia of chronic disease: TIBC is low).
      • High platelet count
        • Likely crossreaction of Epo to cause thrombocytosis, BM overcompensating by upregulating myelogenous cell lines.  (Many heme referrals for thrombocytopenia end up being IDA)
      • Gold Standard: Bone Marrow Biopsy stained with Prussian Blue detects iron stores.
        • Too aggressive, only for research or if unclear picture.
      • Blood film:
        • Microcytosis
        • Anisopoikilocytosis ("aniso" means abnormal size, "poikilo" means abnormal shape)
        • Pencil cells (aka "cigar cells").
        • IronDefSmear.png
      • Ferritin LR of Iron Deficiency
        <18 4.47
        18-45 3.12
        45-100 0.46
        >100 0.13
      • Usually Ferritin < 40 = iron deficiency anemia (good balance).
        • ferritin > 100 => usually excludes IDA
        • ferritin < 15 => for sure rules it in
      • Other lab findings:
        • RDW increases (wide range of cell sizes.. aka anisocytosis on film).
    • Treatment:
      • Oral iron salts:
        • Oral ferrous sulfate 325mg TID (least expensive)
          • Each tablet has 66mg of elemental iron, and 1%-2% of which is absorbed.
          • GI side effects - nausea, abdo pain, constipation... usually start with 1 tab daily and increase.  - 
          • Typically TID for treatment, and OD for maintenance/prevention.
        • Ferrous gluconate
        • Ferrous fumarate (Palafer)  300mg PO TID for treatment OD for maintenance.
        • No studies showing superiority of newer formulations to ferrous sulfate.
        • Delayed release formulations (i.e. "Slow Fe") are more $$$ marketed as better tolerated, but no convincing studies.  Patients often report it helps if cannot tolerate other forms.
      • IV Iron Preparations
        • Indications:
          • Can't absorb PO iron, refuse oral iron, or on dialysis (EPO)
        • Old agent:
          • Iron Dextran: 1% incidence of anaphylaxis.
        • Newer agents:
          • Iron sucrose
          • Ferric gluconate
          • Ferumoxytol
          • (better safety parameters, less anaphylaxis, but no studies head-to-head)
      • Ascorbic acid increases iron absorption, but no data to suggest adding this agent.
        • Tell patients to take it with orange juice or vitamin C tablets.
      • Especially careful with PPI's, have to give vitamin C or orange juice as don't make enough acid to absorb iron.
      • Absorption inhibited by:
        • Antacids, antibiotics, foods (cereals, fibre)... hence recommended not to take iron with meals.
      • Response:
        • Reticulocytosis within 1 week.
        • Noticeable hemoglobin response in several weeks. (4-6 weeks).
        • When Hb returns to normal, continue supplemental iron for 3-6mo (to restore iron stores).
        • (Will take 4-6 weeks to increase ferritin.  If no response, think celiac disease.)
    • Source:
      • MKSAP 16, and University of Toronto lecture by Dr. Frost

    B12 (Cobalamin) DeficiencyEdit section

    • Pathogenesis:
      • B12 is necessary for DNA synthesis.
      • Found in calf's liver, sardines, shrimp, scallops, and other animal meats.
      • On ingestion: B12 released from food by gastric peptidases.
        • In acidic stomach cobalamin bound to R-binders contained in saliva and gastric secretions.
        • In alkaline small bowel cobalamin transferred from R-binders to intrinsic factors.
        • In Ilium: cobalamin bound to intrinsic factor is absorbed.
        • In reticular endothelial system, cobalamin is stored.
      • Extremely large enterohepatic storage of cobalamin.  A deficiency takes > 10 years to develop.
      • Pernicious Anemia
        • A specific cause of cobalamin deficiency (see below).
    • Causes:
      • Deficiency almost always due to malabsorption. (In IDA: due to blood loss).
        • 1. Antibody-directed destruction of gastric parietal cells (make intrinsic factor).
          •  aka "classic pernicious anemia".
        • 2. Malabsorption caused by aging.
          • Older patients develop deficiency due to this.
        • 3. IBD, Celiac disease, Pancreatic insufficiency, bacterial overgrowth, batriatric surgery.
        • 4. Medications:  Metformin and PPI
          • Associated with B12 deficiency.  Likely interfere with calcium-mediated cobalamin absorption in terminal ilium. 
    • Symptoms:
      • Glossitis (smooth red tongue) - seen in B12 deficiency
      • Weight loss.
      • Pale yellow skin.  "Lemon-yellow skin" described.. caused by anemia + low-level hemolysis.
      • Sometimes: Cell line deficiency symptoms (Anemia, thrombocytopenia, leukopenia)
      • Peripheral neuropathy:
        • Posterior column defects: loss of position or vibration sense, can progress to spastic ataxia.
      • Psychiatric:
        • "Megaloblastic mania" hallucinations and frank dementia.
    • Labs:
      • Pancytopenia: Anemia (most common), thrombocytopenia, leukopenia.
      • Low-level hemolysis (low hapto, high LDH, high bili)
      • Peripheral smear: identical to folate deficiency.
        • Hypersegmented neutrophils.  (characteristic of B12 def)
          • Generally 20% of PMNs should can have 5 lobes.
            • >5 nucleus lobes = megaloblastic anemia (such as cobalamin)
              OR
            • >20% PMNs having 5 lobes = also megaloblastic anemia.
        • Basophilic stippling (non-specific).
        • B12DefSmear.png 
           
      • Cobalamin (B12) levels (normal ~200-2000).
        • Many patients with low-normal cobalamin levels, but have tissue cobalamin deficiency.
        • If low-normal, measure homocysteine and methylmalonic acid, can still have tissue cobalamin deficiency.
      • If cobalamin (B12) levels are low-normal (200-400 pg/mL [148-295 pmol/L]), measure homocysteine and methylmalonic acid.
        • Both reflect tissue cobalamin levels.  (Both metabolized by cobalamin-complexed enzymes, so levels go UP if cobalamin deficient).
        • More sensitive and specific in diagnosing cobalamin deficiency than low cobalamin levels.
        • NOTE: with folate deficiency, only homocysteine levels are elevated.
        • Homocysteine.png
    • Pernicious Anemia
      • A specific cause of cobalamin deficiency.
        • Antibodies against hydrogen potassium adeonosine triphosphate in parietal cell membrane.
        • Leads to parietal cell atrophy and reduce intrinsic factor levels. 
        • Can use antibody testing, but poor sensitivity/specificity.
        • Even in low-cobalamin levels sensitivity is 50-84%.  (70% of pts with PA have positive ab test)
        • Previously Schilling test used for diagnosis, but lack of radioactive cobalamin limits its use.
      • Bottom Line:
        • Diagnosis of pernicious anemia does not matter because treatment is the same. 
    • Treatment:
      • ORAL Vitamin B12 1000mcg/day
        • Historically treated with Vitmain B12 (1000mg SC or IV monthly), but now known that oral is just as good, and can resolve cobalamin deficiency (even pernicious anemia).
      • Interestingly ANEMIA of B12 deficiency can be corrected with folate, but not the neuropsychatric symptoms.
        • Before you give folate, ensure pts are not cobalamin deficient.
      • Recovery:
        • In 3-5 days get reticulocytosis, Hb levels will take a few months to normalize.
        • If do not normalize, think of alternative dx (such as myelodysplasia).
        • Neuropsychiatric symptoms will take even longer to resolve (and sometimes don't resolve).

    Folate DeficiencyEdit section

    • Dietary folate: green leafy vegetables, melons, lemons, bananas, grains (fortified). 
    • Dietary floate is conjugated with glutamic acid residues, and absorption requires deglutination to monoglutamate for uptake as methyltetrahydrofolate. 
    • Recommended dietary allowance: 400 ug/day.
    • Risk Factors for folate deficiency:
      • Primary folate deficiency is uncommon (plentiful in diet), usually related to alcohol consumption.
        • Alcohol (inhibits deglutination, decreasing folate absorption).
        • Pregnant women (fetal need to prevent neural tube defects.).
        • High cell turnover (Hemolytic anemia, sickle cell disease, desquamating skin disorders like psoriasis)
        • Drugs: Methotrexate, triamterene, phenytoin can inhibit folate metabolism. 
        • Small bowel disorders (Celiac Disease, IBD, Amyloidosis)
    • Labs:
      • Peripheral smear: IDENTICAL to patients with B12 deficiency and other megaloblastic anemias.
      • Measuring random folate levels in blood unreliable (folate levels go up fast after each folate-containing meal).
        • Fasting level a bit better.
      • Erythrocytefolate better for long term folate balance, but also increased in B12 deficiency.
      • homocystine levels high (Sn and Sp >90%), methylmalonic level normal
            (whereas homocystine and methylmalonic acid levels both rise in B12 deficiency)
      • Homocystine levels are better than RBC folate.  (often just give folate and see if anemia improves).
    • Treatment:
      • Ensure not B12 deficient. 
      • Often just try to treat since treatment is benign and see if the anemia responds.
      • Folate 1-5mg/day, inexpensive, well tolerated

     

    Anemia of Kidney Disease

    • Kidney disease induced anemia.
    • Decreased renal cortical mass and decreased Epo levels in kidney disease can cause anemia.
    • Labs:
      • Normochromic, nomocytic
        • Microcytosis in CKD common if GI bleeding (PUD/angiodysplasia).
      • Reduced Reticulocyte count
      • Blood Film:
        • Echinocytes (aka Burr cells) - Red cells with "burrs" on them.
        • Burr Cells.jpg
    • Diagnosis:
      • Can measure Epo levels (help if patient only has mild renal failure).
        • In the past Epo not sensitive at low levels, but now more reliable. 
    • Treatment:
      • Kidney Disease Improving Gobal Outcomes (KDIGO) Guidelines recommend:
      • KDIGO Guidelines: IV iron recommended to oral because more effective (can reduce dose of ESA)
      •  
      • Ensure iron stores are adequate (serum ferritin >100, Fe Sat > 20%).
      • Target Hb 11-12 g/L (110-120 SI), if >120  = increased complications
        • If >120 stop giving it for a bit of time due to risk.
      • Risks of EPO therapy:
        • Hypertension
        • Cardiovascular events (MI, stroke).
        • Thrombosis
        • Use in cancer worsens survival.
      • Guidelines for Epo use in patients receiving dialysis:

        • Initiation: GFR < 30 mL/min/1.75m2, Hb < 100 g/L

         

        • Target Hb to  10.0 - 11.5 g/dL (100 - 115 g/L) [Try not to go over, unless patient agrees/QOL issues]
        • Ensure stores adequate
          • Target ferritin > 100 (optimally >500)
          • Iron Saturation > 20% (Optimally > 30%)
          • Folate + B12

         

        • If Hb > 120 --> high complications, hold Epo or lower dose until at target

         
      • NOTES:
        • Patients on dialysis recommended to get IV iron (newer agents).  [Iron sucrose, ferric gluconate, and Ferumoxytol, NOT the old Iron Dextran that causes anaphylaxis).
        • Dialysis patients are high risk due to blood loss, must have good iron stores.
        • Careful with aluminum toxicity (phosphate binders and antacids) causing worsening anemia
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