Pocket Oncology (Pocket Notebook Series), 1st Ed.

ANEMIAS OF UNDERPRODUCTION

Patrick W. Burke

Definition (ASH-SAP 2010;1:109)

↓ RBC mass. Hb < 13 g/dL (men), < 12 g/dL (nonpregnant women), < 11 g/dL (pregnant women) w/RI < 2 or absolute retic inapprop for anemia degree.

Microcytic (MCV < 80 fL); Normocytic (MCV 80–100 fL); Macrocytic (MCV > 100 fL).

Fe Deficiency Anemia (ASH-SAP 2010;1:109)

Commonest anemia worldwide. ↑ Developing world. 7% U.S. women aged 12–49 y.

Developed world: Premenopausal women: Menstrual blood loss. Adult Men: GIB.

Infancy: Dietary def (↑↑ cow milk intake/breast milk intake w/o Fe supplementation). Children: Diet def. Developing World: GIB (parasitic infxn).

Blood Loss. ↑ Phlebotomy. HD. Intravascular hemolysis w/hemoglobinuria.

Rapid infancy growth. Pregnancy/lactation (↑Fe demand). Nutritional def. Malabsorption: Celiac disease, gastric bypass, H. pylori, achlorhydria (↑ w/age), gastric/duodenal infiltration or resection. AbNltransferrin function.

• S/s: General anemia sxs. Pica (uncommon), stomatitis, glossitis, koilonychia, esophageal webs: Plummer–Vinson Syndrome (rarer).

• Peripheral Blood Smear: Normocytic RBC (early) or microcytic RBC (later).

Hypochromia, anisopoikilocytosis, ↑ RDW. Cigar/pencil-shaped RBC. ± reactive thrombocytosis (↑EPO cross-reacts w/TPO receptor).

• Lab W/u: ↓↓ Ferritin (< 15 μg/L diagnostic; >100 μg/L unlikely).High nl to ↑ TIBC. ↓↓ Fe sat (<10%). Nl MCV (early) → ↓ to ↓↓ MCV (adv). ↑ RDW. Experimental: ↓ Hepcidin. ↑ Soluble transferrin receptor. Anemia/Fe parameters improve w/Fe administ.

• Tx: Uncomplicated/Mild Fe Deficiency: PO Fe. Ferrous salts ↑ solubility & absorption but ↑ GI tox. Ascorbic acid → ↑ absorption. ↓ Absorption w/antacids, full meals, whole grains, tannins & Ca supplements. Fe sulfate = 66 mg elemental Fe per 325-mg tab.

Complicated Fe Deficiency: Parenteral Fe in true ↓ absorption, gastric or duodenal resection, ↑ Fe deficit, PO Fe intolerance & chronic bleeding.

Fe Dextran: ↓↓cost. Can replete Fe in one infusion. ↑ Risk anaphylaxis (11.3/1000000) → small test dose. Fe Sucrose & Fe Gluconate: ↓↓↓ Rate anaphylaxis → no test dose. A/w arthralgias/myalgias. ↑↑ cost.

Response: ↑ Retics after 4–7 d & ↑ Hb starts 1–2 wks post-tx. Anemia responds over wks (cont tx to replete Fe store). Ferritin ∼ Fe store.

Anemia of Chronic Inflammation (AOCI) (N Engl J Med 2005;352:1011)

• Hypoproliferative anemia (functional Fe def) a/w chronic inflammation: CTD, other autoimmune disorders, chronic infxn, & malignancy.

• Also in post-trauma/–surgery & critical illness. Commonest anemia in hospital.

• Mild/mod. (Hb rarely <7 g/dL) anemia. Sometimes ↑ ESR/CRP.

• Pathogenesis: ↑ Cytokines (TNFα, IL-1, IL-6, IFNs) →↓ response to EPO in RBC precursor, ↓ EPO c/w anemia degree, & mod. ↓ RBC survival.

Altered Fe metabolism (Blood 2003;102:783): ↑ IL-6 →↑ hepcidin →↓ intestinal Fe absorption/↓ Fe release from enterocytes →↓ plasma Fe/Fe def.

• Dx: Nl chromic. Nl/↓ MCV. Nl to ↑ RDW. ↓ to nl Fe. ↓ to low nl TIBC. ↓ Fe sat.

Nl to ↑↑ ferritin. Experimental: Nl sol transferrin receptor/↑ Hepcidin.

• Tx: Tx Fe def if present (Low nl ferritin). Most mild cases resolve w/Tx 1° condition. EPO administration in sev. disease

Megaloblastic Anemia (ASH-SAP 2010;1:109) (N Engl J Med 2013;368;149)

Impaired DNA synthesis → RBC lineage usu affected before other cells

Blood Smear: ↑ MCV earliest sign. Hypersegmented PMNs (≥5% w/5 lobes & some w/≥6 lobes). Macroovalocytes. Cabot Rings. Howell–Jolly Bodies. Promegaloblasts. ↑↑ MCV but may be ↓ /nl w/concurrent microcytic process.

BM: ↓ M:E ratio. ±↑ RS. Other Labs: ↑ LDH, ↑ indirect bili. & ↑ UA.

• Folate Deficiency: Duodenum/proximal jejunum absorption. No A/w neuro sxs.

Etiologies: ↓ Intake, ↓ absorption, ↑ use (chronic hemolysis), drug interaction.

↑Risk in alcoholics, elderly, TPN w/o supplemental folate, duodenal or jejunal resection/infiltration, celiac disease, chronic hemolysis.

Dx: ↓ Serum folate ± RBC folate (may better reflect folate def but also ↓ in B12 Def), ↑ homocysteine, nl methylmalonic acid (MMA). Also a/w falsely ↓ B12 in some cases.

Tx: R/O Ø B12. ↓ Folate: ↑ doses PO folate (1–5 mg/d). Ppx prenatal/pregnancy.

• B12 Deficiency: Multiple steps for dietary B12 absorption in terminal ileum.

Intake (no animal products/vegans). Hypochlorydia (age, PPIs, atrophic gastritis). ↓ Pancreatic Proteases. ↓ Binding B12 & IF (bacterial overgrowth, Diphyllobothrium, pernicious anemia, & gastric resection). ↓ Absorption w/Meds (cholestyramine, colchicine, & metformin). Ileal Resection/Dysfunction (Celiac, NHL, Crohn’s, etc.).

A/w neuropsych sxs: ↓ vibriosensation, spastic paralysis, psychosis/dementia.

Full B12 stores take longer to deplete than folate stores: ∼ few y.

Dx: Subclinical B12 Def (↑ in elderly): Low nl B12, ↑ homocysteine, ↑ MMA.

Clinical B12 Def: ↓ B12, ↑↑ homocysteine, ↑↑ MMA.

Tx: Beware folate supp only correcting anemia & not neuro sxs. IM B12 1 mg/d × 14 d → 1 mg/wk until anemia resolves → 1 mg/mo.

Some respond to PO B12. Quick Δ to parenteral B12 if PO not working.

• Other Megaloblastic Anemias: Pyrimidine Analog

(5-FU), Purine Analog (AZA), DNA Synthesis Inhibitor (cytarabine), Antifolate (MTX), RNA Reductase Inhibitor (hydroxyurea), PPI, NO, Antiepileptic, zidovudine.

• Macrocytic Anemias w/Similar Morphologic Δ’s: Myelodysplasia, erythroleukemia, Lesch–Nyhan Syndrome, Hereditary Orotic Aciduria.

Other Nutrional Deficiency (see table)

↑ Starvation/Anorexia Nervosa: Normochromic/normocytic anemia → BM necrosis.

↓ Cu: Malnourished infants/adults ± TPN. Postbarriatric surgery/gastrectomy. ↑ Zn intake →↓ Cu absorbed → reversible myelodysplasia/sideroblastic anemia.

Endocrinopathy

Gen: Usu mild anemia. Often asymptomatic.

• Hypothyroidism: A/w pernicious anemia (check for ↓ B12). Nl to ↑ MCV. ↓ T3, ↓ T4, ↓ rT3 → ↓ EPO-stimulated erythroid colony formation.

• ↓ Androgens: A/w 1–2 g/dL ↓ Hb. Androgens → ↑ EPO production/response.

• ↓ Cortisol: ↓ RBC mass often masked by ↓ plasma volume.

• ↑ PTH: Potential PTH myelotoxicity & a/w bone remodeling/myelosclerosis.

EPO Deficiency

• CRI/ESRD → ↓ renal cortex peritubular capillary lining cells & ↑↑ uremia → ↓ EPO.

• CKD Anemia a/w nl MCV/normochromic unless concurrent other process.

• Echinocytes in ↑↑ CKD. BM normocellular (hypocellular in long-standing 2° ↑ PTH → osteitis fibrosa). Tx: Follow Fe Sat/ferritin & replete Fe stores. ESA Tx: Goal Hb recs Δ’d in recent y. Balance ↑ QoL vs. ↑ mort, CV, thrombotic outcomes? → esp w/solid tumor. TREAT (N Engl J Med 2009;361:2019). CHOIR (N Engl J Med 2006;355:2085). EPO-CAN-20 (J Clin Oncol 2007;25:1027).

• EPO Resistance: ∼25% HD pts w/some EPO resistance. A/w ↑ inflamm (↑ IL-6).

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Clonal HSC disorder w/Coombs neg intravascular hemolysis & ↑ thrombosis risk → pancytopenia → AA. Blood cells sensitive to activated C′. Dx: ↓ CD55 (DAF) & ↓ CD59 (MIRL) on flow cytometry. Somatic Mt pig-A. Tx w/eculizumab (anti-C5 mAb) → inhibit terminal C′.