ANEMIA, IRON DEFICIENCY - Bruce Block, MD
BASICS
DESCRIPTION
• Anemia due to decreased iron stores
• Poor iron utilization and poor iron re-utilization (e.g., anemia of chronic disease) are also due to iron deficiency, but iron stores are not depleted.
• Onset may be acute with rapid blood loss or chronic with poor diet or slow blood loss.
• Most common cause of anemia in the United States.
• System(s) Affected: Hemic/Lymphatic/Immunologic
• Synonym(s): Anemia of chronic blood loss; Hypochromic; Microcytic anemia; and Chlorosis
ALERT
Geriatric Considerations
60% of anemias in people >65 years
Pediatric Considerations
Frequent problem in infants whose major source of nutrition is cow's milk and juices.
Pregnancy Considerations
Common during pregnancy unless iron supplements are included in the diet.
GENERAL PREVENTION
• Good nutrition with adequate iron intake
• Correction of gynecologic or other problems causing excess blood loss
EPIDEMIOLOGY
• Predominant age: All ages, but especially toddlers and menstruating women.
• Predominant sex: Female > Male
Incidence
• Adults: 7-10%
• Infants and toddlers: 10-20%
• Pregnant patients: 15-45%
Prevalence
• Most likely in the poor and in underimmunized children
ETIOLOGY
• Blood loss (e.g., menses, GI bleed)
• Poor iron intake
• Poor iron absorption (e.g., postgastrectomy)
• Increased demand for iron (e.g., infancy, adolescence, and pregnancy)
• Hookworm infestation
• Gastric carcinoma
DIAGNOSIS
SIGNS AND SYMPTOMS
• Asymptomatic in most cases
• Cheilosis
• Dyspnea on exertion, fatigue, tachycardia, palpitation, or vasomotor disturbances
• Effects of underlying GI ulceration, neoplasm, uterine disorders, or bleeding varices
• Headache, inability to concentrate, irritability, listlessness
• Neuralgic pain, peripheral paresthesias
• Pica (dirt, paint, ice)
• Spoon-shaped, brittle nails
• Susceptibility to infection
TESTS
• Stool guaiac; if positive, GI endoscopy, stool for O P, clotting studies
• Rule out thalassemia: Review prior CBCs for persisting mild anemia and marked micro-ovalocytosis, elevated hemoglobin A2 or hemoglobin F, family history, and especially high or high normal RBC count
• Rule out G6PD deficiency: Assay at least 6 weeks after last drop in hemoglobin
• Rule out poor re-utilization: Trial of iron (oral or parenteral), bone marrow aspiration, and iron stain
• Rule out gastric carcinoma, especially in the elderly
Lab
• Ferritin, repeat CBC with differential, peripheral smear
• Stainable iron in bone marrow aspiration is the gold standard
• Low serum ferritin is the best noninvasive test in adults, but it may miss some deficient patients, because ferritin is an acute phase reactant.
• Fe/total iron binding capacity (transferrin ratio) is no longer recommended, because it is less sensitive and less specific than ferritin.
• A peripheral smear usually shows hypochromia and microcytosis, but may be normal.
• Hemoglobin is usually lower than 12 g/dL, but patients with higher premorbid hemoglobin (such as smokers and patients with chronic hypoxemia) may be anemic at higher hemoglobin levels. Abnormal values for infants and toddlers, and for pregnant persons, are 10.5-11.0 g/dL.
• A low RBC count in chronic bleeding helps to distinguish it from thalassemia trait where the count is high or high-normal.
• Microcytosis with ovalocytosis and anemia unresponsive to iron suggest the thalassemia trait.
• A low MCV may be absent in mild anemia, or hidden by the population of larger cells (e.g., reticulocytes or macrocytes).
• An empiric trial of iron at 3 mg/kg/d may be the best way to diagnose decreased iron stores in infants and children, if reticulocytes are elevated in 7-10 days or hemoglobin is increased >1.0 g/dL after 4 weeks.
• Drugs that may alter lab results: Iron supplements or multivitamin-mineral preparations that contain iron
• Disorders that may alter lab results:
- Ferritin elevated by acute liver disease, cirrhosis, Hodgkin disease, acute leukemia, solid tumors, fever, acute inflammation, renal dialysis
- Hemoglobin may be elevated by smoking or chronic hypoxemia, thereby hiding anemia if standard anemia limits are used.
Imaging
GI endoscopy to discover occult bleeding sites
Pathological Findings
• Absent marrow iron stores
• Marrow: Hyperplastic, micronormoblastic
DIFFERENTIAL DIAGNOSIS
• Bone marrow aspiration
• Sigmoidoscopy
• Gastroscopy
• Colonoscopy
• Defective iron utilization (e.g., thalassemia trait, sideroblastosis, G6PD deficiency)
• Defective iron re-utilization (e.g., infection, inflammation, cancer, other chronic diseases)
• Hypoproliferation (e.g., decreased erythropoietin from hypothyroidism, renal failure, etc.)
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
• Search for the cause and correct it. There can be no excuse for not searching for a bleeding site.
• Avoid transfusions except in rare cases.
Diet
• Limit milk to 1 pint a day (adults).
• Emphasize protein-containing and iron-containing foods (meat, beans, and leafy green vegetables).
• Increase dietary fiber to decrease likelihood of constipation during iron replacement therapy.
• Do not consume milk, other dairy products, antacids, or tetracycline within 2 hours of the drug dosage.
Activity
Patients with hypoxemia, low cardiac output, or angina may require reduced activity prescriptions.
MEDICATION (DRUGS)
First Line
• Ferrous sulfate 300 mg t.i.d. on an empty stomach 1 hour before meals is an ideal dose that provides 180 mg of elemental iron a day.
- Dose can be reduced as needed for GI symptoms, which affect 15% of patients on standard iron therapy, or the dose can be taken with meals, which may reduce the delivery of iron by 50%.
- People with a moderate anemia (hemoglobin = 10 g/dL) need only 1,500-2,000 mg of elemental iron replacement. Reducing the amount of iron per dose as much as necessary to abate symptoms will make parenteral iron therapy unnecessary in almost all cases.
- Special iron formulations and compounds are very expensive and reduce symptoms only to the degree that they reduce the delivery of iron.
• Liquid iron preparations are useful for children with a recommended dose of 3 mg/kg/d given in a single dose. They can be also used in adults when low tolerance to iron pills requires a reduction of dosage.
• Vitamin C provides acidification to reduce the iron and thus increases absorption.
• Continued bleeding is often the cause for "failure to respond" to iron.
• Consider parenteral iron for patients with malabsorption, if higher doses and use of vitamin C fail.
• Contraindications
- Antacids concomitantly
- Tetracycline concomitantly
• Precautions
- Iron preparations cause black bowel movements.
- Iron overdose is highly toxic. Patients should be instructed to keep tablets and liquids out of the reach of small children.
• Significant possible interactions
- Allopurinol
- Antacids
- Penicillamine
- Tetracyclines
- Vitamin E
FOLLOW-UP
PROGNOSIS
Curable with iron therapy if the underlying cause can be discovered and cured
COMPLICATIONS
Neglecting to identify hidden bleeding points, particularly a bleeding malignancy
PATIENT MONITORING
Regularly after return to normal (in order to detect recurrences)
REFERENCES
1. Adams WG, et al. Anemia and elevated lead levels in underimmunized inner-city children. Pediatrics. 1998;101.
2. Farrell R, LaMont JT. Rational approach to iron-deficiency anaemia in premenopausal women. Lancet. 1998;352:1953-1954.
3. Fireman Z, Kopelman Y, Sternberg A. Endoscopic evaluation of iron deficiency anemia and follow-up in patients older than age 50. J Clin Gastroenterol. 1998;26:7-10.
4. Lee RG, Bithell TC, et al. Wintrobe's Clinical Hematology. 9th ed. Philadelphia, PA: Lea Febiger; 1993.
5. Van den Broek, et al. Iron status in pregnant women: Which measurements are valid? Br J Haematol. 1998;103:817-824.
6. Waterbury L. Anemia. In: Barker LR, Burton JR, Zieve PD, eds. Principles of Ambulatory Medicine. 4th ed. Philadelphia, PA: Lippincott Williams Wilkins; 1995:593-607.
7. Williams WJ, Beutler E, Erslev AJ, et al., eds. Hematology. 4th ed. New York, NY: McGraw-Hill; 1990.
Wednesday, December 31, 2008
ANEMIA, IRON DEFICIENCY
ANEMIA, AUTOIMMUNE HEMOLYTIC
ANEMIA, AUTOIMMUNE HEMOLYTIC - Kerry J. Murphy, MD
BASICS
DESCRIPTION
• Acquired anemia induced by binding of autoantibodies to RBC membrane antigens
• 3 main types defined by maximal binding temperature of the autoantibodies
- Warm (37C [98.6F]) reacting IgG antibody
- Cold (0-4C [32-39.2F]) reacting IgM antibody
- Mixed type: Both warm IgG and cold C3 reacting antibodies
- Drug induced: Mostly warm IgG reacting antibodies
- System(s) Affected Hematopoietic/lymphatic/immunologic
GENERAL PREVENTION
None known
EPIDEMIOLOGY
• Predominant age: 50 years
• Predominant sex: Female > Male
ALERT
Geriatric Considerations
Unusual in this age group; rule out neoplasia.
Pediatric Considerations
May occur in pediatric age group
Incidence
4/100,000 per year
RISK FACTORS
• Malignancy
• Autoimmune disorders
• Infection
• Medications
• Prior blood transfusion
• Prior hematopoietic cell transplant
Genetics
Unknown
PATHOPHYSIOLOGY
• Warm autoimmune hemolytic anemia (AIHA)
- IgG attaches to RBCs, which are then ingested by macrophages of the spleen.
• Cold AIHA
- IgM binds RBC surface temporarily, activates complement, deposits C3 on cell surface, and RBCs are ingested by macrophages of the liver.
- Rarely, complete complement cascade activated with membrane attack complex insertion causing intravascular hemolysis.
• Mixed antibody AIHA: Both warm IgG and cold C3 involved.
• Drug induced
- Hapten induced: Drug attaches to rbc membrane inducing IgG production.
- Immune complex: Drug-IgM immune complex binds RBC membrane, activating complement.
- Autoantibody: Drug induces production of anti-RBC IgG.
ETIOLOGY
• Warm antibody (48-70% cases)
- Primary cause: Idiopathic
- Secondary causes
Lymphoproliferative disorders (CLL, Hodgkin disease, NHL)
Autoimmune disorders
Viral infection (especially in children)
• Cold antibody
- Cold agglutinin syndrome (CAS) (16-32%):
Acute: Infection (mycoplasma, mononucleosis, viral)
Chronic: Lymphoproliferative disorders (lymphoma)
- Paroxysmal cold hemoglobinuria
Infection
• Mixed type
- Idiopathic
- Secondary to lymphoproliferative or autoimmune disorders
• Drug induced
- Penicillin: Hapten induced
- Quinine: Immune complex
- -Methyldopa: Autoantibody induced
ASSOCIATED CONDITIONS
• Evans syndrome
• Systemic lupus erythematosus
• Chronic lymphocytic leukemia
• Diffuse lymphomas
DIAGNOSIS
SIGNS AND SYMPTOMS
History
• Weakness/fatigue
• Exertional dyspnea
• Dizziness
• Palpitations
• Malaise
• Association with cold (CAS)
Physical Exam
• Pallor
• Jaundice
• Splenomegaly
• Hepatomegaly
• Tachycardia
• Flow murmur
• Blue gray discoloration of acral surfaces (CAS)
TESTS
Lab
• Direct Coombs' (DAT direct antiglobulin test)
- Positive test indicates presence of antibodies or complement on RBC surface.
• CBC
- Anemia (normocytic, normochromic); may be sudden and life threatening
- Mild to moderate increase in mean corpuscular volume (MCV) depending on level of reticulocytosis
- Increased mean cell hemoglobin concentration (MCHC)
- Spherocytosis
- Poikilocytosis
- Anisocytosis
- Rouleaux
- Reticulocytosis
- Nucleated RBC
- Large polychromatophilic reticulocytes
• Hyperbilirubinemia (unconjugated)
• Decreased haptoglobin
• Elevated LDH
• Hemoglobinemia
• Serology
- IgG antibody (warm, mixed, drug-induced, paroxysmal hemoglobinuria)
- IgM antibody (cold)
• Urinalysis
- Hemoglobinuria, hemosiderinuria
Pathological Findings
• Peripheral blood smear
- Spherocytes, schistocytes
• Bone marrow biopsy
- Bone marrow hyperplasia, increased marrow hemosiderin
DIFFERENTIAL DIAGNOSIS
• Other hemolytic anemias
• Autoimmune thrombocytopenic purpura (ITP)
• Evans syndrome
• Microangiopathic hemolytic disorders
• Aplastic anemia
• Megaloblastic anemia
TREATMENT
GENERAL MEASURES
• Warm antibody
- Folic acid supplementation
- Mild and moderate: See "Medications"
- Severe
Plasmapheresis as a temporizing measure for refractory or life threatening anemia (1)[C]
Packed RBC transfusion for life-threatening anemia (difficult to cross-match; need special blood bank techniques; in emergency, use most compatible cross-match (2)[C]
• Cold antibody
- Cold agglutinin syndrome
Avoid cold, maintain high temperatures indoors, wear additional clothing outdoors
Folic acid supplementation
Plasmapheresis as a temporizing measure for refractory or life-threatening anemia (1)[C]
Packed RBC transfusion for life-threatening anemia (2)[C]
• Paroxysmal cold hemoglobinuria
- Supportive care
• Mixed
- Steroids, splenectomy, and immunosuppressives as in warm AIHA
• Drug-induced
- Stop the offending drug.
- Plasmapheresis/exchange transfusion for severe life-threatening cases
Diet
No special diet
Activity
• Rest until asymptomatic.
• Avoid contact sports if splenomegaly is present.
MEDICATION (DRUGS)
First Line
• Warm antibody
- Glucocorticoids: Prednisone 1 mg/kg/d PO in divided doses
70-80% patients improve within 3 weeks
Taper gradually to 20 mg/d over 2 weeks
May require maintenance dose 10 mg every other day (1)[A]
- Precautions: Significant side effects with long-term use
• Cold antibody
- Malignancy induced: Chemotherapy
- Rituximab for cold AIHA due to chronic lymphoproliferative disorders (1)[C]
• Mixed antibody
- Prednisone as in warm AIHA
Second Line
• Warm antibody
- Immunosuppressive drugs: Recommended for patients who fail splenectomy, relapse after splenectomy, cannot tolerate corticosteroids, and nonsurgical candidates
Cyclophosphamide 50 mg/kg/d for 4 days followed by GCSF for those with refractory anemia (2)[C]
Precautions: Monitor for marrow suppression
Azathioprine (Imuran) 1-2 mg/kg/d within 2 weeks of starting steroids if not responding (3)[C]
Cyclosporine 5-10 mg/kg/d in 2 divided doses
Rituximab (anti-CD20 monoclonal Ab) 375 mg/m2 once weekly for 2-4 weeks for children and refractory cases
Mycophenolate mofetil 500-1000 mg/d in 2 divided doses; increase to 1-2 g daily (2)[C]
- Other medical therapies for refractory cases
Danazol 600-800 mg/d PO
IVIG (1)[C]
• Mixed antibody
- Immunosuppressives if refractory to steroids and splenectomy
SURGERY
• Warm antibody
- Splenectomy is the preferred second-line treatment for warm AIHA for those who have failed steroids.
50% initial response rate
Patients may require low-dose maintenance prednisone 15 mg daily
Post splenectomy: Vaccinate against encapsulated organisms such as pneumonococcus and meningococcus (2)[A]
• Cold antibody
- Surgery not recommended
• Mixed antibody
- Splenectomy
FOLLOW-UP
PROGNOSIS
• Good with appropriate treatment
• Determined by course of the primary disease If secondary to an underlying disorder
COMPLICATIONS
• Shock (severe anemia)
• Venous thromboembolism
• Thrombocytopenic purpura (Evans syndrome)
• Lymphoproliferative disorders in warm AIHA
• Post splenectomy sepsis syndrome
PATIENT MONITORING
• Monitor carefully if transfusion essential
• Use only warm IV fluids and blood products for cold AIHA
• Avoid hypothermic surgical procedures for cold AIHA
REFERENCES
1. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Amer J Hematol, 2002;69:258-271.
2. King KE, Ness PM. Treatment of autoimmune hemolytic anemia. Sem in Hematology, 2005; 42:131-136.
3. Pruss A, Salama A, Ahrens N, Hansen A, Kiesewetter H, Koscielny J, Dorner T. Immune hemolysis-serological and clinical aspects. Clin Exp Med, 2003;3:55-64.
