Megaloblastic Anemia
Julie Adkins, Jill C. Cash, Beverly R. Byram, Cheryl A. Glass, Kristin Ownby, and Pat Obulaney
Definition
A.Megaloblastic anemia is characterized by abnormally large nucleated red blood cell (RBC) precursors. Ninety-five percent of cases are due to vitamin B12 or folic acid, Which occurs when there is a failure of DNA synthesis but RNA synthesis remains unimpaired. The inability to synthesize DNA leads to abnormally large erythroid precursors and RBCs.
B.Pernicious anemia is a type of vitamin B12 deficiency anemia. It is a megaloblastic, macrocytic, normochromic anemia caused by a deficiency of intrinsic factor in the gastric juices produced by the stomach, which results in malabsorption of vitamin B12 necessary for DNA synthesis and maturation of RBCs. There is the production of abnormally large and oval red cells with a mean corpuscular volume (MCV) in excess of 100 fL (femtoliters). The anemia can be severe, with hematocrit (Hct) as low as 10% to 15%.
Incidence
A.The prevalence of vitamin B12 deficiency anemia varies with age: less than 3% in adults between the ages of 20 to 39; 4% of those aged 40 to 59; and 6% for those adults over 70 years old. Twenty percent of adults age 60 or greater have suboptimal vitamin B12 levels with the risk increasing with age. Identified in 30% of diabetic patients taking metformin.
B.Pernicious anemia is common in people of northern European descent. Both sexes are equally affected. It is most prevalent in Scandinavian and English-speaking populations. It usually occurs in the fifth and sixth decades of life; it is rarely seen in persons younger than 35 years, but it can occur in individuals in their 20s. There is an increased incidence in those with other immunologic diseases. The average age of diagnosis is 60. Rarely is pernicious anemia passed down through families. Perncious anemia accounts for 20% to 50% of vitamin B12 deficiency anemia.
C.Less than 1% of the U.S. population is diagnosed with folic acid deficiency related anemia. Approximately 3,000 pregnancies are affected by neural tube defects annually in the United States. Estimates are 11% of chronic alcoholics are folic acid deficient.
Pathogenesis
A.Megaloblastic anemia is caused by deficiency or impairment of utilization of vitamin B12 or folate. Nonmegaloblastic anemia maybe result of liver dysfunction, alcoholism, myelodysplastic syndrome (MDS), or hypothyroidism.
B.Pernicious anemia is possibly due to an autoimmune reaction involving the gastric parietal cell that results in nonproduction of intrinsic factor and atrophy of gastric mucosa. Vitamin B12 deficiency can result from inadequate intake, impaired absorption, increased requirements as in pregnancy, or faulty utilization. Poor intake is rare, occurring most often in strict vegetarians. You get this vitamin from eating foods such as meat, poultry, shellfish, eggs, and dairy products.
Predisposing Factors
A.Vitamin B12 deficiency anemia:
1.People of northern European descent identified as a risk factor for pernicious anemia,
2.Persons over 50 years of age and older,
3.Vegetarian or vegan diet,
4.History of bariatric surgery,
5.Fish tapeworms,
6.Ileostomy, ileal resection, or abnormalities,
7.Atrophic gastritis and achlorhydria mostly in the elderly,
8.Exposure to nitrous oxide,
9.Certain medications including acyclovir, zidovudine, fluorouracil, metformin, proton pump inhibitors (PPIs) oral estrogen contraceptives,
10.Congenital enzyme deficiencies,
11.Autoimmune disorder causing a lack of intrinsic factor leads to pernicious anemia. Medical conditions include Addison’s disease, Graves’ disease, type I diabetes mellitus, or myasthenia gravis.
B.Folate deficiency anemia:
1.Dietary deficiency especially during pregnancy, lactation,
2.Improper food preparation; especially common in the elderly,
3.Alcoholism.
4.Renal dialysis.
5.Psoriasis.
6.Certain medications including phenytoin, methotrexate, valproic acid.
C.Combination of vitamin B12 and folate deficiency anemia):
1.Crohn’s disease.
2.Hypothyroidism.
Common Complaints
A.Weakness and dizziness.
B.Tongue is sore, red, and shiny.
C.Numbness, burning, tingling sensation of arms or legs.
D.Feel heart jumping out of skin.
E.Edema of lower extremities.
F.Anorexia.
G.Diarrhea.
H.Low-grade fevers.
Other Signs and Symptoms
A.Mild anemia:
1.Dyspnea on exertion.
2.Pallor.
3.Weakness.
4.Fatigue.
B.Severe anemia:
1.Pallor.
2.Fatigue.
3.Tachycardia.
4.Exercise intolerance.
5.Angina.
6.Glossitis.
7.Mucositis.
8.Peripheral paresthesia.
9.Palpitations.
10.Abdominal tenderness, organomegaly.
11.Advanced stages: Dementia and depression; spinal cord degeneration.
Classic presentation involves sore tongue and numbness and tingling in the extremities, hands, or feet.
Subjective Data
A.Inquire about onset, duration, and course of presenting symptoms.
B.Ask the patient to describe usual bowel habits. Has there been any blood in stools?
C.If gastrointestinal (GI) complaints are present, inquire about presence of red, burning tongue, abdominal complaints, presence of diarrhea or constipation, abdominal pain, pale colored stool, or stool that floats.
D.If neurologic complaints are present, inquire about presence of pins-and-needles paresthesia and
weakness, unsteadiness due to proprioceptive difficulties, lethargy, and fatigue.
E.Evaluation of diet: Is the patient a vegetarian or vegan or anorexic? Does the patient follow a fad diet?
F.Ask about alcohol consumption: How much? How long? Any history of pancreatitis?
G.Obtain medication history: Over-the-counter (OTC)and prescription drugs.
H.Obtain past medical history, specifically if the patient has a history of gastrectomy, gastric bypass/banding, resection of ileum, or other GI disorders.
I.Review usual weight and recent loss.
J.Inquire about low-grade fevers
Physical Examination
A.Check temperature, pulse, respirations, blood pressure, weight. One-third of patients experience low-grade fever.
B.Inspect:
1.Observe general, overall appearance; observe walking.
2.Conduct oral exam for characteristic red, shiny tongue.
3.Conduct dermal and eye exams for color: Affected patients are slightly icteric.
4.Evaluate the look of the person related to age: Affected patients show premature aging or graying.
C.Palpate:
1.Palpate the abdomen for masses. Splenic tip palpable in 20% of patients.
2.Evaluate pedal edema.
D.Percuss: Percuss the abdomen.
E.Auscultate:
1.Auscultate heart sounds and lungs.
2.Auscultate the abdomen for bowel sounds.
F.Neurologic exam: Assess deep tendon reflexes (DTRs), proprioception, vibratory sense, and mental status:
1.Look for paresthesia involving hands and feet, gait disturbances, or memory loss (mild forgetfulness to dementia or altered thought processes). Poor finger–nose coordination may be seen; positive Romberg’s and Babinski’s signs may be present.
2.Severe B12 deficiency can result in ataxia, impaired proprioception, and vibratory sensation.
Diagnostic Tests
A.Complete blood count (CBC) with differential and peripheral smear: Macroovalocytes and hypersegmented neutrophils may be present on peripheral blood smear. (They are absent in the setting of concurrent iron deficiency.)
B.Serum vitamin B12 level: Less than 100 200 pg/mL. Suboptimal vitamin B12 levels 200 to 350 pg/mL.
C.Serum folic acid levels, serum iron, serum ferritin, and total iron-binding capacity (TIBC).
D.Serum anti-intrinsic factor antibody (anti-IFAB) to rule out pernicious anemia.
E.Lactate dehydrogenase (LDH).
F.Urinalysis.
G.Stool for occult blood.
H.Indirect bilirubin.
I.GI radiographic studies.
J.Gastric analysis: Achlorhydria is found on stimulation testing.
K.Bone marrow aspiration.
L.A woman with low B12 levels may have a false positive Pap smear due to vitamin B12 effects on the epithelial cells.
M.Confirmatory test includes methylmalonic acid and homocysteine levels:
1.Methylmalonic acid and homocysteine levels are elevated with vitamin B12 deficiency.
2.Methylmalonic acid level is normal and homocysteine level elevated with folate deficiency.
Differential Diagnoses
Differential diagnosis of anemia by red cell morphology can be undertaken (MCV, mean corpuscular hemoglobin concentration [MCHC]). Common causes of each type of anemia are as follows:
A.Normochromic, normocytic: Normal MCV = 80 to 100, MCHC = 32% to 36%:
1.Aplastic anemia.
2.Chronic disease including cancer, heart failure, HIV.
3.Early iron deficiency.
4.Hemolysis.
5.Hemorrhage.
B.Microcytic: MCV = 50 to 82, MCHC = 24 to 32:
1.Chronic disease.
2.Iron deficiency.
3.Thalassemia.
C.Macrocytic: MCV greater than 100, MCHC greater than 36:
1.Antimetabolites.
2.Folic acid deficiencies.
3.Vitamin B12 deficiencies including pernicious anemia.
4.Chronic alcoholism.
Note: Iron deficiency anemia can mask megaloblastic anemia.
Plan
A.General interventions:
1.Most common method of determining vitamin B12 deficiency is by serum vitamin B12 assay.
2.Most common method of demonstrating folate deficiency is by measurement of serum folic acid levels.
3.Red cell indices and peripheral smear should be done to determine classification of anemia to facilitate workup.
4.Red cell distribution width (RDW) determination can assist in detecting red cell heterogeneity previously available only by exam of the peripheral smear. The RDW determination overcomes the problems of detecting coexisting microcytic and macrocytic anemias.
B.Patient teaching:
1. 
See Section III: Patient Teaching Guide “Vitamin B12 Including Pernicious Anemia.”
2.Neurologic symptoms usually improve with treatment; however, some neurologic deficits may not be reversible.
C.Pharmaceutical therapy:
1.Bariatric patients should receive 350 to 500 mcg oral daily or 1,000 mcg parenterally monthly for life as prevention. If anemic, then follow protocol for pernicious anemia.
2.Perncious anemia or patients with symptomatic anemia including neurological findings require daily injections of 1,000 mcg of vitamin B12 for 1 week, followed by 1,000 mcg every week for 4 week. Patients with pernicious anemia will require intramuscular (IM) injections of 1,000 mcg monthly for life.
3.If anemic patient is able to ingest and absorb vitamin B12, then may prescribe 1,000 to 2,000 mcg per day orally. Continue until RBC indices and vitamin B12 in normal range. If anemic patient has neurological findings, then consider parenteral administration.
4.Consider B12 supplementation in patients over 50 years of age if not meeting their RDA of B12 through fortified food:
a.Recommended daily allowance for vitamin B12:
i.Adults: 2.4 mcg/d.
ii.Pregnant women: 2.8 mcg/d.