1. Drug Induced Macrocytic Megaloblastic Anemia
DTP Group C
Research: Sunil Bacharanianda
Group Leader: Siobhan Taylor
Narration: Ervin Magic
Scribe: Tara Duesbury
June 16, 2014

2. Hematology Case 3 Overview
History
Physical Examination
Lab Investigations: results and interpretation
Assessment: DDx and most likely Dx
Management
Prognosis and Patient education

3. History
37 year old male. seizure disorder since age 2. At routine neurology check, complained of feeling fatigued, shortness of breath on exertion, and lightheadedness over the past month or so.

4. Additional Relevant History Questions
Any weakness, paresthesias of fingers and toes, loss of coordination of legs, tremors, irritability, somnolence?
Any weight loss, decreased appetite, abdominal pain, night sweats, chronic cough?
Any gastritis, hemoptysis, hematemesis, melena, bleeding disorder?
Is he on a restricted or vegan diet?
Does he have a malabsorption disorder (ie. Short bowel syndrome, Crohn’s disease, Tropical sprue)?
Does he consume excessive alcohol?
Past medical history of: liver disease, thyroid disease, tuberculosis, malignancy or exfoliative dermatitis?
Which medications is he taking for seizures (ie. Phenytoin/Primidone/Phenobarb)? Any recent change in dosage?
Is he on  medications such as Antineoplastic agents, Zidovidine, Methotrexate, Sulpha drugs, Proton pump inhibitors, Metformin, Colchicine, Neomycin or Para-aminosalicylic acid?

5. Physical Exam
Skin pallor noted. Otherwise, physical exam was unremarkable.

6. Laboratory Investigations
RBC 1.24 x 1012/L Hgb 58 g/L Hct MCV 131 fL MCHC 348 g/L RDW WBC 6.1 x 109/L Neutrophils 73 % Lymphocytes 21% Monocytes 1% Eosinophils 4% Basophils 1% Platelets 219 x 109/L
Blood Smear Analysis Red blood cells Normochromic 2+ macrocytosis 2+ anisocytosis many oval macrocytes Occasional teardrop cells and fragments WBC morphology Multiple neutrophils with nuclear hypersegmentation Platelets normal

7. Laboratory Investigations
Bone marrow biopsy:
Numerous Howell Jolly bodies. Increased number of erythroids with megaloblastic maturation.
Neutrophils show premature nuclear segmentation. Giant metamyelocytes and band forms. 
Chemistry:
Serum folate <2 nmol/L
Serum B pmol/L
RBC folate 297 nmol/L

8. Interpretation of Lab Results
Low RBC, Hb, and Hct with raised RDW:
Indicates NORMOCHROMIC ANEMIA
High MCV, normal WBC and normal platelets:
Indicates MACROCYTIC NORMOCHROMIC ANEMIA (w/o pancytopenia)
Blood smear:
RBC: 2+ oval macrocytes, 2+ anisocytosis, teardrop cells; WBC: PMN hypersegmented nuclei
Indicates MACROCYTIC MEGALOBLASTIC ANEMIA
Bone marrow:
Increased erythrocytes with megaloblastic maturation, neutrophils nuclear segmentation, giant metamyeloctes, and band forms present
Chemistry:
Decreased folate levels (<2nm/L) , Normal RBC folate level (297 nm/L), Reduced Serum Vit B12 (100 pmol/L):
Indicates MACROCYTIC MEGALOBLASTIC ANEMIA due to FOLATE and VIT B12 DEFICIENCY

9. Differential Diagnosis with brief explanation of rationale
Macrocytic Megaloblastic Anemia secondary to Folic Acid/Vit B-12 deficiency (due to chronic anti-epileptic drug intake)
Low serum folate, oval macrocytes, PMN hypersegmented nuclei, normal WBCs and platelets
2) Macrocytic Megaloblastic Anemia secondary to Folic Acid/Vit
B-12 deficiency (nutritional, malabsorption, pernicious anemia)
Low serum folate and Vitamin B-12 levels
3) Macrocytic Normoblastic Anemia (secondary to other drugs,
alcoholism, liver disease, hypothyroidism, and reticulocytosis)
Low Hb, Hct, RBC, and high RDW
However, megaloblastic anemia and oval macrocytes go against diagnosis
4) Myelodysplasia
Macrocytic anemia with normoblastic changes, pancytopenia (not present)

10. Most Likely Diagnosis with brief explanation of rationale
Macrocytic Megaloblastic Anemia secondary to Folic acid and Vit B-12 deficiency (due to chronic anti-epileptic drug (AED) intake):
Chronic use of AED may have:
Led to reduced absorption of folic acid and associated Vit B-12 deficiency  resulting in macrocytic megaloblastic anemia
Diagnosis confirmed with:
Blood work (low Hb, Hct and RBC, high RDW, High MCV, normal WBC and platelets)
Blood smear (oval macrocytes, PMN with hypersegmented nuclei, normochromic RBCs, anisocytosis)
Bone marrow report (Howell Jolly bodies, neutrophils with premature segmentation, giant metamyelocytes)
Serum levels (low folic acid and Vit B-12 levels)

11. Pathophysiology Macrocytic Megaloblastic Anemia:
Failure of DNA synthesis results in asynchrony between the maturation of the nucleus and cytoplasm of the hematopoietic cells. [1]
AEDs induce folic acid deficiency through interference of intestinal absorption:
By inhibiting the enzyme intestinal conjugase [2], induction of enzymes in the liver, and interfere with the metabolism of folic acid co-enzymes.[3]
Studies have shown that mean serum folic acid levels were significantly lower in patients on AED polytherapy (in comparison to those on monotherapy).[4]
Long-term Phenytoin therapy can result in folate deficiency, while supplementation with folic acid may lower serum Phenytoin, possibly leading to poorer seizure control.[5]
Vitamin B-12 serum levels in patients under AED treatment vary between normal, high, or decreased, and is controversial. [6]

12. Management Consultation with: Hematologist
Neurologist (regarding anti-epileptic medication and initiating newer AEDs, such as oxcarbazepine/ lamotrigine, that do not appear to alter folate levels) [7]
Hematologist
Correct Folate and Vit B-12 deficiency to negate neurological symptoms [8]:
For AED induced folate deficiency  15mg of folate PO daily until Hb levels normalize. [9] If continued on AEDs after Hb levels become normal, give 0.4-4mg/daily (as maintenance dose). [10]
Vit B-12 replacement therapy  1mg IM daily for 2 weeks, then 1mg weekly until Hct value normal, then 1 mg monthly for life
Consider 1-2mg Vit B-12 orally if intolerant to injection
Labs two weeks after starting treatment  should see increase in Hb and decrease in LDH and MCV
Full hematologic response should be seen within 8 weeks. [11]

13. Prognosis/Patient Education
Our patient has a favourable prognosis as the etiology of the megaloblastosis was identified and  treatment initiated with Vit B12 and folate replacement  
He is at risk for hypokalemia and anemia-related cardiac complications during therapy for Vit B12 and folate deficiency, which would require potassium monitoring and potassium supplements. [12]
Iron deficiency can occur during Vit B12 and folate therapy, due to depletion of iron stores for the production of RBCs. Iron therapy may be required.[12]
Folate may lower blood pressure and blood sugar levels.[12]
Dietary education on foods rich with folic acid and the importance of regular follow-up with the Hematologist and Neurologist must be stressed.

14. References
Macrocytic Anemia, Cecil Essentials of Medicine 8th Edition. Thomas Andreoli, Ivor Benjamin et al
Carl GF, Smith ML (1992). "Phenytoin-folate interactions: differing effects of the sodium salt and the free acid of phenytoin". Epilepsia 33 (2): 372–375
Ono H, Sakamoto A, Eguchi T, Fujita N, Nomura S, Ueda H, et al. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants. Metabolism 1997;46:959–962.
Huemer M, Ausserer B, Graninger G, Hubmann M, Huemer C, Schlachter K. Hyperhomocysteinemia in children treated with antiepileptic drugs is normalized by folic acid supplementation. Epilepsia 2005;46:1677–83.
Apeland T, Mansoor MA, Strandjord RE, Kristensen O. Homocysteine concentrations and methionine loading in patients on antiepileptic drugs. Acta Neurol Scand. 2000;101:217–223.

15. References- continued
Tamura T, Aiso K, Johnston KE, Black L, Faught E. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy. Epilepsy Res 2000;40:7–15
Sabers A, Gram L. Newer anticonvulsants: comparative review of drug interactions and adverse effects. Drugs. 2000;60:23-33
Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci U S A 2007; 104:19995.
9) Mayo Clinic. Folate dosing. Mayoclinic.com. Available at
10) Morrell MJ. Folic acid and epilepsy. Epilepsy Curr. 2002;2:31-34.
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16. References- continued
12- Megaloblastic anemia, treatment and management. Paul Schick,Emmanuel C Besa. Medscape Reference