Drug Induced Macrocytic Megaloblastic Anemia

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 3Overview • 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’sdisease, 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 0.162 MCV 131 fL MCHC 348 g/L RDW 0.184 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 cellsNormochromic2+ macrocytosis2+ anisocytosismany oval macrocytesOccasional teardrop cells and fragments WBC morphologyMultiple 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 B12 100 pmol/L • RBC folate 297 nmol/L

8. Interpretation of Lab Results • Low RBC, Hb, and Hctwith 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 • Indicates MACROCYTIC MEGALOBLASTIC ANEMIA • Chemistry: • Decreased folate levels (<2nm/L) , Normal RBC folatelevel (297 nm/L), Reduced Serum VitB12 (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/VitB-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 normoblasticchanges, pancytopenia (not present)

10. Most Likely Diagnosiswith 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 megaloblasticanemia • 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 VitB-12 levels)

11. Pathophysiology • Macrocytic MegaloblasticAnemia: • 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: • Neurologist (regarding anti-epileptic medication and initiating newer AEDs, such as oxcarbazepine/ lamotrigine, that do not appear to alter folatelevels) [7] • Hematologist • Correct Folate and Vit B-12 deficiency to negate neurological symptoms [8]: • For AED induced folatedeficiency  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] • VitB-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 Hband 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". Epilepsia33 (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. • HuemerM, 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. • ApelandT, Mansoor MA, Strandjord RE, Kristensen O. Homocysteine concentrations and methionine loading in patients on antiepileptic drugs. ActaNeurol 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. ProcNatlAcadSci U S A 2007; 104:19995. 9) Mayo Clinic. Folate dosing. Mayoclinic.com. Available at http://www.mayoclinic.com/health/folate/NS_patient-folate/DSECTION=dosing 10) Morrell MJ. Folic acid and epilepsy. Epilepsy Curr. 2002;2:31-34. 11) http://emedicine.medscapecom/article/204066- treatment#aw2aab6b6b8

16. References- continued • 12- Megaloblastic anemia, treatment and management. Paul Schick,Emmanuel C Besa. Medscape Reference