Drug Induced Macrocytic Megaloblastic Anemia DTP Group C Research: Sunil Bacharanianda Group Leader:...
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Drug Induced Macrocytic Megaloblastic Anemia DTP Group C Research: Sunil Bacharanianda Group Leader: Siobhan Taylor Narration: Ervin Magic Scribe: Tara Duesbury June 16, 2014
Drug Induced Macrocytic Megaloblastic Anemia DTP Group C Research: Sunil Bacharanianda Group Leader: Siobhan Taylor Narration: Ervin Magic Scribe: Tara
Drug Induced Macrocytic Megaloblastic Anemia DTP Group C
Research: Sunil Bacharanianda Group Leader: Siobhan Taylor
Narration: Ervin Magic Scribe: Tara Duesbury June 16, 2014
Slide 3
Hematology Case 3 Overview History Physical Examination Lab
Investigations: results and interpretation Assessment: DDx and most
likely Dx Management Prognosis and Patient education
Slide 4
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.
Slide 5
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, Crohns 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?
Slide 6
Physical Exam Skin pallor noted. Otherwise, physical exam was
unremarkable.
Slide 7
Laboratory Investigations RBC 1.24 x 10 12 /L Hgb 58 g/L Hct
0.162 MCV 131 fL MCHC 348 g/L RDW 0.184 WBC 6.1 x 10 9 /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
Slide 8
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
Slide 9
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 Indicates
MACROCYTIC MEGALOBLASTIC ANEMIA Chemistry: Decreased folate levels
(
Slide 10
Differential Diagnosis with brief explanation of rationale
1)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)
Slide 11
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)
Slide 12
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]
Slide 13
Management Consultation with: 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]
Slide 14
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.
Slide 15
References 1)Macrocytic Anemia, Cecil Essentials of Medicine
8th Edition. Thomas Andreoli, Ivor Benjamin et al 2)Carl GF, Smith
ML (1992). "Phenytoin-folate interactions: differing effects of the
sodium salt and the free acid of phenytoin". Epilepsia 33 (2):
372375 3) 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;46:959962.
4)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;46:167783. 5)Apeland T, Mansoor MA, Strandjord RE,
Kristensen O. Homocysteine concentrations and methionine loading in
patients on antiepileptic drugs. Acta Neurol Scand.
2000;101:217223.
Slide 16
References- continued 6)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;40:715 7)Sabers A, Gram L. Newer anticonvulsants: comparative
review of drug interactions and adverse effects. Drugs.
2000;60:23-33 8)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
http://www.mayoclinic.com/health/folate/NS_patient-
folate/DSECTION=dosing
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- 11)
http://emedicine.medscapecom/article/204066-
treatment#aw2aab6b6b8
Slide 17
References- continued 12- Megaloblastic anemia, treatment and
management. Paul Schick,Emmanuel C Besa. Medscape Reference