DTP Assignment Case # 3 H ematology

1. DTP Assignment Case # 3Hematology “TEAM-Together we achieve more” Stephanie Shaw: History, PE, HxQsEditor/Narrator RuchitaUxa: Pathophysiology, Lab Investigations & interpretation NusratParveen: DDx, Dx & management Maryam Pazoki: Prognosis and Patient education 16th JUNE 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. • During his routine neurology check: • he has complained of feeling fatigued, • shortness of breath on exertion, • lightheadedness over the past month or so.

4. Additional Relevant History Questions • Dietary history, including alcohol intake (Vegan, GI complications) • Past medical history, including recent surgeries/hospitalization, blood transfusions or blood products • Family history, including place of origin and possible hereditary medical conditions (Thalassemia, genetic predisposition) • Medications that you are currently taking for seizure disorder or any other condition (Rx and/or OTC) –Phenytoin • Experience of weight gain, constipation, muscle aches, or feeling unusually cold? (Signs and symptoms of Hypothyroidism, possible cause of Anemia) • Change or absence in sense of touch and feeling? (paresthesia) • Any recent fevers, or infection? (anemia of chronic disease)

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(key findings) • The Blood Count shows that the patient’s RBC, Hgb, Hct are low, MCV, RDW and neutrophils are high. • The Blood smear analysis shows his RBC’s have macrocytosis and anisocytosis, many oval macrocytes present, and multiple neutrophils show nuclear hypersegmentation. • The Bone marrow biopsy shows numerous Howell Jolly bodies present, increased number of erythroids with megaloblastic maturation, neutrophils show premature nuclear segmentation and giant metamyelocytes also seen. • Serum folate & B12 low, RBC folate is in a low normal range. • Lab results point towards normochromic, macrocytic anemia most likely due to Vit B12 and folic acid deficiency.

9. Differential Diagnosis with brief explanation of rationale Macrocytic anemia: Reduced Hemoglobin & raised MCV; causes include megaloblasticanemia & non megaloblasticanemia Megaloblastic anemia: Decreased hemoglobin, High MCV, High RDW, blood smear 2+ macrocytosis,2+ anisocytosis, oval macrocytes hypersegmented neutrophils, giant band cells, Howell jolly bodies, decreased serum Vit B12 & Folate levels; B12 deficiency; Folate deficiency; Drugse.g.zidovudine, hydroxyurea, methotrexate, *phenytoin Non megaloblasticanemia: Liver disease/Alcohol: No h/o of liver disease/alcohol abuse, no coagulopathy, PE normal Hypothyroidism-No history suggestive of thyroid disease, no positive clinical findings Reticulocytosis-lab results consistent with megaloblastic anemia. Myelodysplastic disorder- no h/o bleeding bruising, fever, no hepatosplenomegaly on PE

10. Most Likely Diagnosiswith brief explanation of rationale Megaloblastic anemia secondary to Vitamin B12 & Folic Acid deficiency. • Symptomatic anemia, h/o of antiepileptic drug intake may cause folic acid deficiency, chemistry shows reduced serum folate and serum B12; • Lab investigations, Peripheral smear and bone marrow results consistent with megaloblastic anemia. • To differentiate between FA and B12 further metabolite testing should be done by methylmalonic acid and homocysteine levels (MMA and HC). • If both serum and urinary MMA and serum HC increased; suggestive of Vit B12 deficiency. • If MMA normal and HC increased-suggestive of FA deficiency, if both normal, the cause of anemia may be attributed to drug intake of long duration.

11. Pathophysiology • The common feature in megaloblastosis is a defect in DNA synthesis in rapidly dividing cells. • RNA and protein synthesis are also impaired to a lesser extent. • Since nuclear maturation is arrested, there is unbalanced cell growth and impaired cell division. • More mature RBC precursors in the bone marrow are destroyed before they can enter the blood stream (intra-medullaryhemolysis). • The most common causes of megaloblastosis are Vit B12 and folate deficiencies, medications, HIV infection and myelodysplastic disorders.

12. Management Megaloblastic anemia usually develops gradually; patients adjust to low hemoglobin levels and do not require transfusions. • Restoring healthy dietary habit is essential. • Medication For Vitamin B12 deficiency: IM or deep S/C injections in a dose of 1000 micrograms (1 mg) every day for one week, followed by 1 mg every week for four weeks and then,1 mg every month for the remainder of the patient's life or 1000 micrograms orally daily if intestinal absorption is intact For Folic Acid deficiency: 1 to 5 mg/day PO x 1-4 months or until complete hematologic recovery occurs or 15 mg/day PO x 3 months and then once daily Consult a hematologist, a neurologist and a gastroenterologist.

13. Prognosis/Patient Education • Anemia and other cytopenias should respond completely within 1 to 2 months, but the neurologic manifestations of cobalamin deficiency improve slowly and may be irreversible. • Foods with a lot of vitamin B12 include: • Red meat, Fish and shellfish, Dairy foods, Breakfast cereals that have vitamin B12 added to them • Foods with a lot of folic acid include: • Green leafy vegetables, Oranges and orange juice, Breakfast cereals that have folic acid added to them Females: • Start taking a multivitamin with at least 400 micrograms of folic acid at least 1 month before you start trying to get pregnant

14. References • Bibliography: Uptodate.com.my access.library.utoronto.ca, (2014). my.access — University of Toronto Libraries Portal. [online] Available http://www.uptodate.com.myaccess.library.utoronto.ca/contents/anemias-due-to-decreased-red-cell-production?source=search_result&search=megaloblastic+anemia selected Title=5~93#H11 [Accessed 14 Jun. 2014]. • http://www.uptodate.com.myaccess.library.utoronto.ca/contents/diagnosis-and-treatment-of-vitamin-b12-and-folate-deficiency?source=search_result&search=megaloblastic+anemia selected Title=1~93 [Accessed 14 Jun. 2014]. • http://emedicine.medscape.com/article/204066-treatment#aw2aab6b6b8 [Accessed 14 Jun. 2014]. • Comprehensive medical reference and review-Toronto Notes 2009 edition Toronto Notes for Medical Students Inc. Toronto, Ontario. • Sultan C, Sigaux F, Imbert M, Reyes F. Acute myelodysplasia with myelofibrosis: a report of eight cases. Br J Haematol 1981; 49:11. • Pagliuca A, Layton DM, Manoharan A, et al. Myelofibrosis in primary myelodysplastic syndromes: a clinico-morphological study of 10 cases. Br J Haematol 1989; 71:499.

15. References 7. HvasAM, Ellegaard J, Nexø E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med 2001; 161:1534 8. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood 2008; 112:221 9. Carmel R, Shulman IA. Blood transfusion in medically treatable chronic anemia. Pernicious anemia as a model for transfusion overuse. Arch Pathol Lab Med 1989; 113:995. 10. Essentials of Clinical Examination Handbook-5th Edition 11. Hoffman R, Benz EJ, Furie B, Shattil SJ. Hematology: Basic Principles and Practice. Philadelphia, Pa: Churchill Livingstone; 2009. 12. Basic Skills in Interpreting Laboratory Data, Fifth Edition, Mary Lee, 2013.