DTP Assignment Case # 3
Hematology
“TEAM-Together we achieve more”
Stephanie Shaw: History, PE, HxQs
Editor/Narrator
Ruchita Uxa: Pathophysiology, Lab
Investigations & interpretation
Nusrat Parveen: DDx, Dx & management
Maryam Pazoki: Prognosis and Patient
education
16th JUNE 2014
Hematology Case 3
Overview
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History
Physical Examination
Lab Investigations: results and interpretation
Assessment: DDx and most likely Dx
Management
Prognosis and Patient education
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.
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)
Physical Exam
Skin pallor noted. Otherwise, physical exam was unremarkable.
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 cells
Normochromic
2+ macrocytosis
2+ anisocytosis
many oval macrocytes
Occasional teardrop cells and
fragments
WBC morphology
Multiple neutrophils with nuclear
hypersegmentation
Platelets normal
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
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.
Differential Diagnosis
with brief explanation of rationale
Macrocytic anemia: Reduced Hemoglobin & raised MCV; causes include
megaloblastic anemia & non megaloblastic anemia
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; Drugs e.g.zidovudine,
hydroxyurea, methotrexate, *phenytoin
Non megaloblastic anemia:
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
Most Likely Diagnosis
with 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.
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-medullary hemolysis).
• The most common causes of megaloblastosis are Vit B12 and folate
deficiencies, medications, HIV infection and myelodysplastic
disorders.
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.
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
References
1. 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-decreasedred-cell-production?source=search_result&search=megaloblastic+anemia selected
Title=5~93#H11 [Accessed 14 Jun. 2014].
2. http://www.uptodate.com.myaccess.library.utoronto.ca/contents/diagnosis-and-treatment-ofvitamin-b12-and-folate-deficiency?source=search_result&search=megaloblastic+anemia
selected Title=1~93 [Accessed 14 Jun. 2014].
3. http://emedicine.medscape.com/article/204066-treatment#aw2aab6b6b8 [Accessed 14 Jun.
2014].
4. Comprehensive medical reference and review-Toronto Notes 2009 edition Toronto Notes for
Medical Students Inc. Toronto, Ontario.
5. Sultan C, Sigaux F, Imbert M, Reyes F. Acute myelodysplasia with myelofibrosis: a report of
eight cases. Br J Haematol 1981; 49:11.
6. 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.
References
7. Hvas AM, 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.