UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.

1. Macrocytic Anemia
Abdul-Kader Souid9/26/2018
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Folate/ B12 deficiency → ↓DNA synthesis → ↓erythroid replication →
Macrocytosis (↑MCV) = Megaloblastic anemia
Vitamin B12 (cobalamin)
(animal sources)
Folic acid (vitamin B9)
(vegetable & fruit sources)
Pteridine
Aminobenzoic acid
Glutamic acid

2. Megaloblastic Anemia
• The cause is usually a deficiency of folate or vitamin B12
(cobalamin). It produces distinctive erythroid and
neutrophil morphologic abnormalities.
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In megaloblastic anemia, the marrow is cellular; the anemia results from
ineffective erythropoiesis (active erythropoiesis with ↓red cell production).
Normal marrow Megaloblastic marrow Hypersegmented neutrophils
Must know

3. Folate (Vitamin B9)
Sources
• Vegetables: Asparagus, broccoli, spinach, lettuce, beans
• Fruits: Oranges, lemons, bananas, strawberries, melons
• Others: Liver, kidney, mushrooms, peanuts
– Folate is depleted by excessive cooking.
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Deficiency
• Malabsorption: Gluten-induced enteropathy (celiac disease), Crohn disease,
gastrectomy, jejunal resection, poor nutrition, alcoholism.
↑Requirement
• Pregnancy & infancy (rapidly proliferating tissues)
• Hemolytic anemia (folate is not reutilized after performing its coenzyme
functions).
Must know

4. Folate Deficiency → Neural Tube Defects
Folate supplement (0.4 mg daily) before conception and in
the first 12 weeks of pregnancy reduces the incidence of
neural tube defects (spina bifida) in the fetus by about 50%.
The incidence of cleft palate is also reduced.
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↓Folate → ↓Pyrimidine & Purine Synthesis → ↓Cell Replication
Must know
Meningomyelocele Cleft palateCleft lip

5. Folate-mediated Methylation (CH3) Reactions
5,10-methylene-tetrahydrofolate
dUMP dTMP
A
B
Must know
↓Folate → ↓dTMP (↓pyrimidine synthesis) + ↓Conversion of homocysteine
to methionine (↑thrombophilia, ↑ischemic heart disease & ↑stroke)
Important: 5,10-methylene-tetrahydrofolate (5,10-CH2-THF) is needed for converting
dUMP (deoxyuridine monophosphate) to dTMP (deoxythymidine monophosphate).
5,10-CH2-THF is decreased in cobalamin/ folate deficiency.

6. Homozygous C677T in the methylene tetrahydrofolate reductase (MTHFR) gene →
↓Activity of MTHFR → ↑homocysteine →
↑thrombophilia + ↑ischemic heart disease + ↑stroke
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MTHFR = Methylene Tetrahydrofolate Reductase
THF = Tetrahydrofolate
MTHFR
Optional ↑Homocysteine is thrombogenic.

7. Vitamin B12 (Cobalamin) = Cobalt atom at center of corrin ring
Sources
• Animal sources only: Shellfish, liver, fish, crustaceans
(crab), red meat, dairy products, eggs
– Vegetables, fruits, and foods of non-animal origin are free from
cobalamin.
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Deficiency (Human stores sufficient cobalamin for 3 years.)
• Nutritional → Vegans
• ↓Intrinsic factor (IF) → Pernicious anemia, gastrectomy
• Malabsorption → Ileal resection, Crohn disease, stagnant (blind) loop
• Transcobalamin deficiency (detected by newborn screening)
B12
Must know

8. • Cobalamin is absorbed in the ileum,
mediated by the gastric intrinsic factor
(IF).
• IF is produced in the gastric parietal
cells; its secretion parallels that of
hydrochloric acid (HCl).
• The IF-cobalamin complex enters the
ileal cell, where IF is destroyed.
• Cobalamin appears in portal blood
attached to transcobalamin-II (TC-II)
and delivered to the liver, bone
marrow and other tissues.
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Cobalamin (Vitamin B12)
Must know
Cobalamin is responsible for critical metabolic pathways, including folate-mediated
reactions and folate recycling.

9. Cobalamin Exists in Two Biologic Forms
(1) Methylcobalamin → in the cytosol → cofactor for methionine synthase:
(homocysteine → methionine)
(2) Adenosylcobalamin (AdoCbI) → in the mitochondria → cofactor for
methylmalonyl coenzyme A (CoA) mutase:
(methylmalonyl CoA → succinyl CoA) - an intermediate of the citric acid cycle
Must know

10. Neurologic Manifestations:
• Cobalamin deficiency causes peripheral
neuropathy, demyelination of the pyramidal
tracts of the spinal cord and optic atrophy.
• Patients present with paresthesia, weakness,
difficulty in walking, dementia, psychotic
disturbances, and visual impairment.
• Long-term nutritional cobalamin deficiency in
infancy leads to poor brain development and
impaired intellectual development.
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Cobalamin Deficiency
Scherer K. Images in clinical medicine. Neurologic manifestations of vitamin B12 deficiency. N Engl J Med. 2003 May 29;348(22):2208.
“A 56-year-old woman presented with a four-month history of progressive cognitive decline,
weakness, incoordination, and gait disturbance. She had severe ataxia; reflexes, vibratory
sensation, and the sense of position were absent. Brain MRI demonstrated extensive areas of
high-intensity signal in the periventricular white matter. Spine MRI showed a hyperintense
signal along the posterior columns in all segments. Laboratory tests revealed macrocytic
anemia, hypersegmented neutrophils, a low serum vitamin B 12 (34 pg per milliliter [25 pmol
per liter]), and anti–intrinsic-factor antibodies (pernicious anemia). Vitamin B12 injections
rapidly improved cognitive function, strength and walking.”
Optional

11. Pernicious Anemia
• The term pernicious anemia is reserved for ↓secretion of
intrinsic factor (IF) by atrophic gastric mucosa. It has
insidious onset that begins after 40 y of age.
• It results from immune destruction of the acid- and
pepsin-secreting gastric parietal cells (achlorhydria),
causing atrophic gastritis and reduced intrinsic factor
(IF) secretion. Achlorhydria increases the risk of gastric cancer.
• Studies suggest the gastric atrophy in pernicious anemia is caused by
CD4+ T-cells whose receptors recognize the H+/K+-ATPase (i.e.,
autoimmune disease).
• Antibodies to intrinsic factor (type I, "blocking" antibodies) or the
intrinsic factor–cobalamin complex (type II, "binding," antibodies) are
highly specific to pernicious anemia.
Must know
Gastric Mucosa
• Other autoimmune diseases (e.g., thyroiditis, type 1 diabetes, celiac disease,
and Addison disease) frequently exist.
• Measurement of anti-intrinsic factor (IF) antibodies in serum confirms the
diagnosis of pernicious anemia.

12. DIAGNOSIS OF COBALAMIN & FOLATE
DEFICIENCIES
• ↓ Serum Cobalamin
• Serum cobalamin is measured by an enzyme-linked immunosorbent assay (ELISA).
Normal levels are ≥148 pmol/L (200 ng/L). Patients with megaloblastic anemia have
levels <74 pmol/L (100 ng/L). Values of 74-148 pmol/L (100-200 ng/L) are borderline.
• ↑ Serum methylmalonate and homocysteine
• ↑ Intrinsic Factor (IF) & Parietal Cell Antibodies (=pernicious anemia)
• ↓ Serum Folate: Normal = 11-82 nmol/L (2-15 µg/L). Serum folate reflects recent diet.
• ↓ Red Cell Folate
• It is less affected by recent diet and sample hemolysis
• Normal values are 880–3520 µmol/L (160–640 µg/L) of packed red cells.
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Must know

13. High-doses of oral vitamin B12 can be used to treat patients with
megaloblastic anemia, including those with pernicious anemia.
Which one of the following statements about oral vitamin B12
administration to patients with megaloblastic anemia and
pernicious anemia is correct?
A. It is effective only in patients with normal intrinsic factor
secretion.
B. It is not effective in patients with anti-intrinsic factor antibodies.
C. It is not effective in patients with atrophic gastritis.
D. Its dose is the same as parenteral vitamin B12.
E. Treatment requires close monitoring to assure compliance.
F. Methylmalonate and homocysteine levels increase with the
treatment.
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14. 1. Pernicious anemia
2. Megaloblastic anemia
3. ↑MCV
4. Ineffective erythropoiesis
5. Neural tube defects
6. ↑Cardiovascular disease
7. Neurological manifestations
8. ↑Serum methylmalonate
9. Animal sources
10. ↓DNA synthesis
11. Achlorhydria
12. Intrinsic factor (IF) antibody
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A. Folate
B. Cobalamin
C. Both

15. Required Reading
1. Williams Hematology – Chapter 41. Folate, Cobalamin, and Megaloblastic
Anemias
2. Harrison’s Online – Chapter 105. Megaloblastic Anemias
3. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med.
2013;368:149-60.
4. Heilman CB, Zerris VA. Images in clinical medicine. Combined-system disease.
N Engl J Med. 2009;360:2655.
5. Balcı YI, Ergin A, Karabulut A, et al. Serum vitamin B12 and folate
concentrations and the effect of the Mediterranean diet on vulnerable
populations. Pediatr Hematol Oncol 2014;31:62.
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