1. Ecuador
Carlos Andrade Marín
Hospital
Megaloblastic Anemia
Juan Carlos Ayala Sandoval
2013

2. COBALAMIN
• 5-deoxyadenosylcobalamin (ado)
CoA Methyl-manolilmutasa
• Methylcobalamin
Methionine-synthase
• Hydroxocobalamin

3. Food source and requirements
Western Food: 5-30pg/día
Elimination: 1-3 pg/día
Body Reserves: 2-3 mg

4. Absorption

5. Transport
Transcobalamin I
(TC I)
Neutrophil granules
2/3 Saturated with cobalamin
Glycoprotein receptors
Cobalamin analogues
Transcobalamin II
(TC II)
Hepatic synthesis
20-60 ng / L plasma
controlled by a receptor endocytosis

6. FOLATE
Folic Acid
Folate precursor compound
Reduced to DHF or THF
Containing one carbon unit
Folate polyglutamates
Nutritional content: >100 pg/100 g
Western Food: 250 pg/día
Daily requirements: 100 pg
Body Reserves: 10 mg

7. Absorption
Upper small intestine
5-MethylTHF in intestinal mucosa
Monoglutamate traveling by active transport
> 400 Folic acid
< 400: 5-MTHF
Bile: 60-90 pg

8. Transport
• 1/3 Albumin
• 2/3 Free
• Body fluids: 5-MTHF monoglutamate
• Folate receptor high affinity
• Folate membrane transporter

10. CLINICAL FEATURES

11. General tissue effects of cobalamin and
folate deficiences
Ephitelial surfaces
Complications of Pregnancy
Neural tube defects
• Macrocytosis
• Multinucleated cells increased
• Infertility
• Prematurity
• Abortion
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Anencephaly
Myelo meningioma
Encephalocele
Spina bifida

12. General tissue effects of cobalamin and
folate deficiences
Cardiovascular disease
Malignacy
Neurologyc and Psychiatric manifestations
•Homocystinuria > 100 pmol/L
•Vascular injury
•ALL
•Polymorphism MTHFR 677
•Polymorphism MTHFR A1298C
•Colorectal cancer
•Posterior and piramidal tracts of the spinal cord
•paresthesias
•muscle weakness
•dementia
•psychosis
•visual disturbances

13. HEMATOLOGIC FINDINGS
Peripheral blood
• MCV > 100 fl
• Neutrophils hypersegmented
• Leukopenia > 1.5x109/L
• Platelets < 40 x109/L
Bone marrow
• Hypercellular marrow
• Accumulation primitive cells
• Giant and abnormally shaped metamyelocytes
• Enlarged hyperpolyploid megakaryocytes

14. HEMATOLOGIC FINDINGS
Chromosomes
• Ramdom breaks
• Reduced contraction
• Spreading of the centromere
• Overprominent satellites
Ineffective hematopoiesis
• Unconjugated bilirrubin in plasma
• Raised urine urobilinogen
• Reduced aptoglobins
• Positive urine hemosiderine

15. CAUSES OF COBALAMIN DEFICIENCY
Inadequate Dietary Intake
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Adults
Infants
Pernicious Anemia
Gastric Biopsy
Serum antibodies
Juvenil pernicious anemia
Congenital Intrinsic Factor Deficiency or Funtional Abnormality
Gastrectomy
Food Cobalamin Malabsorption

16. DIAGNOSIS OF COBALAMIN
DEFICIENCIES
Intestinal Causes of
Cobalamin
Malabsorption
• Intestinal Stagnant Loop Syndrome
• Ileal resection
• Selective Malabsorption of Cobalamin with Proteinuria
• Tropical Sprue
• Fish Tapeworn Infestation
• Gluten-Induced Enteropathy
• Severe Chronic Pancreatitis
• HIV infection
• Zollinger-Ellison Syndrome
• Radiotherapy
• Graft-versus-Host Disease
• Drugs

17. CAUSES OF FOLATE DEFICIENCY
Nutritional
Malabsorption
Excess Utilization or Loss
• Pregnancy
• Prematurity
• Hematologic Disorders
• Inflamatory Conditions
• Homocystinuria
• Long-tern Dialysis
• Congestive Heart Failure, Liver Disease
Antifolate Drougs
Congenital Abnormalities of Folate Metabolism

18. DIAGNOSIS OF COBALAMIN
DEFICIENCES
Serum
ELISA
Cobalamin
160-200 ng/L to 1000 ng/L
100 and 200 ng/L are regarded as borderline
Serum Methyl
manolate and
Homocysteine
The serum MMA level is raised (Patients with cobalamin deficiency sufficient to cause anemia or neuropathy)
Serum MMA levels fluctuate in renal failure
30% Healthy volunters (350 ng/L)
15% Elderly subjects (>350 ng/L)
Serum Homocysteine (Cobalamin and Folate deficiency)
Cobalamin
Abosrption
Urinary excretion test
Patient is fasted ivernight
Cyanocobalamin oral
Radiactive Cyanocobalamin or Hydroxocobalamin (1mg)
24-hour urine specimen
After 48 hours with IF

19. DIAGNOSIS OF FOLATE DEFICIENCES
Serum
Folate
ELISA
2pg/L - 15pg/L
Serum folate rises in severe cobalamin deficiency
Intestinal stagnant loop syndrome
Red Cell
Folate
Less afected tan the serum assay by recent diet
160 – 640 pg/L
False normal results

20. TREATMENT – MEGALOBLASTIC ANEMIA
Platelets > 800 X109 /L

21. TREATMENT OF COBALAMIN
DEFICIENCY
Borderline cobalamin levels
Hydroxocobalamin
Cyanocobalamin
Malabsorption of cobalamin
Rises in serum MMA levels
Indications for starting
cobalamin therapy
• Well-documented megaloblastic
anemia
• Hematologic abnormality
• Neuropathy due to the deficiency
Total gastrectomy or Ileal recection
Patients who have undergone gastric reduction for
control of obesity
Reciving long-term treatment with proton pump
inhibitors

22. Hydorxocobalamin
• Replenishment of body stores
Six 1000 µg IM/3-7 days
• Maintenance therapy
1000 µg IM / month for 3 months
Cyanocobalamin (Poorer retention)
Small fraction of cobalamin can be absorbed passively through mucous membranes
Large daily oral doses can be used in PA
Sublingual therapy
Oral therapy: Important to monitor compliance
2000 pg

23. TREATMENT OF FOLATE DEFICIENCY
5-15 mg
It is a customary ton continue therapy for -4 months
Cobalamin deficiency must be excluded
USA: Food fortification with folic acid
Long-term folic acid therapy
• Deficiency cannot be corrected
• Gluten-Inuduced enteropathy
• Important to measure the serum cobalamin

24. FOLINIC ACID
• Stable form of fully reduced folate
• Toxic efects of
• Methotrexate
• DHF reductasa inhibitors

25. PROPHYLACTIC FOLIC ACID
Chronic dialysis
Pregnancy
Parenteral feeds
• 400 µg daily
• 5 mg daily (previous fetus with a
neural tuve defects)
Reduce homocysteine levels
Cognitive function in the
elderly
Infancy and Childhood
• Smallest premature babies (first 6
weeks of life)
• Folic acid 1mg daily (< 1500 g)
• Normal premature babies