Megaloblastic Anemias

deficiency: pernicious anemia, growing older
B12 Deficiency Symptoms
Lab testing for diagnosis,

bone marrow smear
B12 Deficiency: treatment, folate deficiency treatment
Summary and used references

ultimately active form
use of antimetabolite drugs
Macrocytosis also caused by
Liver

disease with inadequate cholesterol esterification
Alcohol abuse independent of folate (MCV 100-105)
Myelodysplasia
Post-splenectomy
HIV drugs
Dilantin

Definition: Macrocytic Anemia

requirement 6-9 mcg/d
Total body store 2-5 mg (half in liver)

Helps

to synthesize thiamine, thus deficiency leads to problems with DNA replication

Vitamin B12: Cobalamin

acid and pepsin, then binds to R factors in saliva

and gastric acids
Freed from R factors by pancreatic proteases them binds to Intrinsic Factor secreted by gastric parietal cells
Absorbed together (Cbl + IF) in ileum
Released from IF in ileal cell then exocytosed bound to trans-Cbl II
Cbl bound to transcobalamin II binds to cell surface receptors and is endocytosed

types of anti-IF antibody
Blocks attachment of Cbl to IF
Blocks attachment

of Cbl-IF complex to ileal receptors
Chronic atrophic gastritis
Autoantibody against parietal cells (H-K-ATPase) though pathology indicates destruction by CD4+ T cells
Increased risk of gastric cancer (carcinoid and intestinal- type)

Causes of B12 Deficiency: Pernicious Anemia

up to 40% in institutionalized patients
Unclear mechanism
gastric atrophy
inadequate intake
Achlorhydria
Causes of

B12 Deficiency: Growing Older

Crohn’s)
Enteropathies (protein losing, chronic diarrhea, celiac sprue
Fish tapeworm (Diphyllobothrium latum)

infection
Bacterial overgrowth
HIV infection
Chronic alcoholism
Sjogren’s syndrome
Pancreatic Exocrine Insufficiency
Strict vegan diet
Inherited
Trans-Cbl II or IF deficiency
decreased uptake of IF-Cbl (Imerslun-Grasbeck’s or juvenile megaloblastic anemia) - also presents with proteinuria
Homocysteinuria, severe abnormalities of methionone synthesis, abnormal lysosomal exporter
Decreased absorption from medication
Neomycin
Metformin (biguanides) up to 10-25%
PPI
Nitric oxide (inhibits methionine synthase)

Causes of B12 Deficiency: Surgery, Medication, Worms, Etc.

changes
Hyperhomocysteinemia
Neurologic symptoms (next slide)
Copper deficiency can cause similar neurologic symptoms

B12

Deficiency Symptoms

position sense
Symmetric neuropathy legs>arms
Severe weakness, spasticity, clonus, paraplegia and incontinence


Subacute

combined degeneration of the dorsal (posterior) and lateral spinal columns
Due to a defect in myelination

NOT ALL PATIENTS WITH B12 DEFICIENCY RELATED NEUROLOGIC ABNORMALITIES ARE ANEMIA OR MACROCYTOSIS

B12 Symptoms: Neurologic

columns
Subacute Combined Degeneration

breakdown due to ineffective hematopoiesis
Retic, WBC & platelets normal to

low
Hypersegmented neurophils
Also occur in renal failure, fe deficiency, inherited

B12 Lab findings

and delayed nuclear maturation
Methionine deficiency may play a central role
Bone

Marrow

requirement in hemolytic anemia and exfoliateive skin disease
Body stores: 5-10mg

Folate

methotrexate, pyrimethamine) inhibit dihydrofolate reductase

impairs enterohepatic cycle and inhibits absorption
Increased requirement in hemolytic anemia,

pregnancy, exfoliative skin disease
IBD, celiac sprue
Drugs
Trimethoprim, Methotrexate, Primethamine (inhib DHFR)
Phenytoin: blocks FA absorption, increases utilization (mech unknown)

Causes of Folate Deficiency

classically:
Alcoholic
Very poor dietary intake
Older
Depressed
Living alone

Folate deficiency symptoms

neurologic s/sx
Alcoholics
Malnourished, particularly the elderly
Vegans if no hx of supplementation
Diabetics

on metformin with new onset neuropathy

Whom should you test for B12 or Folate deficiency?

can interfere with the B12 assay as can a single

meal. It is best to add-on tests to blood already in the lab, particularly for inpatients due to the variability of the test.

Intrisic factor antibody assay can be falsely positive if pt has recently received a B12 shot with B12 >800, thus important to add-on.

at the same time to saturate tissue stores
2. 24h urine

to assess absorption
>5% normal
<5% impaired
3. PART 2: Repeat w/oral IF
if now normal =PA
if abnormal = malabsorption
4. Can continue with antibiotics to look for bacterial overgrowth, pancreatic enzymes for exocrine insufficiency

Shilling Test

1 month
Then 1000mcg monthly for life for PA
Oral high dose

1-2 mg daily
As effective but less reliable than IM
Currently only recommended after
full parenteral repletion
Sublingual, nasal spray and gel formulations available

B12 Deficiency: Treatment

most of which contain B12 from Pseudomonas sp., Propionibacterium sp.

or Streptomyces sp.
 Red Star Vegetarian Support Formula
 Twinlab Natural Nutritional Yeast
Probiotics are NOT sufficient to provide adequate B12
Keep supplements in the fridge and out of light
Encourage supplement for prenatal counseling of vegan or ovo-lacto vegetarian women (prenatal vitamin is sufficient unless deficient)

B12: Are You Getting It? By Jack Norris, RD
VeganHealth.org

Vegan B12 Recommendations

recovery
Rule out B12 deficiency prior to treament as folic acid

will not prevent progression of neurologic manifestations of B12 deficiency
Repeat testing for B12 deficiency may be reasonable for those on long-term folic acid therapy if hematologic (macrocytosis or ↑LDH) or neurologic sx persist

Folate Deficiency Treatment

other cytopenias
Slowly developing anemia, usually well compensated
Response to therapy rapid

and dramatic
Treatment necessary to avoid other complications
Anemia is secondary to other disease process

Summary

Arch Intern Med 1996; 156:1097
Food and Nutrition Board, Institute of

Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.
Hvas, AM, J Ellegaard and A Nex. Vitamin B12 Treatment Normalizes Metabolic Markers But Has Limited Clinical Effect: A Randomized Placebo-controlled Study. Clinical Chemistry 47:8.1396–1404 (2001)
Kaptan, K, C Beyan, AU Ural et al. Helicobacter pylori –Is it a novel causative agent in Vitamin B12 deficiency? Arch Intern Med 2000; 160:1349
Norris, Jack. B12: Are You Getting It? Vegan Outreach. Available online: http://www.veganhealth.org/b12, Accessed October 26, 2009
Schrier, S. Etiology and clinical manifestaqtions of vitamin B12 and folic acid deficiency. Up to date. Version 17.2. Accessed October 26, 2009.
Schrier, S. Diagnosis and treatment of vitamin B12 and folic acid deficiency. Up to date. Version 17.2 Accessed October 26, 2009.

References