Central University of EcuadorCarlos Andrade Marín Hospital

Megaloblastic Anemia

Juan Carlos Ayala Sandoval

2013

COBALAMIN

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

Food source and requirements

Western Food: 5-30pg/díaElimination: 1-3 pg/díaBody Reserves: 2-3 mg

Absorption

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

FOLATE

Folic Acid Folate precursor compoundReduced to DHF or THFContaining one carbon unitFolate polyglutamates

Nutritional content: >100 pg/100 gWestern Food: 250 pg/díaDaily requirements: 100 pgBody Reserves: 10 mg

Absorption

Upper small intestine

5-MethylTHF in intestinal mucosa

Monoglutamate traveling by active transport

> 400 Folic acid< 400: 5-MTHF

Bile: 60-90 pg

Transport

• 1/3 Albumin• 2/3 Free• Body fluids: 5-MTHF monoglutamate

• Folate receptor high affinity• Folate membrane transporter

CLINICAL FEATURES

General tissue effects of cobalamin and folate deficiences

Ephitelial surfaces• Macrocytosis• Multinucleated cells increased

Complications of Pregnancy• Infertility• Prematurity• Abortion

Neural tube defects• Anencephaly• Myelo meningioma• Encephalocele• Spina bifida

General tissue effects of cobalamin and folate deficiences

Cardiovascular disease•Homocystinuria > 100 pmol/L•Vascular injury

Malignacy•ALL•Polymorphism MTHFR 677•Polymorphism MTHFR A1298C•Colorectal cancer

Neurologyc and Psychiatric manifestations•Posterior and piramidal tracts of the spinal cord•paresthesias•muscle weakness•dementia•psychosis•visual disturbances

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

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

HEMATOLOGIC FINDINGS

CAUSES OF COBALAMIN DEFICIENCY

• Adults• Infants• Pernicious Anemia• Gastric Biopsy• Serum antibodies

Inadequate Dietary Intake

Juvenil pernicious anemia

Congenital Intrinsic Factor Deficiency or Funtional Abnormality

Gastrectomy

Food Cobalamin Malabsorption

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

CAUSES OF FOLATE DEFICIENCYNutritional

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

DIAGNOSIS OF COBALAMIN DEFICIENCES

Serum Cobalamin

ELISA

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

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

TREATMENT – MEGALOBLASTIC ANEMIA

Platelets > 800 X109 /L

TREATMENT OF COBALAMIN DEFICIENCY

Hydroxocobalamin Cyanocobalamin

Indications for starting cobalamin therapy• Well-documented megaloblastic

anemia• Hematologic abnormality• Neuropathy due to the deficiency

Borderline cobalamin levels

Malabsorption of cobalamin

Rises in serum MMA levels

Total gastrectomy or Ileal recection

Patients who have undergone gastric reduction for control of obesity

Reciving long-term treatment with proton pump inhibitors

Hydorxocobalamin• Replenishment of body stores Six 1000 µg IM/3-7 days• Maintenance therapy 1000 µg IM / month for 3 monthsCyanocobalamin (Poorer retention)

Small fraction of cobalamin can be absorbed passively through mucous membranes

Large daily oral doses can be used in PA 2000 pg

Sublingual therapy

Oral therapy: Important to monitor compliance

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

• Deficiency cannot be corrected• Gluten-Inuduced enteropathy• Important to measure the serum cobalamin

Long-term folic acid therapy

FOLINIC ACID

• Stable form of fully reduced folate• Toxic efects of• Methotrexate• DHF reductasa inhibitors

PROPHYLACTIC FOLIC ACID

Chronic dialysis

Parenteral feeds

Reduce homocysteine levels

Cognitive function in the elderly

Pregnancy• 400 µg daily• 5 mg daily (previous fetus with a

neural tuve defects)

Infancy and Childhood• Smallest premature babies (first 6

weeks of life)• Folic acid 1mg daily (< 1500 g)• Normal premature babies