Megaloblastic anemia

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Megaloblastic anemia
Classification and external resources
Peripheral blood blood smear showing hypersegmented neutrophils, characteristic of megaloblastic anemia.
ICD-10	D51.1, D52.0, D53.1
ICD-9	281
DiseasesDB	29507
eMedicine	med/1420  ped/2575
MeSH	D000749

Megaloblastic anemia is an anemia (of macrocytic classification) which results from inhibition of DNA synthesis in red blood cell production.^[1] This is often due to deficiency of vitamin B₁₂ and/or folic acid. Megaloblastic anemia not due to hypovitaminosis but may be caused by antimetabolites which poison DNA production, such as some chemotherapeutic or antimicrobial agents (for example azathioprine or trimethoprim).

It is characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow,^[2] and also by hypersegmented or multisegmented neutrophils.

Contents 1 Causes 2 Hematological findings 3 Possible associated neurological findings 4 Analysis 5 References

[edit] Causes

• Vitamin B12 deficiency:
  • achlorhydria-induced malabsorption
  • Deficient intake
  • Deficient intrinsic factor (pernicious anaemia or gastrectomy)
  • Biological competition for B12 by diverticulosis, fistula, intestinal anastomosis, and infection by the marine parasite Diphyllobothrium latum
  • Selective B12 malabsorption (congenital and drug-induced)
  • Chronic pancreatitis
  • Ileal resection and bypass
  • Nitrous oxyde anaesthesis

• Folate deficiency:
  • alcoholism
  • Deficient intake.
  • Increased needs: pregnancy, infant, rapid cellular proliferation, and cirrhosis
  • Malabsorption (congenital and drug-induced)
  • Intestinal and jujenal resection

• Combined Deficiency (Tropical sprue): Vitamin B12 & Folate.

• Inherited Pyrimidine Synthesis Disorders: Orotic Aciduria

• Inherited DNA Synthesis Disorders: Deficient thiamine and factors (e.g. enzymes) responsible for folate metabolism.

• Toxins and Drugs:
  • Folic acid antagonists (methotrexate)
  • Purine synthesis antagonists (6-mercaptopurine)
  • Pyrimidine antagonists (cytosine arabinoside)
  • Phenytoin

• Erythroleukemia

[edit] Hematological findings

The blood film can point towards vitamin deficiency:

• Decreased red blood cell (RBC) count and hemoglobin levels^{[citation needed]}
• Increased mean corpuscular volume (MCV, >95 fl) and mean corpuscular hemoglobin (MCH)
• Normal mean corpuscular hemoglobin concentration (MCHC, 32-36 g/dL)
• The reticulocyte count is decreased due to destruction of fragile and abnormal megaloblastic erythroid precursor.
• The platelet count may be reduced.^{[citation needed]}
• Neutrophil granulocytes may show multisegmented nuclei ("senile neutrophil"). This is thought to be due to decreased production and a compensatory prolonged lifespan for circulating neutrophils, which increase numbers of nuclear segments with age.^{[citation needed]}
• Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
• Macrocytes (larger than normal RBCs) are present.
• Ovalocytes (oval-shaped RBCs) are present.
• Howell-Jolly bodies (chromosomal remnant) also present.

Blood chemistries will also show:

• Increased homocysteine and methylmalonic acid in B₁₂ deficiency
• Increased homocysteine in folate defiency

Normal levels of both methylmalonic acid and total homocysteine rule out clinically significant cobalamin deficiency with virtual certainty. ^[3]

Bone marrow (not normally checked in a patient suspected of megaloblastic anemia) shows megaloblastic hyperplasia.

[edit] Possible associated neurological findings

Subacute combined degeneration of spinal cord and its symptoms may be present, due to demyelination secondary to deficiency of vitamin B₁₂.

[edit] Analysis

The gold standard for the diagnosis of B₁₂ deficiency is a low blood level of B₁₂. A low level of blood B₁₂ is a symptom which normally can and should be treated by injections, supplementation, or dietary or lifestyle advice, but it is not a diagnosis. Hypovitaminosis B₁₂ can result from a number of mechanisms, including those listed above. For determination of etiology, further patient history, testing, and empirical therapy may be clinically indicated.

A measurement of methylmalonic acid can provide an indirect method for partially differentiating B12 and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency. But direct measurement of blood cobalamin remains the gold standard because the test for elevated methylmalonic acid is not specific enough. Vitamin B₁₂ is one necessary prosthetic group to the enzyme methylmalonyl-coenzyme A mutase. B₁₂ deficiency is but one among the conditions that can lead to dysfunction of this enzyme and a buildup of its substrate, methylmalonic acid, the elevated level of which can be detected in the urine and blood.

Due to the lack of available radioactive B₁₂, the Schilling test is now largely a historical artifact. The Schilling test was performed in the past to help determine the nature of the vitamin B₁₂ deficiency. An advantage of the Schilling test was that it often included B₁₂ with intrinsic factor.

[edit] References

v • d • e Pathology: hematology · myeloid hematologic disease (primarily D50-D77 · 280-289) Red blood cells ↑ Polycythemia · Macrocytosis ↓ Anemia Nutritional Micro-: Iron deficiency anemia (Plummer-Vinson syndrome) Macro-: Megaloblastic anemia (Pernicious anemia) Hemolytic (mostly Normo-; thalassemia) Hereditary enzymopathy: G6PD · glycolysis (PK, TI, HK) hemoglobinopathy: Thalassemia (alpha, beta, delta)  · Sickle-cell disease/trait · HPFH membrane: Hereditary spherocytosis (Minkowski-Chauffard syndrome) · Hereditary elliptocytosis (Ovalocytosis) · Hereditary stomatocytosis Acquired Autoimmune (WAHA, CAD, PCH) membrane (PNH) MAHA · TM (HUS) Drug-induced autoimmune hemolytic anemia · Drug-induced nonautoimmune hemolytic anemia Aplastic (mostly Normo-) Hereditary: Fanconi anemia · Diamond-Blackfan anemia Acquired: PRCA · Sideroblastic anemia · Myelophthisic Blood tests MCV (Normocytic, Microcytic, Macrocytic) · MCHC (Normochromic, Hypochromic) Other Methemoglobinemia · Sulfhemoglobinemia · Reticulocytopenia Coagulation/ coagulopathy/ bleeding diathesis ↑ Thrombocytosis Essential thrombocytosis Hypercoagulability primary: Antithrombin III deficiency · Protein C deficiency/Activated protein C resistance/Protein S deficiency/Factor V Leiden · Hyperprothrombinemia acquired: DIC (Congenital afibrinogenemia, Purpura fulminans) · autoimmune (Antiphospholipid) ↓ Thrombocytopenia/ purpura Nonthrombocytopenic purpura: Henoch-Schönlein Thrombocytopenic purpura: ITP (Evans syndrome) · TM (TTP) Heparin-induced thrombocytopenia Platelet function adhesion (Bernard-Soulier syndrome) · aggregation (Glanzmann's thrombasthenia) · platelet storage pool deficiency (Hermansky-Pudlak syndrome, Gray platelet syndrome) Clotting factor Hemophilia (A/VIII, B/IX, C/XI) • Von Willebrand disease • Hypoprothrombinemia/II · XIII Monocytes/ macrophages ↑ Histiocytosis · Chronic granulomatous disease -cytosis: Monocytosis ↓ -penia: Monocytopenia Granulocytes ↑ -cytosis: granulocytosis (Neutrophilia, Eosinophilia, Basophilia, Bandemia) ↓ -penia: Granulocytopenia/agranulocytosis (Neutropenia/Kostmann syndrome · Eosinopenia · Basopenia) see also myeloid malignancy and immune disorders ↑ means increased, ↓ means decreased