Macrocytic Anemia

This refers to the large atypical erythroblasts that develop in association with abnormal DNA synthesis

"Megaloblastic"

**This term often applied for classification purposes since the most common causes of megaloblastic anemia (B12 and Folate deficiencies) can be related to inadequate nutritional intake

"Nutritional"

What are the gastric abnormalities that cause B12 deficiencies?

1) **Pernicious Anemia** 2) Gastrectomy/Bariatric Sx 3) H. Pylori infection (Gastritis) 4) Autoimmune metaplastic atrophic gastritis

What are drugs that cause folate?

1) Alcohol* 2) Methotrexate: Rheumatoid Arthritis, Psoriasis treatment** 3) Sulfasalazine: Crohn's, UC, AS 4) Triamterene: K+ sparing diuretic; Component of Maxide 5) Pyrimethamine: antiparasitic 6) Septra: Widely used antibiotic 7) Diphenylhydantoin - Phenytoin 8) Barbituates 9) Hydroxyurea: Interferes w/DNA metabolism**

What are the nutritional causes of folate deficiency?

1) Decreased dietary intake 2) Alcohol creates a "dual deficiency" by interfering with initial absorption as well as the enterohepatic circulation

What is the Diagnosis and Laboratory distinction made in Megaloblastic?

1) Direct B12 and folate measurement 2) Homocysteine level - Elevated in both B12 and folate deficiency 3) Methylmalonic acid level - Elevated in B12 deficiency alone

How does alcohol cause macrocytic anemia?

1) Exact etiology to macrocytic anemia uncertain although theories include: - DIRECT BONE MARROW toxicity given relative pancytopenia pattern - Abnormal RBC lipid metabolism as above - Interference with folate metabolism 2) Macrocytosis may often be present prior to development of severe alcoholic liver disease 3) Macrocytosis may resolve within 2-4 months of abstinence if irreversible damage has not occurred 4) Good "warning" for patients with ongoing alcohol abuse who have not yet developed irreversible complications

What is the treatment of megaloblastic anemia when it caused by B12 deficiency?

1) For pernicious anemia, replacement MUST be parenteral 2) Typically 1000mcg monthly unless neurologic dysfunction is suspected. If so, then aggressive therapy on a daily or weekly basis (temporarily) to prevent irreversible damage 3) Otherwise oral replacement is acceptable 4) Hypersegmented neutrophils will usually disappear within 10-14 days

What are clinical features of Myelodysplastic Syndromes?

1) Hematologic - Macrocytic anemia typically w/ MCV 105 or greater - Cytopenias in other cell lines (WBCs, platelets) - Monocytosis (only in CMML) 2) Increased risk for developing acute myelogenous leukemia 3) MDS are considered as "pre-leukemia" or "neoplastic anemia" 4) ~30% of patients w/ MDS eventually develop Acute Myelogenous Leukemia

What is the prevalence of Myelodysplastic Syndromes (MDS)?

1) Increasing incidence and prevalence with age, especially after 60, although it may rarely affect children 2) Approximately 50,000 cases in US at any given time with approximately 10,000 new cases diagnosed per year 3) Generally considered idiopathic as 80% of cases have no well-defined risks (primary MDS) 4) Secondary MDS often characterized by prior treatment or exposures - Chemotherapy - Radiation therapy - Toxic substances (i.e. benzene)

What are the lipid abnormalities in macrocytic anemias?

1) Liver Disease 2) Hypothyroidism 3) Hyperlipidemia

What are the gastrointestinal features of megaloblastic anemia?

1) Macroglossitis 2) Malabsorptive Syndromes

How is the diagnosis of Myelodysplastic Syndromes made?

1) Maintain high clinical suspicion in the appropriate age-group with typical hematologic features that are not explained by another cause 2) Bone marrow biopsy with expert hematopathologist interpretation

What are the small bowel disease causes of B12 deficiencies?

1) Malabsorption syndrome 2) Ileal resection or bypass 3) Crohn's Disease 4) Blind loops

What is the treatment of Myelodysplastic Syndromes?

1) No single effective therapy given limited understanding of pathophysiology - Only approximately 20% of patients receive any measurable benefit from any therapy after diagnosis - Majority of patients have limited treatment options given coexisting morbidities at time of diagnosis 2) Transfusions- RBCs and Platelets as required 3) Hematologic stimulating factors - (RBC- Procrit or Aranesp, WBC- Neupogen or Neulastia) 4) Bone marrow transplant 5) Other therapies (experimental chemotherapy, immunosuppression)

What is the treatment of megaloblastic anemia when it caused by Folate deficiency?

1) Oral replacement is acceptable for nearly all patients 2) Typical dose is 1mg daily

What situations cause Increased requirements that lead to folate deficiencies?

1) Physiologic (PREGNANCY, infancy, etc.) 2) Pathologic (hemolytic anemia, other diseases associated with increased cell turnover, i.e. psoriasis)

What are the Shifts to Immature/Stressed RBCs in macrocytic anemia?

1) Reticulocytosis 2) Aplastic anemia

What are the dietary causes of B12 deficiency?

1) Strict Vegans 2) Vegetarian diet in preg

How is folate absorbed?

1) Throughout the small intestine 2) Enterohepatic recirculation (rides the bile train back into the intestine)

What are the the abnormalities of DNA metabolism in macrocytic anemia?

1) Vit B12 deficiency or Folate deficienct (MC) 2) Drugs (Hydroxyurea, MTX)

What are the considerations that need to be made in macrocytic anemia?

1) What else could explain the increased MCV besides B12 and Folate? 2) Are there hypersegmented neutrophils on the peripheral smear? ***HYPERSEGMENTED NEUTROPHILS AND MACRO-OVALOCYTES STRONGLY SUGGEST MEGALOBLASTIC ANEMIA. 3) If there is not a nutritional or drug-induced cause, how elevated is the MCV? - Around 100: hypothyroidism, pregnancy, liver dz, alcohol abuse - >105: Bone marrow d/o (MDS, late megaloblastic anemia) 4) Careful attention to social history 5) Is a coexisting process blunting the macrocytosis?

Again, what are the three questions to be asked in macrocytic anemia?

1) What is the MCV? • >100 = macrocytic 2) What is the basic mechanism of the anemia? • Mostly related to cell formation disruption 3) What else do I know about this patient? • social history, medication usage and a few medical conditions

What are the malabsorptive causes of folate deficiencies?

1) With normal intestinal mucosa (i.e. congenital) 2) With abnormal intestinal mucosa (i.e. Sprue, IBD, etc.)

How much B12 is stored in the liver?

2000-5000 mcg stored in the liver

What is the normal absorption of B12?

5mcg/d

What is the MCV in Macrocytic Anemia?

> 100

What causes an unknown mechanism for how it causes macrocytic anemia?

Alcohol abuse

How does Chronic Liver disease cause Macrocytic anemia?

Any process causing impaired hepatic function also impairs lipid metabolism. Although exact etiology is uncertain, excess lipids are thought to be deposited in RBC lipid bilayer, resulting in increased size and thus macrocytosis The above mechanism DOES NOT precisely account for the anemia per se although patients with chronic liver disease often have anemia from other mechanisms (i.e. ANEMIA OF CHRONIC DISEASE) as well as other cell line abnormalities (i.e. thrombocytopenia due to reduced thrombopoietin production).

What causes hypersegmented neutrophils?

Asynchronous cellular (including RBCs) nuclear and cytoplasm maturation, leading to excess cytoplasm and abnormal nuclei.

What is the average loss/use of B12?

Average daily loss/use is 3-5 mcg/d

Purine synthesis, and subsequently DNA synthesis, is disturbed when ____ is absent, resulting in abnormal (ineffective) erythropoiesis

B12

What are the genital features of megaloblastic anemia?

Cervical or uterine dysplasia

What are the cardiopulmonary features of megaloblastic anemia?

Congestive Heart Failure

Why is a folate deficiency more clinically significant than a B12 deficiency?

Daily usage is greater and therefore clinically significant findings will develop sooner (i.e. weeks to months instead of years as seen with B12 deficiency)

What are the psychiatric features of megaloblastic anemia?

Depressed affect and cognitive dysfunction

How is the diagnosis pernicious anemia made?

Diagnosis is confirmed by B-12 deficiency w/ NORMAL folate and presence of typical autoantibodies.

What are the neuropsychiatric features of megaloblastic anemia?

Disruption of proprioception, neuropathic pain and parasthesias

How does folate deficiencies cause megaloblastic anemia?

Folate is a co-factor in cellular reactions, but does not participate in the methylmalonic acid metabolism (Lab results = nl MMA, abnl homocysteine)

How does pregnancy cause macrocytic anemia?

Increased folate requirements may account for mild macrocytosis which is rarely >100. -Folate supplementation during pregnancy also significantly reduces the risk of neural tube defects in the child

What are the reproductive features of megaloblastic anemia?

Infertility or Sterility

What are the hematologic clinical features of megaloblastic anemia?

Macrocytic anemia leading to pancytopenia w/ megaloblastic marrow

This is described as MCV spuriously increased when there are excessive reticulocytes due to their greater size than RBCs. Usually transiently observed in patients with massive hemolysis without a coexisting microcytic process

Marked Reticulocytosis

What are the dermatologic features of megaloblastic anemia?

Melanin pigmentation and premature graying

How does hypothryroidism cause macrocytic anemia?

Mild macrocytic anemia may be related to relative erythrocyte hypoproliferation in response to reduced metabolism. -Hypothyroid patients should also be evaluated for pernicious anemia given polyglandular association

What else do I know about this patient?

Mostly answered by questions concerning social history, medication usage and a few medical conditions

What is the basic mechanism of macrocytic anemia?

Mostly related to cell formation disruption

These are Heterogeneous bone marrow disorders characterized by ineffective blood cell production

Myelodysplastic Syndromes (MDS)

What are the primary bone marrow disorders in macrocytic anemia?

Myelodysplastic syndromes

What does a folate deficiency cause?

Neural tube defects

Is pure B12 deficiency anemia common?

No it is rare

This is an autoimmune disease w/ antibodies to gastric parietal cells as well as intrinsic factor. Strong hereditary component with Caucasian predominance.

Pernicious anemia

What is the source of folate?

Plant matter (Nutritional deficiencies more common)

What will Unrecognized and untreated B12 deficiency lead to?

Profound systemic consequences beyond the hematologic system such as neuropsychiatric sx

T or F. The Body's folate storage is roughly equivalent to that of B12 (up to 5000 micrograms) but daily usage is greater

True

Can Pancreatitis/Insufficiency cause B12 deficiency?

Yes

What is the Summary of B12 vs Folate Deficiency Differerntiation:

• B12 Def: elevated Homocysteine, elevated MMA • Folate Def: elevated Homocysteine, normal MMA