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What is the main problem in megaloblastic anemias? This results in ineffective hematopoiesis: this means that the marrow is packed full of hematopoietic precursor cells, but most of them die before they become fully mature and leave the marrow. Thus, the marrow is packed full, but the blood is empty.
Impaired DNA Synthesis
What cells in the body are affected by megaloblastic anemias?
All dividing cells (it is due to impaired DNA synthesis) -- bone marrow, lining of GI, and skin are most rapidly dividing cells in body
What are the primary causes of megaloblastic anemias?
- Cobalamin (Vitamin B12) Deficiency
- Folic Acid (Folate) Deficiency
- Anti-Folate Drugs -- methotrexate, trimethoprim/sulfa antibiotics
- Other Drugs -- nucleoside inhibitors (zidovudine [AZT])
Are megaloblastic anemias normocytic, microcytic, or macrocytic?
This is a specific subset of megaloblastic anemia; it is a chronic autoimmune gastritis with loss of intrinsic factor production and consequent inability to absorb vitamin B12 (intrinsic factor produced in the stomach is required for efficient absorption of vitamin B12).
If something destroys the enterohepatic circulation, the body stores of what can be depleted much more quickly?
What is the most common cause of a Folate Deficiency?
Inadequate diet, often combined with alcoholism
What conditions can increase the need for folic acid due to increased cell turnover?
- Chronic Hemolytic Anemias
What is the primary dietary sources of folic acid?
Fresh fruits and vegetables
What are the primary dietary sources of cobalamin?
Meat, eggs, dairy
How long can the body stores of folate last (typically)? Cobalamin?
What is the most common cause of a cobalamin deficiency?
Malabsorption: intrinsic factor is required for B12 absorption; transcobalamin II is the B12 transporter in the blood
Efficient absorption of cobalamin requires what two things?
- Intrinsic Factor: produced by gastric parietal cells; required for B12 absorption; transcobalamin II is the B12 transporter in the blood
- Terminal Ileum: only place in GI where B12 is absorbed
What are the steps of Cobalamin absorption?
- B12 bound to food protein
- Gastric acid & pepsin digest if off
- R-binders from salivary glands bind to B12, blocking IF
- Pancreated enzymes digest R-binders off of B12
- IF binds B12
- IF-B12 complex absorbed in terminal ileum
- B12 transported in blood by transcobalamin II
What is the most common cause of cobalamin malabsorption (most cases subclinical)?
What is the most common OVERT cobalamin deficiency?
- Food-cobalamin malabsorption
- Pernicious anemia
What freshwater fish tapeworm, common in some fish in cold northern lakes, can be aquired when the fish is eaten raw, and compete for vitamin B12, causing a deficiency?
A food-cobalamin malabsorption is due to the inability to absorb B12 bound to food proteins. What are three common causes of this?
- Gastric Surgery: deficiency of pepsin and gastric acid
- Chronic Gastritis: deficiency of pepsin and gastric acid
- Antacids: may exacerbate
- Metformin: may exacerbate
What type of anemia is revealed in the slide on the right (compared to normal on left)?
Pernicious Anemia: notice the thinning of the mucosa, destruction of many of the gastric crypts, and inflammation in the lamina mucosa
Pernicious anemia has a familial predisposition, and can be associated with the production of antibodies. Which antibodies, seen in ~90% of patients, is sensitive but not specific for PA? Which antibodies, seen in ~50-60% of patients, is specific for PA but not sensitive?
- Anti-Parietal Cell Antibodies
- Anti-Intrinsic Factor Antibodies
In the metabolism of cobalamin and folate, the first step involves the synthesis of dTMP from dUMP; dTMP is required to make dTTP, which is required to make DNA. What enzyme converts dUMP to dTMP? What is required for this reaction to take place, and is required for the regeneration of this required molecule?
- Thymidylate Synthetase
- 5,10-methylene tetrahydrofolate (methylene-FH4)
- Cobalamin is required to regenerate this form of folate
What enzyme is involved in the conversion of homocysteine to methionine? What two things are required for this reaction (this is the only reaction that involves both of them)? What is methionine converted to, and what is the formed product required for the synthesis of?
- Methionine Synthetase
- Folate (methyl-FH4) & Cobalamin
- S-adenosyl-methionine (SAM) -- required for myelin synthesis
What symptoms are associated with megaloblastic anemia?
- Painful Tongue & Mouth
- Weight Loss
- Loss of Appetite, N&V
- Loose Stools
What are the signs of megaloblastic anemia?
- "Lemon Yellow" Color
- Angular Cheilitis
- Dry, Smooth Skin
- Smooth, "Beefy" Red Tongue
- Silvery or Premature Graying Hair
Megaloblastic anemia is called an anemia because that does tend to be most striking, but it is actually a what?
Identify the anemia from the blood smear below:
Megaloblastic Anemia: hypersegmented neutrophils & macrocytic ovalocytic RBCs (oval macrocytes)
Identify the anemia type from the bone marrow shown below:
Megaloblastic Anemia: bone marrow is hypercellular with marked erythroid hyperplasia. There is "megaloblastic maturation" with large, immature nuclei in erythroid precursors, and giant bands and metamyelocytes
What are the three key laboratory findings in hemolytic anemias, as well as in megaloblastic anemias?
- Marked increase in lactic dehydrogenase (LDH)
- Increased bilirubin -- predominantly unconjugated
- Decreased Haptoglobin
Cobalamin deficiency is often associated with neurological symptoms. What are they? Is Folate deficiency associated with neuro symptoms?
- Early: paresthesias of distal extremities, reduced vibration & position sensation
- Later: clumsiness, ataxia, weakness, hyperreflexia, positive Babinski & Romberg signs
What is the pathophysiology related to the neurologic manifestations of cobalamin deficiency?
- Myelin Degeneration
- Loss of axons in dorsal and lateral columns of spinal cord and cerebral cortex
- Both motor and sensory systems affected: "subacute combined degeneration" & "combined systems disease"
What are the cortical manifestations of a cobalamin deficiency?
- Alterned Mental Status
- Bizarre Behavior
- (these may occur in absense of neuropathy or spinal cord manifestations)
The hematologic manifestations of folate and cobalamin deficiency are identical. What is a strong indicator of cobalamin, rather than folate, deficiency?
Neurologic Disease -- though not always seen
What are the lab values related to a cobalamin defiency (are the factors below increased or decreased)?
- Serum B12: Decreased
- Serum Folate: Normal - Increased
- RBC Folate: Decreased
- Serum MMA: Increased
- Homocysteine: Increased
What are the lab values associated with a folate deficiency (are the factors below increased or decreased)?
- Serum B12: Normal
- Serum Folate: Decreased
- RBC Folate: Decreased
- Serum MMA: Normal
- Homocysteine: Increased
To diagnose a folate deficiency, the serum folate level is labile -- it reflects last few meals, so may appear falsely normal if the patient was fed before the level was drawn. What is a better index of folate body stores?
Erythrocyte Folate: reflects last 1-2 weeks
To diagnose a cobalamin deficiency, serum cobalamin is not the msot sensitive test for cobalamin deficiency. What is?
Serum Methylmalonic Acid (MMA) -- increases in cobalamin deficiency
There is a combined nutritional deficiency in which folate or vitamin B12 deficiency may cause _______ malabsorption due to atrophy of the GI tract. This may cause a dimorphic RBC population, and hypersegmented neutrophils may be present. What is the usual effect on MCV?
How is a folate deficiency treated?
Oral therapy usually adequate
How is a cobalamin deficiency treated?
- Parenteral therapy is conventional: intial loading period, then monthly IM shots
- MUST CONTINUE LIFELONG