8/5- Sideroblastic and Megaloblastic Anemias Flashcards
Causes of microcytic anemia (broadly)?
- Iron deficiency anemia
- Sideroblastic anemia
- Thalassemias
- Anemia of chronic disease
What is sideroblastic anemia?
Disorders with finding of ring sideroblasts in the bone marrow
- Iron overload
- Impaired biosynthesis of heme
- Iron does not incorporate into protoporphyrin
- Builds up in mitochondrion
- Mitochondria encircle the erythroid progenitor nucleus- “ringed siderbolast” is a pathologic finding of large blocks of staining material (iron staining in normal erythroid progenitors shows up as blue dots “sideroblasts”- a normal finding)
**Ringed sideroblasts are pathologic findings whereas a sideroblast is a normal finding**
What does this show?
Bone marrow- sideroblastic anemia
What is a Peappenheimer body?
Iron seen in mature circulating RBCs
What does bone marrow show in sideroblastic anemia?
Bone marrow shows erythroid hyperplasis
- In effective erythropoiesis
- Signal to gut to increase iron absorption
Different forms of sideroblastic anemia?
Inherited (uncommon)
- Mostly X-linked ALAS2
Acquired:
- Drugs
- MDS
Characteristics of Congenital Sideroblastic Anemia?
- Most often X-linked
- Deficiency of RBC delta aminolevulinic acid synthase—the first enzymatic step in heme porphyrin production
- No Heme, no incorporation of iron into hemoglobin, iron builds up in the mitochondria
- Microcytic Anemia
- Pyridoxine is a cofactor of the enzyme and in some patients replacement improves the anemia
Characteristics of Hereditary Sideroblastic Anemia?
(only need to know the first one)
- X-linked: delta-ALA (dALA) synthase deficiency; pyridoxine may be effective
- Autosomal recessive
- Mitochondrial:
—Pearson’s Pancreatic Syndrome
—Abcb7 deficiency and ataxia
—Thiamine responsive megaloblastic anemia syndrome—TRMA
—MLASA-myopathy lactic acidosis-SA
What can lead to acquired sideroblatsic anemia?
- Alcohol
- Lead
- Copper deficiency (years after gastric bypass, zinc excess as from denture adhesive, peripheral neuropathy)
- INH if pyridoxine (B6) is not given
- Chloramphenicol (antibiotic still in use in underdeveloped countries)
If a pt presents with anemia, bilateral wrist drop and this peripheral blood smear, which of the following is most likely to be the cause of his anemia?
A. Copper
B. Gold
C. Lead*
D. Krypton
E. Silver
If a pt presents with anemia, bilateral wrist drop and this peripheral blood smear, which of the following is most likely to be the cause of his anemia?
A. Copper
B. Gold
C. Lead
D. Krypton
E. Silver
- Lead poisoning is associated with neuropathy—in this case foot drop. In children—often it is colic.
- Lead inhibits ALA dehydratase and also a house keeping enzyme 5’ nucleotidase. When the latter is inhibited RNA is not degraded and coarse basophilic stippling is found
- Iron deficient children have pica and may eat paint chips from old walls or cribs—and then get lead poisoning as well
- Note that fine basophilic stippling may just be an exaggerated form of the polychromasia seen with a reticulocyte.
- In children with relative iron deficiency lead further blocks iron absorption in the gut and sideroblasts may not be evident in the marrow.
What is characteristic of RBCs in Acquired Sideroblastic Anemia/Myelodysplastic Syndrome?
Dual population of RBCs:
- Microcytic RBCs are a sub-population
- Macrocytic RBCs predominate
- MCV is typically increased
Other characteristics of Acquired Sideroblastic Anemia/Myelodysplastic Syndrome?
Treatment?
- Pseudo Pelger Huet WBC in Myelodysplastic syndromes (more later)
- Increased serum iron, and increased % Sat
- High Ferritin
- Presence of Ringed Sideroblasts in bone marrow
Treatment: Pyridoxine, Erythropoietin, Transfusions
Case)
A 65-year-old black man, a retired minister, presents with anemia. He is diabetic but has done well on a diet. He is referred to you for evaluation of mild anemia: Hct 28 %, MCV 110, and folate, B12, and iron studies are normal. His physical exam is unremarkable, he has no splenomegaly……
?
What is this showing?
Peripheral blood film shows a dimorphic population of RBCs: hypochromic/microcytic and macrocytic
What is this showing?
Bone marrow aspirate show iron present in large chunks in a perinuclear distribution– consistent with mitochondrial iron (Perl’s Prussian Blue stain)
Differential Diagnosis of Sideroblastic Anemia?
Myelodysplaisa- clonal disorders of ineffective hematopoiesis
- SF3B1 mutation with pre mRNA splicing
- V617F JAK2 mutation with sideroblastic anemia and thrombocytosis
- Chromosomal changes
What are the levels of serum iron, TIBC, % saturation, and ferritin with the following:
- Iron deficiency
- Anemia of chronic disease
- Thalassemia minor
- Sideroblastic anemia
IMPORTANT SLIDE!!!
What are the cellular mechanisms behind megaloblastic anemias?
- DNA synthesis is impaired
- Arrest of cellular division
- Increased apoptosis
- Ineffective erythropoiesis
- Normal RNA synthesis and cytoplasmic differentiation
- Macrocytosis
- B12 and folate deficiency are the main causes
- Other tissues with rapid turn over may be affected
What does this show?
Megaloblatsic anemia
- Big red cells
- Hypersegmented neutrophils (from improper mitosis)
What does this show?
Macro-ovalocytosis
- Basophilic stippling
- Howell Jolly bodies
- Cabot rings (very very very rare)
What does this show?
Megaloblastic erythropoiesis
- Nuclear cytoplasmic dyssynchrony In megaloblastic states, there is delay in maturation of the nucleus, so cells that ought to be mature by looking at their cytoplasm have wide open young nuclei
- The cytoplasm matures but the nucleus does not divide—so you end up with a macrocyte.
What two key molecules are required for DNA synthesis?
- Folate
- B12 (cobalamin)
What results from deficiencies in folate or B12?
- Impaired DNA synthesis but continued protein synthesis
- Cells should divide to be the normal size, but don’t– hence the nuclear cytoplasmic asynchrony
What are dietary sources of B12 (cobalamin)?
Must get from diet!
- Meat
- Liver
- Seafood
- Dairy products
- Not found in plants
How much B12 is needed each day? Absorbed?
Stored where?
- RDA: 2.4 mcg/day
- Diet has 5-30 mcg/day
- 1-5 mcg/day is absorbed
- Liver stores are good for 3-4 years
What two pathways require B12?
1. Conversion of homocysteine to methionine (then used as a methyl group donor and many reactions); this also requires folate as a co-factor
2. Transformation of methylmalonyl-CoA to succinyl CoA in fatty acid metabolism
What is the process of B12 absorption?
- Heptocorrin (R-protein) from saliva binds B12 in the stomach; protects at low pH
- IF from healthy stomach parietal cells grabs B12 in the duodenum; protects it from digestion at high pH and delivers to IF/CBL receptor cubulin in the terminal ileum
- B12 then exported to plasma where it binds transcobalamin
What may cause cobalamin deficiency?
IMPAIRED ABSORPTION
Gastric:
- Pernicious Anemia (PA)
- Gastric bypass
- Gastrectomy
- Zollinger Ellison Intestinal
- Ileal resection or disease (Crohn’s)
- Blind loop syndrome
- Fish tapeworm
- Metformin
Pancreatic insufficiency
Decreased intake (Vegans)
What causes pernicious anemia? Effects?
Autoimmune attack on parietal cell
- H/K ATPase attacked by CD4+ T cells, anti-parietal cell autoantibodies; possible role for H. pylori
- Blocking anti-IF antibodies
Results in:
- Absence of effect of IF
- Decreased B12 absorption
What are some clinical manifestations of B12 deficiency?
- Megaloblastic Anemia
—Ineffective erythropoiesis
—Increased apoptosis
- Thrombocytopenia
- Leukopenia
- Increased LDH, low haptoglobin
- Increased MMA, Homocysteine levels
- Cardiomyopathy
- Pale “lemon” yellow skin (increased indirect bilirubin)
- Gastric atrophy gastric CA, gastric carcinoid
Diagnosis of B12 deficiency?
- Low B12 level
- Serum iron often increased
- TIBC normal, % saturation increased
- Ferritin increased
- Increased MMA/homocysteine
- Anti-parietal cell antibodies
- High gastrin level
- Give B12 and see what happens
- Do endoscopy if you are concerned about gastric CA
Other autoimmune problems?
- Vitiligo
- Thyroid disease
- Addison’s
- Type I DM
- Acquired hypo-gammaglobulinemia
What is shown here?
Glossitis
- Gut may also be affected, and possibly abnormal pap smear
What effect does B12 deficiency have on the CNS (specifically spinal cord)
Combined systems disease, degeneration of:
- DC: balance issues, nighttime troubles
- Lateral CST
Neurologic Diseases from B12 deficiency?
- Dorsal column—lost of position sense
- Lateral column—spastic paresis
- Peripheral neuropathy
- Alzheimer’s like disease
- Altered taste, smell, vision
- Paranoia, Megaloblastic Madness
- Can be isolated—no anemia
- May be irreversible
**Folate may improve anemia, but worsen neurotoxicity of b12 deficiency**
B12 treatments for deficiency?
- 1000 mcg day IM for a week, then weekly for a month, then monthly life long
- 1000-2000 day PO
- Transfuse sparingly—patients become volume overloaded easily
What is the RDA for folic acid? Dietary sources of folate?
RDA = 400 mcg folate
= 240 mcg folic acid
Sources: Green leafy vegetables, Beans, Liver, Yeast Extract, Whole grains, Egg yolk, Milk and milk products, Oranges and orange juice, Beets, Wholemeal bread, Beer
Causes of folate deficiency?
Nutritional:
- Goats milk diet
- Old age
- Poverty
Dialysis
Malabsorption
- Sprue
- Gastric bypass surgery
- IBD
Increased utilization
- Pregnancy
- Hemolysis Drugs/ETOH
What substance levels/measurements can help distinguish between folate and B12 deficiency?
Folate deficiency: increased homocysteine
B12 deficiency: increased homocysteine AND MMA
(Also, neurological diseases likely point to B12 deficiency rather than folate)
What does folate deficiency cause?
- Megaloblastic anemia
- Megaloblastic changes in other rapid turnover tissues
- Increase in Homocysteine levels
- RDA based on intake to avoid anemia
- Supplementation suggested for
—Pregnancy, lactation
—Hemolytic anemia
—Gastric bypass
—Hemodialysis
What can result from folate deficiency during pregnancy? What stage of pregnancy?
- Neural tube defects
- Periconception period
What neural tube defects may result from folate deficiency?
- Anencephaly
- Spina bifida
- Meningomyelocele
- Iniencephaly
- Encephlocele
Possibly also:
- Cleft lip/palate
- Cardiac
- Cognition
40% of pregnancies in Europe are unplanned; folate not taken by disadvantaged women
(grains are fortified in US/Canada)
Treatment for folic acid deficiency?
Deficient pts are uncommon with current diet
- Treat with multivitamin with 400 mcg
- Take 1 mg/day as a prescription
What are some other causes of megaloblastic anemia (other than B12/folate deficiency)?
Nitrous oxide
Drugs
- DHF reductase inhibitors (methotrexate)
- Antimetabolites (hdyroxyurea, etc)
- DNA synthesis inhibitors
- Anti-convulsants
- Oral contraceptives
Inborn errors of metabolism
Myelodysplastic syndrome
What may cause macrocytosis (just plain big RBC)?
- Megaloblastic anemia
- Certain Sideroblastic anemias
- Liver Disease
- Extreme reticulocytosis (if very young)
- Hypothyroidism
- Artifactual
—Cold Agglutinin Disease
Case)
An 85 year old woman presents with anemia with hemoglobin of 5, MCV is 120, WBC and platelet count are low. She has decreased position sense in her lower extremities and very brisk reflexes.
Which one of the following is most likely to be deficient?
A. Iron
B. Folate
C. B12
D. B6
Which one of the following is most likely to be deficient?
A. Iron
B. Folate
C. B12
D. B6
Flowchart of hypoproliferative/ineffective anemias
