Micro and Macrocytic Anemias - Weir 03.17.15

Question 1

Describe the iron absorption pathway.

Answer 1

• Inorganic ferric Fe3+ iron reduced to ferrous Fe2+ form by ferrireductase enzyme (Dcytb) in the duodenum
• Fe2+ transported into cell via DMT-1 active transport, and stored in cell as ferritin or exported via ferroportin
• Fe2+ reoxidized to Fe3+ as it exits enterocyte, and bound to transferrin for transport to the liver or macros
• Heme iron absorbed via separate receptor
• NOTE: anything that acidifies the lumen of the gut will help with conversion of iron from ferric to ferrous

Question 2

How is hepcidin involved in iron regulation?

Answer 2

• Upregulated hepcidin (i.e., via chronic inflammation) inhibits absorption by intestine and release by macros (by downregulating and degrading ferroportin)
• There are many factors that can affect hepcidin, incl: IL-6 (UP), EPO and HIF (DOWN)
• HFE: mut in predominant # of cases of hemochromatosis (chronic reduction of hepcidin, and unopposed absorption of iron)

Question 3

What is going on here?

Answer 3

• Iron-deficiency anemia
• Angular cheilosis: fissuring and ulceration at corners of the mouth
• Uncertain mechanism, but may be similar to that for nail, mucosal, and pharyngeal changes

Question 4

What is going on here?

Answer 4

• Iron-deficiency anemia
• Koilonychia: nails are concave, ridged, and brittle
• Cause uncertain, but may be related to iron requirement of many enzymes present in epi and other cells

Question 5

What do you see here?

Answer 5

• Iron-deficiency anemia
• Glossitis: bald, fissured appearance of tongue caused by flattening and loss of papillae

Question 6

Describe what you see here. Diagnose.

Answer 6

• Iron-deficiency anemia: hypochromic, microcytic RBCs
• Some poikilocytes present, incl thin, elongated “pencil” cells and occasional target cells
• Plentiful platelets

Question 7

What is the one best measurement of iron storages in the body? Know this table.

Answer 7

• Ferritin
• BUT it is an acute phase reactant, and is falsely elevated with chronic inflammation
• From table:
  1. Iron deficiency: DEC serum iron, % sat, ferritin, INC TIBC
  2. ACD: DEC TIBC, serum iron, % sat, INC ferritin
  3. Iron overload: INC serum iron and ferritin

Question 8

Describe what you see here. Which one is normal?

Answer 8

• Bone marrow iron

A. Normal iron stores indicated by blue staining in macrophages (normal siderotic granule in erythroblast -> magnified cell in upper right)

B. Absence of blue staining (no hemosiderin) in iron deficiency (no siderotic granules in erythroblasts)

Question 9

What is going on with this jolly fellow?

Answer 9

• Hemochromatosis: characteristic bronze appearance
• Hyperpigmentation due to melanin deposited in skin

Question 10

What is HFE? Describe the epi.

Answer 10

• Hemochromatosis gene
• Most common in N Europe (5 per 1,000 people homo for this mutation there)
• Autosomal recessive
• Type 1 most common: C282Y mut (90%) -> diagnostic
• Penetrance is variable

Question 11

What does iron absorption look like in hemochromatosis?

Answer 11

• Marked increased absorption from the duodenum, and infiltration of and damage to normal cells (instead of only being stored in macros like it’s supposed to be)

Question 12

What do you see in this needle liver biopsy of a 30 y/o woman?

Answer 12

• Primary hemochromatosis
• Heavy siderosis of parenchymal cells with sparing of Kupffer cells

Question 13

What is the treatment for hemosiderosis?

Answer 13

• Phlebotomy to get ferriting level below 50

Question 14

What do you see here?

Answer 14

• Ring sideroblasts with perinuclear ring of iron granules in sideroblastic anemia
• Could be myelodysplastic syndromes, other sideroblastic anemias
• Hemochromatosis would NOT cause this

Question 15

What is going on here? What might have caused this?

Answer 15

• Lead poisoning
• Lead line in gums -> poisoning from prolonged exposure to molten lead

Question 16

What is going on here?

Answer 16

• Lead poisoning
• Punctate basophilia: caused by precipitates of undegraded RNA due to inhibition by lead of pyrimidine 5 nucleotidase, one of the enzymes responsible for RNA degradation

Question 17

What are the causes of macrocytosis other than megaloblastosis (9)?

Answer 17

• Alcohol
• Liver disease
• Hypothyroidism
• Myelodysplasia, incl acquired sideroblastic anemia
• Aplastic anemia and red cell aplasia
• Raised reticulocyte count
• Hypoxia
• Myeloma and other paraproteinemias
• Cytotoxic drugs
• Pregnancy

Question 18

What are the causes of megaloblastic anemia associated with Vit B12?

Answer 18

• Inadequate diet: veganism, maternal deficiency
• Malabsorption:
  1. Gastric: pernicious anemia- acquired autoimmune & congenital, IF deficiency, partial/total gastrectomy
  2. Intestinal: stagnant loop syndrome, ileal resection, Crohn’s disease, chronic tropical sprue, tapeworm, drugs (i.e., Metformin)
• NOTE: anything that affects ileum or IF can affect B12

Question 19

What are the 2 major causes of megaloblastic anemia?

Answer 19

• Folate
• Vit B12

Question 20

What are the causes of megaloblastic anemia associated with folate deficiency?

Answer 20

• Inadequate diet: poverty, institutions, goat milk, etc.
• Excess losses: dialysis, CHF
• Drugs: anti-convulsants, barbiturates
• Mixed: alcohol, liver disease
• Malabsorption: gluten-induced enteropathy, dermatitis herpetiformis, tropical sprue, congenital, systemic infections
• Increased utilization: pregnancy, prematurity, excess marrow turnover (e.g., hemolytic anemias), malignancy (i.e., myeloma, carcinoma), inflammatory disease (Crohn’s, RA, widespread eczema)

Question 21

Know this. What is the bottom line here?

Answer 21

• These deficiencies disrupt making of DNA

Question 22

Describe the absorption of B12.

Answer 22

• Vit B12 freed from binding proteins in food via action of pepsin in the stomach -> binds salivary protein haptocorrin
• In duodenum, bound B12 released from haptocorrin by pancreatic proteases and binds intrinsic factor (IF released from parietal cells)
• Complex transported to ileum, where it is endocytosed by ileal enterocytes with cubilin receptor for IF -> once in ileal cells, B12 binds transcobalimin II and is secreted into plasma -> delivered to liver, rapidly dividing cells

Question 23

What is pernicious anemia? Who gets it?

Answer 23

• Atrophic gastritis due to autoimmune disorder
• Parietal cell Abs in 90% of PA (sensitive): can have these Abs, but not have PA
• IF Abs found in 50% of PA (specific): usually give both of these tests to be sure
• All races; greatest in Northern European
• Usually over 60 years old, but black women under 50 have an increased incident
• Associated with other autoimmune disorders
• Increased incidence of gastric cancer
• IMAGE: positive stain for parietal cell autoantibody

Question 24

What is going on here?

Answer 24

• Megaloblastic anemia: pallor and mild icterus (jaundice) in pt with Hg 7.0 g/dL and MCV 132 fL

Question 25

What is this?

Answer 25

• Megaloblastic anemia: glossitis caused by B12 deficiency in 55 y/o woman with untreated pernicious anemia
• Tongue beefy red and painful, esp. with hot and acidic foods -> identical appearance in folate deficiency due to impaired DNA synthesis in mucosal epi

Question 26

What do you see here?

Answer 26

Macroovalicite (classic cell for macrocytic anemia)

Question 27

What do you see here?

Answer 27

• Hypersegmented poly
• Normally 3 or 4 lobes, but clearly 5-7 here
• Classic cell in macrocytic anemia

Question 28

What do you see here?

Answer 28

• Red cell chromatin filled with tiny white spaces; classic for megaloblastic anemia

Question 29

What are the symptoms of the neurologic disorder with B12 deficiency?

Answer 29

• Early: paresthesia of hands and feet, somnolence and dementia, decreased vibratory and proprioception, loss of position sense
• Late: spastic paralysis from demyelination of dorsal and lateral columns (not reversible), combined system disease
• NOTE: important to know the differential physical effects of folate and B12 deficiency (no neurologic symptoms with folate deficiency)

Question 30

What do you see here?

Answer 30

• Pernicious anemia
• Demyelination of posterior and lateral columns; subacute combined degeneration of the spinal cord
• Light colored area is the abnormal area

Question 31

What is the treatment for B12 deficiency?

Answer 31

• IM B12: 1000 ug of B12 daily for 1 wk, then weekly for 4 wks, then monthly for life.
• Consider oral B12 2000 ug daily once stores replete (start IM, then tablets for home) -> bone marrow resolves in 2-3 days, and Hgb normal in 1-2 months
• Folate and B12 affect all cell lines
• May accelerate neurologic complications of B12 def if you give folate to someone who is megaloblastic with no clear cause (check for both)