Microcytic and Macrocytic Anemias

Question 1

Where is iron absorbed normally?

Answer 1

duodenum through the intestinal wall and then is bound by transferrin

Question 2

Where is iron commonly stored?

Answer 2

bone marrow and macrophages in the liver and spleen

Question 3

How is iron absorbed?

Answer 3

Iron is reduced as it enters the GI tract and is absorbed into intestinal cells via DMT-1 transporters.

daily absorption ~1mg (also ~1mg lost in urine daily)

Question 4

What are the major fates of reduced iron inside intestinal cells?

Answer 4

can be transformed in ferritin or it can be transported out of the cell via ferroportin where it is then re-oxidized

Question 5

What does hepcidin do?

Answer 5

decrease iron transport into blood from GI tract or from storage in bone marrow/macrophages

produces a functional iron deficiency

Question 6

Signs of iron deficiency?

Answer 6

angular cheilosis- cracking at corners of the mouth

koilonychia (spooning of finger nails)- nails are concave, rigid, and brittle.

glossits- loss of papillae on tongue

craving for ice (pika)

Question 7

How do iron deficient red cells appear? Would transferrin be increased?

Answer 7

in a peripheral blood smear, the red cells appear hypochromic and microcytic with enlarged central pallor areas and some may appear as target cells (long and slender)

increased transferrin with 5% saturation would be seen

Question 8

What color does iron stain?

Answer 8

blue via prussian blue. Thus, in bone marrow iron deficient people will show no blue

Question 9

T or F. Inflammation increases the amount of hepcidin circulating in the body

Answer 9

T. This is a defense mechanism geared toward limiting the amount of iron available to bacteria in the blood

Question 10

What is hemochromatosis?

Answer 10

too much iron is deposited into tissue (skin-brawnzing of skin, liver- cirrhosis, heart- heart failure, joints- arthritis, endocrine organs- diabetes hypopituitarism)

Question 11

What is hemochromatosis most commonly caused by? Common where?

Answer 11

defect in HFE gene. Most common in Northern Europe (there, 5 out of 1000 people are homozygous for mutation of the HFE gene)

Question 12

MOI of genetic hemochromatosis?

Answer 12

AR

Question 13

What is the most common mutation of genetic hemochromatosis?

Answer 13

C282Y mutation (90%) and is diagnostic

penetrance is variable however

Question 14

What does mutated HFE cause?

Answer 14

decreased hepcidin levels

Question 15

How is hemochromatosis treated?

Answer 15

phlebotomy regularly (once a week for a couple weeks, then once every 2 weeks, etc.) to make patient iron deficient, which will hopefully cause iron release from tissues

want ferritin less than 50 ng/ml

Question 16

What is sideroblastic anemia? Causes?

Answer 16

defect in prophyrin ring enzymes that causes iron to accumulate into mitochondria in red cells that can be seen with prussian blue stain

Causes:

• defect in ala synthase
• myelodysplasia
• lead poisoning
• tuberculosis therapy (isoniazid)

Question 17

Describe the development of hemoglobin in detail.

Answer 17

hemoglobin synthesis in developing red cells begins as iron enters the cell with transferrin and is combined with protoporphyrin, synthesized largely from glycine and succinyl-CoA in mitochondria, to form heme. One molecules of heme attaches to one of the globin polypeptide chains to from a unit of hemoglobin (1 of 4). Transferrin enter the cell by receptor-mediated endocytosis and then iron is release by a fall in pH, and the apotransferrin and receptor are recycled to plasma and membrane, respectively. Hypochromic anemias arise from lack of iron or failure of heme synthesis.

Question 18

Basophilic stippling is common in what?

Answer 18

lead intoxication. Caused by precipitates of undegraded ribonucleic acid (RNA), the result of inhibition by lead of pyrimidine 5’-nucleotidase, one of the enzymes responsible for RNA degradation

Question 19

What are some causes of macrocytosis? 11 things

Answer 19

• b12 and folate deficiency (most common)
• alcohol toxicity
• hypothyroidism
• myelodysplasia
• aplastic anemia
• liver disease
• hypoxia
• raised reticulocyte counts
• myeloma
• cytotoxic drugs
• pregnancy

Question 20

Why do b12 and folate deficiency result in macrocytic anemias?

Answer 20

Because they result in megaloblastic anemias, in which the maturation of nucleus is delayed because of defects in DNA synthesis

Question 21

Why are folate and b12 important?

Answer 21

diertary folate that circulates as methyl-THF must be transformed into THF using vitamin B12 (as homocysteine is converted to methionine- important in nerve development) in order to be used for pyrimidine synthesis

Question 22

Almost all of the B12 we use comes from diet. How is cycled through the body?

Answer 22

Haptocorrin binds B12 in the mouth and then is degraded in more acidic environments (jejunem), where IF binds and transports B12 into blood in the ileum

Question 23

What is pernicious anemia?

Answer 23

autoimmune disorder that leads to atrophic gastritis/ gastric cancer that binds IF

Question 24

What tests can be used to diagnose pernicious anemia?

Answer 24

parietal cell antibodies (sensitive- found in 90% of patients, but not specific- i.e. can have these antibodies without this disease)

intrinsic factor antibodies- found in about 50% of PA but VERY specific (if you have these, you have the disease)

Question 25

Pernicious anemia is common in which patients?

Answer 25

usually over 60 y/o, but black women under 50 have increased incident

Question 26

Symptoms of B12 deficiency?

Answer 26

glossitis that is more beefy and painful, particularly with got and acidic foods than the glossitis that occurs with iron deficiency

neurologic disorder- balance problems (not true in folate deficiency)

Question 27

What are the early neurologic symptoms of B12 deficiency?

Answer 27

paresthesia of hands and feet

somnolence and dementia

decreased vibratory and proprioception

loss of position sense

Question 28

What are the late neurologic symptoms of B12 deficiency?

Answer 28

spastic paralysis from demyelination of dorsal and lateral columns. Not reversible

combined system disease

Question 29

How do B12 or folate deficient red cells look?

Answer 29

large and oval shaped, as opposed to round

will also see hypersegmented neutrophils (5-6 segments)

Question 30

How are pernicious anemia patients treated?

Answer 30

parenteral (IM) B12 (1000 micrograms of B12 daily for 1 week, then weekly for 4 weeks, then monthly for life)

If you give very lose doses of B12 you can overcome the IF deficiency, so oral B12 2000 micrograms daily can work even if IF is absent

**However, if you give folate/folic acid without B12 the symptoms (neurologic/balance in particular) will be worsened!!

Question 31

What test is most helpful in diagnosing iron deficiency?

Answer 31

ferritin. Iron deficiency is the ONLY thing that causes ferritin?

Question 32

What red cell morphology is most suggestive of autoimmune hemolysis?

Answer 32

microspherocyte

Question 33

What test best defines inadequate marrow function in anemia patients?

Answer 33

reticulocyte count

Question 34

Would hepcidin be high or low in pregnancy related anemia?

Answer 34

Low

Question 35

How would you differentiate between chronic disease anemia and iron deficiency anemia?

Answer 35

iron deficiency anemia - low serum iron and elevated iron binding capacity (ie. low saturation) and low ferritin

chronic disease anemia- both are lower (saturation is slightly lower than normal) and ferritin normal