Microcytic anemia

Question 1

What is the common cause of microcytic anemias?

Answer 1

decreased production of hemoglobin. RBC progenitor cells in the bone marrow are large and divide multiple times to produce smaller mature cells. microcytosis is due to an “extra” cell division.
remember: hemoglobin is made of heme + globin. heme = Fe + protoporphyrin.

Question 2

sideroblastic anemia: pathophysiology

Answer 2

anemia due to underproduction of heme.
heme = Fe + protoporphyrin.
In sideroblastic anemia, there is a problem with the production of protoporphyrin.
protoporphyrin synthesis:
succinyl CoA is converted to ALA (aminolevulinic acid) by ALAS (aminolevulinic acid synthetase). This is the rate limiting step and requires vitamin B6. ALA is converted to porphobilinogen by ALAD (ALA dehydrogenase). additional reactions convert porphobilinogen to protoporphyrin. ferrochelatase converts protoporphyrin + iron to make heme. This reaction occurs in the mitochondria.
if any of the steps in the production of protoporphyrin is disrupted, we see decreased heme synthesis and a relative iron overload. iron builds up in the mitochondria and appears as rings around the nucleus of the erythroid precursors –> ringed sideroblasts. Use a prussian blue stain for iron.

Question 3

causes of sideroblastic anemia

Answer 3

1. Congenital. usually due to a deficiency in ALAS (rate-limiting enzyme of protoporphyrin synthesis. aka aminolevulinic acid synthetase).
2. Alcoholism: mitochondrial poison
3. Lead poisoning: inhibits ferrochelotase (converts Fe and protoporphyrin to heme) and ALAD (converts ALA to porphobilinogen).
4. vitamin B6 deficiency: required cofactor for ALAS. most commonly seen as a side effect of isoniazid treatment.

Question 4

lab findings in sideroblastic anemia

Answer 4

high ferritin, low total iron binding capacity, high serum iron, high percent iron saturation.

Question 5

lead poisoning: pathophysiology, symptoms, treatment

Answer 5

inhibits ferrochelatase, and ALAD (ALA dehydrogenase). causes a sideroblastic microcytic anemia. increases
also inhibits rRNA degradation, causing RBCs to retain aggregates of rRNA (basophilic stippling). protoporphyrin and d-ALA (aminolevulinic acid) accumulate.
symptoms: LEAD: lead lines on gingivae and on metaphyses of long bones on x ray.
encephalopathy and erythrocyte basophilic stippling
abdominal colic and sideroblastic anemia
drops: wrist and foot drop.
(in kids, causes mental deterioration; in adults, causes headache, memory loss, demyelination)
dimercaprol and EDTA are first line for adults; succimer is used for chelation in kids.

Question 6

normal hemoglobin; general thalassemia definition

Answer 6

thalassemia: defect in globin synthesis causes low hemoglobin and a microcytic anemia.
may protect against P. falciparum malaria.
normal hemoglobin types: HbF (a2g2), HbA (a2b2), and HbA2 (a2d2).

Question 7

alpha thalassemia

Answer 7

usually due to a gene deletion. normally, 4 alpha genes are present on chromosome 16.
variable presentations:
1. 1 gene deleted: asymptomatic
2. 2 genes deleted: mild anemia with incr. RBC count. cis deletion associated with incr. risk of severe thalassemia in offspring. seen in asians. trans deleition is one deletion on each chromosome copy; most common in Africans.
3. 3 genes deleted: severe anemia. beta chains form tetramers (HbH) that damage RBCs and can be seen on electrophoresis.
4. 4 genes deleted- lethal in utero (hydrops fetalis). gamma chains form tetramers that damage RBCs.

Question 8

beta thalassemia

Answer 8

due to point mutations in promoter or splicing sites. seen in Africans/mediterraneans.
2 beta genes present on chromosome 11. mutation causes absent or diminished production of beta globin.
Thalassemia minor: normal gene/diminished gene. mildest disease. usually asymptomatic w/ incr. RBCs. microcytic, hypochromic RBCs and target cells seen on blood smear. electophoresis shows slighlty decr. HbA with slightly increased HbF and HbA2.
Thalassemia major: no beta chains made. presents a few months after birth (HbF, which is a2g2, is protective at birth). symptoms include:
1. aggregation of alpha tetramers damage RBCs and cause ineffective erythropoeisis and extravascular hemolysis.
2. massive erythroid hyperplasia –> expansion of hematopoeisis into the skull/facial bones (chipmonk facies, XRay crew cut), extramedullary hematopoeisis with hepatosplenomegaly, and risk of aplastic crisis with parvovirus B19 infection.
tx: chronic transfusions. can cause secondary hemochromatosis.
smear shows hypochromic RBCs with target cells and nucleated RBCs.

Question 9

acute intermittent porphyria

Answer 9

problem with porphobilinogen deaminase. porphobilinogen, ALA (aminolevulinic acid), and coporphobilinogen found in urine.
symptoms:
painful abdomen, port-wine colored urine, polyneuropathy, psychologic disturbances, autonomic instability. precepitated by drugs, alcohol, and starvation. anything that activates CYP450 can precipitate this, since CYP450 contains a heme. increasing CYP450 depletes heme and stimulates protoporphyrin synthesis.
treatment: glucose and heme, which inhibit ALA synthase.

Question 10

porphyria cutanea tarda

Answer 10

uroporphyrinogen decarboxylase is deficient. this is an enzyme needed for one of the intermediate steps between porphobilinogen and protoporphyrin.
causes a build up of uroporphyrin in the urine (tea-colored urine).
causes blistering cutaneous photosensitivity.

Question 11

HbS/beta thalassemia heterozygote

Answer 11

mild to moderate sickle cell disease, depending on the amount of beta globin production

Question 12

iron deficiency anemia: causes, manifestations

Answer 12

iron is consumed in heme (meat-derived) and non-heme sources; heme sources are better absorbed. absorption occurs in the dudodenum (remember, enterocytes then use ferroportin to transfer it to the blood if the body needs iron. then, transferrin transports iron in teh blood and delivers it to liver/bone marrow macrophages for storage bound to ferritin).

labs: serum iron low, ferritin low, total iron binding capacity high, % saturation low.
causes: breast feeding, nutritional deficits, peptic ulcer disease, menorrhagia, colon polyps/CA, Necator or Ancylostoma duodenale (hookworms), malabsorption, gastrectomy (acid aids iron absorption by keeping it in Fe2+ form).

Stages of iron deficiency anemia:

1. storage iron depleted: decr. ferritin, incr. total iron binding capacity
2. serum iron depleted: decr. serum iron, decr. % saturation
3. normocytic anemia: bone marrow makes fewer RBCs
4. microcytic anemia: smaller and fewer RBCs

Question 13

clinical features and lab findings of iron deficiency anemia

Answer 13

anemia, koilomychia, pica.
labs: microcytic, hypochromatic RBCs with inrc. red cell distribution witdth.
decr. ferritin, incr TIBC, decr. serum iron, decr. % saturation.
incr. free erythrocyte protoporphyrin.
give ferrous sulfate.
consider plummer-vinson syndrome: iron deficiency anemia, esophageal webs (dysphagia), and glossitis.

Question 14

anemia of chronic disease

Answer 14

chronic inflammation causes production of acute phase proteins from the liver, incl. hepcidin. hepcidin sequesters iron in storage sites by:

1. limiting iron transfer from macrophages to erythroid precursors
2. suppressing EPO.
   labs: high ferritin, low TIBC, low serum iron, low % saturation. high free erythrocyte protoporphyrin.