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LAMP Week 3 > Evaluation of Microcytic Anemias > Flashcards

Evaluation of Microcytic Anemias Flashcards

1
Q

microcytosis

A

Normal Range for MCV is Age and Laboratory Dependent!

Microcytosis is defined as automated red cell MCV below the normal range for age/gender/ethnicity

*Remember that MCV must be compared to an individual’s baseline and for some people “microcytosis” could be at the low end of what the laboratory calls “normal range”

Remember that human beings can have more than one process affecting their MCV; marked anemia with “normal range” MCV can be seen when someone has two pathologic processes one that increases MCV and a second that decreases MCV… ex: The classic diseases that would give a falsely normal MCV would be GI conditions like celiac sprue or Crohn’s where you have a combination of microcytic anemia from blood loss and macrocytic anemia from malabsorption of B12.

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2
Q

What is hypochromasia?

A
  • By morphology, the red cell central pallor is more than 1/3 of the diameter of the cell
  • By indices, the MCHC is below the normal range
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3
Q

What makes cells “small”?

A
  1. decrased membrane

2. decreased stuffing

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4
Q

What is the one congenital cause of decreased red cell membrane causing a low MCV?

A

Hereditary elilptocytosis

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5
Q

What is the cause of decreased stuffing?

A

decreased hemoglobin

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6
Q

Decreased hgb production leads to ______ and _____ RBCs

A

SMALL (low MCV microcytic)

PALE (low MCHC hypochromic) –> this value may LAG BEHIND hypochromic morphology

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7
Q

What causes decreased Hgb?

A

decreased heme

decreased globin

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8
Q

What are the etiologies of hypochromic microcytic anemia?

A

Anything that cuases decreased Hgb production

  1. Low Fe supply - IDA
  2. Disorder of Fe cycling - AOCD
  3. Disorders of incorporation of Fe into protoporphyrine to make heme - protoporphyria, sideroblastic anemia
  4. decreased syntehsis of globin
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9
Q

What is the MCC of hypochromic microcytic anemia?

A

IDA

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10
Q

IDA in infants and children

A

• Inadequate dietary intake (did you know that breast milk
contains little or no iron?)
• increased requirement

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11
Q

IDA in premenopausal women

A
  1. menstrual blood loss

2. pregnancy

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12
Q

IDA in adult men and postmenopausal women

A
  1. GI/GU bleeding (often due to malignancy
  2. malabsorption (gastric surgery, celiac sprue, crohn’s)
  3. inadequate intake
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13
Q

What does Fe do?

A
  1. heme: OXYGEN CARRIAGE (protoporphyrin + Fe = heme)
  2. Electrong transport and ENERGY GENERATOIN in mitochondrial respiration
  3. Ribonucleotide reductase ==> DNA SYNTHESIS
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14
Q

Where is fe stored?

A

Ferritin in the mitochondria

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15
Q

How is Fe metabolized?

A
  1. Iron is absorbed from the GI tract and bound to apotransferrin to form transferrin
  2. Circulating transferrin- bound iron can deliver ferric iron (Fe+3) to red cell precursors in bone marrow, macrophages in liver or bone marrow or other sites, and to muscle tissue
  3. Iron is delivered to the red cell precursors (nucleated red cells) in the bone marrow by transferrin
  4. Transferrin receptors take up the iron and deliver it to the mitochondria that surround the precursor red cell nucleus
  5. In the mitochondria, ferrochelatase and pyridoxine (vitamin B6) are needed in order to incorporate iron into protoporphyrine to make heme
  6. In the mitochondria, IF the pathway to heme (Fe+2) which includes ferrochelatase and pyridoxine is blocked, iron is stored as FERRITIN (Fe+3) in the mitochondria
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16
Q

WHat happens to Fe if it can’t be incorporated into heme?

A

In the nucleated red cell, the mitochondria are adjacent to and ring around the nucleus.

If iron can t be incorporated into heme, it collects as ferritin in the mitochondria and shows up as blue granules adjacent to the nucleus when cells are stained with a chemical that binds to ferric iron (Fe+3). Heme is ferrous iron (Fe+2) so hemoglobin doesn t bind the stain.

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17
Q

What regulates the amount of Fe that can enter the RBC to make heme?

A

the amount of circulating transferrin and the number of transferrin receptors on the surface of the nucleated red cell.

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18
Q

how is Fe absorbed?

A

duodenal mucosal cells

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19
Q

where does dietary Fe come from?

A

– Heme iron: small portion of dietary iron • 20-30% absorbed
– Nonheme iron: greater portion of dietary iron
• Less than 5% absorbed
• Must be converted from ferric (Fe3+) to ferrous (Fe2+) form

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20
Q

What leads to increased Fe absorption?

A

– Iron deficiency, ineffective erythropoiesis

– Enhanced by ascorbic acid

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21
Q

What leads to reduced Fe absorption?

A

– Phytates, tannates, phosphates

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22
Q

What happens to RBCs and in turn Fe at the end of their life?

A

RBCs are phagocytosed by tissue macrophages.
Heme oxygenase releases Fe from heme for recycling.
- returned to plasma transferrin or diverted to intracellular ferritin

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23
Q

What is ferritin?

A

intracellular protein that stores Fe in nontoxic form

24
Q

What is hemosiderin?

A

Some ferritin converted to hemosiderin
– Water-insoluble
– Stores Iron in higher amounts, but less available form.

25
Q

Where is Fe stored?

A

Ferritin
some hemosiderin

  • Remainder of iron stored in myoglobin, heme and nonheme enzymes
  • Main iron storage sites: liver, bone marrow, spleen and muscle
26
Q

What is the physiologic response to IDA?

A
  • Less iron means less hemoglobin production
  • Less hemoglobin means smaller red cells with less oxygen carrying capacity -
  • Less oxygen delivery stimulates erythropoietin production which can drive up red cell count and variation in red cell size
  • Less circulating iron stimulates production of transferrin and transferrin receptors
27
Q

Classic severe IDA has what characteristic labs?

A

low RBC
low MCV
low mCHC
high RDW

28
Q

What is the diff between early IDA and moderate IDA?

A
  • Early IDA: HIGH RBC, low normal MCV, normal MCHC, slightly increased RDW
  • Moderate IDA: normal RBC, LOW MCV, normal or LOW MCHC, increased RDW
29
Q

What labs are characteristic of Fe def w/ vit B12 or folate def?

A

normal or low RBC, normal or low MCV, normal or low MCHC, increased RDW

30
Q

What labs should you get to evaluate IDA?

A

Serum Fe studies

Ferritin, transferrin, Fe

31
Q

In IDA serum ferritin is expected to be…

A

LOW!

HOWEVER – Ferritin is an Acute phase reactant; can be falsely elevated into normal range

32
Q

In IDA serum transferrin is expected to be…

A

HIGH!

HOWEVER – Transferrin can be in normal range or even low when iron deficiency is combined with anemia of chronic disease

33
Q

What is serum Fe used for?

A

Can t be interpreted alone; serum iron is used to calculate % iron saturation which can be used to interpret the ferritin and transferrin levels when confusing or complicated

34
Q

How do you treat IDA?

A

– Oral ferrous sulfate or ferrous gluconate – Parenteral iron dextran

35
Q

What is seen lab wise in treated IDA?

A

– Reticulocytosis and increasing Hgb after 7-8 days
• More rapid in children
– Normal Hgb after 6 wks!

36
Q

What should you think if someone’s Hgb does NOT improve after 6 weeks?

A

Treatment failure!

– Incorrect diagnosis
– Continued bleeding (Such as with GI cancer)
– Infection, inflammation, neoplasia (superimposed anemia of chronic disease)

37
Q

53 yo F attorney presents to clinic complaining of feeling tired

Hgb 8
Hct 29.8
RBC wnl
MCV 70 L
MCHC 26.8 L
RDW 25.9 H

Ferritin 9L

Low ferritin means….
2. Why is the transferrin level normal (not high) if she is iron deficient????

A

Some Key Points:
1. Low ferritin means IRON DEFICIENCY; although inflammation can elevate ferritin into normal range, there is no other cause except iron deficiency for a low ferritin.

There is likely a component of AOCD complicating the picture

38
Q

What causes AOCD?

A

Chronic infection, inflammation (e.g. autoimmune disorders), malignancy, renal disease

RELEASE –>

• Pro-inflammatory cytokines
• Increased acute-phase reactants
– increased plasma viscosity, increased ESR, increased rouleaux.

  • 25% are microcytic
  • Mild to moderate anemia
39
Q

What is hte key central regulator in AOCD?

A

hepcidin - decreases RELEASE of Fe into the blood

It is synthesized in the liver (d) and secreted in plasma and binds to the cellular iron export channel ferroportin causing its internalization and degradation, thereby decreasing iron efflux from iron exporting enterocytes (a) and macrophages (c) into plasma

40
Q

How do increased inflammatory proteins lead to AOCD?

A

IL-6, IFN

  • Down regulate production of transferrin receptors on red cells
  • Up regulate circulating proteins (lactoferrin) that deliver iron to macrophages but not to red cells
  • Up regulate hepcidin that blocks iron release from macrophages
  • Retention of iron in macrophages due to hepcidin results in increased ferritin synthesis
  • Increased ferritin synthesis drives up circulating ferritin
41
Q

What is the end result of AOCD?

A

Redistribution of iron from circulating RBC s to macrophages
– Reduced iron supply to erythroblasts means decreased heme production means RBC s become smaller, sometimes becoming microcytic

42
Q

what are typical CBC findings indicative of AOCD?

A

– RBC can be normal or low
– Hgb is low
– MCV is usually low normal but can be low or very low – MCHC can be normal or low
– RDW can be normal or high

*In other words, CBC can look like any other normocytic anemia or microcytic anemia including iron deficiency

43
Q

What studies can be used to diagnose AOCD?

A
  1. Iron studies : Classic Pattern Increased ferritin, decreased transferrin, normal iron saturation (because it is the saturation of transferrin which is also decreased)
  2. New tests (not for screening)
    – Soluble transferrin receptor assay (Recall that transferrin receptors are down regulated in response to inflammation)
    – Serum or urine Hepcidin assay (Recall that inflammatory proteins up regulate hepcidin production)
44
Q

Should soluble transferrinreceptor and hepcidin tests be used for screenin?

A

NO! They’re expensive

45
Q

How do you treat AOCD?

A
  • Treat underlying inflammatory disorder
  • Recombinant erythropoietin
  • Iron supplementation (without erythropoietin and treatment of the inflammatory process) is usually ineffective
46
Q

Sideroblastic anemias can be caused by what two things?

A
  1. Abnormal Fe metabolism w/in RBC precursors

2. Enzymatic defects in heme biosynthesis

47
Q

Examples of Abnormal Fe metabolism w/in RBC precursors…

A

Iron sequestered in RBC mitochondria; unavailable for heme synthesis: INEFFECTIVE erythropoiesis

48
Q

Example of Enzymatic defects in heme biosynthesis

A
  1. aminolevulinic acid (ALA) synthase
    • 1st step of heme biopsynthesis pathway
    – Committed step in protoporphpyrin synthesis
    – Pyridoxine (vitamin B6) is a cofactor
    • Inhibited by lead
  2. ferrochelatase activity
    • Iron to protoporphyrin
    • Inhibited by ethanol
    • Poisoned by lead or high levels of zinc

**EtOH is the MC cause

49
Q

What happens in the mitochondria, IF the pathway to heme (Fe+2) which includes ferrochelatase and pyridoxine is blocked?

A

iron is stored as FERRITIN (Fe+3) in the mitochondria

In the nucleated red cell, the mitochondria are adjacent to and ring around the nucleus. If iron can t be incorporated into heme, it collects as ferritin in the mitochondria and shows up as blue granules adjacent to the nucleus when cells are stained with a chemical that binds to ferric iron (Fe+3). Heme is ferrous iron (Fe+2) so hemoglobin doesn t bind the stain.

50
Q

What is the difference between congenital vs acquired sideroblastic anemia?

A

Congenital is rare!
– Usually X-linked
– Usually very microcytic
– Usually respond to vitamin B6 supplementation
– Pathologic complications of iron overload

Acquired
– Due to toxins
• Ethanol is a common cause and usually normocytic or macrocytic
• Heavy metals (like lead) usually are microcytic
– Due to a myeloid neoplasm (MDS, myeloproliferative neoplasm or myeloid leukemia)
• Usually normocytic or macrocytic

51
Q

How do you diagnose sideroblastic anemia on CBC?

A

Routine CBC - All sideroblastic anemias are characterized by very high RDW; congenital sideroblastic anemias and heavy metal toxicity (eg: lead) USUALLY have a low MCV
• Routine iron studies will show a very high ferritin level

52
Q

What does a blood smear show in sideroblastic anemia?

A

A blood smear morphology review is a helpful next step if a sideroblastic anemia is suspected; the hypochromic red cells often contain precipitated iron giving them a stippled appearance

53
Q

What is hte defining test in sideroblastic anemia?

A

iron staining of bone marrow

– Erythroblasts have perinuclear ring of coarse iron granules

54
Q

Two year old boy admitted to hospital with URI. No prior illness
Key Points: Note the high RDW and serum ferritin; what are the causes of sideroblastic anemia that you are concerned about in a two year old?

A

Lead poisoning!

55
Q

Summary of microcytic anemias…

A

Microcytic Anemias: Diagnostic Approach
• Differential diagnosis:
– iron deficiency anemia
– Thalassemia (and some hemoglobinopathies)
– anemia of chronic disease
– sideroblastic anemia (microcytic ones are typically congenital or lead poisoning)
– Rare congenital membrane defects (Elliptocytosis)
• Clinical data can be very helpful
• RBCindices
– RBC, Hgb, MCV and RDW
• Iron studies
– Ferritin, transferrin, iron saturation (and sometimes soluble transferrin receptors and ?hepcidin?)
• Blood smear morphology can frequently give you a quick answer…

DON’T IGNORE LOW MCV EVEN IF THE PATIENT IS NOT ANEMIC.

LAMP Week 3 (11 decks)

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