Nutritional Anemias

Question 1

Transferrin receptor

Answer 1

enables the uptake of iron-bound transferrin from the plasma through the transferrin cycle

Question 2

Ferritin

Answer 2

provides a bioavailable intracellular storage depot for iron, protecting the cell from toxicity

Question 3

Hepcidin

Answer 3

a circulating hormone that controls both the absorption of dietary iron from the gut and release of recycled iron from macrophages

Question 4

ferrireductase

Answer 4

Reduces ferric iron (Fe₃⁺) to its ferrous form (Fe₂⁺). Present at the villous tips of duodenal enterocytes, allowing iron to enter the cell through a luminal transmembrane channel, the divalent metal transporter DMT1.

Question 5

Ferroportin

Answer 5

The only known cellular iron exporter, localized within the plasma membrane on the abluminal or basolateral side of the enterocyte

Question 6

Export of iron from duodenal enterocytes is blocked by . . .

Answer 6

Export of iron from duodenal enterocytes is blocked by hepcidin, a small polypeptide hormone that is produced by hepatocytes and secreted into the plasma.

Hepcidin carries out this critical negative regulatory function by binding to ferroportin, triggering its internalization and subsequent degradation.

Question 7

The expression of hepcidin in hepatocytes

Answer 7

Tightly regulated at the transcriptional level, in part by iron, allowing the body to adjust iron uptake from the gut according to iron stores.

Question 8

The body’s iron stores and utilization

Answer 8

Question 9

Enterocyte iron regulation

Answer 9

Question 10

heme oxygenase

Answer 10

Enzyme in intestinal epithelium that degrades dietary hemoglobin or myoglobin, resulting in the release of iron that is either stored as ferritin or exits from the cell via ferroportin

Question 11

Why is there rarely ever free serum iron?

Answer 11

The plasma protein transferrin binds ferric iron at two sites with extraordinarily high affinity. As a result, the concentration of free iron in the plasma is too low to be easily measured. Thus transferrin effectively protects tissues and cells from the toxicity of “free” iron during its transport in the plasma

Question 12

Iron-dependent regulation of the rate of translation of ferritin and transferrin

Answer 12

When the intracellular iron level is low, iron regulatory proteins (IRPs) bind to a consensus stem loop iron regulatory element in the respective mRNAs, resulting in suppression of ferritin translation and enhancement of transferrin receptor mRNA levels.

When the intracellular iron level is high, the IRPs do not bind to the stem loops. The translation of ferritin is unimpeded and transferrin receptor mRNA is degraded

Question 13

Transferrin receptor affinity

Answer 13

Transferrin molecules loaded with two iron atoms (Fe-transferrin) have much greater affinity for the receptor than do those with either a single atom or none

Question 14

plasma Fe-transferrin uptake

Answer 14

Question 15

Heme biosynthesis occurs. . .

Answer 15

. . . in the mitochondrion

Question 16

__% of transferrin-bound iron is utilized in erythropoiesis.

Answer 16

90% of transferrin-bound iron is utilized in erythropoiesis.

Question 17

___ upregulate the expression and secretion of hepcidin from hepatocytes, blocking not only iron uptake by enterocytes, but also the efflux of iron from macrophages.

Answer 17

Inflammatory cytokines such as interleukin-6 (IL-6) upregulate the expression and secretion of hepcidin from hepatocytes, blocking not only iron uptake by enterocytes, but also the efflux of iron from macrophages. Thus, if inflammation is sustained, anemia often results

Question 18

With its increasing accumulation, some cellular ferritin becomes denatured and is converted to ___.

Answer 18

With its increasing accumulation, some cellular ferritin becomes denatured and is converted to hemosiderin, from which iron is less readily mobilized.

Question 19

TIBC

Answer 19

Total iron binding capacity

The amount of iron that the transferrin in serum can hold.

Question 20

Serum ferritin under different conditions

Answer 20

Question 21

Serum Fe to TIBC

Answer 21

provides an index of the fractional iron saturation of transferrin.

Question 22

Fractional transferrin saturation in patients with chronic inflammation

Answer 22

Patients with inflammatory disorders have both low serum iron levels and low levels of total transferrin. Accordingly, fractional transferrin saturation is often normal.

Question 23

Serum ferritin levels are generally ___ in iron deficiency and ___ in patients with iron overload.

Answer 23

Serum ferritin levels are generally low in iron deficiency and elevated in patients with iron overload.

Question 24

Interpretation of serum ferritin may be confounded in these two commonly encountered clinical settings:

Answer 24

1. Inflammation, regardless of cause, increases ferritin synthesis by hepatocytes
2. Liver disease may result in leakage of ferritin into the plasma.

Question 25

In patients with iron deficiency and concurrent inflammation or liver disease. . .

Answer 25

. . . serum ferritin levels may be normal or even elevated

Question 26

Prussian blue

Answer 26

Dye that specifically stains iron. Way to assess iron stores in various tissues.

Question 27

Serum transferrin receptor

Answer 27

A small fraction of transferrin receptor is released from **maturing erythroid precursors** and enters the plasma, where it can be measured. Because a very large proportion of the body’s transferrin receptor is expressed on **erythroid cells**, the level of serum transferrin receptor is a **good surrogate for erythropoietic activity.** Thus, serum levels are **low in patients with marrow aplasia** and **elevated in patients with ineffective erythropoiesis** and **erythroid hyperplasia**, for example in the setting of hemolysis.

Question 28

Common etiologies of iron deficiency

Answer 28

* Insufficient intake * Menstrual bleeding * GI bleeding * Pregnancy * Parasite infection * Malabsorption

Question 29

Infants whose diets consist primarily of ___ often become iron deficient.

Answer 29

Infants whose diets consist primarily of **cow’s milk** often become iron deficient.

Question 30

Celiac disease-associated anemia

Answer 30

Gluten-sensitive enteropathy causes poor absorption of iron in the duodenum.

Question 31

Efficiency of iron absorption is enhanced by \_\_\_.

Answer 31

Efficiency of iron absorption is enhanced by **low gastric pH**. So, those with autoimmune gastritis, gastric achlorhydria, and *H. pylori* are at increased risk of becoming iron deficient

Question 32

Iron-refractory iron deficiency anemia

Answer 32

Mutations in the gene **matripase-2**, which lead to robust **overexpression of hepcidin and the blockade of duodenal iron absorption.**

Question 33

\_\_\_ may be a behavioral symptom of iron deficiency anemia, but not other anemias.

Answer 33

**Pica** may be a behavioral symptom of iron deficiency anemia, but not other anemias.

Question 34

What is going on in this patient?

Answer 34

Koilonychia or 'spoon nail' Symptom of chronic iron deficiency anemia.

Question 35

Plummer-Vinson syndrome

Answer 35

Syndrome of chronic iron deficiency: * Koilonychia * fissures at the angles of the mouth * thin membrane web in the esophagus that can cause dysphagia * Sometimes pica

Question 36

Incipient or latent iron deficiency

Answer 36

Characterized by **normal hemoglobin, hematocrit, red cell indices, and serum iron level** and the **absence of iron stores in the bone marrow.** As the deficiency becomes more **severe/prolonged,** the mean cell volume **(MCV) falls**, followed by a d**ecrease in hematocrit and hemoglobin concentrations**. Serum ferritin and iron levels fall, whereas total iron binding capacity (transferrin) rises, resulting in **decreased transferrin saturation.** Final stages are **microcytosis accompanied by hypochromia.**

Question 37

Iron deficiency anemia blood smear

Answer 37

* microcytosis * increased central pallor * aberrantly shaped red cells ('pencil' forms) * anisocytosis (abnormally wide range in red cell volume)

Question 38

Anisocytosis

Answer 38

abnormally wide range in red cell volume

Question 39

Treatment of iron deficiency anemia

Answer 39

Oral administration of iron salts, particularly ferrous sulfate. However, many patients have **difficulty tolerating oral iron owing to gastrointestinal symptoms such as heartburn and constipation.** IV iron is also safe and effective. **1 week post administration** via either method, body responds with a burst of reticulocytes. Hematocrit and volume return to normal levels in a few weeks.

Question 40

Menorrhagia

Answer 40

Menstrual periods with abnormally heavy blood loss

Question 41

Reasons an individual might have substantial "hemorrhagic" iron loss

Answer 41

* Menorrhagia * Frequent blood donations * Occult blood in stool

Question 42

Typical diagnostic inquiry for iron deficiency anemia

Answer 42

1. **Thorough** history to ascertain possibility of blood loss or poor nutrition. 2. **Fecal occult blood test** 3. If no satisfactory answer has been found in the history, also include **radiologic/endoscopic evaluation of the gastrointestinal tract**, particularly in males and post-menopausal women

Question 43

Clinical picture of iron deficiency vs iron overload

Answer 43

Question 44

Target organs vulnerable to damage in iron overload

Answer 44

**heart, liver,** and **endocrine cells**, particularly hormone-producing cells in the **pituitary**, **pancreatic islets**, and **gonads**

Question 45

Hereditary hemochromatosis

Answer 45

Inherited disorders of iron overload are caused by defects involving **hepcidin** or its receptor, **ferroportin.** Most commonly a mutation in ***HFE***, an MHC analog that participates in the upregulation of **hepcidin transcription**. In those affected, the signs and symptoms are **not apparent until middle age or later.** **Unfettered iron absorption from the gut and egress from macrophages.** can have increased skin pigmentation and complain of fatigue and arthralgia

Question 46

Enterocyte iron regulation diagram

Answer 46

Question 47

Macrophage iron regulation diagram

Answer 47

Question 48

How does anemia feed back into the regulation of iron absorption?

Answer 48

If you are anemic, less oxygen will be delivered to the liver. If less oxygen is delivered to the liver, hepcidin transcription decreases. If hepcidin transcription decreases, more iron is taken up.

Question 49

Regulation of hepcidin transcription

Answer 49

Question 50

Signs and symptoms of iron deficiency

Answer 50

Signs: pallor, angular stomatitis, glossitis, spoon nails, Plummer-Vinson esophageal webs (rare) Symptoms: Malaise, decreased work performance, fatigue, dyspnea on exertion, pica

Question 51

Notes on Anemia of Inflammation

Answer 51

* Very common anemia in hospital patients * Most chronic inflammatory conditions: rheumatoid arthritis, IBD, chronic infections, malignancy * Rarely severe enough to require transfusion

Question 52

Clinical picture for anemia of inflammation

Answer 52

Question 53

\_\_\_ accounts for the iron abnormalities in the anemia of chronic disease/inflammation

Answer 53

**A relative hepcidin excess** accounts for the iron abnormalities in the anemia of chronic disease/inflammation

Question 54

\_\_\_ can confound the MCV measure.

Answer 54

**Reticulocytosis** can confound the MCV measure. Since reticulocytes tend to be larger than mature erythrocytes on average.

Question 55

As a rule of thumb, non-megaloblatic macrocytic anemias have an MCV \_\_\_\_.

Answer 55

As a rule of thumb, non-megaloblatic macrocytic anemias have an **MCV \< 105**

Question 56

Biochemistry of folate and b12 in DNA synthesis

Answer 56

Question 57

Markers specific to B12 deficiency

Answer 57

**Elevated methylmalonic acid**. Builds up because methylmalonyl-CoA mutase cannot operate without cobalamine.

Question 58

Markers of **both** B12 and folate deficiency

Answer 58

Homocysteine buildup

Question 59

Normoblastic vs megaloblastic bone marrow

Answer 59

Question 60

If there are so many erythroid precursors in megaloblastic anemia, why are no erythrocytes being generated?

Answer 60

An apoptosis program is initiated once they are at reticulocyte-form and their contents are spilled out into the bone marrow. This means that there will be high LDH and bilirubin levels, which may cause scleral icterus and clinical jaundice.

Question 61

Symptoms unique to B12 deficiency

Answer 61

Neurologic and related to the demyelination process of B12 deficiency. * Numbness/tingling * Abnormal gait * Loss of proprioception * Fine motor deficit * Degeneration of the posterior columns of the spinal cord

Question 62

B12 absorption

Answer 62

Question 63

Folate absorption

Answer 63

Question 64

How might one acquire a B12 or folate deficiency?

Answer 64

Question 65

B12 deficiencies will sometimes present only as \_\_\_.

Answer 65

B12 deficiencies will sometimes present only as **neurologic symptoms**

Question 66

Patients with B12 deficiency that are misdiagnosed with folate deficiency and given folate will . . .

Answer 66

. . . **improve hematologically. However, this will have no effect on the demyelination and neurologic symptoms.**

Question 67

If erythrocytes are normocytic, but patient is very anemic and RDW is uncharacteristically huge, what is likely going on?

Answer 67

**Combined iron deficiency anemia and B12/folate deficiency**

Question 68

In normal individuals, what is the major source of iron bound to serum transferrin used for erythropoiesis?

Answer 68

Breakdown of senescent red blood cells by reticuloendothelial macrophages.

Question 69

How is the mean corpuscular volume calculated?

Answer 69

Hematocrit / RBC count

Question 70

Hepcidin regulation

Answer 70