Exercise VI: Blood Physiology

Clinical Case: Iron-Deficiency Anemia

A healthy 55-year old man presents to the doctor's office complaining of increasing fatigue for the past four to five months.
He exercises daily, but lately he has noticed becoming short of breath while jogging. He denies orthopnea, paroxysmal nocturnal
dyspnea (PND), or swelling in his ankles. The patient reports occasional joint pain, for which he uses over-the-counter Ibuprofen.
He denies bowel changes, melena or bright red blood per rectum, but he reports vague left-sided abdominal pain for a few months,
on and off, not related to food intake.
He weighs 210 lbs. He is febrile. On examination, there is a slight pallor of the conjunctivae, skin and palms. No
lymphadenopathy was noted. Cardiovascular system reveals a regular rate and rhythm. Grade I/V systolic ejection murmur is heard.
He has no extremity edema, cyanosis or clubbing. Hemoglobin is 8.2 g/dL.

Learning Objectives:
1. Discuss the epidemiology and common causes of IDA.
a. Epidemiology
i. Menstruating women are at especially high risk. Their monthly loss of blood increases their routine need for
iron, which often is not met. Women of childbearing age do not receive proper iron supplementation,
pregnancy and nursing can lead to a loss of nearly 900 mg of iron which further depletes iron stores.
ii. Growing children also are at risk. Growth requires iron for the cytochromes of all new cells, myoglobin for
new muscle cells and hemoglobin in the additional RBCs needed to supply oxygen for a large body.
Increasing need for iron as the child grows can be coupled with dietary inadequacy, especially in
circumstances of poverty or neglect.
iii. IDA is relatively rare in men and postmenopausal women because the body conserves iron so tenaciously
and these individuals lose only about 1 md/day.
iv. March hemoglobinuria (exercise-induced hemoglobinuria)
1. Soldiers subjected to prolonged maneuvers and long distance runners also can develop IDA. RBCs
are hemolyzed by foot-pounding trauma and iron is lost as hemoglobin in the urine.
b. Common causes
i. IDA develops when the intake of iron is inadequate to meet the standard level of demand, when the need
for iron expands without compensated intake, when there is impaired absorption or when there is chronic
loss of hemoglobin from the body.
1. Inadequate Intake
a. When the RBC is starved for iron. Each day, approximately 0.6mg (Fe excreted) is lost
from the body for men while additional quantities of iron are lost when bleeding occurs. For
women additional menstrual loss of blood brings long-term iron loss to an average of about
1.3mg/day. Daily replacement of at least 1 mg of iron from the diet maintains iron balance
and supplies the body’s need for RBC production as long as there is no other source of
loss.
2. Increased need
a. This is the case in periods of rapid growth, such as infancy, childhood, and adolescence.
Pregnancy and nursing place for developing fetus or nursing infant in addition to her own
iron needs. In each of these instances, what had previously been an adequate intake of
iron for the individual becomes inadequate as the need for iron increases.
3. Impaired absorption
a. Impairments may be pathologic, as with malabsorption due to celiac disease. Others may
be inherited mutations of iron regulatory proteins (matriptase 2 protein) that lead to a
persistent production of hepcidin, causing ferroportin (Fe2+ transporter) inactivation which
results in decreased iron uptake across intestines.
b. Diseases that decrease stomach acidity impair iron absorption by decreasing the capacity
to reduce dietary ferric iron to the absorbable ferrous form.
i. Due to normal aging, gastrectomy or bariatric surgeries
4. Chronic blood loss
a. Develops with chronic hemorrhage or hemolysis that results in the loss of small amounts of
heme iron from the body over a prolonged period of time.
b. Excessive heme iron can be lost through chronic gastrointestinal bleeding from the ulcers,
gastritis due to alcohol or aspirin ingestion, tumor, parasitosis, diverticulitis, ulcerative colitis
or hemorrhoids.
c. Heme iron can also be lost excessively through the urinary tract with the kidney stones,
tumors or chronic infections.
i. Individuals with paroxysmal nocturnal hemoglobinuria can develop IDA due to loss
of iron in hemoglobin passed into the urine.

2. Discuss the altered physiology in IDA.

a. About 70% of iron in the body is found in the heme groups of hemoglobin. Consequently, hemoglobin synthesis
requires an adequate supply of iron in the diet. Most dietary iron comes from red meat, beans, spinach and
iron-fortified bread.
i. Iron is absorbed in the small intestine by active transport. A carrier protein called transferrin binds iron and
transports it in the blood. The bone marrow takes up iron and uses it to make the heme group of
hemoglobin for developing red blood cells.
ii. In cases that there is excess iron, it is stored, mostly in the liver. Iron stores are found inside a spherical
protein called molecule ferritin. Smaller quantities of iron in the storage pool are in an extremely insoluble
form called hemosiderin.
 IDA develops slowly, progressing through stages that physiologically blend into one another but are useful delineations for
understanding disease progression. Iron is distributed among three compartments: the storage compartment, principally as ferritin in
the bone marrow macrophages and liver cells; the transport compartment of serum transferrin, and the functional compartment of
hemoglobin, myoglobin, cytochromes.

a. Stage 1 of iron deficiency

i. Characterized by progressive loss of storage iron (ferritin). RBC development is normal, however, because
the body’s reserve of iron is sufficient to maintain the transport and functional compartments through this
phase. There is no evidence of iron deficiency in the peripheral blood because RBCs survive 120 days, and
the patient does not experience symptoms of anemia.

b. Stage 2
i. Defined by the exhaustion of the storage pool of iron. For a time, RBC production continued as normal,
relying on the iron available in the transport compartment. Hemoglobin content of reticulocytes begins to
decrease, which reflects the onset of iron deficient erythropoiesis, but because the bulk of the circulating
RBCs were produced during the period of adequate iron availability, the overall hemoglobin measurement
is still normal. As long as the serum iron remains within the normal range, hemoglobin synthesis is
unaffected despite the dwindling iron stored. Once transferrin saturation falls to 15-20%, hemoglobin
synthesis becomes impaired
1. Serum iron and ferritin levels decrease whereas total iron-binding capacity increases.
2. TIBC is an indirect measure of transferrin. Transferrin receptors increase on the surface of
iron-starved cells as they try to capture as much as available iron as possible. They also shed into
the plasma, so the soluble transferrin receptor levels increase measurably.
c. Stage 3
i. Stage 3 of iron deficiency is frank anemia. Hemoglobin and hematocrit are low relative to the reference
intervals. Depletion of storage iron and diminished levels of transport iron prevent normal development of
RBC precursors. The RBCs become microcytic and hypochromic as their ability to produce hemoglobin is
restricted.
1. As expected, serum ferritin levels are exceedingly low. The hemoglobin contents of RBCs will
continue to drop.

3. State and explain the physiologic effects of IDA.

a. Synthesis of hemoglobin begins in the proerythroblasts and continues even into the reticulocyte stage of the RBCs.
i. Succinyl-CoA (from TCA) binds with glycine to form a pyrrole molecule.
ii. Four pyrroles combine to form protoporphyrin IX which combines with iron to form the heme
iii. Each heme molecule combines with a long polypeptide chain, a globin → a subunit of hemoglobin
b. Each hemoglobin chain has a heme prosthetic group containing an atom of iron. Each of these can bind loosely
with one molecule of oxygen, making a total of four molecules of oxygen that can be transported by each
hemoglobin molecule.
c. In cases of IDA, the patient experiences the nonspecific symptoms of anemia, typically fatigue, weakness and
shortness of breath. Pallor is evident in light-skinned individuals but also can be noted in the conjunctivae, mucous
membranes or palmar creases of dark-skinned individuals.
i. When there is a decrease in serum iron, heme synthesis would be greatly affected. Decreased heme in
hemoglobin will also lead to decreased oxygen transport → tissues would then be hypoxic
ii. Oxygen is required to produce ATP → if cells are hypoxic, there will be impaired electron transport chain,
unable to reduce oxygen to water and to produce ATP through ATP synthase → diminished ATP → fatigue
(?)
iii. Since heme is a red-colored compound, when the blood with low hemoglobin flows to the capillaries of the
skin, it appears to be light or less red causing pallor of the conjunctivae and more evidently in the skin and
palm.
iv. The brain has a high demand for oxygen, therefore, when hemoglobin is decreased, there is an impaired
oxygen transport to the brain, most likely to lead to cerebral and tissue hypoxia that contributes to the bad
headaches, confusion, fatigue and some nausea that the patients experienced.
4. Describe the diagnostic approach in the assessment of anemia.
a. Analyze the CBC and MCV
i. To detect anemia, CBC is used to determine the RBC count, hemoglobin concentration, hematocrit, RBC
indices, white blood count (differential count) and platelet count.

ii. RBC indices include mean cell volume, mean cell hemoglobin and mean cell hemoglobin concentration.

RBC INDICES

𝐻𝑐𝑡
𝑀𝐶𝑉 = 𝑅𝐵𝐶 𝑐𝑜𝑢𝑛𝑡
𝑥 100
Mean Cell Volume - indicator of the mean volume of the red blood cell Normal value: 80 to 100 fL

Microcytic = less than 80 fL

Normocytic = 80 to 100 fL
Macrocytic = greater than 100 fL

𝐻𝑔𝑏
𝑀𝐶𝐻 = 𝑅𝐵𝐶 𝑐𝑜𝑢𝑛𝑡
𝑥 100
Mean Cell Hemoglobin - expresses the mass of the average hemoglobin
in individual erythrocyte Normal value: 26 to 32 picograms

𝐻𝑔𝑏
𝑀𝐶𝐻𝐶 = 𝐻𝑐𝑡
𝑥 100

Mean Cell Hemoglobin Concentration - measures the mean average Normal value: 32 to 36 g/dL
concentration of hemoglobin in erythrocyte
Hypochromic = less than 32 g/dL
Normochromic = 32 to 36 g/dL
Hyperchromic = greater than 36 g/dL

b. Describe the morphology of RBC in patients with IDA.

i. As hemoglobin level continues to fall in IDA, microcytosis and hypochromia become more prominent, with
progressive declining values for MCV, MCH and MCHC.
ii. Poikilocytosis, including occasional target cells and elliptocytes, may be present, although no particular
shape is characteristic or predominant.
iii. Anisocytosis is present because of a decrease in mean rbc volume.
c. Interpret the leukocyte count and platelet count.
i. Thrombocytosis may be present, particularly if IDA results from chronic bleeding, but this is not a diagnostic
parameter.
ii. White blood cells are typically normal in number and in appearance.