Friday, December 1, 2000
10:30am – 12:30pm
A 35 year old woman is seen for easy fatigue for many months. She is now 24 weeks pregnant with her 3rd child in 3 years. She does not see any obstetrician and does not take any vitamins. Lately, she has developed a taste for eating ice. She has no other complaint. Family and past history are negative. She does not smoke or drink. Physical examination is positive for pale conjunctiva, mild spooning of nails, and a II/VI systolic murmur at left lower sternal border. Stools are negative for occult blood.
Labs: Complete blood count (CBC) - Hg 7.1 gm/dl, Hct 23%, WBC 5,400/mm3 (differential is normal), platelets 450,000/mm3; Mean Corpuscular volume (MCV) is 74 fl (normal 85-95 fl); Red cell Distribution Width (RDW) is 17.1% (normal 13-15).
QUESTIONS
1.What test would you like to do first to diagnose her anemia? Lab calls you with her total reticulocyte count which is 2.5%. The absolute reticulocyte count is 69,000/mm3.
THE RETICULOCYTE COUNT
Reticulocytes are defined as immature red cells seen in the peripheral blood that contain at least two dots of reticulin material reactive with new methylene blue (NMB) in their cytoplasm. More immature forms have multiple dots and small networks of skeins of bluish material. These remnants are residual ribosomal RNA used for hemoglobin synthesis in the developing erythrocyte. The RNA is too finely distributed to form networks on Wright's stain; a supravital stain causes precipitation and aggregation of the RNA and creates the dots and skeins of reticulin. RNA-containing red cells are usually grayish on Wright's stain and contrast well with mature, orthochromic or pink red cells, providing a clue to the presence of a reticulocyte response. Reticulocytes are counted as the number of NMB-reactive cells per 1,000 red cells and expressed as percent reticulocytes (absolute number per 100 red cells). Interobserver variation and uneven distribution of reticulocytes on the new methylene blue smear introduces a high analytic variation in reticulocyte counting; interlaboratory coefficients of variation in the 20% range are common, a degree of imprecision of which every clinician should be aware. Duplicate reticulocyte counts or 3-day average values may help to reduce the imprecision of the raw reticulocyte count.
Effective red cell production is a dynamic process; the number of reticulocytes "born" or released from the marrow should be compared with the number released in a nonanemic patient, who produces 1% of 5 x 1012/L (5 x 106/µl) red cells daily for an absolute reticulocyte production of 50 x 109/L (50,000/mm3). Clinicians generally use the corrected reticulocyte count rather than the absolute number or proportion counted by the laboratory.
Raw Percent Observed x
Patient's Hematocrit Value
Corrected Reticulocyte Count =
40 (normal Hct)
2. Calculate the corrected reticulocyte count? What information do you get from this value? What is the importance of absolute reticulocyte count?
Reticulocyte count. This test helps to categorize the anemia into hypo-or hyper-proliferative type.
Corrected reticulocyte count is 2.5 x 23 / 40. It is 1.2%. Since this number is less than 2%, her anemia is hypoproliferative type. This means that the anemia is due to underproduction of red cells by the bone marrow. The absolute reticulocyte count can also distinguish between hypo/hyperproliferative anemia. If the absolute reticulocyte count is 100,000 mm3 or higher, the anemia is hyperproliferative type (ie hemolytic anemia or anemia of acute blood loss). If it is less than 100,000 mm3 the anemia is hypoproliferative (iron, B12, or folic deficiency, anemia of chronic disorder etc.).
3. How do MCV and RDW help you in the diagnostic work-up of anemia? Do the other indices-Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC)-add anything?
MCV divides the anemia in micro, normo, and macrocytic types. Each of these categories suggest a particular differential diagnosis. RDW (red cell distribution width) measures anisocytosis. RDW is abnormal in a majority (more than 90%) of cases of iron deficiency. It is however normal in thalassemias and anemia of chronic disorder. Thus a patient who has low MCV and high RDW is very likely to have iron deficiency anemia. On the other hand if the RDW is normal the low MCV may suggest a thalassemic syndrome or an anemia or chronic disorder. MCH and MCHC do not provide additional information.
4. What further tests would you like to do in this patient? Her serum iron is 21 microgram/dl and total iron binding capacity 408 microgram/dl. Serum Ferritin is 3 (Normal 32-100).
She should have serum iron, TIBC and serum ferritin levels.
5. Calculate her iron saturation? How useful is iron saturation in the diagnosis of anemias?
Her iron saturation is about 5%. Values below 15% suggest persence of iron deficiency. However, this is not a very reliable way of diagnosing iron deficiency anemia. In anemia of chronic disorder both iron and TIBC can be low giveing a low saturation value.
6. What is ferritin? How do you interpret low and high ferritin values?
Ferritin is protein that carries iron. Its exact function is not known. Ferritin values however reflect the total iron stores of the body very well. Low ferritin values are diagnostic of iron deficiency. Since ferritin is an acute phase reactant high values do not necessarily rule out iron deficiency. Very high values (about 1,000) may indicate presence of hemochromatosis.
7. If this patient was African-American, would you want to obtain a hemoglobin electrophoresis?
Hemoglobin electrophoresis should not be ordered at this time. She could have an alpha thalessemia trait but hemoglobin electrophoresis is not of any help in diagnosing that condition. In iron deficiency, levels of Hg A2 and F may also be low, making diagnosis of ß-thalassemias more difficult.
8. Should one do a bone marrow test in this patient?
The bone marrow should not be done. There is already strong evidence for iron deficiency anemia.
9. Could she have 'anemia of chronic disorder'? What are the known mechanisms of anemia of chronic disorder?
She should not have anemia of chronic disorder. There are no apparent chronic disorders. Iron studies in ferritin values, along with RDW suggest iron deficiency anemia. In anemia of chronic disorder, Fe utilization is poor, red cell survival is shorter. This anemia is mediated through various cytokines, especially TNF, IL-1.
10. Based on the information available information, make a complete diagnosis of her anemia. Your intern wants you to order a B12 and folate level also, for sake of completeness. Is that justifiable?
This patient has iron deficiency anemia due to multiple pregnancies in a short period of time. It is not justifiable to order a B12 and folic acid level in this patient.
11. What is the daily requirement of iron for a normal adult? Is it different for females or pregnant women?
The daily requirement in a adult male is 1mg. In woman it is 1.5 to 2mg. per day because of menstrual loss. Pregnancy requires an additional intake of .9 to 1 gm of iron. Therefore, during pregnancy iron supplements are necessary.
12. In which part of GI tract is iron absorbed? What else is necessary for iron absorption?
Iron is absorbed in duodenum and proximal jejunum. Hydrochloric acid produced by the stomach is helpful in iron absorption, as it reduces ferric to ferrous form.
13. What treatment would you prescribe for this patient? and for how long?
This patient should be put on iron supplements, along with vitamin supplement for the duration of her pregnancy plue 6 to 8 months afterwards.
14. This patient's old records indicate that she did not have a murmur in the past. Should one obtain an echocardiogram to rule out valvular heart disease?
She very likely has a flow murmur due to her anemia. If her murmur persist after iron therapy, further studies can be undertaken.
Serum Iron Quantitation and Total Iron-Binding Capacity
Purpose. Serum iron and total iron-binding capacity (TIBC) determinations are particularly useful in mild iron deficiency anemia, in which decreased serum iron levels may precede changes in red cell morphology or in red cell indices, and in distinguishing iron deficiency anemia from other microcytic hypochromic anemias.
Principle. All transport iron in the plasma is bound in the ferric form to the specific iron-binding protein, transferrin. Serum iron refers to this transferrin-bound iron. TIBC, the concentration iron necessary to saturate the iron-binding sites of transferrin, is a measure of transferrin concentration. Saturation of transferrin is calculated by the following formula:
Serum Iron (mol/L)
% Transferrin Saturation = X 100.
TIBC (µmol/L)
Normal mean transferrin saturation is approximately 30%. Unsaturated iron-binding capacity (UIBC) is the difference between TIBC and serum iron.
Interpretation.
The representative normal range of values for serum iron is 12.7 to 35.9 µmol/L (60 to 180 µg/dl); for TIBC, 45.2 to 77.7 µmol/L(250 to 410 µg/dl); and for percent saturation, 20% to 50%. The serum iron level is low, and percent saturation is characteristically reduced in both iron deficiency anemia and the anemia of chronic disease. Although the value for percent saturation is often reduced to levels <16% in iron deficiency anemia and is more frequently > 16% in anemia of chronic disease, values overlap in the two conditions. The TIBC is uniformly increased in severe uncomplicated iron deficiency anemias and is decreased or normal in the microcytic anemia of chronic disease. In mild iron deficiency anemia, both the serum iron and TIBC may be normal. Serum iron concentration is increased in the sideroblastic anemias and in some cases of thalassemia.
Notes and Precautions.
Because of diurnal variations in serum iron levels (maximum, 7 to 10 a.m.), and the fact that stated ranges are for morning normal levels, specimens should be drawn in the morning. Iron therapy should be withdrawn 24 hours before the blood sample is drawn. Iron dextran administration causes plasma iron levels to be elevated for several weeks. A normal plasma iron level and iron-binding capacity do not rule out the diagnosis of iron deficiency when the hemoglobin level of the blood is above 90 g/L (9 g/dl) (females) and 110 g/L (11g/dl) (males).