 |
|
Diagnosis of Iron Deficiency Anemia in the Elderly by Transferrin Receptor–Ferritin Index
Ephraim Rimon, MD;
Shmuel Levy, MD;
Alexander Sapir, MD;
Gregorius Gelzer, MD;
Ronit Peled, MPH;
David Ergas, MD;
Zev M. Sthoeger, MD
Arch Intern Med. 2002;162:445-449.
ABSTRACT
| |
Background The diagnosis of iron deficiency anemia (IDA) in the elderly is difficult
because of the prevalence of chronic diseases, which can cause anemia with
high ferritin levels, even in the presence of iron deficiency. Therefore,
we studied the sensitivity and specificity of a serum transferrin receptor
assay, which is not affected by chronic diseases, in the diagnosis of IDA
in elderly patients.
Methods We performed a prospective controlled study of 49 consecutive male and
female patients older than 80 years who were admitted to an acute geriatric
department. Bone marrow aspirate confirmed IDA in all 49 patients. Fourteen
additional patients, also older than 80 years, with anemia but without evidence
of iron deficiency on results of bone marrow examination, served as a control
group. All patients underwent evaluation by means of a detailed medical history
and results of complete physical examination, routine blood tests, and specific
tests for diagnosis and evaluation of anemia. Examination of bone marrow aspirate
was performed for all patients. Levels of transferrin receptor in serum were
determined by means of a specific enzyme-linked immunosorbent assay. The transferrin
receptor–ferritin index (TR-F index) was defined as the ratio of serum
transferrin receptor level to log ferritin level.
Results Only 8 patients could be diagnosed as having IDA by means of routine
blood test results (serum iron, ferritin, and transferrin saturation levels).
In contrast, the TR-F index disclosed IDA in 43 of the 49 patients, thus increasing
the sensitivity from 16% to 88%.
Conclusions The diagnosis of IDA in the elderly by means of routine blood tests
has a very low sensitivity. The TR-F index is much more sensitive, and when
results are positive, the TR-F index can eliminate the need for bone marrow
examination.
INTRODUCTION
ANEMIA IS a common clinical problem at all ages, especially among the
elderly. Its prevalence among adults older than 70 years is about 2%,1 and this rises to 28% in men 85 years and older.2 Iron deficiency anemia (IDA) accounts for about half
of these cases.3 In industrialized nations,
IDA is rarely due to dietary deficiency.3 Gastrointestinal
tract abnormality can be identified in more than half of elderly patients
with IDA, including gastric tumors, colonic polyps, and carcinoma of the colon.4 Thus, the presence of IDA in the elderly demands investigation
of the upper and lower gastrointestinal tract. However, x-ray or gastroscopy/colonoscopy
investigation in the elderly involves great inconvenience and hazardous complications.5 Therefore, an accurate assay for IDA in elderly patients
with high specificity and sensitivity is mandatory.
The diagnosis of IDA in the elderly is often difficult owing to the
presence of multiple abnormalities.6 The routine
diagnostic tests have a low sensitivity in this group of patients.7-8 Serum iron and transferrin saturation
levels have a limited value in the diagnosis of IDA in elderly patients.9 An increased level of free erythrocyte protoporphyrin
is a late and nonspecific finding of IDA.10
Serum ferritin level is considered the best single test for the diagnosis
of iron deficiency because its concentration is proportional to total-body
iron stores.11-12 However, in
the elderly, serum ferritin level is not a reliable test, because levels increase
with age13-14 and because the
lower reference range for elderly subjects is not well defined.6
Moreover, levels of serum ferritin increase in chronic disorders and in malignancy,
which are common in the elderly.15 Thus, in
more than half of elderly patients with IDA, serum ferritin level is high
or within the reference range, probably due to the concomitant presence of
other illnesses.13
The definitive test for the diagnosis of IDA is the presence of less
than 10% of normoblasts stained by Prussian blue in a bone marrow aspiration
sample.16 However, this procedure is invasive,
painful, and expensive, and therefore is not performed regularly. Thus, an
alternative sensitive and noninvasive test for the diagnosis of IDA in the
elderly is needed.
Transferrin receptor (TR) is a transmembrane glycoprotein that is expressed
on most cells, especially those that require high iron levels such as immature
erythroid cells.17 It has a major role in the
internalization of iron into the cells.18 Transferrin
receptor is susceptible to proteolysis, thus producing soluble serum TR forms.19 The serum levels of TR reflect the amount of membranous
TR, which inversely correlates to iron storage levels.20
Kohgo et al21 developed a radioimmunoassay
for the measurement of serum TR. They were the first to report that high serum
TR levels correlate with iron deficiency. Flowers et al22
developed an enzyme-linked immunosorbent assay for the detection of TR in
patients' serum samples. Using this assay, Skikne et al23
also demonstrated that high serum TR levels are specific markers for IDA.
Serum TR levels increase in IDA, but not in inflammatory states.24-27
The value of serum TR measurement in the diagnosis of IDA in the elderly is
not precisely defined, since most previous studies focused on younger populations.21, 24-29
Moreover, the level of expression of TR on cell membranes and the rate of
TR proteolysis may be different in older patients compared with younger ones.
The data on TR levels in IDA in older patients are quite limited.30-31 We therefore conducted a study comparing
the sensitivity and specificity of the routine laboratory tests for IDA (the
combination of serum levels of iron, transferrin saturation, and ferritin)
with those of a TR-ferritin (TR-F) index in elderly patients (aged >80 years)
with bone marrow–proved IDA.
PATIENTS AND METHODS
SUBJECTS
We studied 106 consecutive patients older than 80 years who were admitted
to the Department of Acute Geriatric Medicine, Kaplan Medical Center, Rehovot,
Israel, between January 1, 1995, and December 31, 1997, with a diagnosis of
anemia (hemoglobin level, <13.0 g/dL in men and <12.0 g/dL in women).
Exclusion criteria included acute gastrointestinal tract bleeding, inability
or refusal to sign an informed consent, significant vitamin B12
or folic acid deficiency, current iron therapy, known malignancy, and renal
or hepatic failure. Sixty-three patients were eligible for the study. All
patients underwent a complete medical history and a thorough physical examination
on admission, with routine laboratory tests including a complete blood cell
count, erythrocyte sedimentation rate, kidney and liver function tests, and
serum levels of iron, transferrin, ferritin, vitamin B12, folic
acid, C-reactive protein, and TR. Examination of bone marrow aspirate was
performed in all patients. All blood samples were drawn before any blood transfusions
or iron supplements were given to the patients. All patients agreed to participate
in the study by signing an informed consent that was approved by the hospital
ethics committee.
DIAGNOSIS OF IDA BY MEANS OF BONE MARROW EXAMINATION
Bone marrow was aspirated from the sternum or iliac crest. The smears
were stained using the combined May-Grünwald and Giemsa methods (Orion
Diagnostica, Helsinki, Finland), and the iron stores were stained by the Prussian
blue method.16 The presence of less than 10%
of normoblasts stained blue was considered evidence for diagnosis of iron
deficiency.
DIAGNOSIS OF IDA BY MEANS OF ROUTINE LABORATORY TESTS
Blood cell counts were measured with an automated analyzer (Technicon
H*2; Technicon Instruments Corp, Terrytown, NY). Serum iron level (reference
range, 59-158 µg/dL [10.6-28.3 µmol/L] for men and 37-145 µg/dL
[6.6-26.0 µmol/L] for women) was measured using an iron FZ assay (Hoffmann-La
Roche, Basel, Switzerland) based on a guanidine hydrochloride/Ferrozine reaction.24 Transferrin level (reference range, 200-400 mg/dL
[2.0-4.0 g/L]) was measured with an immunoturbidimetric assay (Boehringer
Mannheim, Mannheim, Germany). Transferrin saturation level was calculated
with the following equation:
where iron level is measured in micromoles per liter and transferrin
level in grams per liter (reference value, 20%). The ferritin level (reference
range, 24-300 ng/mL [53.9-674.1 pmol/L] for men and 15-307 ng/mL [33.7-689.8
pmol/L] for women) was measured using a chemiluminescence assay (Access Immunoassay
System; Beckman Instruments Inc, Chaska, Minn). Iron deficiency was diagnosed
by means of routine laboratory test results when serum iron, transferrin saturation,
and ferritin levels were all abnormal.32
DIAGNOSIS OF IDA BY MEANS OF TR
Serum TR assays were performed using a commercially available kit based
on polyclonal antibodies in a sandwich enzyme-linked immunosorbent assay format
(Clinigen; R&D Systems, Minneapolis, Minn). According to the assay kit
from the manufacturers, the central 95th percentile of the reference distribution
of TR concentration is 0.85 to 3.05 mg/L (n = 1000). To make the test more
specific, we calculated the ratio of TR to log ferritin level (TR-F index).
An index value of greater than 1.5 was considered diagnostic of iron deficiency.24, 28-29 All TR values herein
are presented as TR-F index. To ascertain analytic quality, all TR assays
in the present study were performed in duplicate.
CONTROL GROUP
The control group consisted of 14 patients older than 80 years. These
patients also underwent investigation for IDA, but the results of their bone
marrow aspirate examinations demonstrated that more than 10% of normoblasts
contained iron, thus excluding the diagnosis of IDA.
STATISTICAL ANALYSIS
Sensitivity was defined as [TP/(TP + FN)] x 100 and specificity
as [TN/(TN + FP)] x 100, where TP is true positive; FN, false negative;
TN, true negative; and FP, false positive. Positive predictive value was defined
as [TP/(TP + FP)] x 100; negative predictive value, [TN/(TN + FN)] x
100. Unless otherwise indicated, data are given as mean ± SD.
RESULTS
Sixty-three (59%) of 106 patients with anemia (22 men and 41 women)
who met the inclusion criteria were enrolled into the study. The mean age
of the patients was 83.0 ± 2.8 years (range, 80.2-88.7 years); the
mean level of hemoglobin, 10.1 ± 0.9 g/dL. Results of bone marrow aspirate
studies demonstrated IDA in 49 of those patients. All patients had comparable
levels of vitamin B12, folic acid, and thyrotropin within the reference
range (data not shown).
The results of routine laboratory tests for IDA (combination of serum
iron, transferrin saturation, and ferritin tests) identified only 8 of those
patients (sensitivity, 16%). As can be seen in Table 1, the mean hemoglobin levels of these 8 patients (9.4 ±
0.9 g/dL) was similar to that of the other groups. However, the mean corpuscular
volume and mean serum levels of iron, transferrin saturation, ferritin, and
C-reactive protein were significantly lower compared with those of the other
groups of patients. The TR-F index clearly identified IDA in these 8 patients,
with a mean value of 4.2 ± 1.3.
|
|
|
|
Table 1. Routine Laboratory Tests and TR-F Index in 49 Study Patients
and 14 Control Patients*
|
|
|
By using the TR-F index, we were able to identify another 35 (71%) of
the 49 patients who had bone marrow–proved IDA. None of these 35 patients
could have been identified by means of the routine laboratory tests for IDA.
In 6 other patients with bone marrow–proved IDA (12%), the diagnosis
could not be established by means of either method. These 6 patients had high
levels of ferritin and C-reactive protein (Table 1).
The control group of 14 patients had anemia with mean hemoglobin levels
of 10.3 ± 0.7 g/dL, which were similar to the hemoglobin levels of
the 49 patients with bone marrow–proved IDA (Table 1). In 13 (93%) of these patients, the TR-F index was lower
than 1.5, excluding iron deficiency as the cause of anemia. The only patient
in the control group who had slightly raised levels of TR-F index (1.68) demonstrated
low levels of serum iron (19.0 µg/dL [3.4 µmol/L]) and transferrin
saturation (16%) with high levels of ferritin (847 ng/mL [1903.2 pmol/L]).
Although we cannot rule out the possibility that this patient had an early
stage of iron deficiency, combined with anemia due to chronic disease (ACD),
the presence of a normal content of iron stores in the bone marrow does not
support this assumption.
COMMENT
The present study clearly demonstrated the important role of the TR-F
index in the diagnosis of IDA in elderly patients with anemia. The TR-F index
has high specificity (93%) and sensitivity (88%) for the diagnosis of IDA
in the elderly compared with the low sensitivity (16%) of the routine laboratory
tests now used for the evaluation of IDA.
Iron deficiency anemia is a serious medical problem in the elderly.
The high rate of gastrointestinal tract malignancy in these patients makes
the study of the gastrointestinal tract obligatory.4
However, these studies are inconvenient and carry a high risk for complications,
especially in elderly patients.5 Thus, one
should not recommend those studies without a clear indication, ie, a definite
diagnosis of IDA. Serum iron, transferrin saturation,7-9
and ferritin levels13 often conceal the diagnosis
of IDA in elderly patients, mainly because of the coexistence of ACD in many
of those patients.6 The present study confirms
these previous observations, demonstrating a very low sensitivity of the routine
laboratory tests for the diagnosis of IDA in the elderly (Table 1 and Table 2).
The use of routine laboratory tests in our studies did not disclose the diagnosis
of IDA in 41 (84%) of 49 patients. This low sensitivity rate for IDA diagnosis
is not acceptable. Therefore, bone marrow examination is used for more accurate
diagnosis of IDA.33
|
|
|
|
Table 2. Specificity, Sensitivity, and Negative and Positive Predictive
Values of Routine Laboratory Tests and TR-F Index in the Diagnosis of IDA
in the Elderly*
|
|
|
The TR serum levels have been shown to be sensitive markers for IDA.21, 24-29
We used the TR–log ferritin ratio, the TR-F index, because it was shown
to improve the diagnostic efficiency for IDA compared with serum TR level
alone or the TR-ferritin ratio.24, 27-28
The TR-F index is an accurate marker for IDA, because it represents the total-body
iron stores and the availability of iron for erythropoiesis.24
To our knowledge, our report is the first study of patients older than 80
years in whom the results of bone marrow examinations and routine blood tests
and TR-F index have been compared. In agreement with previous observations
in younger groups of patients, we found the TR-F index to be a specific and
sensitive test for the diagnosis of IDA in the elderly (Table 2). Our data also support the previous observation of Gimferrer
et al,34 who demonstrated that the TR assay
exceeds the diagnostic value of routine laboratory tests for IDA during the
early stages of iron depletion.
The routine laboratory tests pointed to the diagnosis of IDA in 8 patients
with low mean corpuscular volume and very low levels of serum iron, transferrin
saturation, and ferritin. In 35 other patients with higher serum iron levels,
the diagnosis could be established only by means of the TR-F index (Table 1). Moreover, in most elderly patients,
IDA develops concomitantly with ACD. The most important clinical issue is
not to differentiate between those 2 morbidities, but rather to have a good
diagnostic tool to identify IDA in the presence of ACD. The routine laboratory
tests for IDA are of no value in this situation (Table 1 and Table 2). In contrast, the TR-F index findings led to the diagnosis of IDA in 19 patients
with high inflammatory variables (C-reactive protein level, >20 mg/dL; erythrocyte
sedimentation rate, >50 mm/h), whereas results of routine laboratory tests
led to the diagnosis of IDA in only 1 of those 19 patients. Although measurement
of TR-F index is about 5 times more expensive than routine laboratory tests,
it is less expensive than bone marrow examination, and its diagnostic efficiency
is much better than that of the routine laboratory tests for IDA. Thus, it
is a cost-effective assay for the diagnosis of IDA.
CONCLUSIONS
This study supports the high specificity and sensitivity of the TR-F
index in the diagnosis of IDA in elderly patients. It is a simple, noninvasive
test. A positive finding on the TR-F index (>1.5) can accurately establish
a diagnosis of IDA and may eliminate the need for bone marrow examination.
On the other hand, a normal finding on the TR-F index in elderly patients
with inflammatory variables does not exclude IDA; thus a bone marrow examination
should be considered in those patients.
AUTHOR INFORMATION
Accepted for publication July 12, 2001.
Corresponding author and reprints: Zev M. Sthoeger, MD, Department
of Internal Medicine B, Kaplan Medical Center, Rehovot, Israel 76100 (e-mail: Sthoeger{at}inter.net.il).
From the Departments of Geriatrics (Drs Rimon, Levy, Sapir, and Gelzer
and Ms Peled) and Internal Medicine B (Drs Ergas and Sthoeger), Kaplan Medical
Center, Rehovot, Israel, which is affiliated with the Hebrew University and
Hadassah Medical School, Jerusalem, Israel.
REFERENCES
| |
1. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA. 1997;277:973-976.
ABSTRACT
2. Izaks GJ, Westendorp RGJ, Knook DL. The definition of anemia in older persons. JAMA. 1999;281:1714-1717.
FREE FULL TEXT
3. Ania BJ, Suman VJ, Fairbanks VF, Rademacher DM, Melton III LJ. Incidence of anemia in older people: an epidemiologic study in a well
defined population. J Am Geriatr Soc. 1997;45:825-831.
ISI
| PUBMED
4. Joosten E, Ghesquiere B, Linthoudt H, et al. Upper and lower gastrointestinal evaluation of elderly inpatients who
are iron deficient. Am J Med. 1999;107:24-29.
FULL TEXT
|
ISI
| PUBMED
5. Gurwitz JH, Noonan JP, Sanchez M, Prather W. Barium enemas in the frail elderly. Am J Med. 1992;92:41-44.
FULL TEXT
|
ISI
| PUBMED
6. Guyatt GH, Patterson C, Ali M, et al. Diagnosis of iron-deficiency anemia in the elderly. Am J Med. 1990;88:205-209.
FULL TEXT
|
ISI
| PUBMED
7. Lynch SR, Finch CA, Monsen ER, Cook JD. Iron status of elderly Americans. Am J Clin Nutr. 1982;36:1032-1045.
FREE FULL TEXT
8. Yip R, Johnson C, Dallman PR. Age-related changes in laboratory values used in the diagnosis of anemia
and iron deficiency. Am J Clin Nutr. 1984;39:427-436.
FREE FULL TEXT
9. Patterson C, Turpie ID, Benger AM. Assessment of iron stores in anemic geriatric patients. J Am Geriatr Soc. 1985;33:764-767.
ISI
| PUBMED
10. Hastka J, Lasserre JJ, Schwartzbeck A, Strauch M, Hehlmann R. Zinc protoporphyrin in anemia of chronic disorders. Blood. 1993;81:1200-1204.
FREE FULL TEXT
11. Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an index of iron stores. N Engl J Med. 1974;290:1213-1216.
12. Krause JR, Stolc V. Serum ferritin and bone marrow biopsy iron stores, II: correlation
with low serum iron and Fe/TIBC ratio less than 15%. Am J Clin Pathol. 1980;74:461-464.
ISI
| PUBMED
13. Loria A, Hershko C, Konijn AM. Serum ferritin in an elderly population. J Gerontol. 1979;34:521-524.
ISI
| PUBMED
14. Casale G, Bonora C, Migliavacca A, Zurita IE, de Nicola P. Serum ferritin and aging. Age Ageing. 1981;10:119-122.
FREE FULL TEXT
15. Witte DL. Can serum ferritin be effectively interpreted in the presence of the
acute-phase response? Clin Chem. 1991;37:484-485.
FREE FULL TEXT
16. Fairbanks VF, Beutler E. Iron deficiency. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill Medical Publishing
Division; 2001:447-470.
17. Huebers HA, Beguin Y, Pootrakul P, Einspahr D, Finch CA. Intact transferrin receptor in human plasma and their relation to erythropoiesis. Blood. 1990;75:102-107.
FREE FULL TEXT
18. Dautry-Varsat A, Ciechanover A, Lodish HF. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci U S A. 1983;80:2258-2262.
FREE FULL TEXT
19. Beguin Y, Huebers HA, Josephson B, Finch CA. Transferrin receptors in rat plasma. Proc Natl Acad Sci U S A. 1988;85:637-640.
FREE FULL TEXT
20. Pietrangello P, Rocchi E, Casalgrandi G, et al. Regulation of transferrin, transferrin receptor, and ferritin genes
in human duodenum. Gastroenterology. 1992;102:802-809.
ISI
| PUBMED
21. Kohgo Y, Niitsu Y, Kondo H, et al. Serum transferrin receptor as a new index of erythropoiesis. Blood. 1987;70:1955-1958.
FREE FULL TEXT
22. Flowers CH, Skinke BS, Covell AM, Cook JD. The clinical measurement of transferrin receptor. J Lab Clin Med. 1989;114:368-377.
ISI
| PUBMED
23. Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood. 1990;75:1870-1876.
FREE FULL TEXT
24. Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis
of iron deficiency. Blood. 1997;89:1052-1057.
FREE FULL TEXT
25. Ferguson BJ, Skikne BS, Simpson KM, Baynes RD, Cook JD. Serum transferrin receptor distinguishes the anemia of chronic disease
from iron deficiency anemia. J Lab Clin Med. 1992;119:385-390.
ISI
| PUBMED
26. Punnonen K, Irjala K, Rajamaki A. Iron-deficiency anemia is associated with high concentrations of transferrin
receptor in serum. Clin Chem. 1994;40:774-776.
FREE FULL TEXT
27. Nielsen OJ, Andersen LS, Hansen NE, Hansen TM. Serum transferrin receptor levels in anaemic patients with rheumatoid
arthritis. Scand J Clin Lab Invest. 1994;54:75-82.
ISI
| PUBMED
28. Cermak J, Brabec V. Transferrin receptor–ferritin ratio: a useful parameter in differential
diagnosis of iron deficiency and hyperplastic erythropoiesis [letter]. Eur J Haematol. 1998;61:210-212.
ISI
| PUBMED
29. Suominen P, Punnonen K, Rajamaki A, Irjala K. Serum transferrin receptor and transferrin receptor–ferritin
index identify healthy subjects with subclinical iron deficits. Blood. 1998;92:2934-2939.
FREE FULL TEXT
30. Chua E, Clague JE, Sharma AK, Horan MA, Lombard M. Serum transferrin receptor assay in iron deficiency anaemia and anaemia
of chronic disease in the elderly. QJM. 1999;92:587-594.
FREE FULL TEXT
31. Jolobe OM. Serum transferrin receptor assay in iron deficiency anaemia and anaemia
of chronic disease in the elderly [letter]. QJM. 2000;93:198.
FREE FULL TEXT
32. Massey AC. Microcytic anemia: differential diagnosis and management of iron deficiency
anemia. Med Clin North Am. 1992;76:549-566.
ISI
| PUBMED
33. Lee GR. Iron deficiency and iron-deficiency anemia. In: Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Williams &
Wilkins; 1999:979-1010.
34. Gimferrer E, Ubeda J, Royo MT, et al. Serum transferrin receptor levels in different stage of iron deficiency. Blood. 1997;90:1332-1334.
PUBMED
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Iron Deficiency Anemia
Clark
Nutr Clin Pract 2008;23:128-141.
ABSTRACT
| FULL TEXT
Sensitivity, Specificity, and Predictive Value of Serum Soluble Transferrin Receptor at Different Stages of Iron Deficiency
Choi
Annals of Clinical & Laboratory Science 2005;35:435-439.
ABSTRACT
| FULL TEXT
Editorial: Hot Topics in Geriatrics
Morley
J. Gerontol. A Biol. Sci. Med. Sci. 2003;58:M30-36.
FULL TEXT
Serum Ferritin vs Transferrin Receptor-Ferritin Index
Dosh et al.
Arch Intern Med 2002;162:1782-1783.
FULL TEXT
Ferritin Is More Cost-effective Than Transferrin Receptor-Ferritin Index for the Diagnosis of Iron Deficiency
Ruivard et al.
Arch Intern Med 2002;162:1783-1783.
FULL TEXT
|
