Diagnosis of Iron Deficiency Anemia in the Elderly by Transferrin Receptor–Ferritin Index

ORIGINAL INVESTIGATION 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

Background: The diagnosis of iron deficiency anemia amination of bone marrow aspirate was performed for (IDA) in the elderly is difficult because of the preva- all patients. Levels of transferrin receptor in serum were lence of chronic diseases, which can cause anemia with determined by means of a specific enzyme-linked im- high ferritin levels, even in the presence of iron defi- munosorbent assay. The transferrin receptor–ferritin in- ciency. Therefore, we studied the sensitivity and speci- dex (TR-F index) was defined as the ratio of serum trans- ficity of a serum transferrin receptor assay, which is not ferrin receptor level to log ferritin level. affected by chronic diseases, in the diagnosis of IDA in elderly patients. Results: Only 8 patients could be diagnosed as having IDA by means of routine blood test results (serum iron, Methods: We performed a prospective controlled study ferritin, and transferrin saturation levels). In contrast, the of 49 consecutive male and female patients older than TR-F index disclosed IDA in 43 of the 49 patients, thus 80 years who were admitted to an acute geriatric depart- increasing the sensitivity from 16% to 88%. ment. Bone marrow aspirate confirmed IDA in all 49 patients. Fourteen additional patients, also older than 80 Conclusions: The diagnosis of IDA in the elderly by years, with anemia but without evidence of iron defi- means of routine blood tests has a very low sensitivity. ciency on results of bone marrow examination, served The TR-F index is much more sensitive, and when re- as a control group. All patients underwent evaluation by sults are positive, the TR-F index can eliminate the need means of a detailed medical history and results of com- for bone marrow examination. plete physical examination, routine blood tests, and specific tests for diagnosis and evaluation of anemia. Ex- Arch Intern Med. 2002;162:445-449

NEMIA IS a common clini- The diagnosis of IDA in the elderly cal problem at all ages, es- is often difficult owing to the presence of pecially among the el- multiple abnormalities.6 The routine di- derly. Its prevalence among agnostic tests have a low sensitivity in this adults older than 70 years group of patients.7,8 Serum iron and trans- is about 2%,1 and this rises to 28% in men ferrin saturation levels have a limited value A 2 85 years and older. Iron deficiency ane- in the diagnosis of IDA in elderly pa- mia (IDA) accounts for about half of these tients.9 An increased level of free erythro- cases.3 In industrialized nations, IDA is cyte protoporphyrin is a late and nonspe- rarely due to dietary deficiency.3 Gastroin- cific finding of IDA.10 Serum ferritin level testinal tract abnormality can be identified is considered the best single test for the in more than half of elderly patients with diagnosis of iron deficiency because its IDA, including gastric tumors, colonic concentration is proportional to total- From the Departments of polyps, and carcinoma of the colon.4 Thus, body iron stores.11,12 However, in the el- Geriatrics (Drs Rimon, Levy, the presence of IDA in the elderly de- derly, serum ferritin level is not a reliable Sapir, and Gelzer and mands investigation of the upper and lower test, because levels increase with age13,14 Ms Peled) and Internal gastrointestinal tract. However, x-ray or and because the lower reference range for Medicine B (Drs Ergas and gastroscopy/colonoscopy investigation in elderly subjects is not well defined.6 More- Sthoeger), Kaplan Medical the elderly involves great inconvenience over, levels of serum ferritin increase in Center, Rehovot, Israel, which 5 is affiliated with the Hebrew and hazardous complications. There- chronic disorders and in malignancy, 15 University and Hadassah fore, an accurate assay for IDA in elderly which are common in the elderly. Thus, Medical School, Jerusalem, patients with high specificity and sensi- in more than half of elderly patients with Israel. tivity is mandatory. IDA, serum ferritin level is high or within

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 PATIENTS AND METHODS measured with an immunoturbidimetric assay (Boe- hringer Mannheim, Mannheim, Germany). Transferrin satu- SUBJECTS ration level was calculated with the following equation: [Iron/(Transferrinϫ23)]ϫ100, We studied 106 consecutive patients older than 80 years who where iron level is measured in micromoles per liter and were admitted to the Department of Acute Geriatric Medi- transferrin level in grams per liter (reference value, 20%). cine, Kaplan Medical Center, Rehovot, Israel, between Janu- The ferritin level (reference range, 24-300 ng/mL [53.9- ary 1, 1995, and December 31, 1997, with a diagnosis of ane- 674.1 pmol/L] for men and 15-307 ng/mL [33.7-689.8 mia (hemoglobin level, Ͻ13.0 g/dL in men and Ͻ12.0 g/dL pmol/L] for women) was measured using a chemilumines- in women). Exclusion criteria included acute gastrointesti- cence assay (Access Immunoassay System; Beckman In- nal tract bleeding, inability or refusal to sign an informed con- struments Inc, Chaska, Minn). Iron deficiency was diag- sent, significant vitamin B or folic acid deficiency, current 12 nosed by means of routine laboratory test results when iron therapy, known malignancy, and renal or hepatic fail- serum iron, transferrin saturation, and ferritin levels were ure. Sixty-three patients were eligible for the study. All pa- all abnormal.32 tients underwent a complete medical history and a thor- ough physical examination on admission, with routine DIAGNOSIS OF IDA BY MEANS OF TR laboratory tests including a complete blood cell count, erythrocyte sedimentation rate, kidney and liver function tests, and Serum TR assays were performed using a commercially serum levels of iron, transferrin, ferritin, vitamin B , folic acid, 12 available kit based on polyclonal antibodies in a sandwich C-reactive protein, and TR. Examination of bone marrow as- enzyme-linked immunosorbent assay format (Clinigen; pirate was performed in all patients. All blood samples were R&D Systems, Minneapolis, Minn). According to the assay drawn before any blood transfusions or iron supplements were kit from the manufacturers, the central 95th percentile given to the patients. All patients agreed to participate in the of the reference distribution of TR concentration is 0.85 study by signing an informed consent that was approved by to 3.05 mg/L (n=1000). To make the test more specific, the hospital ethics committee. we calculated the ratio of TR to log ferritin level (TR-F index). An index value of greater than 1.5 was considered DIAGNOSIS OF IDA BY MEANS 24,28,29 OF BONE MARROW EXAMINATION diagnostic of iron deficiency. All TR values herein are presented as TR-F index. To ascertain analytic quality, Bone marrow was aspirated from the sternum or iliac crest. all TR assays in the present study were performed in The smears were stained using the combined May- duplicate. Gru¨ nwald and Giemsa methods (Orion Diagnostica, Hel- sinki, Finland), and the iron stores were stained by the Prus- CONTROL GROUP sian blue method.16 The presence of less than 10% of normoblasts stained blue was considered evidence for di- The control group consisted of 14 patients older than 80 agnosis of iron deficiency. years. These patients also underwent investigation for IDA, but the results of their bone marrow aspirate examina- DIAGNOSIS OF IDA BY MEANS tions demonstrated that more than 10% of normoblasts con- OF ROUTINE LABORATORY TESTS tained iron, thus excluding the diagnosis of IDA. Blood cell counts were measured with an automated ana- STATISTICAL ANALYSIS lyzer (Technicon H*2; Technicon Instruments Corp, Ter- rytown, NY). Serum iron level (reference range, 59-158 Sensitivity was defined as [TP/(TP+FN)]ϫ100 and speci- µg/dL [10.6-28.3 µmol/L] for men and 37-145 µg/dL [6.6- ficity as [TN/(TN+FP)]ϫ100, where TP is true positive; 26.0 µmol/L] for women) was measured using an iron FZ FN, false negative; TN, true negative; and FP, false posi- assay (Hoffmann-La Roche, Basel, Switzerland) based on tive. Positive predictive value was defined as [TP/(TP+FP)] a guanidine hydrochloride/Ferrozine reaction.24 Transfer- ϫ100; negative predictive value, [TN/(TN+FN)]ϫ100. Un- rin level (reference range, 200-400 mg/dL [2.0-4.0 g/L]) was less otherwise indicated, data are given as mean±SD.

the reference range, probably due to the concomitant pres- teolysis, thus producing soluble serum TR forms.19 The ence of other illnesses.13 serum levels of TR reflect the amount of membranous The definitive test for the diagnosis of IDA is the pres- TR, which inversely correlates to iron storage levels.20 ence of less than 10% of normoblasts stained by Prus- Kohgo et al21 developed a radioimmunoassay for the mea- sian blue in a bone marrow aspiration sample.16 How- surement of serum TR. They were the first to report that ever, this procedure is invasive, painful, and expensive, high serum TR levels correlate with iron deficiency. Flow- and therefore is not performed regularly. Thus, an alter- ers et al22 developed an enzyme-linked immunosorbent native sensitive and noninvasive test for the diagnosis of assay for the detection of TR in patients’ serum samples. IDA in the elderly is needed. Using this assay, Skikne et al23 also demonstrated that Transferrin receptor (TR) is a transmembrane gly- high serum TR levels are specific markers for IDA. Se- coprotein that is expressed on most cells, especially those rum TR levels increase in IDA, but not in inflammatory that require high iron levels such as immature erythroid states.24-27 The value of serum TR measurement in the di- cells.17 It has a major role in the internalization of iron agnosis of IDA in the elderly is not precisely defined, since into the cells.18 Transferrin receptor is susceptible to pro- most previous studies focused on younger popula-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Routine Laboratory Tests and TR-F Index in 49 Study Patients and 14 Control Patients*

49 Patients With IDA‡

Routine TR-F Index Laboratory Tests Variables† (Group 1) Ͼ1.5 (Group 2) Յ1.5 (Group 3) Control Patients§ No. (%) of patients 8/49 (16) 35/49 (71) 6/49 (12) 14 Hb, g/dL (men, Ͼ13.0 g/dL; 9.4 ± 0.9 10.3 ± 0.9 9.4 ± 0.6 10.3 ± 0.7 women, Ͼ12.0 g/dL) MCV, fL (80-99 fL) 77.0 ± 5.2࿣ 89.0 ± 6.7 90.4 ± 3.9 88.6 ± 6.2 Reticulocytes, % (0.5%-1.5%) 1.5 ± 0.7 1.9 ± 4.8 0.67 ± 0.4 1.12 ± 2.0 Serum iron, µg/dL (36.9-145.3 µg/dL)¶ 20.7 ± 7.8࿣ 45.8 ± 27.4 58.1 ± 55.3 115.1 ± 113.4# Transferrin saturation, % (20%-45%) 5.3 ± 2.8࿣ 19.1 ± 11.0 29.3 ± 28.5 42.1 ± 9.9# Ferritin, ng/mL†† (men, 24-300 ng/mL; 13.7 ± 5.2 144.5 ± 131.3 385.1 ± 336.4** 363.9 ± 222.2‡‡ women, 15-307 ng/mL) CRP, mg/L (0.01-8.00 mg/L) 19.3 ± 14.9 48.1 ± 45.4 58.3 ± 38.4 54.5 ± 33.0 ESR, mm/h (men, 0-20 mm/h; 51.6 ± 17.8 65.6 ± 40.3 62.0 ± 27.8 64.6 ± 31.2 women, 0-30 mm/h) TR-F index (Յ1.5) 4.2 ± 1.3࿣ 2.1 ± 0.5࿣ 1.1 ± 0.3# 1.1 ± 0.2#

*Unless otherwise indicated, data are given as mean ± SD. TR-F index indicates transferrin receptor–ferritin index; IDA, iron deficiency anemia; Hb, hemoglobin; MCV, mean corpuscular volume; CRP, C-reactive protein; and ESR, erythrocyte sedimentation rate. †Unless otherwise indicated, data in parentheses indicate reference ranges or reference values. ‡Indicates 49 patients with IDA as defined by bone marrow evaluation results (Ͻ10% blue-stained normoblasts). Only 8 patients (group 1) were identified by means of routine laboratory test results (combination of serum iron, transferrin saturation, and ferritin assays); 35 additional patients were identified by means of TR-F index (group 2); and 6 patients (group 3) were not identified by means of routine laboratory tests or TR-F index. §Control group represents 14 patients with anemia in whom results of bone marrow aspirate examination demonstrated more than 10% blue-stained normoblasts, thus excluding the diagnosis of IDA. ࿣PϽ.001 compared with all other groups. ¶To convert to micromoles per liter, multiply by 0.179. #PϽ.001 compared with groups 1 and 2. **PϽ.01 compared with group 1. ††To convert to picomoles per liter, multiply by 2.247. ‡‡PϽ.001 compared with group 1; PϽ.005 compared with group 2.

tions.21,24-29 Moreover, the level of expression of TR on iron, transferrin saturation, ferritin, and C-reactive pro- cell membranes and the rate of TR proteolysis may be tein were significantly lower compared with those of different in older patients compared with younger ones. the other groups of patients. The TR-F index clearly The data on TR levels in IDA in older patients are quite identified IDA in these 8 patients, with a mean value of limited.30,31 We therefore conducted a study comparing 4.2±1.3. the sensitivity and specificity of the routine laboratory By using the TR-F index, we were able to identify tests for IDA (the combination of serum levels of iron, another 35 (71%) of the 49 patients who had bone mar- transferrin saturation, and ferritin) with those of a TR- row–proved IDA. None of these 35 patients could have ferritin (TR-F) index in elderly patients (aged Ͼ80 years) been identified by means of the routine laboratory tests with bone marrow–proved IDA. for IDA. In 6 other patients with bone marrow–proved IDA (12%), the diagnosis could not be established by RESULTS means of either method. These 6 patients had high levels of ferritin and C-reactive protein (Table 1). Sixty-three (59%) of 106 patients with anemia (22 men The control group of 14 patients had anemia with and 41 women) who met the inclusion criteria were en- mean hemoglobin levels of 10.3±0.7 g/dL, which were rolled into the study. The mean age of the patients was similar to the hemoglobin levels of the 49 patients with 83.0±2.8 years (range, 80.2-88.7 years); the mean level bone marrow–proved IDA (Table 1). In 13 (93%) of of hemoglobin, 10.1±0.9 g/dL. Results of bone marrow these patients, the TR-F index was lower than 1.5, aspirate studies demonstrated IDA in 49 of those pa- excluding iron deficiency as the cause of anemia. The tients. All patients had comparable levels of vitamin B12, only patient in the control group who had slightly folic acid, and thyrotropin within the reference range (data raised levels of TR-F index (1.68) demonstrated low not shown). levels of serum iron (19.0 µg/dL [3.4 µmol/L]) and The results of routine laboratory tests for IDA transferrin saturation (16%) with high levels of ferritin (combination of serum iron, transferrin saturation, and (847 ng/mL [1903.2 pmol/L]). Although we cannot rule ferritin tests) identified only 8 of those patients (sensi- out the possibility that this patient had an early stage tivity, 16%). As can be seen in Table 1, the mean of iron deficiency, combined with anemia due to chron- hemoglobin levels of these 8 patients (9.4±0.9 g/dL) ic disease (ACD), the presence of a normal content of was similar to that of the other groups. However, the iron stores in the bone marrow does not support this mean corpuscular volume and mean serum levels of assumption.

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 strated that the TR assay exceeds the diagnostic value of Table 2. Specificity, Sensitivity, and Negative and Positive routine laboratory tests for IDA during the early stages Predictive Values of Routine Laboratory Tests and of iron depletion. TR-F Index in the Diagnosis of IDA in the Elderly* The routine laboratory tests pointed to the diagnosis of IDA in 8 patients with low mean corpuscular vol- Routine Laboratory Tests† TR-F Index ume and very low levels of serum iron, transferrin satu- Specificity, %‡ 100 92.9 ration, and ferritin. In 35 other patients with higher serum Sensitivity, % 16.3 87.8 PPV, % 100 97.7 iron levels, the diagnosis could be established only by NPV, % 22.2 68.4 means of the TR-F index (Table 1). Moreover, in most elderly patients, IDA develops concomitantly with ACD. *TR-F index indicates transferrin receptor–ferritin index; IDA, iron The most important clinical issue is not to differentiate deficiency anemia; PPV, positive predictive value; and NPV, negative between those 2 morbidities, but rather to have a good predictive value. †Includes serum iron, transferrin saturation, and serum ferritin assays. diagnostic tool to identify IDA in the presence of ACD. Diagnosis of IDA was made when all values were below reference levels. The routine laboratory tests for IDA are of no value in ‡Bone marrow evaluation was considered the gold standard for definitive this situation (Tables 1 and 2). In contrast, the TR-F in- diagnosis of IDA. dex findings led to the diagnosis of IDA in 19 patients with high inflammatory variables (C-reactive protein level, Ͼ20 mg/dL; erythrocyte sedimentation rate, Ͼ50 mm/ COMMENT h), whereas results of routine laboratory tests led to the diagnosis of IDA in only 1 of those 19 patients. Al- The present study clearly demonstrated the important role though measurement of TR-F index is about 5 times more of the TR-F index in the diagnosis of IDA in elderly pa- expensive than routine laboratory tests, it is less expen- tients with anemia. The TR-F index has high specificity sive than bone marrow examination, and its diagnostic (93%) and sensitivity (88%) for the diagnosis of IDA in efficiency is much better than that of the routine labo- the elderly compared with the low sensitivity (16%) of ratory tests for IDA. Thus, it is a cost-effective assay for the routine laboratory tests now used for the evaluation the diagnosis of IDA. of IDA. Iron deficiency anemia is a serious medical prob- CONCLUSIONS lem in the elderly. The high rate of gastrointestinal tract malignancy in these patients makes the study of the gas- This study supports the high specificity and sensitivity trointestinal tract obligatory.4 However, these studies are of the TR-F index in the diagnosis of IDA in elderly pa- inconvenient and carry a high risk for complications, es- tients. It is a simple, noninvasive test. A positive finding pecially in elderly patients.5 Thus, one should not rec- on the TR-F index (Ͼ1.5) can accurately establish a di- ommend those studies without a clear indication, ie, a agnosis of IDA and may eliminate the need for bone mar- definite diagnosis of IDA. Serum iron, transferrin satu- row examination. On the other hand, a normal finding ration,7-9 and ferritin levels13 often conceal the diagnosis on the TR-F index in elderly patients with inflamma- of IDA in elderly patients, mainly because of the coex- tory variables does not exclude IDA; thus a bone mar- istence of ACD in many of those patients.6 The present row examination should be considered in those pa- study confirms these previous observations, demonstrat- tients. ing a very low sensitivity of the routine laboratory tests for the diagnosis of IDA in the elderly (Table 1 and Accepted for publication July 12, 2001. Table 2). The use of routine laboratory tests in our stud- Corresponding author and reprints: Zev M. Sthoeger, ies did not disclose the diagnosis of IDA in 41 (84%) of MD, Department of Internal Medicine B, Kaplan Medical 49 patients. This low sensitivity rate for IDA diagnosis Center, Rehovot, Israel 76100 (e-mail: [email protected]). is not acceptable. 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