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 pa- tients. 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 spe- cific 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 (REPRINTED) ARCH INTERN MED/ VOL 162, FEB 25, 2002 WWW.ARCHINTERNMED.COM 445 ©2002 American Medical Association. All rights reserved. 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, eryth- rocyte 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.