- Email: [email protected]
Prospective Evaluation of the Gastrointestinal Tract in Patients With Iron Deficiency and No Systemic or Gastrointestinal Symptoms or Signs
Prospective Evaluation of the Gastrointestinal Tract in Patients with Iron Deficiency and No Systemic or Gastrointestinal Symptoms or Signs C. Mel Wilcox, MD, Lorraine N. Alexander, RN, W. Scott Clark, PhD, Atlanta, Georgia
BACKGROUND: Although endoscopic evaluation of the gastrointestinal tract is commonly performed to evaluate iron deficiency, little data is available regarding the underlying causes, yield of evaluation, and long-term outcome for those in whom gastrointestinal and systemic symptoms and signs are absent. METHODS: In- or out-patients seen by the gastroenterology consultative service at a large inner-city hospital over a 56-month period were considered eligible for the study when iron deficiency (serum ferritin õ50 ng/mL) was documented. Exclusion criteria included: any gastrointestinal or systemic symptoms/signs, radiographic or endoscopic examinations of the gastrointestinal tract within 3 and 5 years, respectively, or obvious source of blood loss. Patients underwent colonoscopy and if no lesions other than carcinoma were found, upper endoscopy was then performed with a pediatric colonoscope. RESULTS: Fifty-two patients were evaluated (mean age, 66 { 13 years; range, 20 to 89 years; 32 men/20 women). At the time of evaluation, the mean ({SD) hematocrit was 25% { 7% (range, 14% to 42%). Overall, 23 patients (44%; 95% CI 30% to 59%) had an identifiable gastrointestinal lesion considered the cause of iron deficiency, including: colonic carcinoma, 11 (21%); colonic and/or esophagogastric/duodenal vascular ectasias, 9 (17%); and gastric carcinoma, colonic polyposis, and colonic ulcers in 1 patient each. Long-term follow-up (median 24 months, range 2 to 63 months) identified only 1 patient with a cause found (colonic carcinoma), and in this patient, complete colonoscopy was not technically possible at the time of initial
From the Division of Digestive Diseases (CMW, LNA), Department of Medicine, Emory University, the Emory University School of Public Health (WSC); and The Medical Service of Grady Memorial Hospital, Atlanta, Georgia. Requests for reprints should be addressed to C. Mel Wilcox, MD, University of Alabama at Birmingham, Division of Gastroenterology & Hepatology, Birmingham, Alabama 35294-0007. Manuscript submitted January 23, 1997 and accepted in revised form April 29, 1997.
evaluation. There were no clinical or laboratory features that distinguished patients with an etiology for iron deficiency to the idiopathic group. CONCLUSIONS: Approximately half of patients with iron deficiency in whom gastrointestinal or systemic signs or symptoms are absent have an underlying gastrointestinal lesion. Nevertheless, despite a thorough endoscopic evaluation, some patients will have no etiology found; the prognosis for these patients is excellent. Am J. Med. 1997;103:405–409. Q 1997 by Excerpta Medica, Inc.
I
ron deficiency is the most common cause of anemia. Because the differential diagnosis is broad, clinicians rely heavily on the patient’s symptoms and signs to point to the underlying cause. In any patient with iron deficiency, however, there is concern about the possibility of gastrointestinal blood loss, particularly in elderly patients. When gastrointestinal blood loss is suspected, localization of symptoms to either the upper or lower gastrointestinal tract will help direct the evaluation. Although prior studies have reported the underlying gastrointestinal lesions in symptomatic patients with iron deficiency anemia,1 – 5 there has been limited study of patients in whom gastrointestinal or systemic symptoms and signs are absent. Determining the prevalence and causes of gastrointestinal lesions in these patients will be necessary to make appropriate recommendations for evaluation. Therefore, the purposes of our study were to evaluate endoscopically patients with iron deficiency but without gastrointestinal or systemic symptoms or signs to determine the prevalence and location of gastrointestinal lesions, and to assess the long-term outcome for those patients in whom no gastrointestinal cause could be identified.
PATIENTS AND METHODS The study was conducted prospectively from August 1, 1990 through March 31, 1995 at Grady Memorial Hospital, a large inner-city hospital serving primarily the indigent population of metropolitan Atlanta, Georgia. The protocol was approved by the institutional review board of Emory University, and
Q1997 by Excerpta Medica, Inc. All rights reserved.
/ 2213 5132 Mp
405
0002-9343/97/$17.00 PII S0002-9343(97)00168-X
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
405
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
all patients gave written informed consent for all endoscopic procedures. Study candidates were obtained from those patients evaluated by our in-patient gastroenterology consultative service, as well as from patients referrred to our outpatient clinic. To be eligible for the study, the patient had to have documented iron deficiency defined as a serum ferritin concentration õ50 ng/mL. Anemia was not required as an inclusion criteria. Exclusion criteria included the following: acute gastrointestinal blood loss resulting in anemia; prior history of evaluation for iron deficiency anemia; clay ingestion; previous gastric surgery, barium enema, and/or upper gastrointestinal radiographic series within 3 years of evaluation; prior upper endoscopy and/or colonoscopy within 5 years of evaluation; any upper or lower gastrointestinal symptoms including heartburn, dysphagia, abdominal pain, rectal bleeding, alteration in bowel habits, menorrhagia considered excessive by gynecological consultation, weight loss, chronic fever, or paraneoplastic syndromes such as deep venous thrombosis, etc., or an unreliable history for antecedent symptoms. Patients with long-standing mild intermittent symptoms discovered during the initial assessment for which medical attention had not previously been sought, such as heartburn or constipation, were not excluded if there was no change in the frequency or severity of these symptoms. A careful history for nonsteroidal antiinflammatory drug use was sought, including the use of over-the-counter preparations, as previously described.6 All patients were personally interviewed by the principal investigator (CMW). If the entry criteria were met, patients underwent colonoscopy after routine colonic preparation with a video colonoscope (Olympus Corporation, Lake Success, New York). All identified abnormalities were recorded at the time of colonoscopy. The colonic mucosa was carefully evaluated during intubation to more accurately identify vascular ectasias. The ileum was not routinely examined. Multiple biopsies were performed of all endoscopic mucosal abnormalities with routine histologic examination. If no lesion other than carcinoma was identified, upper endoscopy was performed with a pediatric colonoscope (PCF-20). The stomach was minimally inflated to ensure deep intubation of the proximal jejunum. At the time of upper endoscopy, the small bowel mucosa was closely evaluated for any endoscopic pattern suggestive of celiac sprue7; if identified or suspected clinically, small bowel biopsy was performed. Endoscopic therapy was performed in standard fashion on vascular ectasias, where possible, using heater probe coagulation. The following lesions were considered gastrointestinal causes of iron deficiency: carcinomas or sar406
TABLE I Selected Clinical Features of the Patients n Age (range)* Male/Female Race, % black NSAID use, n (%) History of anemia, n (%) History of peptic ulcer, n (%) Heart disease, n (%)† Chronic renal failure, n (%) Guaiac (/) stool, n (%) Symptomatic anemia, n (%) Hemoglobin, g* Creatinine (mg/dL)* Ferritin (mg/dL)*
* Mean { SD. † Defined as coronary artery disease and/or congestive heart failure.
comas, erosive esophagitis, gastric and/or duodenal ulcers ú1 cm in greatest dimension as assessed by open biopsy forceps, vascular ectasias, colonic polyps ú2 cm in greatest dimension, inflammatory bowel diseases, and celiac sprue. The endoscopic diagnosis of vascular ectasia was based on the study of Zuckerman et al.8 Based on the results of the evaluation, patients were referred for surgery and placed on iron therapy. The duration of iron therapy was at the discretion of the primary physician. Patients were followed-up either in gastroenterology clinic or by phone regularly to September 1, 1996, noting the presence of any new gastrointestinal symptoms such as bleeding, recurrent iron deficiency, subsequent endoscopic or radiographic evaluation, or death. Standard descriptive statistics, including means, standard deviations, ranges, and frequency counts were used to characterize the sample. Statistical comparisons of the patients with endoscopic lesions versus those with idiopathic iron deficiency were carried out using Wilcoxon rank sum tests from continuous measures and Fisher’s exact test for categorical variables. For comparisons, a two-sided type I error of 0.05 was used to assess significance.
RESULTS Fifty-two patients met the inclusion criteria for the study; no patient meeting the entry criteria refused to participate. The demographics of these patients are listed in Table I. Consistent with our population, the majority of our patients were black. There were slightly more women than men. Of the 13 patients with a prior history of anemia, no patient had documented iron deficiency, and no patient had a previous gastrointestinal evaluation for iron deficiency. Nonsteroidal anti-inflammatory drug use was common. Over-the-counter NSAIDs were used by 26 pa-
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
406
Friday Oct 17 02:57 PM
52 66 { 13 (20–89) 20/32 90 27 (52) 13 (25) 1 (2) 15 (29) 4 (8) 23 (44) 29 (56) 8.6 { 4 1.4 { 1.4 12 { 10
EL–AJM (v. 103, no. 4)
5132
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
tients (50%) and 23 patients (44%) were receiving prescription NSAIDs, most commonly aspirin for cardiovascular disease. A prior history of ulcer disease and renal insufficiency was uncommon. All but 7 patients were anemic. Thirty-three patients were evaluated while hospitalized, with 29 of these patients admitted for symptomatic anemia. Thirty-nine patients underwent upper endoscopy following colonoscopy; one became combative during the procedure and the procedure could not be completed, and the other refused consent for upper endoscopy. The colonic preparation was considered adequate in all but 1 patient who had formed stool that could not be completely cleared from the left colon; subsequent barium enema did not reveal any lesions. Upper gastrointestinal small bowel follow was not routinely performed but was at the discretion of the primary care physician; 12 patients underwent this test, and all tested normal; no patient underwent small bowel enteroclysis. The gastrointestinal lesions that were identified and considered the cause of iron deficiency are presented in Table II. The most commonly identified lesion was colonic carcinoma. These tumors were found in the rectum and in the sigmoid colon in 1 patient each; 2 patients had lesions at the hepatic flexure, and the remaining carcinomas were identified in the cecum. All of these lesions were hemicircumferential or circumferential mass lesions typical for adenocarcinoma. Two patients had metastatic disease to the liver at the time of diagnosis identified by abdominal computed tomography and confirmed at surgery. Ectasias were identified in the colon in 7 patients, with all of these patients having lesions in the cecum except for 1 who had prominent isolated rectal involvement; this patient had no prior history of pelvic radiation. Of the patients with vascular ectasias, upper endoscopy was performed in 8. Four patients with colonic ectasias also had duodenal and/or jejunal lesions. Two patients had vascular ectasias limited to the upper gastrointestinal tract including the duodenum and jejunum. Of the these 2 patients, the lesions were not isolated distal to the second duodenum. Ectasias were multiple in all patients. The patient with colonic ulcers had several large ulcerations of the right colon with diaphragms, compatible with NSAID use9 – 11; she had been receiving long-term diclofenac therapy for arthritis. The patient with colonic polyps has multiple (approximately 10) polyps, most of which were ú2 cm in greatest dimension. Histologically, these polyps were all adenomatous, some of which had carcinoma in situ. Three patients underwent small bowel biopsy to exclude celiac sprue; the biopsy was histopathologically normal in each patient. Incidental findings at the time of colonoscopy and upper en-
TABLE II Identified Causes of Iron Deficiency N (%) Colon carcinoma Vascular ectasias Gastric carcinoma Colonic ulcers Colonic polyps No cause identified
11 (21) 9 (17) 1 (2) 1 (2) 1 (2) 29 (56)
doscopy included: colonic diverticulosis, 14 (27%); gastric ulcers, 4 (8%); internal hemorrhoids, 2 (4%); and colonic polyps, 9 (17%). The incidental gastric ulcers were all õ1 cm in size, had no stigmata of bleeding, and were endoscopically benign; 2 of these patients were receiving prescription NSAIDs. All colonic polyps were histologically benign and õ2 cm in size. Of the four patients with chronic renal failure, 1 had colon cancer and the other vascular ectasias. Of the 7 nonanemic patients, a cause for iron deficiency was established in 2 (vascular ectasias, colonic polyps). Follow-up was obtained in all patients with idiopathic iron deficiency. The median follow-up was 24 months (range, 2 to 63 months). All but 3 patients had follow-up for at least 1 year. During the course of follow-up, 14 patients died; no deaths were related to gastrointestinal disease. Four patients subsequently had overt gastrointestinal bleeding from vascular ectasias (previously identified), colonic diverticulosis, hemorrhoids, or gastric ulcer, which were diagnosed by endoscopic examinations. One patient had an incomplete colonoscopy at the time of initial evaluation due to a technical inability to intubate the cecum. At that time, barium enema was recommended but was not performed. Eighteen months later, she presented with recurrent iron deficiency anemia, right lower quadrant pain, and weight loss. Barium enema documented a cecal mass that was confirmed at surgery. This patient was considered to have iron deficiency anemia caused by this tumor. No other patient had a cause of iron deficiency identified on follow-up. All patients responded to iron supplementation with most patients receiving longterm iron treatment. The only patient with recurrent iron deficiency was the patient with the missed colonic carcinoma. Three additional patients had further radiologic evaluation on follow-up, which was requested by the primary care physicians, and which included barium enema and small bowel followthrough, which were normal. Patients in whom a diagnosis was made were also followed-up; 3 patients with colonic carcinoma were not followed up. None of these patients had recurrent iron deficiency or an-
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
407
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
407
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
other cause of iron deficiency found during longterm follow-up. A number of comparisons were made between patients with endoscopic lesions considered the cause of anemia to those patients with idiopathic iron deficiency. There were no differences detected in age, race, gender, use of NSAIDs, stool guaiac positivity, comorbidity, or laboratory studies.
DISCUSSION Our study sought to address the yield of endoscopic evaluation of the lower and upper gastrointestinal tract in a cohort of patients with iron deficiency who lacked systemic or gastrointestinal symptoms and signs. We found that almost half of the patients had underlying gastrointestinal lesions that were considered the likely etiology of iron deficiency, with colon cancer being the most commonly identified cause. Of the patients in whom no underlying gastrointestinal cause was found, the long-term prognosis was excellent provided initial endoscopic examination was adequate. Consistent with prior studies,4,12 small bowel tumors were not identified in any patient at the time of inital evaluation or on follow-up. A number of studies have addressed the yield of gastrointestinal tract evaluation in patients with iron deficiency anemia. Although diseases of the colon have long been considered the most common source of blood loss, recent studies suggest that upper gastrointestinal lesions may be more frequent than previously recognized.1,3 – 5,13 Rocky and Cello4 identified a potential cause of iron deficiency anemia in 62 of 100 patients, with 36% of patients having upper gastrointestinal pathology. In this study,4 lesions of the upper gastrointestinal tract were more comman than colonic lesions; duodenal and gastric ulcers were the most common identifiable causes, identified in 19%. Similarly, Kepczyk et al5 found that 56% of patients with iron deficiency anemia had potential lesions at upper gastrointestinal endoscopy. We identified colon cancer in a higher percentage of patients than in these studies, which may be due to our specific patient population. It is important to note that in these studies, gastrointestinal symptoms of either the upper or lower gastrointestinal tract were usually present. Indeed, Rockey and Cello4 found that localizing symptoms to either the upper or lower gastrointestinal tract were predictive for disease. In contrast, our study uniquely focused on patients without gastrointestinal symptoms, as it is this group of patients in whom the appropriate evaluation has not been well defined. We did not identify occult celiac sprue at the time of evaluation or on long-term follow-up in any patient. Celiac sprue has been documented in other se408
ries as the cause of iron deficiency.3 It is likely that this disease was rare in our study, due to the racial predominance of blacks at our center. In addition, prior studies of patients with iron deficiency and celiac sprue point out that most patients present with diarrhea or have a history of intermittent diarrhea for many years.14 Nevertheless, small bowel biopsy should be considered in the appropriate epidemiologic setting even when diarrhea is absent. Traditionally, radiographic evaluation of the small bowel is performed in iron deficient patients when colonoscopy and upper endoscopy are nondiagnostic. Given our previous findings15 as well as those of others4 that have shown a very low yield of enteroclysis in this setting, we chose to follow-up patients clinically rather than perform routine small bowel examination. Using this conservative approach, no patients were identified on follow-up with occult malignant small bowel disease. Similar to the studies by McIntyre and Long1 and Gordon et al,3 we did not identify any clinical parameters that were predictive for those patients in whom a diagnosis was established, including the use of fecal occult blood testing. This contrasts with the study of Rocky and Cello,4 in which fecal occult blood testing was found to be predictive of gastrointestinal lesions. The reason for these differences is unknown. It is likely that peptic ulcer and colitis were rarely seen in our study, given that these diseases are most often symptomatic. A strength of our study was the long-term followup of patients in whom no diagnosis was established. We felt that this was critical to best exclude the possibility of any missed gastrointestinal lesions. Only 1 patient had a lesion identified on follow-up, and in this patient, a complete evaluation at the time of the index colonoscopy was not technically possible. Our findings are similar to those of Rocky and Cello4 and Gordon et al,12 in which 38% and 41%, respectively, had no diagnosis established following endoscopic evaluation. In the study by Gordon et al,12 long-term follow-up (mean, 39 months) in 69 patients (ú50 years of age with idiopathic iron deficiency) identified only 1 patient who had a subsequent diagnosis (duodenal vascular ectasias), and this patient required transfusions for recurrent anemia. In this study, 60% of patients presented initially with gasitrointestinal symptoms. Similarly, Rocky and Cello4 did not identify any patients with a diagnosis on follow-up. The cause of iron deficiency for patients without an etiolgic diagnosis remains speculative. Celiac sprue appears unlikely, based on the initial endoscopic and biopsy findings as well as long-term follow-up. Occult small bowel tumors are also unlikely, given our long follow-up period. None of our patients
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
408
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
had an obvious inadequate dietary intake, although lack of adequate oral intake may be one possibility. Another likely possibility is a defect in absorption of iron. Given the age of our patients, hypochlorhydria due to atrophic gastritis may be likely. Vascular ectasias distal to the proximal jejunum and limited to the small intestine may also be a potential cause.16 Based on the results of our study, we recommend a thorough gastrointestinal tract evaluation for patients with iron deficiency, even when gastrointestinal or systemic symptoms are absent. Given the high prevalence of colonic carcinoma as well as vascular ectasias, we recommend first evaluating the colon endoscopically rather than by barium enema, given the prevalence of carcinoma and ectasias, both of which require colonoscopic evaluation for diagnosis and treatment. Endoscopic therapy for ectasias should be performed where possible. Although upper endoscopy in our patients had a low yield, treatable lesions were identified including gastric cancer and vascular ectasias. If no cause is found after endoscopic evaluation, the patient can be followed symptomatically. Our findings in combination with those of other studies suggest that radiographic evaluation of the small bowel is not required provided symptoms are absent. Long-term follow-up is essential to detect recurrent iron deficiency anemia, which may point to an underlying missed lesion. Celiac sprue should be considered in the younger patient, and small bowel biopsy should be limited to the appropriate clinical and endoscopic setting.
ACKNOWLEDGMENTS A portion of this work was presented at the annual meeting of the Southern Medical Association, Gastroenterology section, 1996, and published in abstract form (South Med J. 1996;89:S40–41.)
REFERENCES 1. McIntyre AS, Long RG. Prospective survey of investigations in outpatients referred with iron deficiency anaemia. Gut. 1993;34:1102–1107. 2. Sahay R, Scott BB. Iron deficiency anemia: how far to investigate? Gut. 1993;34:1427–1428. 3. Gordon SR, Smith RE, Power GC. The role of endoscopy in the evaluation of iron deficiency anemia in patients over the age of 50. Am J Gastroenterol. 1994;89:1963–. 4. Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with iron deficiency anemia. NEJM. 1993;329:1691–1695. 5. Kepczyk MT, Kadakia CS. Prospective evaluation of gastrointestinal tract in patients with iron deficiency anemia. Dig Dis Sci. 1995;40:1283–1289. 6. Wilcox CM, Shalek KA, Cotsonis G. Striking prevalence of over-the-counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Intern Med. 1994;154:42–46. 7. Jabbari M, Wild G, Goresky CA, et al. Scalloped valvulae conniventes: an endoscopic marker of celiac sprue. Gastroenterology. 1988;95:1518–1522. 8. Zuckerman GR, Cornette GL, Clouse RE, et al. Upper gastrointestinal bleeding in patients with chronic renal failure. Ann Intern Med. 1985;102:588–592. 9. Huber T, Ruchti C, Halter F. Nonsteroidal antiinflammatory drug-induced colonic strictures: a case report. Gastroenterology. 1991;100:1119–1122. 10. Anthony A, Dhillon AP, Sim R, et al. Ulceration, fibrosis and diaphragm-like lesions in the caecum of rats treated with indomethacin. Aliment Pharmacol Ther. 1994;8:417–424. 11. Whitcomb DC, Martin SP, Trellis DR, et al. ‘‘Diaphragmlike’’ stricture and ulcer of the colon during diclofenac treatment. Arch Intern Med. 1992;152: 2341–2343. 12. Gordon S, Benson S, Smith R. Long term follow-up of older patients with iron deficiency anemia after a negative GI evaluation. Am J Gastroenterol. 1996;91:885–889. 13. Zuckerman G, Benitez J. A prospective study of bidirectional endoscopy (colonoscopy and upper endoscopy) in the evaluation of patients with occult gastrointestinal bleeding. Am J Gastroenterol. 1992;87:62–66. 14. Ackerman Z, Eliakim R, Stalnikowicz R, Rachmilewitz D. Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia. Am J Gastroenterol. 1996;91:2099–2102. 15. Wilcox CM, Forsmark CE, Thoeni RF, Cello JP. Utility of enteroclysis in the evaluation of undefined gastrointestinal bleeding (GIB). Gastroenterology. 1990;98:A210. 16. Lewis BS, Waye JD. Chronic gastrointestinal bleeding of obscure origin: role of small bowel enteroscopy: role of small bowel enteroscopy. Gastroenterology. 1988;94:1117–1120.
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
409
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
409
BACKGROUND: Although endoscopic evaluation of the gastrointestinal tract is commonly performed to evaluate iron deficiency, little data is available regarding the underlying causes, yield of evaluation, and long-term outcome for those in whom gastrointestinal and systemic symptoms and signs are absent. METHODS: In- or out-patients seen by the gastroenterology consultative service at a large inner-city hospital over a 56-month period were considered eligible for the study when iron deficiency (serum ferritin õ50 ng/mL) was documented. Exclusion criteria included: any gastrointestinal or systemic symptoms/signs, radiographic or endoscopic examinations of the gastrointestinal tract within 3 and 5 years, respectively, or obvious source of blood loss. Patients underwent colonoscopy and if no lesions other than carcinoma were found, upper endoscopy was then performed with a pediatric colonoscope. RESULTS: Fifty-two patients were evaluated (mean age, 66 { 13 years; range, 20 to 89 years; 32 men/20 women). At the time of evaluation, the mean ({SD) hematocrit was 25% { 7% (range, 14% to 42%). Overall, 23 patients (44%; 95% CI 30% to 59%) had an identifiable gastrointestinal lesion considered the cause of iron deficiency, including: colonic carcinoma, 11 (21%); colonic and/or esophagogastric/duodenal vascular ectasias, 9 (17%); and gastric carcinoma, colonic polyposis, and colonic ulcers in 1 patient each. Long-term follow-up (median 24 months, range 2 to 63 months) identified only 1 patient with a cause found (colonic carcinoma), and in this patient, complete colonoscopy was not technically possible at the time of initial
From the Division of Digestive Diseases (CMW, LNA), Department of Medicine, Emory University, the Emory University School of Public Health (WSC); and The Medical Service of Grady Memorial Hospital, Atlanta, Georgia. Requests for reprints should be addressed to C. Mel Wilcox, MD, University of Alabama at Birmingham, Division of Gastroenterology & Hepatology, Birmingham, Alabama 35294-0007. Manuscript submitted January 23, 1997 and accepted in revised form April 29, 1997.
evaluation. There were no clinical or laboratory features that distinguished patients with an etiology for iron deficiency to the idiopathic group. CONCLUSIONS: Approximately half of patients with iron deficiency in whom gastrointestinal or systemic signs or symptoms are absent have an underlying gastrointestinal lesion. Nevertheless, despite a thorough endoscopic evaluation, some patients will have no etiology found; the prognosis for these patients is excellent. Am J. Med. 1997;103:405–409. Q 1997 by Excerpta Medica, Inc.
I
ron deficiency is the most common cause of anemia. Because the differential diagnosis is broad, clinicians rely heavily on the patient’s symptoms and signs to point to the underlying cause. In any patient with iron deficiency, however, there is concern about the possibility of gastrointestinal blood loss, particularly in elderly patients. When gastrointestinal blood loss is suspected, localization of symptoms to either the upper or lower gastrointestinal tract will help direct the evaluation. Although prior studies have reported the underlying gastrointestinal lesions in symptomatic patients with iron deficiency anemia,1 – 5 there has been limited study of patients in whom gastrointestinal or systemic symptoms and signs are absent. Determining the prevalence and causes of gastrointestinal lesions in these patients will be necessary to make appropriate recommendations for evaluation. Therefore, the purposes of our study were to evaluate endoscopically patients with iron deficiency but without gastrointestinal or systemic symptoms or signs to determine the prevalence and location of gastrointestinal lesions, and to assess the long-term outcome for those patients in whom no gastrointestinal cause could be identified.
PATIENTS AND METHODS The study was conducted prospectively from August 1, 1990 through March 31, 1995 at Grady Memorial Hospital, a large inner-city hospital serving primarily the indigent population of metropolitan Atlanta, Georgia. The protocol was approved by the institutional review board of Emory University, and
Q1997 by Excerpta Medica, Inc. All rights reserved.
/ 2213 5132 Mp
405
0002-9343/97/$17.00 PII S0002-9343(97)00168-X
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
405
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
all patients gave written informed consent for all endoscopic procedures. Study candidates were obtained from those patients evaluated by our in-patient gastroenterology consultative service, as well as from patients referrred to our outpatient clinic. To be eligible for the study, the patient had to have documented iron deficiency defined as a serum ferritin concentration õ50 ng/mL. Anemia was not required as an inclusion criteria. Exclusion criteria included the following: acute gastrointestinal blood loss resulting in anemia; prior history of evaluation for iron deficiency anemia; clay ingestion; previous gastric surgery, barium enema, and/or upper gastrointestinal radiographic series within 3 years of evaluation; prior upper endoscopy and/or colonoscopy within 5 years of evaluation; any upper or lower gastrointestinal symptoms including heartburn, dysphagia, abdominal pain, rectal bleeding, alteration in bowel habits, menorrhagia considered excessive by gynecological consultation, weight loss, chronic fever, or paraneoplastic syndromes such as deep venous thrombosis, etc., or an unreliable history for antecedent symptoms. Patients with long-standing mild intermittent symptoms discovered during the initial assessment for which medical attention had not previously been sought, such as heartburn or constipation, were not excluded if there was no change in the frequency or severity of these symptoms. A careful history for nonsteroidal antiinflammatory drug use was sought, including the use of over-the-counter preparations, as previously described.6 All patients were personally interviewed by the principal investigator (CMW). If the entry criteria were met, patients underwent colonoscopy after routine colonic preparation with a video colonoscope (Olympus Corporation, Lake Success, New York). All identified abnormalities were recorded at the time of colonoscopy. The colonic mucosa was carefully evaluated during intubation to more accurately identify vascular ectasias. The ileum was not routinely examined. Multiple biopsies were performed of all endoscopic mucosal abnormalities with routine histologic examination. If no lesion other than carcinoma was identified, upper endoscopy was performed with a pediatric colonoscope (PCF-20). The stomach was minimally inflated to ensure deep intubation of the proximal jejunum. At the time of upper endoscopy, the small bowel mucosa was closely evaluated for any endoscopic pattern suggestive of celiac sprue7; if identified or suspected clinically, small bowel biopsy was performed. Endoscopic therapy was performed in standard fashion on vascular ectasias, where possible, using heater probe coagulation. The following lesions were considered gastrointestinal causes of iron deficiency: carcinomas or sar406
TABLE I Selected Clinical Features of the Patients n Age (range)* Male/Female Race, % black NSAID use, n (%) History of anemia, n (%) History of peptic ulcer, n (%) Heart disease, n (%)† Chronic renal failure, n (%) Guaiac (/) stool, n (%) Symptomatic anemia, n (%) Hemoglobin, g* Creatinine (mg/dL)* Ferritin (mg/dL)*
* Mean { SD. † Defined as coronary artery disease and/or congestive heart failure.
comas, erosive esophagitis, gastric and/or duodenal ulcers ú1 cm in greatest dimension as assessed by open biopsy forceps, vascular ectasias, colonic polyps ú2 cm in greatest dimension, inflammatory bowel diseases, and celiac sprue. The endoscopic diagnosis of vascular ectasia was based on the study of Zuckerman et al.8 Based on the results of the evaluation, patients were referred for surgery and placed on iron therapy. The duration of iron therapy was at the discretion of the primary physician. Patients were followed-up either in gastroenterology clinic or by phone regularly to September 1, 1996, noting the presence of any new gastrointestinal symptoms such as bleeding, recurrent iron deficiency, subsequent endoscopic or radiographic evaluation, or death. Standard descriptive statistics, including means, standard deviations, ranges, and frequency counts were used to characterize the sample. Statistical comparisons of the patients with endoscopic lesions versus those with idiopathic iron deficiency were carried out using Wilcoxon rank sum tests from continuous measures and Fisher’s exact test for categorical variables. For comparisons, a two-sided type I error of 0.05 was used to assess significance.
RESULTS Fifty-two patients met the inclusion criteria for the study; no patient meeting the entry criteria refused to participate. The demographics of these patients are listed in Table I. Consistent with our population, the majority of our patients were black. There were slightly more women than men. Of the 13 patients with a prior history of anemia, no patient had documented iron deficiency, and no patient had a previous gastrointestinal evaluation for iron deficiency. Nonsteroidal anti-inflammatory drug use was common. Over-the-counter NSAIDs were used by 26 pa-
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
406
Friday Oct 17 02:57 PM
52 66 { 13 (20–89) 20/32 90 27 (52) 13 (25) 1 (2) 15 (29) 4 (8) 23 (44) 29 (56) 8.6 { 4 1.4 { 1.4 12 { 10
EL–AJM (v. 103, no. 4)
5132
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
tients (50%) and 23 patients (44%) were receiving prescription NSAIDs, most commonly aspirin for cardiovascular disease. A prior history of ulcer disease and renal insufficiency was uncommon. All but 7 patients were anemic. Thirty-three patients were evaluated while hospitalized, with 29 of these patients admitted for symptomatic anemia. Thirty-nine patients underwent upper endoscopy following colonoscopy; one became combative during the procedure and the procedure could not be completed, and the other refused consent for upper endoscopy. The colonic preparation was considered adequate in all but 1 patient who had formed stool that could not be completely cleared from the left colon; subsequent barium enema did not reveal any lesions. Upper gastrointestinal small bowel follow was not routinely performed but was at the discretion of the primary care physician; 12 patients underwent this test, and all tested normal; no patient underwent small bowel enteroclysis. The gastrointestinal lesions that were identified and considered the cause of iron deficiency are presented in Table II. The most commonly identified lesion was colonic carcinoma. These tumors were found in the rectum and in the sigmoid colon in 1 patient each; 2 patients had lesions at the hepatic flexure, and the remaining carcinomas were identified in the cecum. All of these lesions were hemicircumferential or circumferential mass lesions typical for adenocarcinoma. Two patients had metastatic disease to the liver at the time of diagnosis identified by abdominal computed tomography and confirmed at surgery. Ectasias were identified in the colon in 7 patients, with all of these patients having lesions in the cecum except for 1 who had prominent isolated rectal involvement; this patient had no prior history of pelvic radiation. Of the patients with vascular ectasias, upper endoscopy was performed in 8. Four patients with colonic ectasias also had duodenal and/or jejunal lesions. Two patients had vascular ectasias limited to the upper gastrointestinal tract including the duodenum and jejunum. Of the these 2 patients, the lesions were not isolated distal to the second duodenum. Ectasias were multiple in all patients. The patient with colonic ulcers had several large ulcerations of the right colon with diaphragms, compatible with NSAID use9 – 11; she had been receiving long-term diclofenac therapy for arthritis. The patient with colonic polyps has multiple (approximately 10) polyps, most of which were ú2 cm in greatest dimension. Histologically, these polyps were all adenomatous, some of which had carcinoma in situ. Three patients underwent small bowel biopsy to exclude celiac sprue; the biopsy was histopathologically normal in each patient. Incidental findings at the time of colonoscopy and upper en-
TABLE II Identified Causes of Iron Deficiency N (%) Colon carcinoma Vascular ectasias Gastric carcinoma Colonic ulcers Colonic polyps No cause identified
11 (21) 9 (17) 1 (2) 1 (2) 1 (2) 29 (56)
doscopy included: colonic diverticulosis, 14 (27%); gastric ulcers, 4 (8%); internal hemorrhoids, 2 (4%); and colonic polyps, 9 (17%). The incidental gastric ulcers were all õ1 cm in size, had no stigmata of bleeding, and were endoscopically benign; 2 of these patients were receiving prescription NSAIDs. All colonic polyps were histologically benign and õ2 cm in size. Of the four patients with chronic renal failure, 1 had colon cancer and the other vascular ectasias. Of the 7 nonanemic patients, a cause for iron deficiency was established in 2 (vascular ectasias, colonic polyps). Follow-up was obtained in all patients with idiopathic iron deficiency. The median follow-up was 24 months (range, 2 to 63 months). All but 3 patients had follow-up for at least 1 year. During the course of follow-up, 14 patients died; no deaths were related to gastrointestinal disease. Four patients subsequently had overt gastrointestinal bleeding from vascular ectasias (previously identified), colonic diverticulosis, hemorrhoids, or gastric ulcer, which were diagnosed by endoscopic examinations. One patient had an incomplete colonoscopy at the time of initial evaluation due to a technical inability to intubate the cecum. At that time, barium enema was recommended but was not performed. Eighteen months later, she presented with recurrent iron deficiency anemia, right lower quadrant pain, and weight loss. Barium enema documented a cecal mass that was confirmed at surgery. This patient was considered to have iron deficiency anemia caused by this tumor. No other patient had a cause of iron deficiency identified on follow-up. All patients responded to iron supplementation with most patients receiving longterm iron treatment. The only patient with recurrent iron deficiency was the patient with the missed colonic carcinoma. Three additional patients had further radiologic evaluation on follow-up, which was requested by the primary care physicians, and which included barium enema and small bowel followthrough, which were normal. Patients in whom a diagnosis was made were also followed-up; 3 patients with colonic carcinoma were not followed up. None of these patients had recurrent iron deficiency or an-
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
407
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
407
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
other cause of iron deficiency found during longterm follow-up. A number of comparisons were made between patients with endoscopic lesions considered the cause of anemia to those patients with idiopathic iron deficiency. There were no differences detected in age, race, gender, use of NSAIDs, stool guaiac positivity, comorbidity, or laboratory studies.
DISCUSSION Our study sought to address the yield of endoscopic evaluation of the lower and upper gastrointestinal tract in a cohort of patients with iron deficiency who lacked systemic or gastrointestinal symptoms and signs. We found that almost half of the patients had underlying gastrointestinal lesions that were considered the likely etiology of iron deficiency, with colon cancer being the most commonly identified cause. Of the patients in whom no underlying gastrointestinal cause was found, the long-term prognosis was excellent provided initial endoscopic examination was adequate. Consistent with prior studies,4,12 small bowel tumors were not identified in any patient at the time of inital evaluation or on follow-up. A number of studies have addressed the yield of gastrointestinal tract evaluation in patients with iron deficiency anemia. Although diseases of the colon have long been considered the most common source of blood loss, recent studies suggest that upper gastrointestinal lesions may be more frequent than previously recognized.1,3 – 5,13 Rocky and Cello4 identified a potential cause of iron deficiency anemia in 62 of 100 patients, with 36% of patients having upper gastrointestinal pathology. In this study,4 lesions of the upper gastrointestinal tract were more comman than colonic lesions; duodenal and gastric ulcers were the most common identifiable causes, identified in 19%. Similarly, Kepczyk et al5 found that 56% of patients with iron deficiency anemia had potential lesions at upper gastrointestinal endoscopy. We identified colon cancer in a higher percentage of patients than in these studies, which may be due to our specific patient population. It is important to note that in these studies, gastrointestinal symptoms of either the upper or lower gastrointestinal tract were usually present. Indeed, Rockey and Cello4 found that localizing symptoms to either the upper or lower gastrointestinal tract were predictive for disease. In contrast, our study uniquely focused on patients without gastrointestinal symptoms, as it is this group of patients in whom the appropriate evaluation has not been well defined. We did not identify occult celiac sprue at the time of evaluation or on long-term follow-up in any patient. Celiac sprue has been documented in other se408
ries as the cause of iron deficiency.3 It is likely that this disease was rare in our study, due to the racial predominance of blacks at our center. In addition, prior studies of patients with iron deficiency and celiac sprue point out that most patients present with diarrhea or have a history of intermittent diarrhea for many years.14 Nevertheless, small bowel biopsy should be considered in the appropriate epidemiologic setting even when diarrhea is absent. Traditionally, radiographic evaluation of the small bowel is performed in iron deficient patients when colonoscopy and upper endoscopy are nondiagnostic. Given our previous findings15 as well as those of others4 that have shown a very low yield of enteroclysis in this setting, we chose to follow-up patients clinically rather than perform routine small bowel examination. Using this conservative approach, no patients were identified on follow-up with occult malignant small bowel disease. Similar to the studies by McIntyre and Long1 and Gordon et al,3 we did not identify any clinical parameters that were predictive for those patients in whom a diagnosis was established, including the use of fecal occult blood testing. This contrasts with the study of Rocky and Cello,4 in which fecal occult blood testing was found to be predictive of gastrointestinal lesions. The reason for these differences is unknown. It is likely that peptic ulcer and colitis were rarely seen in our study, given that these diseases are most often symptomatic. A strength of our study was the long-term followup of patients in whom no diagnosis was established. We felt that this was critical to best exclude the possibility of any missed gastrointestinal lesions. Only 1 patient had a lesion identified on follow-up, and in this patient, a complete evaluation at the time of the index colonoscopy was not technically possible. Our findings are similar to those of Rocky and Cello4 and Gordon et al,12 in which 38% and 41%, respectively, had no diagnosis established following endoscopic evaluation. In the study by Gordon et al,12 long-term follow-up (mean, 39 months) in 69 patients (ú50 years of age with idiopathic iron deficiency) identified only 1 patient who had a subsequent diagnosis (duodenal vascular ectasias), and this patient required transfusions for recurrent anemia. In this study, 60% of patients presented initially with gasitrointestinal symptoms. Similarly, Rocky and Cello4 did not identify any patients with a diagnosis on follow-up. The cause of iron deficiency for patients without an etiolgic diagnosis remains speculative. Celiac sprue appears unlikely, based on the initial endoscopic and biopsy findings as well as long-term follow-up. Occult small bowel tumors are also unlikely, given our long follow-up period. None of our patients
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
408
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
PROSPECTIVE EVALUATION OF GI TRACT/WILCOX ET AL
had an obvious inadequate dietary intake, although lack of adequate oral intake may be one possibility. Another likely possibility is a defect in absorption of iron. Given the age of our patients, hypochlorhydria due to atrophic gastritis may be likely. Vascular ectasias distal to the proximal jejunum and limited to the small intestine may also be a potential cause.16 Based on the results of our study, we recommend a thorough gastrointestinal tract evaluation for patients with iron deficiency, even when gastrointestinal or systemic symptoms are absent. Given the high prevalence of colonic carcinoma as well as vascular ectasias, we recommend first evaluating the colon endoscopically rather than by barium enema, given the prevalence of carcinoma and ectasias, both of which require colonoscopic evaluation for diagnosis and treatment. Endoscopic therapy for ectasias should be performed where possible. Although upper endoscopy in our patients had a low yield, treatable lesions were identified including gastric cancer and vascular ectasias. If no cause is found after endoscopic evaluation, the patient can be followed symptomatically. Our findings in combination with those of other studies suggest that radiographic evaluation of the small bowel is not required provided symptoms are absent. Long-term follow-up is essential to detect recurrent iron deficiency anemia, which may point to an underlying missed lesion. Celiac sprue should be considered in the younger patient, and small bowel biopsy should be limited to the appropriate clinical and endoscopic setting.
ACKNOWLEDGMENTS A portion of this work was presented at the annual meeting of the Southern Medical Association, Gastroenterology section, 1996, and published in abstract form (South Med J. 1996;89:S40–41.)
REFERENCES 1. McIntyre AS, Long RG. Prospective survey of investigations in outpatients referred with iron deficiency anaemia. Gut. 1993;34:1102–1107. 2. Sahay R, Scott BB. Iron deficiency anemia: how far to investigate? Gut. 1993;34:1427–1428. 3. Gordon SR, Smith RE, Power GC. The role of endoscopy in the evaluation of iron deficiency anemia in patients over the age of 50. Am J Gastroenterol. 1994;89:1963–. 4. Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with iron deficiency anemia. NEJM. 1993;329:1691–1695. 5. Kepczyk MT, Kadakia CS. Prospective evaluation of gastrointestinal tract in patients with iron deficiency anemia. Dig Dis Sci. 1995;40:1283–1289. 6. Wilcox CM, Shalek KA, Cotsonis G. Striking prevalence of over-the-counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Intern Med. 1994;154:42–46. 7. Jabbari M, Wild G, Goresky CA, et al. Scalloped valvulae conniventes: an endoscopic marker of celiac sprue. Gastroenterology. 1988;95:1518–1522. 8. Zuckerman GR, Cornette GL, Clouse RE, et al. Upper gastrointestinal bleeding in patients with chronic renal failure. Ann Intern Med. 1985;102:588–592. 9. Huber T, Ruchti C, Halter F. Nonsteroidal antiinflammatory drug-induced colonic strictures: a case report. Gastroenterology. 1991;100:1119–1122. 10. Anthony A, Dhillon AP, Sim R, et al. Ulceration, fibrosis and diaphragm-like lesions in the caecum of rats treated with indomethacin. Aliment Pharmacol Ther. 1994;8:417–424. 11. Whitcomb DC, Martin SP, Trellis DR, et al. ‘‘Diaphragmlike’’ stricture and ulcer of the colon during diclofenac treatment. Arch Intern Med. 1992;152: 2341–2343. 12. Gordon S, Benson S, Smith R. Long term follow-up of older patients with iron deficiency anemia after a negative GI evaluation. Am J Gastroenterol. 1996;91:885–889. 13. Zuckerman G, Benitez J. A prospective study of bidirectional endoscopy (colonoscopy and upper endoscopy) in the evaluation of patients with occult gastrointestinal bleeding. Am J Gastroenterol. 1992;87:62–66. 14. Ackerman Z, Eliakim R, Stalnikowicz R, Rachmilewitz D. Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia. Am J Gastroenterol. 1996;91:2099–2102. 15. Wilcox CM, Forsmark CE, Thoeni RF, Cello JP. Utility of enteroclysis in the evaluation of undefined gastrointestinal bleeding (GIB). Gastroenterology. 1990;98:A210. 16. Lewis BS, Waye JD. Chronic gastrointestinal bleeding of obscure origin: role of small bowel enteroscopy: role of small bowel enteroscopy. Gastroenterology. 1988;94:1117–1120.
November 1997 The American Journal of MedicineT Volume 103
/ 2213 5132 Mp
409
Friday Oct 17 02:57 PM
EL–AJM (v. 103, no. 4)
5132
409