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AGA Technical Review on Gastrointestinal Evaluation of Iron Deficiency Anemia

2020; Elsevier BV; Volume: 159; Issue: 3 Linguagem: Inglês

10.1053/j.gastro.2020.06.045

1528-0012

Don C. Rockey, Osama Altayar, Yngve Falck‐Ytter, Denise Kalmaz,

Gastrointestinal disorders and treatments

Iron deficiency anemia (IDA) is the commonest cause of anemia in the United States and worldwide. In the United States, it has been estimated that some 5%–11% of women and 1%–4% of men are iron deficient, and approximately 5% and 2%, respectively, have IDA.1Looker A.C. Dallman P.R. Carroll M.D. et al.Prevalence of iron deficiency in the United States.JAMA. 1997; 277: 973-976Crossref PubMed Google Scholar Although the cause of IDA may include inadequate iron intake or absorption, which are common in children and premenopausal women, IDA in adult men and postmenopausal women is often the result of chronic occult gastrointestinal bleeding. Although iron homeostasis is complicated, a basic understanding of its biology is important in the context of IDA (see Fleming,2Fleming M.D. The regulation of hepcidin and its effects on systemic and cellular iron metabolism.Hematology Am Soc Hematol Educ Program. 2008; : 151-158Crossref PubMed Scopus (84) Google Scholar Ganz and Nemeth,3Ganz T. Nemeth E. Hepcidin and iron homeostasis.Biochim Biophys Acta. 2012; 1823: 1434-1443Crossref PubMed Scopus (676) Google Scholar Camaschella,4Camaschella C. Iron and hepcidin: a story of recycling and balance.Hematology Am Soc Hematol Educ Program. 2013; 2013: 1-8Crossref PubMed Scopus (59) Google Scholar and Anderson and Frazer5Anderson G.J. Frazer D.M. Current understanding of iron homeostasis.Am J Clin Nutr. 2017; 106: 1559S-1566SCrossref PubMed Scopus (138) Google Scholar for review). In brief, non-heme iron is absorbed primarily in the proximal small intestine (the absorption of heme iron is poorly understood), although active absorption is via the divalent metal transporter-1, which is expressed in the proximal duodenum (Figure 1). It is well recognized that in some forms of gastric bypass in which the typical iron-absorbing segment of the duodenum is bypassed, iron malabsorption ensues. The ferroportin/hepcidin axis is also critically important in iron homeostasis. Hepcidin, a 25-amino acid peptide produced by hepatocytes via complex regulatory mechanisms, is distributed via the circulation to its target sites, where it binds to its receptor, ferroportin. Ferroportin is highly expressed at the basolateral surface of duodenal enterocytes, where it acts as a cellular iron exporter. Increased levels of hepcidin limit membrane insertion of ferroportin, blocking iron exit, with iron-laden enterocytes sloughed during their natural cycle of epithelial renewal, serving as a primary mechanism for removal of excess iron. Therefore, when the body is iron replete, hepcidin concentrations are high and iron delivery to the circulation is reduced. In contrast, in the iron-deficiency state, hepcidin levels are low and there is active iron delivery to the circulation. Important regulators of hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis. Disturbances in the regulation of hepcidin contribute to the pathogenesis of many iron disorders. For example, hepcidin deficiency causes iron overload in hereditary hemochromatosis and nontransfused β-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic kidney disease, chronic inflammatory diseases, some cancers, and inherited iron-refractory IDA. Under normal conditions, iron homeostasis is tightly regulated.6Hentze M.W. Muckenthaler M.U. Andrews N.C. Balancing acts: molecular control of mammalian iron metabolism.Cell. 2004; 117: 285-297Abstract Full Text Full Text PDF PubMed Scopus (1279) Google Scholar,7Tussing-Humphreys L. Pusatcioglu C. Nemeth E. et al.Rethinking iron regulation and assessment in iron deficiency, anemia of chronic disease, and obesity: introducing hepcidin.J Acad Nutr Diet. 2012; 112: 391-400Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Typical daily elemental iron loss is 0.25–0.75 mg from iron lost via sloughing of intestinal epithelial cells and microscopic gastrointestinal bleeding. With daily blood loss of 0.5–1.5 mL/d, a stool weight of 150 g, and circulating hemoglobin of 15 g/dL, stool hemoglobin concentration is 0.5–1.5 mg/g. In aggregate, the average daily iron loss is approximately 1 mg (Figure 1), which is precisely balanced by the same amount of iron absorption. Because the absorptive capacity of the small intestine for iron can increase in response to iron depletion, iron deficiency results only when iron loss exceeds the absorptive capacity of the small bowel. It is critical to emphasize that iron absorption is not only complex as highlighted above, but is limited (see Abbaspour et al8Abbaspour N. Hurrell R. Kelishadi R. Review on iron and its importance for human health.J Res Med Sci. 2014; 19: 164-174PubMed Google Scholar and Camaschella9Camaschella C. Iron deficiency.Blood. 2019; 133: 30-39Crossref PubMed Scopus (81) Google Scholar for review), so that iron depletion only occurs when intestinal absorptive capacity of iron is outstripped by iron loss. The degree to which blood can be “hidden” in the gastrointestinal tract is emphasized by the observation that although instillation of 50–100 mL of blood into the stomach may produce melena, patients losing 100 mL of blood per day may have grossly normal-appearing stools.10Schiff L. Stevens R.J. Shapiro N. et al.Observations on the oral administration of citrate blood in man.Am J Med Sci. 1942; 203: 409Crossref Google Scholar,11Rockey D.C. Occult gastrointestinal bleeding [see comments].N Engl J Med. 1999; 341: 38-46Crossref PubMed Scopus (0) Google Scholar This concept is consistent with the clinical observation that truly occult bleeding is a common cause of IDA. Virtually any gastrointestinal tract lesion that causes a mucosal defect can bleed enough to lead to occult blood loss and therefore cause IDA. Indeed, the clinical spectrum of IDA is broad because many different lesions occurring in many different sites in the gastrointestinal tract are capable of bleeding in an occult manner.11Rockey D.C. Occult gastrointestinal bleeding [see comments].N Engl J Med. 1999; 341: 38-46Crossref PubMed Scopus (0) Google Scholar,12Ahlquist D.A. McGill D.B. Schwartz S. et al.Fecal blood levels in health and disease. A study using HemoQuant.N Engl J Med. 1985; 312: 1422-1428Crossref PubMed Google Scholar Endoscopic evaluation of patients with IDA has shown that nearly two-thirds of patients will have lesions identified in the gastrointestinal tract that are believed to be capable of causing occult bleeding (Figure 2).13Rockey D.C. Occult and obscure gastrointestinal bleeding: causes and clinical management.Nat Rev Gastroenterol Hepatol. 2010; 7: 265-279Crossref PubMed Scopus (60) Google Scholar Although gastrointestinal tract malignancies, especially right-sided colonic cancers, have historically been considered to be the most common and important lesions identified during endoscopy, cancers have been identified in patients with IDA in all parts of the gastrointestinal tract and, furthermore, the most common causes of occult bleeding in patients with IDA are inflammatory ulcerative upper gastrointestinal tract lesions (Figure 2).13Rockey D.C. Occult and obscure gastrointestinal bleeding: causes and clinical management.Nat Rev Gastroenterol Hepatol. 2010; 7: 265-279Crossref PubMed Scopus (60) Google Scholar Only a small proportion of patients will be found to have a lesion capable of occult bleeding and causing IDA in each the upper and lower gastrointestinal tract simultaneously14Rockey D.C. Occult gastrointestinal bleeding.Gastroenterol Clin North Am. 2005; 34: 699-718Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (Figures 2 and 3). Notwithstanding, because of the propensity for a variety of gastrointestinal tract lesions to bleed in an occult fashion, the standard of care for postmenopausal women and men with IDA is to evaluate the gastrointestinal tract in search of a bleeding lesion.13Rockey D.C. Occult and obscure gastrointestinal bleeding: causes and clinical management.Nat Rev Gastroenterol Hepatol. 2010; 7: 265-279Crossref PubMed Scopus (60) Google ScholarFigure 3The role of endoscopy in IDA. In patients who have gastrointestinal (GI) tract lesions, occult bleeding leads to IDA, which usually should be pursued with endoscopy. In asymptomatic patients, if initial bidirectional endoscopy fails to identify a lesion, best evidence suggests that a trial of iron therapy is the most appropriate management approach. If that fails to correct IDA, further evaluation is typically indicated. ∗See Figure 2 for typical lesions. ∗∗Bidirectional endoscopy at the same sitting is preferred over sequential endoscopy at separate times. Note, in patients with IDA and symptoms, endoscopy should be directed first at the source of symptoms. If endoscopy in that location (ie, upper or lower tract) is negative, the portion of the gastrointestinal tract (ie, upper or lower tract) not yet investigated should be examined.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Although the effectiveness of fecal occult blood tests (FOBTs) has been well validated for use in colon cancer populations, the use of FOBTs in other populations has been more controversial. In theory, because FOBTs detect occult bleeding, it is possible that they may be useful in detection of occult bleeding in patients with IDA.15Rockey D.C. Cello J.P. Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia.N Engl J Med. 1993; 329: 1691-1695Crossref PubMed Scopus (438) Google Scholar, 16Bini E.J. Micale P.L. Weinshel E.H. Evaluation of the gastrointestinal tract in premenopausal women with iron deficiency anemia [see comments].Am J Med. 1998; 105: 281-286Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 17Kepczyk T. Cremins J.E. Long B.D. et al.A prospective, multidisciplinary evaluation of premenopausal women with iron-deficiency anemia [see comments].Am J Gastroenterol. 1999; 94: 109-115Crossref PubMed Scopus (0) Google Scholar, 18Green B.T. Rockey D.C. Gastrointestinal endoscopic evaluation of premenopausal women with iron deficiency anemia.J Clin Gastroenterol. 2004; 38: 104-109Crossref PubMed Scopus (48) Google Scholar, 19Fireman Z. Zachlka R. Abu Mouch S. et al.The role of endoscopy in the evaluation of iron deficiency anemia in premenopausal women.Isr Med Assoc J. 2006; 8: 88-90PubMed Google Scholar, 20Majid S. Salih M. Wasaya R. et al.Predictors of gastrointestinal lesions on endoscopy in iron deficiency anemia without gastrointestinal symptoms.BMC Gastroenterol. 2008; 8: 52Crossref PubMed Scopus (0) Google Scholar, 21Cilona A. Zullo A. Hassan C. et al.Is faecal-immunochemical test useful in patients with iron deficiency anaemia and without overt bleeding?.Dig Liver Dis. 2011; 43: 1022-1024Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 22Ayling R.M. Lewis S.J. Cotter F. Potential roles of artificial intelligence learning and faecal immunochemical testing for prioritisation of colonoscopy in anaemia.Br J Haematol. 2019; 185: 311-316Crossref PubMed Scopus (7) Google Scholar, 23Lee M.W. Pourmorady J.S. Laine L. Use of fecal occult blood testing as a diagnostic tool for clinical indications: a systematic review and meta-analysis.Am J Gastroenterol. 2020; 115: 662-670Crossref PubMed Scopus (0) Google Scholar In a systematic review of the use of FOBTs in patients with IDA, it was found that the sensitivity of FOBTs for presumptive causes of IDA detected at endoscopy was 0.58 (95% confidence interval [CI], 0.53–0.63), with a specificity of 0.84 (95% CI, 0.75–0.89).23Lee M.W. Pourmorady J.S. Laine L. Use of fecal occult blood testing as a diagnostic tool for clinical indications: a systematic review and meta-analysis.Am J Gastroenterol. 2020; 115: 662-670Crossref PubMed Scopus (0) Google Scholar Results were similar in both guaiac-based testing and fecal immunochemical testing. Given this poor sensitivity and specificity, the Panel did not believe that the result of an FOBT would substantially influence the decision as to whether to perform endoscopy or not, and it was decided not to specifically address the use of FOBT in the evaluation of IDA. This assessment should not preclude future consideration of the use of FOBT in an algorithm in certain populations of patients with IDA. This technical review will not discuss the details of the presentation of anemia, but rather will focus on the diagnosis and evaluation of IDA. This review will also not address patients with overt gastrointestinal bleeding. In patients with IDA, blood loss is typically chronic and occult, and therefore rarely associated with overt bleeding or hemodynamic compromise, unless the lesion responsible for chronic occult bleeding begins bleeding aggressively. Indeed, a syndrome of acute on chronic gastrointestinal bleeding, in which patients known to have IDA spontaneously develop acute bleeding, has been recognized.24Rockey D.C. Hafemeister A.C. Reisch J.S. Acute on chronic gastrointestinal bleeding: a unique clinical entity.J Investig Med. 2017; 65: 892-898Crossref PubMed Scopus (1) Google Scholar Recognition of this entity emphasizes the wide spectrum of lesions in many different locations in the gastrointestinal tract that can bleed, and that often present with highly variable clinical features. Despite the publication of a number of observational studies focused on IDA, and the presence of several scholarly reviews, there remains a great deal of controversy about best practices in the evaluation and management of IDA. Although it is well-appreciated that occult gastrointestinal bleeding is likely to be responsible for IDA in postmenopausal woman and in men, and therefore endoscopy is warranted, best practices regarding the type of endoscopy and the appropriate evaluation for Helicobacter pylori, celiac disease, atrophic gastritis, and of the small bowel, are not well established. Given a number of questions surrounding the most appropriate approach to the gastrointestinal evaluation of IDA, the American Gastroenterological Association Institute called for a technical review of the clinical spectrum of IDA, with a focus on optimal evaluation and management approaches. The main purpose was to critically review studies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and to generate summary evidence and estimates for the Guidelines Panel to develop evidence-based recommendations. It should be noted that this technical review does not address evaluation of patients with iron deficiency without anemia. In addition, it does not specifically address the evaluation of patients with IDA and prominent gastrointestinal symptoms (eg, dysphagia, odynophagia, abdominal pain, diarrhea, change in bowel habit, and intermittent hematochezia). These patients should be evaluated as indicated based on their gastrointestinal symptoms. It should be emphasized that a careful history is fundamentally important in these patients because subtle symptoms are often present and should be sought after. The guideline addresses the gastrointestinal evaluation of IDA primarily in patients without dominant gastrointestinal tract symptomatology, who we have considered asymptomatic. Although iron replacement therapy is an important consideration in IDA patients, the Review Panel believed that addressing the type of iron therapy and route of treatment (ie, oral vs intravenous administration) was outside the scope of this review. We look forward to future guidelines, perhaps in collaboration with hematological societies, to address this important issue. The technical review and its accompanying guideline were conducted according to the GRADE framework.25Guyatt G.H. Oxman A.D. Schunemann H.J. et al.GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.J Clin Epidemiol. 2011; 64: 380-382Abstract Full Text Full Text PDF PubMed Scopus (1223) Google Scholar The American Gastroenterological Association Clinical Guideline Committee selected the members of the Technical Review and Clinical Guideline Panels who were screened to minimize any conflict of interest. The technical review collected and evaluated pertinent literature concerning the diagnosis and endoscopic evaluation of IDA, as well as appropriate investigations for H pylori, celiac disease, atrophic gastritis, and of the small bowel. Using these data, the Clinical Guideline Panel produced the final set of recommendations, as described.26Ko C.W. Siddique S.M. Patel A. et al.AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia.Gastroenterology. 2020; 159: 1085-1094Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar The Technical Review and Guideline Panel formulated the clinical questions using the PICO format, which frames a clinical question by defining a specific patient population (P), intervention (I), comparator (C), and outcome(s). The Panel finalized 5 questions on the topic (Table 1).Table 1PICO QuestionsQuestion no.Diagnosis or intervention related questionPICO questionPopulationIntervention(s)ComparatorOutcome1Establishing an accurate diagnosis of IDA?Adults with anemia defined as hemoglobin <13 g/dL in men and <12 g/dL in nonpregnant womenFerritinBone marrow biopsy (gold standard)Diagnosis of IDA2What is the utility of bidirectional endoscopy in patients with suspected endoscopic gastrointestinal lesion as a source of IDA?Women aged ≥45 y and menBidirectional endoscopyDo nothing (observation only)All-cause mortality, morbidity related to anemia (eg, cardiac events), mortality related to gastrointestinal lesions, morbidity related to gastrointestinal lesions, endoscopy-related or periprocedural morbidity, endoscopy-related or periprocedural mortalityPremenopausal women aged <45 y3aShould we obtain routine gastric biopsies for H pylori in patients with IDA?Adults with IDA undergoing endoscopic workup without endoscopic gastric pathologyRoutine gastric biopsies for H pyloriDo nothing, noninvasive testingResolution of anemia3bShould we obtain routine gastric biopsies for chronic autoimmune atrophic gastritis in patients with IDA?Routine gastric biopsiesDo nothing4Should we obtain routine small bowel biopsies for celiac disease in patients with IDA?Adults with IDA undergoing endoscopic workup without endoscopic small bowel pathologyRoutine small bowel biopsies for celiac diseaseDo nothing, noninvasive testing5In asymptomatic IDA patients with negative bidirectional endoscopy, should small bowel investigations be pursued?Adults with IDA without warning signs.Any small bowel investigation (endoscopy or imaging)Do nothingAll-cause mortality, morbidity related to anemia (eg, cardiac events), mortality related to gastrointestinal lesions, morbidity related to gastrointestinal lesions, endoscopy-related or periprocedural morbidity, endoscopy-related or periprocedural mortality.PICO, population, intervention, comparator, outcome. Open table in a new tab PICO, population, intervention, comparator, outcome. When direct evidence to inform any of the PICO questions was not available, we identified indirect evidence. We aimed to define the prevalence of gastrointestinal neoplastic and/or malignant lesions, celiac disease and/or small intestinal villous atrophy, H pylori infection, and chronic atrophic autoimmune gastritis in patients with IDA. We aimed to define the diagnostic accuracy of ferritin cutoffs, as well as tissue transglutaminase (TTG) IgA antibodies to diagnose celiac disease in patients with IDA. Before conducting any systematic review, we identified systematic reviews published on any of the PICO questions. If we could not identify any systematic review or the available systematic reviews had low methodological quality, we conducted a de novo systematic review for the PICO question. The systematic review is reported according the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) proposal.27Liberati A. Altman D.G. Tetzlaff J. et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.BMJ. 2009; 339: b2700Crossref PubMed Scopus (7579) Google Scholar,28Stroup D.F. Berlin J.A. Morton S.C. et al.Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-Analysis of Observational Studies in Epidemiology (MOOSE) group.JAMA. 2000; 283: 2008-2012Crossref PubMed Google Scholar The Technical Review Panel developed a protocol to guide the systematic review a priori. Under the guidance of the Technical Review Panel, an experienced medical librarian conducted a comprehensive search of the following databases from prespecified start dates to April 2019: MEDLINE Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily, MEDLINE, EMBASE Classic, EMBASE, and Wiley’s Cochrane Library. The prespecified start dates of the date range of the search and the study designs of interest were determined by the Technical Review Panel for each PICO question separately. The search was limited to English and human studies. Controlled vocabulary and keywords were used to search for the studies. The final search strategies are available in Appendix 1. To assure comprehensiveness, the reference lists of previously published systematic reviews, clinical guidelines, and the included studies were searched to identify other relevant studies that may have been missed by the search strategy. We aimed to include randomized controlled trials (RCT) and/or nonrandomized comparative studies of different diagnostic and/or intervention strategies for each of the PICO questions. When we could not identify any RCT or nonrandomized comparative studies, we tried to identify diagnostic test accuracy studies of the different diagnostic strategies. If none of the aforementioned study designs was available, we included single cohort and prevalence studies to inform rates of occurrence (ie, prevalence or incidence rates). Except for PICO 1 (the diagnostic accuracy of ferritin for IDA), we aimed to include studies of patients with IDA without overt gastrointestinal bleeding. Due to the scarcity of data on asymptomatic patients and to account for the variability seen in clinical practice, we included studies regardless of FOBT, the severity of anemia, and the presence of symptoms. Studies that included patients with overt gastrointestinal bleeding were included only if they reported separate results for patients without overt bleeding. For studies of celiac disease, we only included studies from the United States due to the variable prevalence of celiac disease between countries.29Singh P. Arora A. Strand T.A. et al.Global prevalence of celiac disease: systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2018; 16: 823-836.e2Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar Except for studies from large databases, we only included studies that diagnosed celiac disease based on biopsies. The references identified by the search strategy were uploaded to Rayyan, a web-based platform for the initial steps of systematic reviews.30Ouzzani M. Hammady H. Fedorowicz Z. et al.Rayyan—a web and mobile app for systematic reviews.Syst Rev. 2016; 5: 210Crossref PubMed Scopus (1527) Google Scholar The title and abstract of each reference were reviewed by 2 blinded reviewers for inclusion. The full texts of eligible references were reviewed then abstracted using Microsoft Excel sheets. The outcomes of interest for each PICO question are summarized (Table 1). When comparative studies were available, we used the DerSimonian-Liard random-effects model to pool their relative risks.31DerSimonian R. Laird N. Meta-analysis in clinical trials.Control Clin Trials. 1986; 7: 177-188Abstract Full Text PDF PubMed Scopus (25362) Google Scholar To pool the proportions from prevalence studies, we used the double arcsine transformation with the inverse-variance the fixed-effects model.32Barendregt J.J. Doi S.A. Lee Y.Y. et al.Meta-analysis of prevalence.J Epidemiol Community Health. 2013; 67: 974-978Crossref PubMed Scopus (694) Google Scholar We used this approach to allow larger studies, which are more inclusive than smaller studies and less prone to selection bias, to have an appropriately larger effect on the pooled estimates. We used the I2 statistic to quantify heterogeneity with a threshold of 50% for comparative relative effect estimates as an indicator of substantial heterogeneity.33Higgins J.P. Thompson S.G. Deeks J.J. et al.Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560Crossref PubMed Google Scholar We assessed for publication bias using funnel plot asymmetry tests if there was a sufficient number of studies with no significant heterogeneity.34Ioannidis J.P. Trikalinos T.A. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey.CMAJ. 2007; 176 (1091–1016)Crossref PubMed Scopus (552) Google Scholar The statistical analyses were conducted using the package meta 4.9-2 in R 3.5.3.35R Core TeamR: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria2018Google Scholar,36Schwarzer G. meta: {A}n {R} package for meta-analysis.R News. 2007; 7: 40-45Google Scholar The risk of bias for the individual studies was assessed depending on the study design. RCTs and nonrandomized comparative studies were assessed using the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials and the Newcastle-Ottawa Scale, respectively.37Higgins J.P. Altman D.G. Gotzsche P.C. et al.The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.BMJ. 2011; 343: d5928Crossref PubMed Scopus (12328) Google Scholar,38Wells G.A. Shea B. O'Connell D. et al.The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomized Studies in Meta-Analyses. Volume 2018. Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canda2011Google Scholar For single cohort studies and studies of prevalence, we used the Joanna Briggs Institute tool for assessing risk of bias in prevalence studies.39Munn Z. Moola S. Lisy K. et al.Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data.Int J Evid Based Healthc. 2015; 13: 147-153Crossref PubMed Scopus (340) Google Scholar We used the GRADE approach to assess the certainty (quality) of evidence for the body of evidence from the systematic reviews and meta-analyses. In this approach, the evidence is graded for each outcome as very low, low, moderate, or high. Evidence derived from RCTs start at a high certainty of evidence, but then is rated down for risk of bias, inconsistency, indirectness, imprecision, and/or other factors. Evidence derived from observational studies starts at low certainty of evidence, but certainty in the evidence can be rated up for large magnitude of effect and/or the presence of dose–response relationship, where appropriate.25Guyatt G.H. Oxman A.D. Schunemann H.J. et al.GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.J Clin Epidemiol. 2011; 64: 380-382Abstract Full Text Full Text PDF PubMed Scopus (1223) Google Scholar As this technical review was conducted to inform clinical practice guidelines, in addition to the comprehensive critical evaluation of the available evidence on risk and benefits of the different interventions and diagnostic tests, we also considered information about patients’ preferences and values, resource utilization, and cost-effectiveness when available. Because we were unable to identify evidence to support one evaluation and management approach over another, we performed simple modeling analyses to assess the utility of different ferritin thresholds, serologic tests or biopsy for celiac disease, and noninvasive tests or biopsy for H pylori using reimbursement data from the Centers for Medicare and Medicaid Services as a surrogate for the costs to compare them (https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/index). The certainty in the evidence with regard to the use of ferritin to make a diagnosis of iron deficiency is high, suggesting that this test be used to make the diagnosis of IDA. We used a commonly defined threshold of a hemoglobin level <13 g/dL in men and <12 g/dL in nonpregnant women for anemia. A ferritin level of 45 ng/mL was identified to have the optimal tradeoff between sensitivity and specificity for the diagnosis of IDA (Table 2). NOTE. Summary of findings: PICO (population, intervention, comparator, outcome) 1: Should ferritin <45 ng/mL vs ferritin <15 ng/mL be used to diagnose iron deficiency in patients with anemia? Patient or population: Patients with anemia. Setting: Outpatient. New test: Ferritin cutoff value: 45 ng/mL and 15 ng/mL. Reference test: Bone marrow biopsy. Pooled sensitivity ferritin <45 ng/mL: 0.85 (95% CI, 0.82–0.87). Pooled specificity ferritin <45 ng/mL: 0.92 (95% CI, 0.91–0.94). Pooled sensitivity ferritin <15 ng/mL: 0.59 (95% CI, 0.55–0.62). Pooled specificity ferritin <15 ng/mL: 0.99 (95% CI, 0.89–0.99). FN, false negative; FP, false positive; TN, true negative; TP, true positive. Because anemia is a common clinical condition and its diagnosis can lead to invasive testing, it is essential to verify