INT J TUBERC LUNG DIS 18(11):1337–1339 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.14.0143 E-published ahead of print 18 September 2014 Elevated hepcidin at HIV diagnosis is associated with incident tuberculosis in a retrospective cohort study P. A. Minchella,* A. E. Armitage, † B. Darboe, ‡ M. W. Jallow, ‡ H. Drakesmith, † A. Jaye, ‡ A. M. Prentice, § J. M. McDermid* *Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA; † Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; ‡ Medical Research Council Unit (UK), Fajara, The Gambia; § International Nutrition Group, Department of Nutrition and Public Health Intervention Unit, London School of Hygiene & Tropical Medicine, London, UK SUMMARY Hepcidin inhibits ferroportin-mediated iron efflux, leading to intracellular macrophage iron retention, possibly favoring Mycobacterium tuberculosis iron acquisition and tuberculosis (TB) pathogenesis. Plasma hepcidin was measured at human immunodeficiency virus (HIV) diagnosis in a retrospective HIV-prevalent, antiretroviral-na¨ ıve African cohort to investigate the association with incident pulmonary and/or extra- pulmonary TB. One hundred ninety-six participants were followed between 5 August 1992 and 1 June 2002, with 32 incident TB cases identified. Greater hepcidin was associated with significantly increased likelihood of TB after a median time to TB of 6 months. Elucidation of iron-related causal mechanisms and time-sensitive biomarkers that identify individual changes in TB risk are needed. KEY WORDS: Africa; biomarker; iron; nutrition; in- flammation IDENTIFYING tuberculosis (TB) risk factors is challenging due to variable disease latencies. Host- pathogen iron homeostasis has previously been implicated, and hepcidin, a small liver-derived peptide that promotes degradation of the intracellular inor- ganic iron exporter ferroportin, may also play a part. 1 Expression is stimulated by pro-inflammatory cyto- kines, resulting in a blockade of iron release from intestinal enterocytes and macrophages. Through its influence on host iron homeostasis, hepcidin may promote conditions favorable to Mycobacterium tuberculosis. The present study was designed to investigate the relationship between hepcidin and susceptibility to TB using a retrospective analysis of a longitudinal cohort. METHODS From a historical human immunodeficiency virus (HIV) prevalent cohort in The Gambia (described elsewhere 2 ), 196 participants aged 718 years with a plasma sample obtained within 3 months of HIV diagnosis were included. To address temporality, plasma samples were obtained at least 28 days before an incident TB diagnosis, and prevalent TB cases were excluded. Provisional TB diagnoses were independently reexamined according to study-specif- ic incident TB case definitions: confirmed pulmonary TB (PTB) was defined as acid-fast bacilli (AFB) in direct smear or culture from sputum or lavage, smear- negative PTB was diagnosed if clinical symptoms were strongly suggestive of and radiographic signs consistent with PTB, and/or extra-pulmonary TB (EPTB) was confirmed when AFB was detected in biopsy/aspirates of a lymph node; probable EPTB was presumed when clinical features were strongly suggestive of EPTB. Ethical approval was granted by the Joint Gambian Government/Medical Research Council (Banjul, The Gambia), the London School of Hygiene & Tropical Medicine (London, UK) and Cornell University (Ithaca, NY, USA). Plasma hepcidin was quantified using a competitive enzyme immunoassay (Bachem, Torrance, CA, USA). Samples were assayed in duplicate and dilutions based on ferritin concentrations. Hepcidin concen- trations were interpolated from four-parameter lo- gistic standard curves. The lower limit of detection (LoD) was interpolated at three standard deviations (SDs) from the all-plate mean OD450 readings (wells containing diluent in lieu of hepcidin standard or sample). Undiluted samples ,LoD were imputed with LoD/2. Concentrations outside the linear region Correspondence to: Joann M McDermid, Division of Nutritional Sciences, Cornell University, 310 Savage Hall, Ithaca, NY 14853, USA. Tel: ( þ 1) 607 255 2490. Fax: ( þ 1) 607 255 1033. e-mail: jmm585@cornell.edu Article submitted 18 February 2014. Final version accepted 13 June 2014.