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 extrapulmonary 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. K E Y W O R D S : Africa; biomarker; iron; nutrition; inflammation
IDENTIFYING tuberculosis (TB) risk factors is challenging due to variable disease latencies. Hostpathogen iron homeostasis has previously been implicated, and hepcidin, a small liver-derived peptide that promotes degradation of the intracellular inorganic iron exporter ferroportin, may also play a part.1 Expression is stimulated by pro-inflammatory cytokines, 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.
independently reexamined according to study-specific incident TB case definitions: confirmed pulmonary TB (PTB) was defined as acid-fast bacilli (AFB) in direct smear or culture from sputum or lavage, smearnegative 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 concentrations were interpolated from four-parameter logistic 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
METHODS From a historical human immunodeficiency virus (HIV) prevalent cohort in The Gambia (described elsewhere2), 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
Correspondence to: Joann M McDermid, Division of Nutritional Sciences, Cornell University, 310 Savage Hall, Ithaca, NY 14853, USA. Tel: (þ1) 607 255 2490. Fax: (þ1) 607 255 1033. e-mail: [email protected] Article submitted 18 February 2014. Final version accepted 13 June 2014.
1338
The International Journal of Tuberculosis and Lung Disease
covariates considered a priori as representing greater immunosuppression or inflammation, lower BMI and HIV-1, were associated with a non-statistically significantly greater probability of TB in unadjusted models (Figure 2, bottom).
DISCUSSION
Figure 1 Incident TB classified by hepcidin quartiles at human immunodeficiency virus diagnosis. TB ¼ tuberculosis; CI ¼ confidence interval.
of the curve or with an intra-assay coefficient of variation .15% were re-assayed. As an indicator of inflammation, alpha-1-antichymotrypsin (ACT) was measured using a nephelometric assay (DakoCytomation Inc, Ely, UK). Associations were assessed using Poisson regression (STATA/MP 11.1; Stata Corp, College Station, TX, USA) and expressed as incidence rate ratios (IRR) with incident TB (all TB) as the main outcome. Covariates considered a priori were sex and baseline ACT, absolute CD4 cell count, type of HIV, age and body mass index (BMI).
RESULTS Incident TB cases (n ¼ 32) were identified from 196 participants followed for 496 person-years (median follow-up 1.8 years, interquartile range [IQR] 1.3– 2.3]. Median time to TB diagnosis was 0.5 years (IQR 0.3–1.1). Baseline differences between incident TB and non-cases were not statistically significant for hepcidin (median 22.1 ng/ml, IQR 3.3–85.9), CD4 (median 250 cells/ll, IQR 91–502), age (mean 34.4 years 6 SD 10.3), hemoglobin (mean 10.5 g/dl 6 SD 2.3), ACT (mean 0.49 g/l 6 SD 0.27) or BMI (mean 19.9 kg/m2 6 SD 4.3); 60.2% of patients had HIV-1 and 55% were female. A dose-response association with a possible threshold effect was observed between hepcidin and the likelihood of incident TB (Figure 1). The upper hepcidin quartile was associated with the greatest probability of developing TB, with the upper quartile accounting for .40% of all incident TB cases. Comparing the upper hepcidin quartile to the lower three quartiles combined revealed a two-fold increase in the incidence of TB (unadjusted IRR 2.05, 95% confidence interval [CI] 1.01–4.16]. The magnitude and direction of associations were consistent between the unadjusted and adjusted hepcidin models (Figure 2, top); however, only the model with hepcidin adjusted for HIV type was statistically significant (adjusted IRR 2.10, 95%CI 1.03–4.26). As expected,
A unique strength of this study is our ability to investigate the temporal association between hepcidin as a risk factor for TB susceptibility rather than TB prognosis. These data suggest that, in HIV infection, higher hepcidin concentration is associated with a significantly greater risk of developing TB. A recent report from Indonesia indicated that median hepcidin concentrations at cohort entry were also significantly higher among 45 incident TB cases compared to controls with HIV infection;3 however, this was evident only among cases diagnosed between 31 and 60 days after cohort enrollment. Using a different statistical analysis, our findings demonstrate that the window may extend further, as baseline hepcidin was associated with incident TB diagnosed a median of 6 months after enrollment. While hepcidin is most likely part of a complex multi-parameter risk profile with the relevant time period remaining to be identified, together these findings suggest that rising hepcidin may be a proxy biomarker for subclinical TB. The mechanisms explaining the association between hepcidin and incident TB in HIV infection are unknown. Hepcidin appears to fit into a larger picture of inflammatory iron redistribution, including hemoglobin, plasma iron, ferritin, soluble transferrin receptor and transferrin, that has been previously reported by this group using a larger subset of the same cohort participants.4 Hepcidin has an important regulatory role in host iron homeostasis during infection, and pathogen iron homeostasis, including both iron acquisition and storage, influences TB pathogenesis.5–8 However, how elevated hepcidin modulates the host iron environment to favor M. tuberculosis is unknown. Interestingly, emerging evidence suggests that M. tuberculosis may actually manipulate host cellular hepcidin production9 to create a pathogen iron-favorable environment. If this is the case, expanding ongoing research investigating hepcidin antagonists10 to consider hepcidin antagonists in the prevention of TB or augmentation of existing anti-tuberculosis treatment may be warranted. In summary, greater hepcidin concentrations at HIV diagnosis are associated with a greater probability of TB with HIV co-infection. Understanding the relationship between hepcidin, host-pathogen iron homeostasis, immune activation/inflammation and TB pathogenesis may guide evidence-based decisions in the clinical management of people at high risk of
Hepcidin and TB susceptibility in HIV
1339
Figure 2 Plasma hepcidin at HIV diagnosis (top) and additional baseline risk factors (bottom) in relation to incident tuberculosis. Variables were continuous except for hepcidin concentrations (classified in quartiles with the combined lower three quartiles as the referent), absolute CD4 cell counts (classified in clinical categories ,200, 200–500, and .500 cells/ll as the referent), HIV type (classified as HIV-1 plus HIV-dual, or HIV-2 as the referent) and BMI (classified as ,18.5 kg/m2 or 718.5 kg/m2 as the referent). The fully adjusted model included HIV type, absolute CD4 cell count, ACT, age, sex and BMI. All models included 196 participants, except for models with missing data for CD4 (182 participants included), BMI (151 participants included) and the fully adjusted model (145 participants included). IRR ¼ incident rate ratio; CI ¼ confidence interval; ACT ¼ a-1-antichymotrypsin; BMI ¼ body mass index; HIV ¼ human immunodeficiency virus.
iron-deficiency anemia and TB, both major health concerns in many regions of the developing world. Overall, this study contributes evidence needed to create a profile identifying who is at greatest risk of progressing to clinical TB, and when transition from an infected-stable state to an infected-progressing state occurs, obstacles that need to be overcome to improve individual TB management and populationlevel TB control.
3
4
5
Acknowledgments 6
The authors thank the Medical Research Council (MRC) HIV Clinical Cohort participants and staff for contributions to the study, and in particular, G Thomas, Data Manager, MRC West Africa Collaboration. This work was supported in part by the National Science Foundation Graduate Research Fellowship Program under Grant No. NSF 12–599, Cornell University Unrestricted Funds (Ithaca, NY, USA) and the UK Medical Research Council (MC-A7605QX00) (London, UK). Conflicts of interest: none declared.
7
References
9
1 Steinbicker A U, Muckenthaler M U. Out of balance-systemic iron homeostasis in iron-related disorders. Nutrients 2013; 5: 3034–3061. 2 van der Sande M A, Schim van der Loeff M F, Aveika A A, et al. Body mass index at time of HIV diagnosis: a strong and
8
10
independent predictor of survival. J Acquir Immune Defic Syndr 2004; 37: 1288–1294. Wisaksana R, de Mast Q, Alisjahbana B, et al. Inverse relationship of serum hepcidin levels with CD4 cell counts in HIV-infected patients selected from an Indonesian prospective cohort study. PLOS ONE 2013; 8: e79904. McDermid J M, Hennig B J, van der Sande M, et al. Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study. BMC Infect Dis 2013; 13: 48. Drakesmith H, Prentice A M. Hepcidin and the iron-infection axis. Science. 2012; 338: 768–772. Wagner D, Maser J, Lai B, et al. Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell’s endosomal system. J Immunol 2005; 174: 1491–1500. De Voss J J, Rutter K, Schroeder B G, Su H, Zhu Y, Barry C E, 3rd. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc Natl Acad Sci USA 2000; 97: 1252–1257. Ryndak M B, Singh K K, Peng Z, et al. Transcriptional profiling of Mycobacterium tuberculosis replicating ex vivo in blood from HIV and HIVþ subjects. PLOS ONE 2014; 9: e94939. Sow F B, Florence W C, Satoskar A R, Schlesinger L S, Zwilling B S, Lafuse W P. Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol 2007; 82: 934–945. Fung E, Nemeth E. Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica 2013; 98: 1667–1676.
Hepcidin and TB susceptibility in HIV
i
RESUME
L’hepcidine inhibe l’efflux de fer m e´ di e´ par la ferroportine, induisant une r´etention de fer dans les macrophages intracellulaires, ce qui pourrait favoriser l’acquisition de fer par les souches de Mycobacterium tuberculosis et la pathogen`ese de la tuberculose (TB). L’hepcidine plasmatique a e´ t´e mesur´ee lors du diagnostic du virus de l’immunod´eficience humaine (VIH) dans une e´ tude r´etrospective d’une cohorte africaine a` forte pr´evalence de VIH, n’ayant jamais eu de traitement antiretroviral, afin d’´etudier l’association avec la TB
pulmonaire incident et/ou extra-pulmonaire. Cent quatre-vingt-seize participants ont e´ t´e suivis du 5 aout ˆ 1992 au 1er juin 2002, avec 32 cas de TB incident identifi´es. Une e´ l´evation de l’hepcidine e´ tait associ´ee avec une augmentation significative de la probabilit´e de TB apr`es un intervalle m´edian de 6 mois. Il est n´ecessaire d’´elucider les m´ecanismes d’action li´es au fer et de trouver des biomarqueurs sensibles au temps susceptibles d’identifier les modifications individuelles du risque de TB. RESUMEN
La hepcidina inhibe el flujo del hierro mediado por la ferroportina y provoca retencion ´ intracelular en los macrofagos, ´ lo cual tal vez facilita la adquisicion ´ del hierro por parte de Mycobacterium tuberculosis y favorece la patogenia de la tuberculosis (TB). La concentracion ´ plasma´tica de hepcidina se midio´ en el momento del diagnostico ´ de infeccion ´ por el virus de la inmunodeficiencia humana (VIH) en una cohorte retrospectiva de pacientes seropositivos sin antecedente de tratamiento antirretrov´ırico, a fin de investigar la asociacion ´ con un episodio nuevo de TB pulmonar o
extrapulmonar. Se practico´ el seguimiento de 196 participantes del 5 de agosto de 1992 al 18 de junio del 2002, durante el cual se detectaron 32 casos nuevos de TB. Una concentracion ´ ma´s alta de hepcidina se asocio´ con una mayor probabilidad de padecer TB, con una mediana de 6 meses despu´es de la inclusion ´ en el estudio. Es necesario aclarar los mecanismos causales asociados con el hierro y definir biomarcadores que evolucionen en el tiempo y permitan detectar las variaciones individuales del riesgo de padecer la TB.
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 extrapulmonary 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. K E Y W O R D S : Africa; biomarker; iron; nutrition; inflammation
IDENTIFYING tuberculosis (TB) risk factors is challenging due to variable disease latencies. Hostpathogen iron homeostasis has previously been implicated, and hepcidin, a small liver-derived peptide that promotes degradation of the intracellular inorganic iron exporter ferroportin, may also play a part.1 Expression is stimulated by pro-inflammatory cytokines, 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.
independently reexamined according to study-specific incident TB case definitions: confirmed pulmonary TB (PTB) was defined as acid-fast bacilli (AFB) in direct smear or culture from sputum or lavage, smearnegative 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 concentrations were interpolated from four-parameter logistic 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
METHODS From a historical human immunodeficiency virus (HIV) prevalent cohort in The Gambia (described elsewhere2), 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
Correspondence to: Joann M McDermid, Division of Nutritional Sciences, Cornell University, 310 Savage Hall, Ithaca, NY 14853, USA. Tel: (þ1) 607 255 2490. Fax: (þ1) 607 255 1033. e-mail: [email protected] Article submitted 18 February 2014. Final version accepted 13 June 2014.
1338
The International Journal of Tuberculosis and Lung Disease
covariates considered a priori as representing greater immunosuppression or inflammation, lower BMI and HIV-1, were associated with a non-statistically significantly greater probability of TB in unadjusted models (Figure 2, bottom).
DISCUSSION
Figure 1 Incident TB classified by hepcidin quartiles at human immunodeficiency virus diagnosis. TB ¼ tuberculosis; CI ¼ confidence interval.
of the curve or with an intra-assay coefficient of variation .15% were re-assayed. As an indicator of inflammation, alpha-1-antichymotrypsin (ACT) was measured using a nephelometric assay (DakoCytomation Inc, Ely, UK). Associations were assessed using Poisson regression (STATA/MP 11.1; Stata Corp, College Station, TX, USA) and expressed as incidence rate ratios (IRR) with incident TB (all TB) as the main outcome. Covariates considered a priori were sex and baseline ACT, absolute CD4 cell count, type of HIV, age and body mass index (BMI).
RESULTS Incident TB cases (n ¼ 32) were identified from 196 participants followed for 496 person-years (median follow-up 1.8 years, interquartile range [IQR] 1.3– 2.3]. Median time to TB diagnosis was 0.5 years (IQR 0.3–1.1). Baseline differences between incident TB and non-cases were not statistically significant for hepcidin (median 22.1 ng/ml, IQR 3.3–85.9), CD4 (median 250 cells/ll, IQR 91–502), age (mean 34.4 years 6 SD 10.3), hemoglobin (mean 10.5 g/dl 6 SD 2.3), ACT (mean 0.49 g/l 6 SD 0.27) or BMI (mean 19.9 kg/m2 6 SD 4.3); 60.2% of patients had HIV-1 and 55% were female. A dose-response association with a possible threshold effect was observed between hepcidin and the likelihood of incident TB (Figure 1). The upper hepcidin quartile was associated with the greatest probability of developing TB, with the upper quartile accounting for .40% of all incident TB cases. Comparing the upper hepcidin quartile to the lower three quartiles combined revealed a two-fold increase in the incidence of TB (unadjusted IRR 2.05, 95% confidence interval [CI] 1.01–4.16]. The magnitude and direction of associations were consistent between the unadjusted and adjusted hepcidin models (Figure 2, top); however, only the model with hepcidin adjusted for HIV type was statistically significant (adjusted IRR 2.10, 95%CI 1.03–4.26). As expected,
A unique strength of this study is our ability to investigate the temporal association between hepcidin as a risk factor for TB susceptibility rather than TB prognosis. These data suggest that, in HIV infection, higher hepcidin concentration is associated with a significantly greater risk of developing TB. A recent report from Indonesia indicated that median hepcidin concentrations at cohort entry were also significantly higher among 45 incident TB cases compared to controls with HIV infection;3 however, this was evident only among cases diagnosed between 31 and 60 days after cohort enrollment. Using a different statistical analysis, our findings demonstrate that the window may extend further, as baseline hepcidin was associated with incident TB diagnosed a median of 6 months after enrollment. While hepcidin is most likely part of a complex multi-parameter risk profile with the relevant time period remaining to be identified, together these findings suggest that rising hepcidin may be a proxy biomarker for subclinical TB. The mechanisms explaining the association between hepcidin and incident TB in HIV infection are unknown. Hepcidin appears to fit into a larger picture of inflammatory iron redistribution, including hemoglobin, plasma iron, ferritin, soluble transferrin receptor and transferrin, that has been previously reported by this group using a larger subset of the same cohort participants.4 Hepcidin has an important regulatory role in host iron homeostasis during infection, and pathogen iron homeostasis, including both iron acquisition and storage, influences TB pathogenesis.5–8 However, how elevated hepcidin modulates the host iron environment to favor M. tuberculosis is unknown. Interestingly, emerging evidence suggests that M. tuberculosis may actually manipulate host cellular hepcidin production9 to create a pathogen iron-favorable environment. If this is the case, expanding ongoing research investigating hepcidin antagonists10 to consider hepcidin antagonists in the prevention of TB or augmentation of existing anti-tuberculosis treatment may be warranted. In summary, greater hepcidin concentrations at HIV diagnosis are associated with a greater probability of TB with HIV co-infection. Understanding the relationship between hepcidin, host-pathogen iron homeostasis, immune activation/inflammation and TB pathogenesis may guide evidence-based decisions in the clinical management of people at high risk of
Hepcidin and TB susceptibility in HIV
1339
Figure 2 Plasma hepcidin at HIV diagnosis (top) and additional baseline risk factors (bottom) in relation to incident tuberculosis. Variables were continuous except for hepcidin concentrations (classified in quartiles with the combined lower three quartiles as the referent), absolute CD4 cell counts (classified in clinical categories ,200, 200–500, and .500 cells/ll as the referent), HIV type (classified as HIV-1 plus HIV-dual, or HIV-2 as the referent) and BMI (classified as ,18.5 kg/m2 or 718.5 kg/m2 as the referent). The fully adjusted model included HIV type, absolute CD4 cell count, ACT, age, sex and BMI. All models included 196 participants, except for models with missing data for CD4 (182 participants included), BMI (151 participants included) and the fully adjusted model (145 participants included). IRR ¼ incident rate ratio; CI ¼ confidence interval; ACT ¼ a-1-antichymotrypsin; BMI ¼ body mass index; HIV ¼ human immunodeficiency virus.
iron-deficiency anemia and TB, both major health concerns in many regions of the developing world. Overall, this study contributes evidence needed to create a profile identifying who is at greatest risk of progressing to clinical TB, and when transition from an infected-stable state to an infected-progressing state occurs, obstacles that need to be overcome to improve individual TB management and populationlevel TB control.
3
4
5
Acknowledgments 6
The authors thank the Medical Research Council (MRC) HIV Clinical Cohort participants and staff for contributions to the study, and in particular, G Thomas, Data Manager, MRC West Africa Collaboration. This work was supported in part by the National Science Foundation Graduate Research Fellowship Program under Grant No. NSF 12–599, Cornell University Unrestricted Funds (Ithaca, NY, USA) and the UK Medical Research Council (MC-A7605QX00) (London, UK). Conflicts of interest: none declared.
7
References
9
1 Steinbicker A U, Muckenthaler M U. Out of balance-systemic iron homeostasis in iron-related disorders. Nutrients 2013; 5: 3034–3061. 2 van der Sande M A, Schim van der Loeff M F, Aveika A A, et al. Body mass index at time of HIV diagnosis: a strong and
8
10
independent predictor of survival. J Acquir Immune Defic Syndr 2004; 37: 1288–1294. Wisaksana R, de Mast Q, Alisjahbana B, et al. Inverse relationship of serum hepcidin levels with CD4 cell counts in HIV-infected patients selected from an Indonesian prospective cohort study. PLOS ONE 2013; 8: e79904. McDermid J M, Hennig B J, van der Sande M, et al. Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study. BMC Infect Dis 2013; 13: 48. Drakesmith H, Prentice A M. Hepcidin and the iron-infection axis. Science. 2012; 338: 768–772. Wagner D, Maser J, Lai B, et al. Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell’s endosomal system. J Immunol 2005; 174: 1491–1500. De Voss J J, Rutter K, Schroeder B G, Su H, Zhu Y, Barry C E, 3rd. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc Natl Acad Sci USA 2000; 97: 1252–1257. Ryndak M B, Singh K K, Peng Z, et al. Transcriptional profiling of Mycobacterium tuberculosis replicating ex vivo in blood from HIV and HIVþ subjects. PLOS ONE 2014; 9: e94939. Sow F B, Florence W C, Satoskar A R, Schlesinger L S, Zwilling B S, Lafuse W P. Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol 2007; 82: 934–945. Fung E, Nemeth E. Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica 2013; 98: 1667–1676.
Hepcidin and TB susceptibility in HIV
i
RESUME
L’hepcidine inhibe l’efflux de fer m e´ di e´ par la ferroportine, induisant une r´etention de fer dans les macrophages intracellulaires, ce qui pourrait favoriser l’acquisition de fer par les souches de Mycobacterium tuberculosis et la pathogen`ese de la tuberculose (TB). L’hepcidine plasmatique a e´ t´e mesur´ee lors du diagnostic du virus de l’immunod´eficience humaine (VIH) dans une e´ tude r´etrospective d’une cohorte africaine a` forte pr´evalence de VIH, n’ayant jamais eu de traitement antiretroviral, afin d’´etudier l’association avec la TB
pulmonaire incident et/ou extra-pulmonaire. Cent quatre-vingt-seize participants ont e´ t´e suivis du 5 aout ˆ 1992 au 1er juin 2002, avec 32 cas de TB incident identifi´es. Une e´ l´evation de l’hepcidine e´ tait associ´ee avec une augmentation significative de la probabilit´e de TB apr`es un intervalle m´edian de 6 mois. Il est n´ecessaire d’´elucider les m´ecanismes d’action li´es au fer et de trouver des biomarqueurs sensibles au temps susceptibles d’identifier les modifications individuelles du risque de TB. RESUMEN
La hepcidina inhibe el flujo del hierro mediado por la ferroportina y provoca retencion ´ intracelular en los macrofagos, ´ lo cual tal vez facilita la adquisicion ´ del hierro por parte de Mycobacterium tuberculosis y favorece la patogenia de la tuberculosis (TB). La concentracion ´ plasma´tica de hepcidina se midio´ en el momento del diagnostico ´ de infeccion ´ por el virus de la inmunodeficiencia humana (VIH) en una cohorte retrospectiva de pacientes seropositivos sin antecedente de tratamiento antirretrov´ırico, a fin de investigar la asociacion ´ con un episodio nuevo de TB pulmonar o
extrapulmonar. Se practico´ el seguimiento de 196 participantes del 5 de agosto de 1992 al 18 de junio del 2002, durante el cual se detectaron 32 casos nuevos de TB. Una concentracion ´ ma´s alta de hepcidina se asocio´ con una mayor probabilidad de padecer TB, con una mediana de 6 meses despu´es de la inclusion ´ en el estudio. Es necesario aclarar los mecanismos causales asociados con el hierro y definir biomarcadores que evolucionen en el tiempo y permitan detectar las variaciones individuales del riesgo de padecer la TB.
