• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Clin Infect Dis. Author manuscript; available in PMC Aug 1, 2011.
Published in final edited form as:
PMCID: PMC2897927
NIHMSID: NIHMS203286

Increased Serum Iron Levels and Infectious Complications after Liver Transplantation

Jennifer K. Chow, MD, MS,1 Barbara G. Werner, PhD,2 Robin Ruthazer, MPH,3 and David R. Snydman, MD, FACP1

Abstract

Background

Elevated serum iron levels have been associated with infectious outcomes in various patient populations but have never been studied after liver transplantation.

Methods

The relationship between serum iron levels and infectious outcomes after liver transplantation was evaluated in a nested case control study using prospectively collected data and serum. Unadjusted and adjusted hazards ratios (HR) were calculated for each iron marker predictor variable (iron, unsaturated iron binding capacity [UIBC], total iron binding capacity, transferrin saturation and ferritin) and time to development of each of 6 outcomes (cytomegalovirus [CMV] disease, invasive fungal infection [IFI], bacteremia, both IFI or bacteremia, any infection, and 1 year mortality).

Results

Serum measurements (n=109) corresponding to increased levels of serum iron were independently associated with an increased risk for any infection and death. After adjusting for number of red blood cell (RBC) transfusions, donor CMV seropositive status and fungal colonization, ferritin was independently associated with the development of any infection [HR 1.09 (95% CI 1.04–1.14)]. After adjusting for number of RBC transfusions, development of CMV disease and administration of IV steroids for treatment of rejection, ferritin was also was independently associated with death [HR 1.11 (95 % CI 1.04–1.18)]. Similar results were found for UIBC for the same 2 outcomes.

Conclusions

A better understanding of iron metabolism and its relationship to infection could help guide future infection prognosis, prevention and management efforts in this high-risk population.

Keywords: Liver Transplantation, Iron, Infection, Risk Factors

Introduction

Infections following orthotopic liver transplantation (OLT) are an important cause of morbidity and mortality despite improvements in surgical techniques, post-transplant immunosuppressant management and use of antimicrobial agents for infection prophylaxis. With a better understanding of risk factors for infections among OLT patients, efforts can be directed towards preventing such complications. Previous studies have identified several risk factors for bacterial, viral and fungal infections after OLT [17]. Of particular note, the number of cellular blood products, including red blood cells (RBC) transfused intra-operatively, has been identified as an independent risk factor for various types of infections, such as surgical site infections and intra-abdominal abscesses, in several studies of OLT recipients [3, 811]. This increased risk of bacterial and fungal infections associated with RBC transfusions also occurs in other surgical populations in a dose-dependent fashion [1218].

A potential hypothesis to explain the increased risk of infection associated with RBC transfusions is the increased availability of iron, a known vital growth factor for most bacteria, and fungi, in the transfused recipient’s blood. Although viruses do not require iron, infected host cells need this element to synthesize viral particles. In vitro studies support the role of iron in the pathogenesis of human viral infections, such as cytomegalovirus, hepatitis C, herpes simplex virus and human immunodeficiency virus [1922]. Multiple in vitro studies and animal models have demonstrated that iron, including from heme sources [23], promotes increased virulence of bacterial and fungal infections by counteracting the presence of unsaturated iron-binding proteins and other innate antimicrobial effects of host plasma [2426]. Readily available serum iron is metabolized by pathogen iron and heme enzyme systems, facilitating increased bacterial and fungal growth which may overwhelm other host defenses and result in clinical infection. Host iron sequestration, which occurs with “stress hypoferremia” in response to acute infection or injury [27, 28], reverses this pathogenic effect and restores the antimicrobial properties of host serum [29, 30]. This decrease in iron availability, or iron-withholding, may serve as a defense mechanism after infection or other stressful events [31].

Although the role of iron in the pathogenesis of infection has been well documented, its exact role in the clinical setting of infection remains unclear. Approximately a dozen studies have explored the relationship between host iron and clinical outcomes, including bacterial and fungal infections, however these studies were not controlled for many common risk factors for infection [5, 3243]. In addition, serum markers of iron metabolism have never been studied in the clinical setting of infection after OLT. The objective of this study was to examine whether serum iron markers [iron, ferritin, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), and transferrin saturation (%TSAT)] that correlate with increased levels of serum iron are associated with an increased risk for bacterial, viral or fungal infections after OLT in a well-defined cohort of patients.

Materials and Methods

Patients and Serum Samples

We conducted a retrospective analysis of a nested cohort study of data and serum collected prospectively during a randomized, double-blinded placebo controlled trial that evaluated the effect of cytomegalovirus immunoglobulin (CMVIg) prophylaxis on the prevention of cytomegalovirus (CMV) disease and its complications in patients who underwent OLT [44]. The original trial included 146 children and adults who underwent liver transplantation between December 1987 and June 1990 at four university hospitals in Boston, Massachusetts. All liver transplantation candidates and all liver donors were screened for CMV antibody. Patients were enrolled at the time of transplantation and followed clinically for up to one year. Subjects in the original study were randomized to receive either intravenous CMVIg or placebo (1% serum albumin). CMVIg was assayed for iron and none was detected. Patients were given standard immunosuppressive therapy for the time during which the study was conducted, which generally included cyclosporine, azathioprine, corticosteroids and murine monoclonal antibody to T3 antigen (OKT3). In the original study, 35% of patients received induction OKT3. Acute rejection was treated primarily with IV bolus steroid infusion. Refractory or recurrent rejection was treated with OKT3. Details regarding the timing of the intervention, serum sampling and follow-up are described elsewhere [44].

Definitions of Infection

CMV disease was defined as clinical indication of organ dysfunction with biopsy proven CMV in the affected organ documented either by virus isolation or histopathologic evidence [44]. Bacteremia was defined as isolation of a bacterial organism from blood of patients with symptoms and/or signs of infection. Isolation of a gram-negative organisms, Staphylococcus aureus, Streptococcus species, Listeria monocytogenes, or clostridial species from a single blood specimen was sufficient to qualify for a true bacteremia. Bacteremia due to other gram-positive organisms was considered significant and not due to contamination if the organism was isolated from at least 2 blood specimens taken from different sites simultaneously or at different times but within 7 days [2, 45]. Invasive fungal infection (IFI) was defined as the identification of fungal or yeast species by culture or histology from a normally sterile site. Fungal colonization was defined as isolation of a fungal or yeast species by culture or histology from non-sterile sites (i.e. urine, throat, sputum, skin) [8]. Decisions to obtain bacterial, fungal, or viral cultures or histologic specimens were made by individual transplant teams based on clinical judgment. Details regarding surveillance cultures for CMV and serologic studies for CMV are reported elsewhere [44].

Measurement of Serum Iron Markers

A subset of serum samples collected from patients at least one week after OLT but before any infectious events of CMV disease, bacteremia, or IFI with sufficient volume remaining were thawed and analyzed for this study. This single timepoint selected for serum iron measurements is similar to previous studies that examined iron levels at a single timepoint and clinical outcomes [33, 35, 38, 39, 42]. The serum specimens had been stored at −20°C. Serum iron, unsaturated iron binding capacity (UIBC) and ferritin were assessed at the Tufts Medical Center clinical laboratory using standard CLIA approved methods by individuals blinded to patients’ clinical characteristics. Total iron binding capacity (TIBC) and transferrin saturation (TSAT) were calculated from [Iron + UIBC = TIBC] and [Iron ÷ TIBC= TSAT].

Covariate Variables

Demographic, pre-transplant, intra-operative and post-transplantation variables were analyzed for association with 6 different outcomes: CMV disease, bacteremia, IFI, bacteremia or IFI, any infection, and death. Pre-transplant variables included: age, gender, race, CMV donor and recipient serostatus, primary liver disease leading to transplantation and creatinine clearance. Intra-operative variables included: type and number of blood products units transfused (RBC, platelets, and fresh frozen plasma), and transplantation surgical time. Post-transplantation variables included: immunosuppressant medications for induction and rejection, major intra-abdominal operation, liver re-transplantation, vascular/biliary complications, rejection and receipt of CMV immune globulin for CMV infection prophylaxis.

Statistical Analysis

All analyses were performed in SAS 9.1. The means of each iron marker (iron, TSAT, TIBC, UIBC, and ferritin) were compared between subjects with and without each outcome (CMV disease, IFI, bacteremia, IFI or bacteremia, any infection, and 1 year mortality) using a Student’s t-test. Serum samples were selected at the timepoint at least one week after transplantation and before development of an outcome of interest, where applicable. Unadjusted hazards ratios (HR) were calculated for each iron marker predictor variable and time to development of each of the six outcomes using Cox Proportional Hazard survival models. Multivariate adjusted HR for the two most predictive iron markers, UIBC and ferritin, were calculated after building models using covariates that were significant at p<0.10 on univariate analysis for two outcomes, any infection and 1 year mortality. Because the number of peri-operative RBCs transfused was considered to be an important a priori confounder, this variable was forced into each multivariate survival model. The proportional hazards assumption was tested in all final multivariable models by examining the correlation of Schoenfeld residuals with rank to time.

Results

Of the 146 patients in the original clinical trial, specimens from 37 patients were either not available or in poor condition. The 37 patients with missing samples ranged in age from 1 month to 65 years with a median age of 42 years and included 11 of the 13 pediatric subjects enrolled in the original study. Among the 26 adult patients with missing samples, many had infectious events including bacteremia (n=10, 39%), CMV disease (n=8, 31%), IFI (n=10, 39%) and any infection (n=15, 58%). Among these 26 adult patients with missing serum samples, the 1 year mortality rate was 46% (n=12).

This left 109 (75%) patients from whom serum iron markers were measured in samples taken at a median time of 10 days after OLT (interquartile range [IQR] 9–14 days) and at a median time of 22 days (IQR 13–36 days) before the infectious event. Select cohort characteristics and outcomes are summarized in Table 1. Approximately one third of the subjects who had any infection also died (n=14). Among the entire cohort of subjects, one tenth experienced both outcomes of any infection and death. Among those who died, most were CMV donor seropositive (62%), half experienced one or two episodes of rejection (53%), and the majority was treated with solumedrol (71%).

Table 1
Patient characteristics and outcomes in liver transplant recipients

Serum iron markers were most closely associated with the outcomes of any infection (CMV, bacterial or fungal) and 1 year mortality. Mean values for the five different iron measurements by outcome of any infection and 1 year mortality are shown in Table 2. Markers that correspond to higher levels of serum iron (iron, TSAT, ferritin) were higher in the groups with any infection or death. The measurements of TIBC and UIBC are inversely related to iron and were lower in the groups with any infection or death.

Table 2
Serum Iron Markers in Patients by Outcome of Any Infection and Death (1 year mortality)

Unadjusted hazards ratios (HR) for the outcomes of time to any infection and time to death as a function of iron marker measurements are summarized in Table 3. Because TIBC and UIBC are inversely related to iron, 1/HR for TIBC and UIBC are reported. Higher measurements of TSAT and ferritin and lower measurements of UIBC, which all correspond to higher levels of serum iron, were associated with a statistically significant increased risk of any infection. Likewise, higher measurements of TSAT and ferritin and lower measurements of TIBC and UIBC were associated with an increased risk of one year mortality. On univariate analysis, TSAT and ferritin had the strongest associations with the two outcomes, time to any infection and death. Similar univariate relationships were found between the iron markers of UIBC and ferritin and the outcomes of CMV disease and bacteremia (data not shown). No statistical differences in iron markers were found between patients with and without IFI. Of note, the majority of IFIs were Candida infections and none were Mucor infections.

Table 3
Univariate and Multivariate Relationships between Serum Iron Markers and the Outcomes of Any Infection and 1 Year Mortality

The adjusted HR for the outcomes of time to any infection and time to death as a function of iron marker measurements are also summarized in Table 3. Because the measurements of TIBC, UIBC and TSAT are inter-related, we are only reporting the multivariate HR for UIBC, which demonstrated the most statistically significant relationship to the outcomes. We found that decreasing levels of UIBC and increasing levels of ferritin were both independently associated with an increased risk for any infection after adjusting for number of RBC transfusions, donor CMV+ serostatus and fungal colonization. In addition, decreasing levels of UIBC and increasing levels of ferritin were independently associated with an increased risk of death after adjusting for number of RBC transfusions, development of CMV disease and administration of IV steroids for treatment of rejection.

Given the large percentage (32%) of patients who received OKT3 for treatment of rejection, we performed a subgroup analysis comparing those who did to those who did not receive OKT3 (data not shown). The association between increased iron markers and risk of infection or death did not change in this subgroup analysis.

Discussion

We show an independent association between serum iron markers measured at least 1 week after OLT and the outcomes of infectious complications and 1 year mortality after OLT. Specifically, high TSAT, high ferritin and low UIBC, which all correspond to increased levels of tissue iron stores, are associated with an increased risk after OLT of CMV disease, bacteremia, any infection (CMV, bacterial, IFI) and death. No independent associations were found between any of the serum iron markers and IFI, however the number of subjects with this outcome was small (n=9) and therefore the power to detect a difference was limited.

UIBC and ferritin were the strongest predictors with the most statistically significant associations found between these covariates and the outcomes of any infection and death. Even after adjusting for other risk factors for infection previously described in the literature [15, 9, 10, 46], including treatment with OKT3, CMV donor and recipient status, and number of peri-operative RBC transfusions, these associations remained. Because RBCs contain iron in the form of hemoglobin and exposure to intra-operative RBC transfusions has been found to be an independent risk factor for post-operative bacterial infections in patients undergoing OLT [3, 811], we adjusted all of our multivariate models to include this important confounding factor. In the analysis of the original trial, RBC transfusions were independently associated with the development of severe CMV-associated disease post-OLT [44].

It is not surprising that serum iron itself was not independently associated with an increased risk of infection. Serum iron has considerable hour-to-hour physiologic variability in normal individuals. In addition, low serum iron does not necessarily reflect low iron stores. The more informative measurement is transferrin saturation (TSAT) which is calculated from serum iron and UIBC. [Iron + UIBC = TIBC; Iron ÷ TIBC = TSAT]. Transferrin is the major extracellular transport protein that is normally only 30–40% saturated. Increases and decreases in tissue iron stores correspond to increases and decreases in transferrin saturation, respectively. The intracellular correlate of transferrin is ferritin which is present in virtually all cells, including hepatocytes. Plasma levels of ferritin also correlate closely with tissue concentrations of iron. Bone marrow and liver biopsies and/or hepatic MRI imaging are more specific ways to measure tissue iron stores; however, serum iron indices are less invasive, less expensive, and clinically available.

Our findings are supported by other studies that have explored the relationship between host iron and adverse clinical outcomes, including bacterial and fungal infections [5, 3243]. Among hematopoietic stem cell transplantation recipients, increased iron stores measured in various forms such as by serum iron markers, quantitative hepatic iron content and qualitative bone marrow iron content have been associated with increased invasive fungal infections [34, 39, 41]. Among OLT recipients, quantitative hepatic iron content of the explanted livers has been associated with increased fungal and bacterial infections [32, 47]. Most of these studies, however, had small sample sizes and because these studies collected data retrospectively, they were unable to adjust for other known infectious risk factors, such as prior antibiotic exposure or the presence of central venous catheters, or potential confounders, such as receipt of RBC transfusions or immunosuppression.

The strengths of this analysis included the use of a well-characterized, prospectively followed cohort with well-defined clinical events. Data on a number of known infectious risk factors were carefully collected including administration of RBC transfusions. Because data were collected prospectively, we were able to use time-dependent analyses to enhance the power of our study.

There are a few limitations to this analysis. First, some subjects had missing blood samples, many of whom experienced an infectious outcome. The 26 missing adult samples can be attributed to their blood samples being used in previous studies. Because the pediatric subjects had smaller volumes of blood taken for the study, most of them had missing blood samples. Therefore, our results may not be applicable to pediatric OLT recipients. We also were not able to account for the time of day during which the blood samples were drawn. Because iron measurements normally exhibit diurnal variation, this could have introduced a measurement bias to our results.

Although we selected a single timepoint for measuring serum iron, all previous studies described in the literature also used a single timepoint [5, 3242]. This single measurement and our retrospective analysis limit the study results as hypothesis-generating and exploratory. A prospective longitudinal study with serial iron measurements is currently underway to further explore our association found between increased serum iron markers and infection and death after liver transplantation. Prospectively measuring the iron regulatory hormone, hepcidin, concurrently with serum iron levels will provide more insight into potential cause-and-effect relationships between iron levels and clinical outcomes. Hepcidin is a small, acute phase peptide predominantly produced by the liver and is thought to be the single, central regulator hormone of extracellular iron homeostasis [48]. Hepcidin synthesis is induced by infection and inflammation, [4951] and also by iron loading or iron stores by yet unknown, complex mechanisms [5153]. Conversely, hepcidin production is suppressed by anemia, hypoxia [54] and erythropoiesis [55, 56]. Hepcidin acts by decreasing iron influx into plasma from tissues engaged in iron transport and storage [51]. Without hepcidin measurements, one cannot determine whether serum iron measurements are increased as a result of iron overload or in reaction to early infection/inflammation.

In terms of generalizability, this is an older OLT cohort that received more blood transfusions, less effective antimicrobial prophylaxis (i.e. non-systemically absorbed anti-fungals such as nystatin), and more intense immunosuppressive medications for both prophylaxis and treatment of rejection, all of which differ from current OLT surgical and medical management practices. These older clinical practices likely contributed to higher rates of infectious complications although the types of infections have remained the same over time. However, we statistically adjusted our multivariate model to account for all of these differences, and we were still able to demonstrate an independent and significant relationship between serum iron measurements and infection or mortality.

Our study found that increased serum iron markers were an independent risk factor for infectious complications and 1 year mortality in liver transplant recipients. If a better understanding of iron metabolism and its relationship to infection in OLT recipients is elucidated in future studies, this could potentially help guide infection prognosis, prevention and management efforts in this high-risk population.

Acknowledgments

Financial Support

NIH training grant T32A1055412 and NIH career award K23DK083504 (to J.C.)

Footnotes

Conflicts of Interest

All authors: no conflicts.

References

1. Collins LA, Samore MH, Roberts MS, et al. Risk factors for invasive fungal infections complicating orthotopic liver transplantation. J Infect Dis. 1994;170(3):644–52. [PubMed]
2. Falagas ME, Snydman DR, Griffith J, Werner BG. Exposure to cytomegalovirus from the donated organ is a risk factor for bacteremia in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group. Clin Infect Dis. 1996;23(3):468–74. [PubMed]
3. Hadley S, Samore MH, Lewis WD, Jenkins RL, Karchmer AW, Hammer SM. Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression. Transplantation. 1995;59(6):851–9. [PubMed]
4. Hollenbeak CS, Alfrey EJ, Souba WW. The effect of surgical site infections on outcomes and resource utilization after liver transplantation. Surgery. 2001;130(2):388–95. [PubMed]
5. Singh N, Gayowski T, Wagener MM, Marino IR. Bloodstream infections in liver transplant recipients receiving tacrolimus. Clin Transplant. 1997;11(4):275–81. [PubMed]
6. Falagas ME, Snydman DR, George MJ, et al. Incidence and predictors of cytomegalovirus pneumonia in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group. Transplantation. 1996;61(12):1716–20. [PubMed]
7. Falagas ME, Snydman DR, Griffith J, Werner BG, Freeman R, Rohrer R. Clinical and epidemiological predictors of recurrent cytomegalovirus disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group. Clin Infect Dis. 1997;25(2):314–7. [PubMed]
8. George MJ, Snydman DR, Werner BG, et al. The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland. Am J Med. 1997;103(2):106–13. [PubMed]
9. Patel R, Portela D, Badley AD, et al. Risk factors of invasive Candida and non-Candida fungal infections after liver transplantation. Transplantation. 1996;62(7):926–34. [PubMed]
10. Paya CV, Wiesner RH, Hermans PE, et al. Risk factors for cytomegalovirus and severe bacterial infections following liver transplantation: a prospective multivariate time-dependent analysis. J Hepatol. 1993;18(2):185–95. [PubMed]
11. Munoz-Price LS, Slifkin M, Ruthazer R, et al. The clinical impact of ganciclovir prophylaxis on the occurrence of bacteremia in orthotopic liver transplant recipients. Clin Infect Dis. 2004;39(9):1293–9. [PubMed]
12. Banbury MK, Brizzio ME, Rajeswaran J, Lytle BW, Blackstone EH. Transfusion increases the risk of postoperative infection after cardiovascular surgery. J Am Coll Surg. 2006;202(1):131–8. [PubMed]
13. Chang H, Hall GA, Geerts WH, Greenwood C, McLeod RS, Sher GD. Allogeneic red blood cell transfusion is an independent risk factor for the development of postoperative bacterial infection. Vox Sang. 2000;78(1):13–8. [PubMed]
14. Carson JL, Altman DG, Duff A, et al. Risk of bacterial infection associated with allogeneic blood transfusion among patients undergoing hip fracture repair. Transfusion. 1999;39(7):694–700. [PubMed]
15. Claridge JA, Sawyer RG, Schulman AM, McLemore EC, Young JS. Blood transfusions correlate with infections in trauma patients in a dose-dependent manner. Am Surg. 2002;68(7):566–72. [PubMed]
16. Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006;34(6):1608–16. [PubMed]
17. Palmieri TL, Caruso DM, Foster KN, et al. Effect of blood transfusion on outcome after major burn injury: a multicenter study. Crit Care Med. 2006;34(6):1602–7. [PubMed]
18. Silverboard H, Aisiku I, Martin GS, Adams M, Rozycki G, Moss M. The role of acute blood transfusion in the development of acute respiratory distress syndrome in patients with severe trauma. J Trauma. 2005;59(3):717–23. [PubMed]
19. Crowe WE, Maglova LM, Ponka P, Russell JM. Human cytomegalovirus-induced host cell enlargement is iron dependent. Am J Physiol Cell Physiol. 2004;287(4):C1023–C1030. [PubMed]
20. Romeo AM, Christen L, Niles EG, Kosman DJ. Intracellular chelation of iron by bipyridyl inhibits DNA virus replication: ribonucleotide reductase maturation as a probe of intracellular iron pools. J Biol Chem. 2001;276(26):24301–8. [PubMed]
21. van Asbeck BS, Georgiou NA, van der BT, Oudshoorn M, Nottet HS, Marx JJ. Anti-HIV effect of iron chelators: different mechanisms involved. J Clin Virol. 2001;20(3):141–7. [PubMed]
22. Kartikasari AE, Georgiou NA, de Geest M, et al. Iron enhances endothelial cell activation in response to Cytomegalovirus or Chlamydia pneumoniae infection. Eur J Clin Invest. 2006;36(10):743–52. [PubMed]
23. Skaar EP, Humayun M, Bae T, DeBord KL, Schneewind O. Iron-source preference of Staphylococcus aureus infections. Science. 2004;305(5690):1626–8. [PubMed]
24. Boelaert JR, de Locht M, Van Cutsem J, et al. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. J Clin Invest. 1993;91(5):1979–86. [PMC free article] [PubMed]
25. Bullen JJ, Wilson AB, Cushnie GH, Rogers HJ. The abolition of the protective effect of Pasteurella septica antiserum by iron compounds. Immunology. 1968;14(6):889–98. [PMC free article] [PubMed]
26. Bullen JJ, Spalding PB, Ward CG, Rogers HJ. The role of Eh, pH and iron in the bactericidal power of human plasma. FEMS Microbiol Lett. 1992;73(1–2):47–52. [PubMed]
27. Elin RJ, Wolff SM. The role of iron in nonspecific resistance to infection induced by endotoxin. J Immunol. 1974;112(2):737–45. [PubMed]
28. Kluger MJ, Rothenburg BA. Fever and reduced iron: their interaction as a host defense response to bacterial infection. Science. 1979;203(4378):374–6. [PubMed]
29. Al Younes HM, Rudel T, Brinkmann V, Szczepek AJ, Meyer TF. Low iron availability modulates the course of Chlamydia pneumoniae infection. Cell Microbiol. 2001;3(6):427–37. [PubMed]
30. Schaible UE, Collins HL, Priem F, Kaufmann SH. Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J Exp Med. 2002;196(11):1507–13. [PMC free article] [PubMed]
31. Weinberg ED. Iron loading and disease surveillance. Emerg Infect Dis. 1999;5(3):346–52. [PMC free article] [PubMed]
32. Alexander J, Limaye AP, Ko CW, Bronner MP, Kowdley KV. Association of hepatic iron overload with invasive fungal infection in liver transplant recipients. Liver Transpl. 2006;12(12):1799–804. [PubMed]
33. Altes A, Remacha AF, Sureda A, et al. Iron overload might increase transplant-related mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29(12):987–9. [PubMed]
34. Altes A, Remacha AF, Sarda P, et al. Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis. Bone Marrow Transplant. 2004;34(6):505–9. [PubMed]
35. Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood. 2007;109(10):4586–8. [PMC free article] [PubMed]
36. Caroline L, Rosner F, Kozinn PJ. Elevated serum iron, low unbound transferrin and candidiasis in acute leukemia. Blood. 1969;34(4):441–51. [PubMed]
37. Hoen B, Kessler M, Hestin D, Mayeux D. Risk factors for bacterial infections in chronic haemodialysis adult patients: a multicentre prospective survey. Nephrol Dial Transplant. 1995;10(3):377–81. [PubMed]
38. Karp JE, Merz WG. Association of reduced total iron binding capacity and fungal infections in leukemic granulocytopenic patients. J Clin Oncol. 1986;4(2):216–20. [PubMed]
39. Kontoyiannis DP, Chamilos G, Lewis RE, et al. Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in patients with high-risk hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation. Cancer. 2007;110(6):1303–6. [PubMed]
40. Lambert CC, Hunter RL. Low levels of unsaturated transferrin as a predictor of survival in pneumococcal pneumonia. Ann Clin Lab Sci. 1990;20(2):140–6. [PubMed]
41. Maertens J, Demuynck H, Verbeken EK, et al. Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant. 1999;24(3):307–12. [PubMed]
42. Miceli MH, Dong L, Grazziutti ML, et al. Iron overload is a major risk factor for severe infection after autologous stem cell transplantation: a study of 367 myeloma patients. Bone Marrow Transplant. 2006;37(9):857–64. [PubMed]
43. Teehan GS, Bahdouch D, Ruthazer R, Balakrishnan VS, Snydman DR, Jaber BL. Iron storage indices: novel predictors of bacteremia in hemodialysis patients initiating intravenous iron therapy. Clin Infect Dis. 2004;38(8):1090–4. [PubMed]
44. Snydman DR, Werner BG, Dougherty NN, et al. Cytomegalovirus immune globulin prophylaxis in liver transplantation. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1993;119(10):984–91. [PubMed]
45. Arbo MD, Snydman DR. Influence of blood culture results on antibiotic choice in the treatment of bacteremia. Arch Intern Med. 1994;154(23):2641–5. [PubMed]
46. George DL, Arnow PM, Fox AS, et al. Bacterial infection as a complication of liver transplantation: epidemiology and risk factors. Rev Infect Dis. 1991;13(3):387–96. [PubMed]
47. Singh N, Wannstedt C, Keyes L, et al. Hepatic iron content and the risk of Staphylococcus aureus bacteremia in liver transplant recipients. Prog Transplant. 2007;17(4):332–6. [PubMed]
48. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101(7):2461–3. [PubMed]
49. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A. 2001;98(15):8780–5. [PMC free article] [PubMed]
50. Kemna E, Pickkers P, Nemeth E, van der HH, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood. 2005;106(5):1864–6. [PubMed]
51. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–6. [PMC free article] [PubMed]
52. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(11):7811–9. [PubMed]
53. Lin L, Valore EV, Nemeth E, Goodnough JB, Gabayan V, Ganz T. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood. 2007;110(6):2182–9. [PMC free article] [PubMed]
54. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110(7):1037–44. [PMC free article] [PubMed]
55. Vokurka M, Krijt J, Sulc K, Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res. 2006;55(6):667–74. [PubMed]
56. Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108(12):3730–5. [PMC free article] [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...