Elevated Hepcidin Is Part of a Complex Relation That Links Mortality with Iron Homeostasis and Anemia in Men and Women with HIV Infection

Abstract

Background: Early and chronic inflammation is a hallmark of HIV infection, and inflammation is known to increase hepcidin expression. Consequently, hepcidin may be a key determinant of the iron homeostasis and anemia associated with poorer HIV prognoses. Objective: The objective of this study was to understand how hepcidin is related to anemia, iron homeostasis, and inflammation at HIV diagnosis and to investigate associations between hepcidin and all-cause mortality in HIV infection. Methods: In a retrospective cohort, baseline plasma hepcidin was measured by competitive enzyme immunoassay within 3 mo of HIV diagnosis in 196 antiretroviral-naive Gambians. Iron homeostasis [hemoglobin, plasma transferrin, ferritin, iron, soluble transferrin receptor (sTfR)] and inflammation [α1-antichymotrypsin (ACT)] from the same plasma sample were available, as were absolute CD4 cell counts, age, gender, body mass index (BMI), and HIV type. Results: Anemia was common across the spectrum of immunosuppression [CD4 cell counts (prevalence of anemia): >500 cells/μL (68%), 200–500 cells/μL (73%), and <200 cells/μL (89%); P = 0.032] and in men (81%) and women (76%). Increasing hepcidin was associated with iron homeostasis biomarkers (higher ferritin and lower transferrin, hemoglobin, and sTfR), inflammation (higher ACT), and key health indicators (lower CD4 or BMI, advancing age, and male gender; P < 0.001 except for hemoglobin, P = 0.021). Elevated hepcidin was associated with greater all-cause mortality in a dose-dependent manner [intermediate vs. lowest tertile: unadjusted HR (95% CI), 1.95 (1.22, 3.10); upper vs. lowest tertile: 3.02 (1.91, 4.78)]. Principal components analysis identified 2 patterns composed of hepcidin-ferritin-transferrin, with or without ACT, and iron-sTfR-hemoglobin that may distinguish inflammation and erythropoiesis iron functions. Conclusions: Elevated hepcidin is independently associated with greater mortality in men and women with HIV infection, and hepcidin is also part of a complex relation linking iron homeostasis, anemia, and HIV. Understanding the mechanisms and role of hepcidin modulation may further guide evidence-based interventions needed to counter detrimental iron homeostasis and anemia in HIV infection.

Serum ferritin thresholds for the diagnosis of iron deficiency in pregnancy: a systematic review

“…The authors attempted to correct for the impact of HIV infection by adjusting the results based on C‐reactive protein (CRP) levels. HIV infection is an independent contributor to iron deficiency (Minchella et al ., ). The effect of HIV status of included women in the study by van den Broek et al .…”

Effects of heme degradation products on reactivation of latent HIV-1

“…HIV/AIDS, similarly to other chronic infections, has been reported to lead to immune-mediated anemia of chronic disease, iron deficiency anemia or their combination (Kerkhoff and Lawn, 2015;Minchella et al, 2015), in which differential expression of hepcidin, hemojuvelin, ferroportin and other factors plays an important role (Drakesmith and Prentice, 2012;Krijt et al, 2004;Theurl et al, 2011;Xu et al, 2010). Consequently, iron supplements have often been administered.…”

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

“…Following the first studies showing a Toll-like receptor (TLR) 4-dependent induction of hepcidin by LPS, in vivo mouse studies showed increased levels of hepcidin during infections with Salmonella [ 35 , 36 ], Pseudomonas aeruginosa , group A Streptococcus [ 37 ], Vibrio vulnificus [ 38 ], and Candida albicans or Influenza A virus [ 39 ]. Additionally, in humans, several types of infections, including HIV, Salmonella , tuberculosis, sepsis, and malaria, have been reported to be accompanied by increased levels of serum hepcidin [ 40 , 41 , 42 , 43 , 44 ]. In marked contrast, the Hepatitis C virus inhibits hepcidin production in humans, which contributes to the pathology of this disease [ 45 ].…”