Anemia is the most common morbidity of HIV infection and is associated with increased progression to AIDS and higher mortality.1 Iron deficiency without anemia represents a moderate form of iron deficiency in which iron-dependent function is impaired but anemia is not present, and iron deficiency anemia represents the severe end of the spectrum in which iron deficiency and anemia are both present. The main cause of iron deficiency in women of childbearing age is dietary intake of iron that is inadequate to meet the increased demand for iron because of menstrual blood loss. The richest dietary sources of iron include meat, poultry, and fish, which contain the more bioavailable form of heme iron as hemoglobin and myoglobin.2 Iron is essential for the binding and transport of oxygen, muscle function and energy metabolism, and electron transfer reactions.3
The consequences of anemia include fatigue and a decreased sense of well-being, and an increased need for expensive human recombinant erythropoietin therapy, transfusions, and hospitalization may be more common in HIV/AIDS.1 The consequences of iron deficiency and iron deficiency anemia include reduced work capacity, lower aerobic capacity, and decreased endurance.4 Anemia caused by iron deficiency can account for a large proportion of anemia among female injection drug users and a substantial proportion of the anemia encountered in HIV/AIDS.5 Women now comprise nearly a quarter of newly diagnosed AIDS cases in the United States, and injection drug use is the route of acquisition of HIV infection in 42% of AIDS cases among women.6
Our recent studies show that approximately 40% of female injection drug users in inner-city Baltimore have iron deficiency and that iron deficiency anemia accounts for approximately half of the anemia among these women.5 The prevalence of iron deficiency in the United States among adolescent girls and women of childbearing age is 9% to 11%.7 The risk factors for iron deficiency and iron deficiency anemia among female injection drug users are not well characterized. It is not known whether HIV-positive women have a higher risk of iron deficiency or whether iron deficiency is associated with injection drug use. We characterized risk factors for iron deficiency and iron deficiency anemia in a cross-sectional study of female injection drug users in Baltimore, Maryland.
In this cross-sectional study, the subjects consisted of all women seen during an 18-month period from January 2000 to June 2001 in the AIDS Linked to Intravenous Experiences (ALIVE) study in Baltimore, Maryland. The ALIVE study is an ongoing longitudinal study of the risk factors and natural history of HIV infection among injection drug users.8 The ALIVE study consists of 2960 injection drug users recruited in 1988 or 1994. Participants in the ALIVE study are seen every 6 months; at that time, a history, physical examination, interview, complete blood cell count, and T-cell subset studies are obtained or performed.8 For HIV-positive subjects, plasma HIV RNA is measured every 6 months. Complete blood cell counts were conducted using a Beckman Coulter hematology analyzer (Fullerton, CA). Plasma ferritin was measured by enzyme-linked immunosorbent assay (ALPCO, Waltham, MA).
Univariate comparisons between groups were made using the Wilcoxon rank-sum test for continuous variables and the χ2 or Fisher exact test for categoric variables.
Plasma ferritin <30 μg/L was considered consistent with iron deficiency,9 and iron deficiency anemia was defined as a hemoglobin <120 g/L and ferritin <30 μg/L.1 In multivariate logistic regression analyses, only complete cases (198 of 200) were used, except for cases with missing hepatitis C virus serostatus data (n = 48), which were handled using the missing indicator method.10
Of 200 women (134 HIV-positive and 66 HIV-negative), 36.5% had iron deficiency. The characteristics of women with and without iron deficiency are shown in Table 1. Women who were iron deficient were younger (P = 0.042), more likely to have a history of injection drug use in the last 6 months (P = 0.0052), and less likely to be seropositive for hepatitis C virus (P < 0.0001). There were no significant differences between the groups by race, education, income, body mass index, HIV status, use of iron supplements, or CD4+ lymphocyte count. Among HIV-positive women, there were no significant differences between women with and without iron deficiency by CD4+ lymphocyte count or plasma HIV load.
Multivariate logistic regression models were used to examine risk factors for iron deficiency among all women (Table 2A). Increasing age (per every 5-year increase) was associated with a lower risk of iron deficiency (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.60 to 0.99). Any injection drug use within the last 6 months was associated with an increased risk of iron deficiency (OR = 2.61, 95% CI: 1.33 to 5.09), and hepatitis C virus status was associated with a decreased risk of iron deficiency (OR = 0.14, 95% CI: 0.04 to 0.47). Multivariate logistic regression models were used to examine risk factors for iron deficiency among HIV-positive women only (see Table 2B). In a multivariate model that adjusted for age and CD4+ lymphocyte count <200 cells/μL, any injection drug use within the last 6 months was associated with iron deficiency (OR = 2.43, 95% CI: 1.08 to 5.48). Hepatitis C virus status was associated with a decreased risk of iron deficiency (OR = 0.15, 95% CI: 0.02 to 1.07).
Iron Deficiency Anemia
A total of 15.5% of women had iron deficiency anemia. The characteristics of women with and without iron deficiency anemia are shown in Table 3. A higher proportion of women with iron deficiency anemia reported using injection drugs in the last 6 months compared with women without iron deficiency anemia (P < 0.0003). There were no significant differences between women with and without iron deficiency anemia by age, race, education, legal income, body mass index, HIV status, hepatitis C virus status, or CD4+ lymphocyte count. Among HIV-seropositive women only, there were no significant differences between women with and without iron deficiency anemia and CD4+ lymphocyte count. Among HIV-positive women, those with iron deficiency anemia had a higher log plasma HIV load compared with women without iron deficiency anemia (P = 0.07).
Multivariate logistic regression models were used to examine risk factors for iron deficiency anemia among all women (Table 4A). A history of injection drug use in the last 6 months was associated with an increased risk of iron deficiency anemia (OR = 6.65, 95% CI: 2.33 to 18.9). Hepatitis C virus seropositivity was associated with a decreased risk of iron deficiency anemia (OR = 0.14, 95% CI: 0.03 to 0.61). Multivariate logistic regression models were used to examine risk factors for iron deficiency anemia among HIV-positive women only (Table 4B). Among HIV-positive women only, in a multivariate model that adjusted for age, hepatitis C virus status, and CD4+ lymphocyte count <200 cells/μL, a history of injection drug use was associated with an increased risk of iron deficiency anemia (OR = 6.05, 95% CI: 1.82 to 20.1).
This study suggests that current injection drug use is associated with iron deficiency and iron deficiency anemia among HIV-positive and HIV-negative women in the inner city. The association between injection drug use and iron deficiency was consistent, even after adjusting for age and CD4+ lymphocyte count. To our knowledge, the association between injection drug use and iron deficiency has not been described previously in the scientific literature. A causal association cannot be definitively established from this cross-sectional study; however, it is worthwhile to discuss 2 potential explanations for this epidemiologic association. Injection drug use could ultimately contribute to iron deficiency anemia because injecting is associated with a higher prevalence of skin abscesses and endocarditis.11,12 An increase in circulating inflammatory cytokines associated with cellulitis and endocarditis,13 such as tumor necrosis factor-α (TNFα), may potentially interfere with erythropoiesis14,15 and could contribute to iron deficiency anemia.
The second possible explanation is that iron deficiency increases the risk of addiction to cocaine. Studies in rats have shown that iron deficiency causes an impairment of the nigrostriatal and mesolimbic dopamine systems by decreasing the densities of D1 and D2 receptors and the dopamine transporter in the terminal fields, caudate-putamen, and nucleus accumbens.16,17 Iron-deficient rats have decreased sensitivity to cocaine and raclopride, a dopamine D2 antagonist.17 Iron deficiency could affect sensitivity to drugs that affect the central dopamine systems and possibly increase the risk of cocaine self-administration. There are some animal data to support this idea, because the temporary impairment of the mesolimbic dopamine pathways in rats by use of dopamine receptor antagonists increased the self-administration of cocaine at higher doses.18,19 In the ALIVE study, approximately 80% of injection drug use involves the use of cocaine mixed with heroin, a combination known as “speedball”.20
This study is limited in that information was not collected on dietary intake of iron in all participants or anorexia. Another possible explanation for the association between iron deficiency and injection drug use is that women who are actively injecting drugs have altered dietary intake of iron-rich foods. There is a paucity of data on iron intake among injection drug users, and future studies need to address dietary iron intake in this risk group. In the present study, no information was collected on self-reported menstrual blood loss; however, active injection drug use is more often associated with amenorrhea in women of childbearing age.21 In this study, the prevalence of iron deficiency was lower among women with hepatitis C virus infection. This apparent lower prevalence might be attributable to the presence of more inflammation among women with hepatitis C virus, because ferritin is a positive acute phase reactant.
In conclusion, self-reported injection drug use within the last 6 months was an independent risk factor for iron deficiency and iron deficiency anemia among HIV-positive and HIV-negative women in inner-city Baltimore. Further longitudinal studies may help to provide insight into the possible direction of this epidemiologic association.
The authors thank the Nutrition Group staff, Phyllis Friello, Faith Nufer, and Rene Kitchens as well as the ALIVE study staff, Lisa McCall, Recardo Stinnette, Stacey Meyerer, and Erin Pilibosian for their work with the study participants. The authors thank Jag Khalsa, our project officer at the National Institute for Drug Abuse, for his continuing support.
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