Calcium channel blocker use and serum ferritin in adults with hypertension.

Iron overload cardiomyopathy is becoming more prevalent, and early recognition and intervention may alter outcomes. Calcium channels are key transporters of iron under iron-overloaded conditions, and potentially represent a new therapeutic target for iron overload. The purpose of this study was to examine the relationship between Calcium channel blocker (CCB) use and serum ferritin among adults with diagnosed hypertension. We analyzed the nationally representative NHANES (National Health and Nutrition Examination Survey) 1999-2002 for adults ≥40 years with diagnosed hypertension. The association between CCBs and serum ferritin was assessed using a t-test and adjusted multiple regressions.The study population included 2143 individuals (representing 37.4 million individuals, 42.0 % males). 12.6 % of the population reported taking CCBs in the last month. Individuals taking CCBs had lower mean serum ferritin (129.3 ng/mL versus 154.5 ng/mL, p = 0.02). After adjusting for age, sex, menopause and hysterectomy status for women, race/ethnicity, and C-reactive protein, mean serum ferritin for individuals taking CCBs was 26.3 ng/mL lower than for those not taking CCBs (p = 0.01). In an adjusted regression, individuals who took CCBs and had a daily vitamin C intake of ≥500 mg had a mean serum ferritin that was 60.1 ng/mL lower than people not taking CCBs and with daily vitamin C < 500 mg (p < 0.001). In conclusion, this study found an association between use of CCBs and lower serum ferritin levels in individuals with hypertension. Further studies are needed to assess the possible use of CCBs as non-traditional chelating agents for treatment of iron overload cardiomyopathy.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids: is the early-morning serum adrenocorticotropic hormone (ACTH) a useful screening test?

BACKGROUND: Hypothalamic-pituitary-adrenal axis suppression (HPAS) in asthmatic children treated with inhaled corticosteroids (ICS), with or without nasal steroids (NS), may be more common than previously thought. Only dynamic testing will identify children at risk of adrenal crisis. It is impractical to test all asthmatic children for HPAS with a gold standard adrenal function test, i.e. the metyrapone or insulin tolerance test. OBJECTIVE: To determine which clinical or biochemical parameter is the most useful screening test for HPAS in asthmatic children. METHODS: Twenty-six asthmatic children, 5-18 yr old, on ICS ± NS, not treated with oral or topical steroids in the preceding year were recruited. Height, weight, height velocity, weight velocity and a change in systolic blood pressure from the recumbent to the standing position (ΔSBP) were recorded. Early-morning urine for urinary free cortisol (UFC) and urinary cortisol metabolites (UCM) was collected. UFC was analysed by both a chemiluminescent assay and gas chromatography/mass spectrometry (GC-MS). Morning serum cortisol and adrenocorticotropic hormone (ACTH) levels were measured. The overnight metyrapone test was performed if the fasting morning serum cortisol was >83 nmol/l. HPAS was diagnosed if the ACTH failed to rise >100 pg/ml after metyrapone. Spearman correlation coefficients (r) were calculated between the post-metyrapone ACTH and each variable. A receiver-operating characteristics (ROC) curve was drawn for the most promising test, and the diagnostic performance was calculated. RESULTS: All clinical and biochemical parameters investigated were weakly and non-significantly correlated with the post-metyrapone ACTH, except for the morning serum ACTH (r = 0.68; p <0.001). The best discrimination between those who have and those who do not have HPAS is a morning serum ACTH level of 11.7 pg/ml. This corresponds to a sensitivity of 0.89 (0.57-0.98), a specificity of 0.77 (0.53-0.90), a positive predictive value of 0.67 (0.39-0.87), a negative predictive value of 0.93 (0.69-0.99), an accuracy of 0.81 (0.61-0.94), a positive likelihood ratio of 3.78 (1.68-9.49) and a negative likelihood ratio of 0.15 (0.03-0.60). CONCLUSIONS: The morning serum ACTH level was found to be the most useful screening test to detect HPAS in this sample of children receiving ICS ± NS. A larger study should be undertaken to refine the diagnostic precision of the morning serum ACTH level.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids--more common than expected?

BACKGROUND: Hypothalamic pituitary adrenal axis suppression (HPAS) when treating asthmatic children with inhaled corticosteroids (ICS) is thought to be rare. OBJECTIVE: To determine the prevalence of HPAS in asthmatic children treated with ICS and nasal steroids (NS). METHODS: Twenty-six asthmatic children were recruited. Clinical features of HPAS, height, weight, height and weight velocity, steroid dose, adherence, symptom control and lung functions were documented. Metyrapone test was performed if the serum cortisol was > 83 nmol/L (> 3 microg/dL). RESULTS: No child had a serum cortisol < 83 nmol/L (< 3 microg/dL). Prevalence of HPAS was 35 (CI = 17%-56%). Daily NS dose/ m2 and cumulative NS dose/m2 were significantly (p = 0.03) inversely correlated with the post-metyrapone ACTH (r = -0.42 for both). Current ICS dose was not associated with the post-metyrapone ACTH (r = 0). There was a weak correlation with the daily ICS dose/m2 (r = -0.12) and cumulative ICS dose/m2 (r = -0.26). CONCLUSIONS: A third of asthmatic children on ICS and NS develop HPAS. Contributing factors are the use of NS, body size and cumulative dose of ICS.

Iron availability and infection.

BACKGROUND: To successfully sustain an infection, nearly all bacteria, fungi and protozoa require a continuous supply of host iron. METHODS: Literature review. RESULTS: Mechanisms of microbial iron acquisition are determinants for the kinds of cells, tissues and hosts in which pathogens can flourish. As a corollary, hosts possess an array of iron withholding devices whereby they can suppress or abort microbial invasions. GENERAL SIGNIFICANCE: Awareness of environmental and behavioral methods that can prevent iron loading plus development of pharmaceutical agents that can block microbial access to iron may help to reduce our dependence on antibiotics.

Malaria and iron: history and review.

To cause infection, nearly all protozoa, fungi, and bacteria must obtain growth-essential iron from their hosts. To suppress infection, hosts have evolved iron-withholding defense systems. Enhancement of iron withholding is a potential target for the development of novel therapeutic agents. This review focuses on the association of iron with current and emerging antimalarial drugs. Proposed mechanisms of antimalarial action of (1) iron-requiring agents, the artemisinins, are compared with (2) a spectrum of compounds that withdraw iron by chelation. A novel approach to malarial chemotherapy might involve the sequential use of a member of each of the two categories.

Iron withholding: a defense against disease.

Excessive and misplaced iron promotes an array of neurodegenerative and endocrine diseases as well as cardiomyopathy, arthropathy, neoplasia and infection. Vertebrates maintain an iron withholding defense system designed to prevent accumulation of redox-active (free) iron in sensitive sites and to sequester the metal in innocuous packages. Numerous genetic, behavioral and environmental factors counteract the defense system. Our increasing awareness of the pathologic roles of iron, as well as of the methods for prevention of iron loading coupled with intensified research and development of tissue specific iron chelator drugs, can be expected to yield marked improvements in human health.

Role of iron in osteoporosis.

Osteoporosis is a remarkably frequent complication of iron loading conditions such as thalassemia, sicklemia, African siderosis, hemochromatosis, smoking, alcoholism, HIV infection, and cessation of menstruation. The metal suppresses osteoblast formation of bone and may also stimulate osteoclast resorption of bone. Iron also inhibits anterior pituitary synthesis of gonadotrophs. This, in turn, results in depressed formation of gonadal hormones. The tendency of iron-loaded persons to become osteoporotic may be enhanced by gonadal hormone deficiency. Iron binding agents that could specifically withhold excess skeletal iron (and be excreted as the iron chelate) might have therapeutic utility.

Therapeutic potential of iron chelators in diseases associated with iron mismanagement.

A considerable array of diseases are now recognized to be associated with misplacement of iron. Excessive deposits of the metal in sensitive tissue sites can result in formation of destructive hydroxyl radicals as well as in stimulation of growth of neoplastic and microbial cell invaders. To counteract potential iron damage, hosts employ the iron chelators, transferrin and lactoferrin. These proteins have been recently developed into pharmaceutical products. Additionally, a variety of low molecular mass iron chelators are being used/tested to treat whole body iron loading, and specific diseases for which the metal is a known or suspected risk factor.

The therapeutic potential of lactoferrin.

Lactoferrin (Lf), a natural defence iron-binding protein, is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus and seminal fluid. Additionally, Lf is produced in polymorphonuclear leukocytes and is deposited by these circulating cells in septic sites. A principal function of Lf is that of scavenging non-protein-bound iron in body fluids and inflamed areas so as to suppress free radical-mediated damage and decrease accessibility of the metal to invading bacterial, fungal and neoplastic cells. Adequate sources of bovine and recombinant human Lf are now available for development of commercial applications. Among the latter are use of Lf in food preservation, fish farming, infant milk formula and oral hygiene. Other readily accessible body compartments for Lf administration include skin, throat and small intestine. Further research is needed for possible medicinal use in colon and systemic tissues. Although Lf is a natural product and should be highly biocompatible, possible hazards have been documented.

Physiological Effects of a Physical Training Program in Children with Exercise-Induced Asthma.

Twelve boys with atopic asthma, ages 9-14 years, were divided equally into exercise and control groups. Identical measurements were made before and after a 3-month trial period during which the exercise group was trained. The trained group, but not the control group, showed significant improvements in parameters of physical fitness including maximum oxygen consumption (V̇O2max) and peak running velocity during the maximal treadmill test (p>0.05). Treadmill velocity at the lactate tumpoint was greater and heart rate during submaximal exercise was lower in the trained subjects after the trial period. Subjective and objective findings (less use of medication, fewer asthmatic attacks, increased physical activity) suggested that clinical asthma improved with training. However exercise-induced asthma (EIA), measured by the airway's response to a standardized treadmill run, did not alter with training.

Effects of iron modulation on growth and viability of Rhodococcus equi and expression of virulence-associated protein A.

OBJECTIVE: To determine the importance of iron for in vitro growth of Rhodococcus equi, define potential iron sources in the environment and mechanisms by which R equi may obtain iron from the environment, and assess expression and immunogenicity of iron-regulated proteins. SAMPLE POPULATION: 10 virulent and 11 avirulent strains of R equi. PROCEDURE: In vitro growth rates and protein patterns of R equi propagated in media with normal, excess, or limited amounts of available iron were compared. Immunoblot analyses that used serum from foals naturally infected with R equi and monoclonal antibody against virulence-associated protein (Vap)A were conducted to determine immunogenicity and identity of expressed proteins. RESULTS: Excess iron did not alter growth of any R equi strains, whereas growth of all strains was significantly decreased in response to limited amounts of available iron. Virulent R equi were able to use iron from ferrated deferoxamine, bovine transferrin, and bovine lactoferrin. Only virulent R equi expressed an iron-regulated, immunogenic, surface-associated protein identified as VapA. CONCLUSIONS AND CLINICAL RELEVANCE: Iron is required for the growth and survival of R equi. Sources of iron for R equi, and mechanisms by which R equi acquire iron in vivo, may represent important virulence factors and novel targets for the development of therapeutic and immunoprophylactic strategies to control R equi infection in foals. Expression of VapA is substantially upregulated when there is a limited amount of available iron.

Screening for hypothalamic-pituitary-adrenal axis suppression in asthmatic children remains problematic: a cross-sectional study.

OBJECTIVE: To determine which parameter is the most useful screening test for hypothalamic-pituitary-adrenal suppression in asthmatic children. DESIGN: Cross-sectional study. SETTING: Paediatric allergy clinics in Cape Town, South Africa. PARTICIPANTS: 143 asthmatic children of mostly mixed ancestry, aged 5-12 years. OUTCOME MEASURES: Primary outcome measures included Spearman correlation coefficients (r) calculated between the postmetyrapone (PMTP) serum adrenocorticotropic hormone (ACTH), 11-deoxycortisol (11DOC), 11DOC+ cortisol (C) and height, weight, height velocity, weight velocity, change in systolic blood pressure from supine to standing, early morning urinary free cortisol (UFC), morning C, ACTH and dehydroepiandrosterone sulfate (DHEAS). Secondary outcome measures were the receiver operating characteristics (ROC) curve and the diagnostic statistics for the most promising test. RESULTS: All screening variables were weakly correlated with the three PMTP outcomes. Only DHEAS and UFC (nmol/m(2)) were statistically significant-DHEAS for PMTP ACTH and 11DOC (r=0.20, p=0.025 and r=0.21, p=0.017); UFC (nmol/m(2)) for PMTP 11DOC and 11DOC+C (r=0.19, p=0.033 and r=0.20, p=0.022). The area under ROC curve for DHEAS in the 5-year to 9-year age group was 0.69 (95% CI 0.47 to 0.92). At DHEAS cut-off of 0.2 µmol/L: sensitivity=0.88 (CI 0.47 to 1.00), specificity=0.61 (CI 0.42 to 0.78), positive predictive value=0.37 (CI 0.16 to 0.62), negative predictive value=0.95 (CI 0.75 to 1.00), accuracy=0.67 (CI 0.50 to 0.81), positive likelihood ratio=2.26 (CI 1.35 to 3.78), negative likelihood ratio=0.20 (CI 0.03 to 1.30). CONCLUSIONS: No parameter is useful as a universal screening test. DHEAS may be suitable to exclude HPAS before adrenarche. Further research is needed to confirm these findings and identify factors, for example, genetic that may predict or protect against HPAS.

Complications of TNF-α antagonists and iron homeostasis.

TNF-α is a central regulator of inflammation and its blockade downregulates other pro-inflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficial effect, the use of TNF-α antagonists is associated with an increased risk for infections and neoplasms; the basis for these complications is unclear. This cytokine also participates in iron homeostasis and the sequestration of this metal, mediated by TNF-α, is considered protective. We hypothesize that treatment with TNF-α antagonists predisposes the patient to infections and neoplasms by reversing the sequestration of host iron mediated by the cytokine and increasing available concentrations of this metal. It is recommended that patients who are to receive TNF-α antagonists be tested for iron overload and the use of these agents in those individuals with excess iron should be reconsidered. Furthermore, it is predicted that alternative attempts to treat inflammatory diseases by blocking other pivotal cytokines that also participate in iron homeostasis (e.g. IFN-γ, IL-1, and IL-6) will similarly be associated with infections and neoplastic complications.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children.

BACKGROUND AND OBJECTIVE: Hypothalamic-pituitary-adrenal axis suppression (HPAS) when treating children with corticosteroids is thought to be rare. Our objective was to determine the prevalence of and predictive factors for various degrees of HPAS. METHODS: Clinical features of HPAS, doses, adherence, asthma score, and lung functions were recorded in 143 asthmatic children. The overnight metyrapone test was performed if morning cortisol was >83 nmol/L. Spearman correlations coefficients (r) were calculated between 3 postmetyrapone outcomes and each continuous variable. A multiple linear regression model of √postmetyrapone adrenocorticotropic hormone (ACTH) and a logistic regression model for HPAS were developed. RESULTS: Hypocortisolemia was seen in 6.1% (1.8-10.5), hypothalamic-pituitary suppression (HPS) in 22.2% (14.5-29.9), adrenal suppression in 32.3% (23.7-40.9), HPAS in 16.3% (9.3-23.3), and any hypothalamic-pituitary-adrenal axis dysfunction in 65.1% (56.5-72.9). Log daily nasal steroid (NS) dose/m(2) was associated with HPAS in the logistic regression model (odds ratio = 3.7 [95% confidence interval: 1.1-13.6]). Daily inhaled corticosteroids (ICSs) + NS dose/m(2) predicted HPAS in the univariate logistic regression model (P = .038). Forced expiratory volume in 1 second/forced vital capacity <80% was associated with HPAS (odds ratio = 4.1 [95% confidence interval: 1.0-14.8]). Daily ICS + NS/m(2) dose was correlated with the postmetyrapone ACTH (r = -0.29, P < .001). BMI (P = .048) and percent adherence to ICS (P < .001) and NS (P = .002) were predictive of √postmetyrapone ACTH (R(2) = .176). CONCLUSIONS: Two-thirds of children on corticosteroids may have hypothalamic-pituitary-adrenal axis dysfunction. In one-third, central function had recovered but adrenal suppression persisted. Predictive factors for HPAS are NS use, BMI, and adherence to ICS and NS.

The hazards of iron loading.

Excessive or misplaced tissue iron now is recognized to pose a substantial health risk for an extensive array of endocrinological, gastrointestinal, infectious, neoplasmic, neurodegenerative, obstetric, ophthalmic, orthopedic, pulmonary and vascular diseases. Ingested, injected, inhaled and decompartmentalized iron contributes not only to disease, but also to aging and mortality. Iron is dangerous by catalyzing free radical formation and by serving as an essential nutrient for microbial and neoplasmic cell invaders. Our body cells exhibit wide variation in sensitivity to iron toxicity. Efficacy of our iron withholding defense system is modulated by numerous environmental, behavioral and genetic factors. A notable variety of methods for prevention and therapy of iron toxicity are now becoming available.

Iron toxicity: new conditions continue to emerge.

During the past half century, excessive/misplaced iron has been observed to be a risk factor for an increasing number and diversity of disease conditions. An extensive list of conditions and of the types of iron association were published in early 2008. Within the subsequent year, four additional disorders have been recognized to be enhanced by iron: aging muscle atrophy, viral replication, rosacea and pulmonary alveolar proteinosis. This paper adds new data and emphasis on these disorders as entities associated with increased iron load and toxicity.

Survival advantage of the hemochromatosis C282Y mutation.

The hemochromatosis C282Y mutation is present in up to 12.5% of people in populations of northern and central European origin. The prevalence of this mutation suggests that it may confer some type of epidemiologic advantage. One hypothesis has proposed that female heterozygotes have enhanced dietary iron absorption during their reproductive years, but evidence in support of this concept is not available. A second hypothesis is based on the observation that macrophages in iron-loaded C282Y homozygotes are very low in iron. These persons would be predicted to have increased resistance to pathogens that require iron for growth in macrophages. Notable examples of such pathogens are S. typhi and M. tuberculosis, the bacteria that cause typhoid fever and tuberculosis. Several cellular models that provide evidence for the low-iron macrophage hypothesis have recently been described.