Perspectives on Iron Deficiency as a Cause of Human Disease in Global Public Health.

Iron (Fe) is a necessary trace element in numerous pathways of human metabolism. Therefore, Fe deficiency is capable of causing multiple health problems. Apart from the well-known microcytic anemia, lack of Fe can cause severe psychomotor disorders in children, pregnant women, and adults in general. Iron deficiency is a global health issue, mainly caused by dietary deficiency but aggravated by inflammatory conditions. The challenges related to this deficiency need to be addressed on national and international levels. This review aims to summarize briefly the disease burden caused by Fe deficiency in the context of global public health and aspires to offer some hands-on guidelines.

Folic Acid-Fortified Iodized Salt and Serum Folate Levels in Reproductive-Aged Women of Rural India: A Nonrandomized Controlled Trial.

Importance: India has a disproportionately high prevalence of neural tube defects, including spina bifida and anencephaly (SBA), causing a high number of stillbirths, elective pregnancy terminations, and child mortality; India contributes a large proportion of the global burden of SBA. Thirty years after folic acid was shown to be effective in reducing SBA prevalence, only about one-quarter of such births are prevented globally through cereal grain fortification. Objective: To determine the association of folic acid-fortified iodized salt with serum folate concentrations among nonpregnant and nonlactating women of reproductive age. Design, Setting, and Participants: This nonrandomized controlled trial using a preintervention and postintervention design was conducted in 4 rural villages in Southern India from July 1 to November 30, 2022. All households in the villages agreed to participate in the study. Preintervention and postintervention serum folate levels were analyzed among study participants at baseline and after 4 months, respectively. Intervention: Consumption of approximately 300 µg/d of folic acid using double fortified salt (folic acid plus iodine). Median serum folate concentrations were assessed at baseline and 4 months. Main Outcomes and Measures: Change in median serum folate levels between baseline and study end point as the primary outcome of the study. Results: A total of 83 nonpregnant nonlactating women aged 20 to 44 years (mean [SD] age, 30.9 [5.1] years) were eligible for the study and provided serum samples for analysis at baseline and the end point of the intervention. The median serum folate concentration increased from 14.6 (IQR, 11.2-20.6) nmol/L at baseline to 54.4 (IQR, 43.5-54.4) nmol/L at end of study, a 3.7-fold increase from baseline to study end point. Two-tailed Wilcoxon signed rank test showed the median difference in preintervention and postintervention serum folate concentrations to be highly significant (P < .001). The participants found the salt acceptable in color and taste. Conclusions and Relevance: Use of folic acid-fortified iodized salt was associated with increased serum folate concentrations in women of reproductive age. This novel evidence can inform public health policy to accelerate SBA prevention. Trial Registration: ClinicalTrials.gov Identifier: NCT06174883.

Micronutrient deficiency and supplements in schoolchildren and teenagers.

PURPOSE OF REVIEW: The essential micronutrients are corner stones in the functional and physical development. Early deficiency has life-long consequences. While awareness about iron deficiency is relatively high, it remains lower for other micronutrients. This review aims at reporting on recent data and attracting attention to the high prevalence of micronutrient deficiencies in school-age and adolescent individuals. RECENT FINDINGS: Iron deficiency anaemia remains highly prevalent worldwide and the most frequent deficiency but can be corrected with simple tools ranging from food fortification, nutritional intervention, and to supplements. The link between micronutrient (MN) deficiency and neurobehavioral disorders is increasingly established and is worrying even in Western countries. Paediatric individuals are prone to imbalanced diets and picky eating behaviour, and their diets may then become incomplete: the highest risk for deficiency is observed for iron, zinc and vitamin D. SUMMARY: There is not much new information, but rather confirmation of the importance of health policies. Well conducted randomized controlled trials confirm that deficiencies can be corrected efficiently including with food fortification, and result in clinical benefits. Individual complementation should be considered in children and adolescents with proven deficiency.

Vitamin D3 Bioaccessibility from Supplements and Foods-Gastric pH Effect Using a Static In Vitro Gastrointestinal Model.

Vitamin D3 deficiency is a global phenomenon, which can be managed with supplementation and food fortification. However, vitamin D3 bioaccessibility may depend on factors such as matrix composition and interactions throughout the gastrointestinal (GI) tract. This research focused on the effect of different matrices on vitamin D3 content during digestion, as well as the effect of pH on its bioaccessibility. The INFOGEST protocol was employed to simulate digestion. Three different types of commercial supplements, two foods naturally rich in vitamin D3, and three fortified foods were investigated. High-Performance Liquid Chromatography was used to determine the initial vitamin D3 content in the supplements and foods, as well as after each digestion stage. The results indicate that the foods exhibited higher bioaccessibility indices compared to the supplements and a higher percentage retention at the end of the gastric phase. The pH study revealed a positive correlation between an increased gastric pH and the corresponding content of vitamin D3. Interestingly, exposing the matrix to a low pH during the gastric phase resulted in an increased intestinal content of D3. Vitamin D3 is more bioaccessible from foods than supplements, and its bioaccessibility is susceptible to changes in gastric pH. Fasting conditions (i.e., gastric pH = 1) enhance the vitamin's bioaccessibility.

Market assessment of fortified parboiled rice in Burkina Faso.

Micronutrient deficiency remains a daunting issue in many parts of the world. Effective interventions are needed to deal with the problem, which should consider production and consumption traditions and trends to improve their success. Parboil rice is a growing staple in Burkina Faso, where micronutrient deficiency remains high. This paper assesses the market feasibility of fortified rice through parboiling using a limited-water soaking method. Our findings suggest that consumers are willing to pay a premium for fortified rice versus conventional parboiled rice after they are informed about the importance of the problem and the potential benefits of fortified rice. A stylized cost analysis also reveals that the cost of producing fortified rice using a limited-water soaking method could exceed the premiums consumers are willing to pay, and therefore that public intervention may be needed to improve the odds of adoption by consumers. The findings have implication beyond Burkina Faso, and could guide market development in other regions where production and consumption of parboiled rice is well established.

Update on the impact of voluntary folic acid fortification of corn masa flour on red blood cell folate concentrations-National Health and Nutrition Examination Survey, 2011-March 2020.

BACKGROUND: Folic acid is a micronutrient that is effective at preventing neural tube defects (NTDs). In 2016, the FDA authorized the voluntary fortification of corn masa flour (CMF) with folic acid to reduce disparities in NTDs among infants of women who do not regularly consume other fortified cereal grains, in particular Hispanic women of reproductive age (WRA). METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020 assessing the impact of voluntary fortification of CMF on the folate status of Hispanic WRA. We analyzed folic acid usual intake and red blood cell (RBC) folate concentrations among non-pregnant, non-lactating Hispanic WRA, comparing pre-fortification (2011-2016) to post-fortification (2017-March 2020) data. RBC folate concentrations were used to create model-based estimation of NTD rates. RESULTS: The proportion of Hispanic WRA with folic acid usual intakes <400 µg/d did not change (2011-2016: 86.1% [95% Confidence Interval, CI: 83.7-88.5]; 2017-March 2020: 87.8% [95% CI: 84.8-90.7]; p = .38) nor did the proportion of Hispanic WRA with RBC folate below optimal concentrations (<748 nmol/L, 2011-2016: 16.0% [95% CI: 13.7-18.2]; 2017-March 2020: 18.1% [95% CI: 12.1-24.0]; p = 0.49). Model-based estimates of NTD rates suggest further improvements in the folate status of Hispanic WRA might prevent an additional 157 (95% Uncertainty Interval: 0, 288) NTDs/year. CONCLUSIONS: Voluntary fortification of CMF with folic acid has yet to have a significant impact on the folate status of WRA. Continued monitoring and further research into factors such as fortified product availability, community knowledge, and awareness of folic acid benefits would inform and improve future public health interventions.

Vitamin D fortification of foods - sensory, acceptability, cost, and public acceptance considerations.

In terms of vitamin D food fortification, there are a number of important considerations in relation to selection of the food vehicle and fortificant. While there has been much research focus on the ability of fortified foods to improve vitamin D status, other considerations, such as sensory properties and acceptability, cost, and public attitudes around vitamin D-fortified foods, have received less attention. Thus, the present narrative review aimed to summarize the existing knowledge around these important considerations. In summary, its findings suggest that: i) vitamin D addition to various food vehicles, at levels consistent with the supply of part or all the recommended intake, does not alter their sensory characteristics or overall acceptability; ii) overall, vitamin D fortification of foods is relatively cost-effective, despite the fact that some attitudinal studies highlighted participant concerns about the potential cost/expense of vitamin D-fortified foods; iii) evidence from various attitudinal studies suggest a high level of acceptance and/or purchase intention (i.e., extent to which customers are willing and inclined to buy) of vitamin D-fortified food products by the general public; and iv) there have been repeated calls for vitamin D public health educational/information campaigns to help educate consumers about the health risks associated with vitamin D deficiency and nutritional benefits associated with consumption of vitamin D-fortified foods. Such campaigns could positively mediate attitudes and acceptance of vitamin D-fortified foods amongst the public, and could also help address misconceptions and allay fears around vitamin D for concerned individuals. Lastly, the findings of the present review also highlight the existence of between-country differences, even within Europe, in relation to attitudes and purchase intention of vitamin D-fortified foods and the perceived appropriateness of certain food vehicles for vitamin D fortification, as well as the best mix of communication channels for a vitamin D public health educational/information campaign.

Maize gets an iron boost: Biofortification breakthrough holds promise to combat iron deficiency.

This commentary describes recent research discovering that the NAC transcription factor gene ZmNAC78 controls iron intake in maize and its implications for biofortification of this important crop. Using ZmNAC78, iron levels in maize can be more than doubled compared with current varieties.

Mandatory fortification of rice in the public distribution system in India: An ethics perspective.

In response to the continuing high prevalence of anaemia recorded in the National Family Health Survey-5, the Indian government launched a policy for mandatory iron fortification of the rice provided through public nutrition programmes in India. This was done even though a rigorous evidence analysis had already concluded that rice fortification was not effective in preventing anaemia or iron deficiency at the population level. Fortification also poses a potential risk of iron toxicity over time, but there is no stated time period for the policy's implementation. The risk is particularly high in segments of the population who already have a high habitual iron intake, and who could be exposed to simultaneous fortification in different staples and food commodities along with the ongoing weekly Iron and Folic Acid tablets supplementation programme. Finally, this fortification policy also requires significant additional funding and resources to implement. It is crucial to examine such mandatory health actions, and to weigh the benefits and risks of harm, using the principles of public health ethics.

Effect of vitamin D supplementation or fortification on bone turnover markers in women: a systematic review and meta-analysis.

Vitamin D is a vital indicator of musculoskeletal health, as it plays an important role through the regulation of bone and mineral metabolism. This meta-analysis was performed to investigate the effects of vitamin D supplementation/fortification on bone turnover markers in women. All human randomised clinical trials reported changes in bone resorption markers (serum C-terminal telopeptide of type-I collagen (sCTX) and urinary type I collagen cross-linked N-telopeptide (uNTX)) or bone formation factors (osteocalcin (OC), bone alkaline phosphatase (BALP) and procollagen type-1 intact N-terminal propeptide (P1NP)) following vitamin D administration in women (aged ≥ 18 years) were considered. Mean differences (MD) and their respective 95 % CI were calculated based on fixed or random effects models according to the heterogeneity status. Subgroup analyses, meta-regression models, sensitivity analysis, risk of bias, publication bias and the quality of the included studies were also evaluated. We found that vitamin D supplementation had considerable effect on sCTX (MD: -0·038, n 22) and OC (MD: -0·610, n 24) with high heterogeneity and uNTX (MD: -8·188, n 6) without heterogeneity. Our results showed that age, sample size, dose, duration, baseline vitamin D level, study region and quality of studies might be sources of heterogeneity in this meta-analysis. Subgroup analysis also revealed significant reductions in P1NP level in dose less than 600 µg/d and larger study sample size (>100 participants). Moreover, no significant change was found in BALP level. Vitamin D supplementation/fortification significantly reduced bone resorption markers in women. However, results were inconsistent for bone formation markers.

Firm-Level and Public-Sector Costs Make Small-Scale Maize Flour Fortification Challenging in Uganda.

BACKGROUND: Maize flour in Uganda is milled by hundreds of enterprises, mostly small- (5-20 metric tons [MT]/day) and micro-scale (<5 MT/day) mills or firms. A mandatory maize flour fortification program exists for medium-scale mills (>20 MT/day) and policymakers are considering including smaller-scale millers. OBJECTIVE: We estimated the private and public costs of maize flour fortification at different scales and explored their implications for extending the mandatory fortification to include smaller-scale mills. METHODS: We used secondary data on the structure of the maize flour market and primary data on milling and fortification costs to estimate mill and regulatory costs at 3 scales of flour production: micro, small, and medium. RESULTS: For micro-, small-, and medium-size operations, respectively, operational costs of fortification were US$13, US$9, and US$7 per metric ton (MT) of maize flour, which represented 20%, 16%, and 16% of annual operating costs, and the ratio of fortification equipment cost to mill equipment costs was higher for micro-scale mills (2.7) than for small- (0.38) and medium-scale (0.54) maize mills. Governmental regulatory costs rise if smaller-scale mills are included due to the increased number of facility inspections. CONCLUSIONS: Fortification and regulatory costs increase as production scale decreases. Up-front capital costs of fortification would be daunting for micro- and small-scale mills. Medium-scale mills, which supply social protection programs, might be able to manage fortification costs and other challenges. Decision-makers should consider all costs and cost burdens, and the realities of enforcement capabilities before expanding fortification programs to include smaller-scale operations.

Plain language titleCosts of Small-scale Maize Flour Fortification in UgandaPlain language summaryA study of the costs of adding vitamins and minerals by small-scale maize flour millers in Uganda was undertaken to understand if it would be commercially beneficial from a business and operations perspective for them to do so, and if requiring them to do so would impose additional cost burdens on government to ensure that fortification standards were met.Why was the study done?Maize flour is consumed by the majority of Uganda's population, especially the rural poor. If the flour were fortified, it would reduce vitamin and mineral deficiencies among those at risk. The most important constraint to market-wide fortification is the presence of many small-scale mills or firms that neither have the resources nor the technology to adopt and sustain the fortification process. To date, no study has been done to calculate the costs that small-scale mills would have to face to fortify flour, or what the cost implications for government would be for including smaller-scale mills in a national fortification program, including the costs of enforcing regulations.What did the researchers do?The researchers interviewed millers of several scales of operation to collect cost information on their operations and interviewed representatives of government regulatory bodies to estimate the costs of testing maize flour to ensure compliance with regulations. Researchers estimated the cost to the mills of adding fortification to their business models, and the impacts on the government costs (eg, testing additional samples, etc.) of including smaller-scale mills in the fortification program.What did the researchers find?The researchers looked at 3 different types of mills based on their capacity to mill maize flour­micro-scale firms milled less than 5 metric tons (MT) a day, small-scale firms milled 5 to 20 MT per day, and medium-scale firms milled over 20 MT a day. For micro-, small-, and medium-size firms, respectively, fortification increased operational costs by US$13, US$9, and US$7 per MT of maize flour, which represented 20%, 16%, and 16% of annual operating costs. Similarly, governmental regulatory costs rose if smaller-scale mills were included because of the increased number of facility inspections required since the current legislation requires mandatory annual inspections.What do the findings mean?Fortification and regulatory costs increase as the scale of production by the millers decreases. If fortification by small- and micro-scale mills were made mandatory, up-front costs of fortification equipment and materials would be daunting for micro- and small-scale millers. Ugandan medium-scale millers might manage fortification costs and other challenges, but only if the social protection programs they supplied were of sufficient volume and regularity.

Preventing and Controlling Zinc Deficiency Across the Life Course: A Call to Action.

Through diverse roles, zinc determines a greater number of critical life functions than any other single micronutrient. Beyond the well-recognized importance of zinc for child growth and resistance to infections, zinc has numerous specific roles covering the regulation of glucose metabolism, and growing evidence links zinc deficiency with increased risk of diabetes and cardiometabolic disorders. Zinc nutriture is, thus, vitally important to health across the life course. Zinc deficiency is also one of the most common forms of micronutrient malnutrition globally. A clearer estimate of the burden of health disparity attributable to zinc deficiency in adulthood and later life emerges when accounting for its contribution to global elevated fasting blood glucose and related noncommunicable diseases (NCDs). Yet progress attenuating its prevalence has been limited due, in part, to the lack of sensitive and specific methods to assess human zinc status. This narrative review covers recent developments in our understanding of zinc's role in health, the impact of the changing climate and global context on zinc intake, novel functional biomarkers showing promise for monitoring population-level interventions, and solutions for improving population zinc intake. It aims to spur on implementation of evidence-based interventions for preventing and controlling zinc deficiency across the life course. Increasing zinc intake and combating global zinc deficiency requires context-specific strategies and a combination of complementary, evidence-based interventions, including supplementation, food fortification, and food and agricultural solutions such as biofortification, alongside efforts to improve zinc bioavailability. Enhancing dietary zinc content and bioavailability through zinc biofortification is an inclusive nutrition solution that can benefit the most vulnerable individuals and populations affected by inadequate diets to the greatest extent.

The impact of replacing milk with plant-based alternatives on iodine intake: a dietary modelling study.

PURPOSE: Cow's milk is the primary source of iodine in the UK, but consumption of plant-based milk alternatives (PBMA) is increasing and these products are often not fortified with iodine. We evaluated the impact that replacing current milk consumption with PBMA would have on iodine intake. METHODS: We used data from the National Diet and Nutrition Survey (2016-2019) for children (1.5-10 years), girls 11-18 years, and women of reproductive age (WRA). We used a dietary modelling approach with scenarios using brand-level iodine-fortification data (0, 13, 22.5, 27.4 and 45 µg/100 mL). Relative to usual diet, we calculated change in iodine intake, and the proportion with intake below the Lower Reference Nutrient Intake (LRNI) or above the upper limit. RESULTS: For all groups, replacement with PBMA, either unfortified or fortified at the lowest concentration, resulted in a meaningful decrease in iodine intake, and increased the proportion with intake < LRNI; compared to usual diet, iodine intake reduced by 58% in children 1.5-3 years (127 vs. 53 µg/day) and the proportion with intake < LRNI increased in girls (11-18 years; 20% to 48%) and WRA (13% to 33%) if an unfortified PBMA was used. Replacement of milk with PBMA fortified at 27.4 µg/100 mL had the lowest impact. CONCLUSION: Replacing milk with commercially available PBMAs has potential to reduce population iodine intake, depending on the fortification level. PBMAs fortified with ≥ 22.5 and < 45 µg iodine/100 mL would be required to minimize the impact on iodine intake. Research is needed on the impact of total dairy replacement.

Iron deficiency anemia: a critical review on iron absorption, supplementation and its influence on gut microbiota.

Iron deficiency anemia (IDA) caused by micronutrient iron deficiency has attracted global attention due to its adverse health effects. The regulation of iron uptake and metabolism is finely controlled by various transporters and hormones in the body. Dietary iron intake and regulation are essential in maintaining human health and iron requirements. The review aims to investigate literature concerning dietary iron intake and systemic regulation. Besides, recent IDA treatment and dietary iron supplementation are discussed. Considering the importance of the gut microbiome, the interaction between bacteria and micronutrient iron in the gut is also a focus of this review. The iron absorption efficiency varies considerably according to iron type and dietary factors. Iron fortification remains the cost-effective strategy, although challenges exist in developing suitable iron fortificants and food vehicles regarding bioavailability and acceptability. Iron deficiency may alter the microbiome structure and promote the growth of pathogenic bacteria in the gut, affecting immune balance and human health.

Revisiting the significance of nano-vitamin D for food fortification and therapeutic application.

OBJECTIVE: Vitamin D (a prohormone) is an important micronutrient required by the body for skeletal homeostasis and a range of non-skeletal actions. Calcitriol, the active form of vitamin D, regulates a variety of cellular and metabolic processes through both genomic and nongenomic pathways. Often prescribed for treating rickets and osteoporosis, vitamin D deficiency can exacerbate various other medical conditions. SIGNIFICANCE, METHODS, AND RESULTS: Despite its multifunctional uses, the sensitivity of vitamin D makes formulating an efficient drug delivery system a challenging task, which is further complicated by its poor aqueous solubility. Enhancing the oral absorption of vitamin D is vital in utilizing its full efficacy. Recent developments in encapsulation and nanotechnology have shown promising results in overcoming these constraints. CONCLUSION: This review thus offers an insight to adequately comprehend the mechanistic pharmacology of vitamin D, its pathophysiological role, and justification of its medical indications, along with the benefits of utilizing nanotechnology for vitamin D delivery.

Relationship of dietary intake of food folate and synthetic folic acid intake from fortified foods with all-cause mortality in individuals with chronic kidney disease.

OBJECTIVE: To evaluate the association of the dietary intake of food folate (natural folate) and synthetic folic acid intake from fortified foods with the risk of all-cause mortality and end-stage kidney disease (ESKD) among the chronic kidney disease (CKD) population in regions with folic acid fortification. METHODS: 4028 individuals with established CKD in Chronic Renal Insufficiency Cohort (CRIC) were included. Diet was assessed using a validated diet history questionnaire at the baseline, year 2, and year 4, and nutrient intake, including food folate and folic acid from fortified foods, was estimated using the National Nutrient Database. The outcomes were all-cause mortality and ESKD. The results for all-cause mortality were further validated using the data from National Health and Nutrition Examination Surveys (NHANES). RESULTS: During a median follow-up of 11.1 years, 1155 deaths and 938 ESKD cases occurred. Compared with the first quartile of food folate intake, the third (HR: 0.74; 95% CI: 0.62, 0.90) and fourth (HR: 0.79; 95% CI: 0.63, 0.98) quartiles had a lower risk of all-cause mortality. Nevertheless, there was no significant association of synthetic folic acid intake from fortified foods with all-cause mortality. Similar results were observed for ESKD. Consistently, in NHANES, food folate intake and serum 5-methyltetrahydrofolate, but not folic acid intake, were inversely associated with all-cause mortality, while serum unmetabolized folic acid was positively associated with all-cause mortality in CKD participants. CONCLUSIONS: Higher intake of dietary natural folate, but not synthetic folic acid intake from fortified foods, was associated with lower risks of all-cause mortality and ESKD among CKD participants.

Biofortification's contribution to mitigating micronutrient deficiencies.

Biofortification was first proposed in the early 1990s as a low-cost, sustainable strategy to enhance the mineral and vitamin contents of staple food crops to address micronutrient malnutrition. Since then, the concept and remit of biofortification has burgeoned beyond staples and solutions for low- and middle-income economies. Here we discuss what biofortification has achieved in its original manifestation and the main factors limiting the ability of biofortified crops to improve micronutrient status. We highlight the case for biofortified crops with key micronutrients, such as provitamin D3/vitamin D3, vitamin B12 and iron, for recognition of new demographics of need. Finally, we examine where and how biofortification can be integrated into the global food system to help overcome hidden hunger, improve nutrition and achieve sustainable agriculture.

Osmolality of fortified donor human milk: An experimental study.

BACKGROUND: We quantify the osmolality of human milk fortified with human milk fortifiers (HMFs), powder infant formulas and protein additives. METHODS: Commercial liquid HMFs and powder infant formulas were added to pasteurized pooled donor human milk in triplicate and stirred. The osmolality of unfortified and fortified human milk at 22, 24, 26, 27, 28, and 30 kcal/oz (0.73, 0.8, 0.87, 0.9, 0.93, and 1 kcal/ml, respectively) was determined using freezing-point depression. RESULTS: The osmolality of fortified human milk associated with energy density in a linear relationship regardless of the fortification strategies. Multiple liquid HMFs and every powder infant formula exceeded the osmolality threshold of 450 mOsm/kg H2 O within the energy densities tested. CONCLUSION: The osmolality of fortified human milk is highly variable and should be considered when selecting a fortifying agent for human milk.