Lifestyle Strategies to Boost Total Body Iron

Abstract

Patients who switch to a whole food plant-based eating pattern (WFPBD) generally have an uneventful transition, but may present with dizziness and lightheadedness. Research demonstrates that anemia is no more common when transitioning to a WFPBD than in the normal population, but Iron deficiency is possible in the context of a transition to a whole food plant-based diet resulting in either microcytic or normocytic anemia. All six pillars of lifestyle medicine; diet, activity, sleep, stress, social engagement, and risky substances, can affect absorption of Iron and are discussed. This paper discusses how the use of lifestyle modifications can potentiate iron supplementation, or replace the need for it altogether, to reverse anemia.

“All six pillars of lifestyle medicine can be used to treat patients and improve their iron stores.”

Introduction

The most commonly deficient nutrient in the world is iron. ¹ While transitioning patients to a health-promoting whole food plant-based eating pattern or diet (WFPBD), clinicians may expect to encounter patients who develop anemia for many reasons. While the transition to a WFPBD may be challenging psychologically, some may also have medical difficulties with the switch. A switch to a WFPBD has primarily positive side effects, namely, improved glycemic control, lower inflammatory activity, and altered neurotransmitter metabolism. ² There are some side effects to be aware of that are associated with potential nutritional shortfalls. ³ This paper is inspired by a patient successful in switching to a WFPBD and began feeling light-headed with the complete removal of meat from his diet. Eleven strategies to potentially resolve symptomatic normocytic iron deficiency anemia are discussed in this paper; discussing timing, promoters and inhibitors of iron absorption, diet, exercise, gut microbiota, stress and inflammation, supplementation, stress, sleep, alcohol, and social connection and their effects on iron homeostasis.

Discussion

First, let us briefly review iron metabolism in the body, which is finely regulated. ⁴ Humans can absorb both heme and non-heme iron, but by two entirely different pathways using the divalent metal transporter-1 (DMT-1) and heme carrier protein (HCP1). Once inside the cell, iron can be stored as ferritin, which is then exported as ferroportin (FPN1) to be transported in the blood to distant sites. One homeostatic component that keeps blood iron levels low is hepcidin. Hepcidin blocks exportation from the cell and then ferroportin is digested and degraded, keeping the extracellular iron concentration low. When hepcidin is absent, the ferroportin is maintained on the surface of the cell membrane and iron transportation ensues.

Transferrin, soluble transferrin receptor and hepcidin have all been found to be important factors in iron transport. In general, most proteins play a large role in iron trafficking and metabolism; ferritin and transferrin are the predominant iron transport shuttles in the blood. One way that we can prevent iron from being absorbed into the blood is by chelation; specifically with phytates. Phytates will inhibit the absorption of iron from the gastrointestinal tract lumen and they especially chelate calcium, iron, and zinc. ⁵

When patients transition to a WFPBD, they can occasionally experience iron deficiency. The prevalence of iron depletion in vegetarians ranges from 9–29%. ⁶ Ferritin stores are observed to be higher in populations that are non-vegetarian, especially for premenopausal women. This may be due to the relatively lower bioavailability of iron from plant sources, approximately 5%. ⁷ The predominant theory explaining why non-heme iron is less available than heme iron is that most plants have naturally occurring absorption inhibitors like phytates, oxalates, and polyphenols. These components are found in relatively high amounts in whole grains, legumes, and nuts. Due to the aforementioned reasons, the Institute of Medicine has stated that iron requirements for vegetarians are 1.8 times higher than those for non-vegetarians. ⁷ So, even with adequate intake for the population as a whole, our vegetarian patients may still need more total iron. Large amounts of iron can be obtained with a diverse WFPBD, but some patients may not respond to this intervention.

When patients transition to a WFPBD, one would assume that any resulting anemia is typically a vitamin B12 deficiency with a macrocytic anemia and steps should be taken to ensure adequacy of and the possible supplementation with vitamin B12 and evaluate the adequacy of therapeutic or dietary supplementation with a vitamin B12 assay. Folic acid deficiency would also likely lead to macrocytic anemia, and these patients generally get plenty of folate with their new diet, so this is also seen as unlikely. Iron deficiency anemia is typically a microcytic anemia, but can occasionally present as a normocytic anemia. ⁸ These patients with normocytic anemia still have iron deficiency, but their bone marrow is able to keep up filling each erythrocyte with an adequate amount of hemoglobin (normocytic), rather than filling erythrocytes with too little iron. Most patients with a new onset anemia should have a fecal occult blood screen to screen for gastrointestinal cancers or bleeds. It is suggested that a therapeutic trial of iron replacement should be considered in patients with mild normocytic anemia prior to an extensive workup.

One should expect both antihyperglycemic ⁹ and antihyperlipidemic ¹⁰ effects when patients move toward a WFPBD or nutritarian eating pattern. It is not unusual for patients to no longer rely on anti-diabetic and antihyperlipidemic medications after a transition to a WFPBD to prevent diabetes or hyperlipidemia.

Because iron is absorbed in the duodenum, a prior colectomy likely would not play a large role in the development of anemia. ¹¹ If the patient does not have any obvious sources of blood loss, and the symptoms resolve with the intake of iron-rich foods (i.e., chicken, beef, etc.), that may be enough evidence to decide to move forward with lifestyle strategies to increase the bioavailable iron. It is also possible that because normal ranges are set at ±2 SD, these patients may be in the 2.5% of patients with iron levels less than the reference range for our population. ¹²

Lifestyle Strategies to Increase Total Body Iron

Lifestyle medicine is built around six pillars; a whole food plant-based eating pattern, regular physical activity, restful sleep, stress management, positive social interactions, and the avoidance of risky substance use; all of these pillars are all present in the list below:

• 1. Timing of iron-rich dietary intake. Hepcidin and IL-6 peak 3–6 hours after exercise, making this window suboptimal for iron absorption. In runners, it was found that those who consumed iron 30 minutes following a 90-minute morning run absorbed 40% more iron than those who ran in the afternoon. ¹³ There appears to be a morning window in the immediate post-exercise period which promotes the absorption of iron and counteracts the rise in IL-6 and Hepcidin. This morning window may also be the optimal window for the more sedentary population to increase iron absorption.

• 2. Iron absorption is improved when acidic foods are present, but for unknown reasons the acidic pH of an empty stomach does not seem to be equally effective for improving iron absorption. ¹³ This demonstrates a multifactorial nature of iron absorption. ¹⁴

• 3. Avoidance of inhibitors: phytates or polyphenols. ¹⁵ It seems to be more important to avoid inhibitors of iron absorption rather than to add potentiators of iron absorption.^16,17 Spinach and legumes have much iron, but also high phytate concentrations and may be suboptimal if patients are limiting the quantity of food eaten. Phytate degradation has been shown to improve absorption from cereals and legumes. ¹⁸ Enzymatic phytic acid degradation is a recommended strategy for boosting iron absorption in situations where iron status is insufficient in the majority of the population. Activation of these endogenous phytase enzymes, already in plant foods may boost the bioavailability of zinc, calcium and iron. This is generally accomplished by using normal cooking methods; such as soaking, germination and fermentation. These methods, when conducted under optimal conditions, were all able to reduce the phytate content of cereals and vegetables. ¹⁷ Similar results may be achieved by adding phytase to the foods. This phytate inhibition may be overcome by the proper timing of food intake, as described above.

• 4. Eat WHOLE foods, not derivatives: Iron-fortified flours and derivatives contain much iron, but are processed and stripped of some of their nutrients. These iron-fortified products still do contain much of their phytic acid content. ¹⁸ Tofu, raisins, whole grains, spinach, and legumes do contain a lot of iron, but they also have a lot of phytates which bind iron and reduce absorption, so if patients are going to eat these foods, have them go for seconds! As described above, cooking methods may decrease phytate concentrations, but may be irrelevant because the adequate absorption in the presence of phytates may still occur with an increase in the quantity of iron-rich foods. A focus on a high-carbohydrate diet may increase iron absorption. Athletes on a high-carbohydrate diet had significantly lower IL-6 and hepcidin levels when compared to low-carbohydrate diets which may negatively impact iron metabolism and decrease iron absorption. ¹⁹ In another study, athletes on low-carbohydrate diets had elevated markers of inflammation with significantly increased IL-6, hepcidin, cortisol levels, and white blood cell counts when compared to low calorie diets.^20,21

• 5. Avoidance of extremely strenuous activity until anemia resolves. Exercise-related inflammation can interfere with absorption.^22,23 In a study of rowers completing a maximal 2,000m test on a rowing ergometer, all of the subjects were found to have significantly decreased iron levels in the recovery period when compared to the pre- and post-exercise periods. ²⁴ 39 subjects were exposed to two exercise tests: incremental running until exhaustion (test A), and 45 minute constant speed running at 70% VO2MAX (test B). This demonstrated that the strenuous activity in test A increased serum Transferrin receptor concentrations slightly, but that the more moderate activity in test B did not show a significant effect. They also found that while the concentration of serum Transferrin receptors did increase during test A, they also found that plasma volumes in subjects decreased and they came to the conclusion that the changes in serum Transferrin receptors are primarily attributed to exercise induced changes in volume. ²⁵ Samples taken after 2 hours of running when compared to 1 hour of running ²⁶ exercise have been linked to 2-times greater increases in hepcidin levels.

• 6. Develop a healthy gut microbiome. A healthy gut microbiome will increase absorption of non-heme iron. ²⁷ Further research is needed to understand the effect of human intestinal microbiota on the bioavailability of iron from plant foods. In vitro studies, however, have demonstrated that the bioavailability of iron in the colon is actually higher than it is in the small bowel.

• 7. Reduce stress and inflammation. ²⁸ This mechanism is through an increase in the acute phase protein hepcidin; transcription of which is increased during stress and inflammation. Hepcidin degrades ferroportin proteins. The ferroportin proteins allow for the recycling of iron as they help with the reabsorption of endogenous iron. Thereby, increased levels of hepcidin will decrease the concentrations of ferroportin proteins and reduce the iron available for heme synthesis, causing subsequent anemia. Increasing levels of Interleukin-6 (IL-6) are associated with increasing hepcidin levels. ²⁹ A sustained military operations protocol was used to study the effects of physical stressors including negative energy balance on iron absorption. It was observed that these sustained military operations did decrease iron absorption in all subjects, but the subjects with the greatest energy deficit had the lowest absorption of iron. ³⁰

• 8. Supplementation. Try to get your iron through dietary routes, however, if the anemia is persistent, supplement until the body is able to normalize. Avoid supplementation as a first-line defense, but rather as a last resort if other lifestyle methods have failed. When supplementing, do so with a meal, preferably in an acidic medium. Supplementation while eating iron-rich foods daily is a probable solution for iron deficiency. It was also found that alternate day dosing of iron supplements increased the absorption of iron. ³¹

• 9. Regular sleep has a very large effect on iron indices. ³² Night sleepers reach their peak iron and transferrin saturation values at 12.6 and 12.8 hours, respectively, whereas day sleepers shift their peaks to approximately 7 hours and switch which analyte reaches its peak first with iron at 19.7 and transferrin saturation at 19.3 hours. ³² Serum iron, transferrin, and transferrin saturation all rose throughout the day after sleep. Sleep disturbances for both day or night sleepers can cause up to a 50% reduction in serum iron concentrations. ³³ Regardless if patients are morning larks, night owls, or work the swing shift; both, a full night sleep or full day sleep will improve iron indices. While most iron indices showed diurnal variation, ferritin did not.

• 10. Alcohol does in fact increase the absorption of iron, ³⁴ likely because of the acidic content, which leads to unregulated iron absorption and intestinal permeability that contributes to the iron overload in chronic alcoholics. However, the detrimental effects of even moderate alcohol use likely outweigh the slight benefit to iron absorption, and is therefore not recommended as a primary treatment in patients with low total body iron stores.

• 11. Social connection is important for a happy life, and apparently also for iron indices. ³⁵ Lack of social support and depression is significantly associated with anemia in older adults in Iran. Interestingly, a lack of social connection in infants is also associated with poorer cognitive effects as well as anemia. ³⁶ It appears that iron deficiency has behavioral effects consistent with dopaminergic dysfunction. ³⁷ There is also a higher prevalence of iron deficiency in children with ADHD in Africa. ³⁸ It appears that iron deficiency and lack of social connection may be a two way street or a self-fulfilling prophecy: the less iron one has, the less inhibitory control and executive functioning skills one has, which will generally lead to less social connection. In adolescents in India, social cohesion was shown to be associated with mental functioning. ³⁹ A vicious and self-deteriorating cycle can begin; with both iron deficiency and social cohesion being tied to mental functioning.

Conclusion

All six pillars of lifestyle medicine can be used to treat patients and improve their iron stores. These pillars are the bedrock of treatment and allow the body’s natural predisposition to heal, to assist the iatrogenic process. After careful review of the literature, it appears that there is no increased risk of developing anemia after eating healthier whole plant foods than that in the normal population. Even though iron deficiency anemia is not common after transition to a WFPBD, indefinite iron supplementation may be necessary as an adjunct to lifestyle modifications. Caution should be exercised in this situation to rule out life-threatening causes of chronic blood loss, but if done properly, anemia may typically be managed over the course of a couple of months. Generally, anemia is not a common finding after switching to a WFPBD, but should be treated similarly to anemia in other contexts. Over time, the anemia due to inadequate non-heme iron absorption may correct, and while it may be necessary to supplement with iron, lifestyle modifications may still be effective when used as an initial treatment for anemia of a dietary cause. Over time, these patients may be able to adapt to lower levels of iron intake, gradually.

ORCID iD

Scott Moore https://orcid.org/0000-0002-1548-8462