Tiekou Lorinczova H, Begum G, Temouri L, Renshaw D, Zariwala MG. Co-administration of iron and bioavailable curcumin reduces levels of systemic markers of inflammation and oxidative stress in a placebo-controlled randomised study. Nutrients. 2022;14(3):712.
To determine if coadministration of iron (ferrous sulfate) with a bioavailable form of curcumin reduces systemic inflammation and/or gastrointestinal (GI) side-effects
High-dose iron may lead to darker stools, and curcumin may offset this known effect.
Double-blind, placebo-controlled, randomized trial
Investigators recruited participants who were generally healthy with ferritin levels within normal limits (>15 ng/mL). They recruited 155 healthy participants (79 males, 26.42 years ± 0.55; and 76 females, 25.82 years ± 0.54).
Ethnicity data for participants include the following: Caucasian 64.3%, Asian 22.1%, African 3.2%, Central or South American 2.6%, and other 7.8%.
Investigators excluded those with low hemoglobin, known medical conditions, taking supplements or medications, consuming excessive alcohol, or with chronic GI symptoms, eating disorders, psychological conditions, or any hypo/hypertensive blood pressure measurements. One participant was excluded from data analysis due to a high body mass index (>40 kg/m2).
The trial consisted of 5 arms:
- Iron placebo and curcumin placebo
- Low-dose (18-mg) iron and curcumin placebo
- Low-dose iron and curcumin
- High-dose (65-mg) iron and curcumin placebo
- High-dose iron and curcumin
Investigators used ferrous sulfate as the form of iron, and they gave the curcumin (HydroCurc) at dosages of 500 mg/ day. Instructions included taking the intervention at least 1 hour before or 2 hours after food consumption. The study duration was 6 weeks.
Study Parameters Assessed
Biochemical assessment included hemoglobin, serum ferritin, C-reactive protein (CRP), serum iron (Fe), total iron binding capacity (TIBC), transferrin saturation (TS), and unsaturated iron-binding capacity (UIBC), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 1 beta (IL-1b), tumor necrosis factor (TNF), and thiobarbituric acid reactive substances (TBARS).
Subjective assessment included the Fatigue Severity Scale (FSS), Fatigue Visual Analog Scale (F-VAS), and Questionnaire to Assess GI Symptoms after Oral Ferrous Iron Supplementation, as well as a question related to darkened or black stool.
Assessments were completed at baseline, mid-point, and endpoint, and participants completed the GI questionnaire daily online.
The primary outcome measures were markers of system inflammation: IL-1, IL-6, TNF, and TBARS. All other measures, both subjective and objective, were secondary.
There was a significant reduction in mean plasma TNF levels (0.65 pg/mL ± 0.17, P=0.0018) when comparing mid-point levels to end-point mean levels in the high-dose iron-and-curcumin arm. Also, a significant reduction of mean plasma TNF (0.35 pg/mL ± 0.13, P=0.0288) occurred in the low-dose iron-and-curcumin arm, as well as in the high-dose iron-and-placebo arm (0.39 pg/mL ± 0.15, P=0.0363).
There was a significant association of darker stools when comparing the dual placebo group to the group taking 65 mg of iron and a curcumin placebo (P=0.002, Fisher’s exact test).
Lastly, there was a significant reduction in IL-6 when comparing the mid-point to the endpoint in the group taking high-dose iron plus curcumin (0.06 pg/mL ± 0.02, P=0.0073).
The funder, Gencor Pacific Ltd., who makes HydroCurc, was involved in the study-design process but not in data collection or analysis. The authors declare no other conflict of interest.
Practice Implications & Limitations
Studying healthy subjects does have a role in determining the safety of interventions as well as detecting subtle changes. However, it can make seeing changes more difficult. One technique the investigators employed involved performing subgroup analysis of participants with low-normal ferritin levels either less than 30 ng/mL or less than 50 ng/mL. The rationale for these cut-offs is to achieve greater sensitivity than the World Health Organization’s recommendation of 15 ng/mL.3-4 Reduced bone marrow stores or latent iron deficiency may be seen in levels less than 50 ng/mL.5 This may be referred to as iron deficiency without anemia or, more colloquially, as suboptimal levels.
From a practice-application perspective, this study has significant limitations due to its recruiting young, healthy, and non-obese participants with normal iron status. In clinical practice, higher-dose iron supplementation in the absence of objective need is uncommon. Essentially, the investigators were seeking to identify effects on inflammation in those who show no frank signs or symptoms of inflammation.
One of the more common objective markers of inflammation in clinical practice is C-reactive protein, an acute-phase protein manufactured by the liver. CRP increases in relation to IL-6 and is often elevated due to systemic inflammation or infection.6 However, in this study, no statistically significant change was seen in CRP between any arms of the study. Perhaps it is not a sensitive enough marker when the inflammatory cascade is already normal in a healthy population.
However, changes in plasma IL-6 were seen in the high-dose iron-and-curcumin arm (P=0.0073) in the subgroup analysis of those with ferritin levels greater than 30 ng/mL. Similar effects were seen with circulating TNF. IL-1b and IL-10 were not affected by the intervention. While helpful in research, these cytokines and indicators of inflammation are not often assessed in clinical practice.
Serum iron levels, which are routinely measured in practice, were unchanged during this intervention; this is not surprising given the population studied. However, ferritin levels were affected in both curcumin-placebo and curcumin-active arms but in inconsistent ways. In the high-dose iron-and-curcumin-placebo arm, ferritin increased more significantly than in the high-dose iron-and-curcumin arm. This may lead readers to suspect that bioavailable curcumin may inhibit iron absorption or storage; however, in the low-dose iron arms and low-normal (>30 ng/mL) ferritin analysis, the active-curcumin arm had stronger responses than the placebo. Furthermore, a previous study on this same material saw no inhibitory effects.7
From a practice-application perspective, this study has significant limitations due to its recruiting young, healthy, and non-obese participants with normal iron status."
Subjective ratings of fatigue were not significantly different throughout the study between any arms. Perhaps the most compelling, clinically useful consideration of this study was the change in darkened stools. For patients requiring a higher dose or longer duration of treatment or who report darkened stools with lower-dose iron, bioavailable curcumin seems to be a promising adjunctive recommendation.
Since iron supplementation can induce pro-inflammatory side effects, the use of a well-regarded anti-inflammatory intervention is reasonable. The curcumin used in this study was HydroCurc, which is described as a bioavailable curcumin product with 85% curcuminoids. The delivery system is patented and may include processes or materials objectionable to some patients and/or practitioners. Several attempts at improving the pharmacokinetic profile of curcumin and its parent material turmeric have been commercialized. Some questions that remain following this study involve whether other curcumin products have the same or similar effect, if the dose used in this study is the most appropriate, and if the duration of the study is long enough to see clinically relevant effects.
The author is employed by a company that sells turmeric products but not the product that is the subject of this study and otherwise declares no conflict of interest.