Iron inhibition by plant polyphenols: an adjunct to treatment in hereditary haemochromatosis.
Hereditary haemochromatosis is a genetic multi-organ disorder associated with a polymorphism in the haemochromatosis gene (HFE) (Pietrangelo 2010). Individuals with HH lack the capability to limit iron absorption into the bloodstream and thus the disorder is characterised by excessive iron accumulation in the tissues, resulting in the development of diabetes, arthropathy, cardiomyopathy, cirrhosis and hepatocellular carcinoma (Pietrangelo 2010). Disease progression is insidious and affected individuals are often asymptomatic before diagnosis is confirmed with elevated serum ferritin and gene testing for HFE (Frenkel 2011).
Primary management of HH relies on weekly blood removal (venesection) until transferrin saturation falls below 50%, following which treatment is indicated less frequently (Crawford 2005). Secondary approaches are aimed at reducing iron absorption from the gastrointestinal tract (GIT), primarily through the avoidance of vitamin C which has been shown to enhance the uptake of dietary iron by up to 350% (Thankachan 2008) and the use of proton pump inhibitors (PPIs). PPIs are effective in reducing iron absorption from the duodenum (McColl 2009) and have to some extent superseded the emphasis on dietary approaches to managing HH. This is reflected in current recommendations for patients with HH which suggest dietary modification is not necessary for managing the condition (Barton 1998). In addition to vitamin C there are several food constituents known to enhance iron absorption, including alcohol (Olynyk 2005), fructose (O'Dell 1993) and muscle tissue, or meat (Hurrell 2010). Factors limiting iron absorption include calcium, magnesium, manganese and zinc (Osiecki 2010), polyphenol containing beverages including tea, coffee and wine (Hurrell 2010) and soluble fibres such as pectin (Monnier 1980).
Perhaps the most well studied food constituent compounds with regard to their effect on iron absorption are the polyphenols, notably those of tea (Camellia sinensis). Polyphenolic constituent compounds such as chlorogenic acid, gallic acid, monomelic flavonoids and tannins are known to form insoluble compounds with iron and render it unavailable for absorption (Thankachan 2008). Epidemiological studies suggest a linear relationship between tea consumption and iron deficiency among populations with marginal iron intake (Temme 2002, Mennen 2007, Hogenkamp 2008). A number of clinical studies have also been performed with regard to polyphenol containing beverages and their effect on iron absorption (Samman 2008, Thankachan 2008, Hurrell 1999, Kaltwasser 1998, Cook 1995) however the clinical significance of research to managing iron overload syndromes has scarcely been addressed to date (Kaltwasser 1998). The following article aims to review current literature regarding polyphenol consumption and iron absorption and its relevance as an intervention in the management of HH.
The author searched online databases Google Scholar, PubMed, MedLINE, EBSCO and ProQuest from 1992 onwards to retrieve suitable articles for review. Search terms included hemochromatosis, haemochromatosis, hereditary hemochromatosis, diet, iron, absorption, ironoverload, tea, polyphenol, tannin, gallic acid, gallate, ferritin, wine and coffee in various combinations. Using evidence based practice guidelines for best clinical relevance (Straus 2005) articles chosen for inclusion were limited to full text, peer reviewed articles in the format of controlled trials. Animal trials, in vitro studies and case analyses were not chosen for inclusion. Following a search a total of 7 articles were identified that met criteria for inclusion. After closer investigation, two cross sectional studies were excluded and retained for wider reading, and the remaining five articles were entered for review.
Thankachan et al (2008) used a randomised controlled design to observe the effects of both tea and ascorbic acid (AA) on iron absorption in a group of iron deficient women. Subjects were randomised to receive a test meal labelled with radioactive iron in combination with 1 cup of black tea (78 mg polyphenols) or AA in water solution (at a 2:1 molar ratio). Each subject then consumed a second test meal with 300 mL water (control) and subjects were then crossed over to receive the opposing intervention with a third test meal. Red cell radioactivity was measured prior to each meal and again 14 days following consumption; and was used to estimate whole body iron accumulation from each test meal. Blood hemoglobin (Hb), serum ferritin and serum transferrin were also measured in all subjects before and following each intervention.
Results indicated that the addition of tea to the meal significantly inhibited iron absorption in both iron deficient and iron replete subjects compared with water; however inhibition was slightly less in the iron deficient group. This was acquiescent with the authors' hypothesis that iron deficiency is a stronger predictor of iron absorption than meal composition alone (Thankachan 2008). Ascorbic acid was shown to significantly increase iron absorption in both deficient and replete subjects, however absorption was again increased among the iron deficient group. The authors also identified a dose dependent relationship between polyphenol consumption and iron inhibition among healthy controls where consumption of 78 mg or 156 mg polyphenols resulted in a 50% or 70% reduction in iron absorption respectively (Thankachan 2008).
Authors Samman et al (2001) investigated the addition of green tea or rosemary (Rosmarinus officinalis) extract to meals and their effect on iron absorption. Twenty-seven female subjects were randomised to receive either green tea extract (37.3 mg polyphenols) or rosemary extract (32.7 mg polyphenols) with a meal for 4 days. Each subject then consumed 4 meals, two with added extract (A) and two controls with no extract (C) in the sequence ACCA. Iron absorption from the meals was measured using whole body radioactive counting before consumption of the test meals and 2 weeks after consumption; while blood Hb and serum ferritin were measured at both enrolment and completion. Results indicated that while serum ferritin and Hb were unchanged following the intervention, both the tea and rosemary extracts significantly reduced the amount of iron absorbed from the test meal by 28% and 21% respectively (Samman 2001).
Hurrell and colleagues (1999) examined the efficacy of a range of polyphenol containing beverages (tea, herbal tea, coffee and cocoa) on iron absorption in 77 healthy subjects. The trial consisted of 8 separate absorption studies involving groups of 9 or 10 subjects in which each individual consumed 4 test meals in combination with 3 different beverages and a water control. The authors utilised measures of red cell radioactivity to assess iron uptake, both before consumption and 14 days after consumption of each test meal. Polyphenol content of the beverages ranged from 396 mg (black tea) to 177 mg (peppermint) to 52 mg (camomile).
Following interpretation of the results the authors identified a logarithmic relationship between iron absorption and polyphenol consumption with the highest polyphenol containing beverage (black tea) reducing absorption by 90%; while beverages with low polyphenol content (herbal teas) hindered absorption by just 30% (Hurrell 1999). Interestingly the authors found that black tea diluted to 5% of original strength still reduced iron absorption by 70%; concluding that black tea polyphenols were significantly inhibitory even at low concentrations and therefore may be a useful strategy in reducing iron absorption in patients with overload disorders (Hurrell 1999).
The effect of polyphenols in various wines was examined by Cook and colleagues (1995) using a non randomised experimental design. The researchers conducted 4 controlled absorption studies in a similar fashion to Hurrell et al (1999), each with 7 or 8 subjects consuming 4 radio labelled test meals accompanied by 3 wines and a water control. The highest content of polyphenols was found in the red pinot noir wine (2.98 g/L) followed by the red aramon (1.95 g/L) and the white wine (0.19 g/L). Again red cell radioactivity was measured at baseline and 14 days following consumption of each test meal as a measure of iron absorption. Results followed a similar trend to previous experiments where polyphenol content mirrored inhibition of iron absorption; with maximal inhibition achieved with a 358 mg polyphenol dose. However inhibition of iron absorption was not seen to be statistically significant in any of the wines studied, despite their relatively high polyphenol content.
Complexities in the study design reveal a number of confounding factors that may have been responsible for non significant results. Alcohol itself is a known potentiator of iron absorption (Olynyk 2005) though to what extent this relationship exists is unknown. The authors accounted for this relationship by comparing a low alcohol form of each wine with its full alcohol counterpart, and expectedly the low alcohol wines showed a greater inhibitory effect on iron absorption. However the authors failed to account for the effect of the iron content of the wines themselves, later quantified as almost 10% of daily required intake (Cook 1995). If not for the multiple confounders, the data suggests there exists a potential for low alcohol red wines as a component of dietary intervention for those individuals with iron overload who continue to consume alcohol.
Kaltwasser and colleagues (1998) conducted a more recent non randomised controlled trial involving 18 subjects, all of whom were diagnosed with hereditary haemochromatosis. The study observed the effect of tea drinking on iron accumulation over a period of 52 weeks. An initial absorption study was performed in each subject who first consumed an iron radio labelled test meal and was then assessed for whole body radioactivity 7 days and 14 days following consumption. Subjects then consumed a second test meal with tea, and iron absorption was again measured after 7 and 14 days. Among all individuals intestinal absorption of iron was inhibited by 70% when the test meal was consumed with tea (Kaltwasser 1998).
Subjects were then assigned to either the intervention group or the control. All subjects consumed their regular diet for the next year; with the intervention group instructed to consume black tea with meals 3 times daily, and the control group permitted to drink only water or non polyphenol containing beverages with meals for the subsequent period. All subjects also abstained from venesection treatments until completion of the study. Blood measurements for Hb, packed cell volume (PCV), mean cell volume (MCV), mean cell Hb, serum iron, total iron binding capacity (TIBC), TIBC saturation and serum ferritin were recorded every 4 weeks for all subjects, and iron storage levels and total body iron were calculated from venesection at completion of the experiment.
At completion results indicated a reduction in both serum ferritin and TIBC saturation in the treatment group compared with the control group, as well as a reduction in iron storage levels and total iron removal required at final venesection (Kaltwasser 1998). The study design allowed for variation in polyphenol consumption by the treatment group who were not assigned a specific brand of tea, brewing method or polpyhenol concentration; however overall all blood markers were significantly improved in the treatment group compared with the control. The authors noted that while all results from the experiment were promising, of particular significance to individuals with HH was the reduction in blood required to be drawn at post experimental venesection (Kaltwasser 1998).
Small study populations, short durations and variability in experimental composition retract somewhat from the potency of the reviewed literature, however despite methodological shortcomings there is a uniformity of results in favour of the treatment. Whilst the clinical relevance of absorption studies conducted in healthy or iron deficient subjects is also questionable when considering patients with inherent disorders of absorption, of particular interest is the work by Kaltwasser and colleagues which demonstrated an inverse relationship between polyphenol consumption and the requirement for venesection in patients with established HH. The available research indicates that plant polyphenols, in particular those of tea (Camellia sinensis), are potent inhibitors of iron absorption from the GIT, and suggests that in combination with the avoidance of known potentiators of iron uptake (meat, alcohol, fructose and vitamin C) consumption of tea polyphenols may be beneficial in individuals with HH and aid in the management of their condition.
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|Title Annotation:||Evidence based practice|
|Publication:||Australian Journal of Herbal Medicine|
|Date:||Dec 1, 2012|
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