Editor's Note: Part 1 of this article appeared in the Jan. 15 issue.
Evidence is growing that the silymarin complex of flavonolignans from milk thistle can impact serum ferritin and iron overload in various clinical circumstances. There are three recent clinical trials of this extract in patients with ß-thalassemia, mainly used in conjunction with the drug desferrioxamine.
Beta-thalassemia is a relatively common genetic hemoglobin disorder that leads to severe chronic anemia and requires regular blood transfusions, resulting in iron overload and extremely high serum ferritin levels. When the iron-binding capacities of transferrin and ferritin are exceeded, the excess iron also generates harmful free radicals, and causes tissue and multi-organ damage.12
Chelation therapy with the drug desferrioxamine is standard therapy for these iron-induced complications. A key drawback, however, is about one-third of patients find it difficult to comply with the almost-daily subcutaneous infusions of this drug that are required.11
In the first trial, patients were treated with the combination of desferrioxamine and 420 mg/day of silymarin (n=49) or desferrioxamine and placebo (n=48) for nine months using a randomized, double-blind design.11 Serum ferritin levels decreased significantly from the beginning to the end of silymarin treatment (3,028.8 ± 2,002.6 versus 1,972.2 ± 1,250.6 ng/mL); however, no significant change in serum ferritin was observed in the patients receiving placebo (2,249.0 ± 1,304.2 versus 2,015.6 ± 1,146.8 ng/mL).
Patients on silymarin therapy also had a significant decrease in serum levels of hepcidin and soluble transferrin receptor after the nine-month treatment period. (Hepcidin is a peptide hormone produced by the liver and involved in iron homeostasis.) A significant improvement in serum transaminases (liver function test) also was observed in the silymarin-treated group.
Measurements of soluble transferrin receptor (sTfR) are helpful in monitoring the erythropoietic (red blood cell production) response to various forms of therapy, in particular when changes in hemoglobin are not yet apparent. Increased values of sTfR are detectable in thalassemia syndromes due to ineffective erythropoiesis. The study revealed that combination therapy of silymarin and desferrioxamine significantly reduced levels of sTfR after the nine-month treatment compared with baseline values. To the best of the study authors' knowledge, this was the first evidence to show the effect of iron chelation therapy (via silymarin and the drug) on sTfR levels in ß-thalassemia major.
The second trial was conducted over six months and involved 40 children (average age approximately 5 years) with ß-thalassemia major and a serum ferritin level of more than 1,000 ng/mL.13 Patients included in the study (group I) were divided into two subgroups (group IA and group IB) by simple random allocation.
Group IA received a combination of oral desferrioxamine, 20 to 40 mg/kg/day (supplied in orally dispersible tablets dissolved in water or juice and administered on an empty stomach), together with oral silymarin in the form of 140 mg tablets, one hour before each meal (in other words, three times daily). Group IB received oral desferrioxamine, 20 to 40 mg/kg/day, and placebo. Group II included 20 healthy children matched in age and sex, and served as a control group.
Serum ferritin levels markedly decreased from baseline by around 67 percent in group IA compared with 43 percent for group IB (P = 0.001). However, levels were still well above those measured in the healthy control children. Serum iron also was reduced.
In the third study, the immunomodulatory effects of silymarin were investigated in an open-label, 12-week clinical trial in two groups of patients. In the combined-therapy group (n=25), patients continued subcutaneous desferrioxamine at a dose of 40 mg/kg/day and silymarin tablets (420 mg daily) were added.14 In the silymarin-only group (n=5), patients who were unable or unwilling to use desferrioxamine received just silymarin.
Immunological tests were assessed at the beginning and the end of the trial. Serum tumour necrosis factor (TNF-α) levels were significantly decreased in both groups. The analysis of cell culture supernatants of activated T cells showed increased production of interferon gamma (IFNy) and interleukin (IL)-4 after silymarin treatment in both groups.
The authors concluded that silymarin stimulated cell-mediated immune responses in ß-thalassemia major, possibly through a direct action on cytokine-producing mononuclear cells. The reduction in TNF-α also suggested an anti-inflammatory effect.
Silymarin's hepatoprotective and iron-bonding capacities suggest a role in iron overload disorders such as ß-thalassemia and hemochromatosis, and now there is a reasonable body of clinical evidence supporting its value in the former and preliminary evidence for the latter (see below). While the trial designs were not strong, the substantial ferritin reductions observed suggest a clinically relevant effect.
In terms of hereditary hemochromatosis, one small study found that a single dose of silymarin (140 mg) with food reduced subsequent iron absorption in patients with this disorder. In addition, silymarin reduced serum ferritin in chronic hepatitis C patients. Iron from damaged liver cells could contribute to the inflammatory pathology of this disorder.
In a randomized, open-label, dose-finding study, the impact of silymarin (360, 720 or 1,080 mg/day) as the phosphatidylcholine (lecithin) complex was assessed in 37 patients with chronic hepatitis C and liver fibrosis.15 There was a highly significant 12 percent decrease in mean serum ferritin from baseline to the end of treatment 12 weeks later (P = 0.0005). In all, 78 percent of patients responded with a decrease in this factor.
The potential clinical value of silymarin's impact on iron overload extends well beyond the above disorders. One good example is type 2 diabetes. There is now a strong link between this common disorder and serum ferritin and tissue iron stores, and the relationship is thought to be causal.16 In fact, type 2 diabetes (T2D) has reversed with a reduction in iron status. Based on a recent meta-analysis, there is a 1 percent increased risk of T2D for every 5 ng/mL ferritin increment and 224 percent for every 5 mg/day intake of dietary heme iron.17 However, supplemental iron is not implicated.18
In addition, silymarin can help manage blood glucose levels. In two clinical trials in T2D patients, silymarin improved glycemic control.19-20 It also improved BMI8 and hepatic transaminases,9 and reduced urinary albumin in T2D patients with nephropathy.21
References
(Click here to see references from Part 1, some of which appear in Part 2 as well.)
12. Moayedi B, Gharagozloo M, Esmaeil N, et al. A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in ß-thalassemia major patients receiving desferrioxamine. Eur J Haematol, 2013;90(3):202-209.
13. Hagag AA, Elfrargy MS, Gazar RA, et al. Therapeutic value of combined therapy with deferasirox and silymarin on iron overload in children with Beta thalassemia. Mediterr J Hematol Infect Dis, 2013;5(1):e2013065.
14. Gharagozloo M, Karimi M, Amirghofran Z. Immunomodulatory effects of silymarin in patients with ß-thalassemia major. Int Immunopharmacol, 2013;16(2):243-247.
15. Bares JM, Berger J, Nelson JE, et al. Silybin treatment is associated with reduction in serum ferritin in patients with chronic hepatitis C. J Clin Gastroenterol, 2008;42(8):937-944.
16. Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab, 2013:17(3):329-341.
17. Kunutsor SK, Apekey TA, Walley J, et al. Ferritin levels and risk of type 2 diabetes mellitus: an updated systematic review and meta-analysis of prospective evidence. Diabetes Metab Res Rev, 2013;29(4):308-318.
18. Bao W, Rong Y, Rong S, et al. Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and meta-analysis. BMC Med, 2012;10:119.
19. Hussain SA. Silymarin as an adjunct to glibenclamide therapy improves long-term and postprandial glycemic control and body mass index in type 2 diabetes. J Med Food, 2007;10(3):543-547.
20. Huseini HF, Larijani B, Heshmat R, et al. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res, 2006;20(12):1036-1039.
21. Fallahzadeh MK, Dormanesh B, Sagheb MM, et al. Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: a randomized, double-blind, placebo-controlled trial. Am J Kidney Dis, 2012;60(6):896-903.
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