The Mushroom Agaricus Blazei and Chronic Hepatitis B
The Mushroom Agaricus Blazei and Chronic Hepatitis B
By David Kiefer, MD. Dr. Kiefer is a Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; and Adjunct Faculty at Bastyr University, Seattle; Dr. Kiefer reports no financial relationships relevant to this field of study.
Medicinal mushrooms are increasingly being used for a variety of medical conditions, from hypercholesterolemia and diabetic neuropathy, to the treatment of specific forms of cancer. Agaricus blazei is one example of a medicinal mushroom with a rich history of traditional use. However, more recent clinical studies point to very interesting physiological effects, some of which may be useful in treating chronic hepatitis B infection, an otherwise difficult-to-treat problem.
History and Traditional Use
The medicinal use of mushrooms from the Agaricus genus appears as far back as the 4th century A.D. Byzantine medical treatises; later pharmacopeias from the same region describe its use for laryngeal tumors.1 The species Agaricus blazei is thought to be native to the highland forests of Sao Paolo province, Brazil.1,2 It has many different traditional usestreating fatigue, emotional stress, hepatitis and cancer, stimulating the immune system, reducing cholesterol, and improving digestion.1,3
A mushroom specialist from Japan supposedly discovered Agaricus in 1960, and sent it abroad for definitive identification and phytochemical determination, spawning a popular movement in Asia using Agaricus as a functional, or medicinal, food.1
Botany and Pharmacology
Agaricus blazei Murill, the complete scientific name, is in the family Agaricaceae, although references in the literature also suggest it is related to the Basidiomycetes family of mushrooms. There are numerous common names, including cogumelo piedade and cogumelo do sol (Brazil), Himematsutake, Agarikusutake, and Kawarihiratake (Japan), Ji Song Rong (China), and Brazil mushroom, Brazil sun-mushroom, and sun mushroom.1,2 Agaricus has a "classic" mushroom shape, with a small to large white-yellow-brown fruiting body.1 There are numerous other species of Agaricus with a wide geographical and ecological distribution.1
Agaricus blazei contains physiologically active phytochemicals that primarily fall into the classes of alpha- and beta-glucans, and polysaccharides; these compounds may be found only in the mycelia, the fruiting bodies, or both.1,2 Included in these are specific polysaccharides and protein-bound polysaccharides with anti-tumor activity through a variety of mechanisms named FIII-2-b, ATOM, LM-3, and ATF fractions.2 The most immunologically-active phytochemicals seem to be glucans such as (1-3)-beta-D-linked glucose polymers.1
Mechanism of Action
Agaricus extracts appear to have numerous immunological effects that may be relevant to its use in chronic hepatitis B. The beta-glucans within Agaricus stimulate the immune system by binding to Toll-like receptor 2 and dectin-1, activating MYC88 and inducing cytokine production,4 or by stimulating natural killer cells;3 the latter effect, combined with anti-angiogenic effects, may account for its anti-cancer activity in some in vitro and in vivo models.3 In one in vitro study, aqueous extracts of Agaricus were applied to a human monocyte cell line, and effects on gene expression via mRNA were measured.3 The Agaricus fraction upregulated immune function and pro-inflammatory genes, such as those for interleukin 1B and interleukin 8, and did so in a unique way compared to known immunologically-active compounds that were used as controls. The authors postulated that Agaricus acts like a Th1 response, a specific cytokine profile thought to help the body fight off viral, bacterial, and fungal infections, as well as to combat cancer. In addition, the polysaccharides in Agaricus may increase production of interferon and interleukins, preventing viruses such as hepatitis B from entering into cells and causing damage.5,6 Furthermore, some of the polysaccharide fractions from Agaricus mycelia (named AB-1, AB-2, AB-3, AB-4, AB-5) have antioxidant ability, as exemplified in several in vitro assays.7
Additional in vitro research has further examined possible anti-viral effects of Agaricus. For example, water extracts of cultured Agaricus fruiting bodies and mycelia were fractionated with ethanol and applied to monkey kidney cells to see if inhibition of morphological change occurred when those cells were infected with several different viruses, including western equine encephalitis (WEE), vacinia, herpes simplex virus (HSV), measles and polio.8 The 44% and 50% ethanol fractions of the mycelia (but not the fruiting bodies) completely inhibited the cytopathic effects of WEE; there was also a slight protection of the cells infected with HSV. Various percentage ethanol fractions of the fruiting bodies inhibited the cytopathic effects of the polio virus. The authors describe how this research adds to accumulating evidence of anti-viral and cell-protective effects for several mushroom species and their isolated phytochemicals.
Another study found that an extract of dried fruiting bodies of Agaricus given to mice could increase the immunogenicity of a DNA vaccine to hepatitis B core antigen.9 After a primary injection there was no antibody response, but after a second injection co-administered with the Agaricus extract, there was a three- to fourfold increase in antibody production when compared to the DNA vaccine alone. The authors found that there was an increase in macrophage activation as well as T-cell proliferation.
In one open-label clinical trial, four people who were chronic hepatitis B carriers (HbsAg (+) for more than three years) and who had alanine aminotransferase (ALT) > 100 IU/mL were given 500 milligrams of Agaricus three times daily 30 minutes after meals for one year.5 The product was an extract of dried fungal bodies using a standard processing technique. At the end of the study, ALT levels decreased from 151 to 46.1 and aspartate aminotransferase (AST) levels decreased from 246 to 61.3. The authors note an absence of adverse effects (though what exactly they were looking for or evaluating on this front was not detailed) and that renal function was not adversely affected. This preliminary trial is interesting, but without looking at viral load, and in the absence of a significant number of subjects, placebo control, or randomization, it is difficult to draw too many definitive conclusions.
Agaricus has also been used in patients with hepatitis C. Agaricus was given to four hepatitis C patients for one week.4 There was a slight, but non-significant, decrease in viral load. The authors suggest that gene expression changes demonstrated in the blood indicate that beta-glucans, the probable physiologically-active phytochemicals, are absorbed and act systemically.
Dosages and Forms
Water and alcohol-based extracts of both Agaricus mycelia and fruiting bodies have been used in research and clinical trials. The most commonly used extract and dose in humans appears to be 1500 milligrams daily (either at once or in divided doses) of an extract of dried fungal bodies.
Adverse Effects, Contraindications, and Drug Interactions
Specifics about adverse effects are lacking, though given that Agaricus is a food and with safety hinted at in the few clinical trials conducted so far, it seems to be a reasonably safe substance. One subchronic toxicity study was conducted using an extract of Agaricus mycelium and fruiting bodies in rats for 90 days at several different amounts, the highest percentage of food intake (5%) corresponding to what has been approved in Japan for food additive consumption.10 None of the groups had changes in weight, clinical signs, or food intake. Male rats had a significant increase in BUN for the 2.5% and 5% Agaricus groups, but decreased creatinine; histopathology did not show any renal damage, leading the authors to conclude that the laboratory changes were not related to direct or indirect kidney effects from Agaricus. The authors conclude that Agaricus has little or no toxicity and they set the no-observed-adverse-effect level (NOEL) at 5%; these results expand on the lack of mutagenic effects noted in various assays.10
Of note, Agaricus extracts (1500 milligrams daily of an extract of dried fungal bodies) have been used in people with type 2 diabetes and been shown to lower insulin resistance and serum insulin values, in theory creating the possibility of additive effects with diabetes medications leading to normoglycemia.11
Agaricus species and many other mushrooms have the tendency to accumulate heavy metals and radioactive substances from the environment, leading to a theoretical risk of contamination.1 Also, cancer researchers have found that one possible mechanism of action is for Agaricus to downregulate cytochrome P4501A (CYP1A), decreasing the conversion of xenobiotics to procarcinogens, but also theoretically causing an increase in levels of pharmaceuticals metabolized through that enzyme system.1 Furthermore, there are three case reports of hepatotoxicity in cancer patients taking extracts of Agaricus blazei;1 further details and mechanism of this effect are pending.
Agaricus blazei Murill has a long history of use in Brazil, and comes from a genus of mushrooms used worldwide for both culinary and medicinal purposes. Research over the past 50 years has yielded numerous immunological and anti-cancer effects, stemming primarily from the beta-glucans and other polysaccharide compounds. It also appears that these compounds may act to inhibit the ability of viruses to enter cells, perhaps related to possible beneficial effects in chronic hepatitis B infection. Clinical research has only just begun; one small open-label trial did show some improvement in liver enzyme elevation in people with chronic hepatitis B infection. The most commonly used dose is 1500 milligrams daily (usually in divided doses) of an extract of dried fungal bodies. Agaricus appears to be safe, drawing this conclusion from its use as a food, some comments in clinical trials, and one rat toxicity study, though there are preliminary concerns about its ability to accumulate toxins from the environment, downregulate CYP1A, and cause liver toxicity in cancer patients. Further examination of the clinical efficacy and safety is, however, clearly warranted.
Options for people with chronic hepatitis B infection are relatively few in number and include interferon alfa, lamivudine, adefovir dipivoxil, and entecavir.12 It seems plausible that Agaricus may have some role in protecting the liver from viral damage and helping the body to mount a protective immune response, if not prevent the development of cancer. The most-convincing data are from in vitro research; it cannot yet be said that Agaricus is clinically efficacious, but preliminary results look promising, and it appears to be safe. This agent is not recommended for use at this time, pending further research, but it is a potential aid that readers will likely read more about in the near future, especially as it relates to viral disorders like hepatitis.
1. Firenzuoli F, et al. The Medicinal Mushroom Agaricus blazei Murrill: Review of Literature and Pharmaco-Toxicological Problems. eCAM. 2008;5(1):3-15.
2. Barbisan LF, et al. Influence of aqueous extract of Agaricus blazei on rat liver toxicity induced by different doses of diethylnitrosamine. J Ethnopharmacol. 2002;83:25-32.
3. Ellertsen LK, et al. Effect of a medicinal extract from Agaricus blazei Murill on gene expression in human monocytes. Int Immunopharmacol. 2006;6(2):133-143.
4. Grinde B, et al. Effects on gene expression and viral load of a medicinal extract from Agaricus blazei in patients with chronic hepatitis C infection. Int Immunopharmacol. 2006 Aug;6(8):1311-1314. (ePub ahead of print.)
5. Hsu CH, et al. The mushroom Agaricus blazei Murill extract normalizes liver function in patients with chronic hepatitis B. J Altern Complement Med. 2008 Apr;14(3):299-301.
6. Nakajima A, et al. Effect of hot water extract from Agaricus blazei Murill on antibody-producing cells in mice. Int Immunopharmacol. 2002;2:1205-1211.
7. Ker YB, et al. Antioxidant capability of polysaccharides fractionated from submerge-cultured Agaricus blazei mycelia. J Agric Food Chem. 2005;53(18):7052-7078.
8. Sorimachi K, et al. Inhibition by Agaricus blazei Murill fractions of cytopathic effect induced by western equine encephalitis (WEE) virus on VERO cells in vitro. Biosci Biotechnol Biochem. 2001;65:1645-1647.
9. Chen L, et al. Coimmunization of Agaricus blazei Murill extract with hepatitis B virus core protein through DNA vaccine enhances cellular and humoral immune response. Int. Immunopharmacol. 2004;4(3):403-409.
10. Kuroiwa Y, et al. Lack of subchronic toxicity of an aqueous extract of Agaricus blazei Murrill in F344 rats. Food Chem Toxicol. 2005;43(7):1047-1053.
11. Hsu CH, et al. J Altern Complement Med. 2007;13:97-102.
12. Hoofnagle JH. Hepatitis BPreventable and Now Treatable. NEJM. 2006;354(10):1074-1076.Keifer, D. The Mushroom Agaricus Blazei and Chronic Hepatitis B. Alter Med Alert. 2008:11;76-78.
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