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The Efficacy and Safety of Cordyceps militaris in Korean Adults Who Have Mild Liver Dysfunction

Purpose: The aim of this study is to determine the efficacy and safety of Cordyceps militaris in Korean adults with mild liver dysfunction. C. militaris is a mushroom traditionally used for several clinical purposes in East Asian territory, including China, and has been found to be effective in improving liver function through animal studies. Methods: The C. militaris group was administered 1.5 g/day of C. militaris (2 capsules per dose, twice per day) and the placebo group was administered the same volume of placebo. Laboratory test (white blood cell, hemoglobin, platelet, aspartate aminotransferase, alanine aminotransferase, gamma glutamyltranspeptidase, lactic dehydrogenase, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine), liver computed tomography (CT) were performed, and visual analogue scale score for subjective symptoms and fatigue severity scale were measured. Results: In analysis of the liver CT scan at 8 weeks after administration compared to baseline, the mean ratio of change of Hounsfield unit of 8 segments of liver increased by an average of 21.43%±45.11% in the C. militaris group and 9.64%±11.41% in the placebo group. Others showed no statistically significant inter-group difference. Conclusion: C. militaris extract was used safely as a functional food in patients with mild liver dysfunction, and is expected to protect against progression of fatty liver or cirrhosis caused by suppression of lipid accumulation in hepatocytes.


INTRODUCTION
Cordyceps militaris, a mushroom in the category of ascomycetes, has been used for improving liver and renal functions, enhancing immunity through activation of basal metabolism in Asia. Recently, the attention to its ability of enhancing immunity is increasing. [1][2][3][4][5][6][7] Liver plays an important role in the human body and is involved in metabolism of protein synthesis, carbohydrate, Journal of Clinical Nutrition lipid, hormone, vitamin and mineral, and production of bile acid, which helps digestion, including metabolism of endogenous substances as well as those absorbed from the outside.
In particular, liver protects the human body from a number of risk factors by detoxifying endogenous or exogenous toxins. Therefore, the risk of damage caused by alcohol, drugs, viruses, and toxins contained in the blood flow of the liver is higher because of its abundant distribution.
C. militaris has low content of carbohydrate, which is the energy source, and contains vitamin A and minerals in abundance compared to other Cordyceps spp. 8,9 Cordycepin, secondary metabolite of C. militaris, is introduced as a physiologically active substance having the effect of fatigue recovery and liver protection. Awareness of C. militaris as a functional food is increasing.
As a result of research in terms of safety, it has been reported as safe based on toxicity data on acute single oral administration of C. militaris. Therefore, in the current situation, where there is no available medication for early care and treatment of liver injury which may lead to chronic liver disease, Cordyceps spp. was open to development as a functional food to improve liver function. While diverse types of animal testing on the effect of C. militaris on liver function have been conducted, [10][11][12] almost no testing has been conducted in human beings. Therefore, we studied the effect of C. militaris on liver function and its safety in human being.

1) Participants
The participants were 20 to 65 years old adults with alanine aminotransferase (ALT) of 1.5 to 3 times the upper limit of normal, and not taking hepatotonics, drug that can affect the liver function, nutritional supplements, or alcohol for two weeks before screening.
Those with ALT more than three times the upper limit of normal, who had systemic disease, such as rheumatoid arthritis, metabolic syndrome, autoimmune disease, or malignancy, infectious disease, such as chronic hepatitis B or C, or AIDS, severe infectious disease, such as pneumonia, or tuberculosis, severe hepatic failure, heart failure, renal failure, or history of hypersensitivity to functional food, or were allergic to mushrooms, including Cordyceps spp., were excluded from the experiment. Those considered unfit for the experiment by the doctor were also excluded.

2) Ethics consideration
To protect the participants ethically, the study was conducted under the approval of the Institutional Review Board of Bundang Jesaeng General Hospital (Seongnam, Korea) (IMG 12-03). The participants were given a full explanation of the purpose of the experiment, the efficacy of the experimental product, and its adverse reaction and gave written consent before starting the experiment.

3) Study design and treatments
The aim of this single center, randomized, double blind- The C. militaris group was given 1.5 g/day of C. militaris (2 capsules per dose, twice per day) and the placebo group was given the same volume of placebo for four weeks from day 0 to the closing day. Blood sampling was performed three times: before administration, after four weeks of administration, and after eight weeks of administration. CT scan was performed before administration and after eight Volume 7, Number 3, December 2015

2) Tablet preparation
Each tablet contained 375 mg of dried extract of C. militaris and placebo was manufactured in the same volume, consisting mainly of microcrystalline cellulose and lactose.

Statistical analysis
All data were expressed as a mean±standard error of the Men showed a higher rate than women in both groups, but there was no statistically significant inter-group difference (P=0.9605; Table 1).

ALT, AST, and GGT
The ratio of change of ALT at 4 weeks after administration compared to baseline was 19.07±24.12 in the C.
militaris group and 16.61±40.36 in the placebo group. The ratio increased in C. militaris group as well as placebo group, but there was no statistically significant inter-group difference ( Table 3).
The normalized rate of ALT at 4 weeks after administration compared to baseline was 17.9% in the C. militaris group and 34.5% in the placebo group. The placebo group showed a higher normalized rate than the C. militaris group, but there was no statistically significant inter-group difference ( Table 4).
The results of AST and GGT did not differ from ALT, and also there was no statistically significant inter-group difference between C. militaris group and placebo group (

1) VAS
In analysis of VAS score of subjective symptoms at 4 and 8 weeks after administration compared to baseline, chronic fatigue, general weakness, and abdominal bloating increased in the C. militaris group, but there was no statistically sig- nificant inter-group difference (Table 5).

2) FSS
In measurement using a questionnaire composed of 9 items, there was no statistically significant inter-group difference in all items (Table 6).

Adverse effect
No case of serious adverse effects related to administration was reported during the study (8 weeks On the other hand, the normalization rate of serum level of ALT, AST, and GGT showed no significant inter-group difference after administration compared to baseline. Serum level of ALT, AST, and GGT showed a tendency to increase at every point but without statistical significance. It is believed that C. militaris extract does not have hepatotoxicity compared to placebo, but additional studies will be needed.
On the VAS score, none of the 7 subjective symptoms associated with liver function showed statistically significant inter-group difference, and the FSS questionnaire consisting of 9 items showed no statistically significant inter-group difference either. Thus there was no improving effect according to intake of C. militaris extract. However, because our participants had only mild liver dysfunction and their symptoms were mild, it is possible that the effect of C. militaris extract on this group was insufficient. Also, it is possible that the SEM was overestimated, because our sample size is small.
There was no adverse effect during the study period and no abnormal laboratory tests. Thus C. militaris extract was safe to administer to the human body. As a result of this study, C. militaris extract was a safe functional food that improved liver CT scan for male and female adults with mild liver dysfunction.
This study is meaningful in that liver CT scan was used for functional testing. As a result, C. militaris extract was used safely in patients with mild liver dysfunction as a func-

Journal of Clinical Nutrition
tional food, and is expected to protect against progression of fatty liver or cirrhosis caused by suppression of lipid accumulation in hepatocytes. However, because we studied adults with only mild liver dysfunction, it is possible that its effect of improving liver function was insufficient. Therefore, further study aimed at moderate to severe liver dysfunction will be needed.

ACKNOWLEDGMENTS
This work carried out with the support of the Next Gene-