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The Efficacy and Safety of Cordyceps militaris in Korean Adults Who Have Mild Liver Dysfunction
경증의 간 기능 이상 소견을 보이는 성인에 대한 동충하초 추출물의 기능 및 안전성
Journal of the Korean Society for Parenteral and Enteral Nutrition 2015;7:81-86
Published online December 31, 2015
© 2015 Korean Society for Parenteral and Enteral Nutrition.

Jin Young Heo1, Hyun Wook Baik1, Hyuk Jung Kim2, Jae Min Lee1, Hyung Woo Kim1, Yong Sun Choi1, Jung Ho Won1, Hyun Mi Kim1, Won Il Park1, and Chul Young Kim1
허진영1, 백현욱1, 김혁중2, 이재민1, 김형우1, 최용선1, 원정호1, 김현미1, 박원일1, 김철영1

1Department of Internal Medicine, Bundang Jesaeng Hospital, Seongnam, Korea,
2Department of Diagnostic Radiology, Bundang Jesaeng Hospital, Seongnam, Korea
1분당제생병원 내과,
2분당제생병원 영상의학과
Correspondence to Hyun Wook Baik Department of Internal Medicine, Bundang Jesaeng Hospital, 20 Seohyeon-ro 180beon-gil, Bundang-gu, Seongnam 13590, Korea Tel: +82-31-779-0249, Fax: +82-31-779-5079, E-mail: hbaik@dmc.or.kr
Received June 22, 2015; Revised August 26, 2015; Accepted November 9, 2015.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract

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.

Keywords : Cordyceps, Cordycepin, Liver
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.1-7

Liver plays an important role in the human body and is involved in metabolism of protein synthesis, carbohydrate, 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,10-12 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.

MATERIALS AND METHODS

1. Methods

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 blinded, placebo controlled clinical trial was to determine the effects and safety of C. militaris for Korean adults with mild liver dysfunction. The study performed at Bundang Jesaeng Hospital between February 2013 and January 2014.

Laboratory test (white blood cell, hemoglobin, platelet, aspartate aminotransferase (AST), ALT, gamma glutamyltranspeptidase (GGT), lactic dehydrogenase, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine), liver computed tomography (CT), visual analogue scale (VAS) score of subjective symptoms, and fatigue severity scale (FSS) were measured to determine the effect of C. militaris on liver function and the adverse effects of administration were examined to determine its safety.

An independent statistician unrelated to the clinical trial used the Proc Plan procedure of SAS version 9.1 (SAS Institute, Cary, NC, USA) to randomly assign the participants before starting the trial.

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 weeks of administration.

Two subjects dropped out of the C. militaris group and one subject dropped out of the placebo group. The dropout was excluded from the statistical analysis.

2. Materials

1) Cordyceps militaris extracts

C. militaris used in this study was supplied by Mushtech (Hoengseong, Korea). For species identification, DNA was extracted from C. militaris and fungal DNA was amplified using the highly conserved fungal rRNA gene primers (ITS1F and ITS4). To identify the isolates, sequences were subjected to the basic local alignment search tool (BLAST) search with the NCBI database (http://www.ncbi.nlm.nih.gov/). The BLAST search revealed a 99% similarity with the C. militaris ITS sequence.

Dried C. militaris was crushed, extracted in 50% ethanol at room temperature and at normal pressure for three days, filtered, concentrated, sterilized, and spray-dried. The major active component of C. militaris is cordycepin. Its content is approximately 1.9 mg/g, acceptable within a range (80% to 120%).

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.

3. Statistical analysis

All data were expressed as a mean±standard error of the mean (SEM). The Hounsfield unit (HU) of liver CT and the ratio of change of laboratory test were analyzed using Wilcoxon rank sum test and two sample t-test. The normalized rate of laboratory test was evaluated using Pearson’s chi-square test and Fisher’s exact test. P-values <0.05 were considered statistically significant in safety test, <0.1 were considered statistically significant in function test.

RESULTS

1. Clinical characteristics of participants

Regarding the clinical characteristics of the participants, there was no statistically significant inter-group difference in the mean age: 40.93±10.08 years for the C. militaris group and 41.28±10.46 years for the placebo group (P=0.8570). Men showed a higher rate than women in both groups, but there was no statistically significant inter-group difference (P=0.9605; Table 1).

Baseline characteristics

   CharacteristicC. militaris group (n=28)Placebo group (n=29)P-value
Age (y)40.93±10.0841.28±10.460.8570
Sex0.9605
 Male25 (89.3)25 (86.2)
 Female3 (10.7)4 (13.8)
Laboratory test
 WBC (103/μL)7.00±1.866.70±1.290.4833
 Hemoglobin (g/dL)15.37±1.1115.02±1.010.2198
 Platelet (103/μL)244.11±51.46234.69±51.840.4942
 BUN (mg/dL)13.68±3.6914.59±4.630.4187
 Creatinine (mg/dL)1.12±0.221.17±0.150.2954
 LDH (IU/L)370.17±73.16364.32±61.200.7442
 ALT (IU/L)77.07±14.2076.10±15.800.8086
 AST (IU/L)48.18±16.9151.38±20.420.5215
 GGT (IU/L)126.18±113.4569.03±51.820.0199
 ALP (IU/L)206.93±66.60228.93±65.850.2152
 Total bilirubin (mg/dL)0.77±0.420.79±0.360.8203

Values are presented as mean±standard error of the mean or number (%).

C. militaris = Cordyceps militaris; WBC = white blood cell; BUN = blood urea nitrogen; LDH = lactic dehydrogenase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma glutamyltranspeptidase; ALP = alanine aminotransferase.

2. Liver CT scan

In analysis of the liver CT scan at 8 weeks after administration compared to baseline, the mean ratio of change of HU 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, and showed a statistically significant difference (two sample t-test, P=0.0987). The mean ratio of change of HU of the caudate lobe increased by an average of 18.18%±34.16% in the C. militaris group and 8.35%±15.77% in the placebo group, which showed statistically significant difference in the two groups (two sample t-test, P=0.0902) but others showed no statistically significant inter-group difference (Table 2).

The mean ratio (%) of change of HU of liver CT at 8 weeks after administration compared to baseline

SegmentC. militaris group (n=28)Placebo group (n=29)P-value
Total21.43±45.119.64±11.410.0987
Caudate lobe18.18±34.168.35±15.770.0902
Superior subsegment of the lateral segment28.59±83.1717.72±24.170.2594
Inferior subsegment of the lateral segment69.08±355.898.86±29.450.1944
Left medial segment14.05±46.3410.46±19.730.3559
Inferior subsegment of the anterior segment17.66±49.4912.33±15.630.2981
Inferior subsegment of the posterior segment28.09±65.107.77±17.790.0637
Superior subsegment of the posterior segment−40.59±245.6319.47±32.470.8908
Superior subsegment of the anterior segment42.03±131.0010.74±21.500.1154

Values are presented as mean±standard error of the mean.

HU = Hounsfield unit; CT = computed tomography; C. militaris = Cordyceps militaris.

3. 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 ratio (%) of change of ALT, AST, and GGT at 4 and 8 weeks after administration compared to baseline

Liver function testC. militaris group (n=28)Placebo group (n=29)P-value
ALT4 wk19.07±24.1216.61±40.360.3903
8 wk20.10±25.3017.92±35.600.3951
AST4 wk16.82±20.9020.35±27.210.7076
8 wk16.75±23.4310.36±65.640.3125
GGT4 wk7.20±24.345.57±22.760.3981
8 wk3.70±31.564.38±26.110.5351

Values are presented as mean±standard error of the mean.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma glutamyltranspeptidase; C. militaris = Cordyceps militaris.

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 normalized rate of ALT, AST, and GGT at 4 and 8 weeks after administration compared to baseline

Liver function testC. militaris group (n=28)Placebo group (n=29)P-value
ALT4 wk5 (17.9)10 (34.5)0.2609
8 wk7 (25.0)5 (17.2)0.6941
AST4 wk19 (67.9)22 (75.9)0.7057
8 wk19 (67.9)20 (69.0)1.0000
GGT4 wk17 (60.7)23 (79.3)0.2133
8 wk17 (60.7)25 (86.2)0.0595

Values are presented as number (%).

ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma glutamyltranspeptidase; C. militaris = Cordyceps militaris.

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 (Table 3, 4).

4. VAS and FSS

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 significant inter-group difference (Table 5).

The ratio (%) of change of VAS score of subjective symptoms at 4 and 8 weeks after administration compared to baseline

Subjective symptomC. militaris group (n=28)Placebo group (n=29)P-value
Fatigue4 wk1.12±91.712.62±69.130.5275
8 wk23.57±75.8728.62±32.040.6266
General weakness4 wk19.52±35.4316.12±60.800.3981
8 wk26.79±33.3425.35±52.400.4508
Dyspepsia4 wk3.02±56.64−5.11±60.960.3019
8 wk12.92±54.17−7.82±84.700.1374
Nausea, vomiting4 wk−43.69±100.584.13±43.620.9868
8 wk−41.25±111.83−4.71±62.410.9315
Poor oral intake4 wk−66.31±187.03−16.59±81.490.8980
8 wk−18.77±82.14−28.86±121.570.3571
Abdominal discomfort4 wk−31.64±111.361.12±57.820.9134
8 wk−55.36±166.96−2.61±78.800.9312
Abdominal bloating4 wk12.35±34.3412.24±47.380.4959
8 wk12.60±57.2111.62±62.360.4756

Values are presented as mean±standard error of the mean.

VAS = visual analogue scale; C. militaris = Cordyceps militaris.
2) FSS

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

The ratio (%) of change of FSS at 4 and 8 weeks after administration compared to baseline

FSS categoryC. militaris group (n=28)Placebo group (n=29)P-value
Decreased desire4 wk16.14±32.6520.50±53.560.6444
8 wk30.73±42.8536.24±27.760.7156
Fatigue during exercise4 wk0.36±41.886.37±49.260.6894
8 wk26.24±30.8119.39±36.190.2222
Easy fatigue4 wk6.10±39.6520.71±36.090.9241
8 wk26.18±39.2828.65±50.290.5817
Difficulty of physical activity4 wk−6.61±63.7014.93±42.800.9290
8 wk19.32±49.9719.53±40.140.5070
Frequent fatigue4 wk−13.10±65.36−1.95±41.660.7759
8 wk5.99±45.275.29±42.690.4759
Continuity of physical activity4 wk−23.00±55.983.45±44.240.9732
8 wk−1.53±53.24−7.47±54.210.3390
Job performance4 wk−20.24±55.272.07±54.460.9346
8 wk−3.63±62.550.40±45.960.6084
Give up of difficult problem4 wk−22.32±82.49−1.14±55.850.8682
8 wk7.56±74.2510.58±46.400.5724
Family and social life4 wk−31.85±88.672.13±52.900.9563
8 wk−8.94±71.510.06±68.490.6851

Values are presented as mean±standard error of the mean.

FSS = fatigue severity scale; C. militaris = Cordyceps militaris.

5. Adverse effect

No case of serious adverse effects related to administration was reported during the study (8 weeks). In addition, no clinically significant difference in clinical indexes, including vital signs and other diagnostic blood test, was observed between before and after administration.

DISCUSSION

C. militaris is a mushroom traditionally used in several area of East Asian territory. Lots of studies have been reported diverse results such as improving liver and renal functions, enhancing immunity through activation of basal metabolism.

Cordyceps spp. contains various chemical with biological activities, such as cordycepin, cordycepic acid, and guanosine, are regarded as the most important substances working these pharmaceutical activities.13

Low density on liver CT scan indicates accumulation of fat, such as triglyceride, in hepatocytes,14 causing failure of hepatocytes and can lead to fibrosis or cirrhosis if lasting a long time.15 In this study, the HU of the liver CT scan showed significant improvement in the C. militaris group compared to the placebo group, as a result of ingestion of C. militaris extract for 8 weeks by male and female adults with mild liver dysfunction (C. militaris 21.43%±45.11% vs. placebo 9.64%±11.41%; two sample t-test, P=0.0987). These results may be caused by a suppression effect of C. militaris extract on accumulation of fat in hepatocytes.

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 functional 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 Generation BioGreen 21 Program (Project No. PJ008321; Rural Development Administration, Republic of Korea).

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