Herbal Medicines Used in Treatment of Nonalcoholic Fatty Liver Disease: A Mini-Review

Maryam Nikkhajoei1, Rasool Choopani1, Mojgan Tansaz1, Ghazaleh Heydarirad1, Fataneh Hashem-Dabaghian2, Shamim Sahranavard3, Mehdi Saberifiroozi4, Mehdi Pasalar5

1Department of Traditional Medicine, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Research Institute for Islamic and Complementary Medicine, Iran University of Medical Sciences Tehran, Iran

3 Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 Digestive Disease Research Institute, Shariati Hospital, Tehran, Iran

5 Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

Introduction

Non-alcoholic fatty liver disease (NAFLD) is characterized by fatty change of hepatocytes in patients with no history of overdrinking alcohol [1]. In a fatty liver, the weight of the deposited fat is greater than 5 percent of the liver’s weight; or rather, the fat covers more than half of the hepatocytes. Up to now, 20-40% of the individuals suffer from NAFLD globally while its prevalence is estimated to be around 5% to 30% in Asia [2]. This figure is about 2.9% to 7.1% in Iranian people and meets 21.5% in southern Iran [3, 4]. Metabolic disorders such as insulin resistance are often observed in NAFLD patients. Epidemiologic information demonstrates that the pathogenesis of fatty liver is related to age, sex, blood lipids, hypertension, obesity, and diabetes mellitus (DM). The NAFLD risk factors comprise of high fat and protein diet, male gender, the presence of metabolic syndrome characteristics, extra meals before sleep, and sedentary lifestyle. As a consequence of the modern lifestyle and the increasing senior population, incidence of fatty liver and the related diseases have been on the rise [4, 5].

The NAFLD is an important progressing liver damage epidemic. Its direct costs include medical and diagnostic expenses whereas the indirect costs are the loss of productivity and reduced health-related quality of life (HRQOL). The NAFLD can also lead to fibrotic change and cirrhosis, which have no proven treatment [6-9]. The main challenge is how to manage successfully the fatty liver, a modern disease, which has become a serious problem for the gastroenterologists [5].

Treatment of liver diseases such as fatty liver, chronic hepatitis, and cirrhosis is not satisfactory enough. The effectiveness of routine medical treatments such as colchicine, interferon, corticosteroids, and penicillamine is not well documented besides the fact that there are side-effects. Both physicians and patients look forward to effective therapeutic agents with as little harm as possible. Medicinal plants potentially constitute such effective agents [10].

There is an increase in the use of complementary and alternative medicine (CAM) [11], especially herbal therapy, by the patients including those with liver diseases [12]. Complementary therapies, such as herbal drugs, have also been tested for treatment of NAFLD [10]. Different schools of CAM including Traditional Persian Medicine (TPM) and Traditional Chines Medicine (TCM) have their own say in the disease treatment [13-15]. In recent years, many investigators have examined specific effects of the plants applied traditionally by native healers and herbalists for the treatment of liver diseases. Their usage has been reported to be efficacious for the treatment of a variety of diseases in addition to their ready availability, little side effects, and proven therapeutic mechanisms and benefits [16, 17].

Several hundred plants have been evaluated for a variety of liver diseases; however, only a small handful of them have been fully studied [10]. In this investigation, we aimed to review the human clinical studies comprehensively, reporting the effectiveness of medicinal plants in the treatment of NAFLD.

Search Strategies

PubMed, Scopus, Cochrane Library and Google Scholar databases were combed for English-language clinical trials from 1966 to Feb. 2016 that were to deal with simple medicinal plants used in the treatment of NAFLD. Three reviewers independently examined the abstracts of identified publications for relevance and extracted pertinent data from the selected reports. The search keywords were “NAFLD”, “medicinal plant”, “fatty liver”, “herb”, “herbal drugs”, and “traditional medicine”. Only publications with available abstracts were reviewed. All human clinical trials were included.

Herbal supplements and diet-based therapies are among the most common complementary remedies used for the treatment of NAFLD [18]. In recent studies, the use of plant extract/decoction, as well as polyherbal formulations, represent the traditional system of medicine, while extracting the active ingredients and their application for the treatment belongs to modern pharmacotherapy. Latest advances in the field of medicinal chemistry have led to the detection of active agents from the whole plant extract. Many phytochemicals have been screened for different human ailments a small number of such phytochemicals are even available in the drug market. Furthermore, synthesis of analogues of natural compounds has turned out to be the concentration point of (many) modern investigators—they have resulted in finding more effective compounds yet. The currently available herbal treatments used for the healing of NAFLD are listed in Table1.

Discussion

As a worldwide critical issue, prevention and treatment of NAFLD are vital for healthcare systems [28]. To date, there is no effective treatment for NAFLD, except for lifestyle modification and weight reduction which are considered as the first-line in disease approach [29]. Nevertheless, pharmacotherapy has also been considered by physicians for treatment [30].

Herbal medicine is a part and parcel of various brands of traditional medicine, extending back to a long time ago. Over the time, a variety of herbs were added to the database of medicine, which has been recorded in herbal pharmacopeia [31]. Indeed, many of new medicaments in common use have an herbal origin. Globally, about 25 percent of prescribed medications have at least one active ingredient of herbal source [32].

The TPM with its dynamic treasure of novel medicinal plants has introduced various options for gastrointestinal system ailments, ranging from prevention to treatment fields [33, 34]; in this regard, liver —as a vital organ—has a fundamental position.

According to our search, few human studies are focusing on this field. As demonstrated in Table 1, in most studies the effect of herbal drugs has been evaluated by changes in the level of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), and the body mass index (BMI); however, there are no adequate data regarding histopathological improvement in these patients. Some clinical trials on medicinal plants showed changes in serum lipids, insulin resistance, and plasma glucose levels, too.

The mechanism of action for these medicinal plants is not crystal-clear; yet, some of them (such as Chlorella vulgaris and silybum marianum) have proven to be effective in decreasing plasma lipid [24, 35]. Decrease in AST was observed in patients with alcoholic liver disease on silymarin comparing to placebo but, it was not attributable to NAFLD patients [36]. Such property could explain their therapeutic role in treating NAFLD patients.

The mechanism of action for Berberis vulgaris effect on NAFLD patients was similar to the latter result in decreasing plasma total cholesterol and triglycerides but, different in liver enzymes. Barberry decreased ALT, AST, and weight in the case group vs. control group significantly which fact could clarify its effectiveness unmistakably [2].

On the other hand, the anti-oxidative stress effects of some medicinal plants such as silymarin and green tea [37, 38] have a crucial role in the treatment of other accompanied ailments such as DM and cardiovascular diseases (CVD). Green tea enriched with catechines, a major component of its extract, reduces body fat composition and CVD risks, too [39, 40]. Green alga and cinnamon consumption could also result in a decline in FBS and lipid profile [19, 20, 27]. Healing of these common concomitant diseases could justify the effectiveness of such plants.

It is not to be forgotten that there are cases where herbal medication does not come ineffective, as, for instance, in the case of chamber bitter [23]. It is not exactly clear to us why in this one case the herbal medication does not act effectively.Unfortunately, there is only one report which has assessed the histological changes by herbal drugs; the rest of the studies have evaluated only the effects of medicinal plants on metabolic profile or radiological changes after treatment.

As the decrease in fibrosis level is the main goal of previous treatments, we cannot assess the exact effect of these medicinal plants on the therapeutic outcome. Thus, need felt for further double-blind randomized controlled trials with an adequate number(s) of NAFLD patients, assessing the histopathological changes of the liver with long-term follow-up.

Our review of current literature revealed that only a small number of medicinal plants showed adverse effects. However, the safety profile of any herbal product could be determined after rigorous evaluations and long-term follow-up.

Conclusion

Medicinal plants have proven to be effective for the correction of the metabolic profile of NAFLD patients, with few reports of adverse effects. Nonetheless, few studies have addressed the effect of herbal remedies on the histopathological characteristics of patients with NAFLD. The evaluating merits of herbals for the management of NAFLD could be the main objective of future research. Well-designed clinical trials with adequate participants and histopathological investigations are needed to evaluate both efficacy and safety of these natural products.

Acknowledgements

This study was supported by a grant from Shahid Beheshti Medical University, Tehran, Iran as the Ph.D. dissertation of Dr. Maryam Nikkhajoei toward the Iranian Board of Traditional Medicine.

Conflict of Interest

The authors declare that there is no conflict of interest.

Table 1. List of Herbal Medicines Used for the Treatment of NAFLD in Clinical Trials

Common name	Scientific name	Number of participants	Duration	Dose	Result	Reference
Green alga	Chlorella vulgaris	60	8 weeks	400 mg/day vitamin E plus four 300-mg tablets of Chlorella vulgaris	Weight, liver enzymes, FBS¥ and lipid profile decreased significantly	Ebrahimi-Mameghani, Aliashrafi et al. [17]
		76	3 months	Chlorella  vulgaris extract (1200 mg/day) + metformin (750 mg/ day) + vitamin E (200 mg/day) or metformin (1250 mg/ day) + vitamin E (200 mg/day)	Serum ALT*, AST#, TG€, uric acid, HbA1c, and insulin resistance index were all reduced in the Chlorella group significantly	Panahi et al. [18]
Green tea	Camelia sinensis	70	12 weeks	Green tea adjusted to 1,080 mg/ 700 ml or 200 mg/700 ml catechin content and green tea flavored beverage (0 mg/700 ml catechin content)	The high-density catechin treatment significantly decreased serum ALT levels and reduced urinary 8-isoprostane excretion as compared with the placebo and low-density catechin group	Sakata, Nakamura et al. [19]
Licorice	Glycyrrhiza glabra L.	66	2 months	one capsule containing 2 g aqueous licorice root extract per day	In the treatment group, the mean ALT and AST level decreased statistically significantly	Hajiaghamohammadi, Ziaee et al. [20]
Chamber bitter	Phyllanthus urinaria	60	24 weeks	400 mg of chamber bitter together with inactive ingredients of microcrystalline cellulose, hydroxypropylmethylcelllose and magnesium stearate	there was no significant difference in the changes in AST, FBS and lipid profile between the two groups	Wong, Wong et al. [21]
Silymarin	silybum marianum	100	24 weeks	280 mg of silymarin	The mean serum ALT levels in the silymarin group decreased. ALT normalization (ALT < 40) was observed in 52% of patients in the silymarin-treated group. AST normalization (AST < 40) was observed in 62% of cases in the silymarin-treated group.	Hashemi, Hajiani et al. [22]
Cumin	cuminum cyminum L.	100	6 months	cumin capsule (25 mg saponin) thrice [before main meals daily]	BMI£, TG, Cholā, ALT, AST, LDL∞, and FBS after treatment decreased compared to baseline but were not statistically significant.	Shavakhi, Torki et al. [23]
Barberry	Berberis Vulgaris L.	80	3 months	750 mg of barberry extract every day	In the treatment group, the mean serum levels of ALT and AST decreased, which was statistically significant compared to the control group.	Iloon Kashkooli, Najafi et al. [24]
Cinnamon	Cinnamomum zeylanicum	50	12 weeks	1500 mg cinnamon daily	In the cinnamon group, the mean serum levels of ALT and AST, gamma glutamine transpeptidase, and high-sensitivity C- reactive protein decreased which was statistically significant in contrast to the control group.	Askari et al. [25]

*ALT: Alanine aminotransferase, #AST: Aspartate aminotransferase, £BMI: Body mass index, āCol: Cholesterol, ¥FBS: Fasting Blood Sugar, € TG: Triglycerides, ∞LDL: Low-density lipoprotein