Herbal Medicines for Fatty Liver Diseases (Review)

Herbal medicines for fatty liver diseases (Review)

Liu ZL, Xie LZ, Zhu J, Li GQ, Grant SJ, Liu JP

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 8 http://www.thecochranelibrary.com

HEADER...... 1 ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 BACKGROUND ...... 3 Figure1...... 4 OBJECTIVES ...... 5 METHODS ...... 5 RESULTS...... 9 Figure2...... 10 Figure3...... 13 Figure4...... 14 DISCUSSION ...... 18 AUTHORS’CONCLUSIONS ...... 19 ACKNOWLEDGEMENTS ...... 20 REFERENCES ...... 20 CHARACTERISTICSOFSTUDIES ...... 29 DATAANDANALYSES...... 141 Analysis 1.1. Comparison 1 Medicinal herbs versus placebo, Outcome 1 ALT (U/L)...... 158 Analysis 1.2. Comparison 1 Medicinal herbs versus placebo, Outcome 2 AST (U/L)...... 159 Analysis 1.3. Comparison 1 Medicinal herbs versus placebo, Outcome 3 Liver/spleen CT ratio...... 159 Analysis 2.1. Comparison 2 Herbal medicines plus lifestyle intervention versus placebo plus lifestyle intervention, Outcome 1AST(U/L)...... 160 Analysis 2.2. Comparison 2 Herbal medicines plus lifestyle intervention versus placebo plus lifestyle intervention, Outcome 2ALT(U/L)...... 160 Analysis 2.3. Comparison 2 Herbal medicines plus lifestyle intervention versus placebo plus lifestyle intervention, Outcome 3ALP(U/L)...... 161 Analysis 2.4. Comparison 2 Herbal medicines plus lifestyle intervention versus placebo plus lifestyle intervention, Outcome 4Liver/spleenCTratio...... 161 Analysis 3.1. Comparison 3 Herbal medicines plus lifestyle intervention versus lifestyle intervention, Outcome 1 ALT (IU/L)...... 162 Analysis 3.2. Comparison 3 Herbal medicines plus lifestyle intervention versus lifestyle intervention, Outcome 2 AST (IU/L)...... 163 Analysis 3.3. Comparison 3 Herbal medicines plus lifestyle intervention versus lifestyle intervention, Outcome 3 Ultrasound:liverscore...... 163 Analysis 3.4. Comparison 3 Herbal medicines plus lifestyle intervention versus lifestyle intervention, Outcome 4 Liver CT withoutimprovement...... 164 Analysis 3.5. Comparison 3 Herbal medicines plus lifestyle intervention versus lifestyle intervention, Outcome 5 Adverse events...... 164 Analysis 3.6. Comparison 3 Herbal medicines plus lifestyle intervention versus lifestyle intervention, Outcome 6 GGT (U/L)...... 165 Analysis 4.1. Comparison 4 Herbal medicines versus conventional therapy, Outcome 1 ALT (IU/L)...... 165 Analysis 4.2. Comparison 4 Herbal medicines versus conventional therapy, Outcome 2 AST (IU/L)...... 167 Analysis 4.3. Comparison 4 Herbal medicines versus conventional therapy, Outcome 3 GGT (U/L)...... 168 Analysis 4.4. Comparison 4 Herbal medicines versus conventional therapy, Outcome 4 ALP (U/L)...... 169 Analysis 4.5. Comparison 4 Herbal medicines versus conventional therapy, Outcome 5 Abnormal ultrasound. . . . 170 Analysis 4.6. Comparison 4 Herbal medicines versus conventional therapy, Outcome 6 Abnormal AST (> 50 U/L). . 170 Analysis 4.7. Comparison 4 Herbal medicines versus conventional therapy, Outcome 7 Abnormal ALT (> 50 U/L). . 171 Analysis 4.8. Comparison 4 Herbal medicines versus conventional therapy, Outcome 8 Adverse events...... 172 Analysis 5.1. Comparison 5 Herbal medicines plus conventional therapy versus conventional therapy, Outcome 1 ALT (IU/L)...... 172

Herbal medicines for fatty liver diseases (Review) i Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.2. Comparison 5 Herbal medicines plus conventional therapy versus conventional therapy, Outcome 2 AST (IU/L)...... 173 Analysis 5.3. Comparison 5 Herbal medicines plus conventional therapy versus conventional therapy, Outcome 3 GGT (IU/L)...... 173 Analysis 5.4. Comparison 5 Herbal medicines plus conventional therapy versus conventional therapy, Outcome 4 Hepatic ultrasound without improvement...... 174 Analysis 6.1. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention,Outcome1ALT(IU/L)...... 175 Analysis 6.2. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention,Outcome2AST(IU/L)...... 177 Analysis 6.3. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 3 GGT (IU/L)...... 182 Analysis 6.4. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 4 L/S CT ratio...... 185 Analysis 6.5. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 5 Ultrasound without improvement...... 186 Analysis 6.6. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 6 Ultrasound: proximal diffuse high echogenic dots...... 187 Analysis 6.7. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 7 Ultrasound: distal end echo attenuation...... 187 Analysis 6.8. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 8 Ultrasound: unclear hepatic vessel structure...... 188 Analysis 6.9. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 9 Ultrasound: reduction of blood ﬂow...... 188 Analysis 6.10. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 10 Liver CT without improvement...... 189 Analysis 6.11. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 11 Adverse events...... 189 Analysis 6.12. Comparison 6 Herbal medicines plus lifestyle intervention versus conventional therapy plus lifestyle intervention, Outcome 12 Ultrasound: liver score...... 190 Analysis 7.1. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 1 Liver/spleenCTratio...... 190 Analysis 7.2. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 2 ALT (U/L)...... 191 Analysis 7.3. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 3 AST (U/L)...... 192 Analysis 7.4. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 4 GGT (U/L)...... 193 Analysis 7.5. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 5 Ultrasound: liver echo intensity...... 194 Analysis 7.6. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 6 Abnormal ultrasound...... 195 Analysis 7.7. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 7 Liver CT value...... 195 Analysis 7.8. Comparison 7 Herbal medicines plus lifestyle intervention plus conventional therapy versus lifestyle intervention plus conventional therapy, Outcome 8 Adverse events...... 196 ADDITIONALTABLES...... 196 APPENDICES ...... 242 CONTRIBUTIONSOFAUTHORS ...... 248 DECLARATIONSOFINTEREST ...... 248 SOURCESOFSUPPORT ...... 248 DIFFERENCES BETWEEN PROTOCOL AND REVIEW ...... 249 INDEXTERMS ...... 249

Zhao Lan Liu1, Liang Zhen Xie2, Jiang Zhu3, George Q Li4, Suzanne J Grant5, Jian Ping Liu1

1Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. 2First Hospital Afﬁliated to Heilongjiang University of Traditional Chinese Medicine, Haerbin, Heilongjiang Province, China. 3College of Humanities, Beijing University of Chinese Medicine, Beijing, China. 4Faculty of Pharmacy, University of Sydney, Sydney, Australia. 5Center for Comple- mentary Medicine Research, University of Western Sydney, Sydney, Australia

Contact address: Jian Ping Liu, Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China. [email protected].

Editorial group: Cochrane Hepato-Biliary Group. Publication status and date: New, published in Issue 8, 2013. Review content assessed as up-to-date: 31 May 2012.

Citation: Liu ZL, Xie LZ, Zhu J, Li GQ, Grant SJ, Liu JP. Herbal medicines for fatty liver diseases. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD009059. DOI: 10.1002/14651858.CD009059.pub2.

ABSTRACT

Background

Fatty liver disease is potentially a reversible condition that may lead to end-stage liver disease. Since herbal medicines such as Crataegus pinnatiﬁda and Salvia miltiorrhiza have increasingly been used in the management of fatty liver disease, a systematic review on herbal medicine for fatty liver disease is needed.

Objectives

To assess the beneﬁcial and harmful effects of herbal medicines for people with alcoholic or non-alcoholic fatty liver disease.

Search methods

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2012), MEDLINE, EMBASE, and Science Citation Index Expanded to 1 March 2012. We also searched the Chinese BioMedical Database, Traditional Chinese Medical Literature Analysis and Retrieval System, China National Knowledge Infrastructure, Chinese VIP Information, Chinese Academic Conference Papers Database and Chinese Dissertation Database, and the Allied and Complementary Medicine Database to 2 March 2012.

Selection criteria

We included randomised clinical trials comparing herbal medicines with placebo, no treatment, a pharmacological intervention, or a non-pharmacological intervention such as diet or lifestyle, or Western interventions in participants with fatty liver disease.

Data collection and analysis

Two review authors extracted data independently. We used the ’risk of bias’ tool to assess the risk of bias of the included trials. We assessed the following domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias. We presented the effects estimates as risk ratios (RR) with 95% conﬁdence intervals (CI) or as mean differences (MD) with 95% CI, depending on the variables of the outcome measures.

Herbal medicines for fatty liver diseases (Review) 1 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Main results We included 77 randomised clinical trials, which included 6753 participants with fatty liver disease. The risks of bias (overestimation of benefits and underestimation of harms) was high in all trials. The mean sample size was 88 participants (ranging from 40 to 200 participants) per trial. Seventy-five different herbal medicine products were tested. Herbal medicines tested in the randomised trials included single-herb products (Gynostemma pentaphyllum, Panax notoginseng, andPrunus armeniaca), proprietary herbal medicines commercially available, and combination formulas prescribed by practitioners. The most commonly used herbs wereCrataegus pinnatifida,Salvia miltiorrhiza,Alisma orientalis,Bupleurum chinense,Cassia obtusifolia, Astragalus membranaceous, and Rheum palmatum. None of the trials reported death, hepatic-related morbidity, quality of life, or costs. A large number of trials reported positive effects on putative surrogate outcomes such as serum aspartate aminotransferase, alanine aminotransferase, glutamyltransferase, alkaline phosphatases, ultrasound, and computed tomography scan. Twenty-seven trials reported adverse effects and found no significant difference between herbal medicines versus control. However, the risk of bias of the included trials was high. The outcomes were ultrasound findings in 22 trials, liver computed tomography findings in eight trials, aspartate aminotransferase levels in 64 trials, alanine aminotransferase activity in 77 trials, and glutamyltransferase activities in 44 trials. Six herbal medicines showed statistically significant beneficial effects on ultrasound, four on liver computed tomography, 42 on aspartate aminotransferase activity, 49 on alanine aminotransferase activity, three on alkaline phosphatases activity, and 32 on glutamyltransferase activity compared with control interventions. Authors’ conclusions Some herbal medicines seemed to have positive effects on aspartate aminotransferase, alanine aminotransferase, ultrasound, and computed tomography. We found no significant difference on adverse effects between herbal medicine and control groups. The findings are not conclusive due to the high risk of bias of the included trials and the limited number of trials testing individual herbal medicines. Accordingly, there is also high risk of random errors.

PLAIN LANGUAGE SUMMARY Herbal medicines for fatty liver diseases Fatty liver disease is a potentially reversible illness where fat builds up within the cells of the liver. It may lead to the liver no longer being able to function properly; this is called end-stage liver disease. This systematic review evaluated the effects and safety of herbal medicines (single herbs, branded herbal medicines, and prescribed formulas) for treating fatty liver disease. We included 77 randomised clinical trials in this review, which tested 75 herbal medicines. All trials had high risk of systematic errors (ie, bias or risk of overestimation of benefits and overestimation of harms) as well as high risks of random errors (ie, play of chance) due to the small number of people in the trials. Herbal medicines tested in the randomised clinical trials included single-herb products (Gynostemma pentaphyllum,Panax notoginseng, andPrunus armeniaca), commercially available branded herbal medicines, and combination formulas prescribed by practitioners. Herbs most commonly included as an ingredient in different products wereCrataegus pinnatifida,Salvia miltiorrhiza,Alisma orientalis,Bupleurum chinense,Cassia obtusifolia,Astragalus membranaceous, andRheum palmatum. We could not combine the results of the trials due to the range of different herbs used. We could not reach any conclusions about the use of herbal medicines for people with fatty liver disease as none of the trials reported results on death, liver-related illnesses, quality of life, or costs. A number of trials showed positive effects of herbal medicines compared with control interventions on enzyme activity (enzymes are proteins that cause chemical reactions in the body; eg, serum aspartate aminotransferase, alanine aminotransferase, glutamyltransferase, alkaline phosphatases), ultrasound scan findings, and computed tomography scan findings. No serious adverse effects were reported for herbal medicines. However, the methodology of the trials had high risk of systematic errors (bias). Furthermore, the individual herbs were seldomly retested, and all trials had relatively low numbers of people, which increases the risk of random errors (play of chance). Therefore, the findings are inconclusive, and rigorously conducted randomised clinical trials are required to establish the benefits and harms of herbal medicines for fatty liver disease.

Herbal medicines for fatty liver diseases (Review) 2 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. BACKGROUND alcohol use (Sanyal 2002; CSHCMA 2007; Fan 2007). Staging for NAFLD, performed using a combination of radiological and laboratory techniques, is recommended to reduce the requirement for invasive liver biopsy (Dowman 2011). Description of the condition Fatty liver disease occurs worldwide in people with excessive alco- Fatty liver disease is potentially a reversible condition that may hol intake, in people who are obese, or in people with metabolic lead to end-stage liver disease. Fatty acids, usually in the form syndrome (Browning 2004a; Browning 2004b; Crabb 2004; Rao of triglycerides, accumulate in the liver cells causing steatosis ( 2004; Zafrani 2004; Adams 2005; Hamaguchi 2005). Diagnos- Zakim 2003; Yao 2004). It is generally believed that there are tic differences make estimating the prevalence of fatty liver dis- four distinct histological states in the natural history of fatty liver ease difficult. Population-based studies estimate the prevalence of disease that indicate the progression of lesions: simple steatosis, NAFLD in the general population to be between 2.8% and 46% steatohepatitis, fibrosis, and cirrhosis (Review 1981; Caldwell (Figure 1), depending on the screening test used for liver imaging 2010). In cirrhosis, the liver is permanently damaged and scarred, (eg, ultrasound, computed tomography, or magnetic resonance and it may not be able to function properly. Fatty liver disease is imaging) (Lazo 2008). The estimated prevalence varies by region: histologically categorised into alcoholic fatty liver disease (AFLD) 16.9% in Asian countries, 23.2% in Europe and North America, and non-alcoholic fatty liver disease (NAFLD) (Reddy 2006). and 34.7% in the Middle East (Lazo 2008). Another study indi- Most people with fatty liver disease are asymptomatic, but some cated that the prevalence of liver steatosis on ultrasound was 57% present with fatigue or fullness, or pain in the right upper quadrant among asymptomatic overweight individuals attending an outpa- of the abdomen (Adachi 2005; Newton 2010). Usually abnor- tient clinic (Haentjens 2009). In a study with Chinese people, mal biochemistry is the only indication of fatty liver disease. El- 63.1% were diagnosed with fatty liver disease on ultrasonography evated serum alanine aminotransferase (ALT) and glutamyltrans- (Wang Y 2010). Most published studies focus on selected subpop- ferase (GGT) activities are considered surrogate markers of fat ac- ulations, particularly on specific subsets within a hospital-based pa- cumulation in the liver, although it is possible for people with tient population (eg, diabetic or obese individuals) (Denzer 2009; fatty liver disease to have normal transaminase activity (Zakim Guajardo-Salinas 2010; Wang Y 2010). Fatty liver disease occurs 2003; Yao 2004). Hence, these surrogate markers are neither suf- in all age groups, and there is evidence that the disease is increas- ficiently sensitive nor specific for the diagnosis of fatty liver, and ing among children, particularly with obesity. One study showed are only clinically useful when combined with clinical findings that the prevalence of NAFLD in junior high school students was (Preiss 2008). Through identifying fatty acid that has infiltrated 4%, which was primarily associated with obesity and reduced daily the liver, imaging studies may assist in the diagnosis of fatty liver physical activity (Tsuruta 2010). In an autopsy study of 742 chil- disease. The gold standard for the diagnosis of fatty liver disease dren and adolescents (aged two to 19 years), the prevalence of is liver biopsy, which is invasive and may even lead to significant fatty liver was 38% in obese and 5% in normal-weight children complications or death (Sanyal 2002). However, physicians sel- (Schwimmer 2006). Severe disease is more prevalent among adults. dom use liver biopsy as an initial diagnosis (Dienstag 2002; Sanyal People with NAFLD, with or without metabolic syndrome, are at 2002). AFLD is mainly diagnosed based on the information of ex- high risk for atherosclerosis (Assy 2010). Fatty liver is an indepen- cessive alcohol consumption, and it is recommended that people dent predictor of the metabolic syndrome, type 2 diabetes, and with suspected AFLD or NAFLD be questioned carefully about cardiovascular disease (Schwimmer 2006).

Herbal medicines for fatty liver diseases (Review) 3 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 1. Prevalence of nonalcoholic fatty liver disease (NAFLD) in general population. (Adapted from Lazo M, Clark JM. The epidemiology of non-alcoholic fatty liver disease: a global perspective. Seminars in Liver Disease 2008;28:339-50.)

Current treatment of NAFLD focuses primarily on risk factors, such as treating insulin resistance, decreasing delivery of fatty acids some people (Menon 2001; Sanyal 2004; Guallar 2005; Beltowski to the liver, and using drugs with potentially hepato-protective 2009; Jacobson 2009). Treatment of AFLD encompasses stop or effects. The current recommended approach for treating NAFLD reduction of alcohol consumption. is to apply lifestyle modification to all participants. People with An increasing number of people use herbal products, including morbid obesity may also benefit from bariatric surgery, while those Chinese herbs, to manage or treat their disease (Eisenberg 1998). who are obese or overweight may benefit from pharmacological Herbal medicines are defined in this review as a product derived therapy (Ahmed 2009). In general, the prognosis of fatty liver from medicinal plants or parts of the plants used for the treatment disease depends on the extent of liver damage. Steatosis alone of a disease, and herbal medicines include the use of plant, animal, generally has a benign course. Data on progression to cirrhosis and and mineral substances in preparations administered as capsules, the precise risk of mortality are limited (Sanyal 2002). tablets, teas, injections, decoctions, and powders. Herbal medicines have been widely used for the management of Description of the intervention fatty liver disease. According to the pathological mechanism of Currently, the only effective treatment for NAFLD is calorie re- traditional Chinese medicine (TCM), fatty liver is characterised striction and weight loss (Ahmed 2009). Weight loss may be asso- by deficiency of three Zang viscera, such as liver, spleen, and kid- ciated with regression of fat within the liver (Ueno 1997; Dixon ney, and manifests as spleen Qi deficiency, and liver and kidney 2004). Pharmacological interventions that have been used for fatty deficiency, resulting in phlegm and dampness retaining, Qi stag- liver disease include drugs that improve insulin resistance (eg, met- nation, and blood stasis. Based on the disorder differentiation, the formin), antioxidants (eg, vitamin C, vitamin E), the so-called treatment methods for fatty liver are to nourish Qi, using herbs ’hepato-protective agents’ (such as ursodeoxycholic acid, and lipid- such as Astragalus membranaceous, to strengthen the liver using lowering drugs (eg, statin and gemfibrozil)), most of which aim to herbs such as Bupleurum chinense, to strengthen the spleen using treat the associated abnormal metabolic conditions (Adams 2006). herbs such as Crataegus pinnatifida, to clear heat using herbs such Several of these interventions have been associated with improve- as Rheum officinalis and Cassia obtusifolia, to discharge phlegm us- ment in liver enzyme activity and liver histology (Harrison 2003; ing herbs such as Alisma orientalis, and to rejuvenate the blood Dixon 2004; Promrat 2004; Rallidis 2004; Abdelmalek 2009). using herbs such as Salvia miltiorrhiza (Xu 2003). Western drugs are generally well tolerated; however, adverse effects, Clinical trials of single herbs, such as Crataegus pinnatifida and including manifestations due to hepatotoxicity, increased risk of Salvia miltiorrhiza, are effective in treating fatty liver disease (Ji death, heart failure, or pro-arrhythmic potential, may occur in 2005; Gu 2007a; Li 2009; Xie 2009; Zhang 2009). One clinical

Herbal medicines for fatty liver diseases (Review) 4 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. trial of Tiaozhi Yanggan (a herbal formula) decoction showed im- AFLD and NAFLD separately, but we also wanted to test their provements in the symptoms, signs, liver function, blood lipids, overall effects on fatty liver disease. and iconographic indices with no serious adverse reactions in people with NAFLD (Gu 2007a). Danning tablets, a Chinese medicinal herb, showed more beneﬁcial effects than ursodeoxycholic acid in improving body mass index and distress in the hepatic region in people with NAFLD (Ji 2005). All medicinal agents poten- OBJECTIVES tially have adverse effects and toxicity, and herbs are no differ- To assess the beneﬁcial and harmful effects of single-herb prod- ent. Adverse effects of herbal medicines may be intrinsic such as ucts, commercially available proprietary medicines, and combina- predictable or idiopathic (allergy, anaphylaxis, etc). Some general tion formulas prescribed by practitioners for people with AFLDor adverse effects may include low appetite, nausea, stomach-ache, NAFLD. abdominal distension, and diarrhoea.

How the intervention might work METHODS Animal studies indicate that the mechanisms of action vary depending on the medicinal herb used. One animal study showed Criteria for considering studies for this review that TCM could produce a marked effect via relieving lipopolysac- charide-induced liver injury (Gao 2008). The cardiotonic tablets Types of studies tested for the prevention of AFLD acted via enhanced expression of the peroxisome proliferator-activated receptor alpha (PPAR-al- We included randomised clinical trials irrespective of blinding, pha) (Horie 2009). The mechanism of action of Xuezhikang (Chi- publication status, or language. We did not include quasi-ran- nese medicinal herb) on fatty liver disease is likely to involve in- domised and observational studies. hibition of the hepatic expression of tumour necrosis factor-alpha (Hong 2007). The single medicinal herb, Crataegus pinnatifida, contains lipase, which promotes the hydrolysis of fat, and a variety Types of participants of organic acids, which can increase protease activity (Sha 2009). Participants of any age, sex, or ethnic origin with AFLD or While some active ingredients from herbal medicines have been NAFLD. identified, the mechanisms of most herbal medicines for the treat- Fatty liver disease was diagnosed based on the following criteria ment of fatty liver disease are still not clear. (Fan 2007; Dowman 2011): 1. Imaging techniques showing evidence of hepatic steatosis or steatofibrosis with or without liver biopsy showing histological Why it is important to do this review alterations including simple steatosis, steatohepatitis, and fibrosis. With a global increase in fatty liver disease, there is considerable 2. Exclusion of other causes of hepatic steatosis or merit in investigating therapeutic options that may be used in ad- steatofibrosis including hepatitis B, hepatitis C, autoimmune dition to lifestyle modification, or where lifestyle modification or hepatitis, and genetic liver diseases such as Wilson’s disease and pharmacological intervention have not worked or are not appro- haemochromatosis. We also excluded participants presenting priate. The evidence from randomised clinical trials on the effects with one or more causes commonly associated with secondary of herbal medicines such as Crataegus pinnatifida,Salvia miltior- NAFLD (drugs and miscellaneous disorders such as hyper-alpha rhiza,and Yiqi Huoxue formula for fatty liver disease are promis- or hypo-beta-lipoproteinaemia (or both), partial lipodystrophy, ing, but the evidence is not conclusive (Ji 2005; Gu 2007a; Li environmental toxins, or total parenteral nutrition). 2009; Zhang 2009). Toour knowledge, there are no meta-analyses People with NAFLD met the following criteria: or systematic reviews of herbal medicines for fatty liver disease. 1. Daily alcohol intake was less than 20 g per day for women A systematic review that critically appraises the available evidence and less than 30 g per day for men (Bayard 2006). on the potential benefits and adverse effects of herbal medicines 2. Liver biopsy (where available) or other diagnostic criteria for fatty liver disease is needed to update the body of evidence, to (see above) supported the diagnosis of NAFLD. identify areas in need of further research, and also to help people People with AFLD met the following criteria: make practical decisions. We wanted to study both AFLD and 1. Daily alcohol intake was more than 20 g per day for women NAFLD in one review to increase the precision and power of our and more than 30 g per day for men (Bayard 2006). analyses. However, we are aware that the two major types of fatty 2. Liver biopsy (where available) or other diagnostic criteria liver disease have pathogenetic differences, and we therefore also (see above) supported the diagnosis of AFLD. wanted to test the effects of the individual herbal medicines on We also accepted diagnosis by national or regional standards.

Intervention Search methods for identification of studies Medicinal herb refers to using a plant’s seeds, berries, roots, leaves, bark, or flowers, or extractions of herbs for medicinal purposes. For inclusion, we considered trials that compared a medicinal Electronic searches herb consisting of a single herb, commercially available propri- We searched The Cochrane Hepato-Biliary Group Controlled Tri- etary medicines, or prescribed formulas versus placebo, no treat- als Register (Gluud 2013), the Cochrane Central Register of Con- ment, a pharmacological intervention, or a non-pharmacological trolled Trials (CENTRAL), MEDLINE, EMBASE, Science Cita- intervention such as diet or exercise. tion Index Expanded (Royle 2003), and Allied and Complemen- We considered any pharmacological intervention that might have tary Medicine Database (AMED). The search strategies with the been administered in addition to the medicinal herb for inclusion time spans of the searches are given in Appendix 1. The listed as long as all trial comparison groups received it. We included all English databases were searched to 1 March 2012. available interventions under this category regardless of potential We also searched the Chinese BioMedical Database, Traditional mechanisms of action. Chinese Medical Literature Analysis and Retrieval System, China For analyses, we grouped the herbal interventions as single herbs, National Knowledge Infrastructure, Chinese VIP Information, proprietary herbal medicine, or prescribed formulas. Chinese Academic Conference Papers Database, and Chinese Dis- sertation Database. The strategies for these databases were in Chi- nese and are available from the review authors on request. We Types of outcome measures searched all Chinese databases to 2 March 2012. We identified additional key words of relevance during electronic or other searches and modified the search strategies for the elec- Primary outcomes tronic databases to incorporate these terms. We included studies 1. Death from any cause. published in any language. 2. Hepatic-related mortality. 3. Hepatic-related morbidity (cirrhosis, variceal bleeding, Searching other resources hepatic encephalopathy, hepato-renal failure, carcinoma). 4. Adverse events. We defined these as any untoward medical We tried to identify additional trials by searching the reference occurrence that may not necessarily have a causal relationship lists of the included trials. with the treatment, but resulted in a dose reduction or discontinuation of treatment (ICH-GCP 1997). We defined severe adverse events as any event that would increase mortality; Data collection and analysis was life threatening; required hospitalisation; resulted in a persistent or significant disability; or any important medical event that may jeopardise the participant or require intervention Selection of studies to prevent it. Two review authors (ZJ or XLZ and LZL) independently selected 5. Health-related quality of life (evaluated by a validated the trials to be included in the review according to the prespecified instrument). selection criteria. We resolved any disagreements by discussion. We included an adapted preferred reporting Items for systematic reviews and meta-analyses (PRISMA) flow chart of study selection Secondary outcomes was included (Liberati 2009). 1. Radiological response (degree of fatty liver infiltration assessed by ultrasound, computed tomography , nuclear magnetic resonance, or other imaging techniques). Data extraction and management 2. Biochemical response (serum activities of aspartate For trials that fulfilled the inclusion criteria, two review authors aminotransferase (AST), alanine aminotransferase (ALT), (ZJ or XLZ, and LZL) independently abstracted data on relevant alkaline phosphatases (ALP), gamma-glutamyl-transpeptidase population and intervention characteristics using standard data (GGT), serum total bilirubin, and ferritin). extraction templates. We resolved any disagreements by discussion, 3. Histological response (number of people without or, if required, by a third review author (JPL). histological improvement in the degree of fatty liver infiltration, We tabulated and assessed adverse events with descriptive or statis- inflammation, and fibrosis). tical analyses between the experimental and control interventions.

Herbal medicines for fatty liver diseases (Review) 6 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Dealing with duplicates and co-publications Incomplete outcome data If we identified more than one publication of the same randomised • Low risk of bias: the numbers and reasons for dropouts and clinical trial, we extracted data from the most recent or most ex- withdrawals in all intervention groups were described or if it was plicit publication. We then listed these multiple publications un- specified that there were no dropouts or withdrawals. der the original publication. • Uncertain risk of bias: the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated. • Assessment of risk of bias in included studies High risk of bias: the number or reasons for dropouts and withdrawals were not described. Two review authors (XLZ and LZL) assessed the methodological quality of each trial independently, using risk of bias domains. We based the definitions on recommendations from the Cochrane Selective outcome reporting Handbook for Systematic Reviews of Interventions (Higgins 2011), • Low risk of bias: predefined, or clinically relevant and the Cochrane Hepato-Biliary Group Module (Gluud 2013), and reasonably expected outcomes were reported. publications by Schulz 1995; Moher 1998; Kjaergard 2001; Egger • Uncertain risk of bias: not all predefined, or clinically 2003; Wood 2008; Lundh 2012; Savovi 2012a; and Savovi relevant and reasonably expected outcomes were reported or 2012b. were not reported fully, or it was unclear whether data on these outcomes were recorded or not. • High risk of bias: one or more clinically relevant and Sequence generation reasonably expected outcomes were not reported; data on these • Low risk of bias: the method used was considered either outcomes were likely to have been recorded. adequate (eg, computer-generated random numbers, table of random numbers) or unlikely to introduce confounding. Other bias • Uncertain risk of bias: there was insufficient information to assess whether the method used was likely to introduce In addition to the above-mentioned biases, we used the following confounding. pattern for industry bias, academic bias, or other bias that could • High risk of bias: the method used (eg, quasi-randomised be detected. • trials) was inadequate and likely to introduce confounding. Low risk of other bias: the trial appeared to be free of other components that could put it at risk of bias. • Uncertain risk of bias: the trial may or may not have been Allocation concealment free of other components that could put it at risk of bias. • High risk of other bias: there were other factors in the trial • Low risk of bias: the method used (eg, central allocation) that could put it at risk of bias; for example, for-profit was unlikely to induce bias on the final observed effect. involvement, authors have conducted trials on the same topic, • Uncertain risk of bias: there was insufficient information to etc. assess whether the method used was likely to induce bias on the estimate of effect. Following the evaluation of the above domains, we judged an • High risk of bias: the method used (eg, open random included trial as a trial with a low risk of bias if the risk of bias was allocation schedule) was likely to induce bias on the final evaluated as ’low’ in all the above domains. If we judged the risk observed effect. of bias as ’uncertain’ or ’high’, then we listed the trial under the group of trials with ’high risk of bias’ trials. We resolved disagreements by consensus or by consultation with Blinding a third review author (JPL). • Low risk of bias: the trial was described as blinded, the parties that were blinded, and the method of blinding was Measures of treatment effect described, so that knowledge of allocation was adequately prevented during the trial. • Uncertain risk of bias: the trial was described as blind, but Dichotomous data the method of blinding was not described, so that knowledge of Dichotomous data (eg, death - yes/no) were expressed as risk ratios allocation was possible during the trial. (RR) with their 95% confidence interval (CI). We calculated the • High risk of bias, the trial was not blinded, so that the risk difference (RD) and number needed to treat for an additional allocation was known during the trial. beneficial outcome (NNTB) in the analysis, whenever relevant.

Herbal medicines for fatty liver diseases (Review) 7 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. When adverse events were reported and data could be analysed, we Assessment of biases calculated the number needed to treat for an additional harmful We used funnel plots to assess potential existence of bias. There outcome (NNTH). We calculated RD, NNTB, and NNTH ac- are a number of explanations for the asymmetry of a funnel plot cording to the guidelines in the Cochrane Handbook for Systematic (Sterne 2001). Therefore, we interpreted the results with care (Lau Reviews of Interventions (Higgins 2011). 2006).

Data synthesis Continuous data We summarised data statistically whenever they were available, Continuous outcomes (eg, scores of quality of life) were expressed sufficiently similar, and of sufficient quality. We performed statisti- as mean difference with 95% CI. cal analyses using Review Manager 5.1 (RevMan 2011) following the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Time-to-event data We performed meta-analyses of data, using both random-effects models and fixed-effect models. When significant heterogeneity Whenever time-to-event data (eg, time until death) were available, existed, we reported the results from both models, but when there the treatment effects were expressed as hazard ratios. was no significant heterogeneity, we presented the results from the fixed-effect model only. However, when heterogeneity was substantial, we did not perform a meta-analysis because the effect es- Unit of analysis issues timate did not reliably reflect the ’true’ value, and we performed Data from intervention groups in randomised clinical trials, the a narrative, qualitative summary instead. In order to contrast ab- first period of cross-over trials, and cluster-randomised trials. solute and relative measures, we also expressed results as NNTB or NNTH. NNTB and NNTH depended, among other things, on the time of follow-up and the baseline risk. Therefore, we tried to adjust for time of follow-up by analysing NNTH and NNTB Dealing with missing data (Mayne 2006). For discrete data, we adjusted for the baseline risk We obtained relevant missing data from authors of the included by analysing change in event proportions. For continuous data, trials. We performed intention-to-treat (ITT) analysis on all data when groups were not matched at baseline, we reported discrete that we obtained from the trial authors. We investigated attri- data descriptively. tion proportions such as dropouts, losses to follow-up, and withdrawals, and we critically appraised issues of missing data as ad- Trial sequential analysis vised in the Cochrane Handbook for Systematic Reviews of Interven- tions (Higgins 2011). Trial sequential analyses (CTU 2011; Thorlund 2011) could reduce the risk of random errors and prevent premature statements of superiority of the experimental or control intervention (Wetterslev 2008). We had planned to perform a trial sequential analysis for Assessment of heterogeneity our primary outcome with a type I error of 5%, type II error of In the event of substantial clinical, methodological, or statisti- 20% (80% power), and adjusted for heterogeneity and diversity cal heterogeneity, we only presented the effect estimates for each among included trials (Brok 2008; Wetterslev 2008; Brok 2009; comparison. We reviewed the trial components, such as partici- Thorlund 2009; Wetterslev 2009; Thorlund 2010). As it was not pants, diseases, interventions, comparisons, and outcomes, in the possible to perform meta-analyses in this review, we could not per- included trials to decide if the heterogeneity was substantiallylarge. form trial sequential analyses. We identified heterogeneity by visual inspection of the forest plots, by using a standard Chi2 test and a significance level of α = 0.1, in view of the low power of such tests. We specifically examined het- Subgroup analysis and investigation of heterogeneity erogeneity with the I2 statistic, quantifying inconsistency across We mainly carried out subgroup analyses when one of the pri- studies to assess the impact of heterogeneity on the meta-analysis mary outcome measures demonstrated statistically significant dif- (Higgins 2002; Higgins 2003). An I2 statistic of 50% and more inferences between the intervention groups. In any other case, sub- dicated a substantial level of inconsistency (Higgins 2011). When group analyses were clearly marked as a hypothesis-generating ex- we found heterogeneity, we attempted to determine potential rea- ercise. sons for it by examining individual trial and subgroup character- We planned the following subgroup analyses: istics. • NAFLD compared to AFLD.

Herbal medicines for fatty liver diseases (Review) 8 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. • Different durations of intervention. Description of studies • Trials with low risk of bias compared to trials with high risk of bias.

Sensitivity analysis Results of the search We performed sensitivity analyses in order to explore the influence of the following factors on intervention effect size. Our initial searches identified 8382 citations. All were from • Repeating the analysis excluding any unpublished trials in electronic searches. After we removed duplicates from different order to establish how much they dominated the results. databases, we retained 4810 potentially relevant articles for further • Repeating the analysis excluding the trials using the assessment. After reading titles and abstracts, we excluded 4719 of following filters: diagnostic criteria, source of funding these articles because they were duplicates, non-clinical studies, or (commercially funded compared with non-(commercially) had study objectives that were different from this review. Ninety- funded), and country. one articles published in Chinese or English were retrieved for further assessment. After screening the full text, we included 76 We also tested the robustness of the results by repeating the analysis randomised clinical trials of the 91 trials and we found another using different statistical models (fixed-effect and random-effects trial through reading reference lists of other references. Therefore, models). we included 77 randomised clinical trials. We excluded 15 studies after reviewing the full papers, and listed the reasons for exclusion in the Characteristics of excluded studies table. We prepared a PRISMA flow diagram to describe the publications found through RESULTS our searches (Figure 2).

Herbal medicines for fatty liver diseases (Review) 9 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 2. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) ﬂow-chart of study selection.

Herbal medicines for fatty liver diseases (Review) 10 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. commercially available proprietary herbal medicines, and combi- Included studies nation formulas prescribed by practitioners (Table 2). The formu- We included 77 randomised clinical trials from 77 publications lations of the herbal medicines were different. The Chinese herbal in this review. Further details are given in the Characteristics of medicines were prepared in the form of capsules, tablets, granules, included studies table. Seventy-four of the included trials were herbal teas, and decoctions (beverages that result from the method published in Chinese. The remaining three trials were published in of decoction). No trial reported the quality standards of the herbal English (Chou 2006; Gu 2007a; Zhang 2008). All of the 77 trials preparations. were conducted in China, and all of them used herbal medicines The following from China. All of the trials employed a parallel two-arm design. herbs were most commonly included as an ingredient in differ- We found no unpublished trials. ent products: Crataegus pinnatifida,Salvia miltiorrhiza,Alisma orientalis,Bupleurum chinense,Cassia obtusifolia,Astragalus membranaceous,Rheum palmatum, Curcuma wenyujin,Citrus reticulata,Poria Participants cocos,Atractylodes macrocephala,Artemisia capillaries,Pinellia ter- We included 6753 participants with fatty liver disease in the 77 nate,Polygonum cuspidatum,Glycyrrhiza uralensis,Codonopsis pilo- trials and only 45 of the 6753 were lost at follow-up. All of the sula,Citrus aurantium,Nelumbo nucifera,Paeonia lactiflora,Panax 6753 participants were recruited from Chinese populations. The notoginseng,and Polygonum multiflorum. They were often used mean sample size of the trials was 88 participants (range 40 to 200 in a formula of multiple ingredients in various combinations. participants) per trial. Twelve trials did not report the age range of OnlyGynostemma pentaphyllum,Panax notoginseng,and Prunus ar- the participants and the ages from the remaining 65 trials ranged meniaca were used as single-herb products. These herbs have the from nine to 70 years. Ten trials did not report the mean age of alleged function of nourishing Qi, strengthening the liver and the participants and the mean age (± standard deviation) of the spleen, clearing heat, discharging phlegm, and restores the blood, participants from the remaining 67 trials was 42.29 ± 5.87 years. and the herbs were chosen based on TCM theory. Detailed infor- Seven trials did not report the numbers of male and female partic- mation is shown in Table 2. ipants (Huang 2005; Li 2006a; Wu 2006; Ma 2010; Wang 2010; Other herbal ingredients Xu 2010; Wang 2011b). Among the 6210 participants in 70 trials, used in the formulas included:Amomum villosum,Carthamus tinc- the proportion of males to females was almost 2:1 (4104 males: torius,Coix lacryma-jobi var. ma-yuen,Corydalis yanhusuo,Curcuma 2106 females). Nine trials included inpatients, 40 trials included longa,Cyperus rotundus,Epimedium brevicornum,Gentiana man- outpatients, 22 trials included both inpatients and outpatients, shurica,Hordeum vulgare,Lysimachia christinae,Psorales corylifo- and six trials did not specify trial settings. lial,Raphanus sativus,Sargassum pallidum. Ilex lutifolia,Acorus tatarinowii,Aloe vera var. chinensis,Amomun kravanh,Angelica Diagnosis sinensis,Arisaema heterophyllum,Clematis armandi,Coptis chinensis,Cuscuta chinensis,Dolichos lablab,Eupatorium fortune,Forsythia Five trials enrolled people with AFLD, 56 trials enrolled people suspense,Gardenia jasminoides,Hedyotis diffusa,Imperata cylindrica with NAFLD, three trials enrolled people with AFLD or NAFLD, var. major,Luffa cylindrical,Massa Fermenata,Morinda offici- and 13 trials did not specify the type of fatty liver disease. Among nalis,Panax ginseng,Plantago asiatica,Pogostemon cablin,Polyporus the 77 included trials, six trials did not specify diagnostic criteria umbellatus,Prunus armeniaca,Prunus persica,Pseudostellaia het- (Table 1), 64 trials followed the fatty liver disease diagnostic criteria erophylla,Pueraria lobata,Scutellaria bicalensis,Sedum sarmento- issued by the Fatty Liver and Alcoholic Liver Diseases Group, sum,Sinapi alba,Sophora flavescens,Trionys sinensis,Trogopterus xan- Society of Hepatology, Chinese Medical Association (see Table thipes,Ziziphus ju- 1). Seven trials specified the diagnostic criteria but did not give jube,Zingiber offcinale,Euonymus ulmoides,Cornus officinalis,Melia citations for diagnostic criteria. toosendan,Chrysanthemum sinense,Uncaria hirsute,Eclipta pros- trata,Trichosanthis kirilowii,Isatis tinctoria, and Lycium chinense. Interventions Detailed information is shown in Table 2. There were large variations in the formulations, dosages, routes of The control interventions included placebo, conventional medicine, lifestyle intervention, or lifestyle intervention plus administration, durations of treatment, and control interventions conventional drug(s). The conventional drugs included Essen- in the included trials among the herbal medicines tested (Table 2 tiale® forte capsules (phosphatidylcholine from soybeans), sim- and Characteristics of included studies). vastatin, ethyl polyenoate soft capsules, ursodeoxycholic acid, Es- In total, 75 different Chinese herbal medicines were tested, and the sentiale® forte + vitamin, polyene phosphatidyl choline capsules, compositions of the herbal medicines were single-herb products,

Herbal medicines for fatty liver diseases (Review) 11 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. tiopronin tablets, methionine plus choline bitartrate tablets, silib- AST, ALT, GGT, and ALP levels, ultrasound findings, computed inin capsules, simvastatin plus diammonium glycyrrihizinate, thi- tomography (CT) scan findings, and adverse effects. All trials mea- ola tablets, reduced glutathione tablets, silybin meglumine tablets sured outcomes at the end of treatment, and no trial reported fol- or Dongbao Gantai (Ansua Danjia Pian) tablets. Detailed infor- low-up data after the end of treatment. No serious adverse events mation is shown in the Characteristics of included studies table. were reported, but some minor adverse effects occurred (see de- The comparisons were: tailed information in Table 2). • Herbal medicines versus placebo (one trial). Twenty-seven of the 77 trials reported details on adverse events • Herbal medicines plus lifestyle intervention versus placebo in the medicinal herb groups. Sixteen trials observed mild adverse plus lifestyle intervention (two trials). events, such as rash, nausea, diarrhoea, gastric discomfort, reduced • Herbal medicines plus lifestyle intervention versus lifestyle appetite, light pain, and stomach ache (Table 2). Eleven trials intervention (five trials). observed no adverse events in the Chinese herbal medicines groups • Herbal medicines versus conventional medicine (17 trials). (Table 2). The remaining 50 trials did not report adverse events • Herbal medicines plus conventional drug versus the same in the intervention groups. conventional drug (two trials). • Herbal medicines plus lifestyle intervention versus conventional drug plus lifestyle intervention (35 trials). Excluded studies • Herbal medicines plus lifestyle intervention plus We excluded 15 studies as they did not meet the inclusion cri- conventional drug(s) versus lifestyle intervention plus the same teria of this review. The reasons for exclusion are listed in the conventional drug(s) (15 trials). Characteristics of excluded studies table. The durations of treatment were one month in five trials, one and a half months in five trials, two months in 15 trials, three months Risk of bias in included studies in 39 trials, six months in 10 trials, 12 months in two trials, and 48 months in one trial (see Characteristics of included studies Most of the trials provided limited information about study de- table). The different treatment durations were not subjected to sign and methodology. Three multicentre randomised clinical tri- a sensitivity analysis because there was an insufficient number of als were identified (Ji 2005; Li 2008; Wang 2008b). Twenty eight homogeneous trials to allow a meta-analysis. trials had prespecified inclusion criteria, and 32 trials had prespec- We found no unpublished trials. ified exclusion criteria (Characteristics of included studies). None of the trials stated that they had performed an ITT analysis to evaluate the data. Assessment of risk of bias is described for each Outcomes included trial in the Characteristics of included studies table. Our None of the trials reported primary outcomes including death judgements about each risk of bias domain are presented as per- from any cause, hepatic-related mortality, hepatic-related morbid- centages across all included trials in Figure 3, and our judgements ity, and health-related quality of life. There were no outcome data about each risk of bias domain for each included trial are shown in any of the trials on costs. Reported outcomes included serum in Figure 4.

Herbal medicines for fatty liver diseases (Review) 12 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Herbal medicines for fatty liver diseases (Review) 13 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 4. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Herbal medicines for fatty liver diseases (Review) 14 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Allocation assessed as not free of other potential sources of bias. Detailed information is shown in the Characteristics of included studies table and Figure 4. Sequence generation and allocation concealment Twenty-eight trials reported detailed information on allocation sequence generation and were regarded as adequate, and 49 trials Effects of interventions did not report the speciﬁc methods of allocation sequence gener- Reported outcomes included adverse effects, ﬁndings from ultra- ation (Characteristics of included studies)(Figure 4). Two of the sound scan or computed tomography scan, and serum levels of 77 included trials reported allocation concealment methods, and AST, ALT, GGT, and ALP. No serious adverse events were re- the methods were assessed as adequate (Ji 2005; Kong 2010). The ported. We could not perform meta-analyses in this review and we remaining trials did not provide information on allocation con- only did qualitative synthesis on the included trials due to hetero- cealment. Detailed information is shown in the Characteristics of geneity in the participants, interventions, and controls. We could included studies table and Figure 4. not do trial sequential analyses to control for risks of random errors because meta-analyses were not performed. Blinding We reported the results according to the outcomes. One trial claimed that it used double-blinding but it did not report who was blinded (Ji 2005). One trial reported that the participants were blinded by using placebo (Chou 2006). One trial reported Primary outcomes that the statisticians and outcome assessors were blinded (Kong 2010). The remaining trials did not mention blinding. Detailed information is shown in the Characteristics of included studies Death from any cause table and Figure 4. None of the trials reported death.

Incomplete outcome data

Three trials gave unclear information on withdrawals and loss to Hepatic-related mortality follow-up (Wang 2008a; Li 2009; Wang 2011b). Three trials reported participants lost to follow-up without providing the rea- None of the trials reported outcomes on hepatic-related mortality. sons for the loss and were assessed as trials with high risk of bias (Ji 2005; Chou 2006; Lin 2011). The remaining 71 trials reported that no participants were lost to follow-up during the trial or spec- Hepatic-related morbidity (cirrhosis, variceal bleeding, iﬁed the numbers and reasons of withdrawal and loss to follow-up hepatic encephalopathy, hepato-renal failure, carcinoma) and were assessed as trials with low risk of bias. Detailed informa- None of the trials reported outcomes on hepatic-related morbidity. tion is shown in the Characteristics of included studies table and Figure 4.

Adverse events Selective reporting Five trials reported adverse events in the intervention and control In 24 trials, some prespeciﬁed outcome measures were not re- group (Zhang 2003; Xu 2008; Jia 2009; Guan 2010; Lin 2011). ported, and the trials were assessed as having high risk of reporting No signiﬁcant differences were found between the intervention bias (Characteristics of included studies and Figure 4). Fifty-three and the control groups (Table 3). We could not perform a meta- trials were considered free of selective reporting (Characteristics of analysis as there was only one trial for each medicinal herb. included studies and Figure 4).

Other potential sources of bias Health-related quality of life (evaluated by a validated instrument) Only one of the included trials reported sample size calculations and was assessed as low risk of other bias (Chou 2006). The re- None of the trials reported outcomes on health-related quality of maining trials did not report the sample size calculations and were life.

Herbal medicines for fatty liver diseases (Review) 15 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Secondary outcomes Ultrasound: distal end echo attenuation One trial reported B-ultrasound results on distal end echo attenuation, and found no signiﬁcant difference between Jiangan Jiangzhi Radiological response (degree of fatty liver inﬁltration tablets plus lifestyle intervention and control groups (Mi 2010) assessed by ultrasound, computed tomography, nuclear (Table 3). magnetic resonance, or other imaging techniques)

Ultrasound: reduction of blood ﬂow

Ultrasound: liver score One trial reported B-ultrasound results on reduction of blood flow, and found no significant difference between Jiangan Jiangzhi Two trials reported ultrasound results, and there were significant tablets plus lifestyle intervention and control groups (Mi 2010) differences between the intervention and control groups (Wang (Table 3). 2008b; Wang 2010)(Table 4). Compared with lifestyle intervention, Jiangzhi Ligan decoction plus lifestyle intervention improved the ultrasound results (Wang 2008b)(Table 4). Compared with fenofibrate sustained release capsules plus lifestyle intervention, Ultrasound: unclear hepatic vessel structure Chaihu Shugan powder plus lifestyle intervention improved the Two trials reported B-ultrasound results on unclear hepatic ves- ultrasound results (Wang 2010)(Table 4). We could not perform sel structure, and found no significant differences between Shuai a meta-analysis because there was only one trial for each medicinal Qingzhi powder plus lifestyle intervention, Jiangan Jiangzhi tablets herb. plus lifestyle intervention and control groups (Dai 2009; Mi 2010) (Table 3). We could not perform a meta-analysis because there was only one trial with each medicinal herb. Ultrasound: liver echo intensity One trial reported ultrasound results, and there was no significant difference between the colon herbs Dialysis therapy plus lifestyle Hepatic ultrasound without improvement: number of intervention and the control groups (Liang 2008)(Table 4). participants Eleven trials reported the number of people without improvement on hepatic B-ultrasound (Ji 2005; Gu 2007a; Liu 2008; Dai 2009; Abnormal ultrasound: number of participants Liu 2009; Zhou 2009; Lin 2010a; Wu 2010; Zhao 2010; Zhu Seven trials reported the outcome data on abnormal ultrasound 2010; Lin 2011)(Table 3). Two trials showed a significant dif- (Wang 2006; Zhang 2007; Huo 2008; Zhang 2008; Guan 2010; ference between the intervention and control groups (Liu 2009; Liang 2011; Zhang 2011). Significant differences were found in Zhou 2009). Compared with compound methionine and choline the intervention and control groups in three trials (Zhang 2007; bitartrate tablets plus lifestyle intervention, Xiaoyu Huatan decoc- Guan 2010; Zhang 2011). Compared with vitamin B and C plus tion plus lifestyle intervention significantly reduced the number glucurolactone tablets, Prunus armeniaca (wild apricot) signifi- of people with no improvement on hepatic ultrasound results (Liu cantly reduced the number of people with abnormal ultrasound 2009). Compared with tiopronin tablets plus lifestyle interven- (Guan 2010). Compared with Essentiale®, Sanyu Huazhuo de- tion, Lishi Huoxue Tongluo decoction plus lifestyle intervention coction significantly reduced the number of people with abnormal significantly reduced the number of people with no improvement ultrasound (Zhang 2007). Comparing tiopronin, Kangzhi for- on hepatic ultrasound results (Zhou 2009). Detailed information mula significantly reduced the number of people with abnormal is shown in Table 3. We could not perform a meta-analysis as there ultrasound (Zhang 2011). Detailed information is shown in Table was only one trial with each medicinal herb. 3.

Liver computed tomography without improvement: number Ultrasound: proximal diffuse high echogenic dots of participants One trial reported ultrasound results on proximal diffuse high Three trials reported the number of people with no improvement echogenic dots, and found no signiﬁcant difference between Jian- on liver computed tomography results. No signiﬁcant difference gan Jiangzhi tablets plus lifestyle intervention and control groups was found between the intervention and control groups (Ji 2005; (Mi 2010)(Table 3). Gu 2007a; Jia 2009)(Table 3).

Herbal medicines for fatty liver diseases (Review) 16 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Liver/spleen computed tomography ratio AST levels Four trials reported the level of liver/spleen computed tomogra- Sixty-four trials reported AST levels, and detailed information is phy ratio (Lou 2008; Fei 2009; Liang 2010; Ma 2010)(Table shown in Table 4. Forty-two trials had significantly lower AST 4). The liver/spleen computed tomography ratio was significantly levels in the intervention group than in the control group (Zhang higher in the intervention group than in the control group in 2002; Jia 2003; Yang 2004; Li 2005; Yang 2005; Zhang 2005a; three trials (Lou 2008; Fei 2009; Liang 2010). Yuqin capsules sig- Cheng 2006; Li 2006b; Song 2006; Wang 2006; Wu 2006; Zhang nificantly increased the liver/spleen computed tomography ratio 2006b; Gu 2007a; Gu 2007b; Li 2008; Liang 2008; Lou 2008; compared with placebo (Fei 2009)(Table 4). When polyene phos- Wang 2008a; Xu 2008; Zhang 2008; Zhou 2008; Dai 2009; Fei phatidylcholine capsules plus lifestyle intervention was compared 2009; Jiang 2009; Li 2009; Liu 2009; Ma 2009; Pu 2009; Yang with Jianpi Huazhuo formula plus lifestyle intervention, Jianpi 2009; Zhou 2009; Chen 2010; Hu 2010; Li 2010; Wu 2010; Huazhuo formula plus lifestyle intervention significantly increased Zhu 2010; Cao 2011; Huang 2011; Liang 2011; Lin 2011; Wang the liver/spleen computed tomography ratio (Liang 2010). When 2011a; Zhang 2011). We could not perform a meta-analysis as Yiqi Sanju placebo plus lifestyle intervention was compared with there was only one trial with each medicinal herb. Yiqi Sanju formula plus lifestyle intervention, Yiqi Sanju formula plus lifestyle intervention significantly increased the liver/spleen computed tomography ratio (Lou 2008). Detailed information is Abnormal ALT (greater than 50 U/L): number of participants shown in Table 4. We could not perform a meta-analysis because One trial reported the number of people with abnormal AST levels there was only one trial in each medicinal herb. (greater than 50 U/L) (Yang 2006)(Table 3). Compared with Es- sentiale®, Qingzhifugan decoction significantly reduced the number of people with abnormal ALT levels (Yang 2006)(Table 3). Liver computed tomography density value

One trial reported liver computed tomography density value (Li ALT activity 2010)(Table 4). Compared with polyene phosphatidylcholine Seventy-seven trials reported ALT activity and detailed informa- capsules plus lifestyle intervention, Xiaotan Jiangzhi formula plus tion is shown in Table 4. Forty-nine trials had significantly lower polyene phosphatidylcholine capsules plus lifestyle intervention ALT levels in the intervention group than in the control group significantly increased the liver computed tomography density (Deng 2003a; Jia 2003; Zhang 2003; Yang 2004; Li 2005; Chou value (Li 2010)(Table 4). 2006; Li 2006b; Song 2006; Wu 2006; Yang 2006; Zhang 2006b; Zhu 2006; Chen 2007b; Dang 2007; Gu 2007a; Guo 2007; Zhang 2007; Li 2008; Liang 2008; Lou 2008; Wang 2008a; Xu Nuclear magnetic resonance 2008; Zhang 2008; Zhou 2008; Dai 2009; Fei 2009; Jiang 2009; None of the trials reported outcomes on nuclear magnetic reso- Li 2009; Liu 2009; Ma 2009; Pu 2009; Yang 2009; Zhao 2009; nance. Zhou 2009; Chen 2010; Hu 2010; Kong 2010; Li 2010; Lin 2010b; Ma 2010; Wu 2010; Xu 2010; Zhu 2010; Cao 2011; Huang 2011; Liang 2011; Lin 2011; Wang 2011a; Zhang 2011). Four trials had significantly higher ALT levels in the intervention Other imaging techniques group than in the control group (Zhang 2002; Zhang 2005a; Liu None of the trials reported outcomes on results of other imaging 2008; Wang 2011b). We could not perform a meta-analysis as techniques. there was only one trial with each medicinal herb.

Biochemical response (serum activities of AST, ALT, ALP, ALP activity GGT, serum total bilirubin, and ferritin) Four trials reported ALP activity (Chou 2006; Zhu 2006; Dang 2007; Wang 2011b; Zhang 2011). Three trials had significantly lower ALP levels in the intervention group than in the control group (Chou 2006; Zhu 2006; Dang 2007). Abnormal AST (greater than 50 U/L): number of participants Compared with placebo plus lifestyle intervention, Gynostemma One trial reported the number of people with abnormal AST levels pentaphyllum plus lifestyle intervention significantly reduced ALP (greater than 50 U/L) (Yang 2006)(Table 3). When compared levels (Chou 2006). Compared with Dongbao Gantai tablets, Shi- with Essentiale®, Qingzhifugan decoction significantly reduced wei Ganzhikang capsules significantly reduced ALP levels (Dang the number of people with abnormal AST levels (Yang 2006) 2007). Compared with ethyl polyenoate soft capsules, Zhixiao (Table 3). capsules significantly reduced ALP levels (Zhu 2006). Detailed

Herbal medicines for fatty liver diseases (Review) 17 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. information is shown in Table 4. We could not perform a meta- We included 77 randomised clinical trials, which involved 6753 analysis as there was only one trial with each medicinal herb. participants with fatty liver disease. The majority of the trials included people with NAFLD, but there was also a number of trials with people having unknown disease aetiology, or including peo- GGT activity ple with AFLD. The mean sample size was 88 participants (range Forty-four trials reported GGT activity (Zhang 2002; Jia 2003; 40 to 200 participants) per trial. Seventy-five different medicinal Yang 2004; Huang 2005; Ji 2005; Li 2005; Xin 2005; Cheng herb products were tested. Six trials showed a statistically signif- 2006; Li 2006b; Wang 2006; Wu 2006; Zhang 2006b; Zhu 2006; icant effect on hepatic B-ultrasound; four trials showed a signifi- Chen 2007a; Dang 2007; Gu 2007a; Guo 2007; Li 2007; Zhang cant increase on liver/spleen computed tomography ratio; 42 trials 2007; Li 2008; Liang 2008; Wang 2008a; Zhang 2008; Dai 2009; showed a significant reduction on AST levels; 49 trials showed a Jiang 2009; Ma 2009; Yang 2009; Zhao 2009; Deng 2010; Guo significant reduction on ALT levels in the herbal group; three trials 2010; Li 2010; Liang 2010; Lin 2010b; Ma 2010; Mi 2010; Xu showed a significant reduction on ALP levels in the herbal group; 2010; Zhao 2010; Zhu 2010; Cao 2011; Liang 2011; Lin 2011; and 32 trials showed a significant reduction on GGT levels. The Wang 2011a; Wang 2011b; Zhang 2011). Thirty-two trials had present systematic review suggests that herbal medicines such as significantly lower GGT levels in the intervention group than in Jiangzhi Ligan decoction, Chaihu Shugan powder, and Qingzhifu- the control group (Zhang 2002; Jia 2003; Yang 2004; Huang gan decoction may have positive effects on fatty liver disease, espe- 2005; Xin 2005; Cheng 2006; Li 2006b; Wu 2006; Zhu 2006; cially on reducing AST and ALT, and improving B-ultrasound re- Dang 2007; Gu 2007a; Guo 2007; Li 2007; Zhang 2007; Wang sults. However, at present there is no sufficient evidence to recom- 2008a; Zhang 2008; Dai 2009; Jiang 2009; Ma 2009; Yang 2009; mend any of these herbal medicines for the treatment of fatty liver Zhao 2009; Xu 2010; Deng 2010; Guo 2010; Liang 2010; Lin diseases due to risk of bias and the lack of homogenous data. The 2010b; Mi 2010; Zhu 2010; Cao 2011; Lin 2011; Wang 2011a; methodological approaches of the included trials meant that they Zhang 2011). One trial had significantly lower GGT levels in were all at high risk of bias. The lack of homogenous trials meant the intervention group than in the control group (Dang 2007). that we could not conduct a meta-analysis. We were unable to find Detailed information is shown in Table 4. We could not perform a a common or predominant herbal medicine used in treating fatty meta-analysis as there was only one trial with each medicinal herb. liver disease because almost every trial included in this systematic review tested one single herbal, or one propriety medicine, or one herbal formula. In the future, large sample, multicentred, high- Serum total bilirubin quality trials should be carried out to give more reliable evidence None of the trials reported outcomes on serum total bilirubin. on the effects of Chinese herbal medicines on fatty liver disease.

Ferritin Overall completeness and applicability of None of the trials reported outcomes on ferritin. evidence The age and sex of participants in the included trials were repre- Histological response (number of people without sentative factors of people with fatty liver disease. All of the par- histological improvement in the degree of fatty liver ticipants were recruited from Chinese populations, and this may infiltration, inflammation, and fibrosis) have had an impact on the applicability of the interventions to None of the trials reported outcomes on histological response. other populations. No primary outcome data and no data longer than six months on any of the review or single trials outcomes were reported in the included trials. Therefore, the long-term ef- Costs fects and safety of the tested herbal medicines needs to be tested in the future. Some trials only recruited people with certain types None of the trials reported outcomes on cost. of patterns of disharmony according to herbal medicines (Dang 2007). The results of this systematic review can only be used to guide clinical practice for the tested herbal medicines and population that we have evaluated in our review. Many types of herbal DISCUSSION medicines with possible effects on fatty liver disease have not been investigated in randomised clinical trials, including the possible toxicity of these herbal medicines (Stedman 2002; Stickel 2005). Summary of main results Therefore, the evaluation of these herbs should be addressed in future trials.

Herbal medicines for fatty liver diseases (Review) 18 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Quality of the evidence Agreements and disagreements with other studies or reviews All of the randomised trials included in this review were of high risk of bias in terms of their design, methodology, and reporting. Three systematic reviews focusing on traditional Chinese herbal They provided only limited descriptions of study design, alloca- medicines for fatty liver disease have been published in Chinese tion concealment, and baseline data. Only one multicentre, large- journals (Li 2002; Liu 2005; He 2010). We found one system- scale randomised trial was identified (Ji 2005). With regards to atic review of TCMs for fatty liver disease published in 2012 (Shi methods, poorly designed trials could show larger differences be- 2012). This review included randomised clinical trials, non-ran- tween experimental and control groups than those conducted rig- domised clinical studies, and clinical experiences on NAFLD and orously (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; only searched two databases (PubMed and the China National Lundh 2012; Savovi 2012a). However, the insufficient number Knowledge Infrastructure). The review by Shi included 62 trials of adequate trials prohibited us from performing sensitivity analy- and reached the conclusion that TCM is of modest benefit to ses. Moreover, the included trials were heterogeneous with regards the treatment of NAFLD. Of the reviews published in Chinese to the interventions (75 herbal medicines tested only once), and journals, one review included 11 trials using a TCM in the in- heterogeneous with regards to the reported outcomes. tervention group and a Western medicine in the control group There were wide variations among the tested herbal medicines and (He 2010). A second review included 23 trials with a TCM in the control interventions. We could not perform sensitivity analysis intervention group and a Western medicine in the control group on treatment duration because there was an insufficient number of (Li 2002). The third review included eight trials with TCM in the trials. There was a lack of information on the quality standards for intervention group and a Western medicine or blank or supportive the development of the herbal preparations or the good manufac- therapy in the control group (Liu 2005). Two of the reviews only turing practice of the manufacture of the herbal products. Future reported the outcome of curative effect (an integrated outcome, trials should provide information about standardisation including different standard used in different included trials) and combined composition, quality control, detailed dose regimen, and duration the odds ratio (OR) irrespective of the interventions and controls of treatment. (Li 2002; Liu 2005). The review by He 2010 reported outcome The primary goal of the treatment for fatty liver disease is to pre- on ALT, AST,GGT,ALP,total cholesterol, triglycerides, and high- vent hepatic-related morbidity and hepatic-related mortality. No density lipoprotein and did meta-analyses on different compar- trial reported primary outcomes including quality of life in peo- isons of interventions and controls. None of the three reviews gave ple with fatty liver disease. Other outcomes from the included definite conclusions on the effects and safety of TCM on fatty trials are mainly putative surrogate outcomes, that is, AST, ALT, liver disease (Li 2002; Liu 2005; He 2010). Five of the clinical ALP, GGT, B-ultrasound results, and computed tomography re- trials included in our review were included in the review by He sults (Gluud 2007). 2010 (Zhu 2006; Chen 2007a; Dang 2007; Zhang 2007; Wang The toxicity of herbal medicines, especially hepatotoxicity, is in- 2008a). The remaining studies included in the systematic reviews creasingly recognised as herbal medicines become more popular by Li 2002, Liu 2005, and He 2010 were not included in our (Stedman 2002; Stickel 2005). While, there was inadequate re- review because they were retrospective studies, clinical controlled porting on adverse events in the included trials, and we cannot studies, or studies that claimed to be randomised clinical trials that make to firm conclusions about the safety of herbal medicines. In did not provide information on sequence generation, allocation order to obtain more information on the adverse effects of Chi- concealment, and blinding; had included ineligible participants; nese herbal medicines, safety needs to be further examined and or did not provide results on outcomes. We recommend that sys- reported in clinical trials and observational studies such as cohort tematic reviews should be reported under the guidance from the studies and monitoring studies. PRISMA statement (Liberati 2009).

Potential biases in the review process AUTHORS’ CONCLUSIONS All of the 77 trials were conducted in China and only three of them were published in English. Most of the trials had small sample Implications for practice sizes. We tried to avoid language bias and location bias, but we could not exclude potential publication bias. Though we did not Based on this systematic review, a large number of randomised ﬁnd unpublished material, we could not exclude the possibility clinical trials on herbal medicines have shown positive effects on that trials with negative ﬁndings may have remained unpublished. secondary outcomes including biochemical and radiological re- Two review authors independently selected trials for inclusion in sponses. However, we cannot be certain of the effectiveness and the review, and two review authors independently extracted data safety of the studies in our review of herbal medicines for the treat- and bias risk in the trials. ment of fatty liver diseases. The evidence is inconclusive due tothe

Herbal medicines for fatty liver diseases (Review) 19 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. high risk of bias of the included trials and the limited number of pharmacology of the interventions and clinical outcomes should trials with each of the Chinese herbs and Chinese herbal formulas, be emphasised for herbal medicines. Information about species, as well as the limited number of included participants and patient- geographical origin of herbs, season for collecting the herbs, and relevant outcomes. quality of the preparations should be provided (Gagnier 2006). Standardised monitoring and reporting should be used to assess adverse events. Implications for research To obtain a high level of evidence on herbal medicines on fatty liver disease and give guidance on clinical practice, international, multicentre, rigorously designed, high-quality trials with large ACKNOWLEDGEMENTS sample sizes are required. Attention should be paid to the sample size estimation, the deﬁnition of outcomes, duration of treat- We thank Dimitrinka Nikolova for her revisions of the full review. ment and follow-up, and the reporting of adverse events. In ad- We thank Sarah Louise Klingenberg from the Cochrane Hepato- dition, the following methodological issues should be addressed: Biliary Group and Iris Gordon from the Cochrane Eyes and Vision the trial design should be according to the SPIRIT Statement ( Group for their help in the development of the search strategies www.spirit-statement.org), including the methods of randomisa- and performing electronic research in English databases for this tion and blinding with the use of placebo with the same appear- review. We thank Xinxue Li, Ya Nan Wu, and Xi’e Zhuang for ance, taste, and smell; registering the trial protocol in one of the their contribution on study selection and downloading of full-text World Health Organization Registry Network or an International articles. Committee of Medical Journal Editors approved registry before Dr Jian Ping Liu thanks the National Institutes of Health, Na- the start of the trial (www.clinicaltrials.gov; www.who.int/ictrp/ tional Center for Complementary and Alternative Medicine (R24 network/primary/en/index.html); and reporting trials accord- AT001293) for partial funding of the review project. ing to the CONSORT statement (www.consort-statement.org) (Schulz 2010). To improve the quality of future trials, we suggest Zhaolan Liu acknowledges the support from the Australian En- that all researchers receive the necessary training on clinical trial deavour Award Program (Award holder number 2758˙2012). methodology before designing a trial and register the trial on an Peer reviewers: Si-Yuan Pan, China; Ming-Hua Zheng, China; internationally recognised public trial registry. Bruna Z Schild, Brazil. From the results of the present review, rigorous description of the Contact editor: Christian Gluud, Denmark.

REFERENCES

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Herbal medicines for fatty liver diseases (Review) 23 Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Zhou 2008 {published data only} Li 2004 {published data only} Zhou YA, Liu JM, Shi YX. Observation on effects of LI XH. Clinical observation of “liver discharging and blood- treating fatty liver by Kezhi capsule. Chinese Medicine acting decoction” in treating fatty liver. Shanghai Journal of Modern Distance Education of China 2008;6(8):850–2. Traditional Chinese Medicine 2004;38(2):24–5. Zhou 2009 {published data only} Liu 2009a {published data only} Zhou B, Cai GX, Bai ZP, Zeng SL, Fu SH. Clinical Liu YH. Theory and clinical study on treatment of observation of 60 cases on Lishi Huoxue Tongluo decoction non-alcoholic fatty liver diseases by Qingretongxia and in treating non-alcoholic steatohepatitis. Guiding Journal Shuganlidan method. Wan Fang Thesis Database 2009. of Traditional Chinese Medicine and Pharmacy 2009;15(7): Mohammadi 2010 {published data only} 13–5. Mohammadi HA, Shokri Shirvani J, Jabbari M. The efﬁcacy Zhu 2006 {published data only} of licorice root extract in decreasing transaminase activities Zhu PS, Wang YL, Peng C. Treatment of non-alcoholic in non-alcoholic fatty liver disease. Journal of Hepatology fatty liver by Zhixiao capsule: a clinical observation of 50 2010;52 Suppl 1:S143. cases. New Journal of Traditional Chinese Medicine 2006;38 Tao 2008 {published data only} (4):31–2. Tao L, Zhang SS. Clinical observation of 30 cases on Zhu 2010 {published data only} Shugan Huazhuo Huoxue method in treating non-alcoholic Zhu YQ. Clinical study of Xiaotan Hugan decoction on fatty liver disease. China Journal of Traditional Chinese treatment of 30 cases with fatty liver disease. Shanxi Journal Medicine and Pharmacy 2008;23(6):552–3. of Traditional Chinese Medicine 2010;31(5):527–8. Wu 2008a {published data only} Wu QQ. Treatment of Shuyuhuohua decoction on 80 cases References to studies excluded from this review of nonalcoholic fatty liver. Modern Journal of Integrated 2008;17(24): Deng 2003 {published data only} Traditional Chinese and Western Medicine Deng DQ, Jin HY. The treatment of Shugan Jianpi Huashi 3749–50. Tang on fatty liver diseases, a report of 35 cases. Jiangsu Zhang 2005b {published data only} Journal of Traditional Chinese Medicine 2003;24(10):30–1. Zhang CZ, Zhang AZ, Yan HM, Wang HM. Research on Jiangzhi Yigan Tang treating non-alcoholic fatty hepatitis. Deng 2005 {published data only} Sponsored By Hubei College of Traditional Chinese Medicine Deng YQ, Fan XF, Li YD. Clinical observation on treatment 2005;27(5):5–7. of non-alcoholic fatty liver diseases by Silyben. China Journal of Chinese Materia Medica 2005;30(13):1044–5. Zhao 2003 {published data only} Zhao H, Xu HM, Wei HG. Preservation of Qianggan Gao 2002 {published data only} Jiangzhi Tang on fatty liver diseases. Liaoning Journal of Gao ZL, Hu XH, Wu X, Cheng FT. Clinical research on Traditional Chinese Medicine 2003;30(5):379. Shaji Keli treating liver ﬁbrosis. China Journal of Chinese Medicine 2002;10(3):39–40. Additional references

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Characteristics of included studies [ordered by study ID]

Cao 2011

Methods Trial design: randomised, parallel group trial. Language: Chinese. Type of publication: journal article. Date of trial: October 2009 to December 2010. Judgement of the quality of the trial: high risk of bias.

Participants Number of study centres: 1. Setting: Zhang Jiakou Infectious Disease Hospital, Hebei Province Origin of the participants: outpatients. Sample size calculation: not done. Number of participants: 90. 45 received Huazhuo Xiaozhi decotion, 45 received Bai- sainuo Sex ratio: 49 males (54.4%), 41 females (45.6%). Mean age: 43.5 years (range 26-67 years) in the treatment group; 46.2 years (range 27- 68 years) in the control group Duration of fatty liver diseases: 3.2 years (range 0.7-5.7 years) in the treatment group; 3.1 years (range 1.1-5.2 years) in the control group Diagnostic criteria: Group of Fatty Liver and Alcoholic Liver Diseases, Society of Hep- atology, Chinese Medical Association, diagnostic standard of non-alcoholic fatty liver (draft), Chinese Journal of Hepatology 2001 (CMA 2001a). Inclusion criteria: not described. Exclusion criteria: not described. Dropouts: all participants randomised were analysed. ITT analysis: not done. Sources of funding: not speciﬁed.

Interventions Intervention: Huazhuo Xiaozhi decoction, 1 decoction, 400 mL, twice/day Control: Baisainuo, 50 mg, po, 3 times/day. Post-treatment follow-up: none. Both groups received the same lifestyle changes. Treatment duration: 2 months.

Outcomes Outcome(s): symptoms, signs, ALT, AST, GGT, TG, TC, LDL-C.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information on random sequence gen- bias) eration.

Allocation concealment (selection bias) Unclear risk No allocation concealment method was described.

Blinding (performance bias and detection Unclear risk Not described. bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No withdrawals or dropouts were reported. All outcomes All participants randomised were analysed

Selective reporting (reporting bias) Low risk All predeﬁned outcomes in the methods section of the article were reported in the results section

Other bias High risk Sample size calculation was not reported.

Blinding of participants and personnel Unclear risk Not described. (performance bias) All outcomes

Blinding of outcome assessment (detection Unclear risk Not described. bias) All outcomes

Chen 2007a

Methods Trial design: randomised, parallel group trial. Language: Chinese. Type of publication: journal article. Date of trial: not speciﬁed. Judgement of the quality of the trial: high risk of bias.

Participants Number of study centres: 1. Setting: the First Afﬁliated Hospital of Guangzhou University of Traditional Chinese Medicine Origin of the participants: outpatients. Sample size calculation: not done. Number of participants: 60. 30 received Zini Zhigan prescription, 30 received liptor Sex ratio: 37 males (61.7%), 23 females (38.3%). Mean age: 43.43 years in the treatment group; 41.30 years in the control group Duration of fatty liver diseases: not speciﬁed. Diagnostic criteria: Haozhu Chen, Practice of Internal Medicine, People’s Medical Pub- lishing House 2005 (Chen 2005). Inclusion criteria: aged 18-65 years; the diagnosis were NAFLD and Pixushisheng type Exclusion criteria: current liver disease or previous episode of liver disease; current excessive drinking or history of heavy drinking; severe diseases of respiratory, digestive, circulatory, endocrine, and renal system or history of these diseases; gestation or lactating women; people taking drugs with drug-related drug allergy; psychosis or dementia

Dropouts: all participants randomised were analysed. ITT analysis: not done. Sources of funding: not speciﬁed.

Interventions Intervention: Zini Zhigan decoction, 1 dose, twice/day. Control: liptor, 10 mg, po, once daily. Post-treatment follow-up: none. Treatment duration: 8 weeks.

Outcomes Outcome(s): symptoms, signs, B-ultrasonography, ALT, AST, GGT, TG, TC, LDL-C, HDL-C