nonalcoholic fatty liver disease ( nafld ) is one of the most common chronic liver diseases worldwide and occurs predominantly in obese , sedentary people and patients with type ii diabetes ( 1 ) . nafld includes a wide variety of liver disorders from simple steatosis to hepatic fibrosis and cirrhosis ( 2 ) . it is usually associated with metabolic disorders such as obesity , insulin resistance ( 3 ) , hypertension , dyslipidemia and impaired fat metabolism ( 4 ) , and it can increase mortality risk due to the associated cardiovascular disease ( 5 ) . although there is no proven treatment for this disorder , researchers have suggested a combination of modified diet and exercise for treatment ( 6 ) . previous studies have shown that a diet rich in antioxidants and anti - inflammatory agents can be effective in the treatment of nafld ( 7 ) . ginger is the root of zingiber officinale and is one of the most used spices in many countries . ginger contains active ingredients such as gingerol , shogaol , zingerone and -bisabolene ( 8) . in ancient medical practice , ginger was used for treatment of various disorders such as rheumatoid arthritis , neurodegenerative diseases , inflammation and asthma ( 9 ) . previous studies have shown that ginger and its active compounds can exhibit anti - diabetes , anti - cancer and anti - inflammatory properties ( 10 , 11 ) . it has been shown that ginger extract can exhibit antioxidant activity and reduce the levels of pro - inflammatory biomarkers ( 12 ) . moreover , recent studies on patients with type ii diabetes and hyperlipidemia have shown that ginger can reduce insulin resistance and serum triglyceride concentration ( 13 , 14 ) . accordingly , the hypothesis of this study was that ginger supplementation can be introduced as a new therapeutic strategy for nafld by improving the body s antioxidant activity , and reducing levels of inflammation and insulin resistance . a randomized double - blind study was designed to evaluate this hypothesis in order to examine the effectiveness of ginger supplementation in patients with nafld . inclusion criteria included the presence of steatosis on fibroscan ( cap score > 270 ) and a high concentration of liver enzyme ( alanine aminotransferase ( alt ) greater than 1.5 times the upper limit of the normal range ) at the time of randomization . exclusion criteria included chronic liver diseases such as various types of hepatitis , diabetes mellitus , cancer , inherited disorders affecting the liver condition ( storage disorders of iron , copper , and others ) , non - treated hypothyroidism , as well as , alcohol use , taking any medications , weight loss surgery in the last year or strict diets to lose weight in the past three months , pregnancy , lactation , autoimmune diseases , weight loss more than ten percent of initial body weight during the intervention , unwillingness to continue the study protocol , and not taking more than ten percent of supplements in any follow - up visit . eligible patients with nafld were invited to participate in this study . at first , all participants were informed about the study protocol by being given a complete description of the objectives , benefits and potential harms of the study . the study was approved by the ethics committee of tehran university of medical sciences and informed consent was received from the participants who elected to participate in the study . participants were randomly allocated based on age , sex and severity of steatosis into two groups . randomization lists were computer - generated by a statistician and participants , project managers and employees at the clinic were completely unaware ( blind ) about the intervention and control groups . at the first visit , baseline data were gathered and patients were advised to consume two capsules , each containing 500 mg of ginger ( green plants of life pharmaceutics co. , iran ) or identical placebos ( starch ) one hour after breakfast and two capsules after dinner for 12 weeks . for all patients , capsules were given in the first week for three weeks , and in each visit a new series of supplements were prescribed . in both groups , patients were advised to follow a modified diet and physical activity plan , according to the clinical guidelines on the identification , evaluation , and treatment of overweight and obesity in adults from the national institutes for health ( nih ) and the north american association for the study of obesity ( 15 ) . according to these groups , less than 30% of energy from lipids ( 10% from sfas , 15% from mufas and 5% from pufas ) , 15% to 18% of energy from proteins and 52% to 55% of energy from carbohydrates were provided . also , patients were advised to limit their dietary cholesterol intake to less than 300 mg per day and consume 20 to 30 grams of fiber per day . all patients were advised to exercise  30 min , three times per week . to remind the participants about supplement consumption phone calls for all patients , anthropometric parameters , including weight , height , waist and hip circumference , were measured at the beginning ( week 0 ) and the end ( week 12 ) of the study . body mass index ( bmi ) was calculated by dividing weight to height squared ( m ) , and waist to hip ratio ( whr ) was calculated by dividing the waist to hip circumference . all the measurements were made by one person in order to reduce measurement errors . to assess food intake , all participants of the study were asked to complete a three - day food record at the beginning and at the end of the study . blood samples were received from all patients after 10 to 12 hours of fasting at the beginning ( week 0 ) and the end ( week 12 ) of the study . g - glutamyltransferase ( ggt ) was measured using an enzymatic colorimetric assay ( parsazmoun ) . alt and aspartate aminotransferase ( ast ) concentrations were measured using a photometric assay ( parsazmoun ) . the concentration of tnf- was measured using an elisa kit ( ebioscience , inc . , san diego , ca , usa , cat no : 109957025 ) and high - sensitivity c - reactive protein concentration was also measured by elisa kit ( parsazmun co. , tehran , iran , cat no : 93001 ) . insulin resistance was measured by the homeostasis model formula ( homa - ir - ir ) as follows : homa - ir = [ fasting insulin ( mu / l )  3 fasting blood glucose ( mg / dl)]/405 ( 16 ) . the steatosis and hepatic fibrosis in patients was measured using ultrasound elastography at the beginning and the end of the study . the physical activity of patients was measured by the metabolic equivalent of task ( met ) questionnaire at the beginning and the end of the study . normal distribution of data was assured using the kolmogorov - smirnov and shapiro - wilk tests . baseline characteristics of variables were compared among the two groups using independent sample t - test , mann - whitney u test and chi - square test . within - group comparisons , before and after the intervention , were made with the student s t - test or wilcoxon . in order to eliminate the effects of confounding factors , all ancova models were adjusted for the baseline value of each variable and mean changes in bmi , whr , met and energy . inclusion criteria included the presence of steatosis on fibroscan ( cap score > 270 ) and a high concentration of liver enzyme ( alanine aminotransferase ( alt ) greater than 1.5 times the upper limit of the normal range ) at the time of randomization . exclusion criteria included chronic liver diseases such as various types of hepatitis , diabetes mellitus , cancer , inherited disorders affecting the liver condition ( storage disorders of iron , copper , and others ) , non - treated hypothyroidism , as well as , alcohol use , taking any medications , weight loss surgery in the last year or strict diets to lose weight in the past three months , pregnancy , lactation , autoimmune diseases , weight loss more than ten percent of initial body weight during the intervention , unwillingness to continue the study protocol , and not taking more than ten percent of supplements in any follow - up visit . eligible patients with nafld were invited to participate in this study . at first , all participants were informed about the study protocol by being given a complete description of the objectives , benefits and potential harms of the study . the study was approved by the ethics committee of tehran university of medical sciences and informed consent was received from the participants who elected to participate in the study . eventually 50 patients who met the inclusion criteria were selected . participants were randomly allocated based on age , sex and severity of steatosis into two groups . randomization lists were computer - generated by a statistician and participants , project managers and employees at the clinic were completely unaware ( blind ) about the intervention and control groups . at the first visit , baseline data were gathered and patients were advised to consume two capsules , each containing 500 mg of ginger ( green plants of life pharmaceutics co. , iran ) or identical placebos ( starch ) one hour after breakfast and two capsules after dinner for 12 weeks . for all patients , capsules were given in the first week for three weeks , and in each visit a new series of supplements were prescribed . in both groups , patients were advised to follow a modified diet and physical activity plan , according to the clinical guidelines on the identification , evaluation , and treatment of overweight and obesity in adults from the national institutes for health ( nih ) and the north american association for the study of obesity ( 15 ) . according to these groups , less than 30% of energy from lipids ( 10% from sfas , 15% from mufas and 5% from pufas ) , 15% to 18% of energy from proteins and 52% to 55% of energy from carbohydrates were provided . also , patients were advised to limit their dietary cholesterol intake to less than 300 mg per day and consume 20 to 30 grams of fiber per day . all patients were advised to exercise  30 min , three times per week . to remind the participants about supplement consumption phone calls for all patients , anthropometric parameters , including weight , height , waist and hip circumference , were measured at the beginning ( week 0 ) and the end ( week 12 ) of the study . body mass index ( bmi ) was calculated by dividing weight to height squared ( m ) , and waist to hip ratio ( whr ) was calculated by dividing the waist to hip circumference . all the measurements were made by one person in order to reduce measurement errors . to assess food intake , all participants of the study were asked to complete a three - day food record at the beginning and at the end of the study . blood samples were received from all patients after 10 to 12 hours of fasting at the beginning ( week 0 ) and the end ( week 12 ) of the study . g - glutamyltransferase ( ggt ) was measured using an enzymatic colorimetric assay ( parsazmoun ) . alt and aspartate aminotransferase ( ast ) concentrations were measured using a photometric assay ( parsazmoun ) . , san diego , ca , usa , cat no : 109957025 ) and high - sensitivity c - reactive protein concentration was also measured by elisa kit ( parsazmun co. , tehran , iran , cat no : 93001 ) . insulin resistance was measured by the homeostasis model formula ( homa - ir - ir ) as follows : homa - ir = [ fasting insulin ( mu / l )  3 fasting blood glucose ( mg / dl)]/405 ( 16 ) . the steatosis and hepatic fibrosis in patients was measured using ultrasound elastography at the beginning and the end of the study . the physical activity of patients was measured by the metabolic equivalent of task ( met ) questionnaire at the beginning and the end of the study . normal distribution of data was assured using the kolmogorov - smirnov and shapiro - wilk tests . baseline characteristics of variables were compared among the two groups using independent sample t - test , mann - whitney u test and chi - square test . within - group comparisons , before and after the intervention , were made with the student s t - test or wilcoxon . in order to eliminate the effects of confounding factors , all ancova models were adjusted for the baseline value of each variable and mean changes in bmi , whr , met and energy . fifty patients were included in the study and were randomly assigned to take either two grams of ginger ( n = 25 ) or the identical placebo ( n = 25 ) . two patients in the ginger group ( due to unwillingness to continue ) and four patients in the control group ( two persons due to immigration and two persons due to unwillingness to continue ) were excluded , and 44 people , including 23 patients in the ginger group and 21 patients in the control group were entered into the final analysis . eighty - eight percent of patients in the study successfully completed 12 weeks of treatment . no significant difference was found between demographic index levels , weight , bmi , nutritional intake ( energy , selenium , vitamin d , vitamin e , vitamin c , omega-3 and omega-6 ) , physical activity , and especially , the steatosis degree and liver fibrosis between the two groups at baseline . however , there was a significant difference between the two groups in levels of hs - crp and ast liver enzyme at the beginning of the study . abbreviations : bmi , body mass index ; met , metabolic equivalent of task ; whr , waist to hip ratio . serum levels of the alt in both groups had a significant reduction ( p < 0.05 ) , but it declined significantly more in the ginger group compared with the placebo group ( p = 0.02 ) ( table 2 ) . also , it remained significant after adjusting the results for the energy , physical activity , whr and bmi variables ( p = 0.045 ) ( table 3 ) . abbreviations : alt , alanine aminotransferase ; ast , aspartate aminotransferase ; ggt , -glutamyl transferase ; homa - ir , homeostasis model formula for insulin resistance ; hs - crp , high - sensitivity c - reactive protein ; tnf- , tumor necrosis factor alpha . p1 and p2 value , difference compared with the value at the beginning of the study within groups ( paired t - test ) . pt value , mean difference of changes between the two groups ( independent t - test ) . abbreviations : alt , alanine aminotransferase ; ast , aspartate aminotransferase ; ggt , -glutamyl transferase ; homa - ir , homeostasis model formula for insulin resistance ; hs - crp , high - sensitivity c - reactive protein ; tnf- , tumor necrosis factor alpha . anthropometric measures , including weight , bmi , waist circumference , hip circumference and waist - to - hip ratio , decreased significantly in both groups at the end of study , but this reduction was not significantly different between the two groups except for hip circumference , which reduced significantly more in the ginger group in comparison to the placebo group ( p = 0.015 ) . improvements in serum levels of ast and ggt were observed in both groups ; however , this reduction was significant only in the ginger group . after adjusting the results for baseline values , this reduction was significant only for ggt ( p < 0.01 ) , and ast changes between the two groups was not significant ( p = 0.886 ) . a substantial improvement in most liver indicators was observed within each group and between the two groups before and after the adjustment for confounder variables . patients taking ginger capsules compared to the placebo group had a significantly greater decrease in the steatosis score ( p < 0.001 ) , but the difference in fibrosis score between the two groups was not significant ( p = 0.39 ) . at the end of the study , there was a significant reduction in levels of tnf- and hs - crp in both groups , but the decline was greater in the ginger group ( 0.01 and 0.016 , respectively ) . furthermore , the ginger supplement compared to the placebo caused greater reduction in the levels of insulin resistance index ( homa - ir ) ( p = 0.022 ) . no severe effects were reported due to the ginger or placebo supplementation by the patients . only one patient complained of mild headache and one of heartburn caused by the ginger supplements , both of which were resolved by recommendations of the nutritional consultants . fifty patients were included in the study and were randomly assigned to take either two grams of ginger ( n = 25 ) or the identical placebo ( n = 25 ) . two patients in the ginger group ( due to unwillingness to continue ) and four patients in the control group ( two persons due to immigration and two persons due to unwillingness to continue ) were excluded , and 44 people , including 23 patients in the ginger group and 21 patients in the control group were entered into the final analysis . eighty - eight percent of patients in the study successfully completed 12 weeks of treatment . no significant difference was found between demographic index levels , weight , bmi , nutritional intake ( energy , selenium , vitamin d , vitamin e , vitamin c , omega-3 and omega-6 ) , physical activity , and especially , the steatosis degree and liver fibrosis between the two groups at baseline . however , there was a significant difference between the two groups in levels of hs - crp and ast liver enzyme at the beginning of the study . abbreviations : bmi , body mass index ; met , metabolic equivalent of task ; whr , waist to hip ratio . serum levels of the alt in both groups had a significant reduction ( p < 0.05 ) , but it declined significantly more in the ginger group compared with the placebo group ( p = 0.02 ) ( table 2 ) . also , it remained significant after adjusting the results for the energy , physical activity , whr and bmi variables ( p = 0.045 ) ( table 3 ) . abbreviations : alt , alanine aminotransferase ; ast , aspartate aminotransferase ; ggt , -glutamyl transferase ; homa - ir , homeostasis model formula for insulin resistance ; hs - crp , high - sensitivity c - reactive protein ; tnf- , tumor necrosis factor alpha . p1 and p2 value , difference compared with the value at the beginning of the study within groups ( paired t - test ) . pt value , mean difference of changes between the two groups ( independent t - test ) . abbreviations : alt , alanine aminotransferase ; ast , aspartate aminotransferase ; ggt , -glutamyl transferase ; homa - ir , homeostasis model formula for insulin resistance ; hs - crp , high - sensitivity c - reactive protein ; tnf- , tumor necrosis factor alpha . anthropometric measures , including weight , bmi , waist circumference , hip circumference and waist - to - hip ratio , decreased significantly in both groups at the end of study , but this reduction was not significantly different between the two groups except for hip circumference , which reduced significantly more in the ginger group in comparison to the placebo group ( p = 0.015 ) . improvements in serum levels of ast and ggt were observed in both groups ; however , this reduction was significant only in the ginger group . after adjusting the results for baseline values , this reduction was significant only for ggt ( p < 0.01 ) , and ast changes between the two groups was not significant ( p = 0.886 ) . a substantial improvement in most liver indicators was observed within each group and between the two groups before and after the adjustment for confounder variables . patients taking ginger capsules compared to the placebo group had a significantly greater decrease in the steatosis score ( p < 0.001 ) , but the difference in fibrosis score between the two groups was not significant ( p = 0.39 ) . at the end of the study , there was a significant reduction in levels of tnf- and hs - crp in both groups , but the decline was greater in the ginger group ( 0.01 and 0.016 , respectively ) . furthermore , the ginger supplement compared to the placebo caused greater reduction in the levels of insulin resistance index ( homa - ir ) ( p = 0.022 ) . no severe effects were reported due to the ginger or placebo supplementation by the patients . only one patient complained of mild headache and one of heartburn caused by the ginger supplements , both of which were resolved by recommendations of the nutritional consultants . to our knowledge , this is the first randomized , double - blind clinical trial study that examined the effects of ginger supplementation with lifestyle intervention on liver enzymes , inflammatory markers , steatosis and hepatic fibrosis scores in patients with nonalcoholic fatty liver disease ( nafld ) . in this study , daily consumption of two grams of ginger supplement for 12 weeks resulted in a significant decrease in inflammatory marker levels , alt and ggt liver enzymes and liver steatosis . insulin resistance is one of the major risk factors in the pathogenesis of nafld ( 16 ) . our study has shown that ginger supplementation reduces insulin resistance , which is in line with previous studies . have shown that ginger supplementation can ameliorate levels of insulin resistance markers ( 14 ) . furthermore , mozaffari et al . showed that a daily intake of three grams of ginger powder for eight weeks resulted in a significant reduction in fasting blood sugar levels and insulin resistance ( 17 ) . thus , our study confirmed these previous studies , and showed that as little as two grams / day of ginger can reduce insulin resistance . according to the other studies , inflammatory agents play an important role in the pathogenesis of nafld . some studies have shown that in patients with nafld , polymorphisms of tnf- promoter , at positions 238 ( tnfa ) and 308 ( tnf2 ) , are common and its expression increases ( 18 ) . tnf - a plays a critical role in both insulin resistance and liver fibrosis and increases fatty acids oxidation ( 19 , 20 ) . so , reduction of tnf- and other inflammatory factors can improve the treatment of nafld . in this study , it was shown that ginger supplementation caused a significant decrease in serum levels of tnf- and hs - crp , which is consistent with previous studies such as those by lee et al . the hepatic steatosis score in the group receiving ginger supplements reduced significantly more than the control group , while liver fibrosis showed no significant difference between the two groups . hepatic steatosis is characterized by overload of triglycerides in hepatocytes that can injure the liver ( 23 ) . animal studies have shown that the active compounds in ginger can enhance the antioxidant defense systems , such as glutathione peroxidase and glutathione s - transferase , and reduce levels of malondialdehyde ( mda ) and hepatic steatosis ( 24 , 25 ) . it seems that one of the main reasons for this protective feature is the effect of ginger on the expression of proliferating cell nuclear antigen ( pcna ) . pcna is a nuclear protein that is involved in regulating cell proliferation . in liver disorders such as nafld and cirrhosis , the expression of pcna is increased , which ultimately can result in excessive and uncontrolled proliferation of tissue to replace the damaged tissue and causes liver fibrosis progression . previous studies have shown that ginger supplementation can reduce the expression of pcna and prevent the intensification of liver fibrosis ( 26 ) . in this study , no significant decrease was observed in liver fibrosis score in the ginger group compared to the placebo group . this can be due to the short - term of the intervention , because it takes a long time for regeneration of hepatic tissue and reduction of fibrotic tissue . the lack of using liver biopsy to derive a pathology score of disease was one of the limitations of this study . researchers were not able to use this method in this study due to its invasive nature , however , we evaluated the hepatic steatosis and fibrosis with transient elastography , which provides quantitative , noninvasive results . the advantage of this study was that it is the first study evaluating the effects of ginger supplementation on nafld . in conclusion , this randomized controlled clinical trial found some evidence that ginger supplementation could increase the effectiveness of lifestyle interventions ( diet modification and physical activity ) compared with lifestyle interventions alone for treatment of nafld . whether these effects will be sustained and/or augmented with longer treatment durations remains to be determined .