Table 1.
Overview of reviewed clinical studies regarding the influence of administration of EPL on FLD
| Clinical study | Age/sex (n) | Study population and design | Effects | Remarks |
|---|---|---|---|---|
| Watanabe et al9 | Mean 46 yr/4 m and 8 f | Open controlled study: of 12 patients with obesity with FL, six received 0.5 g EPL po tid vs six 0.5 g nicotinic acid (niceritol) tid for 2 months. | EPL: TC and TG ↓ (P<0.05); fat in the liver ↓ as seen from CT (P<0.02). No ADR. Niceritol: TC and TG ↓, fat in the liver and CHE (P<0.05); 1× flush. ALT, oral glucose tolerance test, obesity index, and skin-fold thickness improved in both groups, too. |
BT: diet and physical exercise. Comparable efficacy in both groups. |
| Gonciarz et al13 | EPL: mean 54 yr/4 m and 11 f Placebo: mean 49 yr/8 m and 7 f |
Randomized double-blind study: of 30 patients with diabetes with FL, 15 received 0.6 g EPL po tid vs 15 corresponding placebo for 6 months. | EPL: liver size and y-GT ↓ (P<0.05); glucose ↓ (P<0.01). Histology: marked improvements in four cases. Final patients’ evaluation: eight improvements. Placebo: glucose ↓ (P<0.05). Histology: marked improvement in one case (no fatty infiltration but cirrhosis developed). Final patients’ evaluation: one patient improvement. No ADR. |
2 Weeks pretreatment phase: no hepatoprotectors. Obesity allowed. Diet in case of obesity. 1.0–1.5 g tolbutamide in five placebo and seven EPL patients. Statistics: U-test and Wilcoxon match-paired signed test. |
| Cairella et al10 | 46.1±12.2 yr/15 m and 25 f | Open controlled study: of 40 patients with obesity with FL, 20 received 0.6 g EPL po tid vs 20 diet only for 3 months. | EPL: 14 of 19 patients improved US, out of which six normalized. Control: three of 20 patients improved US. EPL vs control: more frequent normalization of AST, AP, y-GT, and serum and urine bilirubin (P<0.001). |
BT: diet. Additionally, single cases presentation. |
| Koga et al11 | 42.6±11.4 yr/29 m and 22 f | Open study: 51 patients (39 obese, six diabetic, five alcoholic, and one unknown) with FL received 0.5 g EPL po tid for 6 months. | All cases included: US improved or normalized in 51% of patients (P<0.001); AST (P ns), ALT, and y-GT ↓ in males (P<0.01). Improvement in LFT in 72% of patients. Alcohol-excluded evaluation: US improved or normalized (P<0.01); AST, ALT, and y-GT improved or normalized (P<0.01, P<0.001, and P<0.05, respectively). No further improvement after 16 weeks. Subjective symptoms improved or disappeared. |
No diet or alcohol consumption. Statistics: Wilcoxon test. Greater efficacy in cases of more disturbed liver function and in cases with decreasing disturbed lipid levels. |
| Li et al12 | EPL: 44.1±8.2 yr/15 m and 9 f Placebo: 46.2±7.5 yr/5 m and 7 f |
Randomized double-blind study: of 36 patients with obesity with FL, 24 received 0.6 g EPL po tid + one tablet of vitamins/d vs 12 corresponding placebo and vitamins for 3 months. | EPL: increased TC ↓ by 10%, TG ↓ by 9% (P<0.05). ALT and AST normalized in 87.5%. FLD improved as seen from CT (P<0.05). Placebo: no significant change of TC, TG, AST, and ALT. No change in CT. Mean reduction between groups P<0.01. EPL significantly effective in 21 and effective in three patients. No ADR. |
2 Weeks pretreatment phase: no liver protective agents. No alcohol or animal fat. Statistics: t-test for comparison. |
| Yin and Kong14 | EPL: mean 56 yr/73 m and 52 f Control: mean 55 yr/33 m and 27 f |
Open controlled study: of 185 patients with diabetes with FL, 125 received BT + 0.6 g EPL po tid vs 60 BT alone for 3 months. | EPL: curative effect in 78 patients significant, in 35 effective, and in 12 not effective. Total effective rate 90.2% (P<0.05 compared to control). ALT ↓ (P<0.01). TC, TG, and LDL-C ↓ and HDL-C ↑ (P<0.05). Differences significant compared to control (P<0.05). Control: curative effect in three patients significant, in 28 effective, and in 29 not effective. Total effective rate 51.0%. ALT, TC, TG, LDL-C, and HDL-C (P ns). No significant difference for fasting blood glucose between groups. |
Disease since 1–28 yr (mean 9.6 yr). BT: diet, oral antidiabetics, and physical exercise. No blood lipid metabolism affecting drugs. At the night before treatment, high-fat diet and alcohol forbidden. |
| Ohbayashi20 | 51.6±13.9 yr/16 m and 9 f | Open study: 25 patients (18 NASH, 7 with alcoholic FLD) received 0.5 g EPL po tid for 12 months. | NASH: AST and ALT ↓, already significant after 4 weeks therapy (P=0.004 and P=0.005). y-GT remained normal. Improvement sustained throughout the study. ASH: AST, ALT, and y-GT ↓, already significant after 8/4 weeks (P=0.033, P=0.021, trend). Improvement sustained (ALT and y-GT) or continued to normal (AST). ADR: one patient mild gastric discomfort and one patient mild diarrhea and loose stools. |
Lipid levels remained unaltered. |
| Poongothai et al15 | 41±8 yr/14 m and 14 f | Open study: of 28 patients with diabetes with NAFLD, 22 were available for follow-up and received 0.7 g EPL po tid for 6 months. | US: two of four of grade 1 of NAFL improved, one showed no change, and one worsened. In case of grade 2 and 3, five of 12 and five of six improved. Overall, 54.5% improved, 40.9% did not change, and one case worsened. 80% of patients with grade 3 improved in hepatic echotexture, while only 50% of grade 1 patients. LFT: AST, ALT, and y-GT ↓ (P=0.004, P=0.007, and P=0.024, respectively). Even among patients without US changes, decrease in all enzymes. AST and ALT started to improve within 2 months of therapy, y-GT after 6 months. FPG, HbA1c, and TC ↓ (P=0.007, P=0.001, and P=0.046, respectively). No ADR. |
BT: diet and antidiabetics; additionally, 16.6% on a statin and 8.3% on a fibrate. SPSS statistical package 10.0. |
| Ohbayashi et al21 | 30–62 yr/5 m and 3 f | Open study: eight patients with NASH received 0.5 g EPL po tid for 12 months. | AST, ALT, and y-GT ↓ (P=0.012, P=0.005, trend) after 4 weeks, lasting during the 12-month treatment (P<0.05, P<0.01, trend). Histology of patients after 6 months: one of seven improved from stage 2 to 1 (Brunt classification); additionally, fatty liver, ballooning, and/or inflammation of liver lobule and periportal area improved in five cases. One no change and one slight aggravation. No ADR. |
Statistic analysis with JMP Edition 5.1.1a (SAS Institute Inc., Cary, NC, USA). |
| Liang22 | EPL: mean 54 yr/18 m and 12 f GP: mean 52 yr/12 m and 8 f |
Open controlled study: of 50 patients with FL, 30 received 0.6 g EPL po tid for 2 weeks and 0.3 g EPL po tid for 2 weeks vs 20 patients 40 mg GP tid for 4 weeks. | EPL: AST, ALT, TC, and TG ↓ (P<0.01). 28 patients effective (combination of symptoms, US, lipid levels, and LFT) and two ineffective: overall 93.3%. GP: AST and ALT ↓ (P<0.05). Ten patients effective and ten ineffective: overall 50%. Differences between groups P<0.01. No ADR. |
BT: 0.2 g inosin tid and 0.1 g vitamin C tid; diet adjustment and physical exercise. Additionally, drugs to treat the causes of the condition. t-test for comparison. |
| Arvind et al26 | 18–60 yr | Randomized double-blind study: of 40 patients with NAFLD, 20 received 0.35 mg EPL po tid vs 20 UDCA (7–10 mg/kg 1× daily) for 3 months. In each group, ten patients with NAFLD and ten obese. |
EPL: in 45% nausea, malaise, and abdominal distension significantly decreased. AST, ALT, and AP ↓ (P=0.087, P=0.005, and P=0.002, respectively). US: improvement not noteworthy after 1 month but in 20% after 3 months. GLY: in 30% nausea, malaise, and abdominal distension significantly decreased. ALT ↓ (P=0.038), AST and AP ns US improvement not noteworthy after 1 month but in 10% after 3 months. No ADR. |
Intake of all other medications stopped during study. No major differences in response in subgroups. |
| Ohbayashi et al16 | 46 yr/1 f | Case report: one patient with NASH received 7 months 270 mg/d nateglinide, followed by additional 0.5 g EPL po tid for 2 yr. | Steatosis decreased from score 2 to 1; ballooning, intra-acinar, and portal inflammation disappeared after 9 months treatment, corresponding to decrease of staging from 2 to 0 (Brunt classification). After 9 months, US improvement of deep echo attenuation with hepatorenal echo contrast. HOMA-R, AST, ALT, y-GT, and ferritin normalized. |
No diet, exercise, alcohol consumption, or viral hepatitis. Marked laboratory effects after 4 weeks. |
| Shen25 | EPL: 27–60 yr/72 m and 28 f GLY: 25–60 yr/68 m and 32 f |
Randomized open controlled study: of 200 patients with NAFLD, 100 received 0.25 g EPL iv qd as infusion for 1 month, followed by 0.6 g EPL po tid vs 100 patients 60 ml GLY iv/d qd as infusion, followed by 150 mg GLY po tid for 1 month. | EPL: AST, ALT, and TG improved to normal (P<0.01). US: 25 marked effectiveness and 66 effective (91%). GLY: AST and ALT improved to normal (P<0.01), TG ns. US: 14 marked effectiveness and 54 effective (68%). Total efficacy significantly different between groups (P<0.05). |
NAFLD associated in 22 (EPL) and 20 (GLY) patients with chronic hepatitis B and in 13 (EPL) and 16 (GLY) with type II diabetes. SPSS statistical package. |
| Buyeverov et al17 | ≥18 yr | Open controlled study: of 40 patients with mixed steatohepatitis, 25 received 1.7 g/d metformin + 0.6 g EPL po tid vs 15 metformin only for 6 months. | AST, ALT, and y-GT ↓; P<0.05 vs control group. | Diet, exercise, and alcohol abstinence. |
| Sun et al18 | 42±3 yr/40 m and 34 f | Randomized open controlled study: of 74 patients with diabetes with NAFLD, 34 received 0.5 g metformin tid + 0.6 g EPL po tid vs 34 metformin only for 3 months. | EPL: TC, TG, and US appearance improved (P<0.05). Total effective rate 78.4%. Control: TC, TG, and US appearance improved (P<0.05). Total effective rate 54.1%. Differences between groups significant (TC and TG, P<0.01; US appearance and total effective rate, P<0.05). |
BT: diet and physical exercise. SPSS statistical package 11.0. |
| Zhuang and Zhang27 | Mean 41.5 yr/48 m and 34 f | Randomized open controlled study: of 82 patients with NASH, 40 received 0.6 g EPL po tid + 0.25 g UDCA vs 42 only 0.6 g EPL po tid for 6 months. | EPL + UDCA: symptoms disappeared completely. AST, ALT, TC, and TG decreased or normalized (P<0.05). US: 65% improved. 20 patients recovered, nine markedly improved, and seven showed effectiveness (90%). EPL: symptoms disappeared completely. AST, ALT, TC, and TG ↓ (P<0.05). 40.5% improved. US: 40.5% improved. 12 patients recovered, seven markedly improved, and ten showed effectiveness (69%). Combination more effective than EPL alone (P<0.05). |
BT: ao diet, alcohol abstinence, physical exercise. SPSS statistical package 13.0. |
| Zhou and Sun28 | BT + EPL: 17–56 yr/37 m and 17 f BT: 16–60 yr/34 m and 14 f |
Randomized open controlled study: of 102 patients with FLD, 54 received BT + 0.5 g EPL iv/d in 250 mL 5% glucose for 1 month, followed by 5 months BT + 0.6 g EPL po tid vs 48 patients BT alone. | Significant differences in favor of BT + EPL for ALT, AST, and TG ↓; P ns for y-GT, TBA, TC, HDL, and LDL. Significant difference of liver histological improvement (P<0.05). BT + EPL had a rate of 20.4% (11 of 54) and EPL of 10.4% (5 of 48). |
BT: silybin (4 tbl) + glucuronolactone (2 tbl) + vitamin B complex (2 tbl) po tid. SPSS statistical package 13.0. |
| Fan et al23 | EPL: 54.29±10.11/21 m and 21 f XC: 54.62±9.67/20 m and 22 f |
Randomized open controlled study: of 84 patients with NAFLD and hyperlipidemia, 42 received 0.6 g EPL po tid vs 42 patients 0.6 g XC + 5 mg lovastatin 2× daily for 6 months. | EPL: AST, ALT, y-GT, CHE, TC, TG, HDL-C, LDL-C, FPG, TNF-α, and IL-6 ↓ (P<0.01). XC: AST, ALT, y-GT, CHE, TC, TG, HDL-C, LDL-C, FPG, TNF-α, and IL-6 ↓ (P<0.01). No significant differences between the groups. One ADR under XC (diarrhea), no ADR under EPL. |
Other drugs with same effect not allowed. SPSS statistical package 10.0. |
| Guo et al24 | EPL: 42.3±12.1 yr/36 m and 30 f GLY: 41.2±15.5 yr/30 m and 24 f |
Randomized open controlled study: of 120 patients with NASH, 58 received 2× 0.25 g EPL iv/d in 250 mL 5% glucose for 2 weeks, followed by 0.6 g EPL po tid for 4 weeks vs 42 patients 150 mg GLY (gamlixin) iv/d in 5% glucose, followed by 150 mg GLY po tid for 4 weeks. | EPL: Incidence of hepatic pain, abdominal distension, fatigue, and constipation ↓; AST, ALT, y-GT, TB, TC, TG ↓, LDL and HDL ns. Improvement of fatty liver intensity: P<0.001. GLY: Incidence of hepatic pain, abdominal distension, fatigue, and constipation ↓; AST, ALT, y-GT, TB ↓, TC, TG, LDL, and HDL ns. Improvement of fatty liver intensity: P=0.017. Significant differences between groups for fatty liver (from 23 to nine patients under EPL and from 15 to 12 under GLY), and for TC and TG. Two ADR under EPL (transient diarrhea), five under GLY: 2× transient BP ↑ and 3× mild hypo-K+. |
BT: diet and physical exercise. SPSS statistical package 13.0. |
| Sas et al19 | – | Randomized blinded study: of 215 patients with diabetes with NASH, 189 were available for follow-up; 152 patients received BT + 0.6 g EPL po tid vs 37 only BT for 6 months. 114 patients were treated for 7 yr. | ALT, AST, and y-GT ↓ (P=0.02, P=0.04, P=0.03, baseline vs 6 months treatment). US improved during the same time in 101 of 152 patients and remained unchanged in seven of 152 patients (P=0.02). Seven years treatment led to significant decrease in US in 93 of 114 patients and a more effective control of diabetes in 98 of 114 patients (significant reduction in HBA1c). Progress of hepatic fibrosis slowed vs control (P=0.03), and steatosis increased in the control group and decreased under EPL (P=0.02). |
BT: diet, physical exercise and 1 g/d metformin. |
| Knüchel32 | Mean 49 yr/49 m | Randomized double-blind study: of 40 patients with AFLD, 20 received 1.0 g EPL po tid vs 20 corresponding placebo for 2 months. | Under EPL AST, ALT, LAP, GLDH, AP, TC, LDL-C, TG, TB, IgA, IgG, IgM ↓ (P<0.01). Saturated fatty acids and oleic acid decreased, linoleic, linolenic, and arachidonic acid increased. Patients’ evaluation of therapeutic outcome under EPL very good (6) or good (14) vs good (7), moderate (8), and no effect (5) under placebo. Except C18:3, significant differences between EPL and placebo (P<0.01). |
BT: usual diet. No special diet. No treatment with any other liver drugs 2 weeks before study. Statistics: t-test, U-tests. |
| Schüller Pérez and Gonzáles San Martin33 | EPL: 46.0±2.4 yr/18 m and 2 f Placebo: 49.6±2.9 yr/19 m and 1 f |
Randomized double-blind study: Of 40 patients with AFLD, 20 received 1.0 g EPL po tid vs 20 corresponding placebo for 3 months. | AP ↓ (P<0.05) under EPL only. Between groups significant differences of y-GT and TB (P<0.05). All other laboratory variables within normal or normalized in both groups. Physicians’ evaluation of therapeutic outcome under EPL good (3), moderate (14), or no effect (3) vs moderate (9) or no effect (11) under placebo. No ADR. |
Statistics: sign test after Dixon and Mood, Wilcoxon signed-rank test, Mann–Whitney U-test. |
| Panos et al30 | EPL: 45.8±1.4 yr/25 m and 28 f Placebo: 49.3±1.6 yr/22 m and 29 f |
Randomized double-blind study: of 104 patients with ASH, 53 received 2.0 g EPL po tid. vs 51 corresponding placebo for up to 24 months. | 32 patients died (12 EPL, 20 placebo) and 26 (14 EPL, 12 placebo) defaulted or were withdrawn. Improved survival under EPL vs placebo (69 vs 49% (P=0.11)). Greatest tendency for improved survival in Pugh’s B status with two of 12 under EPL (17%) vs seven of 16 under placebo (44%) (P ns). Mean survival time 76 weeks under EPL vs 58.5 weeks under placebo, respectively (P=0.094), in Pugh’s group B 83.9 weeks and 56.6 weeks. No ADR. |
Treatment with any other liver drugs stopped 2 weeks before trial. Statistics: χ2-test (Yate’s modification) or t-test as appropriate. Survival: Kaplan–Meier method. Two-tailed tests of significance. |
| Lieber et al31 | EPL: 48.8±8.2 yr/385 m Placebo: 48.8±9.1 yr/379 m |
Randomized double-blind study: of 789 patients with perivenular/septal fibrosis or incomplete cirrhosis, 396 received 1.5 g EPL po tid vs 393 corresponding placebo for 24 months. | 2-yr biopsy in 202 EPL and 210 placebo patients. EPL not significantly differed from placebo on the stage of fibrosis as alcohol was reduced in both groups to ∼2.5 drinks/d. In a subgroup of 52 patients continuing to drink ≥84 g/d changes in the histological semiquantitative scoring system favored EPL (P=0.184). Improvement in transaminase and bilirubin favoring EPL seen at some time points in hepatitis C virus-positive drinkers or heavy drinkers. Positive trend in favor of EPL for ascites, both on physical examination (P<0.059) and at follow-up report (P<0.057). No ADR. |
History of at least 80 g alcohol/d for ≥19 yr. Statistics: included analysis of variance procedures for continuous data and χ2 procedures for categorical data. Haybittle–Peto method for data safety monitoring. Database and statistical analyses with SAS. |
| Sas et al35 | 41.1±4.9 yr | Randomized blinded study: of 86 patients with not complicated ALD, 56 patients received 0.6 g EPL po tid vs 30 cases 0.4 g/d vitamin E for 6 months. | Between groups significant differences of AST, ALT, and y-GT (P<0.02, P<0.04, and P<0.03, respectively); mean value of disease activity by Metavir scale A1 under EPL and A3 under vitamin E. Histology and Fibromax showed that progress of hepatic fibrosis significantly slowed (Fibromax: F1 vs F3) (P<0.05), and steatosis increased under vitamin E and decreased under EPL (P<0.05). US improved under EPL in 49 of 56 patients, and glucose, insulin levels, and HOMA decreased significantly, too. |
BT: included diet, physical exercise, and no alcohol. |
Abbreviations: ADR, adverse drug reaction; AFLD, alcoholic fatty liver disease; ALD, alcoholic liver disease; ALT, alanine aminotransferase; AP, alkaline phosphatase; ASH, alcoholic steatohepatitis; AST, aspartate aminotransferase; BT, basic treatment; C, cholesterol; CHE, cholinesterase; CT, computed tomography; d, days; EPL, essential phospholipids; f, female; FL, fatty liver; FLD, fatty liver disease; FPG, fasting plasma glucose; γ-GT, gamma-glutamyl transferase; GLDH, glutamate dehydrogenase; GLY, diammonium glycyrrhicinate; GP, gynostemma pentaphyllum gypenosides; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HOMA, Homeostasis Model Assessment; iv, intravenous; Ig, immunoglobulin; IL, interleukin; LAP, leucine amino peptidase; LDL, low-density lipoprotein; LFT, liver function tests; m, male; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ns, not significant; tid, three times daily; po, orally; qd, daily; TB, total bilirubin; tbl, tablet; TC, serum total cholesterol; TG, serum triglycerides; TNF-α, tumor necrosis factor-alpha; UDCA, ursodeoxycholic acid; US, ultrasonography; XC, xuezhikang capsule; yr, year.