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Acta Endocrinologica (Bucharest) logoLink to Acta Endocrinologica (Bucharest)
. 2020 Apr-Jun;16(2):223–231. doi: 10.4183/aeb.2020.223

THE EFFECTS OF REALSIL (SILYBIN–PHOSPHOLIPID–VITAMIN E COMPLEX) ON LIVER ENZYMES IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) OR NON-ALCOHOLIC STEATO-HEPATITIS (NASH): A SYSTEMATIC REVIEW AND META-ANALYSIS OF RCTS

SM Derakhshandeh-Rishehri 1, M Heidari-Beni 2, MH Eftekhari 2
PMCID: PMC7535884  PMID: 33029240

Abstract

Background.

The aim of the present study was to systematically review the effects of Realsil (silybin–phospholipid–vitamin E complex) on liver enzymes in patients with NAFLD or NASH.

Methods.

We searched Web of Science, MEDLINE, Google Scholar, Cochrane Library, Science Direct, ProQuest, Scopus, and 1868 articles were found up to December 2018. Four studies that examined the effect of Realsil intake on liver enzymes among NAFLD or NASH patients were included. Exclusion criteria include: animal studies, studies with the design other than clinical trials, studies on non-adult individuals, studies that assess the effect of vitamin E, silybin, or phospholipid solely, studies that examined the effect of Realsil on other outcomes, or studies with insufficient data.

Results.

The analysis demonstrated that Realsil intake led to a significant decrease in Gamma-Glutamyl Transpeptidase (GGT) levels (standardized mean difference (SMD) =-0.37; 95% confidence interval (CI]): -0.68 to -0.06). Realsil intake non-significantly decrease alanine transaminase (ALT) levels (SMD=-1.02 U/L; 95% CI: -2.23 to 0.20) and non-significantly increase aspartate aminotransferase (AST) levels (SMD = 0.17 U/L; 95% CI: -0.26–0.61).

Conclusion.

Realsil intake was associated with a significantly decreased circulating GGT level without any significant effect on AST and ALT levels.

Keywords: vitamin E, Silybin, Alanine Transaminase, Aspartate Aminotransferases, gamma-Glutamyltransferase

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, which is characterized by hepatic fat accumulation above 5% of liver weight (1, 2). More than 30% of the general population worldwide is suffering from NAFLD (3-5). NAFLD varies from asymptomatic disease, simple steatosis to non-alcoholic steato-hepatitis (NASH) which can progress to end-stage liver disease (ESLD) as cirrhosis with the complication of liver failure and hepatocellular carcinoma (6-8). The major diagnostic procedure is liver biopsy (9).

No consensus regarding pharmacological treatment of NAFLD/NASH is currently available. Some drugs including thiazolidinediones, metformin, lipid-lowering agents and antioxidants which directly reduce oxidative stress and lipid accumulation may improve clinical aspects of NAFLD/NASH (9, 10).

Realsil is a new treatment, which reduces dimethylnitrosamine-induced hepatic fibrosis in the rat. It is a complex of silybin-phospatidylcholine-vitamin E (11). Silymarin is a powerful antioxidant agent that is extracted from milk thistle (Silybum marianum) (12). It contains antioxidant substances including six flavolignans (silybins A and B usually in isoconcentration, isosilibine, silidianin, silicristine, isosilicristine) and a flavonoid (taxifolin)(13). Among these, silybin has the highest concentration and biological effects (14). Silybin has a marked antioxidant activity (in vitro and in vivo) which modulates oxidative stress, inflammation, and regulates glucose homeostasis in hepatocytes (14-16). In Realsil, silybin is conjugated with phosphatidylcholine (PC) and vitamin E to enhance its intestinal absorption and its consequent bioavailability (17). Moreover, vitamin E, as an important antioxidant, can modulate the effects of reactive oxygen species. Based on scientific evidences vitamin E could improve the level of liver transaminases and fibrosis score (18). The active components of one pill of Realsil complex are: silybin 94 mg, phosphatidylcholine 194 mg, vitamin E acetate 50% (α-tocopherol 30 mg) 89.28 mg. This dosage of the Realsil complex is currently utilized in clinical practice and confirmed in a multi-center, Phase III, double-blind clinical trial (19).

Loguercio C et al. (20) reported that12 months interventions with a dietary supplement of Realsil, twice a day significantly improved both liver damage plasma marker levels (AST, ALT, and GGT) and liver histology in about 50% of patients with NAFLD and NASH. Furthermore, another study showed that Realsil in combination with Mediterranean diet led to the significant variation in BMI, waist circumference, total cholesterol and triglycerides; however, ALT, AST, and GGT levels did not change significantly (19). Federico et al. (21), in Italy, reported the same results since 12 month Realsil treatment had no effect on liver enzymes (ALT, AST, or GGT).

The finding of previous randomized clinical trials that investigated weight reduction (phentermine, pioglitazone), cytoprotection, and antioxidant (ursodesoxycholic acid, vitamin E, N-acetylcysteine) components on treatment of NAFLD are inconsistent and there is no consensus on how to treat NAFLD or NASH. So, we aimed to systematic review and meta-analysis on the efficacy of Realsil intake (silybin–phospholipid–vitamin E complex) on liver enzymes and BMI in NAFLD/NASH patients.

MATERIALS AND METHODS

Literature Search

We searched all the published articles in the following databases: web of science, PubMed, Cochrane library, ProQuest, Science Direct, Scopus, and Google Scholar from November 2017 to December 2018. Keywords consist of: “silymarin [Title/Abstract] OR silymarin [MeSH Terms] OR silybin [Title/Abstract] OR silybin [MeSH Terms] OR vitamin E [Title/Abstract] OR Vitamin E [MeSH Terms] OR tocopherol [Title/Abstract] OR tocopherol [MeSH Terms] OR phospholipid [Title/Abstract] OR phospholipid [MeSH Terms] AND liver enzyme[Title/Abstract] OR liver enzyme [MeSH Terms] OR SGPT [Title/Abstract] OR SGPT [MeSH Terms] OR SGOT [Title/Abstract] OR SGOT [MeSH Terms] OR AST [Title/Abstract] OR AST [MeSH Terms]) OR ALT [Title/Abstract] OR ALT [MeSH Terms] OR Alanine aminotransferase [Title/Abstract] OR Alanine aminotransferase [MeSH Terms] OR Aspartate Aminotransferase [Title/Abstract] OR Aspartate Aminotransferase [MeSH Terms] OR GGT [Title/Abstract] OR GGT [MeSH Terms] OR gamma-Glutamyl transferase [Title/Abstract] OR gamma-Glutamyl transferase [MeSH Terms] AND NAFLD [Title/Abstract] OR NAFLD [MeSH Terms] OR NASH [Title/Abstract] OR NASH [MeSH Terms] OR Non-alcoholic fatty liver disease [Title/Abstract] OR Non-alcoholic fatty liver disease [MeSH Terms] OR Nonalcoholic steatohepatitis [MeSH Terms] OR Nonalcoholic steatohepatitis [Title/Abstract]. No restrictions were applied for language. We assessed clinical trials that investigated the effects of Realsil (silybin-vitamin E-phospholipid complex) on liver enzymes (ALT, AST, and GGT) in NAFLD/NASH patients. Exclusion criteria include: animal studies, studies with the design other than clinical trials, studies on non-adult individuals, studies that assess the effect of vitamin E, silybin, or phospholipid solely, studies that examined the effect of Realsil on other outcomes, or studies with insufficient data (such as without control group or lack of end point information). Firstly, we assessed titles and abstracts of articles, and relevant papers were selected.

Relevant papers were selected according to the title and abstract by two authors (SMDR. and MHB). Two independent reviewers (MHE and NN) screened papers and read full texts of relevant papers. They assessed full texts for inclusion criteria and extracted data. Statistical analysis was done by the author (SMDR).

Data extraction

Mean ± standard deviation for BMI, ALT, AST, and GGT before and after the intervention for each of intervention and control groups were extracted. In addition, the mean change ± standard deviation that reported for the BMI, ALT, AST, and GGT within each group of intervention and control groups were extracted. The data of one study without complete data for analysis and two studies without a placebo group were not extracted. Complete information about excluded RCTs is shown in Fig. 1.

Figure 1.

Figure 1.

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The study selection process.

Different doses of Realsil tablet were utilized in the relevant articles. In two studies 2 tablets/ day were used (19, 22), while in another one, 4 tablets/ day were utilized (27). In one study the recommended dosage was unclear (21). Each tablet contains: silybin 94 mg, phosphatidylcholine 194 mg, vitamin E acetate 50% (α tocopherol 30 mg) 89.28 mg.

The process for study selection (i.e., screening, eligibility), method of data extraction (i.e., piloted forms, independently, in duplicate), determination and definition of variables, and processes for obtaining data and confirmation were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 checklist.

Risk of bias assessment

The Critical Appraisal Skills Program (CASP) related to randomize controlled trials was used for assessment of the risk of bias in included studies by two authors (MHE and SMDR). Based on CASP, it is possible to make a qualitative decision whether to use or not the studies.

Statistical analysis

All outcomes were recorded as continuous variables. Pooled meta-analyses were completed for the studies that reported the same outcomes. Mean difference was calculated by subtracting the mean before- and after-intervention values for the experimental and control groups. If it was not directly reported, we calculated the SD of mean differences as,

graphic file with name aeb.2020.223-eq001.jpg

where SDb = SD before, SDa = SD after, and r = correlation between the before and after scores. We used r = 0.5 to calculate SD.

We found that a simple formula:

graphic file with name aeb.2020.223-eq002.jpg

can be used to estimate the mean by using the values of the median (m), low and high end of the range (a and b, respectively). The variance can be estimated using the formula:

graphic file with name aeb.2020.223-eq003.jpg

I-squared and chi-squared tests were used to assess heterogeneity between studies. Fixed-effect model was used to calculate pooled effect size. In the case of heterogeneity random-effect model was applied. 95% confidence intervals were calculated for the standardized mean differences (SMD), and all results were reported at a significance level of 0.05. Egger’s tests were used to assess publication bias. All statistical analyses were done with Stata v. 13 software (College Station, TX, USA).

RESULTS

Among 1868 articles found in the first search, 57 eligible RCTs were entered into our study based on review of title and abstract. Then, we read the full texts of these papers and evaluated the findings again (Fig. 1).

From these, 31 studies considered only vitamin E supplementation, 16 studies considered only silymarin supplementation, and one study considered only phospholipid. Thus, we exclude these studies. In addition, one study with insufficient data, and one study without placebo group were excluded. Finally, 4 articles (totally 168 participants) were included in the present meta-analysis (Table 1).

Table 1:

Author (Year) Age Population Sample size (int/con) Design Duration Intervention (Dos age) Result:
Abenavoli L, et al. (2015) (19) 45 Overweight NAFLD 10:10 RCT 6 months 2 tab/d Mediterranean Diet+Realsil (each one: silybin 94 mg, phosphatidylcholine 194mg, vitamin E acetate 50% (α-tocopherol 30 mg) 89.28 mg.) Mediterranean Diet in combination with Realsil had no effect on AST, ALT, or GGT.
Aller R, et al. (2015) (22) 47.4 ± 11.2 NAFLD 18:18 RCT 3 months 2 tab/d (each one: Silymarin:540.3mg + vitamin E:36mg) + hypocaloric diet Patients in both groups showed a decrease in GGT levels after treatment; however, AST and ALT level did not change significantly after RA treatment.
Trappoliere M, et al. (2005) NAFLD + HCV 53:32 RCT 12 months 4 pieces/d (each:94 mg of silybin, 194 mg of phosphatidylcholine,and 90 mg of vitamin E) Ra treatment significantly lowered ALT and GGT in NAFLD patients.
Federico A, et al. (2017) 42 ± 11 NASH 17:10 RCT 12 months Ra treatment had no effect on AST, ALT, OR GGT.
Loguercio C, et al. (2012) (20) 18-65 NAFLD RCT 12 months 2 tab/d Of patients with elevated baseline AST, ALT, or GGT significantly more reached normal levels with RA.
Stiuso P, et al. (2014) 40.4 ± 11.1 NASH 11:19 RCT 12 months 2 tab/d (active components: silybin 94mg, phosphatidyl choline 194mg, and α-tocopherol 30mg) The chronic treatment with RA decreased AST significantly in both groups of NASH patients; while ALT & GGT decreased significantly only in NASH patients with very high level of TBARS, and NASH patients with very low level of TBARS, respectively
Aller R, et al. (2018) 55.1±11.3 NAFLD 34:20 RCT 6 months 2 tab/d (60% silymarin and 30 IU vitamin E) Treatment with Eurosil 85® (Silymarin + vitamin E) for six months was accompanied by a significant decrease in transaminases (ALT, AST, GGT)
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Realsil and ALT

The Realsil supplementation led to slight and non-significant decrease in ALT level (SMD = -0.39; 95% CI = -1.11 to 0.33), with high heterogeneity (I2 =77.5%; P<0.001%). Publication bias was not significant (Egger’s test P = 0.615) (Fig. 2).

Figure 2.

Figure 2.

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The effect of RA on alanine aminotransferase in published clinical trials.

Realsil and AST

The Realsil supplementation non-significantly increased AST level (SMD=0.17 U/L; 95% CI= -0.26, 0.61) with low heterogeneity (I2 = 0%; P = 0.885). Publication bias was not significant (Egger’s test P = 0.118) (Fig. 3).

Figure 3.

Figure 3.

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The effect of RA on aspartate aminotransferase in published clinical trials.

Realsil and GGT

The Realsil supplementation led to a significant decrease in GGT level (SMD =-0.37; 95% CI = -0.68 to -0.06) with low heterogeneity (I2 = 0%; P = 0.766). Publication bias was not significant (Egger’s test P = 0.362) (Fig. 4).

Figure 4.

Figure 4.

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The effect of RA on gamma-glutamyl transferase in published clinical trials.

Realsil and BMI

The Realsil supplementation led to a non-significant reduction in BMI (SMD =-0.16; 95% CI = -0.83 to 0.50) with low heterogeneity (I2 = 0%; P = 0.844). Publication bias was not significant (Egger’s test P = 0.405) (Fig. 5).

Figure 5.

Figure 5.

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The effect of RA on BMI in published clinical trial.

DISCUSSION

In the present systematic review and meta-analysis of RCTs, we found that Realsil supplementation can significantly decrease GGT levels compared with placebo. No significant effects on BMI, ALT and AST levels were observed with Realsil supplementation.

The traditional roles of GGT include: liver dysfunction, bile duct conditions, and alcohol consumption. Although gamma-glutamyl compounds compromise antioxidants, inflammatory compounds, drug metabolites, and neuro-reactive molecules, the main role of GGT is enabling metabolism of glutathione and glutathionylated xenobiotics. However, raising GGT levels is related to pro-oxidant activity, particularly in the presence of iron or copper. When GGT levels are augmented, red blood cell membranes are hurt as a result of release of these potentially toxic transition metals, which can further result in chain, prooxidant reactions. High levels of prooxidation may cause downstream cell, tissue, and DNA damage caused by oxidative and nitrosative stress and the production of deleterious reactive oxygen species or nitric oxide. This combination of factors is observed with increasing frequency in many chronic diseases (23, 24).

Findings of the current meta-analysis are consistent with most previous trials (20, 22-27). Aller et al. (2015)(22) investigated the effect of hypo-caloric diet or hypo-caloric diet plus silymarin and vitamin E on NAFLD patients. After 6 months, patients in both groups showed a significant reduction in GGT level. Trappoliere M et al. (2005)(27), after 12 month Realsil supplementation, reported that plasma level of liver enzymes (ALT & GGT) ameliorated in the intervention group but not in the control group of NAFLD patients. Stiuso P et al. (2014)(26) demonstrated that after 12 month intervention with Realsil supplementation GGT level significantly decreased only in NASH patients with very low level of Thiobarbituric Acid-Reactive Species (TBARS). In another study the combination of ursodeoxycholic acid (UDCA) and vitamin E reduced the mean serum levels of ALT, AST, and GGT significantly in NASH patients. AST, ALT and GGT reached normal range in 80%, 70% and 65% of the patients, respectively (Pietu 2012)(28). Cacciapuoti F et al. (2013)(29) evaluated the effects of a mixture of Silybum marianum (silymarin), vitamin B12, vitamin E (Epaclin) and a restricted diet on NAFLD patients. They showed beneficial effects on the biochemical, inflammatory and ultrasonic indices of hepatic steatosis. Abenavoli et al. (2015)(19) assessed the effects of a combination of Mediterranean diet plus Realsil in overweight patients with NAFLD which results showed non-significantly changes in ALT, AST, or GGT levels. A recent study in Italy assessed Realsil Supplementation for 12 months and concluded that Realsil had no effect on liver enzyme level (21).

In the present review, Realsil supplementation reduced the high GGT serum levels. Mean serum levels of GGT are above the normal range in NAFLD patients because of obesity, hyperinsulinemia, inflammation and changes in hepatocyte membrane permeability. (Federico 2017)(21).

One possible mechanism is that Realsil consists of silybin which stabilizes the hepatocyte membrane by reducing enzyme dispersion in the extracellular medium, and thus prevents the effects of toxins on the cells (21). Also, silymarin conjugates to vitamin E and phospholipids to improve its bioavailability, and antioxidant and antifibrotic activity (17). Another beneficial ingredient of Realsil is vitamin E which is low in the serum of obese individuals with chronic disease (28). The lipid soluble vitamin E (α-tocopherol) has powerful free radical—scavenging properties in biologic membrane, and it interrupts the propagation of the peroxidation of polyunsaturated fatty acid (30).

We observed that Realsil supplementation had no effect on ALT, or AST levels which is consistent with three previous studies on NASH/NAFLD patients (19, 21, 22). Our results are in contrast with three other studies (Trappoliere, Loguercio, Stiuso)(20, 26, 27). Loguercio C et al. (2012)(20) carried out a placebo-controlled, double-blind randomized clinical trial to assess in NAFLD patients for 12 months. They showed that patients with elevated baseline levels of AST, ALT, or GGT, significantly more reached normal levels. A prospective, double-blind, randomized, placebo-controlled trial reported that 6 months intake of the combination of vitamins E and C alleviated fibrosis in NASH patients without any improvement in the necro-inflammatory activity or ALT concentration (31). Conversely, Kim et al., in 2015(32), reported that short-term vitamin E treatment (for 6 months) significantly reduced ALT levels in NAFLD patients with metabolic syndrome, but metabolic profiles (body weight, lipid and glucose levels) were not affected by vitamin E. One study showed that, after vitamin E treatment, 43% of NASH patients improved clinically their ALT and AST levels and lobular inflammation (33). Similar effects were reported in a clinical study in which vitamin E ameliorated NASH by decreasing the ALT concentration and histological activity, and promoted weight control (34). In another study the effects of Silybum marianum was investigated on NAFLD for 2 months. Results showed Steato test, ALT and AST levels significantly reduced (P <0.001) (35). In 2012 they demonstrated that metformin, pioglitazone and silymarin decreased AST, and ALT levels but a beneficial effect was more in the silymarin group than in another group (36).

Silybin shows antioxidant activity both in vitro and in animal studies, preventing radical formation, scavenging some radical species, interfering with lipid membrane peroxidation and permeability, and augmenting the concentration of scavengers in a dose-dependent manner. In human liver stellate cells, silybin inhibits extracellular signal-related kinase (ERK), MAP/ERK kinase (MEK), and Raf phosphorylation; reduces cell migration; and reduces TGF-β-induced synthesis of procollagen type I and secretion of MMP-2. ERK, MEK-, and mitogen activated protein kinase-related pathways are regulated and regulate Jun N-terminal kinase (JNK) expression, which has a pivotal role in obesity and insulin resistance. Phosphatidylcholine, another component of the Realsil preparation, protects against oxidative stress mediated liver damage (21, 36, 37).

Hypocaloric diet (1400–1600 kcal/day) is recommended for NAFLD patients. This diet includes carbohydrates (50–60%), proteins (15–20%, of which about 50% vegetable proteins), mono- and polyunsaturated fats (less than 30%), saturated fat (less than 10%), cholesterol (less than 300 mg/day) and fibers (25–30 g/day). Micronutrients amount should be balanced in diet (38, 39). One study showed that hypocaloric diet (1520 kcal, 52% of carbohydrates, 25% of lipids and 23% of proteins) with Realsil can ameliorate function hepatic test and non-invasive NAFLD index in patients without loss of 5% of weight. Realsil can be a valid alternative therapeutic option for patients that fail to lose weight with diet (22). Another study showed that 6 months treatment with the Mediterranean diet and Realsil could improve anthropometric parameters, insulin resistance and hepatic fat accumulation (19). Realsil has anti-inflammatory, anti-fibrotic and hepatoprotective actions. It can improve liver enzymes, liver steatosis, insulin sensitivity and cytokines profile, in particular IL-6, IL-8 and TNF-a. Interaction between Realsil and Mediterranean diet improves NAFLD in overweight patients (40, 41). Prescription of Realsil twice daily for 12 months with reduction of simple carbohydrates (glucose, sucrose, and fructose), fatty dressings (butter, mayonnaise), fatty cheeses, sausages, and increases in vegetable proteins and fiber can improve liver enzymes, insulin resistance, and liver histology, without increasing in body weight (20). Further randomized controlled trials with sufficient duration are needed to fully investigate the effect of the diet and Realsil in modifying the natural history of NAFLD, and clinical parameters.

Our review features a number of strengths. This review includes all available RCTs regarding the effect of Realsil intake on liver enzymes, and it is the most up-to-date systematic review and meta-analysis of the topic. Other strengths are detection of biases, such as publication bias as well as deficiencies in the design, conduct, analysis, and interpretation of research, or the ability to identify sources of diversity across various types of studies. Nevertheless, some limitations exist in the present analysis. We used the data of published literature, and the data for each patient were unavailable. Hence, test condition bias might exist. The sample size of the included RCTs was small so that significant metabolic changes associated with Realsil might not have been detected. The differences in dose (2-4 tablets/day) and duration (3-12 months) might have also affected the accuracy of the results. However, in general, meta-analysis cannot improve the quality of the original studies, or cannot address the variability of patient populations, the quality of the data, and the potential for underlying biases.

In humans, no adverse effects (AEs) on liver safety parameters were reported with Realsil supplementation. With this regard, Loguercio et al. in 2012 (20), reported that, however, no serious AEs occurred; we observed some generally transient AEs which included diarrhea, dysgeusia, and pruritus. There is no agreement on recommended dosage of Realsil supplementation.

In conclusion, the current systematic review and meta-analysis on randomized, placebo-controlled clinical trials showed that Realsil intake was associated with a significantly decreased circulating GGT level and did not have any significant effect on BMI, AST and ALT. Further trials are needed to determine the most effective dose and frequency of supplementation.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This research received no specific grant from any funding agency in the public, private or not-for profit sectors.

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