Why the Liver Will Be the Future of Your Practice

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UntitledWith Nonalcoholic Fatty Liver Disease on the Rise and No NHS-Approved Treatment, Nutrient and Botanical Therapies Are Poised as the Next-Best Solutions

As we move well into the 21st century, diseases related to a sedentary lifestyle and an overabundance of food are increasingly common. The rate of type 2 diabetes (T2D), a condition that was estimated to affect 120 million people worldwide in 2000,[1] has quadrupled in global incidence over the last three decades.[2] Diabetes and obesity are often accompanied by nonalcoholic fatty liver disease (NAFLD), a condition characterised by fat, in the form of triglycerides (TGs), accumulating in the liver.[3] Nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD that also involves inflammation, was first described medically in 1952 and only identified as a disease in 1980.[4],[5] Nowadays, recent surveys have shown that about 30 to 40% of adults have NAFLD and 3 to 12% are affected by NASH.[6],[7] The numbers are shockingly high in those who are obese or affected by diabetes: 30 to 90% of individuals who are obese and 60 to 75% of individuals with T2D have NAFLD.[8],[9],[10]

Children are also increasingly affected by these conditions. The incidence of T2D in children has been shown to be increasing by 4.8% yearly, compared to a yearly increase of only 1.8% of type 1 diabetes.[11] At this rate, by the close of the century, T2D will likely overtake autoimmune diabetes as the most common form of paediatric diabetes. In some regions and age groups, T2D already accounts for more than half of all cases of paediatric diabetes.[12] NAFLD, first reported in the paediatric population in 1983,.[15] Genetic susceptibility causes this disease to have a heritable aspect[16],[17] and gives reason for further scrutiny and screening in children whose parents are affected, particularly when they do not present with the typical coexisting conditions of obesity and diabetes.

The role that gut health and dietary choline deficiencies may play in the development of NAFLD are discussed at length in the Summer 2018 issue of FOCUS.[18] The evidence behind directed interventions like supplemental choline,[19] probiotics,[20] and berberine[21] (an alkaloid derived from botanicals such as Oregon grape and barberry) is also reviewed therein. In this issue, we discuss evidence behind vitamin E (both as alpha tocopherols and a blend of delta and gamma tocotrienols), milk thistle seed extract, and essential fatty acids as tools in the fight against NAFLD. We also discuss additional research pertaining to treatment of pediatric NAFLD with probiotics and choline.

Vitamin E

As oxidative stress and diminished antioxidant defences are factors leading the development of NAFLD,[22] it should not be surprising that the use of antioxidants has been investigated as a potential treatment for the condition.

Vitamin E has been studied in several clinical trials for the treatment of NAFLD, both as a standalone and as an adjunctive therapy. In a review of these studies, the dosage of vitamin E was 400 to 1,200 IU/day with study durations from 24 weeks to more than two years.[23] Findings generally were positive, showing that vitamin E supplementation was associated with improvements in histology, steatosis, and/or transaminase levels.[24],[25] In an open-label pilot study including 11 children with NAFLD, supplementation of between 400 to 1,200 IU of vitamin E for four to 10 months was found to normalise transaminase and alkaline phosphatase levels during treatment, yet these parameters returned to abnormal ranges once treatment was stopped.[26] Hepatic echogenicity did not change during the course of treatment.

Tocotrienols are the lesser-studied family of the naturally occurring forms of vitamin E, with tocopherols, more often found in nature, dominating scientific research.[27] Numerous clinical findings indicate that, like tocopherols, tocotrienols may be beneficial for reducing fatty liver changes. Tocotrienols have been shown to improve total cholesterol and its fractions, reducing total and low-density lipoprotein (LDL) cholesterol by 15 to 20%[28],[29] and TGs by up to almost 30%.[30] Tocotrienols have also been shown to have anti-inflammatory and antioxidant effects in vivo, lowering high-sensitivity C-reactive protein (hs-CRP) levels and reducing LDL oxidation.

In adults with ultrasound-diagnosed NAFLD, 200 mg of mixed tocotrienols (sourced from sustainable palm oil, with a high gamma fraction and additionally providing 61 mg of alpha-tocopherol) taken twice daily for one year was shown to significantly normalise hepatic echogenic response and rate of remission compared to placebo.[31] In a second study of patients with ultrasound-diagnosed NAFLD and transaminase elevation, 300 mg of tocotrienols (a 90:10 delta:gamma blend) taken twice daily for 12 weeks significantly decreased AST, ALT, hs-CRP, and malondialdehyde (a marker of oxidative stress) levels, as well as fatty liver index score, compared to placebo.[32]

Milk Thistle

Milk thistle (Silybum marianum) is well known for its liver-protective effects. Not surprisingly, this botanical has also been investigated for the treatment of NAFLD in several clinical studies. The active compounds found in milk thistle, silybin and silymarin, have been shown to activate a nuclear bile acid receptor known as farnesoid X receptor (FXR) in hepatocytes. FXR regulates bile acid, glucose, and lipid metabolism[33]—each of which plays a role in liver health. Activation of FXR by silymarin has been shown to down-regulate inflammatory pathways and metabolic dysfunction induced by high-fat diet (HFD) feeding.[34] Medications that interact with FXR in a similar manner to these milk thistle–derived compounds are also being investigated for the treatment of NAFLD.[35] Silymarin has additionally been shown to increase both hepatic and intestinal glutathione levels, which tend to be lower in individuals with NAFLD.[36],[37]

Clinical studies have shown milk thistle improves various parameters associated with NAFLD. A 2017 meta-analysis found that treatment with milk thistle significantly reduces ALT and AST by 5.08 IU/L and 5.44 IU/L, respectively, in patients with NAFLD.[38] Dosages ranged from 140 mg once a day to 200 mg three times a day, for a duration of eight to 24 weeks. After eight weeks at the lowest dosage of 140 mg daily, significant improvements were seen in fasting blood glucose (FBG), lipid profiles, and serum insulin levels; additionally, AST and ALT were reduced from 56 to 37.77 IU/L and 78.73 to 53.05 IU/L, respectively.[39]

Milk thistle has also been investigated for the treatment of NAFLD in children ranging from five to 16 years of age.[40] In this population, silymarin was provided in divided dosages at mealtime with a total dose of 5 mg/kg/day. Children diagnosed with NAFLD (based on history, physical examination, liver sonography, and liver enzymes) were randomised into two groups, with the control and intervention groups both being recommended lifestyle interventions (LI) of 150 to 250 minutes of walking a week and a low-fat and low-carbohydrate diet. After 12 weeks of the interventions, the children receiving silymarin in addition to LI had a significantly lower grade of fatty liver and significantly improved AST and ALT levels, while none of these parameters changed significantly in the control group.

A combination of milk thistle and vitamin E has also been assessed in clinical studies for the treatment of adults with NAFLD.[41],[42] Again, participants in both the control and intervention groups were assigned LI (hypocaloric diet and regular exercise) while the intervention group also received the combination of milk thistle and vitamin E. In the larger of these two studies,42 a regimen of 420 mg of silymarin (approximately 60% silybin) and 60 IU of vitamin E (form unspecified) taken daily for 90 days was associated with significantly greater reductions in the abdominal circumference, body mass index (BMI), and ultrasound-measured size of right liver lobe, as well as the hepatic steatosis and lipid accumulation indices.

Essential Fatty Acids

Due to their effect on TG levels and inflammation,[43] essential fatty acids (EFAs) have also been the topic of numerous clinical studies for the treatment of both adult and paediatric NAFLD. Supporting this research further, dietary assessment of children with NAFLD has shown a lower consumption of fish (which provides EFAs) and supplemental EFAs than controls.[44]

Multiple meta-analyses investigating the impact of EFAs on NAFLD have been performed,[45],[46],[47] including one that solely looked at paediatric research.[48] The primary findings of these larger analyses, which included daily dosages ranging from 250 mg of docosahexaenoic acid (DHA) to a 50 mL mixture of eicosapentaenoic acid (EPA) + DHA, all supported the use of EFAs for the treatment of NAFLD. A pooled estimate from 11 randomised, controlled trials (RCTs) concludes that essential fatty acids significantly reduce ALT (by 7.53 IU/L), AST (by 7.10 IU/L), and TGs (by 36.16 mg/dL), and marginally reduce liver fat by (5.11%).47 In this same evaluation of the 11 RCTs, a dose-response analysis showed incremental decreases of ALT (3.14 IU/L/g EPA + DHA), AST (2.43 IU/L/g EPA + DHA), liver fat (2.74%/g EPA + DHA), and TGs (9.97 mg/dL/g EPA + DHA) with EFA supplementation. An improvement of histology was also seen in many of the studies that assessed this parameter.45 In children, supplementation of EFAs (with dosages ranging from 250 to 1,300 mg/day) was shown to significantly improve hepatic steatosis ultrasound grade, reducing AST within six months and ALT after 12 months.48

Probiotics and Paediatric NAFLD

Positive findings associated with probiotic supplementation have been demonstrated not only in adults with NAFLD,20 but also in children with NAFLD. In one double-blind, placebo-controlled, pilot study, children (with the average age of 10.7 years) with ultrasound-diagnosed fatty liver changes and persistent transaminase elevation were given 12 billion colony-forming units (CFUs) of Lactobacillus rhamnosus GG or placebo daily for eight weeks. Treatment with the probiotic significantly reduced ALT levels compared to placebo; however, liver echogenicity and AST levels did not change. Significant decreases were seen in a marker of bacteria or bacterial membrane translocation through the intestinal barrier,[49] which can be a factor contributing to hepatic inflammation.[50]

Another study investigated the treatment of children having biopsy-proven NAFLD with a high-potency blend of eight probiotic strains (including Streptococcus thermophilus, three Bifidobacterium spp., and four Lactobacillus spp.), compared to placebo.[51] In children receiving the probiotic blend, fatty liver scores were significantly improved with the probability of none, light, moderate, or severe fatty liver at the end of the study respectively being 21%, 70%, 9%, and 0%, compared to 0%, 7%, 76%, and 17% in the placebo group.

Given the roles that endotoxin translocation and gut dysbiosis play in the development of NAFLD,[52],[53] it is likely that other probiotics and therapies shown to improve these parameters may also improve pediatric NAFLD. As lower levels of bifidobacteria have been seen in children with NAFLD,.

Choline and Paediatric NAFLD

One randomised, double-blind, placebo-controlled study investigated the use of a combination of DHA, vitamin E, and choline for the treatment of paediatric NAFLD. In this study, children with biopsy-proven NASH and persistent aminotransferase elevation were provided with 250 mg of DHA, 37 IU of vitamin E, and 201 mg of choline or placebo daily for a period of six months.[61] All participants were recommended a hypocaloric diet and one hour of physical activity twice weekly. At 12 months (with the oral intervention for only the first six months, and the lifestyle changes for the entire period) it was found that the individuals receiving the supplement combination had significantly greater improvements in liver steatosis (as assessed by ultrasound), ALT, and fasting glucose levels than the placebo group, despite the cessation of the oral intervention six months prior to evaluation.

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Conclusion

Given the rise in NAFLD in both adults and children and the lack of an indicated pharmaceutical treatment, natural strategies for the treatment of this condition stand well-poised as the “next-best thing.” Because many of these therapies address the factors that contribute to the development of NAFLD, they may not only ease the symptoms of the disease, but also effectively address some of its root causes.

References

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