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Innovative Solutions for NAFLD-Decker

by | Jun 1, 2020

Post Categories: Healthy Aging Practices | Integrative Medicine

Nonalcoholic steatohepatitis (NASH), Fatty liver disease (NAFLD), Milk thistle, Bererine, Melatonin, Molecular hydrogen

Innovative Solutions for NAFLD

By Carrie Decker, ND

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 characterized 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 not identified as a disease until 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

Botanical substances with clinical evidence for their use in the setting of NAFLD are milk thistle and berberine. Many are well acquainted with milk thistle as a hepatoprotective herb and with berberine’s metabolic regulating aspects, but they may not be aware of the clinical data in the setting of NAFLD, which will be reviewed herein. Additionally, two nutritional interventions that we probably don’t think of as agents for metabolic and liver disease, melatonin and molecular hydrogen, also have clinical evidence suggesting they may be of benefit and will be discussed in regard to their use for these conditions.

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 metabolism11—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.12 Medications that interact with FXR in a similar manner to these milk thistle–derived compounds are also being investigated for the treatment of NAFLD.13 Silymarin has additionally been shown to increase both hepatic and intestinal glutathione levels, which tend to be lower in individuals with NAFLD.14,15

Clinical studies have shown milk thistle improves various parameters associated with NAFLD. A 2017 meta-analysis found that treatment with milk thistle significantly reduces alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by 5.08 IU/L and 5.44 IU/L, respectively, in patients with NAFLD.16 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.17

Milk thistle has also been investigated for the treatment of NAFLD in children ranging from five to 16 years of age.18 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 randomized 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.

Berberine

Berberine is another botanically derived substance that has numerous mechanisms by which it may help protect against NAFLD and support its resolution.19

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The antidiabetic and lipid-balancing effects of berberine have been demonstrated in several clinical trials,20 and may be means via which berberine positively affects liver function. Berberine has been shown to alter metabolism-related gene expression and bile acid metabolism via pathways involving FXR as well.21 In animals, berberine has been shown to have the effect of preventing HFD-associated obesity and hepatic triglyceride accumulation in wild-type (normal) mice, but not in those that had the genetic elimination of intestinal FXR expression. Berberine has also been shown to suppress obesity-associated inflammation and hepatic steatosis in mice by decreasing phosphorylation of the inflammatory complex known as JNK1,22 a protein kinase implicated in the development of steatohepatitis.23 JNK1 is strongly activated by environmental stressors and pro-inflammatory cytokines. Berberine also has direct anti-inflammatory effects.24

Liver enzyme elevation and fatty liver changes are often seen in gastrointestinal conditions including small intestinal bacterial overgrowth (SIBO),25 celiac disease,26 and inflammatory bowel disease.27 Common to each of these conditions is dysbiosis and increased gastrointestinal permeability, which conventional hepatologists and gastroenterologists even point to as an underlying factor contributing to NAFLD.28,29 The action of berberine in the gut also may be a mechanism via which it improves fatty liver changes, as it has been shown to affect the gut microbial balance and improve tight junction integrity, reducing intestinal permeability.30,31,32

The benefits berberine offers for NAFLD have also been demonstrated in a randomized, parallel controlled, open-label clinical trial.33 Patients with NAFLD (diagnosed if liver fat content exceeded 13%, as assessed by proton magnetic resonance spectroscopy) were prescribed LI changes (diet and exercise per standard guidelines), while one of the groups was additionally prescribed berberine, at a dose of 500 mg thrice daily for 16 weeks. At the end of the study period, the group additionally receiving berberine had significantly lower hepatic fat content and body weight as well as improved glucose and lipid profiles compared to the population who only implemented LI changes. Interestingly, the parallel animal model showed that berberine preferentially distributes to the liver following oral administration, with levels shown to be more than 50 times higher in the liver than the plasma.

Melatonin

In recent years, there has been considerable research regarding the use of melatonin for metabolic disease and its consequences.34,35 In addition to its antioxidant and sleep cycle regulating effects,36 melatonin is involved in metabolism and affects insulin signaling, cellular glucose uptake, the balance of white and brown adipose, and adipokine secretion, among other things.37,38,39

Benefits with melatonin supplementation have been seen in obese patients following a calorie-restricted diet, where, compared to placebo, supplementation of 10 mg of melatonin at bedtime improved markers of oxidative stress, regulated adipokine secretion, and supported weight loss.40 Other clinical studies have also shown melatonin may help ameliorate metabolic issues associated with antipsychotic medication use and the inflammation and oxidative stress associated with obesity.41,42,43,44

Liver disease is accompanied by oxidative stress, whether it is one of the initiating factors or a consequence of disease. Hepatic mitochondrial dysfunction, often due to oxidative stress, is a contributor to hepatic fibrosis.45 Melatonin has been shown in several animal models to improve hepatic mitochondrial dysfunction and associated oxidative stress.46,47 Because melatonin is found at a high concentration in the mitochondria (possibly even being produced by this organelle), this may be one of the key cellular locations where its protective effects have their greatest impact.48,49

In patients with histologically-proven NASH, supplementation with 5 mg of melatonin twice daily (in the morning and before bed) for 28 days significantly improved insulin resistance, AST, ALT, and gamma-glutamyl transferase (GGT) compared to baseline levels.50 In this study, much like the others investigating melatonin as an intervention for metabolic disease, despite the morning dosing, there were no reports of somnolence or other side effects.

A longer three-month study of individuals with biopsy-diagnosed NASH also used this same dosing regimen.51 Those taking melatonin experienced significant improvements in AST and GGT compared to placebo and baseline, with reductions of 38 and 47%, respectively, at 12 weeks. ALT levels were also reduced significantly compared to baseline. With the continuation of the intervention for an additional 12 weeks, improvements were maintained, although an addition 12 weeks later (after discontinuing treatment), AST levels returned close to baseline.52

An additional study investigated melatonin as a therapy for statin-induced liver enzyme elevation, finding that treatment with 5 mg of melatonin twice daily for six months significantly improved AST, ALT, and GGT compared to placebo.53 In this study, mild morning fatigue was noted in 20% of the individuals taking melatonin for the first two weeks, but was not reported after this point.

A review of the research pertaining to melatonin and liver disease suggests that melatonin may be useful for an array of additional insults to the liver including environmental toxicants, mycotoxins, medication overdoses, alcohol use, surgery, radiation exposure, viral infection, and cancer.54

Molecular Hydrogen

Molecular hydrogen (H2) is a novel tool that also may be useful in the fight against metabolic disease and its consequences, as well as numerous other health concerns. With positive findings from more than 15 clinical studies ranging from treatment-resistant psoriasis to Parkinson’s,55,56 the ability of this small molecule with substantial antioxidant and anti-inflammatory potential to easily traverse cellular membranes and biological barriers makes its use as a therapy potentially applicable to every human disease condition.57 Not surprisingly, the in last two decades, there has been over 1000 scientific studies on the therapeutic application of H2,58 reflecting over 170 different human and animal disease conditions or models.59

Both metabolic syndrome and NAFLD have clinical evidence they may be improved by treatment with molecular H2. Clinically, consumption of 900 mL of H2-rich water for eight weeks was shown to significantly decrease levels of modified low-density lipoprotein (LDL) cholesterol; small, dense LDL; and urinary 8-isoprostanes (a marker of oxidative stress) in patients with T2D or impaired glucose tolerance (IGT).60 In four of the six patients with IGT, treatment with the H2-rich water also normalized the oral glucose tolerance test. In an open-label pilot study of subjects with potential metabolic syndrome, consumption of 1.5 to 2 L of H2-rich water daily for eight weeks improved high-density lipoprotein (HDL) cholesterol and the ratio of total cholesterol to HDL cholesterol, also improving markers of antioxidant status and lipid peroxidation.61

Animal models show H2 is hepatoprotective in the common challenges of alcohol and acetaminophen-induced injury, 62,63 restoring glutathione and antioxidant enzyme levels, even promoting liver regeneration. Multiple studies have also investigated H2 as a therapy for fatty liver disease and the prevention of its complications. Similar to the other research, in animal models of fatty liver disease, treatment with H2 decreased oxidative stress, inflammation, and tissue damage, as well as reduced hepatic lipid accumulation.64,65 Investigation into the effect of dose found that treatment with a higher level of H2 was more protective, also resulting in an increase in lean body mass.65 In the standard model of NASH-induced hepatocarcinogenesis, a reduction in the amount of tumors and their size was seen with H2 treatment.64

In a small randomized, double-blind, placebo-controlled study with a two-week washout, the effects of H2 were studied in 12 overweight patients with mild to moderate NAFLD. Participants were instructed to consume 1 L of H2-rich water or placebo daily for 28 days. After treatment with the H2-rich water, individuals were found to have significantly decreased liver fat accumulation (as assessed by dual-echo MRI) compared to treatment with placebo, as well as a reduction in AST levels.66 No other parameters evaluated were significantly altered by the treatment.

Conclusion

Given the increasing rate of incidence of 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.” In addition to these interventions, therapies such as vitamin E (tocopherols and tocotrienols),67,68 essential fatty acids,69 choline,70 and probiotics71 also have substantial evidence suggesting they may help resolve this increasingly common condition.

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    Dr. Carrie Decker

    graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Prior to becoming a naturopathic physician, Dr. Decker was an engineer and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively. Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group as a member of their education and product development team.↩︎

Author

  • Carrie Decker, ND, graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Dr. Decker sees patients at her office in Portland, OR, as well as remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, and chronic fatigue. Prior to becoming a naturopathic physician, Dr. Decker was an engineer and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively.  Dr. Decker continues to enjoy academic research and writing, and uses these skills to support integrative medicine education as a writer and contributor to various resources.

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