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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, in the last two decades, there have 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,69,70,71 also have substantial evidence suggesting they may help resolve this increasingly common condition.
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.
