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Quercetin is another flavonoid that shows promise as an effective therapeutic agent in the treatment of NAFLD. It positively impacts three areas of pathogenicity: inflammation, oxidation, and dysbiosis of the microbiota. One of the ways in which quercetin can prevent or reverse steatosis is by altering the genes involved in de novo lipogenesis. In particular, quercetin has been shown to be effective at suppression of CYP2E1, a significant player in fatty liver induction and a contributor to endoplasmic reticulum stress. As a prebiotic, quercetin stimulates increased production of SCFAs, a substrate for colonocytes that protect the intestinal barrier and prevent endotoxemia. Quercetin's effectiveness as an antioxidant is seen in its ability to significantly reduce pathological levels of IL-6, TNF-alpha, and hepatic NLRP3 inflammasome.14
Choline deficiency is associated with fatty liver; low levels increase de novo lipogenesis, decrease hepatic triglyceride excretion, and lead to an increase in large lipid droplets. Aberrant microbes associated with obesity can further exacerbate these effects by metabolizing choline and decreasing host stores. Because choline is a substrate for lipid metabolism, essential to cell membranes, and a precursor for methylation metabolism, deficiency can negatively impact NAFLD progression in several ways.15
However, caution must be taken when prescribing choline and phosphatidylcholine (PC) because they are precursors for trimethylamine (TMA). TMA is then oxidized to trimethylamine N-oxide (TMAO), a potent vascular oxidant linked to significant atherosclerosis.16 Many of the staple foods of a ketogenic diet are high in choline, including chicken, dairy, eggs, spinach, cauliflower, sunflower seeds, fish and beef. As choline is an effective agent against fat accumulation in hepatocytes, increasing choline may be one of the factors for the effectiveness of a ketogenic diet. It is important to note that conversion of choline to TMA/TMAO only occurs in a setting of intestinal dysbiosis, where there is a prevalence of TMA-producing bacteria. Bacteria that produce TMA/TMAO include Anaerococcus hydrogenalis, Clostridium asparagiforme, C. hathewayi, C. sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri, and Edwardsiella tarda. This once again underscores how crucial it is to support a healthy microbiome when treating metabolic syndrome.17
Melatonin is a promising therapeutic for NAFLD due to its anti-inflammatory and regenerative properties. A 14-month human study with an n of 74 combined phosphatidylcholine 300 mg TID, with either melatonin 10 mg daily, or tryptophan 1000 mg daily. The control group was PC alone. Several biomarkers were significantly reduced in the treatment groups including reduction in GGT, LDL, TG, IL-1, IL-6 and TNF-alpha, which were non-significant in the control group. While liver biopsy was only performed pre and post for nine patients, a significance reversal of NASH to NAFLD was seen in all the subjects of the melatonin or tryptophan group, while liver biopsy in the control group demonstrated no change.8 It is important to note that participants of this study had significant liver disease and also that dosing for tryptophan and melatonin were higher than is commonly prescribed.
When treating NAFLD with a ketogenic diet, one of the factors that will prevent fasting ketosis is poor quality sleep due to adrenal dysfunction. Middle of the night insomnia is often due to a breakthrough cortisol surge. Such a surge has the negative side effect of gluconeogenesis, which in turn will suppress ketosis. Since melatonin is effective at cortisol suppression, improved fasting ketosis is a likely positive side effect. Stress in general has a negative impact on metabolic syndrome progression. Improving both quantity and quality of sleep is foundational in stress reduction. Utilizing melatonin in conjunction with reestablishment of healthy circadian rhythms can be a cost effective component of any treatment plan for NAFLD.
Putting It All Together
The current leading cause of mortality is cardiovascular disease (CD); CD is the most common morbidity associated with NAFLD, and upward of half of Americans are suspected to have NAFLD. These stats move the diagnosis and treatment of hepatic steatosis nearer to the top of the list of chronic illness managed by clinicians today. When we consider NAFLD as one more manifestation of metabolic syndrome, and when we establish clinically relevant biomarkers, recognition and treatment of this under-diagnosed condition will undoubtedly increase.
Treatment of NAFLD must address both metabolic dysfunction and inflammatory insults. There is an imperative for weight loss and permanent reversal of obesity. There is also a need for restoration of metabolic flexibility, allowing fatty acid oxidation, in addition to glycogenolysis. Lifestyle interventions involving nutrition, exercise, and stress reduction with normalization of circadian rhythms should be at the core of treatment. Both a ketogenic diet and a Mediterranean diet have been used successfully for the treatment of metabolic syndrome. A Mediterranean-ketogenic diet may be the best nutritional intervention for NAFLD, particularly for patients with cardiovascular comorbidity.
It is essential to identify and avoid obesogenic and oxidative chemicals, drugs, and foods; while specific depuration protocols can be applied as indicated for each patient. Restriction, or better yet, elimination of alcohol is also prudent. Application of food-based antioxidants and phytonutrients can assist both the safety and efficacy of treatment protocols. While I have mentioned a few here, there are many other compounds that are effective and may be specifically indicated for comorbidities being treated. Utilization of nutraceutical and pharmacological agents should be considered to reduce unwanted side effects from treatment. Microbial dysbiosis and associated endotoxemia must also be assessed and remediated. Finally, individualizing treatment for genetic susceptibilities and concomitant chronic illnesses will reduce risks associated with specific therapeutics in subsets of patients.
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Bonnie Nedrow, ND, lectures nationally on environmental medicine and reproductive health, preconception optimization, and the ketogenic diet for metabolic flexibility. She is currently located in Santa Rosa, California, at Farmacopia, where she has a private practice and teaches classes on her programs to the public. In addition, she offers coaching for her ketogenic detoxification program to patients in Oregon and California. She has co-published two books, The Seasonal Cleanse Workbook and The Cleanse Companion Cookbook. Dr. Nedrow is available for case consultations on the ketogenic diet, single nucleotide polymorphisms, and detoxification. For more about her programs and publications, or to contact Dr. Nedrow, go to keto-cleanse.com.