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Non-Alcoholic Fatty Liver Disease
Non-Alcoholic fatty liver disease (NAFLD) has been cited in the medical literature for over 100 years. However, in the past 20 years the prevalence of NAFLD has increased progressively, and the number of peer-reviewed studies regarding the etiology and natural history of NAFLD has followed suit. The growing incidence of hepatic steatosis parallels the rising obesity epidemic in the United States and worldwide. Current estimates for NAFLD, which is under-diagnosed, range from 15-52% in the US,1 while roughly 30% of adults are obese. Although not all people with fatty liver are obese, nor do all obese subjects present with fatty liver, the overlap is significant and should not be clinically overlooked. Of note, the most common morbidity associated with NAFLD is cardiovascular disease, the number one cause of mortality in the United States.
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Fat accumulation in hepatocytes, in the absence of liver damage from alcohol, viral infections and autoimmune disease, can be best understood as the manifestation of metabolic syndrome in the liver. When carbohydrate consumption exceeds cellular glucose expenditure, glucose is converted to fatty acids that are stored in adipocytes through insulin signaling. Dietary fat also contributes to fat storage when a carbohydrate-rich diet is consumed, due to insulin suppression of fatty acid oxidation. Excess accumulation of fat expands adipocyte tissue, resulting in the production of proinflammatory adiponectins and cytokines that promote insulin resistance. As fat cells become resistant to insulin, serum free fatty acids increase, which are then sequestered by the liver. When the liver is unable to clear excess fat via fatty acid oxidation and triglyceride production, triglycerides move into storage in hepatocytes. Eventually, hepatocytes also become insulin resistant, which triggers gluconeogenesis and de novo lipogenesis (DNL), further fueling insulin resistance and hepatic steatosis.2
In this milieu of insulin excess, hepatic steatosis, and inflammation, hepatocytes become vulnerable to additional insults, namely environmental chemicals and microbial dysbiosis. Endocrine-disruptive chemicals and some prescription drugs are frequently obesogenic, driving the same pathways associated with insulin resistance and metabolic syndrome.3 Some of the well-recognized and extensively studied obesogens include phthalates, bisphenols, PCBs, PBDEs, tributyltin, dioxins, DDT and DDE, nonylphenol and parabens. Many drugs, including the anti-diabetic drugs, glyburide and tolbutamide, are also known obesogens. These endocrine disruptors interfere with peroxisome proliferator-activated receptors, alter estrogen metabolism, and impact satiety and food preferences. The end result is an altered fat metabolism favoring storage over fatty acid oxidation.4 In addition, there are many common foods that act as obesogens, with high fructose corn syrup having the most dramatic effect, particularly on the obesity epidemic in children.
Microbial dysbiosis has been identified as both an initiator and a significant contributor to both obesity and NAFLD. In a state of obesity, there is an increase in microbes that break down indigestible fiber into carbohydrates, leading to over-harvesting of fuel from fiber. This increased carbohydrate load contributes to insulin resistance and associated hepatic steatosis. More importantly, obesity-associated dysbiosis causes intestinal inflammation, barrier defects, and sets off a cascade of inflammatory molecules including lipopolysaccharides, lipoprotein lip-ase, interleukin-1 (IL-1), and tissue necrosis factor-alpha (TNF-α) in hepatic tissue. This is the pathway by which pathological intestinal permeability and endotoxemia produce toxic byproducts that are sequestered by the already over-burdened liver.5
It should be noted that while alcohol is not the prime inducer of NAFLD, it is a hepatocellular insult compounding the disease process. A diagnosis of alcoholic steatosis requires a significant and regular consumption of alcohol somewhere between 1-4 alcoholic beverages per day.2 The added exposure to obesogenic and oxidative toxicants including alcohol, and endotoxemia from dysbiotic flora, overwhelm the natural detoxification and metabolic regulation seen in a healthy liver. As we begin to weigh in on this array of proinflammatory factors, pathogenesis of NAFLD is best explained as a multiple-hit model with metabolic dysregulation increasing the vulnerability of hepatocytes to exogenous and endogenous toxicants.2
Biomarkers for NAFLD
Liver biopsy has long been the gold standard for the diagnosis of NAFLD and nonalcoholic steatohepatitis (NASH), a more progressed form of fatty liver with significant liver injury due to advanced inflammation. More recently, proton magnetic resonance has become the noninvasive gold standard test to quantify liver triglyceride levels. With the rising increase in NAFLD, there is a need for less expensive, non-invasive screening tools. Proposed biomarkers are the liver enzymes ALT, AST, and GGT, triglycerides, HDL, adiponectin, fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR). While all of these markers demonstrate a correlative relationship with NAFLD, ALT stands out as the most reliable single test when the upper range of normal is reduced to less than or equal to 23 IU/L. Further adjustment for sex indicates that women should have an ALT no higher than 21 IU/L, while the upper limit of 24 IU/L may be used for men.7 In other studies, GGT has been shown to be a reliable marker.8 Because all these biomarkers, with the exception of adiponectin, are relatively inexpensive, it would be prudent to monitor them as a group for optimal clinical outcomes.
Uric acid is another biomarker commonly elevated in both metabolic syndrome and NAFLD. A 2015 rodent and cell line study demonstrated that not only is uric acid a biomarker for fatty liver, it is also a causative factor. Uric acid was shown to induce NLRP3 inflammasome (also known as NRLP3, cryoprin and NALP3). NRLP3 is a signaling molecule for both hepatic steatosis and insulin resistance. The researchers documented that lowering uric acid with allopurinol improved glucose metabolism and insulin sensitivity in mice. Other potential mechanisms of cellular metabolism disruption from elevated uric acid include mitochondrial and endoplasmic reticulum injury.9
Carbohydrate Restriction as a Prime Therapy for NAFLD
A 2018 study on a low-carbohydrate diet illustrates three independent mechanisms explaining why this dietary approach has been so successful in treating fatty liver. In this small (n=10) and brief (14 day) human study, biomarkers for metabolic syndrome and fatty liver improved, including lowering of AST, ALT, insulin, HOMA-IR as well as a decrease in DNL and hepatic steatosis as measured by liver biopsy. The first observation was that restricting carbohydrates significantly and rapidly reduces hepatic de novo lipogenesis. Secondly, a very low-carbohydrate diet stimulates fatty acid oxidation, causing metabolism to shift from fat storing to fat burning. This combined effect of reducing fatty acid production and increasing fat oxidation lowers hepatic fat content within the first few days of a ketogenic low-carb diet. The researchers demonstrated the third contributing factor from this nutritional approach being a shift in the microbiota that favors liver fat metabolism.10
It is important to note that a high-fat diet is not the same as a low-carb diet. In fact, the research term “high-fat diet” lacks consistent parameters and often consists of a standard carbohydrate-rich diet with the addition of fat. A moderate to high carbohydrate diet, with the addition of fat, will cause increased fat storage, and over time will produce inflammation, insulin resistance, and fatty liver. Conversely, a low-carbohydrate diet will lower insulin and shift metabolism to fatty acid oxidation, which will reduce fat stores and reverse fatty liver. The addition of fat to a very low-carbohydrate diet produces satiety, making this dietary approach satisfying and sustainable. In the aforementioned study, carbohydrates were limited to < 30 grams per day and the ketone beta-hydroxybutyrate (BHB) was significantly elevated, demonstrating the effectiveness of the diet to produce ketosis.
There are two main goals when applying a ketogenic diet for NAFLD reversal. One is weight loss, as reducing triglyceride stores from visceral adipose tissue reverses the pro-insulin, inflammatory cascade produced by adipocytes. The second is the reestablishment of metabolic flexibility, the ability to utilize either fatty acids through beta-oxidation or glucose through glycolysis for energy production. Meeting both these goals will in turn reverse insulin resistance and create a hormonal and cytokine environment more amenable to weight stabilization and sustained reduction of inflammation.
There are several essential considerations when choosing a ketogenic diet as a therapy for metabolic syndrome and NAFLD. The first is the management of uric acid, which will be discussed below. The second is the need to address both exogenous and endogenous sources of fat-soluble toxicants. As previously noted, many drugs and environmental chemicals have been shown to increase inflammation, are obesogenic, and significantly contribute to metabolic syndrome and fatty liver. A ketogenic diet is very successful at stimulating fat burning; with the side effect of mobilizing fat-soluble toxicants from adipose storage. It is therefore crucial to assess your patients for environmental toxicity and incorporate appropriate depuration practices to protect them from mobilized endogenous toxicants. In addition, education on avoidance of common exposure sources from harmful exogenous compounds will lower the obesogenic toxicant effect. The third consideration is support for the microbiome. A low-carb diet is by design a low-fiber diet, and dietary fiber is crucial for microbial fermentation of short chain fatty acids (SCFAs) and overall intestinal health. For obese subjects with dysbiosis, the microbiome requires restructuring to reverse endotoxemia and over harvesting of fiber. An often-effective approach to correcting obesity associated dysbiosis is avoidance of processed food, consumption of a phytonutrient dense diet, and supplementation with fiber and a broad-spectrum probiotic.
Uric Acid, NLRP3 Inflammasome, and Flavonoids
A prolonged ketogenic, low-carb diet stimulates a series of metabolic changes in nearly every organ system; this metabolic restructuring is referred to here as keto adaptation. Most people can achieve keto adaptation within 6-12 weeks. Within the first few days of significant carbohydrate restriction, the liver upregulates fatty acid oxidation and ketone body production. Once ketosis is sustained, the brain and the muscles also increase fatty acid oxidation, shifting predominant fuel use to BHB in the brain, and various ketones and free fatty acids in muscle tissue. In the first few weeks of keto adaptation, ketone production by the liver transiently exceeds fatty acid oxidation capacity, and excess ketones are excreted in the urine. The renal pathway for excretion of ketones is the same as for uric acid, leading to temporary uricemia due to competition with ketones for excretion. This is not a concern for people who start adaptation with normal uric acid blood levels. Ketosis prior to renal adaptation will cause a slight elevation of uric acid, however levels remain non-pathogenic when uric acid is less than or equal to 5 mg/dL prior to initiating a ketogenic diet. For the subset of patients with high uric acid prior to keto adaptation, additional therapies are indicated to reduce the risk of significant side effects.
As noted earlier, uric acid at high blood levels can stimulate NLPR3 inflammasome, which in turn promotes insulin resistance and hepatic steatosis. Since uric acid associated inflammation drives metabolism away from fatty acid oxidation, your patient with uricemia may be unable to adequately produce and burn ketones. In addition, the risk of gout flare-up is greatly increased by the transient uricemia. Not only will this cause pain and suffering for your patients with gout, it will potentially limit exercise, an important component of any program that supports metabolism and weight loss. Finally, risk of developing uric acid kidney stones will be very high for susceptible individuals.
Patients with uric acid elevation over 5 mg/dL should be treated with uric acid lowering and NRLP3 modulating therapeutics prior to and during keto adaptation. Flavonoids including quercetin, resveratrol, epigallocatechin gallate, rutin and catechin, have demonstrated effective reduction of uric acid and blockade of NRLP3 inflammasome.11 Resveratrol has been shown to increase adiponectin and improve HOMA-IR, serum triglycerides, and hepatic fat content. These significant improvements were associated with suppression of NRLP3 inflammasome activity by resveratrol.12 Moderately low dosing with resveratrol may be adequate to reduce NRLP3 and achieve positive metabolic effects. However, for a patient with active gout, high dose may provide additional benefits through mitochondrial ROS amelioration.13
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