Nutritional and Botanical Approaches for Nonalcoholic Fatty Liver Disease

Abstract

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition both in the United States and worldwide. As obesity increases, the incidence of NAFLD is increasing in lockstep. NAFLD is the leading cause of chronic liver disease in the United States, with an estimated 80 to 100 million people affected by the condition as of 2017.¹ The term NAFLD encompasses two conditions. The first, nonalcoholic fatty liver (NAFL) is defined by hepatic steatosis without fibrosis or inflammation (in other words, simple steatosis). The second, nonalcoholic steatohepatitis (NASH), involves steatosis with the presence of fibrosis and scarring.² Of individuals with NAFL, ∼25% are expected to progress to NASH.¹

A number of risk factors for fatty liver have been defined. People with obesity or type 2 diabetes mellitus (T2DM), men, and Mexican Americans are more frequently affected with NAFLD.³ Additional well-established risk factors include hypertriglyceridemia and metabolic syndrome, while suspected risk factors also include sleep apnea, hypothyroidism, polycystic ovarian syndrome, and excessive consumption of dietary fructose.¹ Insulin resistance is a key factor in the development of the condition.⁴

NAFLD is defined by the presence of steatosis in >5% of hepatocytes by either histology or imaging, with steatosis not explained by any other cause, and with alcohol consumption being <30 g daily for men or <20 g daily for women. Ultrasound of the liver is considered the first-line test for identifying hepatic steatosis in patients with suspected NAFLD. Although transaminases may be elevated in NAFLD, normal levels of liver enzymes do not exclude the condition.⁵ In NAFL, steatosis is present without significant hepatic lobular inflammation. As NAFL progresses to NASH, degeneration of hepatocytes occurs, and increased lobular inflammation and fibrosis appear. Eventually, this may lead to advanced fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma.¹

Hepatic fibrosis is staged by METAVIR (Meta-analysis of Histological Data in Viral Hepatitis) criteria as follows (METAVIR criteria may be used not only in people with NAFLD, but also in those with viral hepatitis):

F0—no fibrosis

F1—portal fibrosis without septa

F2—portal fibrosis with infrequent septa

F3—numerous septa, but no cirrhosis

F4—cirrhosis.

Note that METAVIR scoring requires a biopsy to obtain histology. Although liver biopsy is the gold standard for detecting the presence of fibrosis, other scoring systems have been developed in an attempt to provide noninvasive measures of disease severity. This includes the NAFLD fibrosis score. This score is not a direct measure of fibrosis, but rather noninvasively predicts the likelihood of a patient having the presence of fibrosis on liver biopsy. The score is calculated using age, body mass index (BMI), the presence or absence of diabetes, and serum markers, including transaminase ratio, platelets, and albumin level. This score has been found to have an acceptable sensitivity and specificity in detecting advanced fibrosis, and has also been found to be a prognostic predictor for liver complications and mortality in people with NAFLD.⁶ After a diagnosis of NAFLD, a patient's first assessment for fibrosis should be based on the NAFLD fibrosis score.⁷

NASH is now emerging as the most common indication for liver transplant in Westernized nations; despite this, many people with NASH cirrhosis will unfortunately not be good transplant candidates due to medical comorbidities, including cardiovascular disease (CVD), chronic kidney disease (CKD), obesity, and sarcopenia.^5,8

NAFLD is largely a disease of lifestyle. Romero-Gomez defines NAFLD as a “triple hit behavioral phenotype,” consisting of sedentary lifestyle, low levels of physical activity, and poor quality diet.⁹ To this end, standard management of NAFLD begins with lifestyle change. Numerous regulatory bodies, including the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease, emphasize and agree on the importance of lifestyle modification as first-line treatment. This includes attention to physical activity, healthy diet, and weight loss, with a 7%–10% weight reduction considered a standard goal.⁵ The degree of weight loss is an important driver of improvement: although modest weight loss (5%) does provide benefit, greater weight loss of 10% or more is highly likely to result in improvement of fibrosis by at least one stage and resolution of NASH.⁹

Pharmacologic treatment is generally reserved for patients who have progressed to NASH. No drugs are currently approved by the Food and Drug Administration for the treatment of NASH, so any medications used for these patients specifically for NAFLD are essentially considered off label.

In this article, we will review the key role of nutrition in NAFLD, as well as data on nutritional supplements, the gut microbiome, and botanical medicines for people with this condition. Many of these interventions highlight the importance of considering NAFLD as a multisystem disease. Although NAFLD is primarily thought of as a “liver disease,” it is crucial to remember that this condition may have extrahepatic manifestations, especially CVD, CKD, and T2DM; in fact, the leading cause of death among people with NAFLD is not liver failure, but CVD.^10,11 Kolodziejczyk et al. point out that NAFLD is “the hepatic manifestation of cardiometabolic syndrome.”¹² Because nutrition, lifestyle change, and botanical medicines may target multiple body systems, and may help patients shift or address cardiometabolic risk factors, these therapies may theoretically be uniquely useful in assisting these patients.

Nutrition in NAFLD

As mentioned above, lifestyle change, including an emphasis on good nutrition, should be the primary intervention when working with someone with NAFLD. George et al. reviewed the data on nutrition and NAFLD in 2018 and summarized the evidence with five key dietary recommendations¹³:

Follow a plant-based traditional diet rich in fruits, vegetables, and legumes.

Replace saturated fats in the diet with monounsaturated and polyunsaturated fats, especially omega-3 fatty acids.

Replace processed and refined foods (including fast food, commercial baked goods, added sugars, and sweets) with fiber-rich foods, such as whole grains, vegetables, fruit, and legumes.

Limit consumption of fructose, including high-fructose corn syrup (HFCS), by reducing processed foods and sweetened beverages.

Limit alcohol consumption to ≤20 g daily.

George et al. also note that the Mediterranean diet (MD) meets these criteria, and the MD has been extensively studied in people with NAFLD. The composition of the MD is given in Table 1.

Table 1.

Composition of the Mediterranean Diet

Food	Frequency
Vegetables, fruits, whole grains, olive oil, nuts, seeds, beans, and legumes	Base all meals on these foods
Fish and seafood	2–6 × per week
Eggs	2–4 servings weekly
Poultry	2 servings weekly
Cheese and yogurt	Moderate servings daily to weekly
Red and processed meats	<2 × per week
Sweets	<1–2 × per week

The MD pattern provides a somewhat reduced carbohydrate intake with higher dietary fat, with 35%–40% of energy intake from carbohydrates, 15%–20% of energy from proteins, and 35%–45% of energy from fat sources, largely monounsaturated and omega-3 fats.^9,13 Adherence to the MD successfully reduces liver fat content in men and women with NAFLD and results in reduction of BMI.¹⁴ In a six-month dietary intervention trial in people with NAFLD (N = 46), the percentage of patients with ≥grade 2 hepatic steatosis as assessed by hepatic ultrasound was reduced from 93% to 48% with the MD, and steatosis regressed in 20% of patients. In addition to this, weight loss of 7%, or achievement of normal body weight, was seen in 54% of patients, while liver enzymes significantly decreased (P < 0.01), and several metabolic indicators (such as lipid levels, serum glucose, liver fat score, BMI, and waist/hip ratio) all showed significant improvement with the MD (P < 0.01).¹⁵ In another small trial (N = 12), the MD for six weeks was shown to improve insulin sensitivity in abdominally obese subjects with NAFLD while also reducing liver steatosis as assessed by proton (hydrogen 1 [1H]) magnetic resonance spectroscopy, compared with a low-fat high-carbohydrate diet, which did not improve insulin sensitivity.¹⁶ Importantly, the MD may reduce hepatic steatosis even when it does not result in weight loss.^9,16

Clearly what we eat plays an important role when considering fatty liver, but does when we eat also make a difference? People who regularly eat before bedtime, or who consume more of their daily caloric intake later in the day versus earlier, do have an increased risk of developing NAFLD.^17,18 Some authors suggest a role for various forms of intermittent fasting (IF) in the control of NAFLD, possibly related to its ability to impact insulin resistance.^19,20

A small randomized controlled clinical trial (N = 43) compared the effects of eight weeks of a modified alternate-day calorie restriction (ADCR) diet with those of a control diet in people with NAFLD. Subjects in the ADCR group alternated eating normally one day, with eating 70% of their normal intake during a time-restricted (TR) period (eating only between 2 pm and 8 pm) the next day. The control group continued on their usual diet during the trial, and received no specific dietary advice. At the conclusion of the eight-week trial, body weight and BMI were significantly reduced for ADCR subjects compared with controls (P = 0.001 and P = 0.04). Alanine aminotransferase (ALT) was reduced in the ADCR group (P = 0.04), and liver steatosis and fibrosis scores were significantly reduced in the ADCR group compared with control (P < 0.01). Adherence to the diet was good, ranging from 75% to 83% throughout the trial period.²¹

A larger study by Cai et al. (N = 271) examining alternate-day fasting (ADF) in people with NAFLD also demonstrated benefit. This study specifically looked at the effects of ADF or TR eating on body weight and dyslipidemia (rather than on steatosis itself). Subjects were randomized to one of three groups: ADF, a TR eating plan, or a control group. ADF subjects consumed their regular diet one day, alternating with 25% of their regular intake during a two-hour period on the other day. TR subjects were instructed to eat only during an 8-hour window of choice daily, fasting for the remaining 16 hours daily. Control group subjects were instructed to consume 80% of their calorie needs daily (calculated using the Mifflin Equation), with no other restrictions.

Although the trial lasted for 12 weeks in total, body weight had significantly decreased at the 4-week mark in both the ADF and TR groups compared with control (P < 0.001). At 12 weeks, body weight had decreased even more for the ADF and TR groups (P < 0.001). ADF subjects lost an average of 6.1% body weight after 4 weeks, and a further 5.4% at 12 weeks (TR resulted in <5% weight loss). Notably, weight loss was largely attributable to loss of fat mass. Body fat mass significantly decreased in the ADF and TR groups at the four-week timepoint (P < 0.001). At the 12-week mark, ADF subjects experienced a further significant reduction in fat mass compared with the TR and control subjects (P < 0.001). Total cholesterol also significantly decreased in ADF subjects compared with TR and control group subjects (P < 0.001). Serum triglycerides (TGs) decreased significantly in both the TR and ADF groups at 12 weeks (P < 0.001). Although both TR and ADF patterns of IF conferred some benefits in this study compared with the modest calorie restriction of the control group, the ADF pattern resulted in reductions in both total cholesterol and TGs, and resulted in greater reductions in body weight than did TR.²²

Aside from overall dietary pattern, additional nutritional factors of potential clinical interest include soda pop (and corn syrup/HFCS) consumption, artificial sweetener consumption, coffee intake, dietary choline, and fermented foods as part of the diet.

Sweetened Beverages and Artificial Sweeteners

The monosaccharide fructose, found naturally in fruits, honey, and molasses, did not feature prominently as part of human diets before the development of the sugar industry. HFCS first became commercially available in the 1960s, but was introduced to the food and beverage industries more widely in the 1970s as a lower cost substitute for sucrose.²³ HFCS now comprises the most common source of fructose in the American diet. Although the most commonly used HFCS product is HFCS 55 (which contains 55% fructose), HFCS can vary and may contain up to 90% fructose.²⁴ The most common source of HFCS in the American diet is sugar-sweetened beverages, including soda pop and “fruit” drinks. HFCS is also found in fast foods, flavored dairy products (such as yogurt), cereals, canned fruits and soups, baked goods and desserts, candy, and condiments.²⁵ HFCS stimulates de novo lipogenesis, which is a significant contributor to hepatic fat content in people with NAFLD. Meta-analyses demonstrate that consumption of sugar-sweetened beverages is associated with increased risk of metabolic syndrome.²⁴

Increased intake of soda pop has been shown to be associated with NAFLD, independent of metabolic syndrome. In one study, people with NAFLD were found to consume five times the amount of carbohydrate from soda pop in the diet compared with healthy individuals. In fact, after controlling for diet composition and exercise, sweetened beverage intake was the only independent variable that predicted the presence of NAFLD in 83% of cases in this trial, with a sensitivity of 100% and a specificity of 76%.²⁶ A 2015 meta-analysis of seven observational trials (N = 4639) demonstrated a significant association of soda pop consumption and NAFLD, with a pooled risk ratio of NAFLD of 1.53 in people consuming soda (95% confidence interval [CI] 1.34–1.75).²⁷ A 2019 meta-analysis also demonstrated that this effect is dose dependent; the higher the amount of soda pop consumed, the greater the risk of NAFLD.²⁸ Following a low-sugar diet, which also eliminates sweetened beverages, has been shown to reduce hepatic steatosis in adolescents with NAFLD.²⁹ Although the authors of this trial in adolescents state that reducing sugary foods and drinks as part of the diet is a “plausible but unproven treatment” for NAFLD, common sense dictates that there would be nothing to lose by directing these patients to eliminate soda pop and other sugar-sweetened beverages from the diet. Public health organizations, including the Centers for Disease Control (CDC) and World Health Organization (WHO), continue to recommend a reduced intake of free sugars, including those from sugar-sweetened beverages, for both children and adults.

Public health messaging around reducing sugar-sweetened beverages has clearly had an impact, and consumption of low-calorie and artificial sweeteners as substitutes for these items has increased dramatically in the past few decades among both children and adults. In 1999, 8.7% of children reported consuming artificial sweeteners. In 2012, that number had jumped by 200%, with 25.1% of children reporting consuming artificial sweeteners. In addition, consumption in adults increased by 54% between 1999 and 2012, with 41% of adults reporting consuming artificial sweeteners in 2012. Are these artificial sweeteners acceptable substitutes for their caloric counterparts in the diet when it comes to NAFLD?

Diet soda consumption as part of the diet has been linked to insulin resistance and inflammation, which may, in turn, increase the risk of NAFLD.²⁷ Animal studies show that artificial sweetener consumption increases weight gain and glucose intolerance.³⁰ Significant associations between several parameters related to metabolic syndrome (including increased body weight, waist to hip ratio, higher fasting blood sugar, higher hemoglobin A1c, and greater impairments in glucose tolerance) and the consumption of artificial sweeteners have been demonstrated in people without diabetes.³¹ Artificial sweeteners may also be linked to alterations in antioxidant status (at least in animals). In a mouse study, animals fed aspartame (at a dose equivalent to two cans of diet soda daily in people) caused hepatic glutathione depletion.³² Altered antioxidant status has been suggested as a key driver of the progression of NAFLD to NASH, and the development of NAFLD may be accompanied by reductions in hepatic glutathione.^33,34 Artificial sweetener consumption also induces changes in the gut microbiome³¹; we will revisit the importance of the gut microbiome in NAFLD below. In addition, diet soft drinks frequently contain caramel coloring, an advanced glycation end product, which may also increase inflammation and insulin resistance.³⁵ Despite this, human data specifically looking at consumption of artificial sweeteners and NAFLD remain limited, with just one observational trial showing no association between fatty liver and artificial sweeteners.²⁷ The CDC, WHO, and other governing bodies provide no specific guidelines on the consumption of artificial sweeteners in people with NAFLD.

Coffee Consumption

Turning to coffee intake, there may be some benefits for coffee drinkers with NAFLD. A 2016 meta-analysis included seven studies that evaluated coffee consumption in people with NAFLD, four of which reported hepatic fibrosis scores. All four of those studies reported an inverse association between coffee consumption and the severity of hepatic fibrosis. In addition, both coffee and tea intake were associated with a reduced risk of metabolic syndrome.³⁶

A 2017 study also indicated benefits from coffee intake. This study included two separate meta-analyses. The first included studies evaluating the risk of developing NAFLD among coffee drinkers and noncoffee drinkers. The second included studies evaluating the risk of hepatic fibrosis in coffee drinkers and noncoffee drinkers with existing NAFLD. The risk of developing NAFLD was reduced significantly among coffee drinkers compared with those who do not drink coffee (pooled RR 0.71; 95% CI 0.60–0.85). Also, coffee drinkers with NAFLD had a significantly reduced risk of hepatic fibrosis compared with those who were not coffee drinkers (pooled RR of 0.70; 95% CI 0.60–0.82). The main limitation of this study was that the definition of “regular coffee consumption” varied between included studies.³⁷

Dietary Choline

The essential nutrient choline is found in a variety of foods, such as liver, eggs, beef, soybeans, fish, chicken, potatoes, and kidney beans. Choline is a precursor for the synthesis of acetylcholine and cell membrane phospholipids, and is also a methyl group donor. An adequate supply of choline is required for phosphatidylcholine synthesis in the liver. Hepatic phosphatidylcholine synthesis, in turn, is required for the production of very low-density lipoprotein. Without the presence of sufficient choline needed for phosphatidylcholine synthesis, hepatic triacylglyceride can accumulate (causing fatty liver).³⁸

Both dietary intake of choline and individual choline requirements vary significantly. Choline requirements may be affected by estrogen levels, dietary factors (such as betaine intake), and by the presence of choline or folate metabolism gene polymorphisms.³⁹ Choline deficiency may occur in people receiving total parenteral nutrition (with this state being reversible with intravenous choline supplementation),⁴⁰ and choline-deficient diets lead to liver dysfunction in both animals and people. For example, in men fed a choline-deficient diet, elevations in transaminases were seen after just three weeks.³⁸ In fact, choline-deficient diets are used specifically to induce NAFLD in experimental animal models. All of this has led some authors to propose that choline deficiency may be a contributor to NAFLD. A significant link has indeed been found between choline intake as part of the diet and NAFLD. This link may also be moderated by body adiposity.⁴¹

The Microbiome and Probiotics

Fermented foods and probiotics have been the subject of several interesting trials in people with NAFLD. This study has arisen from interest in the relationship of the microbiome with fatty liver. Liver function may be impacted by the microbiota through a number of mechanisms. Dysregulation of gut endothelial barrier function may be increased by dysbiosis, promoting gut permeability and translocation of microbial components and metabolites to the liver. Alterations to the microbiome may drive increased intestinal production of ethanol and perturbations in the composition of bile acids.⁴² Changes to the microbiome can also result in decreased availability of choline, and choline deficiency, as already mentioned, has been shown to lead to the development of fatty liver in humans.^42,43 The microbiome is also involved in modulating inflammatory and anti-inflammatory signaling, so that alterations in beneficial flora may drive inflammation that contributes to the progression of NAFLD to NASH.¹² Experimental models using gut microbiome transplants in germ-free mice indicate that specific bacteria may reliably induce NAFLD.^12,42

Subjects with NAFLD appear to have alterations in the microbiome that are distinct compared with healthy subjects.¹² NAFLD patients with more advanced hepatic fibrosis have been shown to have a microbial signature favoring increased amounts of proteobacteria.⁴⁴ Levels of bacterial metabolites, including endotoxins and phenylacetic acid, are also associated with the degree of hepatic fibrosis in people with NAFLD.⁴⁴ Additional evidence for the role of the microbiome in NAFLD comes from the study of nonabsorbable antibiotics. For example, treatment of people with NAFLD with the nonabsorbable antibiotic rifaxamin leads to improvements in liver function.¹² People with NASH also have a higher prevalence of small intestinal bacterial overgrowth compared with age- and sex-matched healthy controls.⁴⁵

The question that has naturally arisen from this study is: Does altering the microbiome of people with NAFLD have a therapeutic effect on liver health? Table 2 summarizes human trials that speak of this question, utilizing either probiotic supplemented yogurt or probiotic supplemented capsules as a therapeutic intervention for people with NAFLD.

Table 2.

Clinical Trials Utilizing Fermented Foods or Probiotics in People with Nonalcoholic Fatty Liver Disease

Author (year of publication)	Trial design	Intervention	Subjects	Duration	Results
Bakhshimoghaddam (2018)	Three-arm open-label randomized controlled	300 g yogurt QD containing 108 CFU Bifidobacterium animalis per mL and 1.5 g inulin; or conventional yogurt QD; or control (advised only to follow healthy lifestyle)	N = 102 with NAFLD	24 weeks	NAFLD grade by US significantly decreased with synbiotic compared with conventional yogurt and control (P < 0.001) and LFTs significantly decreased.
Nabavi (2014)	Double-blind randomized controlled	300 g yogurt QD with Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 versus 300 g conventional yogurt QD	N = 72 with NAFLD	8 weeks	Probiotic yogurt resulted in reductions of serum ALT, AST, TC, and LDL of 4.7%, 5.4%, 4.1%, and 6.9%, respectively, compared with control.
Kobyliak (2018)	Double-blind randomized placebo-controlled	Live multi-strain probiotic (14 probiotic bacteria genera Bifidobacterium, Lactobacillus, Lactococcus, Propionibacterium) versus placebo	N = 58 with T2DM and NAFLD	8 weeks	FLI decreased significantly with probiotic (P < 0.001), but did not change with placebo; probiotic reduced AST and GGT; TNF-α and IL-6 levels changed significantly with probiotic.
Sepideh (2014)^a	Double-blind randomized placebo-controlled	Probiotic versus placebo	N = 42 with NAFLD	8 weeks	FBS, insulin level, insulin resistance, IL-6 significantly different between groups after 8 weeks (P < 0.05).
Aller (2011)	Double-blind randomized placebo-controlled	Probiotic with 500 million Lactobacillus bulgaricus and Streptococcus thermophilus QD versus placebo	N = 30 with NAFLD	3 months	ALT, AST, and GGT significantly decreased with probiotic (P < 0.05 for all) and did not change with placebo.
Manzhalii (2017)	Open-label controlled	All subjects followed low-calorie and low-fat diet. Probiotic subjects also took a probiotic cocktail daily.	N = 75 with NASH	12 weeks	Probiotic group had significant (>20%) reduction of ALT compared with control; liver stiffness decreased with probiotic compared with control (P < 0.05). Significant decrease in BMI and TC with probiotic versus control (P < 0.05).

Sepideh A, Karim P, Hossein A, et al. Effects of multistrain probiotic supplementation on glycemic and inflammatory indices in patients with nonalcoholic fatty liver disease: A double-blind randomized clinical trial. J Am Coll Nutr 2016;35:500–505.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CFU, colony forming units; FBS, fasting blood sugar; FLI, fatty liver index; GGT, γ glutamine transferase; IL-6, interleukin-6; LDL, low-density lipoprotein cholesterol; LFTs, liver function tests; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; QD, once daily; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TNF-α, tumor necrosis factor-α; US, ultrasound.

These studies varied from eight weeks to three months in length. Five of these trials were performed in people with NAFLD, and one trial was performed in people with NASH. All studies had a control group. Although varying doses and formulations of probiotics were utilized, encouragingly, even a trial such as Aller et al.’s, which used a very modest dose of probiotic bacteria, demonstrated beneficial effects. Also, although outcome measures varied, all trials demonstrated a beneficial effect with probiotics. These effects ranged from decreased liver function tests (LFTs) and decreased markers of insulin resistance to improvements in hepatic fibrosis, steatosis, or disease grade. Although only two trials used conventional yogurt as a comparator, both of these found that probiotic-supplemented yogurt was superior in the reduction of LFTs.^46

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Nutritional Supplements in NAFLD

Turning from nutrition to nutritional supplements, vitamin E and melatonin supplementation have both been the subject of clinical study for amelioration of NAFLD. Both of these substances may have the ability to impact antioxidant status in the body, and may exert their effects by targeting the oxidative stress that accompanies NAFLD.

Vitamin E in various forms has been used in a number of trials. A 2019 systematic review and meta-analysis summarized several vitamin E trials. It included nine randomized controlled trials (RCTs) published between 2003 and 2015, five of which were in adults and four in children with NAFLD. Doses ranged from 80 to 1000 international units (IU) daily, and duration of treatment ranged from six months to four years (including follow-up periods). The meta-analysis included 889 subjects in total. For trials in adults, vitamin E significantly improved ALT levels. Vitamin E also resulted in reduction in hepatic fibrosis score by −0.52 (95% CI −1.40 to 36; P = 0.24) and improved hepatic histologic findings compared with placebo (95% CI −1.75 to 0.3; P = 0.17). Vitamin E was not associated with significant changes in biochemical or histologic parameters in children with NAFLD.⁵¹

It should be noted that the specific form of vitamin E used in each of the included trials was not discussed. The vitamin E group is composed of eight compounds: four tocopherols and four tocotrienols. While alpha and gamma tocopherols are the main dietary forms of vitamin E, delta and beta tocopherols also have antioxidant activity, as do tocotrienols.^52
–54 Both tocopherol and tocotrienol forms of vitamin E supplementation have been studied and found to have effects in people with NAFLD.^55,56 The American Association for the Study of Liver Diseases recommends that supplementation with 800 IU vitamin E daily can be considered in NASH patients without diabetes, after a discussion of both the risks and benefits of longer term antioxidant supplementation.⁵⁶

The pineal hormone melatonin has also been evaluated for its effects in NAFLD subjects. In a randomized controlled trial in 100 participants with histopathologically confirmed NAFLD, melatonin supplementation for a three-month period was compared with placebo. Melatonin was found to lead to significantly greater improvements in blood pressure, aspartate aminotransferase (AST), and C-reactive protein levels compared with control, and also resulted in a significant reduction in fatty liver grade (P = 0.001). Oddly, the authors of this study did not list the dose of melatonin supplemented during the trial, even though the publication was peer reviewed.⁵⁷

Melatonin may even have effects in people whose NAFLD has progressed to NASH. In a 12-week pilot-scale (N = 42) placebo-controlled trial, melatonin supplementation at 10 mg daily was also shown to lead to significant reductions in AST and gamma glutamine transferase in people with NASH (P < 0.05 for both). Reductions in LFTs persisted even after melatonin was stopped, when assessed at 12 weeks postcompletion of the intervention.⁵⁸

NAFLD is associated with a high rate of sleep disorders. In the National Health and Nutrition Examination Survey, 65% of people with NAFLD reported having sleep apnea, 16% had insomnia, and 4% had restless leg syndrome. The high rate of association between these sleep concerns and NAFLD is most likely related to metabolic conditions that accompany the condition. Whether the effects of melatonin in NAFLD would be mediated through regulation of sleep function, or by other factors (such as changes in antioxidant status), is not completely understood.

Botanical Medicine and NAFLD

Although the list of herbs used in traditional medicine to help support liver function is extensive, clinical research in NAFLD patients has largely focused on a few specific botanical medicines or phytochemicals. Table 3 provides a list of the botanical medicines or phytochemical extracts with clinical research discussed in this article.

Table 3.

Botanical Medicines and Phytochemicals Clinically Studied for Use in Nonalcoholic Fatty Liver Disease

Botanical medicine or phytochemical	Notes	Scientific name of pertinent plant(s)	Plant part traditionally used
Artichoke		Cynara scolymus	Leaves
Milk thistle		Silybum marianum	Seeds and leaves
Curcumin	Found in turmeric	Curcuma longa	Roots
Berberine	Found in goldenseal, European barberry, Oregon grape, and others	Hydrastis canadensis, Berberis vulgaris, Mahonia aquifolium	Stem, bark, roots

Cynara scolymus, the artichoke plant, is a thistle (related to milk thistle), and has been used in traditional herbal medicine practice to support urinary and digestive health in addition to liver function. Extracts of the artichoke leaf have been shown to have several beneficial effects in people with NAFLD. In a randomized double-blind placebo-controlled parallel-group trial, artichoke leaf extract at a dose of 600 mg daily for two months was compared with placebo. One hundred participants with NAFLD confirmed by ultrasound were enrolled and randomized, and 90 participants completed the trial. Subjects who received artichoke had improved hepatic vein blood flow, reduced liver size, and reduced portal vein diameter assessed by ultrasound (P < 0.001 for each). In addition, LFTs were significantly reduced among those receiving artichoke compared with placebo (P < 0.001), as were lipid levels (P = 0.01). There were no side effects reported with the intervention.⁵⁹

Moving to milk thistle, Silybum marianum, we also encountered a plant with a long history of traditional use as a hepatoprotectant and hepatic trophorestorative. Silymarin, a flavonoid compound found in the leaves and seeds of milk thistle, has been the subject of studies in both NAFLD and NASH patients.

A 2017 meta-analysis of RCTs on milk thistle for people with NAFLD confirmed by ultrasound included eight RCTs with 587 patients in total. Doses of silymarin in included trials ranged from 140 to 1080 mg daily, with some administering silymarin in once daily dosing, and others administering in divided doses. Silymarin was found to lead to significant reductions in AST (P = 0.0002) and ALT (P = 0.01) compared with control. The authors point out the ability of silymarin to act as an insulin sensitizer, free radical scavenger, and stabilizer of hepatocyte membrane structure, potentially explaining some of the effects of silymarin in NAFLD.⁶⁰ It should also be mentioned that silymarin works as an antioxidant by increasing hepatic glutathione and protecting the liver from damage by free radicals.⁶¹

What about the use of silymarin in those who have progressed from NAFLD to NASH? In a 48-week randomized double-blind placebo-controlled trial in people with biopsy-confirmed NASH, 99 patients were assigned to receive either a patented silymarin extract at 700 mg three times daily (t.i.d.) or placebo t.i.d. Subjects who took silymarin had greater reductions in histologic hepatic fibrosis than those in the placebo group (22.4% compared with 6.0%, P = 0.02). A decrease of 30% or more in hepatic fibrosis was also significantly greater in the herbal group than in placebo (24.2% compared with 2.3%, P = 0.002). Silymarin group patients also had significant reductions in the fibrosis-4 score and NAFLD fibrosis score (P = 0.04 and P < 0.001), benefits not seen in the placebo group. Despite this, the primary outcome (a 30% or greater reduction in NAFLD activity score) was not significantly different for silymarin than for placebo (32.7% compared with 26.0%, P = 0.47). Adverse events were not significantly different between groups.⁶²

A 2019 randomized double-blind placebo-controlled trial of varying doses of silymarin (420 or 700 mg t.i.d.) in people with NASH found no significant effect of milk thistle on NAFLD fibrosis score compared with placebo. This study suffered from problems with subject selection, as review by a central pathologist later determined that 63% of subjects did not even meet histologic entry criteria for the trial.⁶³ This makes it difficult to draw specific conclusions from this trial. Additional trials of silymarin in people with NASH would be warranted, and would help determine whether the effects of silymarin seen in NAFLD persist once progression to NASH has occurred.

The medicinal compound curcumin, sourced from the root of Curcuma longa, has been the subject of clinical study for NAFLD as well. As a strong antioxidant and anti-inflammatory, curcumin has been shown to have hepatoprotective effects in several experimental models.⁶⁴ A 2019 randomized double-blind placebo-controlled trial in 65 subjects with ultrasound-confirmed NAFLD found that curcumin has a number of helpful effects on serum metabolic markers. Subjects were randomized to receive either a phytosomal curcumin supplement (meant to enhance absorption) at a dose of 250 mg daily (equivalent to 50 mg daily pure curcumin, complexed with phosphatidylcholine) or a placebo for eight weeks. High-density lipoprotein levels significantly increased in people who received curcumin versus those who received placebo (P = 0.01). Serum adiponectin (an adipokine involved in glycemic regulation and lipid metabolism) also significantly increased for those who received curcumin (P < 0.001). Serum leptin (a hormone produced by adipocytes that regulates satiety) significantly decreased (P < 0.001), as did the leptin–adiponectin ratio (P < 0.001).⁶⁵ One interesting aspect of this trial is the complexing of curcumin with phosphatidylcholine. Some of the effects seen with this supplement could potentially be related to the phosphatidylcholine content alone; supplementation of phosphatidylcholine for 24 weeks in people with NAFLD has been found to improve steatosis as assessed by hepatic ultrasound.⁶⁶ Despite this, phytosomal complexing does not appear to be required in order for curcumin to have an effect; a meta-analysis of RCTs also suggests that curcumin (whether phytosomal or not) reduces LFTs in people with NAFLD at doses >1000 mg daily.⁶⁷

Lastly, berberine, an alkaloid compound found in several Berberidaceae family plants (including Mahonia species, and Berberis vulgaris) and Ranunculaceae family plants (including Hydrastis canadensis), also offers benefits for liver function. These plants have been traditionally used as bitters, choleretics, and to balance the gut flora and stimulate normal digestive function. In a randomized open-label parallel-controlled clinical trial, the effects of berberine supplementation were compared with pioglitazone and with simple lifestyle intervention in 184 participants with NAFLD. This trial also included an animal model of NAFLD to assess hepatic berberine content.

In the clinical portion of the trial, patients were randomized to one of three groups, which received the following intervention for 16 weeks:

Control/Lifestyle group: Modification of diet to reduce caloric intake by 500 calories daily; exercise at ≥150 minutes weekly medium intensity aerobic activity.

Berberine group: Berberine supplement 500 mg t.i.d., 30 minutes before meals, in addition to the lifestyle modification already described.

Pioglitazone 15 mg once daily, in addition to the lifestyle modification already described.

At the completion of the trial, hepatic fat levels decreased by 36% in the control group (P < 0.001) and by 57% in the berberine group (P < 0.001). The effect of berberine on hepatic fat content was similar to that of pioglitazone treatment (P = 0.054). LFTs decreased in all groups, with berberine and pioglitazone having similar effects. Effects on blood sugar were found to be similar with berberine and pioglitazone. Berberine was found to have superior effects for weight loss, with participants in the berberine group losing a mean 4.3 kg body weight, whereas those in the control group lost 1.99 kg and those in the pioglitazone group lost 1.94 kg. In the animal portion of this study, berberine was found to be preferentially absorbed by the liver, with berberine levels in liver tissue being 50 times higher than those in plasma after oral dosing.⁶⁸

A follow-up analysis of this trial also found that berberine supplementation led to significant reductions in body weight, BMI, blood sugar, HbA1c level, and lipids compared with control (P < 0.05 for all). For oral glucose tolerance testing (OGTT), berberine reduced the area under the OGTT curve significantly more than lifestyle modification alone (P = 0.04).⁶⁹

Conclusions

NAFLD is considered to be the hepatic manifestation of metabolic syndrome or of the insulin-resistant state. Because NAFLD is largely a disease of lifestyle, first-line management should include a discussion of physical activity and healthy diet. A 7%–10% weight loss is considered a standard goal of care. A plant-based diet offers people with NAFLD numerous benefits, and evidence on the MD in improving body weight and hepatic steatosis can be shared with patients. IF may represent a viable approach for some patients as well. Clinicians should assess for soda pop, sweetened beverage, or other HFCS intake in their patients with NAFLD. Lastly, clinicians and their patients also have the choice of several evidence-based botanical medicines and extracts (including berberine, milk thistle, artichoke, and curcumin) and supplements (including probiotics, melatonin, and vitamin E) to assist patients with NAFLD with their goals.▪

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