Non-Alcoholic Fatty Liver Disease, an Overview

Abstract

Nonalcoholic fatty liver disease (NAFLD) affects 25% of people worldwide. Patients with fatty liver disease are primarily asymptomatic. Currently, specialists are predicting that fatty liver related cirrhosis will the be leading reason for liver transplants in the next 10-20 years, displacing hepatitis C and alcohol related liver transplants. NAFLD exists on a spectrum of simple steatosis to steatosis with inflammation and different levels of fibrosis. It is currently estimated that 20% of simple steatosis patients will progress to nonalcoholic steatohepatitis (NASH). Patients with NASH are at risk for further progression to cirrhosis and hepatocellular carcinoma. There is no single factor that triggers progression from simple steatosis to NASH, however, we do know that NASH is more prevalent in patients with obesity, diabetes, and metabolic syndrome. NAFLD is thought to be the hepatic manifestation of metabolic syndrome, and is closely tied with hyperinsulinemia. Currently there are no approved FDA treatments for NAFLD. NAFLD is typically found incidentally on imaging such as abdominal ultrasound and CT. Elevations in alanine aminotransferase (ALT) may prompt the clinician to evaluate for NAFLD however ALT should not be used as a diagnostic tool. The gold standard for diagnosis of NAFLD and NASH is a liver biopsy. Only a liver biopsy can distinguish simple steatosis from NASH. In patients whom NAFLD is suspected, appropriate biochemical assessment and imaging should be evaluated. Also, the presence of fibrosis should be assessed. Weight loss and dietary modifications are currently the only recommendations provided to NAFLD patients. There is histological improvement seen in in patients whom lose 5-10% of their body weight. Certain dietary factors play a role in the development of NAFLD including excessive caloric intake and high fructose consumption. There are pharmacological treatments currently being studied as well as non-pharmacological agents. This overview focuses on evaluation, management and treatments in NAFLD.

The current discussion of liver disease in natural medicine tends to focus disproportionately on the idea of liver toxicity and attendant detoxification strategies. However, a much larger problem looms outside of this discussion and should command greater attention: non-alcoholic fatty liver disease (NAFLD). Many gastroenterologists and hepatologist now predict that in the next 10-20 years, NAFLD will be the leading cause of orthotropic liver transplantation, displacing hepatitis C and alcoholism. As one of the most significant comorbidities of Metabolic Syndrome, NAFLD is quickly emerging as one of the most significant health issues of our time.

NAFLD is considered the hepatic manifestation of metabolic syndrome, and is closely linked with insulin resistance.¹ The majority of patients with NAFLD are asymptomatic and only a minority are symptomatic with vague complaints such as fatigue, malaise, right upper quadrant abdominal discomfort, and hepatomegaly. Worldwide the condition affects 25% of the population.² In North America NAFLD affects approximately 24% of the population.² Non-alcoholic fatty liver disease manifests on a spectrum ranging from simple hepatic steatosis to steatosis with inflammatory changes and differing levels of fibrosis.¹ NAFLD is defined by the accumulation of triglycerides in the hepatocyte cytoplasm.^1,3 Non-alcoholic steotohepatitis (NASH) is the inflammatory progression of simple hepatic steatosis. Ultimately, cirrhosis and hepatocellular carcinoma can occur in NASH patients though the occurrence of the latter is rare.^1,3 It is estimated that 20-30% of NAFLD patients with simple steatosis will eventually progress to NASH. In those with NASH it is estimated that approximately 7-25% will progress to cirrhosis.³ Histologically NAFLD is indistinguishable from alcoholic liver disease and alcohol-related fatty liver disease must be ruled out.^1,2 Other causes of fatty liver disease that should be excluded include metabolic genetic disorders, type 1 diabetic hepatopathy, Weber-Christian disease, and other genetic or metabolic disorders.¹ Use of corticosteroids, estrogens, amiodarone, carbamazepine is also associated with fatty liver disease.^1,4,5

Pathogenesis

The pathogenesis of NAFLD has not been completely characterized. However, many specific features have been elucidated in the past few years. Previously, NAFLD pathogenesis has been proposed as a ‘two-hit’ hypothesis however more current research reveals that there are ‘multiple-hits’.⁷ Diet, lifestyle, and insulin resistance are largely associated with development of NAFLD as well as the progression towards NASH.^3-6, ^8-12 The farnesoid X receptor (FXR), a tissue specific regulator of bile acid synthesis, highly expressed in the liver is also associated with the development of NAFLD.^13,14 Burgeoning research reveals associations between intestinal bacterial overgrowth and development and progression of NAFLD.^3,15,16 Adiponectin, an adipose-specific hormone, is associated with the development of NAFLD, specifically steatosis.^3,17,18 Other factors associated with NAFLD development and progression include leptin, interleukin-6, and PNPLA3 gene polymorphism.^3,7,19

Association with Metabolic Syndrome, Clinical Assessment, and Assessing Fibrosis

In a study of 304 NAFLD subjects with 120 biopsy confirmed NASH cases, Metabolic Syndrome was present in 88% of the NASH group.⁸ In another study, obesity with BMI greater than 40kg/m² conferred a higher rate of NASH when compared with obesity of BMI between 30-39.9kg/m².⁹ In this same study, NAFLD was found in 15% of non-obese subjects and 3% of the same non-obese subjects were found to have NASH. NASH is present in approximately 22% of people with diabetes, whereas simple steatosis is found in 74%.¹⁰ 72% of NASH patients have dyslipidemias and 67% are hypertensive.² Hossain et al found that in a group of 400 adults with NAFLD, those with moderate-to-severe fibrosis were more likely to have type 2 diabetes.²⁰ NAFLD should be suspected in patients who are overweight, have diabetes, metabolic syndrome, have alanine aminotransferase (ALT) greater than 19 in women or, greater than 30 in men, and post-menopausal women.^3,4,8,9,10 Liver enzymes are not a reliable diagnostic tool for NAFLD. Typically an ALT greater than AST points towards fatty liver disease. However ALT only reaches a sensitivity of 45% for diagnosing NAFLD.⁴ Francanzani et al showed that in a sample of 458 liver biopsied patients, 53% of NAFLD subjects without NASH have elevations in serum ALT while close to 60% of patients with normal ALT showed NASH.⁴ Elevated transaminases warrant repeat testing and liver imaging before NAFLD is diagnosed. Only a liver biopsy can distinguish simple steatosis NAFLD from NASH. The liver biopsy can assess steatosis, inflammation, hepatocellular ballooning, lobular inflammation and degree of fibrosis.

Imaging

Sensitivity and specificity for ultrasound in assessing NAFLD reaches 81.8-100% and 98%, respectively, for moderate-to-severe steatosis. Sensitivity drops to 55% when the hepatic fat content is below 20%.^3,21 Sensitivity and specificity for computed tomography (CT) in assessing NAFLD reaches 50-85% and 75-87%, respectively. CT, like ultrasound is more accurate for moderate-to-severe steatosis.²¹ MRI has the highest diagnostic accuracy in fatty liver disease as it can detect as little as 3% fatty infiltration.²¹ Once NAFLD is suspected based on clinical workup, biochemical assessment and imaging modality, the assessment of fibrosis should be made. There are four stages of fibrosis: (1) portal fibrosis; (2) periportal fibrosis; (3) bridging fibrosis; and (4) cirrhosis.²² It is important to assess a patients risk as this may help determine if more aggressive therapy is warranted. Liver biopsy is the gold standard for quantifying stage of liver fibrosis and cirrhosis, however, imaging such as ultrasound can be used to detect cirrhosis. There are also scoring systems used to assess the absence or presence of significant fibrosis. The NAFLD fibrosis score is an online tool that combines age, BMI, liver transaminases, platelets, albumin, and presence of diabetes to assess the likelihood of having bridging fibrosis and/or cirrhosis. This test reaches a sensitivity and specificity of 90% and 97%, respectively.^23,24 Other noninvasive biomarkers include FIB-4, NAFIC, and FibroTest. Cytokeratin 18 is a liver intermediate filament protein that is currently being studied for use as a noninvasive biomarker in NAFLD.²⁵ Fibroscan is a non-invasive FDA approved transient elastography scan that is used to measure liver stiffness in kPa. Fibroscan cannot distinguish simple steatosis from NASH.²⁶ The likelihood of advancing fibrosis in NAFLD can be predicted in patients with hypertension (OR 1.61 P = .0374), diabetes (OR 1.64, P = .0258), hypertension plus diabetes (OR 1.69 P = .0246). The highest likelihood of worsening fibrosis occurs in patients with hypertension, diabetes, and visceral obesity (OR 1.72 P = .0205).²⁰ In an international study of 619 NALFD patients over 30 years of age, the number one cause of death was cardiovascular disease, the second most common cause of death was non-liver cancer, and the third leading cause of death was cirrhosis complications.²⁷ Hepatocellular cancer occurred in 1% of patients with NAFLD.²⁷

Dietary patterns in NAFLD

Dietary patterns among NAFLD patients parallel the dietary patterns of Metabolic Syndrome. NASH patients have higher caloric intake compared to healthy cohorts (P < .01)²⁸ and the risk for NAFLD and NASH increases with visceral adiposity.²⁹ There is no consensus on the influence of macronutrient intake on the pathogenesis of NAFLD. Some researchers report that saturated fat is a major culprit^30,31 whereas others report that saturated fats only become problematic in the presence of simple sugars.³ The diets of people who have NASH are rich in saturated fats, poorer in polyunsaturated fats, vitamin E and other antioxidants.³¹ In a dietary comparison between NASH and simple steatosis patients, NASH patients were found to consume more carbohydrates, specifically sweets.³²

Fructose and Glucose

Abdelmalek et al assessed dietary patterns of 427 NAFLD patients and found that high fructose consumption correlated with severity of fibrosis.³³ Fructose is of special interest largely because of its metabolism in the liver. The majority of fructose is taken transported into and metabolized by the liver leading ultimately to hepatic lipogenesis.³⁴ Fructose metabolism in the liver is not a tightly regulated biochemical pathway in contrast to glycolysis, where rate-limiting enzyme phosphofructokinase, is present. Glucose, in contrast, does not concentrate in the liver as it is transported into cells via GLUT receptors throughout the body. Fructose does not stimulate insulin secretion, leptin and ghrelin levels are suppressed ultimately contributing to overeating.³⁵ In natural foods such as apples, grapes, and blueberries, fructose content by weight does not typically exceed 5-10%.³⁴ According to the Corn Refiners Association, high-fructose corn syrup contains 42%-55% fructose.³⁶ In a study of 60 ultrasound proven NAFLD patients, per soft drink inventory, 80% of NAFLD subjects had excessive soft drink intake compared to 17% of healthy controls, P < .001.³⁷ In this same study, NAFLD subjects consumed five times more carbohydrates from soft drinks compared to controls P < .001. In another study of 49 biopsy proven NASH patients, NASH patients consumed on average 265 kcal of fructose daily compared to 170 kcal daily amongst controls, P < .05.³⁸ In this same study there was a significant increase in fructokinase and fatty acid synthase via PCR in NASH patients. Soft drink consumption is a predictor of NAFLD, OR 2.0 P < .04.³⁶ High fructose corn syrup is used in many processed packaged foods. High glucose consumption promotes the same biochemical endpoint of excessive fatty acid synthesis, this process is more regulated compared with fructose but clinicians should also be mindful of excessive carbohydrate consumption and glucose.

Pharmacological Intervention

Currently there are no FDA approved drugs for NAFLD. Obeticholic acid (a semi-synthetic bile acid analogue) activates the farnesoid X nuclear receptor which promotes insulin sensitivity, reducing hepatic gluconeogenesis, reducing circulating triglycerides, and increasing expression of hepatic scavenger receptors. In the FLINT trial, 141 biopsy proven NASH patients received obeticholic acid 25 mg daily for 72 weeks or placebo. Compared to placebo, obeticholic acid significantly reduced fibrosis (37% vs 19%, P > .004), reduced hepatocellular ballooning (46% vs 31% P = .03), reduced steatosis (61% vs 38%, P = .001), and reduced lobular inflammation (53% vs 35% P = .006). Obeticholic acid also reduced biochemical liver indices such as ALT, AST, GGT, alkaline phosphatase. Thirty-three percent of the obeticholic acid patients developed pruritus compared with 6% of placebo.³⁹ Obeticholic acid is also associated with liver injury.⁴⁰

Elafibranor is a PPAR-alpha agonist and PPAR delta agonist that is reported to improve glucose homeostasis, insulin sensitivity, lipid metabolism and reduce inflammation. 276 biopsy proven NASH patients were divided into groups of 80mg daily Elafibranor x 52 weeks, 120mg daily Elafibranor x 52 weeks, or placebo. NASH resolution based on a modified definition was reported in the 120mg group compared to placebo group (19% vs 12% P = .045).⁴¹

Pioglitazone, a thiazolidinedione, was given to 80 biopsy-proven NASH patients at 30 mg per day for 96 weeks. When compared with the rate of NASH improvement in the placebo group, improvement with pioglitazone was not significant.⁴² In another study of 55 biopsy-proven NASH patients treated with pioglitazone, there was no significant change in fibrosis. However there was a significant reduction in ALT and hepatic fat content.⁴³ Weight gain is a common side effect of thiazolidinediones.

Other medications studied without significant efficacy include ursodeoxycholic acid, gemfibrozil.^44,45 Subjects taking orlistat, a lipase inhibitor that prevents absorption of fat from diet, had significant ALT reduction and reversal of NAFLD on ultrasound.⁴⁶

Metformin reduces serum glucose levels, increases the effects of insulin and reduces the rate of gluconeogenesis.⁴⁷ In multiple clinical trials, metformin has failed to produce histological improvement in NASH; however it does appear to improve transaminases.^48,49,50

Surgical Intervention

Multiple clinical studies reveal that bariatric surgery significantly improves liver histology and even leads to complete resolve of NASH.^81,82

Weight Loss

Diet and exercise remain the leading therapies with demonstrable impact on NAFLD outcomes. Forty-one morbidly obese NAFLD patients received a 400 kcal diet that resulted in improvement of liver histology. However, patients who lost more than 1.6 kg per week developed mild portal inflammation or mild portal fibrosis.⁵³ In another study of 32 biopsy-proven NASH patients given a 48 week intensive lifestyle intervention, those who lost at least 7% body weight saw significant improvement in steatosis, lobular inflammation, hepatocyte ballooning and NAFLD activity score.⁵⁴ Suzuki et al evaluated 348 men with elevated ALT excluding other liver diseases found that those who were able to lose at least 5% body weight had improvement in ALT.⁵⁵ There appears to be some consensus that patients should aim for 7-10% reduction in body weight.^54-59 Vilar-Gomez et al assessed the outcome of diet and exercise modifications in 293 biopsy-proven NASH patients. Their intervention included lifestyle changes, hypo-caloric diet and moderate intensity exercise for 52 weeks. At the end of the study, NASH resolution occurred in 25% of the patients, 47% of the cohort experienced a reduction in the histological NAFLD activity score and 19% experienced regression of fibrosis. In those whom lost at least 10% body weight, 90% had resolution of NASH.⁵⁹ Several other diet and exercise modification studies in NAFLD have yielded similar results with significant histological improvement.^54-62 A retrospective study of 813 biopsy proven NAFLD patients revealed that vigorous exercise was associated with reduced odds of having NASH OR 0.65) and also reduced odds of advanced fibrosis (OR 0.53).⁶³ Vigorous exercise has a metabolic equivalent of task (MET) value of 6 or greater.

Vitamin E, Phosphatidylcholine

Vitamin E functions as the major lipid-soluble antioxidant in the body and has shown beneficial and significant effects in NAFLD. The PIVENS trial involved 247 non-diabetic, non-cirrhotic, biopsy-proven NASH patients. Subjects received vitamin E 800 IU daily, 30 mg pioglitazone daily, or placebo for 96 weeks. When compared with placebo, vitamin E was superior in improving histological features (43% vs 19% P = .001).⁴² In the TONIC trial, 173 biopsy-proven NASH patients were given vitamin E 400 IU twice daily, metformin 500 mg twice daily, or matching placebo for 96 weeks. In the vitamin E group, there was a statistically significant resolution of NASH when compared to the placebo group (58% vs 28% P = .006).⁶⁴ Vitamin E did not improve fibrosis in either the PIVENS or TONIC trial. There is concern among some clinicians that vitamin E supplementation could raise the risk of prostate cancer however studies have been conflicting.^65-68

Phosphatidylcholine (PPC) is one of the most abundant phospholipids in cell membranes.⁶⁸ PPC, in experimental and clinical observations, has been shown to reduce hepatocyte necrosis and fatty infiltration, reduce liver transaminases, and reduce collagen productio.⁶⁹ In the liver, PPC is required for facilitation of fatty acids into very low-density lipoproteins (VLDLs) and export from the liver. Endogenous production of phosphatidylcholine is catalyzed by phosphatidylethanolamine-N-methyltransferase (PEMT), an enzyme induced by estrogen.⁷¹ Approximately one-third of PPC produced in the liver is catalyzed by PEMT.⁷² In animal models of PEMT knockout mice, an increased susceptibility to NAFLD occurs.⁷² There is thought to be an increased risk of NAFLD is in post-menopausal women compared with menstruating women due to reduced induction of PEMT.^3,70,71 PPC supplementation has shown benefit in people with NAFLD. One hundred twenty-five NAFLD patients with diabetes received diet modification, anti-diabetes medication (not specified), physical exercise and 1.8 grams of essential phospholipids (72-76% PPC) for 3 months; a control group of 60 NAFLD diabetes patients received diet modification, anti-diabetes medication, and physical exercise alone. In the phospholipid group, there was a significant (P < .01) reduction in ALT, triglycerides, and LDL cholesterol.⁷³ This study also claimed resolution of NAFLD in 78 patients, however, it is not clear how this was measured or assessed. In another study of 30 biopsy-confirmed NAFLD diabetics, the intervention group received 1.8 g of essential phospholipids (72-76% phosphatidylcholine) or placebo for 6 months. In the intervention group there was a reduction in liver size and GGT (P < .05) along with improvements in liver histology.⁷⁴ Other researchers have reported similar results, with improvement in transaminases, ultrasound, and NAFLD appearance on CT.^75-77

Botanical Therapies

Gynostemma (Gynostemma pentaphyllum), also known as jiao gu lan, blue ginseng, and sweet vine tea, is an herbaceous climbing vine in the Curcubitaceae family, native to China, northern Vietnam, southern Korea, and Japan.⁷⁸ Gynostemma has been gaining clinical interest in the West for metabolic disease.^79,80 There are very few clinical studies on this herb in NAFLD however the results obtained from animal and human studies are interesting and deserve mention. The active constituents of gynostemma, gypenosides, are associated with up- regulation of mitochondrial processes that affect mitochondrial enzymes and fatty acid beta oxidation.⁸¹ In a hepatocyte primary cell culture exposed to high glucose, insulin, and linoleic acid; lipid accumulation and oxidation of hepatocytes occurred.⁸² In this same study, Gynostemma ethanol extract prevented accumulation of triglycerides, cholesterol, and oxidative stress.⁸² In animal models of NAFLD, gypenosides have been shown to significantly increase mRNA levels of carnitine palmityl-transferase 1, a key enzyme in fatty acid mitochondrial transport, ultimately contributing to more regulated fatty acid oxidation in the liver.⁸³ An animal model using gynostemma pentaphyllum 200 mg/kg/d for 8 weeks in mice, observed an almost 20% reduction in liver weight, and 15% reduction in abdominal lining fat.⁸⁴ As mentioned earlier, NAFLD is the hepatic manifestation of metabolic syndrome and is closely linked with hyperinsulinemia as well as diabetes. In a study of 24 type treatment naive subjects with type 2 diabetes, aqueous infusion of 6 g gynostemma pentaphyllum per day was compared with placebo for 12 weeks. There was a 2% reduction in hemoglobin A_1c compared to 0.2% in the placebo group P < .001. There were no adverse affects and no changes in body weight.⁸⁵ A major limitation of this study was its sample size.

Milk thistle is a popular botanical therapy for liver disease. The main active constituents studied include silymarin, and silybin. Silybin provides the greatest biological activity of the milk thistle plant and is concentrated in the fruits and seeds of the plant.⁸⁶ Silymarin has been studied for its antioxidant, antifibrotic, and hepatoprotective properties.^86,87 In an uncontrolled trial of seventy-two ultrasound-diagnosed NAFLD subjects, after 3 months of a restricted diet, Epaclin was provided. Epaclin is a supplement containing vitamin E, vitamin B₁₂, l-glutathione, l-cysteine, l-methionine, phospholipid, and silymarin extract. After 6 months, there was a significant reduction in hepatorenal brightness (an ultrasound index of hepatic steatosis) and a non-significant reduction in transaminases and gamma glutamyl-transferase (GGT). In NAFLD, milk thistle along with other agents such as vitamin E, and S-adenosyl methionine (SAMe) improved liver enzymes and in very few studies there have been improvements in liver histology seen on biopsy.^88-91 In a randomized-controlled trial of 64 ultrasound along with elevated transaminase diagnosed NAFLD subjects, Solhi and colleagues reported a reported a reduction in liver enzymes, particularly ALT, with 210 mg daily of silymarin orally for 8 weeks.⁸⁸ A placebo-controlled study of one-hundred ultrasound or biopsy-diagnosed NAFLD subjects, revealed signifiant reduction in liver enzymes with 280 mg of silymarin over 24 weeks.⁸⁹ In fifteen ultrasound-diagnosed NAFLD subjects, Giangrandi and colleagues observed a significant reduction of total cholesterol, insulin, ALT, and alkaline phosphatase when subjects were supplemented with 140 mg of silymarin and 200 mg SAMe daily for 12 months.⁹⁰ There was also an improvement in liver echo texture on ultrasound. In a randomized-controlled trial of one-hundred thirty eight NAFLD subjects, Loguercio and colleagues reported a significant reduction in liver enzymes and improvement in liver histology for subjects taking silybin conjugated with phospholipids and vitamin E.⁹¹ There were no serious adverse effects reported. Many botanical studies in NAFLD have major limitations including dosing, quality of botanical extract, and the lack of pre- and post-liver biopsy.

Green tea is another popular therapy for liver disease exerting most of its effects through catechins. Catechins are a group of bioactive chemicals that act as antioxidants.⁹² Xiao et al reported improved liver histology and attenuation of fibrosis in NAFLD rats injected with epigallocatechin gallate (EGCG) at 50 mg/kg three times per week.⁹³ A double-blind placebo controlled randomized trial of ultrasound diagnosed NAFLD subjects given 500 mg of green tea extracts or placebo, revealed significant reduction in ALT and AST after 12 weeks.⁹⁴ In seventeen ultrasound and CT-diagnosed NAFLD subjects, consumption of high-density catechin green tea (700 ml daily with over 1 gram of catechins) over 12 weeks significantly improved liver-to-spleen CT attenuation ratio (a ratio used to assess fat in the liver) and significantly decreased ALT levels when compared to placebo and low density catechin green tea.⁹⁵ Isomura and colleagues conducted a systematic review of randomized controlled trials assessing the safety of green tea. Of the thirty-four trials reviewed, liver-related adverse events were reported in seven subjects total across four trials including elevated liver enzymes without serious liver-related adverse events occurring.⁹⁶ There is one reported case of acute liver failure in an adolescent male using a weight loss product containing green tea extract.⁹⁷

Berberine is used by many integrative practitioners for its anti-diabetic, hyperlipidemic and insulin sensitizing activities. One hundred eighty four patients with hepatic fat content greater than 13% on proton-magnetic resonance spectroscopy were diagnosed with NAFLD and treated with lifestyle recommendations plus berberine 500 mg three times daily, lifestyle recommendations plus pioglitazone 15 mg daily, or lifestyle recommendations alone for 16 weeks. There was a significant reduction in hepatic fat content in the berberine group when compared with the lifestyle group alone (57.2% vs 36.4% P = .008). There was no significant difference in the lifestyle plus pioglitazone group and the lifestyle plus berberine group in lowering transaminases.⁹⁸

Antioxidants

In NAFLD, glutathione (measured by plasma oxidative stress-related parameters), is reduced with progression from simple steatosis to steatohepatitis. There is also a reduction in glutathione transferase, glutathione synthase, and antioxidant capacity.^99-101 Erhdadt et al assessed the plasma antioxidant status of biopsy-proven NASH patients to a control group. The NASH group had significantly reduced alpha-tocopherol (P < .01), lutein P < .0001), zeaxanthin (P < .0001), lycopene (P < .0001), alpha-carotene (P < .005), and beta-carotene (P < .01).¹⁰¹ Antioxidants studied in NAFLD with histological improvement includes vitamin E, vitamin C, and betaine (trimethylglycine).^42,102,103 Betaine is a naturally occurring compound that largely functions as a methyl donor. Hypomethylation is associated with elevated plasma homocysteine, decreased SAMe concentration, inadequate hepatic fat metabolism contributing to hepatic steatosis.¹⁰⁴ Animal models of betaine in NAFLD reveal mixed results.^105,106 In a randomized placebo-controlled study of 55 biopsy proven NASH subjects, betaine 20 mg daily for 12 months did not produce significant improvements in liver histology when compared to placebo.¹⁰²

Omega 3 Poly-Unsaturated Fatty Acid

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors associated with energy homeostasis and metabolic function in the body.¹⁰⁷ PPAR-alpha is a key regulator of hepatic fatty acid synthesis.^108,109 PPAR-alpha agonists are associated with increased fatty acid oxidation, modulation of hepatic lipid metabolism, and increased insulin sensitivity.^110-116 It has been theorized and shown that low levels of circulating n-3 PUFAs may impair PPAR-alpha activity in the liver, contributing to hepatic steatosis through increased hepatic fatty acid uptake, reduced beta-oxidation, and more.^116-118 In isolated animal cells, n-3 polyunsaturated fatty acid (PUFA) was shown to stimulate expression of PPAR-target genes contributing to elevated fatty acid transport proteins.¹¹¹ PUFA in animal models have also been reported to activate PPAR-alpha and down-regulate SREBP-1 protein, leading to reduced expression of a key enzyme in fatty acid production, fatty acid synthase.¹¹² Levy and colleagues reported a reduction in hepatic steatosis rats with n-3 PUFA enriched diets.¹¹³ In hepatocyte PPAR-alpha knockout mice, fatty acid metabolism was impaired and resulted in fatty liver development.¹¹⁰ n-3 PUFAs such as eicosapentaenoic and docosahexaenoic acid exhibit PPAR-alpha agonist activity.^114,115 In two separate studies omega-3 fatty acid supplementation improved liver enzymes in NAFLD patients.^117,119 In a pilot study of 56 NAFLD subjects, omega 3 polyunsaturated fatty acid (n-3 PUFA) one gram daily for 12 months was shown to significantly reduce serum AST, ALT, GGT, and triglycerides when compared to controls.¹¹⁷ There was also improvement in hepatic echo texture on ultrasound. In a pilot trial by Tanaka and colleagues, twenty three biopsy-proven NASH subjects were administered 2700 mg per day of n-3 PUFA over 12 months. Six out of seven subjects underwent post-treatment liver biopsy, there was improvement in hepatic steatosis, fibrosis, hepatocyte ballooning, and lobular inflammation.¹¹⁹ In this study there was also a significant reduction in ALT, serum ferritin, and free fatty acids.

Conclusion

Currently there are no approved treatments for NAFLD. Patients should be encouraged to lose at least 5-10% of their body weight, reduce simple carbohydrate intake, and reduce fructose consumption. Clinicians should be mindful of excessive weight loss, greater than 1.6 kg weekly, that can lead to fibrosis. Botanical therapies, phosphatidylcholine, and vitamin E may be considered however diet and lifestyle modifications are the best studied, currently.

Biography

Asia Muhammad, ND, is in private practice in St. Louis, Missouri.