Nonalcoholic fatty liver disease (NAFLD) is a chronic condition caused by fat accumulated in the liver over time, in the absence of excessive alcohol use. The disease can be classified into the types of non-inflammatory fatty liver (NAFl) and inflammatory nonalcoholic steatohepatitis (NASH)(1).
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of cirrhosis and liver cancer.
According to world statistics, nonalcoholic fatty liver disease (NAFLD) is normally known as a disease of the Western world(2). However, due to the economic prosperity of Southeast Asian(3), the disease also was found in a large number of population in the cities, causing concerns of many scientists in the region(4)(6).
According to the joint assessment of the prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the US, led by the Stanford University School of Medicine, "The prevalence of NAFLD in the United States (U.S.) has risen from 18% in 1988–1991 to 31% in 2011–2012. Estimates of NAFLD prevalence for adults in Western countries is 20–30%, with much higher prevalence in adults with obesity (80–90%), diabetes (30–50%), and hyperlipidemia (90%)"(5).
Among the more affluent regions of China, the prevalence rate of non-alcoholic fatty liver disease (NAFLD) is approximately 15%(6). The number may decrease substantially if the poor rural populations where obesity is non-existence are also taking into account(7).
The exact causes of NAFLD aren't well understood. Some researchers suggested that certain risk factors such as long-term use of certain medications(8), genetic preposition(8), insulin resistance(8), high cholesterol(8) and triglycerides(8) in the blood, polycystic ovary syndrome(8), metabolic syndrome(8), obesity(8), and type 2 diabetes(8) are associated with the onset of the disease.
Recent studies also found that people with obstructive sleep apnea(11), underactive thyroid (hypothyroidism(10) and underactive pituitary gland (hypopituitarism) (9) also at an increased risk of the NALFD.
Some researchers suggested that unhealthy diet such as high-fat diet may also have a strong implication on NAFLD(12)(13).
Dr. Jensen VS, the lead scientist in the study high-fat diet-induced non-alcoholic fatty liver disease, wrote, "In humans and animal models, excessive intake of dietary fat, fructose, and cholesterol has been linked to the development of non-alcoholic fatty liver disease (NAFLD)"(13).
And, " Only HFr-fed rats developed dyslipidemia as characterized by higher levels of plasma triglycerides compared to all other groups (p < 0.0001). Hepatic dysfunction and inflammation was confirmed in HFD-fed rats by elevated levels of hepatic MCP-1 (p < 0.0001), TNF-alpha (p < 0.001) and plasma β-hydroxybutyrate (p < 0.0001), and in NASH-fed rats by elevated levels of hepatic MCP-1 (p < 0.01), increased hepatic macrophage infiltration (p < 0.001), and higher plasma levels of alanine aminotransferase (p < 0.0001) aspartate aminotransferase (p < 0.05), haptoglobin (p < 0.001) and TIMP-1 (p < 0.01) compared to Control"(13).
According to the statistics, in the US, over 100 million people have non-alcoholic fatty liver disease and the condition is more double over the past 20 years(14). The disease also is the most prevalent liver disease in children(14).
The prevalence rate of NAFLD is varied among different ethnic groups in the US. Dr. Rich NE, the lead scientist in the investigation of the ethnicity and NAFLD, wrote, "NAFLD prevalence was highest in Hispanics, intermediate in Whites, and lowest in Blacks, although differences between groups were smaller in high-risk cohorts (range 47.6%-55.5%) than population-based cohorts (range, 13.0%-22.9%)(15)".
And, "Among patients with NAFLD, the risk of NASH was higher in Hispanics (relative risk, 1.09; 95% CI, 0.98-1.21) and lower in Blacks (relative risk, 0.72; 95% CI, 0.60-0.87) than Whites"(15).
The progression of NAFLD and NASH led to cirrhosis, the late stage of liver scarring are well defined, as the liver tries to heal itself by halting inflammation(16), leading to symptoms of ascites(16)(18), swell esophageal varices(16)(19), hepatic encephalopathy(16)(17) and complications of liver cancer(16)(17) and liver failure(16)(17).
Most people at the early stage NAFLD are asymptomatic, however, as the disease progression into the later stage, most patients experience symptoms of right upper abdominal discomfort(20), fatigue(20), and/or malaise(20), and jaundice(20) with yellowing of the skin and eyes(20).
Most patients with NAFLD have elevated levels of liver enzymes gamma-glutamyl transferase (GGT)(21) and/or Aspartate Aminotransferase (AST)(21) to platelet ratio index (APRI) score(21), and/or Alanine Aminotransferase (ALT) (21) which are the markers used to predict the severity of liver disease including the fatty liver. A blood test is required if you suspected to have developing nonfatty liver disease.
Conventionally, as of today, there is no effective treatment of NAFLD(22)(23). Weight loss for overweight and obese patients(22) has been recommended through our the industry accompanied by the change of lifestyles(22) such as moderate exercise and reduced intake of alcohol, depending on individuals.
Patients who are hepatitis virus B and C carriers are also recommended to be vaccinated(22).
Given the nature of the nonalcoholic fatty liver disease, the search for effective treatment for NAFLD from the natural sources used over thousands of years in traditional medicine for the treatment of liver disease has been intensified(23). Many secondary metabolites, whole foods, and herbal medicine have been found to be effective in vivo, vitro and small human trials(24). However, most of them were stopped due to a simple reason. Who will spend billions to prove the thing which has no commercial values? Secondary metabolites, whole foods, and herbal medicine cannot be patented.
Phytochemicals, the natural chemical constituent, protect the plants against diseases and form their outer's color.
Phytochemicals may be the next potential sources of a new medicine for treatment of diseases with little or no side effects(32), including
* Secondary metabolites
Secondary metabolites produced by plants have been used as medicines, flavorings, pigments, and recreational drugs over thousands of year in human history(24).
* Bioactive compounds isolated from plant include vegetables, fruits, and nut.
Triterpenoid is a various unsaturated hydrocarbon, found in essential oils and oleoresins of plants, including Ilex, hainanensis Merr(25).
In the study to test the effect of Triterpenoid-rich fraction (TP) from Ilex hainanensis Merr. on NAFLD with Male Sprague-Dawley (SD) fed with a normal diet (control) or high fat diet (NAFLD model), after 4 weeks, then orally administrated TF (250 mg/kg) for another two weeks(26), researchers showed that TP not only improves the symptoms of the subjects but also decreases the levels of triglyceride(26), total cholesterol(26), low-density lipoprotein cholesterol(26), abnormality of lipid accumulation(26), levels of inflammation(26) and infection(26) and apoptosis response(26) in the liver.
Of these results, TF is effective in protecting the liver against NAFLD by regulating lipids metabolism(26) and alleviating insulin resistance(26), inflammation(26) and oxidative stress(26).
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia(27)., used in traditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc(27)(28). Curcumin is one of the natural phenols in the plant(28).
Curcumin, as an antihyperlipidemic agent, has been found to lower the “bad cholesterol” low-density lipoprotein (LDL) and increase high-density lipoprotein (HDL)(29), thus reducing the risk of fat accumulated in the tissues in the liver(29).
In the support of the above, the water-soluble curcumin derivative was tested for its efficacy against steatohepatitis which is an inflammation of the liver(30)(31) with concurrent fat accumulation in the liver(30)(31), researchers found that the derivative not only significantly alleviates fibrosis(30)(31) but also decreases the grade of liver steatosis(30)(31).
Piperine is a phytochemical alkaloid in the class of organosulfur compound, found abundantly in white and black pepper, long pepper, etc.
Administration of piperine appeared to reverse hepatic steatosis (33) and insulin resistance(33) in mice fed with high fat, probably inactivation of adiponectin-AMPK signaling(33) associated with stimulated fatty acid oxidation and enhance insulin sensitivity.
In other words, piperine not only inhibited hepatic steatosis and insulin resistance by reducing the expressions of lipogenic target genes(33) associated with insulin resistance (33) but also increased the expression of carnitine palmitoyltransferase 1 (CPT1) gene(33) involved in fatty acid oxidation.
Resveratrol, a phytochemical in the class of Stilbenoids found abundantly in many vegetables and fruits as well as herbs and herbal formulas(34) including found abundantly in skins and seed of grape wine, nuts, peanuts, etc.
According to studies, the formulas of berberine and resveratrol not only improved a biochemical and histological change in nonalcoholic fatty liver disease(35)(36), but also inhibited lipid accumulation(36) by up-regulating low-density lipoprotein receptor (LDLR) expression(36), alleviating lipid peroxidation(36), and reducing the production of inflammatory cytokines(36).
Carotenoids are class of phytochemicals that give yellow, orange, or red fat-soluble pigments, including lycopene and carotene, found in ripe tomatoes and autumn leaves(38).
According to studies, in the examination of a total of 2687 in middle-aged and elderly Chinese adults. who completed both NAFLD tests were classified into stable, improved and progressed groups, serum carotenoids(37) are inversely associated with non-alcoholic fatty liver disease (NAFLD)(37) by reducing serum RBP4 and HOMA-IR(37), associated with insulin resistance(37), triglycerides(37), and body max index (BMI)(37).
More precisely, higher levels of α-carotene, β-carotene, lutein + zeaxanthin(39), and total carotenoids(39) have a strong impact on a significant decrease in the severity of NAFLD(39).
Quercetin is a type of flavonoid antioxidant found in leafy greens, tomatoes, berries, and broccoli(40). Recent studies have shown that the beneficial effects of quercetin include the activation of mitochondrial biogenesis(41).
In Male Sprague-Dawley rats fed high-fat diet (HFD) induced alcoholic fatty liver disease (NAFLD), quercetin intake decreased hepatic TG content by 39%,(42) with a 1.5-fold increase in very low-density lipoproteins (VLDL)(42) which transport hepatic lipids to peripheral tissue acquired apoC-II and apoE from high-density lipoprotein (HDL) and exhibited the function of a protein involved in stress response(42) compared with the HFD group.
Injection of quercetin also is found to increase the protein complex expression of lipid transfer with a function to promote the very low-density lipoproteins (VLDL)(42) secreted by the liver.
In other words, these findings suggested that quercetin inhibits the expression NAFLD by increasing hepatic VLDL assembly and autophagy in hepatic lipid metabolism(42).
Additonally, quercetin exhibited hepatoprotective activity in 30-day HFD-induced NAFLD rats by regulating fatty acid related metabolites(43) (adrenic acid, etc.) including the inflammation-related metabolites (arachidonic acid, etc.), oxidative stress-related metabolites(43) (2-hydroxybutyric acid) and other differential metabolites(43) (citric acid, etc.).
Anthocyanins are water-soluble pigments of colored berries, fruits, and vegetables (44). They can protect hepatocytes against injury caused by high glucose-induced oxidative damage(45), by improving the antioxidant status and inhibiting the mitochondria pathways of apoptosis(45).
In male C57BL/6 J mice fed with a high fat high cholesterol (HFC) diet with or without 200 mg/kg B.W Cy-3-G for 8 weeks, injection of cyanidin-3-O-β-glucoside (Cy-3-G) regulated the activation of brown adipose tissue (BAT)(46) and the expression of adipokines in BAT disrupted by HFC diet associated with the induction of fatty liver(46).
In other words, Cy-3-G exerted the liver protective effect of on hepatic lipid accumulation(46) via regulating the secretion of adipokines from BAT(46).
9. Epigallocatechin gallate
Epigallocatechin gallate is the ester of epigallocatechin and gallic acid, belonging to the chemical class of flavan-3-ols (catechins) found most abundant in green tea (Camellia sinensis L.), accounting for about 50% of its total polyphenols(47).
In the examination of gene expression profiles with non-alcoholic fatty liver disease (NAFLD) and associated advanced liver diseases(48), application of Epigallocatechin-3-gallate (EGCG) inhibited the fibrosis-related genes (48)Col1a1, Col1a2, Col3a1, and Col6a3) that have a strong impact on the onset of NAFLD found in an independent mouse dataset (48).
In other words, EGCG protects the liver against genes related to liver fibrosis(48).
Furthermore, EGCG also exhibits multi-pronged preventive and therapeutic activities(49), including promoted lipid(49) and glucose metabolism(49), anti-lipid peroxidation(49) and anti-inflammation activities(49), anti-fibrosis(49), and anti-NAFLD related tumor(49), thus contributing to the mitigation of NAFLD occurrence and progression(49).
Astaxanthin is a phytochemical in the class of Xanthophylls, belonging to the group of Carotenoids (tetraterpenoids), found abundantly in yeast, krill, shrimp, salmon, lobsters, and green microalga(50). Astaxanthin showed to exhibit antifibrotic effects in the liver(51).
On the steatotic liver model by giving mice a methionine and choline-deficient high fat (MCDHF) diet, pretreatment of astaxanthin reduced levels of lipid peroxidation(52) and reduced number of liver cells apoptosis(52) by inhibiting the expression of inflammatory cytokines(2) and gene(52) involved oxidative stress in the liver(32)
Fucoxanthin is one of the most abundant marine carotenoids, accounting for more than 10% of the estimated total carotenoids in nature(53).
Fucoxanthin protected the liver induced by obesity(54) by improving insulin resistance(54) and decreasing blood glucose levels (54) through the regulation of cytokine secretions(54).
On body weight, body fat, liver lipids, and blood biochemistry in obese, non-diabetic female volunteers with non-alcoholic fatty liver disease (NAFLD) and normal liver fat (NLF) content, Xanthigen (brown marine algae fucoxanthin + pomegranate seed oil (PSO)) promoted weight loss(55), reduced body(55) and liver fat content)(55), and improved liver function tests in obese non-diabetic women(55).
Xanthigen may be considered a promising food supplement in the management of obesity(55).
12. Glucoraphanin (4-methyl sulfinyl butyl glucosinolate)
Glucoraphanin (4-methyl sulfinyl butyl glucosinolate), the major glucosinolate is the precursor of sulforaphane found abundantly in broccoli Brussels sprouts and cabbages(56).
Obesity-induced insulin resistance and nonalcoholic fatty liver disease (NAFLD), glucoraphanin, a precursor of the Nrf2 activator sulforaphane, ameliorated obesity by enhancing energy expenditure(57) and browning of white adipose tissue(57), and attenuated obesity-related inflammation(57) and insulin resistance(57) and reduced metabolic endotoxemia(57).
Where nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects.
In chronic inflammation, insulin resistance, and NAFLD in high-fat diet (HFD)-fed mice, Glucoraphanin supplementation attenuated weight gain(58), decreased hepatic steatosis(58), and improved glucose tolerance(58) and insulin sensitivity(58).
Furthermore, glucoraphanin attenuated hepatic lipogenic gene expression(58), lipid peroxidation(58), classically activated M1-like macrophage accumulation(58), and inflammatory signaling pathways(58).
In other words, by promoting fat browning, limiting metabolic endotoxemia-related chronic inflammation, and modulating redox stress, glucoraphanin may have a therapeutic effect for the treatment of obesity(58), insulin resistance(58), and NAFLD(58).
Sinigrin is a major component of commonly consumed cruciferous vegetables, such as horseradish and wasabi(59).
Sinigrin found in glucosinolates, a class of antioxidants has been found to reverse of fatty liver (60) probably through indirect interaction with mitochondrial metabolism(60) which encompasses a range of conditions caused by lipid deposition within liver cells.
In other words, by targeting the mitochondrial metabolism, sinigrin modulates antioxidant molecules for a potential treatment for hepatic steatosis(60).
Taken altogether, phytochemicals, herbal medicines, healthy foods found in the research paper may be considered remedies for the prevention and treatment of non-alcoholic fatty liver disease, pending to large sample size and multicenter human study.
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Kyle J. Norton (Scholar, Master of Nutrition, All right reserved)
Health article writer and researcher; Over 10.000 articles and research papers have been written and published online, including worldwide health, ezine articles, article base, health blogs, self-growth, best before it's news, the karate GB daily, etc.,.
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Nominated for shorty award over last 4 years
Some articles have been used as references in medical research, such as international journal Pharma and Bioscience, ISSN 0975-6299.
(1) Histopathology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis by G. Thomas Brown, M.D., Ph.D., and David E. Kleiner, M.D., Ph.D. (PMC)
(2) Non-alcoholic fatty liver disease in 2015 by Monjur Ahmed. (PMC)
(3) The Global Pattern of Urbanization and Economic Growth: Evidence from the Last Three Decades by Mingxing Chen, Hua Zhang, 2 Weidong Liu, 1 and Wenzhong Zhang. (PMC)
(4) Non-alcoholic Fatty Liver Disease in South Asians: A Review of the Literature by Sital Singh,1 Gabriela N. Kuftinec,2 and Souvik Sarkar. (PMC)
(5) Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States by Michael H. Le,1 Pardha Devaki,2 Nghiem B. Ha,3,4 Dae Won Jun,5 Helen S. Te,6Ramsey C. Cheung,4,7 and Mindie H. Nguyen. (PMC)
(6) Epidemiology of non-alcoholic fatty liver disease in China by Fan JG1, Farrell GC. (PubMed)
(7) Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in the burden of disease by Chris Estes, 1 Homie Razavi, 1 Rohit Loomba, 2 Zobair Younossi, 3 and Arun J. Sanyal. (PMC)
(8) Symptoms & Causes of NAFLD & NASH by NIH
(9) Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. by Nishizawa H1, Iguchi G, Murawaki A, Fukuoka H, Hayashi Y, Kaji H, Yamamoto M, Suda K, Takahashi M, Seo Y, Yano Y, Kitazawa R, Kitazawa S, Koga M, Okimura Y, Chihara K, Takahashi Y. (PubMed)
(10) Non-alcoholic fatty liver disease and thyroid dysfunction: A systematic review by Ahad Eshraghian and Alireza Hamidian Jahromi. (PMC)
(11) Obstructive sleep apnea syndrome and fatty liver: Association or causal link? by Mohamed H Ahmed and Christopher D Byrne, (PMC)
(12) Diets and nonalcoholic fatty liver disease: The good and the bad by Mohamed Asrih, François R. Jornayvaz. (El Sevier)
(13) Dietary fat stimulates the development of NAFLD more potently than dietary fructose in Sprague-Dawley rats by Jensen VS1,2, Hvid H2, Damgaard J2, Nygaard H2, Ingvorsen C3, Wulff EM4, Lykkesfeldt J1, Fledelius C. (PubMed)
(14) Non-Alcoholic Fatty Liver Disease by NICK G. (The American Liver Foundation)
(15) Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis by Rich NE1, Oji S1, Mufti AR1, Browning JD1, Parikh ND2, Odewole M1, Mayo H3, Singal AG. (PubMed)
(16) Emerging Trends Conference: EMERGING TRENDS IN NON-ALCOHOLIC FATTY LIVER DISEASE by AASLD
(17) Hepatic Encephalopathy by the Canadian Liver Foundation
(18) LIVER DISEASE AND ASCITES by Sequana Medical
(19) Nonalcoholic fatty liver disease manifesting esophageal variceal bleeding by Tang CP1, Huang YS, Tsay SH, Chang FY, Lee SD. (PubMed)
(20) Non-alcoholic fatty liver disease by Genetic Home Reference. (NIH)