NUTRACEUTICAL APPROACH TO NON-ALCOHOLIC FATTY LIVER DISEASE: A REVIEW

NUTRACEUTICAL APPROACH TO NON-ALCOHOLIC FATTY LIVER DISEASE: A REVIEW

Bhawna Sharma, Ritu Sanwal * and Sanjay Singh

Department of Pharmacology, Siddhartha Institute of Pharmacy, Near IT Park, Sahastradhara Road, Dehradun, Uttarakhand, India.

ABSTRACT: Nutraceutical is employed to explain a medicinal or nutritional component with a food, plant, or natural material that will be purified or concentrated. It is used to improve health by preventing or treating disease. Non-alcoholic fatty liver disease (NAFLD) is a clinical condition characterized by lipid infiltration of the liver with a high prevalence in the general population affecting 25% of adults with a double prevalence in diabetic and obese patients. Nearly 1/3 of NAFLD progresses to non-alcoholic steatohepatitis (NASH), leading to liver fibrosis and cirrhosis. There are currently no specific drugs approved on the market to treat NAFLD. So the treatment is essentially based on lifestyle optimization. However, some nutraceuticals may contribute to developing liver lipid infiltration and related anthropometric, haemodynamic and/or biochemical parameters. The objective of this article is to review the available clinical data on the effect of nutraceuticals on NAFLD and other parameters related to NAFLD. There are relatively few nutraceutical molecules that are adequately studied for their effects on NAFLD and other related diseases. Among them, we have analyzed the effects of nutrients, vitamins, minerals, different bacteria, food supplements, and other nutraceuticals such as carnitine, omega-3 fatty acids, silymarin, and resveratrol. In conclusion, vitamins (such as E and D), silymarin, and omega-3 fatty acids if administered well and for medium to long periods and associated with lifestyle changes that could have positive effects on NAFLD and their related parameters.

Keywords: Nutraceuticals, Dietary supplements, NAFLD, Clinical parameters

INTRODUCTION: Lifestyles have changed dramatically in the last 50 years due to urbanization, industrialization speed, and rapid change. These things have changed people's habits and forced them to eat fast, fast and tasty food, fast food, and junk food. These habits directly affect our aspect of healthy eating and gradually reduce the amount and quality of nutrients.

As a result of these changed eating habits, the population has increased the incidence of malnutrition, dementia and degenerative diseases. In recent years, people have become more concerned about health and more concerned about health care. Over the past two decades, changes in medicine, phytomedicine, health science, the food industry and health care have attracted widespread attention among health professionals and the public.

Significant advances have been made in nutraceuticals, food products, and phytonutrients. It is a good idea for pharmaceutical companies to be healthy and to prevent disease and treatment. Ayurvedic treatment regimens depend directly on the life of Aahar and Vihaar. Ahirwar is regarded as food and ancient medicine. The concept of Rasayana (re­healing) is widespread in Ayurveda and, in addition to current nutraceuticals ¹.

Nutraceuticals: The term "nutraceutical" comes from "nutrition" and "pharmaceutical". It is defined as a diet or part of a diet that provides health benefits of nutritious foods and helps prevent many diseases ^{2, 3}. Chemicals are natural compounds in our diet by the standards of healthy foods, such as minerals, vitamins, fatty acids, and polysaccharides. Many natural food sources such as fruits, dairy products, vegetables, and poultry contain all the important nutrients in our diet.

For this reason, these nutrients are used to treat and prevent many diseases such as heart disease, diabetes, cancer, osteoporosis, obesity, osteoarthritis and many other diseases. These nutrients contain many water­soluble minerals, antioxidants, fats and vitamins extracted from our diet and are helpful in many of our health problems ⁴.

Reasons for Shift towards Nutraceuticals:

• Increase the number of consumers who are concerned about the cost of healthcare.
• Dissatisfied with medical agents in promoting health. They turn to medication to improve their health and prevent chronic diseases.
• Healthcare professionals note that our supply of highly processed foods derived from plants grown with chemical fertilizers, pesticides, herbicides, and genetically modified seeds lacks the nutrients needed for good health.
• People do not believe in prevention more than in healing.
• Peoplesufferfromchronicdiseasesandhavenotfoundasolutiontoallopathical medicine.
• Patients with financial problems ⁵.

Benefits of Nutraceuticals: There are various benefits of nutraceuticals which are given below;

• It can increase the value of our healthy food.
• It can help us to live longer.
• It can help us avoid certain medical conditions.
• You can gain psychological benefits by doing something for yourself.
• It can be seen as more "natural" than traditional medicine and is less likely to cause side effects.
• It is possible to introduce foods for people with special needs (for example, nutritious foods for the elderly).
• It can be easily obtained and inexpensive ⁶.
• Reduce the spread and duration of infectious and viral diarrhea.
• Reduce inflammation and symptoms associated with intestinal illness.
• It has protective effects to prevent colon cancer.
• It improves the availability of bioavailability and absorption of minerals such as calcium, magnesium, and possible iron.
• Reduce other risk factors for heart disease.
• It promotes saturation and weight loss and prevents obesity ⁷.

Classification of Nutrients and Minerals as Nutraceuticals: The classification of nutrients and minerals as nutraceuticals along with their health benefits are given below;

TABLE 1: NUTRIENTS AND THEIR HEALTH BENEFITS

TABLE 2: MINERALS AND THEIR HEALTH BENEFITS

TABLE 3: DIETARY SUPPLEMENTS AND THEIR HEALTH BENEFITS

Classification of Nutraceuticals: Nutraceuticals are grouped based on their nature and properties, which are given below;

• Chemical constituents.
• Probiotics Microorganisms.
• Nutraceuticals Enzymes.
• Non - traditional nutraceuticals.
• Commercial nutraceuticals.

1. A) Chemical Constituents: It can be divided into nutrients, herbs, and phytochemicals. Phytochemicals plant genes through certain biological functions to support human health, acting in the following ways such as;

• Substrate for chemical reactions.
• Cofactors of enzymatic reaction.
• Inhibitors of enzymatic reaction.
• Abscesses bind and remove unwanted substances from the intestines.
• Improves absorption and stability of essential nutrients.
• Selected growth factor of beneficial bacteria.
• Substrate fermentation of beneficial bacteria.
• Selected inhibitors are harmful bacteria in the gut.
• Active or toxic chemicals.
• Ligands cause pain or resistance to cell location or intracellular receptors ²⁶.

1. B) Probiotics Microorganisms: It takes action to remove bacteria such as yeast, other bacteria and viruses that can cause disease and develop interactions that benefit the human intestinal tract. They have an anti­bacterial effect by altering the microflora, preventing bacterial attachment to the intestinal epithelium, competing with the elements needed to survive the pathogen, producing an antitoxic effect, and eradicating some of the effects of intestinal epithelium infections such as secretion and neutrophils. Probiotics can cure lactose intolerance by producing a specific enzyme (ß-galactosidase) that can hydrolyze harmful lactose into its sugar component.

• In choosing probiotic measurements, safety, operational and technical factors should be considered, as indicated below, as potential health benefits such as.
• Probiotics must be of human origin.
• A typical gram­positive environment.
• It can survive after passing on acid and gallstones.
• It can attach to human intestinal cells and grow in the intestines.
• It may show antagonistic action against pathogenic or carcinogenic bacteria.
• Beneficial clinical outcomes in health care ²⁷.

Role of Different Bacteria in the Body: Different types of bacteria show different health effects, and details about the bacteria are given at the bottom of the table.

TABLE 4: ROLE OF BACTERIA IN THE BODY AND THEIR BENEFICIAL EFFECTS ⁵

C) Nutraceutical Enzymes: Enzymes are an important part of life without which our body would stop working. Those experiencing medical conditions such as hypoglycemia, blood sugar disorders, digestive problems and obesity can eliminate symptoms by adding enzyme supplements to their diet. These enzymes are found in microbial, plant and animal sources.

D) Perbiotics: Prebiotics are foods that we have never eaten before. Instead, they serve as a source of nutrients for good probiotic bacteria.

This encourages probiotic bacteria to grow in a supportive environment, reducing the chances of microbes starting to grow in our digestive tract. Inulin is a prebiotic widely used in processed foods. It is a type of fiber found in the roots of plants such as chicory, Jerusalem artichoke and dandelion ²⁸.

E) Non-traditional Nutraceuticals: A processed food prepared with the help of biotechnology. Food samples contain organisms designed to produce human life products. They are formulated into nutrient-rich nutraceuticals and synthetic nutraceuticals.

1) Strengthened Nutraceuticals: Vitamin and mineral supplements are usually found in that nutrient's 100% Diary Reference Intake (DRI). Creates enriched agricultural foods or with the addition of nutrients and / or ingredients with the addition of folic acid. Other examples milk is combined with cholecalciferol used in vitamin D deficiency ²⁹.

2) Recombinant Nutraceuticals: Energy foods like bread, alcohol, boiled starch, yogurt, cheese, vinegar etc., are produced with the help of biotechnology. The production of probiotics and the extraction of bioactive elements by fermentation/enzyme technology, as well as engineering technology is achieved through biotechnology.

F) Commercial Nutraceuticals: The new molecule is hard to find, more expensive, and more dangerous than before. Many pharmaceutical companies are fenced off to produce healthy food products because there is no doubt a large and growing market. Nutraceuticals offer a wide range of treatments, prescribing anti­arthritics, colds, and coughs, sleep disorders, digestion and prevention of certain cancers, osteoporosis, blood pressure, cholesterol control, pain relief, depression, and diabetes. Recognizing and gaining health in omega-3 fatty acid enriched seafood is one of the most promising developments in human nutrition research and disease prevention over the past three decades. It includes a variety of health food medicines such as dietary supplements, active foods, diet pills, and medications.

i) Medicinal Foods: Foods prepared for use or administered internally under the supervision of a physician and intended for the administration of certain foods or the condition of certain nutritional needs, according to a well­known scientific policy, do not stabilize the medicinal value even if it contains a substance a genetic component that is rarely produced due to a specific disease. I quantify non­use of a variety of health conditions leading to infiltration, digestion, consolidation, or physical activity of traditional cybi such as phenylketonuria, celiac disease, and lactose intolerance ³⁰.

ii) Active Foods: active foods, meaning the most commonly accepted parrot, are simply "any food or ingredient that can provide health benefits from other indigenous ingredients. Active foods are designed to bring consumers" strengthened closer to their status, rather than taking dietary supplements in liquid form or capsule. Functional diets have been enriched or fortified, called the diet process. as added to milk. Fat may be a major source of energy for the body. There are the following types of lipids given as;

Saturated, monounsaturated fatty acids (MFA), polyunsaturated (PUFA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), saturated fats in animal products and MFA or PUF vegetable origin ³¹.

Metal Binding Proteins: Some of the examples of metal-binding proteins are as follows;

• Albumin (copper).
• Ceruloplasmin (copper).
• Metallothionein (copper).
• Ferritin (iron).
• Myoglobin (iron).
• Transferrin (iron) ⁷.

TABLE 5: THE BEST HIGH-FIBER FOODS ³¹

TABLE 6: EXAMPLES OF ANTIOXIDENT & THEIR SOURCES ³¹

Market Interest and Growth of Nutraceuticals: The nutraceutical market is constantly competing with the revenues of major food and pharmaceutical products in the field of nutraceuticals. In addition, many food companies have not yet established their own category of nutraceuticals for a separate product line. Or you can go to the pharmacy; you will be able to buy a food supplement product.

The past few years have marked the entry of major food and pharmaceutical companies into the nutraceutical market, including Kellogg, Heinz, M & M, Quaker Oats, Unilever, Cargill, Ormel, GlaxoSmithKline, Warner­Lambert, Johnson Johnson and Wyeth. The 2004 global nutraceuticals market at the sales level is estimated at $ 106 million and is expected to grow by 6.0% annual average over the period 2004, 2009 to more than $ 140 million in 2009 ³².

The nutraceutical market size is unlikely to grow at $ 180.38 million over the period 2020, 2024, and the rate of rapid market growth during the forecast period. The report provides product market analysis (active food benefits, employment benefits and food ingredients) and geographical location (APAC, Europe, MEA, North America and South America). In addition, the report analyzes the competitive environment in the market and provides details to its various market providers, including AbbottLaboratories, Archer Daniels Midland Co, BASF SE, Cargill Inc., Danone SA, General Mills Inc., Kellogg Co., Nestlé SA, PepsiCo Inc. and CocaCola Co ³³.

Nutraceuticals Approach in Ayurveda: The main goals and objectives of Ayurveda are establishing a state of health and eradicating the disease. In Ayurvedic dietetics, importance given to food in the prevention and treatment of diseases, and herbal remedies are part of the daily diet. According to Acharya Charak, foods that should not provide basic nutrients in the body should be used to help maintain good health and prevent the spread of disease.

A lovely verse from Acharya Lolimbaraja about the importance of food is that if healthy food is given in an orderly manner, there is no need to administer drugs. If no healthy food is used, no drugs need to be given as this is not enough. He cured the disease with a lack of healthy food. The concept of Aahar is a perfect way and is beyond the modern view. The Pathyain difference, Hita­ahita and Satmya­asatmya index, is based on an independent process. Ayurveda places great emphasis on the quality of nutritious foods such as Rasayana (preventing degenerative changes), Balya (nutrition after illness), Brihan (provides inadequate nutrients), Jeevaniya (maintains longevity), Vyadhikshmatva (improves the immune system) and Vajikaran (preserves) and power). The science of nutrition and nutrition in Ayurveda was greatly improved. Acharya Charak divided all food into twelve categories, and Acharya Sushrut became thirteen. There are other divisions based on the compliance of food products such as Ashita (semi­solid, recommended for the elderly), Khadita (solid food, recommended for young people with good digestion), Peeta (consistency fluid, recommended for infants, children, and sick and recommended for summer) and Leeda ( a licked attachment form, recommended for children, recovery and the elderly to prevent or treat high blood pressure, high cholesterol, overweight, osteoporosis, diabetes, arthritis, macular malnutrition, lack of exercise, busy lifestyle, lifestyle ¹.

Current Trends and Future Prospects of Nutraceuticals: Over the past 20 years, there has been a rapid increase in the use of nutraceuticals due to the vast amount of information available on Internet resources and the growing public awareness of health problems ³⁴. Nutraceuticals for medical use are proven on the basis that they cure diseases caused by malnutrition. Strong evidence exists that nutraceutical supplementation improves health and prevents disease ³⁵.

While nutraceuticals have an important promise in promoting human health and disease prevention, health care professionals and regulatory poisons can also strategically work to develop appropriate guidelines for providing superior medical benefits to people ³⁶. In terms of nutraceutical production processes, quality controls, such as the composition and content of active ingredients in natural plants and their storage, are very important.

Intensive safety studies involving acute, subacute, subchronic, chronic, and long term terminology studies, animal husbandry, and human clinical studies are required to establish ^{37, 38}. DNA microarray technology can be used to test the safety and efficacy of drugs, chemicals, dietar supplements, and nutraceuticals. In summary, agriculture, food, and biomedical biotechnologies continue to grow relentlessly to change our lives, and one day our food will likely act as a medicine ³⁹.

Liver- The Largest Gland in the Body: The liver is the largest organ in the body and weighs between 1.2 and 1.5 kg in adults.

Liver Area in the Body: It is located in the abdominal cavity below the lid and has two lobes. Hepatic lobes are elements of the structure and performance of the liver consisting of liver cells arranged within cords. Each lobe is covered with a thin layer of connective tissue called Glisson's capsule.

The bile secreted by the liver cells passes through the hepatic ducts and is stored and concentrated in a small muscle sac called the gallbladder. The gallbladder (cystic duct) and the liver duct form the normal bile duct. The bile duct and pancreatic duct open together in the duodenum as a normal hepatopancreatic duct protected by Oddi's sphincter ⁴⁰.

Schematic relationships of the liver and other organs: The liver interacts with many other organs. After blood flow, the liver receives its blood from the hepatic arteries ⁴¹. The hepatic artery is located away from the celiac trunk and the abdominal aorta, so the liver receives its oxygen­rich blood from the heart. Blood rich in nutrients from the digestive system and blood from the digestive tract enters the liver through the hepatic portal artery. Processed blood that flows from the liver through the hepatic arteries enters the inferior vena cava, completing heart contact. The liver influences digestion by forming bile, which is secreted into the small intestine. The gallbladder is a dense area of the gallbladder of the liver. The liver is filled with lymph nodes that provide fluid flow and support for the immune system. The liver comprises many proteins in the blood, indicating its relationship to those organs. The liver has a nervous system that shows its relationship to the nervous system. Finally, the liver disease often causes problems with the kidney system that show relationships with the kidneys. The liver has many important functions in maintaining the balance of the human body ⁴².

FIG. 1: ASSOCIATION OF LIVER

FIG. 2: ARRANGEMENT OF ARTERIES AND VEINS

Functions of the Liver: The various types of functions performed by the liver are discussed given below;

TABLE 7: FUNCTIONS OF LIVER

Non-Alcoholic Fatty Liver Disease (NAFLD): Non­alcoholic fatty liver disease (NAFLD) is the accumulation of triglycerides (TG) in the hepatocyte without eating alcohol. Fatty liver disease can be caused by the accumulation of TG in hepatocyte to non-alcoholic steatohepatitis (NASH), defined as steatosis accompanied by inflammation, which progresses to fibrosis and then to cirrhosis ⁴³ and eventually to with hepatocellular carcinoma ⁴⁴. NAFLD is the first step in developing irreversible changes in the liver parenchyma leading to cirrhosis (about 1/3 of NAFLD cases are prone to NASH, and 15% of these can turn into cirrhosis) and, on the other hand ' on the other hand, NAFLD itself is a risk factor in the development of heart disease ⁴⁵. A recent meta­analysis of 9 observational studies involving data from 96,595 adult studies (34.1% of them with NAFLD) with 4,654 cases of moderate to severe failure during the 5.2-year review period showed a 37% risk of high renal failure in NAFLD patients. The risk was greater than the rate of lipid penetration into the liver. Since kidney failure and NAFLD are risk factors for heart disease, it is easy to understand how important this association of autoimmune diseases is ⁴⁶. Fat intake is called fatty liver disease and may be due to alcohol abuse (fatty liver disease ­ AFLD) or other metabolic disorders (fatty liver disease NAFLD). The international standard the scientific community chose to distinguish between AFLD and NAFLD is 2 drinks, equivalent to 20 g per day. NAFLD is the most common condition affectingm25­30% of adults, 15% of children, and over 50% of overweight, obese, and type 2 people. NAFLD could be considered a real disease. If it is completely reversed ⁴⁷. The aggressive clinical variation of NAFLD, steatohepatitis (non­alcoholic), characterized by persistent inflammation and degeneration of tissues, affects approximately 5% of adults and 20% of obese individuals ⁴⁸.

Nafld Pathogenesis: The pathogenesis of non­alcoholic fatty alcohol disease has been identified as a major health problem. Metabolic mutations associated with obesity were collected to explain metabolic syndrome, the leading cause of death and morbidity in developed countries ⁴⁹. Metabolic syndrome is characterized by several disorders, including elevated blood pressure, IR, and obesity ⁵⁰. The growing epidemic of metabolic syndrome is accompanied by an increase in liver dysfunction, including NAFLD ⁵¹. In particular, NAFLD is an obvious manifestation of the metabolic system ⁵². Non-alcoholic fatty liver disease is found in 22 to 30% of the world. The prevalence of NAFLD in people with normal weight without complaining of a disease that they think affects the body is about 16% ⁵³. On the other hand, the prevalence of NAFLD is high among obese patients, rising to 73% in obese people and 85% in obese people ^{54, 55}.

Non-alcoholic disease (NAFLD) is the commonest chronic liver disease. It is characterized by various liver changes that can lead to liver fibrosis and cirrhosis. NAFLD is considered a hepatic component of metabolic syndrome (MetS) ⁵⁶ but the mechanisms underlying it and its progression are still being investigated. Numerous studies have shown the presence of insulin resistance ⁵⁷ and increased oxidative stress ⁵⁸ in patients with NAFLD / steatohepatitis (nonalcohol) steatohepatitis (NASH). Thus, according to the “double hit hypothesis”, the first hit represents the accumulation of lipids in hepatocytes, after which oxidative stress can lead to NASH ⁵⁹. This traditional theory has been developed within the complex "multiple parallel impact hypothesis" which includes a wide range of similar effects such as insulin resistance, oxidative stress, genetic and epigenetic pathways, natural substances, cytokines, and changes in microbiota ⁶⁰. These factors can be related in various ways in the presence and absence of MetS. Various therapies have been suggested so far. However, the only effective strategy for obtaining NAFLD treatment for weight loss and vitamin administration is only designed for non­diabetic NASH patients. Significantly, there is currently no approved treatment for NAFLD ⁶¹.

TABLE 8: ROLE OF NUTRACEUTICALS FOR THE TREATMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE AND POSSIBLE TARGETS

Therapeutic Approaches for NAFLD:

Non-Medical Treatment: Many cases of NAFLD are associated with obesity, so exercise and a very low diet are recommended ⁸¹.

Moreover, there is no specific cure for NAFLD other than weight loss, increased exercise, and lifestyle changes, which remain the most important and effective ways to recover from NAFLD ^{82, 83}.

Weight Loss: In a hospital patient with NAFLD, weight loss was accompanied by significant improvement in all parameters of metabolic syndrome, liver function tests and steatosis function ^{84, 85, 86}, lobular inflammation, balloon damage, and fibrosis ⁸⁷. Improvements in liver function tests associated with weight loss have been observed in 40% of obese patients with NAFLD ⁸⁸. In addition, weight loss is the only proven form of NAFLD for children. However, weight loss should be slightly reduced because rapid weight loss can be detrimental to steatohepatitis ⁸⁹.

Exercise: Exercise has been shown to increase the oxidative capacity of muscle cells and use AF oxidation ⁹⁰. It also reduces the accumulation of fatty acids and TG in myocytes and improves insulin sensitivity. In addition, exercise is associated with improved insulin sensitivity ⁹¹.

Medication Methods: Most current approaches to treating NAFLD aim to prevent fat absorption, inflammation, and insulin sensitivity ⁹².

CONCLUSION: There are currently no specific drugs for NAFLD treatment. So, treatment is based on the effectiveness of the lifestyle. However, other nutraceuticals may improve lipid liver penetration and anthropometric, haemodynamic and/or biochemical parameters. Ayurvedic treatment regimens depend directly on the life of Aahar and Vihaar. Aahar was regarded as food and ancient medicine. The concept of Rasayana (rehealing) is a widespread concept in Ayurveda and in addition to current nutraceuticals. This article aims to provide available clinical data on the effect of nutraceuticals based on the NAFLD and NAFLD parameters. Few nutraceutical molecules have been extensively studied for their effects on NAFLD and other related diseases. Among them, we have analyzed the effects of nutrients, vitamins, minerals, various bacteria, dietary supplements, and other nutraceuticals such as carnitine, omega­3 fatty acids, silymarin, and resveratrol. In conclusion, vitamins (such as vitamin E and vitamin D), silymarin, and omega­3 fatty acids, when properly regulated and regulated over a long period, are associated with lifestyle changes that can positively affect NAFLD and their related parameters. It also showed improvements in the liver function tests (LFT) and a positive impact on liver histology.

ACKNOWLEDGEMENT: The authors thanks the Siddhartha group of Institutions for their motivation and support.

CONFLICT OF INTEREST: The authors declare that they have no conflict of interest for this study.

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    Sharma B, Sanwal R and Singh S: Nutraceutical approach to non-alcoholic fatty liver disease: a review. Int J Pharm Sci & Res 2022; 13(9): 3411-24. doi: 10.13040/IJPSR.0975-8232.13(9).3411-24.

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