Fatty liver disease (FLD) is a genetic-environmental-metabolic stress-related disease that is the leading cause of chronic liver disease in developed and affluent regions and poses a serious threat to human health and social development. Pathologically, FLD includes three major types: simple fatty liver, steatohepatitis and cirrhosis, and clinically, there is a distinction between alcoholic and non-alcoholic. Currently, the prevalence of alcoholic liver disease (ALD) remains high and is feminized and juvenile, while the incidence of nonalcoholic fatty liver disease (NAFLD) is increasing and the onset of the disease is also becoming younger, and the coexistence of both and chronic hepatitis B is not uncommon. More frighteningly, NAFLD is not only similar to ALD, which can lead to cirrhosis, liver cancer and liver failure, but is also closely related to type 2 diabetes and atherosclerotic cardiovascular disease. For this reason, FLD has now become a new challenge in contemporary medicine, and research on FLD is progressing rapidly. However, to date, there is still a lack of specific drugs for the prevention and treatment of FLD, and the existing countermeasures are mainly: “awareness, comprehensive prevention and treatment, strengthening education, and emphasis on implementation”. 1, treatment goals ALD is still the leading cause of disability and death from liver disease in Europe and the United States and other developed countries, and alcohol abuse and alcohol dependence can also affect the nervous system, reproductive system and eugenics. For this reason, the primary goal of ALD treatment is lifelong abstinence from alcohol or reducing alcohol consumption as much as possible; the second goal is to control hepatitis activity and stop the progression of liver disease through relevant drugs; for patients with severe hepatitis and decompensated cirrhosis, they can only work to prevent and control complications, aiming to gain time for life-saving liver transplantation. In addition, general education on the health hazards of alcohol consumption and compliance with alcohol cessation treatment should be the basic goals of disease control. Compared to ALD, liver disease in patients with NAFLD usually has a benign course and takes longer to develop and is less likely to be complicated by liver failure and cirrhosis. However, even mild fat accumulation can make the liver more sensitive to other liver-damaging factors and can affect the effectiveness of antiviral therapy for chronic viral hepatitis; most importantly, in overweight and abdominally obese individuals, the presence of a fatty liver suggests “malignant obesity”. Prospective studies have shown that the main causes of death in NAFLD are type 2 diabetes, cardiovascular events, and tumors associated with the metabolic syndrome, while disability and death from liver disease are seen only in some patients with nonalcoholic steatohepatitis (NASH). For this reason, the primary goal of NAFLD treatment is to control metabolic disorders and prevent type 2 diabetes and cardiovascular events, while reversing hepatocellular steatosis and preventing symptomatic cholelithiasis are secondary goals, with the additional requirements of preventing steatohepatitis, halting the progression of liver disease, and reducing the occurrence of cirrhosis. As for whether to strictly abstain from alcohol or reduce drinking (<20g/d), there is still no conclusion, because a small amount of alcohol can improve insulin resistance (IR), increase serum HDL cholesterol level, and reduce the occurrence of diabetes and atherosclerosis. The treatment of FLD includes basic treatment, drug treatment for liver disease and prevention and treatment of liver disease complications, which should follow the program of "early intervention, long-term persistence, overall treatment and individualized medication". Lifestyle changes and treatment of co-morbidities and associated risk factors are the basic prerequisites for holistic treatment. Successful primary therapy can reverse simple fatty liver and its accompanying systemic lesions, improve the effectiveness of liver-protective drugs for steatohepatitis, and prevent the recurrence of FLD after liver transplantation. The specific measures include (1) lifestyle modification, through health education and psychological and behavioral modification treatment, to achieve "reasonable diet, increase exercise, moderate alcohol consumption, careful use of hepatotoxic drugs and avoid exposure to hepatotoxic substances"; (2) treatment of primary diseases, for moderate to severe obesity, especially in combination with Patients with hyperlipidemia with more than 2 risk factors can safely use statins, gemfibrozil, and probucol to lower their lipids to a safe range, and generally do not require intensive liver enzyme monitoring. Those who have not remitted intrahepatic fatty deposits after 3-6 months of basic treatment should consider: (1) the cause or causative factors of FLD have not been removed and are still at work; (2) the real cause of fatty liver has not been found; (3) steatohepatitis and progressive liver fibrosis have occurred. The corresponding countermeasures are: (1) reconsider the etiology and causative factors; (2) strengthen the treatment of the primary underlying disease; (3) combine with liver-protective drugs. For new onset of abnormal liver enzymes, jaundice and cholelithiasis during the course of basic treatment, the occurrence of drug-derived hepatobiliary injury should be alerted, at which time the relevant suspected drugs should be discontinued promptly and liver-protective drugs should be added if necessary. Hepatoprotective drugs are one of the important components of pharmacological interventions, aiming at protecting hepatocytes, antagonizing oxygen stress/lipid peroxidation, anti-inflammation, anti-apoptosis, and anti-fibrosis, in order to improve the ability of simple fatty liver to prevent "second strike", avoid hepatobiliary injury that may be induced by weight loss and lipid-lowering drugs, and reduce or even reverse intrahepatic inflammation, necrosis, and fibrosis in patients with steatohepatitis. Given that the natural course of FLD is not well understood, that many risk factors predicting liver disease progression are not fully understood, and that the effects of liver-protective drugs are limited and the cost of long-term medication is unaffordable, it is not possible to give liver-protective drugs to all patients with FLD detected by imaging. Which patients should be treated with hepatoprotective drugs should be considered from the perspective of evidence-based medicine and the latest clinical trial results. Liver-protective drugs are recommended for the following types of FLD: (1) those with abnormal liver function (e.g., persistently elevated serum ALT, AST, and γ-GT) or liver biopsy suggestive of steatohepatitis or liver fibrosis; (2) those at high risk for steatohepatitis/progressive liver fibrosis, such as those aged >45 years, visceral obesity, hyperglycemia, hypertension, and hypertriglyceridemia, i.e., those with a combination of metabolic syndrome (3) middle-aged and elderly patients with fatty liver who have been abstinent from alcoholic fatty liver for 3 months or non-alcoholic fatty liver whose basic treatment has been ineffective for 6 months, or whose basic treatment is likely to cause damage to the hepatobiliary system, or whose cryptogenic fatty liver has symptoms associated with chronic liver disease. Generally, one or two hepatoprotective drugs such as polyenophosphorylcholine, silymarin, vitamin E and ursodeoxycholic acid are used for six months to more than one year, or until the liver enzymes are normalized and/or the imaging fatty liver subsides. In principle, various Chinese and Western drugs that can only lower serum aminotransferases are not used or are not used alone in the pentamidine class. End-stage FLD needs to be prevented and treated against portal hypertension and liver failure and its complications. For patients with subacute NASH with liver failure and end-stage cirrhosis, liver transplantation may be the only option to save life. However, if weight control and alcohol abstinence are not effectively maintained, FLD is highly likely to recur after transplantation. Therefore, before liver transplantation, patients should strive to reduce their body mass index to below 35 kg/m2 and strictly abstain from alcohol for more than 3-6 months, and continue to adhere to basic treatment after transplantation. Current treatment status The current treatment of FLD is mainly devoted to removing or reducing the two major factors leading to liver damage – alcohol abuse and obesity. Abstinence from alcohol is crucial to the treatment of all types of ALD and to the improvement of survival. Liver steatosis can subside within 1-2 weeks after abstinence from alcohol, and liver inflammatory damage can be slowly recovered within several months. However, some patients with moderate to severe alcoholic hepatitis have persistent liver damage after abstinence, and 25% of these patients progress to cirrhosis within 5 years. Similarly, weight loss is not an ideal treatment for NAFLD. In NAFLD without weight gain, diet and exercise do not help fatty liver regression; and too rapid a rate of weight loss in obese fatty liver (>5 kg per month in adults) may lead to increased inflammation and fibrosis in the liver. In fact, more often than not, it is difficult to adhere to long-term alcohol cessation and effective weight loss, and for obese patients, relying solely on the control of disorders of glucose and lipid metabolism can rarely make fatty liver reversal; so far, there is no special drugs to stop alcohol addiction or alcoholic liver injury, and some patients even appear addicted to alcohol cessation drugs. 3.1, change lifestyle In view of obesity (especially abdominal obesity) and its related disorders of glucose and lipid metabolism are closely related to NAFLD [1, 2], through diet and increase exercise and other measures to change lifestyle aimed at achieving a certain degree of weight loss, as well as the treatment of coexisting obesity, dyslipidemia and diabetes, is now recognized as the first-line measures for the treatment of NAFLD and the most important treatment The most important treatment method. [Although a low-calorie and low-saturated fatty acid diet is commonly recommended for patients with NAFLD, it is not clear how changes in the composition of dietary fat affect the histological damage of the liver in patients with NAFLD. There are few experimental studies in this area, and for this reason, the existing dietary regimens for NAFLD patients are not derived from animal studies. In the absence of evidence, it is prudent to recommend diabetic diets or “heart-healthy recipes” for patients with NAFLD. Existing dietary interventions include control of total caloric intake, dietary fat based on unsaturated fatty acids and limited intake of saturated fatty acids, and carbohydrates based on slow-absorbing complex sugars and fiber but limited intake of fast-absorbing carbohydrates (high glycemic index). A recent meta-analysis showed that dietary guidance did result in varying degrees of weight loss in obese patients, with an average monthly decrease in body mass index (BMI) of 0.1 units (kg/m2) over the 3-12 month dietary intervention trial. However, after discontinuing the dietary intervention, patients tended to gradually regain their weight. A trial of 74 severely obese patients who underwent detailed dietary assessment and liver biopsy showed that: high carbohydrate intake was severely positively associated with the degree of liver histological inflammation, whereas high fat intake was mildly and strongly associated with the degree of liver histological inflammation; and no correlation was found between total dietary calorie or protein intake and liver steatosis, inflammation and fibrosis. If this is the case, the recommendation of a low-fat diet for patients with NAFLD may actually exacerbate their hepatic histological inflammatory damage. Another dietary investigation showed that male NASH patients had higher energy intakes compared to gender- and age-matched chronic hepatitis C or healthy controls. Further dietary guidelines aimed at improving insulin resistance were implemented for these NASH patients, recommending a caloric intake of 40%C45% from carbohydrates (emphasizing fiber-rich complex sugars), 35%C40% from fats (predominantly monounsaturated and polyunsaturated fats), and 15%C20% from protein. repeat liver biopsy after 12 months showed that of the 15 NASH patients 9 cases had significantly improved liver steatosis and NASH score compared to pre-treatment. Another study of 10 patients with NAFLD on a 6-month diet (500 kcal/day reduction in caloric intake) showed improvements in lipids and biochemical parameters of liver function, although the average weight loss was only 4%. A low-carbohydrate diet (a diet rich in low glycemic index) was more effective than a low-fat diet in reducing BMI and improving insulin resistance in the short term, however, this study did not evaluate the therapeutic effects of dietary interventions for NAFLD. Recently, studies have begun to investigate the effects of single dietary component changes on NAFLD. Oligofructans are short-chain oligosaccharides containing D-glucose and D-fructose, which are found in wheat, onions, garlic and bananas and are not readily digested and absorbed. One study reported that after taking oligofructans for 8 weeks in 7 patients with NASH, serum transaminase and insulin levels decreased significantly compared with those before treatment, and the therapeutic effect was better than that of the placebo control group, but its effect on the improvement of dyslipidemia was not significant. A series of animal studies have shown that diets rich in palm oil, fish oil, and high fiber all contribute to the treatment of NAFLD, while fructose-rich diets do not. In a replicated animal model of NAFLD, there was no difference in the degree of hepatocellular steatosis between rats fed a high-fat diet for several weeks and then changed to a normal-fat diet and rats fed a continuous high-fat diet. It is suggested that the increase in hepatic lipid content appears to occur early in the high-fat diet and that the increase in hepatic fat may be more closely related to dietary fat intake than to weight gain, and further studies are needed to determine what the results will be in humans. 3.1.2, Exercise therapy: Physical exercise (aerobic exercise) is highly beneficial for insulin resistance and metabolic syndrome and its related components (obesity, dyslipidemia, diabetes), all of which are risk factors for NAFLD. Physical exercise, while avoiding muscle atrophy, reduces body weight by selective reduction of visceral fat. The ameliorative effect of exercise on insulin resistance is independent of the decrease in BMI, which in turn affects fatty liver formation by reducing peripheral lipolysis, inhibiting hepatic lipid synthesis and stimulating fatty acid oxidation. Numerous studies have shown that most NAFLD patients with some degree of weight loss are often associated with improvements in hepatic biochemical parameters and ultrasonography, however, the effect of weight loss on hepatic histological changes has rarely been reported, although diet moderation, increased exercise, and correction of maladaptive behaviors appear to improve insulin sensitivity and liver lesions in NAFLD patients. In a controlled study of 25 obese adults from Japan, BMI, transaminases, and hepatic tissue steatosis were significantly reduced in 15 patients who received 3-month lifestyle modification therapy, while 10 patients who did not receive any treatment had no significant changes in these indicators during the observation period. The severity of NAFLD was positively correlated with patients’ BMI and negatively correlated with their cardiorespiratory fitness. One study showed that moderate-intensity aerobic exercise improved cardiorespiratory fitness and helped to normalize serum ALT in NASH patients, while no such effect was observed in the other 15 patients who failed to exercise consistently. For this reason, although there is no controlled trial comparing the therapeutic effects of physical exercise alone and diet-based physical exercise in weight loss and improvement of NAFLD, long-term adherence to physical exercise can help prevent weight regain and promote improvement of serum ALT. 3.2. Drug therapy Screening effective drugs to prevent and treat NASH according to the pathogenesis of NASH is a hot topic of current research, and the role and safety of insulin sensitizers, antioxidants and anti-inflammatory therapy and drugs that have the potential to reduce liver lipid content in the prevention and treatment of NASH are of interest. [5] 3.2.1. Insulin sensitizers: These include metformin (improves hepatic insulin resistance), thiazolidinediones (improves peripheral insulin resistance), and α-glucosidase inhibitors (improves postprandial glucose; relatively few studies have used them in the treatment of NAFLD). Several uncontrolled clinical trials have shown that metformin significantly reduces serum ALT levels in patients with NAFLD. However, few studies have looked at its improving effects on liver histology. A recent open randomized controlled trial with pre and post liver biopsy data showed significant improvement in hepatic steatosis, inflammatory necrosis and fibrosis in some cases in the metformin group compared to baseline levels; however, there were no significant differences in hepatic histological improvement between the metformin group and the vitamin E and placebo groups. Another study reported that 24 patients with NASH treated with metformin had nearly 50% improvement in liver histology, and all those with improved liver histology had weight loss, suggesting that the therapeutic effect of metformin on NASH comes at least in part from its side effects (gastrointestinal reactions) and adjunctive weight loss. Thiazolidinediones (pioglitazone and rosiglitazone) are agonists of the peroxisome proliferator-activated receptor gamma and improve insulin resistance mainly by acting on prolipid cells. Several existing small open trials have shown encouraging results of thiazolidinediones in improving serum transaminases and liver histology in NASH patients. A recent 6-month randomized double-blind placebo-controlled trial showed that pioglitazone improved insulin sensitivity and blood glucose levels in 55 patients with NAFLD with combined abnormal glucose tolerance; and more improvements in hepatic steatosis (65% vs. 38%) and inflammatory necrosis (85% vs. 38%) were seen in the treatment group than in the control group, but no improvement in hepatic fibrosis (46% vs. 33%) was significant difference. Whether an anti-fibrotic effect can be observed with an extended course of treatment needs further study. A randomized double-blind placebo-controlled trial reported in abstract form that rosiglitazone was nearly 50% effective in the treatment of NASH and that the mechanism of action was to improve insulin resistance. The disadvantages of this class of drugs are mainly weight gain (up to 4% weight gain in one year of treatment) and potential increased risk of cardiovascular disease, as well as the expensive cost of treatment. For this reason, the cost of treatment, the effect of long-term treatment, and other adverse events need to be carefully considered before recommending thiazolidinediones for routine treatment of NASH. 3.2.2. Antioxidant and anti-inflammatory therapy: including antioxidants (vitamin E and/or vitamin C, glutathione precursor beta-betaine, intravenous bloodletting therapy to remove the adverse effects of iron), anti-inflammatory drugs targeting tumor necrosis factor alpha (hormone cacodyl, etanercept, infliximab, reactive stop, misoprostil), and probiotics and prebiotics (to prevent intestinal bacterial overgrowth, thereby reducing the production of endogenous ethanol and endotoxin in the gut and its associated hepatic oxygen stress and inflammatory damage). In addition, studies have investigated the therapeutic effects of non-specific hepatoprotective drugs (ursodeoxycholic acid) and Pancaspase inhibitors (prevention of apoptosis) on NASH. Although many small open trials have shown that these drugs can reduce serum ALT levels and even reduce liver histologic damage, there are no large randomized trials with placebo controls that have confirmed the efficacy of a drug for NASH in a long course. A histologically confirmed randomized placebo-controlled trial including 166 patients with NAFLD showed that 2 years of ursodeoxycholic acid treatment was not superior to the placebo group in terms of improved biochemical parameters and histology. Another large controlled trial of betaine also showed that the efficacy of the drug was not superior to that of the placebo control group. 3.2.3. Statin lipid-lowering drugs: Given the limited effectiveness of current drug therapy for liver injury in NASH patients, treatment of coexisting disease (including drug therapy) is very important. Most patients with NAFLD usually have indications for treatment with weight loss drugs, hypoglycemic drugs, antihypertensive drugs, and lipid-lowering drugs based on their underlying disease; on the other hand, patients with NAFLD often have abnormal serum transaminases and liver damage, and their ability to process certain drugs is reduced, and the incidence of pharmacogenic liver damage is likely to increase. For this reason clinicians often shy away from using statins to lower serum LDL cholesterol because of increased liver enzymes in patients with NAFLD. In fact, abnormal liver enzymes and hepatic insufficiency are not the same thing. The use of standard doses of statins in patients with elevated liver enzymes does not increase their hepatotoxicity, and abnormal liver function during statin therapy is usually a transient asymptomatic isolated increase in transaminases, which does not indicate significant statin-related liver injury. Therefore, statins are currently considered safe for the long-term treatment of dyslipidemia in patients with NAFLD/NASH without the need for intensive liver enzyme monitoring, and even mild increases in asymptomatic isolated transaminases (less than 120 U/L) during statin therapy do not require dose reduction or discontinuation. [6, 7] 3.3, bariatric surgery For patients with severe obesity, bariatric surgery is the safest and most effective treatment. Bariatric surgery can significantly reduce body weight and thus improve the disorders of glucolipid metabolism and its related complications. The early development of the jejuno-ileal short-circuit surgery is no longer used because of the rapid weight loss in a short period of time leading to increased inflammation and fibrosis of the liver. Currently, bariatric surgery such as gastroplasty can result in slow weight loss and is less likely to lead to malnutrition and related complications. Patients with combined NASH have significantly improved hepatic steatosis and inflammation and even fibrosis after bariatric surgery. In addition, bariatric surgery can reduce and alleviate obesity-related comorbidities such as diabetes, hypertension, dyslipidemia, sleep apnea syndrome, gastroesophageal reflux disease, degenerative joint disease, venous stasis, pseudotumor cerebri, urinary incontinence, and dyspareunia. There is no doubt that these promising bariatric procedures will be used more often in the management of patients with severe obesity for whom bariatric medication is ineffective. [5] 4. Treatment outlook Numerous studies have shown that even simple fatty liver with good prognosis cannot be regarded as benign stationary lesions. Due to the influence of genetic susceptibility and adaptive response mechanisms (potential increase in free fatty acids, depletion of mitochondrial energy reserves, upregulation of uncoupling protein (UCP)-2 expression, apoptotic protein expression, and hepatic astrocyte activation), their liver disease may still progress in a low-level subclinical state (silent steatohepatitis) and may promote IR and metabolic disorders by inducing systemic inflammatory responses and metabolic disorders. The development and progression of IR and metabolic disorders can be promoted by inducing systemic inflammatory responses and metabolic disorders. For this reason, measures to improve IR, reduce oxygen stress, improve hepatocyte viability, and antagonize the systemic inflammatory response are needed to prevent and treat FLD and related events. In addition to lifestyle changes, adjunctive pharmacological interventions vary from person to person. It is currently believed that the effect of weight loss drugs is not limited to weight loss, but new drugs should be developed in terms of the association between FLD and metabolic syndrome in order to improve metabolic disorders comprehensively, among which compelling ones are leptin-related compounds, β3-adrenergic receptor agonists, UCP-2 modulators, gastrointestinal hormones, peroxisome proliferator-activated receptor gamma antagonists, fatty acid oxidation modulators, and carboxypeptidase inhibitors. In order to treat FLD more effectively, we need to further elucidate its pathogenesis and natural history and strengthen the following aspects of research: (1) targeting anti-oxidative stress and reducing lipid peroxidation damage; (2) down-regulating cytochrome P450 (CYP)2E1 and CYP4A activities; (3) protecting hepatocyte energy reserves; (4) antagonizing inflammatory cytokine-mediated inflammation and fibrosis; (5) reducing hepatic tissue iron load, reversing hepatic (6) reduce hepatocyte apoptosis, but promote hepatic astrocyte apoptosis; (7) enhance intestinal mucosal screen function, regulate intestinal flora, and reduce intestinal-derived endotoxin-related injury; (8) promote hepatocyte regeneration and prevent heterogeneous proliferation and carcinogenesis; and (9) formal clinical treatment trials including dietary intervention and lifestyle changes. Research in these areas is expected to open up new avenues for effective prevention and treatment of FLD. However, unless policy makers, educators, pharmaceutical companies, employers, schools, and clinical and prevention personnel in related disciplines work together to promote a sensible diet and physical activity for all, and to make abstinence from alcohol a cultural norm, it will be difficult to stop the FLD epidemic and reduce the harms of FLD. In the face of the global challenge of FLD, we have a long way to go. In conclusion, obesity and its associated NAFLD have become an epidemic in the last decade, posing a serious threat to the health of both Eastern and Western populations. [2] For this reason, patients with obesity and glucolipid metabolism disorders need to be identified by liver enzyme testing and liver ultrasound, and patients with NAFLD need to be better monitored and managed for metabolic disorders. Despite the lack of results from randomized controlled trials, lifestyle changes are still considered essential in the management of NAFLD and its associated metabolic disorders; recent small clinical trials of liver disease in NASH patients have produced encouraging results, but more evidence and clinical safety data need to be accumulated before they can be recommended for the routine treatment of NASH; the management of coexisting diseases in NASH patients is essential to improve the prognosis of patients. The management of coexisting diseases in NASH patients is very important to improve the prognosis of patients, and statins and other drugs can be used safely according to clinical needs; bariatric surgery can be considered for patients with severe obesity who are not treated with bariatric drugs.