Therapeutic Approach to NAFLD-NASH

Abstract

Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) are the hepatic expression of metabolic syndrome and may lead to serious injury to the liver resulting in cirrhosis and hepatocellular carcinoma (HCC). Despite its seriousness, there is no definite treatment to address this life-threatening condition. Weight loss and exercise remain the cornerstone of the therapeutic treatment but also an array of medications can be used with varying degrees on liver inflammation and cirrhosis. There is also an increased risk of cardiovascular events connected to NAFLD/NASH, which should also be addressed. Statins have been shown to reduce the lipid and the inflammatory burden of the liver as well as decrease the cardiovascular risk. Aspirin also has a beneficial effect due to its anti-inflammatory properties as well as Vitamin E in certain cases. The medications (metformin, pioglitazone, GLP-1 agonists, SGLT2 inhibitors) that interfere in glucose metabolism and the activity of insulin seem to play a vital role in the metabolism of glucose and lipids and subsequent amelioration of liver function tests and the inhibition of inflammation. The aim of this review is to highlight the efficacy of current therapeutic strategies and explore the variety of the emerging new agents which target newly discovered pathways associated with the pathogenesis of NAFLD/NASH with promising results.

1. Introduction

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) describes a group of diseases that are characterized by hepatic steatosis without the excessive intake of alcohol. NAFLD/NASH may involve cirrhosis and/or hepatocellular carcinoma (HCC). NAFLD may be differentiated from the more benign state of the nonalcoholic liver to nonalcoholic steatohepatitis (NASH), which is the most serious manifestation of the disease. In the first case, hepatic steatosis presents without indication of inflammation, while in NASH hepatic steatosis is connected to lobular inflammation and apoptosis that may lead to fibrosis and cirrhosis [1] (Figure 1). Therapeutic management is divided into two kinds of measures: Lifestyle intervention and pharmacological/surgical treatment.

Figure 1.

NAFLD-NASH staging and progression.

2. Lifestyle intervention

2.1 Alcohol abstinence

Patients with NAFLD/NASH are suggested to avoid the use of alcohol and especially to avoid the abuse of it, e.g. fourteen drinks per week or over four drinks per day for male and over seven drinks per week or over three per day for female. The use of alcohol is connected to the progression of the disease [2].

2.2 Regulation of cardiometabolic risk factors

Patients with NAFLD/NASH have an increased risk of cardiovascular disease and they often have multiple risk factors (hypertension, diabetes, dyslipidemia, smoking) (Figure 2). The regulation and treatment of these factors have an ameliorating effect on the disease progression and reduce the overall risk of cardiovascular disease [3].

Figure 2.

Score chart: 10-Year risk of fatal cardiovascular disease (CVD).

2.3 Physical activity

For people with NAFLD/NASH, exercise is necessary since it regulates metabolism. These people frequently have a tendency towards obesity and metabolic syndrome, whether or not they also have type 2 diabetes. Additionally, they prompt sedentary lifestyles, which accelerates development [4]. According to reports, increasing daily exercise decreases obesity while increasing the metabolism of fatty acids and glucose. Exercise decreases hepatic fat content, as well as adipose tissue and plasma-free fatty acids, which form the pathophysiologic basis for these alterations. It has been demonstrated that activities with higher intensity and longer duration have a more significant impact on cardiometabolic morbidity and mortality as well as greater benefits for NASH and liver fibrosis [5].

2.4 Loss of weight/diet

The loss of weight is the main treatment for most patients with NAFLD/NASH. It is suggested for all patients that are overweight (BMI > 25 kg/m2) or obese (BMI > 30 kg/m2), because weight loss can lead to amelioration of liver function tests, histologic findings, and insulin resistance. It mainly consists of the restriction of intake calories through the decrease of the metabolism of carbohydrates Table 1. This reduces the glycemic load, and improves the pancreatic b-cell insulin secretion, it increases HDL-C and further decreases serum triglycerides and glucose [6]. The patients are consulted to lose 5 to 7% of the initial body weight with a rate of 0.5 to 1 kg per week. For patients with NASH (suspected or proven by biopsy), the target of weight loss is even higher (7 to 10% of the initial body weight). For some patients, an even greater body loss may be required. If the values of ALT are not normalized, after the achievement of the above-mentioned targets, they are advised to lose even more weight. It has been shown from several studies that at least 5% of the initial body weight is required for the improvement of the hepatic steatosis [7]. In a meta-analysis of eight studies, which include 373 patients, the loss of equal or more to 5% of body weight resulted in the improvement of hepatic steatosis, while the loss of at least 5% of body weight was correlated with a further amelioration of NAFLD/NASH [8]. The above changes need at least a timeline of 6 months to be implemented and reveal significant results.

Table 1.

Indicative diet for weight loss in NAFLD/NASH.

2.5 Bariatric surgery

Bariatric surgery is an option in patients unresponsive to lifestyle changes and pharmacotherapy. It is currently recommended for patients with BMI > 40 kg/m2 and no comorbidities, or in patients with BMI > 35 kg/m2 and serious comorbidities (T2DM, Hypertension, NAFLD/NASH). A review of 29 studies of patients that underwent bariatric surgery showed a significant improvement in liver function tests and a meta-analysis reported a decrease in steatosis, inflammation, and fibrosis [9, 10].

2.6 Immunization

Patients who do not have serologic verification of immunity should receive the hepatitis A and B vaccines. Pneumococcal vaccination and common immunizations offered to the public are additional vaccines for those with chronic liver disease.

3. Pharmacological treatment

Various pharmacological treatments had been studied for the management of patients with NAFLD/NASH (Figure 3). Most of these studies were very short and could not identify a target with important clinical result for the patients (e.g., noncompensated liver cirrhosis), instead referring to certain objective findings, e.g., levels of aminotransferases or histologic findings, often with conflicting results.

Figure 3.

Pathways in metabolism where pharmaceutical interventions are made.

3.1 Vitamin E

800 IU of vitamin E per day is typically advised for patients with biopsy-proven NASH and grade of fibrosis equivalent to or more than 2, who do not have diabetes mellitus. According to certain research, vitamin E helps these patients’ steatosis. Nevertheless, there are a variety of data and safety issues when vitamin E doses are administered, so potential risks and benefits of treatment with vitamin E should be explored and the decision to use vitamin E should be made on an individual basis [11]. The American Society for the study of liver diseases advises against the use of vitamin E in individuals with compensated liver cirrhosis and DM although studies that demonstrated the benefits of vitamin E treatment did include these patients. The use of vitamin E is supported by some but not all randomized research; however, inconsistent results may be attributed to variations in these studies’ design. A meta-analysis of five of these studies could not find histologic benefits with vitamin E, but there was significant heterogeneity among those studies concerning the synthesis of vitamin E that was used, the patient population, the study duration and lifestyle changes. Nevertheless, the biggest of these studies (pioglitazone vs. vitamin E vs. placebo for the treatment of non-diabetic patients with NASH-PIVENS) showed improvements with the use of vitamin E. The study included the randomization of 247 adults with NASH without DM, who received pioglitazone (30 mg per day), Vitamin E (800 IU per day) or placebo for 96 weeks. Patients who were treated with vitamin E, had a higher possibility to have an improvement in the FIB-4 score versus the ones who received placebo (43% vs. 19%) [12]. A meta-analysis of this study showed that the improvement in ALT was more frequent in patients who received vitamin E versus placebo (48% vs. 16%). This is consistent with observational studies that showed improvements in the levels of aminotransferases in patients with NASH that received Vitamin E [13]. This benefit is possibly related to the antioxidative qualities of vitamin E (Figure 4). The very high doses of vitamin E (>400 IU per day) have been co-related in conflicting results with the increase in mortality from other comorbidities. So, a very careful approach and individualization is advised. The use of vitamin E should be avoided in male patients with personal or familiar history of prostate cancer [14, 15].

Figure 4.

Action of Vitamin E in NAFLD/NASH.

3.2 Aspirin

There is some evidence that patients with NAFLD may benefit from taking aspirin daily. When 361 individuals with biopsy-proven NAFLD were recruited for a prospective cohort trial, those receiving daily aspirin treatment had a lower risk of developing NASH and fibrosis than those who did not get daily aspirin treatment [14]. Additionally, in a 3692-person trial, daily aspirin users were less likely to develop advanced fibrosis than non-users among 317 patients who did not have fibrosis at the time of recruitment. These results are very encouraging, and further research may provide evidence supporting aspirin’s hepatoprotective properties [16].

3.3 Statins

The use of statins (HMG-CoA inhibitors) has shown in various studies to improve biochemical and histologic findings in NAFLD/NASH and slow down the progress of fibrosis. These results are attributed to the decrease of the levels of cholesterol and triglycerides, achieved by using statins, as well as their anti-inflammatory properties (Figure 5). Moreover, they decrease the cardiovascular risk associated with fatty liver disease [16].

Figure 5.

Pathway of lipid metabolism and statin action in NAFLD/NASH.

Several data, demonstrating the beneficial effect of statins come from the post-hoc analysis of three perspectives, controlled survival studies. The post-hoc analysis of Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE), included 1600 patients, with coronary heart disease (CHD) and a mean observation time of 3 years. This analysis included 437 patients with NAFLD/NASH. Atorvastatin lowered the levels of serum aminotransferases, normalized the ultrasound imaging of the liver, and decreased cardiovascular events by 64 percent compared to the participants with NAFLD/NASH that did not take statins [17]. Three years later, the researchers of Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) concluded their post-hoc analysis. IDEAL was carried out in four Scandinavian countries and included 8864 patients with cardiovascular disease, of whom 7782 (87.8%) had normal levels of aminotransferases and 1081 (12.2%) elevated levels of ALT, possibly due to NAFLD/NASH. In the patients with elevated ALT, a dose of atorvastatin 80 mg per day, normalized those levels within safety compared to simvastatin 20–40 mg per day. The most important fact was that the patients who received atorvastatin 80 mg per day, suffered half the number of cardiovascular events, strokes and acute coronary events as those who were treated with simvastatin [18]. This shows that the clinical benefit of the treatment with a statin in NAFLD/NASH is a composite special effect and not the result of a class effect of a category of drugs. There was a post-hoc analysis of primary prevention of a multicenter prospective randomized controlled study: Assessing the treatment effect in Metabolic Syndrome Without Perceptible diabetes (ATTEMPT), that included 1123 patients with a mean observation of 4 years that had similar clinical and biochemical benefits with a higher dose of atorvastatin (30 mg per day) in 326 patients who had moderately elevated levels of hepatic enzymes and ultrasonographic findings of NAFLD. In all the above studies, the patients were included only if the level of aminotransferases were less than three times higher than upper normal levels [19, 20].

Due to the fact that there was no proof of the benefit of the statins in NAFLD/NASH based on liver biopsy, a pilot study was conducted on 20 subjects to evaluate the effect of 10 mg per day of rosuvastatin in biopsy-proven NASH. A year later, 19 of 20 patients, showed a total remission of NASH in new biopsy findings with subsequent normalization of liver enzyme and ultrasonographic findings. Another study from Italy with 107 patients with biopsy-proven NASH showed benefits from statin therapy, as well as a larger study with participants from Italy and France.

In a study performed on 5400 military personnel in Northern Greece, the NASH and FIB-4 scores were used to identify the ones that had NASH and NAFLD/NASH. Their final number was 613 (541 males and 72 females). These subjects were also confirmed to have NAFLD by ultrasonographic findings. They were subsequently divided into four categories: a control group, a group that received rosuvastatin, a group that received atorvastatin and a group that received pitavastatin. The dose of the statins was treated according to individualized LDL-C goals. The results of this study showed a clear benefit in all statin groups compared to the control group, after one year of treatment, which was manifested in the improvement of NASH and FIB-4 scores as well as of the levels of aminotransferases. It should be stressed that the beneficial results of the use of statins were equally important to the subjects without metabolic syndrome, compared to the ones with metabolic syndrome, proving that the use of statins may have a crucial effect on the management of patients with a genetic disposition to present with NAFLD/NASH, independently of the presence of metabolic syndrome [20].

3.4 Ω3-Fatty acids

Studies have suggested that people with NAFLD can benefit from the usage of 3-fatty acids. Treatment with 3-Fatty acids was observed to ameliorate hepatic steatosis as well as the levels of AST in a meta-analysis of nine studies involving 355 individuals. Additionally, there was a tendency for the levels of ALT to rise. Only hepatic steatosis continued to improve with therapy with omega-3 fatty acids when the analysis was limited to randomized trials [21, 22].

3.5 Anti-diabetic drugs

Anti-diabetic medications have been shown to improve outcomes in NAFLD/NASH and consequent liver fibrosis, even without an established diagnosis of diabetes mellitus. This is to a different degree due to their mechanism of modification of the metabolic syndrome (Figure 6), the cellular sensitization of insulin, and the effect of insulin itself on tissues.

Figure 6.

Pathogenesis of metabolic syndrome.

3.6 Metformin

The principal treatment for diabetes mellitus type 2 is metformin, which is still recommended in all guidelines unless it is contraindicated. It is the primary cellular insulin sensitizer, interfering with insulin resistance, the primary pathophysiologic mechanism of type 2 diabetes [23]. Inhibiting hepatic gluconeogenesis, a supplementary method to promote normal serum glycemia is another effect of it (Figure 7). Hypertriglyceridemia is also improved by bringing glucose levels back to normal. Metformin uses improved liver ultrasound imaging and the levels of aminotransferases, particularly ALT, according to a meta-analysis of 13 prospective trials, but it did not significantly enhance all patients’ histologic findings. Larger studies must be conducted and for a longer period because the number of patients included in these studies was relatively small and they were followed up for a brief period of time (in most cases 6–12 months). This will allow for a better evaluation of the effectiveness of metformin on NAFLD/NASH [24].

Figure 7.

Action of metformin in multiple sites.

3.7 Peroxisome Proliferator-Activated Receptors (PPAR)

The only medication in this class that is currently in use is pioglitazone. It is regarded as an activator of the PPAR nuclear receptor of the PPARγ subgroup, which is mostly expressed in adipose tissue and associated with the reduction of inflammation, adipocyte differentiation, and lipid and glucose metabolism (Figure 8). Pioglitazone possibly increases peripheral insulin sensitivity by inducing the release of adipokines, promoting the storage of triglycerides in adipose tissue, and boosting insulin’s inhibitory effect on lipolysis. These have the effect of decreasing plasma levels of free fatty acids and causing the liver to reabsorb lipids [25]. Throughout these pathways, it enhances hepatic and peripheral insulin sensitivity and influences the pathophysiology and development of NASH in a beneficial way [13, 26]. The PPARγ sensitizers were reported to improve the hepatic histologic findings of ballooning, lobular inflammation, and steatosis in a meta-analysis that compared the use of Thiazolidinediones to placebo in 334 individuals, but no significant improvement of fibrosis was detected. The favorable benefits were reversed following drug termination, which is proof that a prolonged course of treatment is necessary to provide a substantial benefit [26, 27].

Figure 8.

Action of PPAR sensitizers in NAFLD/NASH.

Apart from PPARγ agonists, there also are other members of the drug family (PPARα and PPARδ) agonists which are expressed mostly in oxidative tissues and are deeply involved in mitochondrial biogenesis and metabolism, fatty acid oxidation, ketogenesis, and fatty acid uptake-triglyceride metabolism. Elafribranor, a dual PPARα—PPARδ agonist, has been proven in animal models to enhance lipid and insulin metabolism and lessen hepatic inflammation and fibrosis. In animal models, the drug Lanifribranor has demonstrated improved glucose metabolism and decreased steatosis. Saroglitazar, a dual PPARα/γ agonist, also increased insulin sensitivity in people with type 2 diabetes. It also decreased hepatic steatosis and inflammation while preventing fibrosis in animal models. All of these agents are tested in ongoing trials [28, 29, 30].

3.8 GLP-1 agonists and DPP-4 inhibitors

GLP-1 is an endogenous hormone of the intestine which acts through the G-protein coupled GLP-1 receptor (GLPR). This directly stimulates the production and release of insulin while simultaneously inhibiting glucagon secretion and reducing food intake. The half-life of GLP-1 in the plasma circulation is only 1–2 minutes, due to the action of dipeptidyl peptidase (DDP-4) which inactivates GLP-1. The enhancement of the action of GLP-1 receptors using GLP-1 receptor agonists has a beneficial effect on the treatment of diabetes based on the lowering of serum glucose (Figure 9). These positive effects on glucose homeostasis coupled with the achievement of weight loss manage to reduce hepatic inflammation and steatosis and to improve liver function tests. The treatment of patients with diabetes melitus type 2 with either exenatide, liraglutide, or semaglutide has proved efficient in the improvement of hepatic steatosis, level of aminotransferases, and inflammatory markers. This effect was clearly associated with the levels of HbA1C and body weight loss. In a study including 52 patients with NASH, who received liraglutide or placebo for 48 weeks, a biopsy was performed at the end of treatment in 23 patients receiving liraglutide and 23 patients receiving placebo. Steatosis was improved in nine patients (39%) receiving liraglutide compared to two patients (9%) receiving placebo. These patients were also less likely to present with the progression of fibrosis. Furthermore, compared to the patients that received placebo, the patients with NASH who received semaglutide achieved a greater percentage of resolution of steatosis with no worsening of fibrosis. More studies are underway with the intention to determine the efficacy of these medications in the treatment of NASH with or without cirrhosis [31, 32, 33].

Figure 9.

Action OF GLP-1 agonists In ANFLD/NASH.

The inhibition of DDP-4 has also been a subject of study. DDP-4 inhibitors have shown to reduce hepatic inflammation, fibrosis, and cirrhosis development in animal models. The problem is that the use of sitagliptin did not prove beneficial during the study of the treatment of NAFLD in humans, despite its favorable metabolic effect [34].

3.9 SGLT2 inhibitors

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a group of sodium-depended glucose transporters which are primarily expressed in the proximal tube epithelium of the kidney and are responsible for the majority (over 90%) of filter glucose reabsorption. Inhibitors of the SGLT2 result in the increased urinary excretion of glucose and the subsequent decrease of serum glucose levels. Their use has been shown to achieve weight loss in many people due to the extensive fluid excretion and the reduction of cardiovascular risk [35].

The above effects have shown that treatment with either Canagliflozin, Empagliflozin, or Dapagliflozine reduced hyperglycemia followed by lower levels of liver enzymes and improvement of liver steatosis. It is hypothesized that the weight loss caused by SGLT2 inhibitors was strongly associated with these effects since SGLT2 is not expressed in the liver (Figure 10). A large retrospective study showed a comparative advantage in the use of Canagliflozin and Dapagliflozin in the improvement of hepatic level enzymes independently of body weight loss and HbA1C reduction. More studies with histologic evaluation need to be conducted to evaluate the usefulness of these agents in NAFLD/NASH [36, 37].

Figure 10.

Potential action of SGLT2 in liver and contribution in NAFLD/NASH treatment.

3.10 Combination treatment

There are currently no randomized clinical trials concerning the combination of treatments mentioned above. From various observation studies, it has been demonstrated that the combination of different treatment methods may have an additional benefit for the patient with NAFLD/NASH compared to individual treatments alone, but further studies should be conducted in that direction. In everyday clinical practice, a combination of different strategies, for example, diet with metformin and statins, is very common, considering that it is the treatment indicated for the conditions which are causally linked to the pathogenesis of NAFLD/NASH.

3.11 Emerging treatments in NAFLD/NASH

Apart from the established treatments, that have been discussed above, there have been also other therapeutic agents that have been shown to be promising in the treatment of NAFLD/NASH (Figures 11 and 12). These agents interfere in various stages of the metabolic pathway and may show significant results in improving the radiologic and histologic findings [36].

Figure 11.

Metabolic pathways in inflammation in NAFLD/NASH and potential sites of action for new pharmaceutical agents.

Figure 12.

Metabolic pathways of lipids in NAFLD/NASH and potential sites of action for new pharmaceutical agents.

3.12 Modulation of nuclear transcription factors

Nuclear transcription factors are molecules that bind to their specific ligand and regulate transcription of specific genes and therefore have a beneficial metabolic effect and possibly therapeutic result in the treatment of NAFLD/NASH.

3.13 Farnesoid X receptor agonist

A crucial regulator of metabolic pathways, including glucose homeostasis, inflammation, and fibrosis, is the farnesoid X receptor (FXR). In patients with NASH, the level of hepatic FXR expression is closely associated with the disease’s severity. The liver, kidneys, gut, and adrenal glands all express it. It controls the metabolism of lipoproteins and participates in the production and enterohepatic circulation of bile acids. Bile acid synthesis, hepatic lipogenesis, cholesterol synthesis, and glucose homeostasis are all directly impacted by FXR activation. In animal models, the treatment of FXR agonists has been shown to resolve steatohepatitis and fibrosis as well as prevent the development of NASH. For the treatment of NASH, several synthetic FXR agonists are currently being developed [38].

Bile acids are cholesterol metabolites that are produced in the liver and absorbed from dietary lipids. Type 2 diabetes mellitus raises their levels. In animal models, nor-ursodeoxycholic acid, a synthetic bile acid homolog, has been demonstrated to decrease liver enzymes, fibrosis, and inflammation. Obeticholic acid (OCA), a different modified bile acid, activates the FXR in individuals and raises insulin sensitivity. The FLINT trial, a double-blind placebo, controlled, randomized clinical trial assessed the effectiveness of OCA in patients with NASH without cirrhosis and NAFLD activity score (NAS) > 4 for 72 weeks. Most of these patients had a decrease in the indices of liver fibrosis and inflammation, but they also showed elevated levels of LDL-C, insulin, and a decrease in HDL-C. Because of this, the improvement in liver markers was offset by a worsening of the lipid profile, which required statin therapy. Another ongoing trial (REGENERATE) also demonstrated a slight reduction in fibrosis as compared to placebo, although it did not completely reverse NASH [39].

Tropifexor is another very potent non-bile acid agonist of FXR, which has been shown to be very effective in NASH in animal models and it is under evaluation [40, 41].

3.14 THR-β agonists

THR-a and THR-b are the two isoforms of the nuclear receptor known as the thyroid hormone receptor (THR). The main liver isoform, THR-b, enhances hepatic fatty acid oxidation and lowers steatosis and hyperlipidemia in animal models, whereas THR-a is important in cardiac function. These agonists, e.g., Resmetirom, have been employed in ongoing studies and have demonstrated a favorable impact on NAFLD [42].

3.15 Inhibitors of de novo lipogenesis

3.15.1 ACCs inhibitors

Acetyl-Coa carboxylases (ACCs) promote de novo lipogenesis through the conversion of Acetyl-CoA to Malonyl-CoA, which is a signaling molecule that suppresses fatty acid oxidation. Thus, ACC inhibition reduces lipid accumulation in the liver and stimulates fatty acid oxidation, improving hepatic steatosis and insulin sensitivity in studies in animal models and humans. The problem that arises, is that it also causes hypertriglyceridemia which may further worsen NAFLD [43].

3.15.2 FAS inhibitors

Malonyl-CoA is used by the enzyme fatty acid synthase (FAS) to create saturated long-chain fatty acids. In NAFLD, the enzyme’s hepatic expression and activity are botH extremely high, and its suppression results in lower liver lipid levels and improved insulin sensitivity. Therefore, FAS inhibition reduces hepatic steatosis and de novo lipogenesis [44].

3.15.3 SCD-1 inhibitors

Stearoyl-CoA Desaturase-1 (SCD-1) transforms saturated fatty acids into mono-unsaturated fatty acids and is widely expressed in adipose tissue and the liver. In NAFLD patients, it is quite active. This inhibition leads to reduced steatosis and improvement of insulin sensitivity [42].

3.15.4 DGAT inhibitors

Diacylglycerol acyltransferase (DGAT) catalyzes the esterification of fatty acids. The inhibition of the two isoforms of the enzyme resulted in lower levels of hepatic free acid, glucose, hepatic steatosis, and inflammation [45, 46, 47].

3.15.5 Ketohexokinase inhibitors

An enzyme called ketohexokinase encourages the phosphorylation of fructose to fructose-1-phosphate. Fatty acid oxidation enhanced de novo lipogenesis, hepatic steatosis, and inflammation that are brought on by the enzyme’s overactivation. Its blockage yields promising outcomes in resolving all the above procedures [46, 47].

3.15.6 MPC inhibitors

The mitochondrial pyruvate carrier (MPC), a combination of two proteins, is crucial for the lipogenesis process in which carbohydrates are converted to fatty acids. Clinical investigations have shown that MPC inhibitors increase insulin sensitivity, reduce liver steatosis, and lower liver enzyme levels.

3.15.7 FGF (Fibroblast growth factors)

FGF19 is a gastrointestinal hormone that regulates the synthesis of bile acids, the metabolism of glucose, and the oxidation of fatty acids in the liver. FGF19 levels are decreased in NASH patients. Hepatic steatosis and liver enzymes were successfully reduced by the injection of FGF analogs. Another hormone that affects metabolism and energy expenditure is FGF21. Elevated FGF21 levels in NAFLD patients are adversely correlated with reduced insulin sensitivity. High doses of recombinant FGF21 were given to reduce body weight, enhance glucose sensitivity, and change liver and plasma lipid levels [48, 49].

3.15.8 Gut microbiome

The gut microbiome produces substances that are involved in several metabolic pathways and affect the activity of certain metabolites such as bile and fatty acids. Additionally, it is known to play a role in the metabolism of lipids and carbohydrates [50, 51, 52]. Numerous studies have demonstrated that the treatment with probiotics, prebiotics, and synbiotics that affect the gut microbiota, may reduce insulin resistance and hepatic inflammation (Figure 13). In addition to these, fecal microbiota transplantation (FMT) is being extensively researched and appears to have great promise for the treatment of NAFLD/NASH [51, 53].

Figure 13.

Gut microbiota and its role in NAFLD/NASH.

4. Conclusions

Nonalcoholic fatty liver disease and its evolution, Non-alcoholic steatohepatitis, constitute a serious cardiometabolic inflammatory process of the liver. Lifestyle modifications such as continued gradual weight loss and exercise are the cornerstone of the therapeutic treatment and have a profound beneficial effect on liver function tests and the co-existing cardiovascular risk. Bariatric surgery could also be advised for certain patients. Several medications have been tried for the treatment of NAFLD/NASH, especially medications that ameliorate the metabolic profile of the patients, insulin sensitivity and lipid oxidation, thus decreasing the lipid burden and improving steatosis and inflammation. Certain new agents have also been under development and show quite promising in the treatment of this complex condition. The implementation of a variety of new agents that target the mechanisms of inflammation and fibrosis in the pathogenesis of NAFLD/NASH will lead us to new effective treatments that will halt the acceleration of the disease and restore normal physiology of the hepatic tissue. Combination therapies may offer a further beneficial effect, but further studies need to be conducted to prove their efficiency.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations

BMI	Body Mass Index BMI
SBP	Systolic Blood Pressure
DBP	Diastolic Blood Pressure
CHOL	Cholesterol
LDL-C	LDL-cholesterol
HDL-C	HDL-cholesterol
TGs	triglycerides
HbA1C	glycated hemoglobin
AST	aspartate transaminase
ALT	alanine transaminase
NAFLD	non-alcoholic fatty liver disease
NASH	non-alcoholic steatohepatitis
FIB-4	Mass fibrosis assessment scale.