Non-Alcoholic Fatty Liver Disease (NAFLD) and its Recent Therapeutic Strategies

 

Nikunja Kishor Mishra*, Amiyakanta Mishra, Rosy Priyadarshini

College of Pharmaceutical Sciences, Puri (Affiliated to Biju Patnaik University of Technology), Baliguali,

Puri - Konark Marine Drive Road, Puri - 752004, Odisha, India.

*Corresponding Author E-mail: montu.mph@gmail.com

 

ABSTRACT:

Non-alcoholic fatty liver disease (NAFLD) is a serious health issue globally. It includes a broad spectrum of alteration from simple steatosis to steatohepatitis and cirrhosis. Obesity and type-2 diabetes mellitus (T2DM) are the major factors that are associated with progression of NAFLD. The disease has been proven to have a higher incidence of hepatic and cardiovascular complications. The aetiopathogenesis is still unclear; however some of many pathophysiological mechanisms that are involved in the development of NAFLD include fatty-acid accumulation in hepatic parenchyma, impaired mitochondrial metabolism, inflammation, oxidative stress, oxygen free radicals. Liver biopsy is the diagnostic gold-standard for NAFLD, but multiple non-invasive techniques like serological biomarkers and radiological techniques have established a new field for research. Since several inter-related pathways are involved in the pathological process, a single therapeutic agent is not helpful. Therefore, a combination therapy towards multiple targets could control the NAFLD. Various new targeted therapies includes apoptosis signal regulating kinase-1(ASK1) inhibitor, FXR (Farnesoid X receptor)-agonists, Caspase Inhibition, SCD-1(Stearoyl coenzyme A desaturase -1) enzyme inhibitors, SIRT1 (Sirtuin1) activator, CCR2 (chemokine receptor 2) and CCR5 (chemokine receptor 5) inhibitors, DPP-4 (Dipeptidyl peptidase-4) inhibitors and NOX (NADPH oxidase)-1/4 inhibitors that are currently under investigation. The treatment for patients with NAFLD is mainly based on loss of body weight and adjuvant management by using insulin sensitizer, anti-oxidants and reducing inflammation. The development of a healthy lifestyle and moderate exercise may be pillars for the treatment of NAFLD.

 

KEYWORDS: NAFLD, Steatosis, Steatohepatitis, Obesity, Insulin sensitizer.

 

 

INTRODUCTION:

A nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases all over the world. It is reported that approximately 25% population is affected by NAFLD globally where as this rate is about 34% in united state.1 The NAFLD can develop a wide variety of clinical and pathological manifestation associated with hepatocyte necrosis, hepatic steatosis, insulin résistance or diabetics.2-5

 

The prevalence of NAFLD is 34% in general population, being much higher in obese patient.6

 

According to histology, NAFLD is established when hepatic fat accumulation is > 5% of hepatocytes and can be presented with a spectrum of diseases including non-alcoholic steatohepatitis (NASH), fibrotic NASH, non-alcoholic fatty liver (NAFL) and hepato cellular carcinoma (HCC).7

 

GLOBAL BURDEN OF NAFLD:

In USA, the prevalence of NAFLD can vary by the ethnicity. However, there has been extensive research to accurately determine the prevalence of NAFLD in USA.8 The incidence of non-communicable diseases has been increased all over the world during the last decades because of public lifestyle modification. NAFLD is related to the burden of liver diseases paralleling the world wide increase of obesity and type-2 diabetes mellitus (T2DM). The global prevalence of NAFLD is currently calculated to be 24%; however, the diagnostic tools that are used are inaccurate.9 Sometimes the levels of alanine amino transferase (ALT) or aspartate aminotransferase (AST) are variably elevated in NAFLD and may be normal in 50-80% of cases.10 Even the Ideal standard in NAFLD diagnosis is a liver biopsy - might give some variability due to use of liver fragment in histopathological examination.11 At recent the liver transplantation is the best therapy for the patient suffering from acute or chronic liver failure however, the disproportion between recipients and donors is still an ongoing problem.12 The individuals with early stage NAFLD a greater improvement is observed after life –style modification and weight loss at regular exercise. However at advanced NAFLD stages, the prescriptions of drugs are highly recommended to reduce hyperlipidemia and insulin resistance.13-15

 

PATHOGENESIS:

The pathogenic mechanism of NAFLD is associated with insulin resistance. A double impact theory is involved in the pathogenic mechanism of NAFLD. At first impact the reduction in cellular capacity to respond to the insulin action leads to compensatory hyperinsulinemia. In adipose tissue because of hyperinsulinemia it acts on the hormone-sensitive lipase (HSL) which leads to lipolysis and release of free fatty acids (FFA) to the liver. Utilization of glucose in the skeletal muscle decreases and hyperinsulinemia develops gluconeogenesis, decrease glycogen synthesis, increase uptake of FFA and alters the transport of triglycerides such as VLDL and also inhibits the β-oxidation process in hepatocyte (Figure 1). These alterations in the fats metabolism are the basis of fatty liver diseases.16 The whole process in first impact results in hepatic resistance to leptin or reduction of adiponectin levels. 

 

The second impact generates the oxidative stress in hepatocytes; this is initially compensated by antioxidant mechanism present in the cell. Because of overloading of FFA at liver generates oxygen free radicals (OFR) in the mitochondria chain which acts upon the fatty acids of the cell membranes and produces lipid peroxidation. OFR induce synthesis of cytokine such as tumor necrosis factor-α (TNF-α), IL-6 and IL-8 which leads to hepatocyte apoptosis. The end products of lipid peroxidation 4-hydroxynonenal (HNE) and malondialdehyde (MDA) induced liver damage due to direct toxicity.17-21 Various clinical situations have been associated with NAFLD (Table 1).22 However, the histological signs of fatty liver disease (FLD) are found in obese person and diabetes meletus.23

 

NAFLD DIAGNOSIS:

Liver biopsy:

The current gold standard for diagnosis of NAFLD is by liver biopsy. Liver biopsy differentia the patients according to the severity of steatosis, stage of fibrosis and degree of inflammation.24 The NASH clinical research recently developed a new scoring system which can differentiate between FLD and NAFLD and assess fibrosis in five stages (Figure 2).25

 

Table 1: Various causes associated with NAFLD

Sr. No.

Classification

Causes

1

Metabolic diseases

Obesity, Hyperlipidemia, Diabetes mellitus, Wilson diseases

2

Drugs

NSAIDS

3

Extra hepatic conditions

Heart failure, pregnancy, Hypothyroidism, Neoplastic diseases

4

Nutritional conditions

Prolong fasting, Protein malnutrition, Carbohydrate diet

5

Infections

HIV infections and Hepatitis B and C

NSAIDS : Nonsteroidal anti-inflammatory drugs; HIV: Human immunodeficiency virus

 

 

Figure 1: Multi pathological and interrelated pathways of NAFLD

 

Figure 2: Scoring system of hepatic fibrosis as per the NASH clinical research

 

Serum/ biochemical markers:

a.     Interleukin-6 (IL-6):

NAFLD is observed with elevated serum IL-6. In case of severity of hepatocyte inflammation with NASH patient IL-6 is positively correlated.26

b.    Serum aminotransferase:

Serum aminotransferase is a widely used surrogate biomarker for the ongoing hepatic inflammation. It also provides information about the hepatic function, disease progression and extent of hepatic damage. ALT and AST levels are found to be increased in hepatic diseases usually. However, patients with NAFLD may have normal transaminase levels. The ratio of AST/ ALT higher than one or more indicates liver damage.27-29

c.     Serum cytokeratin (CK)-18:

It is widely investigated for diagnosis of NASH. The cut off value of CK-18 > 240 U/L indicates hepatic necrosis or apoptosis and a new marker of apoptosis and severity index of NAFLD.30

d.    Serum adiponectin:

Adiponectin is an adipocyte-secreted protein that circulates in higher concentration in the serum and is involved in glucose and lipid metabolism. It is a negative predictor of NASH in fatty liver patients with a cut off value 29.16µg/L.31

e.      Tumor necrosis factor alpha (TNFα):

The patient with high level of TNFα has increased the burden of NAFLD. It is also elevated in patients with NASH.32

f.      Plasma pentraxin 3 (PTX3):

In the case of NAFLD a higher serum concentration of PTX3 level is seen in patient. This indicates more advanced stages of the NAFLD.33

g.     Proprotein convertase subtilisin/ Kexin type 9(PCSK9):

PCSK9 which is secreted from hepatocytes inhibits the uptake of low-density lipoproteins (LDL) by targeting the receptor for degradation. However, recent study indicates that the circulating PCSK9 increases with hepatic fat accumulation and indication of severity of hepatic steatosis.34

 

TREATMENT:

A multi-disciplinary therapy (combination of drugs) in NAFLD is taken into consideration in order to counteract pathological risk factors. These are listed in Table 2 and are discussed below.

Pharmacological therapy for NAFLD:

Insulin Sensitizers:

The NAFLD is closely associated with Insulin resistance (IR). Therefore, the potential therapeutic effects of insulin sensitizers have important roles. Thiazolidinediones (TZDS) are peroxisome proliferator- activated receptor (PPAR) – γ agonist and increase insulin sensitivity.

 

In randomized control trials administration of 30 or 45 mg/day pioglitazone induced significant improvement in serum aminotransferase levels and liver histology as compared with placebo NASH patients. A marked improvement in the extent of fibrosis was not observed. American guidelines for NAFLD have recommended the use of pioglitazone in patients with biopsy-proven NASH.35 However, pioglitazone have several side effects including the risk of edema, heart failure, weight gain and reduction of bone density in women. In addition also it is reported that risk of bladder cancer is increased if pioglitazone is used for above 2- years. Therefore, use of this drug is prohibited in France and Germany. Similarly, Rosiglitazone uses are also prohibited in Europe and restricted in United States.35 

 

Table-2: Various treatment options for NAFLD and NASH

Pharmacological therapy

 

 

 

 

 

 

Insulin sensitizer (Thiazolidinediones)

 

GLP -1 receptor agonist (Liraglutide)

 

Oxidative stress and inflammation regulating agents (ARBs, N- acetyle cystine, α- Tocopherol, UDCA, Pentoxifylline, Betaine)

 

DPP-4inhibitors (Sitagliptin and Vidagliptine)

 

Lipid lowering agents (Statins)

 

Weight loss medications (Orlistat, Lorcaserin and liraglutide)

 

New therapeutic agents (Caspase Inhibition, ASK1 inhibitors, NOX-1/4 inhibitors, FXR-

 

agonists, SCD-1enzyme inhibitors, CCR2 and CCR5 inhibitors, SIRT1 activator)

 

Non-pharmacological

therapy

Change in lifestyle and exercise

Bariatric Surgery

GLP -1: Glucagon like peptide 1, ARBs: Angiotensin II receptor blockers, UDCA: Ursodeoxy cholic acid, DPP-4: Dipeptidyl peptidase-4, ASK1: Apoptosis signal regulating kinase-1, NOX : NADPH oxidase, FXR: Farnesoid X receptor, SCD 1: Stearoyl coenzyme A desaturase 1, CCR: Chemokine receptor, SIRT1: Sirtuin1

 

Metformine is an oral biguanide that is approved to treat type-2 diabetes mellitus. It reduces the hepatic endogenous glucose production and limiting triglyceride production.36 In pilot studies metformine was shown to improve fatty liver diseases, steatosis and aminotransferase abnormalities in a mouse model of NAFLD.36

GLP (Glucagon like peptide)-1 receptor agonist:

GLP-1 is an intestinal incretin hormone that is secreted after intake of high sugar and high fat food. GLP-1 activates the pancreatic response, increases insulin synthesis and inhibits glucagon synthesis.37 Among existing therapies for type-2 diabetes, incretin mimetics which are glucagone like peptide-1 receptor (GLP-1R) agonists was approved for glycamic control in over weight patient. Liraglutide is a long acting GLP-1 analogue which is metabolized much more slowly by the dipeptidyl peptidase-4 (DPP-4) enzyme. The new generation of GLP-1 agonist semaglutide is currently under investigation for the treatment in obesity and NASH. A new study indicates that subcutaneous administration of semaglutide resulted in a significantly higher percentage of patients with NASH than placebo. However, the trial did not show a significant improvement in the fibrosis stage.38

 

Oxidative stress and inflammation regulating agents:

Oxidative stress is associated in the pathogenesis of the NAFLD, so antioxidants may reduce the hepatic damage caused by free radicals.

a.     Angiotensin II receptor blockers (ARBs):

      Telmisartan is an angiotensin receptor blocker type-II, which has demonstrated effects of PPAR-a (Peroxisome proliferator-activated receptor-a) activators on the liver along with improvement in cytolysis and necroinflammation. It also inhibits the proliferation of stellate cells and reduces inflammation and fibrosis.39

b.    N- acetyle cystine :

      N- acetyle cystine increases glutathione levels in the liver. As a result the increased glutathione gives protection to the liver from oxidative stress. It also reduces the histological inflammation.40

c.     α- Tocopherol:

      It is also known as vitamin E which inhibits the intra-hepatic expression of TGF-β (Transforming growth factor –β), lipid peroxidation and superoxide anion formation and suppression of pro-inflammatory cytokines such as TNF- α. Vitamin E increases efficacy along with thiazolidinediones, metformine or UDCA (Ursodeoxy cholic acid).

d.    Ursodeoxy cholic acid (UDCA)

      It is a bile acid with cytoprotective and having membrane stabilizing property which appears to decrease AST (aspartate amino transferase) otherwise known as SGOT (serum glutamic oxaloacetic transaminase). However, the randomized control studies that proves a histological improvement in the NAFLD patients.41

e.     Pentoxifylline

      It inhibits the synthesis of TNF- α and therefore has a favorable effect on liver enzyme activity by inhibiting lipid oxidation. Pentoxifylline is dose dependant and its activity is reversing when treatment is stopped.42

 

f.      Betaine

      It is metabolites of choline which protects the liver from triglyceride deposition and oxidative stress by increasing the levels of S- adenosylmethionine.40

 

DPP-4 (Dipeptidyl peptidase-4) inhibitors:

DPP-4 enzyme is responsible for degradation of endogenous GLP-1. Therefore, DPP-4 inhibitors such as sitagliptin and vidagliptine extend the half-life and improve the activity of this peptide.

 

Lipid lowering agents:

Satins are the lipid lowering agents which cause competitive inhibition of HMG-CoA reductase which leads to decrease in LDL in the blood.  A recent study revealed a significant and decrease in the serum aminotransferases and lipid levels with the treatment of atrovastatin.43

 

Weight loss medications:

Orlistat is a pancreatic lipase inhibitor which is available as an over the counter formulation (60mg) or with prescription 120mg capsules. It improves plasma aminotransferase insulin resistance and weight loss.44

 

Lorcaserin is a selective serotonin 2 c (5HT2c) receptor agonist and appetite suppressant that reduces the body weight by ~ 4% at 1 year in conjugation with lifestyle intervation45 ~ 10% weight loss compared to placebo at 1 year was reported with the combination of the sympathomimetic amine phentermine (Qsymia) at dose 15mg.46 A high dose of liraglutide (3 mg per day, Saxenda) has been approved by the FDA for the treatment of obesity by reduction of 8.5% weight after 56- weeks.47

 

Caspase Inhibition:

Caspase are the enzymes which are required for completion of various apoptotic pathways and for stimulation of cytokines. Emricasan, a pancaspase protease inhibitor has been shown to inhibit inflammation fibrosis and apoptosis in animal model.48 In NAFLD patients a phase-II clinical trial showed a significantly decreased serum ALT and CCK18 (Caspase cleaved cytokeratin 18) levels.49

 

ASK1 inhibitors:

Apoptosis signal regulating kinase-1(ASK1) is a mitogen activated protein 3 kinase which induces apoptosis and fibrosis after activation by ROS. GS4997, an oral small molecule ASK1 inhibitor administered to animals with NASH and the result conformed about significant reduction in body weight, fasting blood glucose, insulin resistance, lipogenesis, cholesterol biosynthesis and plasma AST/ALT levels.50,51

 

 

NOX-1/4 inhibitors:

NADPH oxidase (NOX) is an enzyme which catalyzes the production of ROS. In various preclinical studies indicate that these enzyme promote liver fibrosis and inflammation. GKT137831 is a NOX-1/4 inhibitor significantly decreases the ROS production and can have beneficial effect in decreasing liver fibrosis in NASH patients.52

 

FXR (Farnesoid X receptor)-agonists:

FXR is a nuclear hormonal receptor which regulates lipid metabolism, cholesterol, glucose and bile acid synthesis. The primary function of FXR activation is involved in the suppression of cholesterol-7alpha-hydroxylase, the rate–limiting enzyme in bile acid synthesis from cholesterol. These receptors are associated with the various pharmacological activities by inhibiting gluconeogenesis, glycogenolysis, lipogenesis, maintaining cholesterol balance and improving insulin sensitivity.  Obeticholic acid is a synthetically modified bile acid and potent agonist of FXR that is used to treat liver diseases. In a small clinical trial (pilot study) of diabetic patients having NAFLD, it was observed to decrease weight and serum γ-glutamyl transferase levels as well as improve in liver fibrosis.53 

 

SCD-1 (Stearoyl coenzyme A desaturase -1) enzyme inhibitors:

Aramchol is a conjugation of cholic acid and arachidonic acid. It is a synthetic lipid molecule which decreases lipogenesis and increases fatty acid oxidation by inhibiting SCD-1enzyme.54 The drug was found to decrease significantly liver fat in 60 NAFLD patients who were given 100 or 300 mg of aramchol per day for 3 months. However, a phase-II clinical trial of this drug is going on NASH. Patient having fibrosis (Clinical Trials. gov Identifier: NCT02279524).

 

CCR2 and CCR5 inhibitors:

Cenicriviroc (CVC) is an inhibitor of CCR2 and CCR5. These receptors are mainly expressed in various immune cells like natural killer cells, macrophages, monocytes, kupffer cells, T cells and also stimulate hepatic stellate cells which lead to promotion of fibrosis. At various animal models (diet induced NASH) CVC has shown to decrease fibrosis.55,56,57 At clinical trial phase-II study CVC treatment also blocked CCR2 and CCR5 and improve fibrosis and histological feature in NAFLD.58,59

 

SIRT1 activator:

SIRT1 (Sirtuin1) is an information regulatory protein found in mammals. It has anti-inflammatory effect and increase insulin secretion.60 A decrease in liver expression of SIRT1 was observed in an animal model of NAFLD.61 Resveratrol is a natural compound which activates SIRT1 was shown to improve insulin sensitivity.62 This could be a potential target for the treatment of NAFLD.

 

Non-pharmacological therapy:

Change in lifestyle and exercise:

Dietary modification plays an important role in the reduction of body weight and obesity (both in pediatrics and adults). The best way to lose body weight is to change in eating behavior and reducing caloric intake. Regular exercise, like 30-45min/day at a steady pace may improve insulin sensitivity.63-67 A food rich in omega-3 fatty acid (Fish and fish oil) should be taken and the food rich in saturated fat and omega-6 fatty acid should be excluded from the diet. An omega-3 fatty acid containing diet facilitates fatty acid oxidation and reduction of fatty acid synthesis and improves the lipid profile.68

 

Bariatric Surgery:

Bariatric surgery is also known as weight loss and metabolic surgery. These terms are used in order to reflect the impact on patients’ weight and breakdown of food into energy. This surgery is one of the most effective options to achieve long-term weight loss in highly obese patients. NAFLD has shown the beneficial effects of weight loss on hepatic histology and hepatic enzyme elevation through bariatric surgery.69

 

Liver transplantation:

At the end-stage (terminal stage) of NAFLD patients, liver transplantation should be considered. But this is not a permanent cure as NAFLD may recur in post- transplant liver.70,71 Therefore, weight management, proper diet consumption and glucose control are highly essential before and after transplantation.

 

CONCLUSION:

NAFLD is a leading cause of chronic liver disease worldwide and a global burden disease. The prevalence of the disease is increased due to metabolic syndromes which are associated with diabetes mellitus and obesity. Several factors such as pro-inflammatory cytokines and oxidative stress may intervene in its pathogenesis. The liver biopsy is to be considered as the gold-standard test for NAFLD. A broad spectrum therapeutic range includes physical exercise, lifestyle modification and design of new molecules that will be able to control the various pathological processes of the disease. α- tocopherol and insulin sensitizers TZDS seem to be better treatment but they may cause weight gain as side effect. Although bariatric surgery leads to significant improvement in steatosis, steatohepatitis, fibrosis and biochemical testing, still it is not recommended as a specific treatment for NAFLD patients. Liver transplant is the only choice for the patient who is not responding to medical therapy, but it is an expensive process. Since multi pathological and interrelated pathways are associated with the disease a single therapeutic agent is unlikely to be a safe and effective treatment. Therefore, a combination therapy may be efficient towards multiple targets. Several new target-oriented therapies are under clinical investigation and probable we may have an effective multi-therapy regimen for this disease. Finally in a community more attention should be paid to conduct various education programs for young people, parents and teachers in order to promote physical activity, healthy food and lifestyle.

 

CONFLICTS OF INTEREST:

None.

 

ACKNOWLEDGEMENT:

I am thankful to Dr. A. K. Mishra, Principal, College of Pharmaceutical Sciences, Puri for encouraging me to write this paper.

 

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Received on 04.11.2022         Modified on 06.02.2023

Accepted on 21.04.2023       ©A&V Publications All right reserved

Res.  J. Pharmacology and Pharmacodynamics.2023;15(3):119-126.

DOI: 10.52711/2321-5836.2023.00022