Nonalcoholic fatty liver disease (NAFLD) affects 30% of individuals in the United States. Up to one-third of patients with NAFLD go on to develop nonalcoholic steatohepatitis or NASH, which is characterized by inflammation and fibrosis leading to cirrhosis. As opposed to simple fat in the liver, NASH, if left untreated,can progress to advanced fibrosis, cirrhosis, liver decompensation, and liver-related death. NAFLD isassociated with the metabolic syndrome and patients with NAFLD have a higher risk of cardiovascularrelated death and development of diabetes. The gold standard for the diagnosis of NAFLD or NASHis liver biopsy; however, this has its limitations due to its invasiveness. The utilization of non-invasivemeasurements of hepatic steatosis and fibrosis are evolving to replace liver biopsy. There are currently noapproved therapies for the treatment of NASH nor accepted standard of care. The therapeutic options forNASH are largely limited to lifestyle modification and treatment of underlying conditions such as diabetesand hyperlipidemia. Several agents have been evaluated as potential treatments for NASH by improvingliver inflammation but have a limited effect on reducing hepatic fibrosis. Currently there are severalagents in development which show promise in reduction of hepatic fat content, inflammation, and fibrosis. In summary, the obesity epidemic and its association with the metabolic syndrome have led to NAFLD and/or NASH being the leading cause of liver disease in the United States. The recognition and treatment of this disease with its associated co-morbidities will avoid the long-term complications of this disease.
According to data from the Centers for Disease Control, 42.5% of adult Americans are obese.1 Obesity in association with hypertension, dyslipidemia, and/or insulin resistance constitutes the metabolic syndrome (MS).2 Non-Alcoholic Fatty Liver Disease (NAFLD) is defined as the excessive accumulation of fat in the liver shown either by imaging or histology, in the absence of significant alcohol consumption or other secondary cause3 and is felt to be the hepatic manifestation of MS.The strong association of NAFLD with the MS and obesity has resulted in it being the number one cause of chronic liver disease.4 NAFLD is also associated with a complex relationship between environmental factors such as diet, changes in microbiota, and predisposing genetic variants.5 NAFLD may also encompass non-alcoholic steatohepatitis (NASH) and progress to cirrhosis of the liver. NAFLD is defined as the presence of greater than 5% hepatic steatosis (HS) without evidence of hepatocellular injury in the form of hepatocyte ballooning. NASH is defined as the presence of greater than 5% HS and inflammation with hepatocyte injury (e.g., ballooning), with or without any fibrosis.3 NAFLD is a major health issue due to its association with MS, type two diabetes mellitus (T2DM), and cardiovascular disease (CVD).6 The overall prevalence of NAFLD was found to be 38% and the prevalence of NASH at 14% in a large prospective study of middle-aged US cohort. NASH is more common in Hispanics and those with obesity and type 2 diabetes.7 The most common cause of death in NAFLD patients is not from liver-related causes but rather from coronary artery disease (CAD)8 with 48% of those with NAFLD dying from complications of CVD compared to only 7% due to liver disease.9 However, those with fatty liver disease do have a higher rate of liver-related death compared to the general population.9 Studies have shown that glucose intolerance and insulin resistance have been found to occur in the early stages of chronic liver disease and subjects with NAFLD are three times more likely to develop type 2 diabetes and 50% more likely to develop the MS than the general population.10,11 Conversely, the prevalence of NAFLD in patients with type 2 diabetes mellitus is more than 2-fold higher than in the general population.12 Furthermore, diabetes and obesity have also been associated with the development of liver cancer,13 most likely due to the progression from NAFLD to NASH and then to cirrhosis. NASH is the most rapidly increasing indication for liver transplant in patients without hepatocellular carcinoma (HCC), and has become the leading indication in women without HCC.14
Mechanisms of Hepatic
Damage in NAFLD/NASH
Proposed mechanisms for hepatic damage in NASH involve insulin resistance, toxicity from free fatty acids (FFA), generation of reactive oxidative species (ROS) or hormonal dysregulation. Within the hepatocyte fatty acid oxidation may occur within mitochondria, peroxisomes or endoplasmic reticulum.15 Peroxisome proliferator-activated receptor (PPAR) isoforms may have a role in NASH due to their modulation of fatty acid uptake, beta oxidation, ketogenesis, bile acid synthesis and triglyceride turnover.16 Patients with NASH may also have increased beta-oxidation of fatty acids with elevations in lipid peroxide intermediates and reactive oxygen species.17 Gut hormones such as leptin, ghrelin, and glucagon like peptide 1 may also have a role in the pathogenesis of NASH due to their ability to inhibit lipogenesis, lipo-apoptosis, decrease free fatty acids, increase insulin secretion and glucose uptake, and exhibit anti-inflammatory actions.18
Diagnosis of NASH
The diagnosis of NASH is usually suspected in patients with obesity or those with components of metabolic syndrome who present with abnormalities in liver function testing or incidental findings of fatty changes on imaging studies of the liver. Further evaluation as to the severity of inflammation or fibrosis may consist of liver biopsy. However, due to the invasiveness of this procedure, the diagnosis of NAFLD and or NASH is increasingly being based on non-invasive measures such as aspartate aminotransferase (AST) to platelet ratio index (APRI), FIB-4 index, NAFLD fibrosis score, commercially available testing such as FibrosureTM, FibrotestTM, enhanced liver fibrosis (ELF) scoreTM or imaging utilizing sheer wave elastography, transient elastography, or Magnetic Resonance Elastography (MRE) and proton density fraction measurements (PDFF).19 Traditionally noninvasive testing tends to have a high negative predictive value in ruling out people who have the disease rather than ruling in people who have the disease.20 Combining noninvasive testing utilizing elastography or MRE with FIB-4 testing or vibration controlled transient elastography with AST values may improve positive predictive values, increase area under the receiver operating characteristic curve (AUROC) and improve the detection of people who have the disease.21,22
Treatment of NASH
Currently, there are no approved medications to treat NASH and its secondary complications. Weight loss via dieting and exercise are the initial steps in treating NASH. 5% weight loss leads to reduction in hepatic fat and stabilization of fibrosis whereas 10% or more has been shown to elicit improvement in hepatic inflammation and fibrosis.23,24 In a recent 5-year follow-up of patients with NASH undergoing bariatric surgery, 84.4% had resolution of NASH with 70% showing a regression in fibrosis.25 The effects of exercise on underlying NASH are less clear, but from a large, retrospective assessment of biopsy proven NAFLD patients, moderate intensity exercise metabolic equivalents (METs) of 3.0-5.9 of total exercise per week was not associated with improvement in NASH severity or fibrosis. However, patients meeting vigorous (6 METs) activity did have improvement in NASH. A doubling of the vigorous activity recommendations was required to have a benefit on fibrosis.26 The Mediterranean diet (high complex carbohydrates, fiber and monounsaturated fats with a balanced omega 6-omega 3 ratio) has been shown to lead to reductions in hepatic fat content and improvement in components of the metabolic syndrome in the absence of weight loss.27 Nutritional counseling in association with a Mediterranean diet has been shown to elicit weight loss with normalization of hepatic enzymes, glycemic control, and hyperlipidemia.28 A recent meta-analysis of the Mediterranean diet revealed a reduction in BMI, hepatic fat, hypertriglyceridemia and homeostasis model assessment (HOMA).29 As to whether a greater benefit is seen with diet and/or exercise or weight loss remains to be elucidated. In the meantime, a healthy lifestyle of dieting and exercise are recommended in the treatment of NAFLD.
Vitamin E is the most important lipid-soluble antioxidant located predominately in cell membranes, where it reduces free radicals rendering them inactive.30,31 Long-term administration of vitamin E at 800 U a day for 96 weeks decreased liver enzyme abnormalities, fat accumulation, and inflammation in patients with NASH without diabetes, but not hepatic fibrosis.32 Studies have shown that dietary supplementation with vitamin E is effective in reducing the pathologic progression of hepatic inflammation and steatosis but not fibrosis.33 In a meta-analysis of both adults and pediatric patients, administration of vitamin E was associated with a significant improvement in alanine aminotransferase (ALT), AST, fibrosis, and NAFLD activity score (NAS) at early and late follow up.34 The American Association for the Study of Liver Disease now recommends the use of vitamin E 800 units a day for the treatment of NASH in non-diabetic patients without cirrhosis.19
Silymarin may in fact be one of the most potent antioxidants found in nature due to the properties of free radical scavenger reactivity and favorable membrane-lipid/water partitioning it possesses.35 Studies have shown that courses of silymarin therapy reduce the biochemical and ultrasonographic changes induced by NASH to the liver.36 Silymarin has also been shown to reduce AST and ALT levels in patients with NASH compared to placebo,37 and to improve fatty infiltration of liver and liver function in children and adolescents.41 It may also be effective in preventing or alleviating many of the components of MS39 including CVD40 and diabetes.41 In a meta-analysis of 5 clinical trials in 602 patients, there was lower liver-related mortality and lower rates of hospitalization in patients treated with silymarin.42 In a clinical review of 296 patients utilizing silymarin for the treatment of liver disease, the incidence of death and serious adverse events was lower in the silymarin group with no significant adverse events.43 In a meta-analysis of eight randomized clinical trials, silymarin treatment led to a statistically significant greater reduction in the levels of transaminases compared to placebo, irrespective of weight loss.44
Carnitine is a naturally occurring non-essential amino acid synthesized in the body from amino acids lysine and methionine. It plays a vital role in energy production and fatty acid metabolism by shuttling fatty acids into the mitochondria of cells for energy production especially for cardiac and skeletal muscles. Studies have also shown that carnitine is helpful in insulin resistance45 and weight loss.46 Carnitine at a dose of 2 grams per day for a period of 24 weeks has also been shown to reduce hepatic enzyme abnormalities, hyperlipidemia, insulin resistance and hepatic inflammation in patients with NAFLD.47 Treatment of NAFLD patients with a combination of vitamin E, silymarin and carnitine revealed significant normalization of HOMA and fasting insulin levels, and, downtrends in AST, ALT, TC, TRG, HDL, LDL, HgbA1c, and HSCRP levels.48
Drug Candidates in Clinical Development Peroxisome Proliferator Activated Receptor (PPAR) Agonists
Pioglitazone and Rosiglitazone are thiazolidinediones (TZD), targeting PPAR-Gamma receptors. Trials involving TZDs revealed improvements in steatosis and inflammation but not fibrosis. Rosiglitazone treatment has been shown to improve hepatic enzyme abnormalities and steatosis but not inflammation. Its use has been tempered due to concerns over an increased risk of coronary events.49 Pioglitazone elicits improvement in insulin sensitivity and hepatic inflammation but is associated with weight gain.33 Current AASLD guidelines suggest the use of pioglitazone in biopsy proven NASH in patients with and without diabetes.19 Elafibranor is a dual PPAR alpha/delta agonist that improves glucose homeostasis, increases insulin metabolism, and reduces inflammation. Studies suggest some improvement in hepatic inflammation in NASH.50 However, in the Resolve-IT phase 3 trials, a 72week treatment with elafibranor failed to reach its endpoint of NASH resolution without worsening of fibrosis in comparison to placebo.51 Data for a 16-week trial evaluating saroglitazar, a dual PPAR alpha/gamma agonist for treatment of NAFLD revealed improvements in alanine aminotransferase levels, reductions in hepatic fat content, insulin resistance and dyslipidemia in patients with NASH. No reductions in liver stiffness measurements were noted, however this study may have been limited due to small sample size.52 Lanifibranor is a panPPAR alpha/delta/gamma agonist. Data from a 24-week trial showed significant improvements in steatosis, inflammation and fibrosis.53 This drug candidate is being evaluated in a large phase 3 NASH fibrosis population.
Farnesoid X Receptor Agonist (FXR)
FXRs are nuclear receptor transcription factors, expressed in the liver, that regulate insulin sensitivity and participate in lipid metabolism. Bile acids (BAs), natural ligands of the FXRs, are synthesized in the liver and promote insulin sensitivity and decrease gluconeogenesis and circulating triglycerides when bound to FXRs. Obetacholic acid OCA (6-ethylchenodeoxycholic acid) is a synthetic BA and an FXR activator. It increases peripheral glucose uptake, enhances glucose-stimulated insulin secretion, and inhibits hepatic lipid synthesis.54 In the Regenerate trial, a significant improvement in fibrosis was seen in 23% of the OCA treated group compared with 12% of the placebo.55 However, resolution of NASH did not differ between the treated and placebo group and concerns over pruritus and recent warnings of its use in patients with primary biliary cholangitis and advanced liver disease have hampered its approval by the FDA for the treatment of NAFLD. New generations of FXR agonists are currently in clinical development, both as single agents and in combination with other drug candidates.
Resmetirom is an oral thyroid receptor beta agonist that selectively binds to the liver bypassing the adverse effects of excessive thyroid hormone in extra-hepatic sites. A phase 2B study showed a significant improvement in reduction of liver fat by MRI-PDFF compared to placebo after 36 weeks of treatment. There were favorable reductions in atherogenic lipids such as LDL cholesterol, apolipoprotein-B, triglycerides, and lipoprotein(a).56 Data evaluating 52 weeks of therapy in non-cirrhotic patients with NAFLD revealed 52% reductions in hepatic fat by MRI PDFF and improvements in hepatic fibrosis by noninvasive measurements (26% reduction in elastography 12% for MRE measurements).57
Fatty Acid Derivative – Icosabutate
Icosabutate is an engineered eicosapentaenoic acid derivative with potent anti-inflammatory and antifibrotic effects acting primarily through the G-coupled protein receptor (GPR120) and the arachidonic acid related signaling pathways. In a 52-week phase 2b trial, subjects with biopsy confirmed NASH were randomized to icosabutate vs placebo. An interim analysis showed that treatment with icosabutate elicited reductions in ALT, AST, GGT, and ALP. Significant reductions in noninvasive fibrosis markers PRO-C3 and ELF score (both indirect markers of fibrosis) were seen. This indicates a possible role for this compound in fibrogenesis, glycemic control, and synthesis of key atherogenic lipoproteins.58
Glucagon-like peptide-1 agonists are licensed for the treatment of type 2 diabetes and have been shown to reduce insulin resistance, decrease glucagon and free fatty acid concentrations, improve hgbA1c levels, delay gastric emptying and elicit weight loss.59 Liraglutide was compared to placebo in a phase 2 48-week trial for treatment of NASH. Thirty nine percent of patients on liraglutide had resolution of NASH in comparison to 9% in the placebo group. More patients in the placebo group (36%) had progression of fibrosis in comparison to liraglutide (9%).60 In a similar phase 2 trial, semaglutide, a GLP-1 agonist with a longer half-life, demonstrated a significantly higher efficacy for NASH resolution than placebo. However, there was no significant improvement in fibrosis when evaluated by liver biopsy at week 72.61 Semaglutide is being evaluated in a large phase 3 clinical trial in patients with NASH and Fibrosis. Other compounds including dual modes of action (GLP-1 agonist/Glucagon receptor agonist/GIP) are being evaluated.
Efruxifermin is a fusion protein of human IgG linked to modified fibroblast growth factor 21. This agent is felt to have effects on protein, glucose, and lipid utilization. This agent has been shown to reduce hepatic steatosis, hepatic inflammation and fibrosis62 as well as improve insulin sensitivity and dyslipidemia in patients with type 2 diabetes.63 In a phase 2 trial evaluating efruxifermin there was a 12-13% absolute reduction and 63-72% relative reduction in hepatic fat. Improvement in abnormalities in hepatic enzyme function was seen and regression of fibrosis by 1 stage was seen in 55% and 2 stages in 28% of treated individuals. Complete resolution of NASH was seen in 1/3 of patients.64
The obesity epidemic has resulted in an increase in the incidence of metabolic syndrome and NAFLD and NASH. While several agents have shown improvement in hepatic steatosis and inflammation, their ability to elicit regression in fibrosis remains to be elucidated, notably for more advanced stages of fibrosis. Long term data regarding the ability of these newer agents, or combination therapy, to reduce hepatic inflammation and fibrosis are warranted.
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