{"product_id":"understanding-inflammation-and-scarring-in-fatty-liver-disease-what-new-treatments-may-bring","title":"Understanding Inflammation and Scarring in Fatty Liver Disease: What New Treatments May Bring","description":"\u003cp\u003eThis review explains how non-alcoholic fatty liver disease (NAFLD) develops and progresses, focusing on the inflammation and scarring (fibrosis) that drive serious outcomes. NAFLD affects up to 25% of adults worldwide and can advance to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The authors describe the metabolic, inflammatory, and fibrotic mechanisms behind NASH and review dozens of clinical trials testing potential drug treatments. No drug is approved for NASH yet, but many therapies are under investigation.\u003c\/p\u003e\n\n\u003ch1\u003eUnderstanding Inflammation and Scarring in Fatty Liver Disease: What New Treatments May Bring\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why Fatty Liver Disease Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#what-is\"\u003eWhat Is NAFLD and NASH?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#pathogenesis\"\u003eHow NAFLD Develops: The Role of Metabolism\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#inflammation\"\u003eInflammation and Scarring Inside the Liver\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#er-stress\"\u003eER Stress and the Unfolded Protein Response\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#apoptosis\"\u003eCell Death and Its Consequences\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ppar\"\u003ePPAR Receptors and Lipid Metabolism\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#dnl\"\u003eBlocking New Fat Production in the Liver\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#autophagy\"\u003eAutophagy: The Cell's Recycling System\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#clinical-trials\"\u003eClinical Trials: What Has Been Tested\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#failed-trials\"\u003eTreatments That Did Not Work\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#promising\"\u003ePromising Results and Ongoing Studies\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#emerging\"\u003eEmerging Experimental Approaches\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of Current Knowledge\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eNAFLD affects up to 25% of adults worldwide and is the most common chronic liver condition.\u003c\/li\u003e\n\u003cli\u003eFibrosis (scarring) has the most direct impact on long-term outcomes and death in NASH.\u003c\/li\u003e\n\u003cli\u003eUp to one in three liver cancers in NASH develop without cirrhosis, unlike hepatitis B or C.\u003c\/li\u003e\n\u003cli\u003eNo drug is approved for NASH; many are in trials, with some promising and others failing.\u003c\/li\u003e\n\u003cli\u003eWeight loss through diet and exercise is the most effective and cost-effective approach.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why Fatty Liver Disease Matters\u003c\/h2\u003e\n\n\u003cp\u003eNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition worldwide. It affects up to 25% of the global adult population. The number of people with NAFLD continues to rise because obesity is becoming more common around the world.\u003c\/p\u003e\n\n\u003cp\u003eNAFLD also affects a growing number of children. Environmental factors drive this increase. These factors include highly processed foods rich in fat and sugar. Lockdowns and shelter-at-home measures during the COVID-19 pandemic made these dietary habits worse in many countries. Increased alcohol consumption during the pandemic also contributed to liver damage.\u003c\/p\u003e\n\n\u003cp\u003eNAFLD is the fastest growing cause of hepatocellular carcinoma (HCC, the most common form of primary liver cancer). NAFLD is also the fastest growing reason for liver transplantation. This growing public health burden has sparked intense interest from doctors, pharmaceutical companies, and scientists. Many potential therapies are now in development. However, no drugs are approved for this disease yet, despite promising results in many animal studies.\u003c\/p\u003e\n\n\u003cp\u003eAmong all the features of NASH, fibrosis (liver scarring) has the most direct impact on long-term outcomes and death. Currently, the only definitive way to assess fibrosis is a liver biopsy, which remains the gold standard. Researchers are working hard to develop non-invasive diagnostic tests to replace biopsy, and these efforts are advancing rapidly.\u003c\/p\u003e\n\n\u003cp\u003eRecent advances emphasize that NAFLD is the liver's manifestation of a systemic disease known as the \"metabolic syndrome.\" This means the liver problem is part of a body-wide condition. Weight loss through healthy lifestyle changes (diet and physical exercise) is recognized as the most effective and cost-effective method. This method improves not only NAFLD but also other conditions linked to metabolic syndrome. These related conditions include high blood pressure, insulin resistance, cardiovascular risk, and obesity-associated cancers. However, weight loss and lifestyle modifications are difficult to maintain. This difficulty has led to a growing focus on drug therapies to treat NASH.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is\"\u003eWhat Is NAFLD and NASH?\u003c\/h2\u003e\n\n\u003cp\u003eNAFLD is defined as steatosis (fat accumulation) in more than 5% of hepatocytes (liver cells) when there is no excess alcohol consumption and other liver diseases have been ruled out. NAFLD has two forms. The first is simple steatosis, also called non-alcoholic fatty liver (NAFL). The second is a more advanced inflammatory and fibrogenic stage called non-alcoholic steatohepatitis (NASH).\u003c\/p\u003e\n\n\u003cp\u003eNAFLD progresses to NASH in up to 25% of all patients. NASH leads to fibrosis and complications of end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC, or primary liver cancer).\u003c\/p\u003e\n\n\u003cp\u003eComplications of NASH include not only advanced fibrosis and cirrhosis but also HCC. Almost all liver cancers develop on a background of fibrosis. However, NASH differs from other liver diseases in an important way. In chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, more than 90% of liver cancers occur in patients with cirrhosis. In NASH, up to one in three of all HCCs develop in patients who do not have cirrhosis. This means NASH-related tumors tend to be larger and more advanced when discovered, reducing the hope of curative treatments.\u003c\/p\u003e\n\n\u003cp\u003eFor HCC, public health challenges include screening and identifying patients at risk who need surveillance for liver cancer. It is essential to identify patients with fibrosis because this feature drives outcomes and determines long-term results. As a result, clinical trials for NASH therapies are increasingly focused on the endpoint of improving fibrosis without worsening NASH. This goal is described as \"NASH resolution without worsening of fibrosis.\"\u003c\/p\u003e\n\n\u003cp\u003eMany therapeutic strategies target fibrogenesis (the formation of scar tissue) or the activation pathways of fibrogenic cells called hepatic stellate cells (HSCs). Other strategies aim to reduce hepatic inflammation, which drives fibrosis. Systemic approaches and targets outside the liver may also contribute to disease improvement. These include targeting the gut microbiome, adipose tissue (body fat), and the immune system, among others.\u003c\/p\u003e\n\n\u003ch2 id=\"pathogenesis\"\u003eHow NAFLD Develops: The Role of Metabolism\u003c\/h2\u003e\n\n\u003cp\u003eEarly studies in NASH proposed a \"two-hit\" model. In this model, steatosis was the \"first hit,\" and a \"second hit\" such as oxidative stress provoked disease onset. More recently, more nuanced models of pathogenesis have emerged.\u003c\/p\u003e\n\n\u003cp\u003eFor example, Marchesini and colleagues associated NAFLD with insulin resistance as a feature of the metabolic syndrome. Now NASH is viewed as a metabolic stress response of the liver. This response comes from an overabundance of fatty acids and carbohydrates.\u003c\/p\u003e\n\n\u003cp\u003eOvernutrition from high-caloric foods, combined with low energy expenditure due to a sedentary lifestyle, promotes adipose tissue hypertrophy (enlargement of fat tissue) to store extra calories. This enlargement can provoke adipose tissue hypoxia (low oxygen levels in fat tissue) because the mass of fat cells has greatly expanded. Unlike other tissues, this relative hypoxia is not sufficient to lead to new blood vessel formation. Instead, it results in adipose tissue fibrosis and inflammation. This fibrosis and inflammation further decrease adipose tissue function and increase the circulating levels of glucose and lipids (fats) in the blood.\u003c\/p\u003e\n\n\u003cp\u003eApart from adipose tissue, fatty acids are also derived from the liver through de novo lipogenesis (the creation of new fat). This process is driven especially by high carbohydrate content, particularly fructose, found in sugared beverages.\u003c\/p\u003e\n\n\u003cp\u003eLipid substrates are metabolized by beta-oxidation in the mitochondria or peroxisomes. They can also be temporarily stored in hepatocytes as inert triglycerides before being secreted within VLDLs (very-low-density lipoproteins). Impairment in either hepatic downstream pathways or an overabundance of available substrates leads to the generation of lipotoxic lipid species. These toxic lipids result in ER stress, mitochondrial dysfunction, and oxidative stress. Ultimately, these processes lead to hepatocyte injury, genomic instability, inflammation, HSC activation, and fibrosis complicated by hepatocellular cancer.\u003c\/p\u003e\n\n\u003cp\u003eFactors that trigger hepatic inflammation and NASH originate both from inside the liver and from extrahepatic (outside the liver) sites. Intrahepatic factors include lipotoxicity, apoptosis (programmed cell death), mitochondrial dysfunction, ER stress, and the innate immune response.\u003c\/p\u003e\n\n\u003cp\u003eA \"western diet\" can induce gut dysbiosis (an imbalance in gut bacteria). This imbalance leads to altered gut microbiome composition, destabilization of gut barrier function, and translocation of bacteria and bacterial products into the body. These bacterial products then amplify inflammation, stimulate ethanol production by the gut, and alter bile acid signaling.\u003c\/p\u003e\n\n\u003cp\u003eInsulin resistance impairs glucose uptake in extrahepatic tissues such as adipose tissue and skeletal muscle. This impairment leads to increased release of fatty acids, which enhances hepatic de novo lipogenesis (conversion of glucose to fatty acids). In addition, genetic polymorphisms (gene variations) and other factors such as smoking, fructose consumption, and sleep apnea further contribute to this multifactorial disease.\u003c\/p\u003e\n\n\u003cp\u003eSome of these factors are independent of obesity or insulin resistance. NASH can occur in lean patients, affecting 10% to 20% of those with the disease. It is likely that there is significant variability in which disease drivers lead to NASH across the affected population. Indeed, NASH may reflect the end result of different inputs and may be more than one disease.\u003c\/p\u003e\n\n\u003ch2 id=\"inflammation\"\u003eInflammation and Scarring Inside the Liver\u003c\/h2\u003e\n\n\u003cp\u003eThe role of ER stress in the pathogenesis of NAFLD is well established. The endoplasmic reticulum (ER) is a cell structure central to lipid metabolism. Many proteins that regulate lipid metabolism are located in the ER. These include transcription factors that regulate hepatic de novo lipogenesis, enzymes involved in triglyceride synthesis, and other proteins involved in lipoprotein assembly such as VLDLs.\u003c\/p\u003e\n\n\u003cp\u003eER homeostasis is essential to maintain intrahepatic lipid metabolism, membrane lipid composition, and extrahepatic plasma lipid homeostasis. Chronic overabundance of saturated fatty acids, such as palmitate, leads to ER stress. This stress activates the unfolded protein response (UPR) to restore ER function.\u003c\/p\u003e\n\n\u003cp\u003eMoreover, the UPR may activate the master lipogenic regulators SREBP-1c and SREBP2. This activation stimulates key regulatory genes of hepatic de novo lipogenesis. These genes include fatty acid synthase, stearoyl CoA desaturase 1 (SCD-1), diacylglycerol acyltransferase (DGAT), and acetyl-CoA carboxylase (ACC). The UPR decreases PPAR gamma and FXR (farnesoid X receptor) and increases expression of the VLDL receptor. Together, these effects further enhance hepatic steatosis, hypertriglyceridemia, and the generation of lipotoxic metabolites. This worsens hepatocellular injury and apoptosis.\u003c\/p\u003e\n\n\u003cp\u003eIf ER stress is not alleviated, excessive or prolonged UPR activation can lead to inflammation, inflammasome activation, and hepatocyte death.\u003c\/p\u003e\n\n\u003ch2 id=\"er-stress\"\u003eER Stress and the Unfolded Protein Response\u003c\/h2\u003e\n\n\u003cp\u003eSome compounds aim to reduce ER stress by increasing protein folding capacity in the ER. These compounds have shown hepatoprotective (liver-protecting) effects in preclinical models.\u003c\/p\u003e\n\n\u003cp\u003eFor example, 4-phenyl butyric acid (PBA) is a short-chain fatty acid derivative that decreases steatosis in a genetic mouse model called ob\/ob mice. Although 4-PBA is approved for the treatment of urea cycle disorders, its efficacy in NASH needs further exploration.\u003c\/p\u003e\n\n\u003cp\u003eThe taurine-conjugated ursodeoxycholic acid is approved for primary biliary cirrhosis. This compound can improve steatosis in mice and is hepatoprotective in rats. Further analyses are required to assess its efficacy and applicability in NAFLD.\u003c\/p\u003e\n\n\u003cp\u003eSimilarly, inhibitors of the UPR such as STF-083010 are well characterized to inhibit distinct UPR signaling pathways. STF-083010 inhibits IRE1a and can protect BI-1-deficient mice from high-fat-diet-induced NASH.\u003c\/p\u003e\n\n\u003ch2 id=\"apoptosis\"\u003eCell Death and Its Consequences\u003c\/h2\u003e\n\n\u003cp\u003eProlonged ER stress may result in hepatocellular apoptosis (programmed cell death). This cell death may amplify liver inflammation by activating fibrogenic HSCs and Kupffer cells (immune cells in the liver).\u003c\/p\u003e\n\n\u003cp\u003eHSCs can engulf apoptotic bodies, which enhances fibrogenesis. Kupffer cells phagocytose apoptotic bodies and release TNF alpha, contributing to inflammation. Apoptotic signaling pathways such as TRAIL (TNFSF10) are pro-inflammatory. They release extracellular vesicles and chemokines that stimulate immune cells.\u003c\/p\u003e\n\n\u003cp\u003eIn preclinical models and NAFLD patients, apoptosis signal-regulating kinase 1 (ASK1) is highly activated. This activation leads to activation of JNK and p38 MAPK pathways, which results in cell death and inflammation. ASK1 may also be activated as an intermediary of the IRE1a\/JNK pathway of the UPR.\u003c\/p\u003e\n\n\u003cp\u003eTherapeutic approaches targeting these pathways have included caspase inhibitors (emricasan) and ASK1 inhibitors (selonsertib). ASK1 is expressed by HSCs and inflammatory cells. Its inhibition was therefore expected to block inflammation and fibrosis. Indeed, the ASK1 inhibitor selonsertib improved inflammation and decreased fibrosis in a short clinical trial of 24 weeks.\u003c\/p\u003e\n\n\u003cp\u003eHowever, in two phase 3 trials, the drug was ineffective, and the trials were terminated. One trial assessed fibrosis improvement in patients with bridging fibrosis (F3, called Stellar-3). The other assessed patients with compensated cirrhosis (F4, called Stellar-4). Some have argued that ASK1 inhibition remains an attractive target, but more potent molecules are required.\u003c\/p\u003e\n\n\u003cp\u003eSimilar to the effects of selonsertib, a caspase inhibitor called emricasan was not effective in patients with NASH and fibrosis or cirrhosis. Results of emricasan (ENCORE-LF) assessing event-free survival have not been posted yet.\u003c\/p\u003e\n\n\u003ch2 id=\"ppar\"\u003ePPAR Receptors and Lipid Metabolism\u003c\/h2\u003e\n\n\u003cp\u003eThe UPR may also decrease hepatic PPAR alpha signaling. The nuclear receptors PPAR alpha, gamma, and delta are key regulators in lipid metabolism. PPAR gamma is a key regulator in adipocyte differentiation. PPAR alpha promotes hepatic fatty acid oxidation. PPAR delta decreases de novo lipogenesis and has anti-inflammatory effects.\u003c\/p\u003e\n\n\u003cp\u003eThus, PPAR agonists may alleviate lipid-related toxicity, promote hepatic regeneration, and mitigate hepatocyte stress. Dual PPAR alpha\/delta agonists are effective in murine models of NASH. Yet elafibranor, a dual PPAR alpha\/delta agonist, failed in the phase 3 RESOLVE-IT trial.\u003c\/p\u003e\n\n\u003cp\u003eElafibranor did not show a significant advantage over placebo with regard to NASH resolution without worsening of fibrosis. The response rate was 19.2% for elafibranor versus 14.7% for placebo. Similarly, elafibranor did not significantly reduce fibrosis (24% versus 22.4%).\u003c\/p\u003e\n\n\u003cp\u003eAnother drug, Lanifibranor, is a PPAR alpha\/delta\/gamma agonist. Lanifibranor improved inflammation and fibrosis in a phase 2b 6-month trial. Yet other trials targeting activation of PPARs are ongoing. These include a PPAR alpha\/gamma agonist called Saroglitazar and a PPAR alpha\/gamma\/delta agonist called Lanifibranor. Combination therapies of a PPAR gamma agonist with a GLP1 agonist or an SGLT1 inhibitor are also under evaluation.\u003c\/p\u003e\n\n\u003ch2 id=\"dnl\"\u003eBlocking New Fat Production in the Liver\u003c\/h2\u003e\n\n\u003cp\u003eSeveral therapies are in clinical trials to inhibit hepatic de novo lipogenesis by directly targeting key enzymes. Arachidyl-amidocholanoic acid inhibits SCD-1 and is being tested in the ARMOR trial. This trial includes patients with NASH stage 1 to 3 fibrosis. The primary outcomes are NASH resolution and fibrosis improvement. The trial is active, with no results posted yet, and estimated completion is June 2027.\u003c\/p\u003e\n\n\u003cp\u003eAnother approach targets acetyl-CoA carboxylase (ACC). Firsocostat (GS-0976) is an ACC inhibitor. In a phase 2 trial, it reduced steatosis, selected markers of fibrosis, and improved liver biochemistry. Clesacostat (PF-05221304) is another ACC inhibitor tested in patients with NAFLD and liver fat above 8%. This trial is no longer active as of October 2020.\u003c\/p\u003e\n\n\u003cp\u003eOltipraz is a liver X receptor alpha inhibitor. It was tested in patients with NAFLD who had liver fat above 20% on magnetic resonance spectroscopy (MRS). The primary outcome was improvement in steatosis. The trial is active, with no results posted yet, and estimated completion was October 2021.\u003c\/p\u003e\n\n\u003ch2 id=\"autophagy\"\u003eAutophagy: The Cell's Recycling System\u003c\/h2\u003e\n\n\u003cp\u003eEmerging evidence links macro-autophagy to NASH. Autophagy is the cell's process for breaking down and recycling its own components. Autophagy may be a protective mechanism during ER stress. ER stress can either inhibit or enhance autophagy.\u003c\/p\u003e\n\n\u003cp\u003eAutophagic flux may also be impaired with aging. Features of the metabolic syndrome, including hyperlipidemia with altered membrane lipid composition and insulin resistance, are associated with down-regulation of autophagy-related genes. Aging-related decreases in chaperone-mediated autophagy also occur.\u003c\/p\u003e\n\n\u003cp\u003eLipid droplets are degraded by autophagy, a process called lipophagy. Hepatic impairment of autophagy leads to steatosis, fibrosis, and tumorigenesis. This occurs via Yes-associated protein (YAP), HMGB1, and NRF2. Autophagy is also inversely regulated by the AKT\/mTOR pathway. Overnutrition leads to AKT\/mTOR activation, which may then lead to decreased autophagic flux and Yap activation as well.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-trials\"\u003eClinical Trials: What Has Been Tested\u003c\/h2\u003e\n\n\u003cp\u003eMany drugs and compounds have been tested in clinical trials for NASH. These trials are organized into phase 2 and phase 3 studies. Phase 2 trials test safety and initial effectiveness in a smaller group. Phase 3 trials test effectiveness in a larger group and are required before a drug can be approved.\u003c\/p\u003e\n\n\u003cp\u003eThe following table summarizes selected drugs tested in clinical trials for NASH, including their mechanisms, inclusion criteria, primary outcomes, and current status.\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eAramchol (ARMOR trial, Phase 3):\u003c\/strong\u003e An SCD-1 inhibitor. Included patients with NASH stage 1 to 3 fibrosis. Primary outcomes are NASH resolution and fibrosis improvement. Status: Active, no results posted yet. Estimated completion June 2027.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eBelapectin\/GR-MD-02 (NASH-RX trial, Phase 3):\u003c\/strong\u003e An FGF19 analogue. Included patients with NASH cirrhosis and evidence of portal hypertension. Primary outcome is new esophageal varices. Status: Active, no results posted yet. Estimated completion December 2023.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eCenicriviroc (Aurora trial, Phase 3):\u003c\/strong\u003e A CCR2\/CCR5 antagonist. Included patients with NASH and F2\/F3 fibrosis. Primary outcome is improvement in fibrosis without worsening NASH. Status: Completed (March 9, 2021). No results posted yet.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDapagliflozin (DEAN trial, Phase 3):\u003c\/strong\u003e An SGLT2 inhibitor. Included patients with NASH and type 2 diabetes (HbA1c below 9.5%). Primary outcomes are histological improvement and NASH resolution. Status: Active, no results posted. Estimated completion November 2021.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eElafibranor (RESOLVE-IT trial, Phase 3):\u003c\/strong\u003e A PPAR alpha\/delta ligand. Included patients with NASH and stage 1 to 3 fibrosis. Primary outcomes were resolution of NASH without worsening of fibrosis or improvement in fibrosis without worsening NASH. Status: Failed. No significant improvement in primary or secondary endpoints in the interim analysis.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eObeticholic acid (REVERSE trial, Phase 3):\u003c\/strong\u003e An FXR ligand. Included patients with NASH and stage 4 fibrosis. Primary outcome is improvement in fibrosis without worsening of NASH. Status: Active, not recruiting (last updated April 26, 2021).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eObeticholic acid (REGENERATE trial, Phase 3):\u003c\/strong\u003e An FXR ligand. Included patients with NASH with stage 2 or 3 fibrosis, or stage 1 fibrosis with risk for progression. Primary outcomes are resolution of NASH without worsening of fibrosis or improvement in fibrosis without worsening NASH. Status: Active, not recruiting (last updated April 26, 2021).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eOltipraz (Phase 3):\u003c\/strong\u003e A liver X receptor alpha inhibitor. Included patients with NAFLD (liver fat above 20% on MRS). Primary outcome is improvement in steatosis. Status: Active, no results posted. Estimated completion October 2021.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eResmetirom\/MGL3196 (MAESTRO-NASH trial, Phase 3):\u003c\/strong\u003e A THR-beta agonist. Included patients with NASH stage 2 to 3 fibrosis. Primary outcomes are NASH resolution, long-term outcome, and improvement in fibrosis. Status: Active, no results posted yet. Estimated completion March 2024.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSelonsertib (STELLAR-3 trial, Phase 3):\u003c\/strong\u003e An ASK-1 inhibitor. Included patients with NASH on biopsy with stage 3 fibrosis. Primary outcomes were resolution of NASH without worsening of fibrosis or improvement in fibrosis without worsening NASH. Status: Failed.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSelonsertib (STELLAR-4 trial, Phase 3):\u003c\/strong\u003e An ASK-1 inhibitor. Included patients with NASH on biopsy with stage 4 fibrosis but no ascites, hepatic encephalopathy, or variceal bleeding. Primary outcomes were resolution of NASH without worsening of fibrosis or improvement in fibrosis without worsening NASH. Status: Failed.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"failed-trials\"\u003eTreatments That Did Not Work\u003c\/h2\u003e\n\n\u003cp\u003eSeveral phase 2 trials also did not meet their goals. Understanding these failures helps researchers design better treatments.\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eEmricasan (ENCORE-NF trial, Phase 2):\u003c\/strong\u003e A caspase inhibitor. Included patients with NASH on biopsy with stage 2 or 3 fibrosis, or stage 1 fibrosis with risks for progression. Primary outcome was improvement in fibrosis without worsening NASH. Status: Failed. No significant improvement in NASH endpoints. Possibly more fibrosis and hepatocyte ballooning occurred.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eEmricasan (ENCORE-PH trial, Phase 2):\u003c\/strong\u003e A caspase inhibitor. Included patients with NASH cirrhosis and HVPG (hepatic venous pressure gradient) above 12 mmHg. Primary outcome was improvement in HVPG. Status: Failed. No significant improvement in endpoints.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eEmricasan (ENCORE-LF trial, Phase 2):\u003c\/strong\u003e A caspase inhibitor. Included patients with NASH cirrhosis with a history of variceal bleeding and\/or moderate or severe ascites. Primary outcome was event-free survival. Status: Completed. No results posted.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eGR-MD-02 (NASH-CX trial, Phase 2):\u003c\/strong\u003e A galectin-3 inhibitor. Included patients with NASH cirrhosis and HVPG above 6 mmHg. Primary outcome was improvement in HVPG. Status: Failed. No significant reduction in fibrosis or HVPG.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eIMM-124E (Phase 2):\u003c\/strong\u003e An anti-LPS treatment. Included patients with NASH on biopsy. Primary outcome was improvement in liver fat on MRI. Status: Failed. No significant improvement in clinical endpoints.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMSDC0602K (EMMINENCE trial, Phase 2):\u003c\/strong\u003e An mTOT inhibitor. Included patients with NASH on biopsy with stage 1 to 3 fibrosis. Primary outcome was NAS reduction of more than 2 points without worsening fibrosis. Status: Failed. No significant differences in primary or secondary endpoints.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eVolixibat\/SHP626 (Phase 2):\u003c\/strong\u003e An ASBT inhibitor. Included patients with NASH on biopsy with stage 0 to 3 fibrosis and more than 5% liver fat by MRI. Primary outcome was NASH reduction of more than 2 points without worsening of fibrosis. Status: Interim analysis showed no significant improvement. Study terminated.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"promising\"\u003ePromising Results and Ongoing Studies\u003c\/h2\u003e\n\n\u003cp\u003eDespite many failures, some treatments have shown promising results in phase 2 trials.\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eAldafermin\/NGM282 (Phase 2):\u003c\/strong\u003e An FGF19 analogue. Included patients with NASH on biopsy. Primary outcome was improvement in liver fat by MRI. Results: Significant reduction in liver fat. In an open-label extension study, improved NAS score and fibrosis after 12 weeks.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eCilofexor (Phase 2):\u003c\/strong\u003e An FXR agonist. Included patients with NASH without cirrhosis. Primary outcome was overall safety. Results: Significant improvement in steatosis, liver biochemistry, and serum bile acids.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFirsocostat\/GS-0976 (Phase 2):\u003c\/strong\u003e An ACC inhibitor. Included patients with NASH fibrosis F1 to F3. Primary outcomes were safety profile and adverse events. Results: Reduction of steatosis, selected markers of fibrosis, and improved liver biochemistry.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLanifibranor (NATIVE trial, Phase 2):\u003c\/strong\u003e A pan-PPAR agonist. Included patients with NASH without cirrhosis. Primary outcome was improvement in SAF activity score without worsening of CRN score (fibrosis). Results: SAF score significantly improved in higher dosage according to posted results on clinicaltrials.gov (April 21, 2021).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSemaglutide (Phase 2):\u003c\/strong\u003e A GLP-1 mimetic. Included patients with NASH on biopsy with stage 1 to 3 fibrosis. Primary outcome was resolution of NASH without worsening of fibrosis. Results: Significant improvement in NASH, but no improvement in fibrosis. A phase 3 study was planned for 2021.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePegbelfermin (FALCON1 trial, Phase 2):\u003c\/strong\u003e A pegylated FGF21. Included patients with NASH fibrosis (F3). Primary outcomes were improvement in NASH without worsening of fibrosis and fibrosis improvement without worsening of NASH. Status: Active, no results posted. Estimated completion December 2021.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePegbelfermin (FALCON2 trial, Phase 2):\u003c\/strong\u003e A pegylated FGF21. Included patients with NASH cirrhosis. Primary outcome was improvement in fibrosis without worsening of NASH. Status: Active, no results posted. Estimated completion October 2021.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTropifexor (FLIGHT-FXR trial, Phase 2):\u003c\/strong\u003e An FXR agonist. Included patients with NASH on biopsy with stage 1 to 3 fibrosis or clinical risks for NASH. Primary outcomes were improvement in ALT and liver fat by MRI. Status: Completed (April 6, 2021). No results posted.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTropifexor plus cenicriviroc (TANDEM trial, Phase 2):\u003c\/strong\u003e An FXR agonist plus a CCR2\/5 antagonist. Included patients with NASH on biopsy stage 2 to 3. Primary outcomes were adverse events, resolution of NASH, and improvement in fibrosis. Status: Completed (October 13, 2020). No results posted.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eVK2809 (VOYAGE trial, Phase 2):\u003c\/strong\u003e A THR-beta agonist. Included patients with NASH fibrosis (F1 to F3), NAS score above 4, and MRI-PDFF above 8%. Primary outcome was improvement in steatosis by MRI-PDFF. Status: Active. Estimated completion November 2021.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSAR425899 (RESTORE trial, Phase 2):\u003c\/strong\u003e A GLP-1 and glucagon receptor agonist. Included patients with NASH on biopsy and type 2 diabetes. Primary outcome was resolution of ballooning without worsening of fibrosis. Status: Withdrawn.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"emerging\"\u003eEmerging Experimental Approaches\u003c\/h2\u003e\n\n\u003cp\u003eBeyond the drugs already in clinical trials, researchers are exploring several novel investigational strategies. These approaches are derived from animal models and represent the next generation of potential treatments.\u003c\/p\u003e\n\n\u003cp\u003eThese emerging approaches include:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eThe inflammasome:\u003c\/strong\u003e A protein complex that triggers inflammation. Targeting the inflammasome may reduce liver inflammation.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eEpigenetic reprogramming:\u003c\/strong\u003e Changing how genes are expressed without changing the DNA sequence. This approach may reverse harmful gene activity in liver cells.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHippo signaling:\u003c\/strong\u003e A cellular pathway that controls organ size and cell growth. The Hippo pathway interacts with YAP, which is involved in fibrosis and cancer.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eNotch signaling:\u003c\/strong\u003e A cell communication pathway that influences HSC activation and fibrosis.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eEngineered T cells to remove fibrogenic HSCs:\u003c\/strong\u003e Immune cells modified to specifically target and kill activated hepatic stellate cells. This approach could directly reduce scar-forming cells in the liver.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHSC-specific targeting therapies:\u003c\/strong\u003e Drugs designed to act only on hepatic stellate cells, minimizing effects on other tissues.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eRecently completed and ongoing clinical trials and antifibrotic treatments are discussed in this review. These discussions illuminate the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis review has several important implications for patients with NAFLD and NASH.\u003c\/p\u003e\n\n\u003cp\u003eFirst, NAFLD is not just a liver disease. It is the liver's manifestation of a body-wide metabolic condition. This means that treating the underlying metabolic issues, such as obesity, insulin resistance, and high blood pressure, is essential. Weight loss through diet and exercise remains the most effective and cost-effective approach.\u003c\/p\u003e\n\n\u003cp\u003eSecond, fibrosis (scarring) is the most important predictor of long-term outcomes. Patients with fibrosis need to be identified because this feature drives outcomes. Clinical trials are now focused on improving fibrosis without worsening NASH.\u003c\/p\u003e\n\n\u003cp\u003eThird, NASH can lead to liver cancer even without cirrhosis. Up to one in three liver cancers in NASH patients develop in those without cirrhosis. This is different from other liver diseases like hepatitis B or C, where more than 90% of cancers occur in patients with cirrhosis. This means screening and surveillance for liver cancer are important for NASH patients, even those without cirrhosis.\u003c\/p\u003e\n\n\u003cp\u003eFourth, no drug is approved for NASH yet. However, many drugs are in clinical trials. Some have shown promising results, while others have failed. The research is advancing rapidly, and the authors expect that one or more therapies will yield clinical benefit in the coming years.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of Current Knowledge\u003c\/h2\u003e\n\n\u003cp\u003eSeveral limitations affect our understanding of NAFLD and NASH.\u003c\/p\u003e\n\n\u003cp\u003eFirst, definitive assessment of fibrosis still requires liver biopsy. Biopsy is an invasive procedure. Non-invasive diagnostics are rapidly evolving but are not yet a complete replacement for biopsy.\u003c\/p\u003e\n\n\u003cp\u003eSecond, NASH is a multifactorial disease. It likely reflects the end result of different inputs and may be more than one disease. This variability makes it difficult to develop a single treatment that works for all patients.\u003c\/p\u003e\n\n\u003cp\u003eThird, many clinical trials have failed. Drugs that showed promise in animal models, such as selonsertib and emricasan, did not work in humans. This highlights the gap between animal studies and human disease.\u003c\/p\u003e\n\n\u003cp\u003eFourth, some trials have been completed but no results have been posted yet. This limits the ability to draw conclusions about those treatments.\u003c\/p\u003e\n\n\u003cp\u003eFifth, the review focuses on antifibrotic therapeutics currently under investigation. Other approaches, such as targeting the gut microbiome, adipose tissue, and the immune system, are also being explored but are not the main focus of this review.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\n\u003cp\u003eBased on this review, patients with NAFLD or NASH can consider the following recommendations:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eFocus on lifestyle changes.\u003c\/strong\u003e Weight loss through healthy diet and physical exercise is the most effective and cost-effective method to improve NAFLD and related conditions. These related conditions include high blood pressure, insulin resistance, cardiovascular risk, and obesity-associated cancers.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsk about fibrosis assessment.\u003c\/strong\u003e Fibrosis drives long-term outcomes. Ask your doctor about how your liver fibrosis is being assessed. Liver biopsy remains the gold standard, but non-invasive tests are rapidly evolving.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiscuss liver cancer screening.\u003c\/strong\u003e NASH can lead to liver cancer even without cirrhosis. Up to one in three liver cancers in NASH patients develop without cirrhosis. Ask your doctor whether you need surveillance for liver cancer.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eManage related conditions.\u003c\/strong\u003e NAFLD is part of a systemic metabolic disorder. Managing conditions such as diabetes, high blood pressure, and high cholesterol is important for your overall health.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStay informed about clinical trials.\u003c\/strong\u003e Many drugs are being tested for NASH. Some have shown promising results. Ask your doctor whether any clinical trials might be appropriate for you.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eBe aware that no drug is approved yet.\u003c\/strong\u003e Despite promising data in many animal studies, no drugs are approved for NASH at this time. Be cautious of any product claiming to treat NASH without regulatory approval.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is the difference between NAFLD and NASH?\u003c\/h3\u003e\n\u003cp\u003eNAFLD means fat builds up in more than 5% of liver cells when other causes are ruled out. Simple steatosis, or NAFL, is the milder form. NASH is the more advanced stage with inflammation and scarring. Up to 25% of people with NAFLD progress to NASH, which can lead to cirrhosis and liver cancer.\u003c\/p\u003e\n\u003ch3\u003eHow common is NAFLD?\u003c\/h3\u003e\n\u003cp\u003eNAFLD affects up to 25% of adults worldwide and is the most common chronic liver condition globally. Rates are rising because obesity is becoming more common, and it also affects a growing number of children. Highly processed foods rich in fat and sugar, along with increased alcohol use during the COVID-19 pandemic, contributed to this rise.\u003c\/p\u003e\n\u003ch3\u003eWhy is liver fibrosis important in NASH?\u003c\/h3\u003e\n\u003cp\u003eFibrosis, or liver scarring, has the most direct impact on long-term outcomes and death among all features of NASH. It drives complications like cirrhosis and liver cancer. Clinical trials now focus on improving fibrosis without worsening NASH. Currently, liver biopsy remains the only definitive way to assess fibrosis, though non-invasive tests are rapidly evolving.\u003c\/p\u003e\n\u003ch3\u003eCan NASH cause liver cancer without cirrhosis?\u003c\/h3\u003e\n\u003cp\u003eYes. In NASH, up to one in three liver cancers develop in patients who do not have cirrhosis. This differs from hepatitis B or C, where more than 90% of liver cancers occur in patients with cirrhosis. Because of this, screening and surveillance for liver cancer are important for NASH patients, even those without cirrhosis.\u003c\/p\u003e\n\u003ch3\u003eIs there an approved drug for NASH?\u003c\/h3\u003e\n\u003cp\u003eNo drug is approved for NASH yet. Many therapies are under investigation, and some have shown promising results in phase 2 trials, but others failed in larger phase 3 trials. Be cautious of any product claiming to treat NASH without regulatory approval. Weight loss through diet and exercise remains the most effective and cost-effective approach.\u003c\/p\u003e\n\u003ch3\u003eWhat lifestyle changes help NAFLD and NASH?\u003c\/h3\u003e\n\u003cp\u003eWeight loss through a healthy diet and physical exercise is recognized as the most effective and cost-effective method. It improves NAFLD and related conditions such as high blood pressure, insulin resistance, cardiovascular risk, and obesity-associated cancers. However, maintaining these changes is difficult, which is why drug therapies are also being studied.\u003c\/p\u003e\n\u003ch3\u003eShould I be screened for liver cancer if I have NASH?\u003c\/h3\u003e\n\u003cp\u003eYes, discuss liver cancer screening with your doctor. NASH can lead to liver cancer even without cirrhosis, and up to one in three liver cancers in NASH patients develop without cirrhosis. This makes surveillance important for NASH patients, including those without cirrhosis. Ask your doctor whether you need surveillance for liver cancer.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with fatty liver disease or NASH seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eFibrosis drives long-term outcomes in NASH, and the only definitive way to assess it is liver biopsy, while non-invasive tests are still evolving. A second opinion can help confirm how your fibrosis is staged and whether your liver cancer surveillance is appropriate, since up to one in three NASH-related liver cancers develop without cirrhosis. No drug is approved for NASH yet, so reviewing whether a clinical trial fits is reasonable. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Inflammatory and fibrotic mechanisms inNAFLD—Implications for new treatment strategies\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Youngmin A. Lee and Scott L. Friedman\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e Journal of Internal Medicine, 2022; volume 291, pages 11–31\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1111\/joim.13380\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eKeywords:\u003c\/strong\u003e fibrosis, insulin resistance, lipotoxicity, liver cancer, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAbbreviations used in the original article:\u003c\/strong\u003e HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace consultation with a qualified healthcare provider.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47807295422620,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-understanding-inflammation-and-scarring-in-fatty-liver-disease-what-new-treatments-may-bring-hero.png?v=1792041724","url":"https:\/\/diagnosticdetectives.com\/he\/products\/understanding-inflammation-and-scarring-in-fatty-liver-disease-what-new-treatments-may-bring","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}