Causes of Acute Liver Failure:
Chronic infection with hepatitis C virus (HCV) is known to cause acute liver failure.
Alcohol-induced liver (ALD) disease:
About 26 million patients globally have advanced alcoholic liver disease (ALD) and it accounts for half of liver-related deaths in developed countries.
Genetic analysis has shown a strong association between the HSD17B13 gene and advanced ALD and metabolic-dysfunction-associated steatohepatitis (MASH) which causes a build up of fat in the liver that can eventually lead to scarring and, in some cases, severe liver damage, liver failure and even death.
–GSK990 (GSK): is an investigation RNA interference therapeutic for steatotic liver disease (SLD), an area of substantial unmet need. GSK990 targets HSD17B13 resulting in highly specific binding to receptors that are only expressed on liver cells.
Drug Induced Liver Disease (DILI): accounts for about 13% of cute liver failure in the US and is the 3rd most common cause of acute liver failure.
Steatotic liver disease, also known as fatty liver disease, is a condition where excessive fat accumulates in the liver. It can be caused by various factors, including obesity, diabetes, and high cholesterol, and often presents with no or mild symptoms initially. While early-stage fatty liver disease may be harmless, it can progress to more serious conditions like liver inflammation (NASH) and fibrosis (scarring), potentially leading to cirrhosis and liver failure.
–Treatment:
—–Efimosfermin (GSK): alfa is a long-acting, once-monthly fibroblast growth factor 21 (FGF21) analogue with an extended half-life of 21 days. In a phase 2a multiple dose/ regimen study, efimosfermin alfa led to significant improvements in liver steatosis, markers of liver injury, and fibrosis among patients with MASH
Associated Complications:
Hepatoplumonary syndrome (HPS): is a terrible complication of end stage liver diseases. It occurs in 4-40% of cirrhotic patients and is considered the main cause of high mortality rate in liver cirrhotic patients.
Hepatopulmonary syndrome (HPS) is a severe pulmonary complication of liver disease, not a separate disease, characterized by a triad of liver disease, intrapulmonary vasodilation, and hypoxemia. It is a specific lung vascular disorder caused by liver damage and is often a complication of chronic liver disease like cirrhosis. HPS itself is diagnosed based on this specific triad, and it is distinguished from primary lung diseases, which must be ruled out first.
–treatments:
—–Phosphodiesterase inhibitors: have been reported to prevent HPS associated with liver cirhosis through elecvation of cyclic adenosine monophosphate (cAMP). (Bakr et al. “Diosmin enhances the anti-angiogenic activity of sildenafil and pentoxifyllin against hepatopulmonary syndrome via regulation of TNF-alpha/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways” European J of Pharmacology, 873 (2020))
——-Sildenafil (Sild) is a selective type-5 phosphodiesterase inhibitor that significantly treated many vascular dysfunctions including pulmonary hypertension and erectile dysfunction. Multiple studies demonstrate that Sild has antioxidance, anti-inflammatory, anti-fibrotic and anti-angiogneic activities. (Bakr et al. “Diosmin enhances the anti-angiogenic activity of sildenafil and pentoxifyllin against hepatopulmonary syndrome via regulation of TNF-alpha/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways” European J of Pharmacology, 873 (2020))
——-PTX: is a non-selective phosphodiesterase inhibitor with wide pharmacological applicaitons. It has been reported that PTX could prevent HPS due to anti-TNF0-alpha and anti-angiogenic activity. (Bakr et al. “Diosmin enhances the anti-angiogenic activity of sildenafil and pentoxifyllin against hepatopulmonary syndrome via regulation of TNF-alpha/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways” European J of Pharmacology, 873 (2020))
——-Diosmin (DS): is a well-established anti-oxidant and inti-inflammatory, anti-fibrotic and anti-angiogenic agent. It has reported hepatoprotective roles in combination with Sild or PTX against CBDL-indcued liver cirrhosis. It has also been shown to augment the anti-angiogenic activity of phosphodiesterase inhbitors, Slid and PTX, in an animal model of CBDL-induced HPS. (Bakr et al. “Diosmin enhances the anti-angiogenic activity of sildenafil and pentoxifyllin against hepatopulmonary syndrome via regulation of TNF-alpha/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways” European J of Pharmacology, 873 (2020))
Mechanisms of Action
Developement of autoantibodies:
–Cytochrome P450 2E1 (CYP2E1) is a 493 amino acid enzyme involved in the monooxygenation of drugs and other xenobiotic agents. It has been reported that autoantibodies to CYP2E1 eptiopes contributes to the development of hepatic autoimmune diseases. For example, autoantibodies to CYP2E1 have been identified in persons with drug induced liver injury (DILI). A type of DILI developed develops in susceptible individuals following adminsitration of halogenated volatile anesthetics. Oxidative metabolism of the anesthetic produces trifluoroacetylchloride (TFA) which is a reactive metabolite that can covalently bind to and alter native liver proteins. The TFA-protein complexes, known as drug haptens, are novel autoantigens or hapten autoantigen complexes (neoantigens) capable of eliciting allergic or autoimmune resposnes. A second type of DILI is alcohol induced liver diseases where individuals chronically exposed to alcohol also develop autoantibodies to CYP2E1. Chronic viral infections are also known to induce autoimmunity directed to CYP2E1. For example, chronic infection with HCV is known to induce autoimmune reacions. Individuals with chronic HCV expressed decreased levels of CYP2E1 as well as CYP2E1 autoantibodies. (Njoku (13/203402) discloses a CYP2E1 Gly113-Leu133 epitope that contributes to the development of hepatic autoimmune diseases. T and B cells specific for the Gly113-Leu133 epitope mediate an autoimmune response that contributes to the devleopment of hepatic autoimmune diseases. Methods for using the polypeptide for identifying a mammalain subject at resik of developing hepatic autoimmune disease are also provided.
Susceptible individuals who develop anesthetic-induced DILI have elevated levels of CYP2E1 specific IgG4 autoantibodies. In constrast, exposed susceptible individuals who develop CYP2E1 specific IgG1 autoantibodies remain healthy. Accordingly, pathogenesis in hepatic autoimmune disease is assocaited with emergence of IgG4 autoantibodies and IgG4 autoanitbodies that are specific for the Gly113-Leu133 epitope of CYP2E1 can be used for diagnosing a pateint with hepatic autoimmune diasease.