Hepatic enzymes and CT density of the liver normalized after cessation of amiodarone in the present case. 1988; 8 :1063-8. Hepatology. Read article at publisher's site . Use of 3D Human Liver Organoids to Predict Drug-Induced Phospholipidosis Drug-induced phospholipidosis (PL) is a storage disorder caused by the formation of phospholipid-drug complexes in lysosomes. These conditions can be induced by hepatotoxic drug compounds, and can lead to delays in the drug development process if not properly assessed and mitigated. In order to study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. Its hepatic toxicity is similar to amiodarone, histologically mimicking alcoholic steatohepatitis, associated with phospholipidosis. The exact mechanism of phospholipidosis-induced liver damage is unclear. Phospholipidosis and Steatosis AssayScreen for drug-induced liver phospholipidosis and steatosis Cationic amphiphilic drugs are often associated with the induction of phospholipidosis, which is believed to be a precursor event to liver toxicity. phospholipidosis is observed only in patients with PLL, which is far from being established (15). Treatment with amiodarone leads to an accumulation in the liver of this iodinated compound and hence an increase in the CT density of the liver. late in the liver rather than skeletal muscle and spleen [1]. We have constructed a large-scale transcriptome database of rat liver treated with various drugs. Fulminant acute liver failure and cirrhosis are rare Longterm users should be monitored by serum alanine transaminase or aspartate transaminase every 6 months (JAMA 2007 Sep 19;298:1312) Anabolic steroids: Elevation of liver enzymes, cholestatic jaundice, liver tumors (benign and malignant), peliosis hepatitis Chlorpromazine: Based on this hypothesis, the role of the endogenous opioid system in chloroquine-induced phospholipidosis in rat liver was investigated by morphological, biochemical, and mo-lecular modelling studies. These findings indicate that liver phospholipidosis is relatively common in patients receiving parenteral nutrition and that the degree of liver phospholipidosis depends on the duration of parenteral nutrition. The traditional method to evaluate drug-induced phospholipidosis (DIPL) is visual confirmation of myeloid bodies in tissues by electron microscopy.Electron microscopy has limited utility to monitor DIPL in humans because of the . The aim of this study was to determine whether the endogenous opioid system is involved in chloroquine-induced phospholipidosis. In doing so, we will review the various effects of amiodarone toxicity in various organs. Drug-induced phospholipidosis (PL) is a storage disorder caused by the formation of phospholipid-drug complexes in lysosomes. Intrahepatic Cholestasis and Phospholipidosis Associated with the Use of Trimethoprim-Sulfamethoxazole SANTIAGO J. MmOZ,' ANTONIN0 MARTINEZ-HERNANDEZ~ AND WILLIS c. MADDREY' Departments of 'Medicine and 2Pathology, Jefferson Medical College, Philadelphia, Pennsylvania 191 07 Although liver injury after administration of the trimethoprim-sulfamethoxazole combination is rare, Phospholipidosis occurs in a much larger percentage of patients receiving amiodarone [ 5 ] than actual hepatocellular damage (1% to 3%), which suggests that . Because of the diversity of PL between species, human cell-based assays have been used to predict drug-induced PL in humans. In patients 1-5, intravenous caloric intake was reduced during prolonged home parenteral nutrition: this decision was made on the premise that hypernutrition might be a factor contributing to the development of liver . In conclusion, ketoconazole induced phospholipidosis in not only the liver but also the kidneys, and immunohistochemistry for LAMP-2 and adipophilin could be useful for the pathological evaluation of drug-induced phospholipidosis in mice. The effect of naltrexone as an antagonist of opioid receptors in chloroquine‐induced phospholipidosis in rat liver was investigated by morphological, biochemical, and molecular modelling studies. Similar phospholipase A activities in rat liver were confirmed in other reports [7, 8]. cirrhosis . It is well established 1 that a large number of cationic amphiphilic drugs have the potential to induce phospholipidosis. Phospholipidosis and Steatosis Background Information • Phospholipidosis is a lysosomal storage disorder characterised by excessive accumulation of intracellular phospholipids in tissues, such as the liver, kidney and lung. The traditional method to evaluate drug-induced phospholipidosis (DIPL) is visual confirmation of myeloid bodies in tissues by electron microscopy. Phospholipidosis (PL), a disorder characterized by excessive intracellular accumulation of phospholipids in tissues, can be induced by cationic amphiphilic drugs (CADs), which consist of a hydrophobic ring structure and a hydrophilic side chain with a charged cationic amine group (Nioi et al., 2007; Ryrfeldt, 2000).Since the 1970s, more than 50 CADs capable of inducing PL have been reported . So far, more than 50 novel chemical entities have been identified to induce phospholipidosis. The levels of BMP(44:12) were increased in the liver by chemical-induced phospholipidosis. In patients 1-5, intravenous caloric intake was reduced during prolonged home parenteral nutrition: this decision was made on the premise that hypernutrition might be a factor contributing to the development of liver . Phospholipidosis is a lysosomal storage disorder characterized by excessive accumulation of intracellular phospholipids in tissues, such as the liver, kidney and lung. . This work provides a mechanistic understanding of the impact that hepatic transporter function has on the disposition of drugs and endogenous compounds under normal conditions and in response to altered liver function due to drug-induced phospholipidosis or liver disease, specifically non-alcoholic steatohepatitis. Since they better recapitulate the complex microenvironment of liver tissue, in vitro three-dimensional (3D) cell . The rarity of this condition and vagueness of presenting symptoms make amiodarone-induced liver injury and cir-rhosis a challenging diagnosis. Phospholipidosis & pseudoalcoholic hepatitis: amiodarone, . steatosis and phospholipidosis, as well as genes associated with . To investigate whether amoxillin and pefloxacin perturb lipid metabolism. Therefore, increased levels of BMP is common features of hepatic phospholipidosis and alteration of TGs might be associated with zone-specific events in . Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were . The levels of BMP(44:12) were increased in the liver by chemical-induced phospholipidosis. This amiodarone-associated phospholipidosis may be observed as fine granular depositions in the macrophages of liver biopsy. Liver phospholipidosis might be due to intrahepatic accumulation of intravenous phospholipids provided by fat-emulsion sources. Because of the diversity of PL between species, human cell-based assays have been used to predict drug-induced PL in humans. MeSH terms Aged Aged, 80 and over Amiodarone / adverse effects* Amiodarone / analysis Biopsy Chemical and Drug Induced Liver Injury* We established three-dimensional (3D) human liver organoids as described previously and investigated their liver characteristics through multiple . Serum and tissue concentrations as well as the extent of phospholipidosis do not appear to be a function of the duration of drug application. Guigui B, Perrot S, Berry JP, et al. Rats were treated with therapeutic doses of each antibiotic for 5 and 10 days respectively. The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. 1Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Light, immunohistochemical, and electron microscopic studies Abstract The hepatic morphological findings in 3 patients treated with amiodarone, a potent and effective antiarrhythmic drug, are reported. Phospholipidosis in neurons, the heart, or the eyes might generate more safety concerns. Phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues. The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. The task is further rendered difficult on biopsy, as drugs can mimic all the patterns found in primary liver disease. The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. The phospholipids usually engorge the lysosomal bodies of the hepatocyte. Full text links . 2 | RESULTS On the other hand, several TGs were increased in the liver by CPM, IMI and AMT but decreased by KC. This calcium independent enzyme had an acidic pH optimum and recognized both phosphatidylcholine and phosphatidylethanolamine as substrates. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo >toxicology report database was searched to identify . However, it is now possible to detect intralysosomal accumulations (e.g., phospholipidosis) in the liver of rats (Obert et al. quine-induced phospholipidosis can also be related to endogenous opioid system involvement. @article{osti_22439848, title = {Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug}, author = {Mosedale, Merrie and Wu, Hong and Kurtz, C. Lisa and Schmidt, Stephen P. and Adkins, Karissa and Harrill, Alison H. and University of Arkansas for Medical Sciences, Little Rock, AR72205}, abstractNote . Therefore, increased levels of BMP is common features of hepatic phospholipidosis and alteration of TGs might be associated with zone-specific events in . Breast cancer and liver disorders classification using artificial immune recognition system (AIRS) with performance evaluation by fuzzy resource allocation mechanism. This accumulation of the drug in hepatic lysosomes apparently causes a secondary phospholipidosis. We present the first description of amiodarone toxicity in the liver without phospholipidosis or steatosis. The effect of naltrexone as an antagonist of opioid receptors in chloroquine-induced phospholipidosis in rat liver was investigated by morphological, biochemical, and molecular modelling studies. The patient is a young adult who had cardiac reconstruction as a child for transposition of the great vessels. These toxins bind to phospholipids and inhibit their catabolism. Increased Density of the Liver and Amiodarone-Associated Phospholipidosis. @misc{etde_22439848, title = {Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug} author = {Mosedale, Merrie, Wu, Hong, Kurtz, C. Lisa, Schmidt, Stephen P., Adkins, Karissa, Harrill, Alison H., and University of Arkansas for Medical Sciences, Little Rock, AR72205 (United States)]} abstractNote . The aim of this study was to determine whether the endogenous opioid system is involved in chloroquine‐induced phospholipidosis. The aim of this study was to determine whether the endogenous opioid system is involved in chloroquine‐induced phospholipidosis. Twenty four hours after the last antibiotic treatment and 5 days after antibiotic withdrawal, blood and other tissues (liver, kidney, brain, heart and spleen) were removed from the animals after an overnight fast and analysed for . The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. 2007) and in the liver or kidney of mice (Asaoka et al. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis is a lysosomal storage disorder characterised by . 7 the combination of histopathologic findings is often referred to … Sunao Kojima,1 Shinobu Kojima,1 Hirofumi Ueno,1 Motohiro Takeya,2 and Hisao Ogawa1. It remains uncertain what accounts for this unique presentation. Certain cases may be triggered by medications. 2The Second Department of Pathology, Graduate School of Medical . Phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues. 26 Negative and positive control groups were intraperitoneally injected with 0.9% sterile saline solution and chloroquine . Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease. It is important that physicians Acute hepatitis, with or without cholestasis, is the . Phospholipidosis is a distinct form of lipidosis caused by amphiphilic drugs such as chlorphentermine. Amiodarone-induced phospholipidosis and steatosis in human hepatoma HepaRG cells . In vitro assessment of drug-induced steatosis and . Essentially, drug-induced phospholipidosis is characterized by phospholipid accumulation in affected tissue of which lung, liver, brain, kidney, cornea and others have been reported . Phospholipidosis SunaoKojima,1 ShinobuKojima,1 HirofumiUeno,1 MotohiroTakeya, 2 andHisaoOgawa1 . An adverse effect of some cationic amphiphilic drugs is phospholipidosis that manifests as an intracellular accumulation of phospholipids and formation of concentric lamellar . In doing so, we will review the various effects of amiodarone toxicity in various organs. These . biopsy lacked steatosis and phospholipidosis despite years of amiodarone ingestion. It is well established1 that a number of cationic amphiphilic drugs have the potential to induce phospholipidosis. In order to clarify such a relationship, an ultrastructural study of the liver was performed in 13 patients treated with amiodarone and having normal liver biopsy or various light microscopic abnormalities. Phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues, often stimulated by drugs. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis is a lysosomal … Phospholipidosis has been reported to occur within two months of starting amiodarone therapy [ 6 , 7 ]. A very close correlation, however, was observed between the liver tissue concentration of amiodarone and the amount of dense bodies as a morphological expression of phospholipidosis. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis is a lysosomal storage disorder characterised by intracellular accumulation of phospholipids. Finding liver injury associated with exposure to a drug may indicate a higher risk to others exposed to the same drug Phospholipidosis & pseudoalcoholic hepatitis: amiodarone, . A phospholipase A activity obtained from rat liver lysosomes was first described by Mellors and Tappel in 1967 [6]. This phospholipidosis, which could be only a morphological marker of intrahepatic accumulation of the drug, should not therefore be considered grounds for attributing liver disease to the drug. All rats were intraperitoneally injected once daily for five consecutive days with a dose of 5 mg/kg/d that was chosen as it is known to induce phospholipidosis in liver tissue and adjusted based on the body weight of rats. There is a general agreement that inhibition of lysosomal phospholipase A1, A2 and/or C contributes to the accumulation of cationic amphiphilic drug (CADs)-phospholipid complexes. Light, immunohistochemical, and electron microscopic studies Amiodarone-associated phospholipidosis and fibrosis of the liver. When studying phospholipidosis/steatosis in vitro, IONTOX uses HepG2 cells in combination with LipidTox Red, as our primary model to discriminate . Human liver slice function was stressed by daily dosing of acetaminophen (APAP) or diclofenac (DCF) to investigate injury and repair. Drug induced hepatotoxicity is a leading cause of attrition during drug development. Abstract: The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spect rum of lesions, e.g., steatosis and phospholipidosis. Since they better recapitulate the complex microenvironment of liver tissue, in vitro three-dimensional (3D) cell . We present the first description of amiodarone toxicity in the liver without phospholipidosis or steatosis. Initially, untreated human liver and kidney slices were evaluated with the global human U133A array to assess the extended culture conditions. In addition, X-ray mi- The abnormal accumulation of lipids within the endolysosomal lumen occurs in many conditions, including lysosomal storage disorders, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and drug-induced phospholipidosis. On the other hand, several TGs were increased in the liver by CPM, IMI and AMT but decreased by KC. 2013) by . PHOSPHOLIPIDOSIS: Phospholipidosis is the accumulation of phospholipids instead of fatty acids. In order to study the relationship between amiodarone‐induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. 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