Drug-Induced Liver Injury: A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, and chemicals from the environment.Drug-Induced Liver Injury, Chronic: Liver disease lasting six months or more, caused by an adverse drug effect. The adverse effect may result from a direct toxic effect of a drug or metabolite, or an idiosyncratic response to a drug or metabolite.Liver Diseases: Pathological processes of the LIVER.Drug-Related Side Effects and Adverse Reactions: Disorders that result from the intended use of PHARMACEUTICAL PREPARATIONS. Included in this heading are a broad variety of chemically-induced adverse conditions due to toxicity, DRUG INTERACTIONS, and metabolic effects of pharmaceuticals.Liver Function Tests: Blood tests that are used to evaluate how well a patient's liver is working and also to help diagnose liver conditions.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.): Component of the NATIONAL INSTITUTES OF HEALTH. It conducts and supports basic and applied research for a national program in diabetes, endocrinology, and metabolic diseases; digestive diseases and nutrition; and kidney, urologic, and hematologic diseases. It was established in 1948.Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage.Liver: A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.Alanine Transaminase: An enzyme that catalyzes the conversion of L-alanine and 2-oxoglutarate to pyruvate and L-glutamate. (From Enzyme Nomenclature, 1992) EC 220.127.116.11.Liver Failure, Acute: A form of rapid-onset LIVER FAILURE, also known as fulminant hepatic failure, caused by severe liver injury or massive loss of HEPATOCYTES. It is characterized by sudden development of liver dysfunction and JAUNDICE. Acute liver failure may progress to exhibit cerebral dysfunction even HEPATIC COMA depending on the etiology that includes hepatic ISCHEMIA, drug toxicity, malignant infiltration, and viral hepatitis such as post-transfusion HEPATITIS B and HEPATITIS C.Cholestasis: Impairment of bile flow due to obstruction in small bile ducts (INTRAHEPATIC CHOLESTASIS) or obstruction in large bile ducts (EXTRAHEPATIC CHOLESTASIS).Aspartate Aminotransferases: Enzymes of the transferase class that catalyze the conversion of L-aspartate and 2-ketoglutarate to oxaloacetate and L-glutamate. EC 18.104.22.168.Hepatitis E: Acute INFLAMMATION of the LIVER in humans; caused by HEPATITIS E VIRUS, a non-enveloped single-stranded RNA virus. Similar to HEPATITIS A, its incubation period is 15-60 days and is enterically transmitted, usually by fecal-oral transmission.Hepatitis E virus: A positive-stranded RNA virus species in the genus HEPEVIRUS, causing enterically-transmitted non-A, non-B hepatitis (HEPATITIS E).Necrosis: The pathological process occurring in cells that are dying from irreparable injuries. It is caused by the progressive, uncontrolled action of degradative ENZYMES, leading to MITOCHONDRIAL SWELLING, nuclear flocculation, and cell lysis. It is distinct it from APOPTOSIS, which is a normal, regulated cellular process.Hepatocytes: The main structural component of the LIVER. They are specialized EPITHELIAL CELLS that are organized into interconnected plates called lobules.Diagnostic Errors: Incorrect diagnoses after clinical examination or technical diagnostic procedures.Analgesics, Non-Narcotic: A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS.Wounds and Injuries: Damage inflicted on the body as the direct or indirect result of an external force, with or without disruption of structural continuity.Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group.Risk Factors: An aspect of personal behavior or lifestyle, environmental exposure, or inborn or inherited characteristic, which, on the basis of epidemiologic evidence, is known to be associated with a health-related condition considered important to prevent.Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules.Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another.Retrospective Studies: Studies used to test etiologic hypotheses in which inferences about an exposure to putative causal factors are derived from data relating to characteristics of persons under study or to events or experiences in their past. The essential feature is that some of the persons under study have the disease or outcome of interest and their characteristics are compared with those of unaffected persons.Liver Regeneration: Repair or renewal of hepatic tissue.Liver Neoplasms: Tumors or cancer of the LIVER.Brain Injuries: Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.Reperfusion Injury: Adverse functional, metabolic, or structural changes in ischemic tissues resulting from the restoration of blood flow to the tissue (REPERFUSION), including swelling; HEMORRHAGE; NECROSIS; and damage from FREE RADICALS. The most common instance is MYOCARDIAL REPERFUSION INJURY.Fatty Liver: Lipid infiltration of the hepatic parenchymal cells resulting in a yellow-colored liver. The abnormal lipid accumulation is usually in the form of TRIGLYCERIDES, either as a single large droplet or multiple small droplets. Fatty liver is caused by an imbalance in the metabolism of FATTY ACIDS.Liver Diseases, Alcoholic: Liver diseases associated with ALCOHOLISM. It usually refers to the coexistence of two or more subentities, i.e., ALCOHOLIC FATTY LIVER; ALCOHOLIC HEPATITIS; and ALCOHOLIC CIRRHOSIS.
American Association for the Study of Liver Diseases: The American Association for the Study of Liver Diseases (AASLD) is the leading organization of scientists and health care professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists (including Hans Popper, Leon Schiff, Fred Hoffbauer, Cecil Watson, Jesse Bollman, and Sheila Sherlock, to name a few) to bring together those who had contributed to the field of hepatology.Idiosyncratic drug reactionLiver biopsyRumack-Matthew nomogram: The Rumack-Matthew nomogram, also known as Rumack-Matthews nomogram or the Acetaminophen nomogram is an acetaminophen toxicity nomogram plotting serum concentration of acetaminophen against the time since ingestion in an attempt to prognosticate possible liver toxicity as well as allowing a clinician to decide whether to proceed with N-Acetylcysteine (NAC) treatment or not. It is a logarithmic graph starting not directly from ingestion, but from 4 hours post ingestion after absorption is considered likely to be complete.Liver sinusoid: A liver sinusoid is a type of sinusoidal blood vessel (with fenestrated, discontinuous endothelium) that serves as a location for the oxygen-rich blood from the hepatic artery and the nutrient-rich blood from the portal vein.SIU SOM Histology GIAlanine transaminase: Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALAT) and was formerly called serum glutamate-pyruvate transaminase (SGPT) or serum glutamic-pyruvic transaminase (SGPT).King's College Criteria: The King's College Criteria or the King's College Hospital criteria were devised in 1989 to determine if there were any early indices of poor prognosis in patients with acute liver failure. Acute liver failure is defined as the onset of encephalopathy (altered mental status) or coagulopathy (altered bleeding tendencies) within 26 weeks of a patient diagnosed with liver disease.TransaminaseHepatitis E virus cis-reactive elementCoagulative necrosis: Coagulative necrosis is a type of accidental cell death typically caused by ischemia or infarction. In coagulative necrosis the architecture of dead tissue is preserved for at least a couple of days.Prescription cascade: Prescription cascade refers to the process whereby the side effects of drugs are misdiagnosed as symptoms of another problem resulting in further prescriptions and further side effects and unanticipated drug interactions. This may lead to further misdiagnoses and further symptoms.National Center for Injury Prevention and Control: The U.S.QRISK: QRISK2 (the most recent version of QRISK) is a prediction algorithm for cardiovascular disease (CVD) that uses traditional risk factors (age, systolic blood pressure, smoking status and ratio of total serum cholesterol to high-density lipoprotein cholesterol) together with body mass index, ethnicity, measures of deprivation, family history, chronic kidney disease, rheumatoid arthritis, atrial fibrillation, diabetes mellitus, and antihypertensive treatment.Mir-652 microRNA precursor family: In molecular biology mir-652 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, with expression levels of miRNAs and respective target mRNAs negatively correlated.Jean Emond: Jean C. Emond is the current Thomas S.Metastatic liver disease: A liver metastasis is a malignant tumor in the liver that has spread from another organ affected by cancer. The liver is a common site for metastatic disease because of its rich, dual blood supply (the liver receives blood via the hepatic artery and portal vein).Brain injury: A brain injury is any injury occurring in the brain of a living organism. Brain injuries can be classified along several dimensions.Fatty liverFibroTest: FibroTest, known as FibroSure in the US, is a patented biomarker test that uses the results of six blood serum tests to generate a score that is correlated with the degree of liver damage in people with a variety of liver diseases. FibroTest has the same prognostic value as a liver biopsy.
(1/2195) Lymphocyte proliferation inhibitory factor (PIF) in alcoholic liver disease.
Lymphocyte proliferation inhibitory factor (PIF) was determined in the supernatants of PHA-stimulated lymphocytes from patients with alcoholic liver disease. PIF was assayed by determining inhibition of DNA synthesis in WI-38 human lung fibroblasts. A two-fold greater inhibition in thymidine incorporation into DNA by lung fibroblasts was observed in supernatants of PHA stimulated lymphocytes from patients with alcoholic hepatitis or active Laennec's cirrhosis as compared with that found in control subjects or patients with fatty liver. It is suggested that decreased liver cell regeneration seen in some patients with alcoholic hepatitis may be due to increased elaboration of PIF. (+info)
(2/2195) Structural and functional changes in acute liver injury.
Carbon tetrachloride produces liver cell injury in a variety of animal species. The first structurally recognizable changes occur in the endoplasmic reticulum, with alteration in ribosome-membrane interactions. Later there is an increase in intracellular fat, and the formation of tangled nets of the ergastoplasm. At no time are there changes in mitochondria or single membrane limited bodies in cells with intact plasmalemma, although a relative increase in cell sap may appear. In dead cells (those with plasmalemma discontinuties) crystalline deposits of calcium phosphatase may be noted. Functional changes are related to the endoplasmic reticulum and the plasma membrane. An early decrease in protein synthesis takes place; an accumulation of neutral lipid is related to this change. Later alterations in the ergastoplasmic functions (e.g., mixed function oxidation) occurs. Carbon tetrachloride is not the active agent; rather, a product of its metabolism, probably the CC1, free radical, is. The mechanisms of injury include macromolecular adduction and peroxide propagation. A third possibility includes a cascade effect with the production of secondary and tertiary products, also toxic in nature, with the ability to produce more widespread damage to intracellular structures. (+info)
(3/2195) Various forms of chemically induced liver injury and their detection by diagnostic procedures.
A large number of chemical agents, administered for therapeutic or diagnostic purposes, can produce various types of hepatic injury by several mechanisms. Some agents are intrinsically hepatotoxic, and others produce hepatic injury only in the rare, uniquely susceptible individual. Idiosyncrasy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberation of the host permitting the accumulation of hepatotoxic metabolites. The syndromes of hepatic disease produced by drugs have been classified hepatocellular, hepatocanalicular, mixed and canalicular. Measurement of serum enzyme activities has provided a powerful tool for studies of hepatotoxicity. Their measurement requires awareness of relative specificity, knowledge of the mechanisms involved, and knowledge of the relationship between known hepatotoxic states and elevated enzyme activities. (+info)
(4/2195) Quantitative aspects in the assessment of liver injury.
Liver function data are usually difficult to use in their original form when one wishes to compare the hepatotoxic properties of several chemical substances. However, procedures are available for the conversion of liver function data into quantal responses. These permit the elaboration of dose-response lines for the substances in question, the calculation of median effective doses and the statistical analysis of differences in liver-damaging potency. These same procedures can be utilized for estimating the relative hazard involved if one compares the liver-damaging potency to the median effective dose for some other pharmacologie parameter. Alterations in hepatic triglycerides, lipid peroxidation, and the activities of various hepatic enzymes can also be quantitiated in a dose-related manner. This permits the selection of equitoxic doses required for certain comparative studies and the selection of doses in chemical interaction studies. The quantitative problems involved in low-frequency adverse reactions and the difficulty these present in the detection of liver injury in laboratory animals are discussed. (+info)
(5/2195) Assessment of hepatotoxic potential.
Philosophic concepts and pragmatic approaches toward improved understanding of the effect of drugs in the hepatocyte are reviewed. No set pattern of studies is advocated but rather observations are encouraged within the framework of studies that provide for varied exposure of the hepatocyte. Clinical usage should be imitated to provide earliest possible indications of toxicity in man. The need for definitive characterization through utilization of appropriate methodology derived from cross-fertilization of related disciplines is stressed. Both minimal and maximal dose effects should be established. Selected use of electron microscopy has become essential for characterizing responses of the liver to injury. The advantages of the toluidine blue-stained Epon "thick" sections are emphasized. Such observations are used to implement the utility of serial biopsies from the beagle dog prior to and during long-term study of potential hepatic injury. Examples of the critical effects of drug concentration within the hepatocyte are presented. (+info)
(6/2195) Bile duct epithelial cells exposed to alpha-naphthylisothiocyanate produce a factor that causes neutrophil-dependent hepatocellular injury in vitro.
The acute hepatotoxicity induced by alpha-naphthylisothiocyanate (ANIT) in rats is manifested as neutrophil-dependent necrosis of bile duct epithelial cells (BDECs) and hepatic parenchymal cells. This hepatotoxicity mirrors that of drug-induced cholangiolitic hepatitis in humans. Since BDECs are primary targets of ANIT-induced toxicity, we hypothesized that after exposure to ANIT, BDECs produce a factor(s) that causes neutrophil chemotaxis and neutrophil-dependent hepatocellular injury. To test this hypothesis BDECs were isolated from male Sprague Dawley rats and incubated with ANIT (6.25, 12.5, 25, or 50 microM) or vehicle for 24 h. The conditioned medium (CM) was collected and placed in the bottom chamber of a two-chambered chemotaxis system, while isolated neutrophils were placed in the top chamber. Chemotaxis was indicated by neutrophil migration through a membrane to the bottom chamber. CM from BDECs exposed to each concentration of ANIT was chemotactic, whereas CM from vehicle-treated BDECs was not. ANIT alone caused a modest degree of chemotaxis at 50 microM. The conditioned media were added to isolated hepatocytes or to hepatocyte-neutrophil cocultures and incubated for 24 h. Hepatocyte toxicity was indicated by alanine aminotransferase release into the culture medium. CM from vehicle-treated BDECs did not cause hepatocyte killing in either hepatocyte-neutrophil cocultures or hepatocyte cultures. In contrast, the addition of CM from ANIT-treated BDECs (CM-BDEC-A) to hepatocyte-neutrophil cocultures resulted in hepatocyte killing. The same CM was not cytotoxic to hepatocyte cultures devoid of neutrophils. The hepatocyte killing could not be explained by residual ANIT in the CM, which was below the limit of detection (< or = 0.5 microM). The addition of antiproteases afforded protection against neutrophil-dependent hepatocellular injury induced by CM-BDEC-A. These results indicate that ANIT causes BDECs to release a factor(s) that attracts neutrophils and stimulates them to injure hepatocytes in vitro. (+info)
(7/2195) Effect of central corticotropin-releasing factor on carbon tetrachloride-induced acute liver injury in rats.
Central neuropeptides play important roles in many instances of physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Stressors and sympathetic nerve activation are reported to exacerbate experimental liver injury. Some stressors are known to stimulate corticotropin-releasing factor (CRF) synthesis in the central nervous system and induce activation of sympathetic nerves in animal models. The effect of intracisternal CRF on carbon tetrachloride (CCl4)-induced acute liver injury was examined in rats. Intracisternal injection of CRF dose dependently enhanced elevation of the serum alanine aminotransferase (ALT) level induced by CCl4. Elevations of serum aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels by CCl4 were also enhanced by intracisternal CRF injection. Intracisternal injection of CRF also aggravated CCl4-induced hepatic histological changes. Intracisternal CRF injection alone did not modify the serum ALT level. Intravenous administration of CRF did not influence CCl4-induced acute liver injury. The aggravating effect of central CRF on CCl4-induced acute liver injury was abolished by denervation of hepatic plexus with phenol and by denervation of noradrenergic fibers with 6-hydroxydopamine treatment but not by hepatic branch vagotomy or atropine treatment. These results suggest that CRF acts in the brain to exacerbate acute liver injury through the sympathetic-noradrenergic pathways. (+info)
(8/2195) Influences of Kupffer cell stimulation and suppression on immunological liver injury in mice.
AIM: To study the possible involvement of Kupffer cells (KC) in immunological liver injury in mice. METHODS: Liver injury was induced by i.v. injection of Bacillus Calmette-Guerin (BCG) 5 x 10(7) viable bacilli followed by i.v. injection of lipopolysaccharides (LPS) 7.5 micrograms to each mouse. Indian ink and silica were i.v. injected to suppress KC and retinol was given po to stimulate KC in these mice. Plasma alanine aminotransferase (AlaAT), aspatate aminotransferase (AspAT), nitric oxide (NO), and liver tissue were examined. RESULTS: Injection of LPS following BCG injection resulted in a remarkable elevation of plasma NO, AlaAT, and AspAT levels, and severe liver damage. The damages were enhanced by the activation of KC with retinol and reduced by suppression of KC with silica and Indian ink. CONCLUSION: The degree of liver injury induced by BCG + LPS is closely correlated with the status of KC, and NO from KC plays an important role in the pathogenesis of the liver damage in mice. (+info)