Liver Toxicity PDF

Liver toxicity   Physiology and Pathophysiology Hepatic Functions  The liver is the first organ to encounter ingested nutrients, vitamins, metals, drugs, and environmental toxicants as well as waste products of bacteria that enter portal blood.  Efficient scavenging or uptake processes extract t...

Liver toxicity   Physiology and Pathophysiology Hepatic Functions  The liver is the first organ to encounter ingested nutrients, vitamins, metals, drugs, and environmental toxicants as well as waste products of bacteria that enter portal blood.  Efficient scavenging or uptake processes extract these absorbed materials from the blood for catabolism, storage, and/or excretion into bile.  All the major functions of the liver can be altered detrimentally by acute or chronic exposure to toxicants Structural Organization:  Classically, the liver was divided into hexagonal lobules oriented around terminal hepatic venules (also known as central veins).  At the corners of the lobule are the portal triads (or portal tracts), which contain a branch of the portal vein, a hepatic arteriole, and a bile duct.  The lobule is divided into three regions: the centrolobular, midzonal, and periportal regions. The preferred concept of a functional hepatic unit is the acinus.  The base of the acinus is formed by the terminal branches of the portal vein and the hepatic artery, which extend out from the portal tracts. The acinus has three zones: Zone 1 is closest to the entry of blood, zone 3 abuts the terminal hepatic vein, and zone 2 is intermediate. The three zones of the acinus roughly coincide with the three regions of the lobule.  Acinar zonation is of considerable functional consequence in regard to gradients of components in both blood and hepatocytes. Blood entering the acinus consists of oxygen-depleted blood from the portal vein (60 to 70 percent of hepatic blood flow) and oxygenated blood from the hepatic artery (30 to 40 percent). En route to the terminal hepatic venule, oxygen rapidly leaves the blood to meet the high metabolic demands of the parenchymal cells. Hepatocytes in zone 3 are exposed to substantially lower concentrations of oxygen than are hepatocytes in zone 1. In comparison to other tissues, zone 3 is hypoxic. Other well-documented acinar gradients exist for bile salts, bilirubin, and many organic anions.  Hepatocytes in the mitochondria-rich zone 1 are predominant in fatty acid oxidation, gluconeogenesis, and ammonia detoxification to urea. Gradients of enzymes involved in the bioactivation and detoxification of xenobiotics have been observed along the acinus by immunohistochemistry. Notable gradients for hepatotoxins are the higher levels of glutathione in zone 1 and the greater amounts of cytochrome P450 proteins in zone 3, particularly the CYP2E1 isozyme that is inducible by ethanol. Hepatic sinusoids   Hepatic sinusoids are the channels between cords of hepatocytes where blood percolates on its way to the terminal hepatic vein. The three major types of cells in the sinusoids are endothelial cells, Kupffer cells, and stellate cells. Bile Formation  Bile is a yellow fluid containing bile salts, glutathione, phospholipids, cholesterol, bilirubin and other organic anions, proteins, metals, ions, and xenobiotics.   The formation of this fluid is a specialized function of the liver. Adequate bile formation is essential for the uptake of lipid nutrients from the small intestine, protection of the small intestine from oxidative insults, and excretion of endogenous and xenobiotic compounds.  Hepatocytes begin the process by transporting bile salts, glutathione, and other solutes into the canalicular lumen.  Metals are excreted into bile by a series of partially understood processes that include (1) uptake across the sinusoidal membrane by facilitated diffusion or receptor-mediated endocytosis, (2) storage in binding proteins or lysosomes, and (3) canalicular secretion by lysosomes, a glutathionecoupled event, or a specific canalicular membrane transporter. Biliary excretion is important in the homeostasis of metals, notably copper, manganese, cadmium, selenium, gold, silver, and arsenic. Inability to export Cu into bile is a central problem in Wilson's disease, a rare genetic disorder characterized by the accumulation of Cu in the liver and then in other tissues.  Secretion into biliary ducts is usually but not always a prelude to toxicant clearance by excretion in feces or urine. Exceptions occur when compounds are delivered repeatedly into the intestinal lumen in bile, absorbed efficiently from the intestinal lumen, and then redirected to the liver in portal blood, a process known as enterohepatic cycling.  Note:Neonates are more prone to develop jaundice when treated with drugs that compete with bilirubin for biliary clearance.  Types of Injury and Toxic Chemicals 1-Fatty Liver  This change, which also is known as steatosis, consists of a buildup of lipids in the hepatocyte. Fatty liver can stem from disruptions in lipid metabolism. Steatosis is a common response to acute exposure to many hepatotoxins. Often toxin-induced steatosis is reversible and does not lead to the death of hepatocytes. The metabolic inhibitors ethionine, puromycin, and cycloheximide cause fat accumulation without causing the death of cells. 2-Cell Death  Liver cells can die by two different modes: necrosis and apoptosis. Necrosis is characterized by cell swelling, leakage, nuclear disintegration, and an influx of inflammatory cells. Apoptosis is characterized by cell shrinkage, nuclear fragmentation, the formation of apoptotic bodies, and a lack of inflammation. When necrosis occurs in hepatocytes, the associated plasma membrane leakage can be detected biochemically by assaying plasma (or serum) for liver cytosol-derived enzymes such as alanine aminotransferase (ALT) and glutamyltranspeptidase (GGT).  Mechanisms of toxin-induced injury to liver cells include lipid peroxidation, binding to cell macromolecules, mitochondrial damage, disruption of the cytoskeleton, and massive calcium influx. 3-Canalicular Cholestasis: as a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile, cholestasis is characterized biochemically by elevated serum levels of bile salts and bilirubin. Also they are accumulated in the skin and eyes, producing jaundice, and spills into urine, which becomes bright yellow or dark brown. 4-Bile Duct Damage  Damage to the intrahepatic bile ducts (which carry bile from the liver to the gastrointestinal tract) is called cholangiodestructive cholestasis. A useful biochemical index of bile duct damage is a sharp elevation in serum alkaline phosphatase activity. In addition, serum levels of bile salts and bilirubin are elevated, as is observed with canalicular cholestasis. Chronic administration of toxins that cause bile duct destruction can lead to biliary proliferation and fibrosis resembling biliary cirrhosis. 5-Sinusoidal Damage  Functional integrity of the sinusoid (channels between hepatocytes that carry blood throughout the liver) can be compromised by dilation or blockade of its lumen or progressive destruction of its endothelial cell wall. These disruptions of the sinusoid are considered the early structural features of the vascular disorder known as veno-occlusive disease, which occurs after exposure to pyrrolizidine alkaloids, which are found in some herbal teas and chemotherapeutic agents. 6-Cirrhosis  Cirrhosis is characterized by the accumulation of extensive amounts of collagen fibers in response to direct injury or inflammation. With repeated chemical insults, destroyed hepatic cells are replaced by fibrotic scars. With continuing collagen deposition, the architecture of the liver is disrupted by interconnecting fibrous scars. Cirrhosis is not reversible. 7-Tumors:  Chemically induced neoplasia can involve tumors that are derived from hepatocytes or bile duct cells or the rare, highly malignant angiosarcomas derived from sinusoidal lining cells. Hepatocellular cancer has been linked to abuse of androgens and a high prevalence of aflatoxin-contaminated diets. Multiple types of liver tumors are linked to thorium dioxide exposure. Bioactivation and Detoxification  Hepatocytes have very high constitutive activities of the phase I enzymes that often convert xenobiotics to reactive electrophilic metabolites. Also, hepatocytes have a rich collection of phase II enzymes that add a polar group to a molecule and thus enhance its removal from the body. Ethanol Genetic conditions of high clinical relevance to the bioactivation/detoxification balance are the polymorphisms in the enzymes that control the two-step metabolism of ethanol. Specifically, ethanol is bioactivated by alcohol dehydrogenase to acetaldehyde, a reactive aldehyde, which subsequently is detoxified to acetate by aldehyde dehydrogenase. Both enzymes exhibit genetic polymorphisms. Approximately 50 percent of Asian populations but virtually no white people have the slow aldehyde dehydrogenase; alcohol consumption by people with this slow polymorphism leads to uncomfortable symptoms of flushing and nausea caused by high systemic levels of acetaldehyde. Cytochrome P450  Cytochrome P450–dependent bioactivation as a mechanism of hepatotoxicity is important even for assumedly safe compounds because some P450 isozymes generate reactive oxygen species during biotransformation reactions, and this can lead to liver damage. CYP2E1 generation of reactive oxygen species and other free radicals is a factor in the etiology of serious, end-stage liver damage. Acetaminophen  Typical therapeutic doses of acetaminophen are not hepatotoxic, because most of the acetaminophen gets glucuronidated or sulfated with little drug bioactivation.  Injury after large doses of acetaminophen is enhanced by fasting and other conditions that deplete glutathione and is minimized by treatments with N-acetylcysteine that enhance hepatocyte synthesis of glutathione.  This acquired enhancement often has been attributed to accelerated bioactivation of acetaminophen to the electrophilic N-acetyl-pbenzoquinone imine (NAPQI) intermediate by ethanol induction of CYP2E1. Inducers of CYP3A, including many drugs and dietary chemicals, potentially influence acetaminophen toxicity Schematic depicting the complex cascade of toxin-evoked interactions between hepatocytes and sinusoidal cells. (1) toxin injury to hepatocytes, (2) signals from the injured hepatocyte to Kupffer and Ito cells, followed by (3) Kupffer cell release of cytotoxins and (4) Ito cell secretion of collagen. Activation of Kupffer cells is an important factor in the progression of injury evoked by many toxicants Inflammatory and Immune Responses  Migration of neutrophils, lymphocytes, and other inflammatory cells into regions of damaged liver is a well-recognized feature of the hepatotoxicity produced by many chemicals. In fact, the potentially confusing term hepatitis refers to hepatocyte damage by any insult in cases where hepatocyte death is associated with an influx of inflammatory cells.  The influx of inflammatory cells usually facilitates beneficial removal of debris from damaged liver cells. However, detrimental effects are plausible, because activated neutrophils release cytotoxic proteases and reactive oxygen species.  Immune responses are considered factors in the hepatotoxicity occasionally observed after repeated exposure to chemicals, usually drugs. Individuals who develop infrequent, unpredictable responses are considered hypersensitive. An immune-mediated response is considered plausible when the problem subsides after therapy is halted and then recurs on drug challenge or the restoration of therapy. Proposed scenario of events leading to immune-mediated hepatotoxicity after repeated exposure to a toxicant that produces drug-protein adducts.