Hepatotoxicity hepatic steatosis

Herbal medicines are becoming more and more popular, and indeed some herbal products may be considered to benefit people with liver disease, e.g. Silybum marianum (milk thistle), Picrorhiza kurroa, Phyllanthus, etc. Herbal hepatotoxicity is increasingly being recognised, for example, with kava kava, black cohosh, and many traditional Chinese remedies. The range of liver injury includes minor transaminase elevations, acute and chronic hepatitis, steatosis, cholestasis, zonal or diffuse hepatic necrosis, veno-occlusive disease and acute liver failure. In addition to the potential for hepatotoxicity, herb-drug interactions may affect the safety and efficacy of concurrent medical therapy [15]. 

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT >3x ULN), cholestatic (ALP >2x ULN, ALT/ALP <2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

Hepatic Effects. Carbon tetrachloride has been known for many years to be a powerful hepatotoxic agent in humans and in animals. The principal clinical signs of liver injury in humans who inhale carbon tetrachloride are a swollen and tender liver, elevated levels of hepatic enzyme (aspartate aminotransferase) in the serum, elevated serum bilirubin levels and the appearance of jaundice, and decreased serum levels of proteins such as albumin and fibrinogen (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). In cases of acute lethal exposures, autopsy generally reveals marked liver necrosis with pronounced steatosis (Jennings 1955 Markham 1967 Smetana 1939), and repeated or chronic exposures leads in some cases to fibrosis or cirrhosis (McDermott and Hardy 1963). 

Hepatotoxicity is a concern. During the first few months of therapy, transient elevation of hepatic transaminases occurs in an average 11% (up to 40%) of patients. Fulminant hepatic failure will develop in 1 in 5000-10000 patients. In these cases there is hepatic necrosis, steatosis, and a Reye s syndromelike illness. Fatal hepatic injury is most likely in children less than 2 years old and in those patients on multiple-drug therapy. 

Valproic acid is rapidly distributed and the plasma protein binding is concentration dependent (18). As previously noted, valproic acid is extensively metabolized, primarily in the liver, with about 30-50% of the drug excreted as the glucuronide (phase II metabolism) in the urine, about 30-40%by the phase I mitochondrial j3-oxidation pathway, and about 10-20% by microsomal cytochrome P450-mediated hy droxylation/dehydrogena-tion of the side chain that provides the major phase I metabolites (36). The metabolites of valproic acid have been thought to be the cause of a rare, but fatal hepatotoxicity (35). The synthetic ( )-2,4-diene VPA has been shown to induce the same hepatic microve-sicular steatosis seen in patients, in chronic administration studies in rats (36). The ultimate causative factor (s) of hepatoxicity of valproic acid currently remain undefined (28,29). 

Hepatotoxicity, manifested by microve-sicular steatosis, transient depletion of hepatic glutathione, increased serum activities of alanine and aspartate aminotransferases, and diminished activity of serum alkaline phosphatase, develops in NiClj-treated rats (Donskoy et al. 1986). 

Given the multiple metabolic functions performed by the liver, it should not be surprising that the hepatotoxic effects of xenobiotics are so different several different morphological patterns of xenobiotic-induced hepatotoxicity can be observed (Plaa 1991 Batt and Ferrari 1995 Zimmerman 1999 Plaa and Charbonneau 2001 Kaplowitz 2002 Kaplowitz and DeLeve 2003 Lee 2003). For example, in acute toxicity, cell degeneration leads to necrosis (cell death), and this may or may not be accompanied by steatosis (an accumulation of lipids and fatty liver where hepatic lipid content is >5%). Necrosis may affect small groups of hepatocytes (i.e., focal... 

Though rarely used in current practice, this solvent was an important cause of hepatotoxicity in the past. Its hepatotoxic potential was first identified during its use in the first World War. Animal hepatotoxicity with fatty degeneration of the fiver has been documented in multiple species. Human inhalational exposures manifest in fiver enlargement, jaundice, steatosis with subsequent fiver failure in severe poisonings. Subacute exposure periods of weeks to months is generally required for hepatic injiuy. Liver regeneration oc-... 

Valproic add (2-propyl-n-pentanoic acid, VPA) is an anticonvulsant widely used in the treatment of various epileptic disorders. It has been known that VPA administration caused severe hepatic dysfunction similar to Reye s syndrome in a small number of patients. Deaths from hepatotoxicity were also reptorted. VPA affects carnitine and ammonia levels and other metabolic parameters related to fatty acid oxidation. The potential hepatotoxidty by VPA is caused by its unsaturated metabolites, such as 4-en-VPA. Histologically, miaovesicular steatosis induced by 4-en-VPA is accon )anied by ultrastructural changes characterized by myeloid bodies, lipid vacuoles and mitochondrial abnormaUties. An enhanced excretion of Cg to Cio dicarboxylic acids by patients and rats indicates an interference with mitochondrial 3-oxidation as an important pathogenesis. If the normal pathway of fatty add oxidation is disrupted by VPA, it results in reduced ketone body formation and decrease of free coenzyme-A (CoA) in the liver. Especially, deaeased CoA would limit the activities of one or more enzymes in the pathway of fatty add oxidation. 

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