Acute liver

Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. I he forms of acute liver toxicity are accumulation of lipids in the liver, hepartxiellular necrosis, iii-trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chrome hepatotoxicity are cirrhosis and liver cancer. 

Acute Liver Damage Several compounds (e.g., dimethyl iiitrosoamine, carbon tetrachloride, and thioacetamide) cause necrosis of hepatocytes by inhibiting pro tein syndiesis at the translational level, i.e., by inhibiting the addition of new amino adds into the protein chain being sjTithetized. This is not, however, the only mechanism. Ethioiiine is a compound which inhibits protein synthesis bur doe not induce... 

IIBI TABLE 5.15 Chemical Compounds that Induce Acute Liver Damage... 

Acid-base imbalance Acute liver failure Amphetamines Anaphylaxis Autoimmune diseases Cholestasis Chronic inflammatory diseases... 

Type A HE is induced by acute liver failure, Type B results from portal-systemic bypass without intrinsic liver disease, and Type C occurs with cirrhosis. HE may be classified as episodic, persistent, or minimal. 

The reactions of nucleophiles with benzoquinone and related compounds can also be viewed as Michael reactions. Benzoquinone is one of the reactive metabolites of benzene, a solvent also associated with aplastic anemia (Fig. 8.14). A similar reactive metabolite is responsible for the hepatotoxicity of acetaminophen (Fig. 4.71), the most common cause of acute liver failure however, most of this reactive metabolite is detoxified by reaction with glutathione, and it is only when glutathione is depleted to approximately 10% of the normal level that significant toxicity ensues. 

Its use was associated with a markedly increased risk of acute idiopathic liver injury and acute liver failure [50]. 

Graham, D.J., Drinkard, C.R. and Shatin, D. (2003) Incidence of idiopathic acute liver failure and hospitalized liver injury in patients treated with troglitazone. The American Journal of Gastroenterology, 98, 175—179. 

The reader should note the emphasis in the above paragraphs drug-induced hepatotoxicity is the leading cause of acute liver failure and the number one reason for regulatory actions against drugs in the United States ... 

Hepatic Effects. Hepatic effects have been reported in humans following long-term exposure to 1,4-diehlorobenzene via inhalation. A 60-year-old man and his wife who were exposed to mothball vapor that "saturated" their home for 3-4 months both died of liver failure (acute liver atrophy) within a year of the initial exposure (Cotter 1953). Yellow atrophy and cirrhosis of the liver were reported in a 34-year-old woman who demonstrated 1,4-dichlorobenzene products in a department store and in a 52-year-old man who used 1,4-diehlorobenzene occupationally in a fur storage plant for about 2 years (Cotter 1953). Duration of exposure was not estimated for the 34-year-old woman, but was indicated in the report to be more than 1 year. No estimates of the 1,4-diehlorobenzene exposure levels (other than the use of the term saturated ) were provided in any of these reports, nor was it verified that... 

Workers tolerated short-term exposures to 400-500 ppm without apparent adverse effects. Inhalation of a 98% solution over the course of an evening resulted in acute liver damage, as... 

Active thrombophlebitis or thromboembolic disorders undiagnosed abnormal genital bleeding known or suspected pregnancy acute liver disease benign or malignant... 

Liver Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequent, usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have occurred these latter lesions often are not preceded by symptoms or abnormal liver function tests (see Precautions). For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the RA population. 

Hepatotoxicity Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis, have been reported rarely in postmarketing data in patients receiving infliximab. Autoimmune hepatitis has been diagnosed in some of... 

Paulet and Desbrousses (1974) found no signs of liver effects in rats exposed to atmospheres containing chlorine dioxide levels as high as 10 ppm (28 mg/m ), 2 hours/day for 30 days. On the other hand, Dalhamn (1957) reported acute liver congestion in rats that had been exposed for 4 hours/day over 9 days in a 13-day period. However, the liver congestion may have been secondary to primary respiratory effects. 

Lee, C.H. et al. (2007) Protective mechanism of glycyrrhizin on acute liver injury induced by carbon tetrachloride in mice. Biological ei Pharmaceutical Bulletin, 30 (10), 1898-1904. 

Several types of acute liver porphyrias produce episodic attacks of neurologic and psychological symptoms as well as gastrointestinal distress. 

Johnson SJ, Hines JE, Burt AD. 1992. Macrophage and perisinusoidal cell kinetics in acute liver injury. J Pathol 166 351-358. 

Hepatitis A is common, particularly in areas of poor sanitation, and is transmitted by food or drink contaminated by a sulferer/carrier. Clinical symptoms include jaundice, and are usually mild. A full recovery is normally recorded. Hepatitis B is transmitted via infected blood. Symptoms of acute hepatitis B include fever, chill, weakness and jaundice. Most sufferers recover from such infection, although acute liver failure and death sometimes occur 5-10% of sufferers go on to develop chronic hepatitis B. Acute hepatitis C is usually mild and asymptomatic. However, up to 90% of infected persons go on to develop a chronic form of the condition. Hepatitis D is unusual in that it requires the presence of hepatitis B in order to replicate. It thus occurs in some persons concomitantly infected with hepatitis B virus. Its clinical symptoms are usually severe, and can occur in acute or chronic form. 

Acute liver failure, beginning within one or two days of overdosage, can lead to encephalopathy, haemorrhage, oedema and death. Prolongation of prothrombin time is proportional to the degree of liver injury and is the best guide to severity of liver injury. Peak toxicity is seen 3 days after the overdose is taken. 

Corticosteroids have no value in supportive therapy. Acute liver failure is the main problem and specific features noted below require treatment ... 

Dyspepsia is the most common side effect of zileuton. Liver transaminase levels are elevated in a small percentage of patients taking zileuton. Serum Uver transaminase levels should be monitored and treatment halted if significant elevations occur. Zileuton inhibits the metabolism of theophylline. Thus, when these agents are used concomitantly, the dose of theophylline should be reduced by approximately one-half, and plasma concentrations of theophylline should be monitored closely. Caution should also be exercised when using zileuton concomitantly with warfarin, terfenadine, or propranolol, as zileuton inhibits the metabolism of these agents. Zileuton is contraindicated in patients with acute liver disease and should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. 

There appears to be little difference between benzodiazepines and kava extract in anxiolytic activity. However, kava extracts seem to have fewer side effects. Two studies with more than 3000 patients each found unwanted events in about 2% of patients during treatment with kava extract. The more frequently reported side effects were gastrointestinal complaints, allergic skin reactions, headache, and photosensitivity (Pittler and Ernst, 2000). There have been isolated reports of hepatotoxicity and acute liver failure (Escher et ah, 2001). Kava may potentiate the sedative effects of other medications including barbiturates and benzodiazepines. Kava can also cause behavioral disinhibition in a minority of individuals, including children. The most common problem, which is usually associated with persistent and excessive usage, is a scaly skin rash called kava dermopathy, which is reversible. 

Kortsalioudaki, C., Taylor, R. M., Cheeseman, P., Bansal, S., Mieli-Vergani, G., and Dhawan, A. (2008). Safety and efficacy of N-acetylcysteine in children with non-acet-ammophen-induced acute liver failure. Liver Transpl. 14(1), 25-30. 

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