Hepatocellular injury

Treatment with iron chelators and a-tocopherol protect against lipid p>eroxidation and hepatocellular injury in iron-overloaded rats (Sharma etal., 1990). When hepatocytes are isolated from rats, which have been pretreated with a-tocopherol, there is a significant reduction in iron-induced lipid peroxidation and improvement in cell viability in vitro (Poli et al., 1985). Similar effects were seen when hepatocytes were incubated with iron chelators (Bacon and Britton, 1990). Treatment of moderately, but not heavily, iron-loaded rats with desferrioxamine in vivo inhibits the pro-oxidant activity of hepatic ultrafiltrates (Britton et al., 1990b). 

Diagnosing viral hepatitis may be difficult because most infected individuals are asymptomatic. Because symptoms cannot identify the specific type of hepatitis, laboratory serologies must be obtained (Table 21-2). In addition, liver function tests may be obtained to assess the extent of cholestatic and hepatocellular injury. However, the definitive test to determine the amount of damage and inflammation of hepatic cells is a liver biopsy. 

Herbal remedies that have been reported to be he-patotoxic include chaparral (Larrea tridentata), germander (Teucrium chamaedrys), and life root (Senecio aureus) [18]. Cases reported patients developing jaundice, fatigue, pruritus, markedly elevated serum liver enzyme levels, severe cholestasis, hepatitis, and hepatocellular injury or necrosis documented by serial liver biopsies [19-21]. Signs and symptoms may occur as early as 3 weeks to as late as 7 months following ingestion [20,21]. 

The aminotransferases, aspartate transaminase and alanine transaminase, are enzymes that have increased concentrations in plasma following hepatocellular injury. The highest concentrations are seen in acute viral infections, or ischemic or toxic liver injury. 

Following ingestion of the substance, the gastrointestinal (GI) tract is the site of initial or phase I toxicity to the mucosal surfaces. This toxicity is manifested by swelling, edema, and painful ulceration of the mouth, pharynx, esophagus, stomach, and intestine. With higher levels, other GI toxicity includes centrizonal hepatocellular injury, which can cause elevated bilirubin, and hepatocellular enzyme levels such as AST, ALT, and LDH. 

Hepatotoxicity Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses. 

Hepatotoxicity Naltrexone has the capacity to cause direct hepatocellular injury when given in excessive doses. It is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects. 

Use of carvedilol in patients with clinically manifest hepatic impairment is not recommended. Mild hepatocellular injury, confirmed by rechallenge, has occurred rarely with carvedilol therapy. 

Discontinue nefazodone if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels at least 3 times the upper limit of normal while on nefazodone should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone is reintroduced. Accordingly, do not consider such patients for retreatment. 

The incidence of transaminase elevations is higher among females. There are no other known predictors of the risk of hepatocellular injury. 

Evidence that a drug causes hepatocellular injury, as shown by a serum ALT >3 x the upper limit of normal (ULN). 

No evidence of another cause of hepatocellular injury, such as viral hepatitis, marked hypotension, or congestive heart failure. 

Loyke HF, Maksem JA. 1992. Hepatocellular injury induced by chronic low-dose CCh in spontaneous and renal hypertensive rats a correlation to the reversal of experimental rat hypertensive models. J Environ Pathol Toxicol Oncol 11 38-42. 

Hepatocellular injury may occur with large doses. 

Direct hepatocellular injury, e.g. antituberculous drugs (e.g. rifampicin), erythromycin, high-dose penicillins (e.g. flucloxacillin), fluconazole and flucytosine Granulocytopaenia, e.g. high-dose penicillins/cephalosporins Immune thrombocytopaenia/Coombs positive anaemia, e.g. penicillins, cephalosporins... 

Maeda K. Hepatocellular injury in a patient receiving pioglitazone. Ann Intern Med 2001 135(4) 306. 

Rechallenge was not attempted, but other potential causes of hepatocellular injury were ruled out. 

A 64-year-old woman who was twice treated with pravastatin had cholestasis on both occasions with minimal hepatocellular injury (6). 

The two most serious toxic effects of valproic acid are hepatocellular injury (96) and teratogenesis (97). Since CYP2A6 and CYP2C9 are known to oxidize valproic acid to a 4-ene metabolite that is hepatotoxic, inducers of these isoforms, including other antiepileptic agents, are likely to increase the risk of hepatotoxicity (98). However, valproic acid also is metabolized by several other pathways that may be involved in causing its toxicities (99). 

In three cases chronic hepatocellular injury developed with oral bentazepam (1). 

Response is dose related (as is hepatocellular injury), and both response and increased liver function tests (LFTs) resolve with stopping the drug. 

ALT and AST are enzymes released from hepatocytes when they are damaged, resulting in high serum levels when there is hepatocellular injury. 

In an acute hepatocellular injury, such as following a paracetamol overdose, there may he significant damage over a short period. This results in a marked increase in the AST and ALT levels (which can be in the thousands) due to massive hepatocyte damage or death. The converse can occur with chronic severe disease, where the hepatocyte mass has reduced to such an extent that the AST and ALT levels have returned to normal owing to the reduction in hepatocyte numbers able to release the enzyme (i.e. a false normal result). In fatty liver, ALT and AST levels are likely to be up to three times ULN, whereas in hepatitis ALT and AST levels can range from nearly normal to in the hundreds, depending on how acute the condition is. 

Hepatotoxicity, sometimes requiring liver transplant and/or tatal, has occurred with netazodone use. Risk may be one in every 250,000 to 300,000 patient years. Patients should be advised to report symptoms such as jaundice, dark urine, loss of appetite, nausea, and abdominal pain to prescriber immediately, if patient develops signs of hepatocellular injury, such as increased serum AST or serum ALPT levels >3 times the upper limit of normal, nefazodone treatment should be discontinued. 

One report noted renal tubular nephritis in a worker killed after an explosion inside a plant manufacturing CS agent (Cookson and Nottingham, 1969). Hepatocellular injury has been linked to serious CS inhalation (Krapf and Thahnann, 1981). To date, animal studies have not documented any relationship between RCA exposure and teratogenicity (Himsworth et ah, 1971 Upshall, 1973 Folb and Talmud, 1989). CS did not demonstrate mutagenic potential with the Ames assay (Rietveld et ah, 1983). Similarly, CR did not have carcinogenic effects in mice or hamsters (Blain, 2003) CS lacks mutagenicity in several test systems (Daniken et al, 1981 Wild eta/., 1983). 

Hepatocellular injury (toxic, infectious) leads to decreased activity of drug-metabolising enzymes, which is reflected in diminished plasma clearance of drugs that are metabolised. There is much variation between patients, and often overlap with healthy subjects. 

Romagnnolo, J., Sadowskl, D.C., Lalor, E., Jewell, L., Thomson, AJ3.R. Cholestatic hepatocellular injury with azathioprine A case report and review of the mechanisms of hepatotoxicity. Can. J. Gastroenterol. 1998 12 479 -483... 

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