Defining patient risks from expanded preventive therapies.
In clinical trials, all lipid-lowering agents have been associated with mild, asymptomatic elevations of alanine aminotransferase (ALT) and asparate aminotransferase enzymes. This, along with the fact that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are hepatotoxic in some animals, led the US Food and Drug Administration (FDA) to recommend monitoring of liver enzymes for all lipid-lowering agents, except the bile acid sequestrants. Because the drugs act by different mechanisms, ALT elevations may be a pharmacodynamic effect related to lipid lowering, rather than a direct effect of the drug. Animal studies support this assumption. ALT elevations of 3 times the upper limit of normal occur in <3% of patients in clinical trials of lipid-lowering drugs. The elevations are transient and often dose-related, and they usually revert to normal while continuing therapy and have never been associated with hepatotoxicity. Confounding factors include alcohol, acetaminophen, and pre-existing liver disease, such as chronic hepatitis C and type II diabetes with fatty liver, which are both associated with mild, intermittent elevations of ALT. The more important issue is whether or not lipid-lowering agents are hepatotoxic. There are case reports of hepatotoxicity (cholestasis, jaundice, hepatitis, chronic active hepatitis, fatty liver, cirrhosis and acute liver failure) with all of the drugs, except cholestyramine. To date there are just 5 cases of documented liver failure linked to lovastatin. There is no evidence that monitoring reduces the rate of hepatotoxicity. Mild elevations of ALT that occur with many drugs, including HMG-CoA reductase inhibitors, do not predict hepatotoxicity. Liver enzyme elevations appear to be a class characteristic of lipid-lowering agents. Hepatotoxicity is a rare idiosyncratic reaction, occurring only with sustained released nicotinic acid.
Tolman
K G
KG
Gastroenterology/Liver Division, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015994:Incidence; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000453:epidemiology; D008148:Lovastatin / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008148:Lovastatin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase