Liver drug-induced

Liver Drug-induced liver injury occurs quite often, but is imderreported. A case of cholestatic hepatitis with small duct injury due to celecoxib use was published. 

McMillian M, Nie A, Parker JB, Leone A, Kemmerer M, Bryant S, et al. Drug-induced oxidative stress in rat liver from a toxicogenomics perspective. Toxicol Appl Pharmacol 2005 207 171-8. 

Newsholme SJ et al. Two-dimensional electrophoresis of liver proteins characterization of a drug-induced hepatomegaly in rats. Electrophoresis 2000 21 2122-2128. 

Alkaline phosphatase levels and GGT are elevated in plasma with obstructive disorders that disrupt the flow of bile from hepatocytes to the bile ducts or from the biliary tree to the intestines in condition such as primary biliary cirrhosis, sclerosing cholangitis, drug-induced cholestasis, gallstone disease, and autoimmune cholestatic liver disease. 

Reprinted from J Gin Epidemiol, Vol 46, Danan C, Benichou C. Causality assessment of adverse reactions to drugs-4. A novel method based on the conclusions of international consensus meetings- Application to drug-induced liver injuries pages 1323-1330, Copyright 1993, with permission from Elsevier. 

See Chapter 40, Drug-Induced Liver Disease, authored by William R. Kirchain and Rondall E. Allen, for a more detailed discussion of this topic. 

Liu, Z.X., Kaplowitz, N., Immune-mediated drug-induced liver disease, Clin. Liver Disease, 6, 755, 2002. 

Laskin, D.L. and Gardner, C.R., Role of sinusoidal cells and inflammatory macrophages in hepatotoxicity, in Drug induced Liver Disease, Kaplowitz, N. and DeLeve, L, Eds., Marcel Dekker, New York, 2002, 183-211. 

From investigations of the effect of emorfazone on liver drug-metabolizing enzymes, (3) has been classified as a phenobarbitone (phenobarbital)-type inducer of enzymes [65]. For results of clinical evaluations of emorfazone, see [66, 67],... 

Kaplowilz, N. (2001). Drug induced liver disorders Implications for drug development and regulation. Drug Information Journal, 35 347 100. 

Of course, Rezulin is nof fhe only drug implicated in liver toxicity. In fact, the FDA recently posted a nottce on its website (http //fda.gov/), describing a special interesf and monitoring of drug-induced hepatotoxicity ... 

We call attention also to the web site for the Drug-Induced Liver Injury Network (DILIN) sponsored since 2003 by the National Institutes of Health (NIH), Liver Disease Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). 

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 ... 

Monitoring A high index of suspicion for drug-related hepatic injury is critical if the occurrence of liver damage induced by naltrexone is to be detected at the earliest possible time. 

CYP450 Rifabutin has liver enzyme-inducing properties. The related drug, rifampin, is known to reduce the activity of a number of other drugs. Because of the structural... 

Lammert, C., Einarsson, S., Saha, C Niklasson, A., Bjornsson, E. and Chalasani, N. (2008) Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury search for signals. Hepatology (Baltimore, Md), 47, 2003-2009. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

In vivo, measuring bile acids in plasma and urine should be revived as potential biomarkers in the modern metabolomic era. Then the first-order scientific question will become whether early and time-controlled fasting-level measurement of bile acid concentration in plasma and urine can become a sensitive and specific biomarker for drug-induced cholestasis and ultimately liver injury at later time-points [117] Clinical trials should be conducted to evaluate whether such bile acid measurements can be used as part of a predictive panel to identify patients who are at increased risk of drug-induced cholestasis. 

---