hepatic and biliary disorders
Liver Injury Caused by Drugs
Pathophysiology of Drug Related Liver Injury
The pathophysiology of drug-induced liver injury (DILI) varies depending on the drug (or other hepatotoxin) and, in many cases, is not entirely understood. Drug-induced injury mechanisms include covalent binding of the drug to cellular proteins resulting in immune injury, inhibition of cell metabolic pathways, blockage of cellular transport pumps, induction of apoptosis, and interference with mitochondrial function. In general, the following are thought to increase risk of DILI: Age≥18 years Obesity Pregnancy Concomitant alcohol consumption Genetic polymorphisms (increasingly recognized) DILI can be predictable (when injury usually occurs shortly after exposure and is dose-related) or unpredictable (when injury develops after a period of latency and has no relation to dose). Predictable DILI (commonly, Acetaminophen Poisoning ) is a common cause of acute Biochemically, 3 types of liver injury are generally noted (see table): Hepatocellular hepatotoxicity generally manifests as malaise and right upper quadrant abdominal pain, associated with marked elevation in aminotransferase levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or both), which may be followed by hyperbilirubinemia in severe cases. Hyperbilirubinemia in this setting is known as hepatocellular jaundice and, according to Hy’s law, is associated with mortality rates as high as 50%. If hepatocellular liver injury is accompanied by jaundice, impaired hepatic synthesis, and encephalopathy, chance of spontaneous recovery is low, and Liver Transplantation should be considered. This type of injury can result from drugs such as Cholestatic:Cholestatic hepatotoxicity is characterized by development of pruritus and jaundice accompanied by marked elevation of serum alkaline phosphatase levels. Usually, this type of injury is less serious than severe hepatocellular syndromes, but recovery may be protracted. Substances known to lead to this type of injury includeamoxicillin/clavulanate andchlorpromazine. Rarely, cholestatic hepatotoxicity leads to chronic liver disease and vanishing bile duct syndrome (progressive destruction of intrahepatic bile ducts). Mixed:In these clinical syndromes, neither aminotransferase nor alkaline phosphatase elevations are clearly predominant. Symptoms may also be mixed. Drugs such asphenytoincan cause this type of injury. 