Pathogenetic mechanisms of drug-induced liver damage

Abstract

Drug-induced liver damage (DILD) is a common condition that can lead in some cases to acute liver failure and unfavorable patient outcomes. DILD development mechanisms are of two main types. The first is a direct dose-dependent type and the second is dose-independent idiosyncratic one. Cytochrome P450 system is of great importance in the genesis of direct DILD, since during drugs metabolism highly toxic metabolites can be formed in this liver enzymatic system. As a result, hepatocytes die destructing mitochondria and thus blocking the production of cell energy substrates, triggering oxidative stress and lipid peroxidation. It also leads to direct DNA damage and activation of signaling pathways for apoptosis. In most cases idiosyncratic DILD is associated with individual genetically determined predisposition with a wide range of clinical manifestations. In case of this type of DILD, the immune cells are sensitized to hepatocytes activating humoral and cellular immune response and rather often forming antibodies to some structural element of hepatocytes. The structure of antigens of the main histocompatibility complex as well as receptor-mediated interactions with Fas-ligand participation, interferon gamma and tumor necrosis factor play a certain role in the development of idiosyncratic DILD. By present, hypotheses of immune system activation in idiosyncratic DILD have been proposed, including haptenization hypothesis; the hypothesis of direct interaction of drugs with the molecules of major histocompatibility complex and subsequent activation of the immune system; the hypothesis of changes in structural sequences of endogenous biologically active peptides with impaired interaction in the backbones of major histocompatibility complex and occurrence of autoimmune reactions. Finally, there is the hypothesis of multiple determinants, which postulates that there are various risk factors (for example, genetic polymorphisms, gender, age, etc.) that contribute to DILD onset in case of comorbidity. DILD mechanisms can also be considered according to clinical and morphological type of liver damage. One can distinguish cholestatic DILD type, vascular type, steatosis, and the type when liver tumor develops. The cholestatic DILD type is clinically expressed by cholestasia or inability of bile to enter the lumen of small intestine as a result of abnormal secretion of bile acids by hepatocytes or obstruction of biliary tract. Hepatic steatosis is histologically determined as deposition of triglycerides within hepatocytes. Drug-induced steatosis is reversible unless steatohepatitis or cirrhosis has developed. Vascular DILD type is associated with damage of stellate and endothelial liver cells, lining sinusoidal capillaries. Edema, thrombosis of small intrahepatic vessels, develop as a result of it, leading to obstruction of venous outflow (and impaired lymph outflow), expansion of sinusoids, pressure overload and hepato-hepatic necrosis, and, in some cases, to centrilobular fibrosis. This pathology is known as sinusoidal obstruction syndrome or venous-occlusive disease. DILD type with the development of liver tumor includes hepatocellular adenoma, hepatocellular carcinoma, cholangiocarcinoma. Awareness of pathogenetic DILD correlations is important in real clinical practice, since, on the one hand, it allows to optimize the diagnostic search for the cause of liver disease, and on the other hand, it increases the effectiveness of approaches to treat and prevent such conditions.