Anabolic androgenic steroid-induced liver injury: An update

Figure 1 Proposed mechanisms of anabolic androgen steroid-induced liver injury. A: Oxidative stress in the mitochondria. Anabolic androgenic steroids (AASs) impair mitochondrial respiratory function, which leads to reactive oxygen species (ROS) accumulation. Cell membrane is damaged due to lipid peroxidation and intracellular ATP depletion occurs due to mitochondrial impairment. This results in cellular dysfunction at many levels (e.g., toxic compounds can enter the cell). Mitochondrial morphology is also changed, with reduced cristae and swelling. In addition, there is an increase in lysosome number. Lack of energy supply eventually leads to hepatocyte necrosis; B: Immune cell infiltration of liver parenchyma. Long-term treatment with AASs like nandrolone is associated with immune cell infiltration which maintains proinflammatory state in liver tissue. Under such conditions, Kupffer cells release transforming growth factor beta1 (TGF-β1), tumor necrosis factor alpha (TNFα), and interleukin-1B (IL-1B) which mediate hepatic stellate cell activation: Extracellular matrix and collagen deposition leading to liver fibrosis; C: Hepatocyte hyperplasia causes formation of hepatic tumors. In rats treated with high-dose nandrolone, it was observed that it supported the viability of hepatic stem cells, which are potential reservoir of cancer stem cells. Nodular hepatocyte hyperplasia causes parenchyma distortion and mechanical blockage of vasculature which forms cystic lesions filled with blood, known as peliosis hepatic; D: “Bland cholestasis”. Activation of androgen receptors (ARs) by AASs interferes with bile transporters, mediates intrahepatic microfilament damage, and increases expression of genes for acid bile and bile transporter synthesis, and these changes result in bile acid accumulation, cholestasis, and cholestatic jaundice. SOD: Superoxide dismutase; CAT: Catalase; AR: Androgene receptor; AAS: Anabolic androgenic steroid; AR: Androgen receptor. Figure created with Servier Medical Art, https://smart.servier.com/.