Table 1.

Summary of reported mechanisms responsible for liver injury in patients with HIV.

Mechanism	Contribution	Details	References
Oxidative stress	Moderate	This is a process whereby free reactive oxygen species (ROS) provoke increased activation of Kupffer cells in the liver. In turn, these activated immune cells promote stellate cell activation via nuclear factor kappa-beta (NF-kB) and activator protein 1, leading to increased production of proinflammatory and profibrotic cytokines, resulting in liver damage, fibrosis, and cirrhosis. Nucleoside reverse transcriptase inhibitors (NRTIs) such as didanosine can cause oxidative stress and mitochondrial toxicity.	(21)
Mitochondrial injury	Moderate	As the primary source of energy in the hepatocyte, any process that impairs mitochondrial function may lead to hepatic injury. During HIV, mitochondrial injury can occur through increased stress on the endoplasmic reticulum (ER), initiated by activation of the IRE1/TRAF 2 (Inositol Requiring 1/TNF receptor-associated factor 2) pathway. NRTIs and protease inhibitors (PIs) can directly cause mitochondrial toxicity.	(21, 72, 73)
Immune-mediated injury	Moderate	HIV can interact with hepatic stellate cells (HSCs) via gp120, producing inappropriate activation and increased HSC production of collagen and monocyte chemoattractant protein (MCP-1) (a macrophage chemoattractant). HIV decreases the number of Kupffer cells in the liver, decreasing the ability of the liver to clear products of microbial translocation. HIV provokes alterations in cytokine profiles resulting from imbalance between CD4+ and CD8+ T-cells	(21, 74, 75)
Cytotoxicity	Mild	HIV triggers apoptosis via the HIV gp120 protein-receptor signaling pathway.	(76)
Systematic inflammation	Significant	The systematic inflammation resulting from HIV infection may induce fibrosis via a number of mechanisms, including oxidative stress and mitochondrial dysfunction as a result of ER stress. CD4/CD8 imbalances seen in HIV can lead to underexpression of IFN-gamma (an antifibrotic cytokine), thus favoring induction of apoptosis of activated HSCs, and hepatic progression into a profibrotic state.	(21, 77, 78)
Gut microbial translocation	Significant	This leads to hepatic injury primarily via increased hepatic levels of bacterial lipopolysaccharides (LPS), causing hepatic inflammation. More specifically, hepatic inflammation may result from (i) recruitment and activation of inflammatory cells (Kupffer cells and HSCs), (ii) systemic immune responses promoting hepatocyte cell death, or (iii) production of proinflammatory cytokines and acute phase reactants such as transforming growth factor beta 1 (TGFB1), IL-6, and IL-10	(79–81)
Nodular regenerative hyperplasia	Significant	This is a rare condition in which diffuse transformation of the liver parenchyma into micronodules without intervening fibrosis leads to non-cirrhotic portal hypertension in patients with HIV. Pathophysiologically, it is thought that gut bacterial translocation may be responsible for vascular endothelial disruption, vascular and peri-vascular fibrosis and stenosis, and portal hypertension. The epithelial damage observed in the liver isare thought to either be immune-mediated or possibly related to direct viral damage by HIV.	(82–84)