Adverse effects of antiretroviral therapy on liver hepatocytes and endothelium in HIV patients: An ultrastructural perspective

Abstract

Human immunodeficiency virus and antiretroviral therapy (ART) together can be far more detrimental to liver cells than either of the two unaided. However, ultrastructural aspects of the synergistic effects of HIV and ART have been understudied. In a patient cohort receiving ART, this study characterizes ultrastructurally sinusoidal degeneration, hepatocytic aberrations, mitochondrial dysfunction, accumulation of bulky lipid droplets (steatosis), and occlusion of sinusoidal lumina. Mitochondrial dysfunction causes the accumulation of acetyl-CoA which leads to insulin upregulation and resistance, lipid synthesis, and steatosis. Lipid droplets deposited in the sinusoids could be the source of the blood's lipid profile alterations in HIV patients on ART.

Keywords: Antiretroviral therapy; HIV; endothelium; hepatotoxicity; liver; mitochondria; sinusoid; steatosis.

Figure 1

Light microscopy images (H&E) of two liver biopsies from two participating patients in the ultrastructural study (A & B). Most of the aberrations described in the TEM figures are invisible by light microscopy H&Es with the exception of macrovacuolar steatosis.

Figure 2

Hepatocytic cytolysis. Necrotic hepatocytes presented as degenerate cytoplasm and membranes (A–C), extravasation of RBC between hepatocytes (B), as well as leakage of cellular contents into the sinusoidal lumen, note the loose mitochondria in the serum (C). Partial cytoplasmic degeneration (D).

Figure 3

Damaged hepatocytic mitochondria. The inner membranes of the mitochondria lack definition and the cristae are no longer visible, and matrix amorphous or granular (A–D).

Figure 4

Mitochondria in sinusoids. Mitochondria leaked into the sinusoidal lumen (A–C, arrowheads). Due to heterogeneous nature of the mitochondrial damage, mitochondria appear at various levels of degeneration. RBC: Red blood cells; EN: endothelial nucleus.

Figure 5

Hepatocytic lipid inclusions (macrovesicular steatosis) and small vesicles (microvesicular steatosis). Large lipid droplets of various sizes accumulated within hepatocytes; some have dark speckles within and along the droplet margin (A–D). Lipid droplets coalesce into larger ones (C), accumulate on the side of sinusoid and move into sinusoidal lumen (D and E). Microvesicular steatosis, vesication in the hepatocytes, produced numerous vesicles <0.5 μm in diameter (F).

Figure 6

Degenerate sinusoidal endothelium. Endothelial membranes show poorly defined margins, deterioration, and discontinuity; A and B at low magnification, and C–F at higher magnification. The degenerate endothelium has allowed hepatocytic cellular contents to leak into the sinusoidal lumen, especially large lipid droplets (A). Hepatocytes’ basal surface (adjacent to sinusoidal endothelium) lost its microvilli and the space of Disse was restricted or lacking.

Figure 7

Occluded sinusoids. Sinusoidal lumen filled with cellular debris from necrotic and degenerate hepatocytes (A–D), thick proteinaceous material that may be of hepatocytic cytoplasm (A–D), degenerate endothelium membrane (C), and lipid droplets (A). Some sinusoidal endothelial nuclei are hypertrophic (D).