Age‐related pseudocapillarization of the human liver

Abstract

Age-related changes in liver function are important because they may promote susceptibility to adverse drug reactions, neurotoxicity, atherosclerosis, and other important diseases in older people. Age-related changes in the rat hepatic sinusoidal endothelium, termed pseudocapillarization, have been described recently and these may contribute to hepatic impairment. The present study has examined surgical and post-mortem specimens with immunohistochemistry and transmission electron microscopy to determine whether pseudocapillarization also occurs in older humans. The age of the subject, independent of systemic disease or hepatic pathology in surgical and post-mortem samples of human liver, was associated with increased peri-sinusoidal expression of von Willebrand's factor, collagen I, collagen IV, and staining with Masson's trichrome. Electron microscopy revealed significant age-related thickening of the sinusoidal endothelium (young 165 +/- 17 nm, middle age 222 +/- 11 nm, older 289 +/- 9 nm, p < 0.001) with loss of fenestrations (young 7.7 +/- 0.7 per 10 micro m, middle age 3.6 +/- 0.5 per 10 micro m, older 1.5 +/- 0.4 per 10 micro m, p < 0.001), and age-related deposition of basal lamina and collagen. In conclusion, ageing in humans is associated with morphological changes in the sinusoidal endothelium and space of Disse which are presumptively related to the ageing process and potentially represent an important link between the ageing process and disease susceptibility.

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

“…In the diabetic livers, the LSECs were found to be about 40% thicker and the porosity of fenestrations was reduced by about 50%. These are substantial changes and of a similar magnitude to those reported in old age [5][6][7][8]. In addition, diabetes was associated with increased endothelial production of von Willebrand factor and caveolin-1 and increased Masson's trichrome staining.…”

“…Of interest in diabetes mellitus is the observation that fenestrations in the LSECs appear to act as conduits for the transfer of some lipoproteins, especially chylomicron remnants, between the blood and hepatocytes [2,4]. In old age, a substantial loss of fenestrations in the LSECs occurs [5][6][7][8], which impairs lipoprotein transfer to the hepatocyte [9]. This provides a mechanism for age-related impairment in chylomicron remnant clearance and post-prandial hypertriacylglycerolaemia, thus possibly contributing to enhanced vascular risk among older people [4].…”

Hepatic Steatosis, Fibrosis, and Cancer in Elderly Cadavers

“…The changes are characterized by thickening of sinusoidal endothelium and reduction in the number endothelial fenestrae, accompanied by a sporadic appearance of basal lamina and mild perisinusoidal fibrosis (Le Couteur et al, 2001;McLean et al, 2003). These alterations have been related to impairment of material transfer between sinusoidal blood and hepatocytes, thereby compromising hepatic functions in the elderly.…”

The size of sinusoidal fenestrae is a critical determinant of hepatocyte transduction after adenoviral gene transfer

“…Aging is also associated with hepatic pseudocapillarization. [36][37][38] The size of fenestrae may also be a determinant of hepatocyte transduction after transfer with retroviral or lentiviral vectors, which have a diameter between 126 and 133 nm. [39][40][41] A role of the size of fenestrae in the biodistribution of adenoviral vectors in the adrenal gland has been previously suggested by Wang et al 42 Systemic administration of adenoviral vectors in mice induced transgene expression in the adrenal gland that was comparable but somewhat lower than in the liver and predominant in the zona fasciculata, the part of the adrenal cortex with the largest diameter of fenestrae.…”