Elsevier

The Lancet

Volume 359, Issue 9317, 4 May 2002, Pages 1612-1615
The Lancet

Hypothesis
Hepatic pseudocapillarisation and atherosclerosis in ageing

https://doi.org/10.1016/S0140-6736(02)08524-0Get rights and content

Summary

Cardiovascular disease secondary to atherosclerosis is the main cause of death and disability in industrialised countries, and ageing is the foremost risk factor for atherosclerosis. We present a hypothesis linking age-specific structural change in the liver with accepted pathogenic mechanisms leading to atherosclerosis. Ageing in the liver is associated with pseudocapillarisation of the sinusoidal endothelium, which is characterised by thickening of endothelium, basement membrane formation, and defenestration (loss of pores). Fenestrations (pores) normally form a liver sieve that allows passage of chylomicron remnants for subsequent uptake and metabolism by hepatocytes. Ageing is associated with impaired clearance of chylomicron remnants, postprandial hypertriglyceridaemia, and hence, atherosclerosis, which we propose is linked directly to loss of permeability of the liver sieve because of defenestration associated with pseudocapillarisation. Development of methods to maintain fenestrations of sinusoidal endothelium or to facilitate refenestration might be a new therapeutic strategy for management of cardiovascular disease in old people.

Section snippets

Ageing and the liver sieve

Ageing in the liver was previously thought to be associated with few important changes, apart from reduction in mass and blood flow.4 Motivated by the observation that such changes cannot fully explain the age-related impairment of hepatic drug metabolism,4 we examined structures between the blood vessel and the hepatocyte that could block substrate transfer—ie, the sinusoidal endothelium and space of Disse.

The capillaries within the normal liver are highly specialised. The sinusoidal

The liver sieve and lipid metabolism

Chylomicrons are spherical lipoproteins rich in triglycerides that are formed in the intestine from dietary lipids. They are large particles with diameters of 100–1000 nm that are unable to pass through the fenestrations of hepatic sinusoidal endothelium (figure 3).5, 8 Chylomicrons are metabolised to chylomicron remnants by lipoprotein lipase, which is present on the endothelium of systemic capillaries. In rats that have had hepatectomy, chylomicron remnants accumulate in the blood,10 which

Ageing and postprandial hyperlipidaemia

Ageing is associated with hyperlipidaemia.2 Abbott and colleagues15 however, report a reduction in cholesterol concentrations in the very old, perhaps as a result of concomitant disease and preterminal loss of bodyweight.

Postprandial hyperlipidaemia specifically is common in old age.16, 18 The magnitude of postprandial hypertriglyceridaemia after a fat-rich meal correlates with age in man.16 Fasting triglyceride concentrations are greater in old people, and the rise after a meal is nearly two

Postprandial hyperlipidaemia and atherosclerosis

The hypothesis that postprandial hyperlipidaemia is atherogenic was proposed by Moreton,22 Fraser,23 and Zilversmit,24 and is well established after much review.11

Clinical evidence for the association includes the observation that coronary artery disease is associated with raised postprandial hypertriglyceridaemia independent of fasting LDL and HDL concentrations.11, 25 Furthermore, clearance of chylomicron remnants is reduced substantially in normolipidaemic patients with coronary artery

Testing the hypothesis

The hypothesis is simple, and every step in the pathogenic chain has already been validated. The hepatic sinusoidal endothelium contains pores called fenestrations that allow passage of particles of a certain size (chylomicron remnants; figure 4). With old age, the diameter and frequency of fenestrations lessens, with a rise in matrix in the space of Disse, thus leading to diminished porosity of the liver sieve and consequent reduction in clearance of chylomicron remnants. This impaired

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