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The Hepatic Sinusoid in Aging and Cirrhosis

Effects on Hepatic Substrate Disposition and Drug Clearance

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Abstract

The fenestrated sinusoidal endothelium (‘liver sieve’) and space of Disse in the healthy liver do not impede the transfer of most substrates, including drugs and oxygen, from the sinusoidal lumen to the hepatocyte. Plasma components transfer freely in both directions through the endothelial fenestrations and into the space of Disse. The endothelium is attenuated, there is no basement membrane and there is minimum collagen in the space of Disse, thus minimising any barriers to substrate diffusion.

Both cirrhosis and aging are associated with marked structural changes in the sinusoidal endothelium and space of Disse that are likely to influence bulk plasma transfer into the space of Disse, and diffusion through the endothelium and space of Disse. These changes, termed capillarisation and pseudocapillarisation in cirrhosis and aging, respectively, impede the transfer of various substrates. Capillarisation is associated with exclusion of albumin, protein-bound drugs and macromolecules from the space of Disse, and the progressive transformation of flow-limited to barrier-limited distribution of some substrates.

There is evidence that the sinusoidal changes in cirrhosis and aging contribute to hepatocyte hypoxia, thus providing a mechanism for the apparent differential reduction of oxygen-dependent phase I metabolic pathways in these conditions. Structural change and subsequent dysfunction of the liver sieve warrant consideration as a significant factor in the impairment of overall substrate handling and hepatic drug metabolism in cirrhosis and aging.

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Acknowledgements

We acknowledge funding from the National Health and Medical Research Council, Department of Veterans Affairs, and the Ageing and Alzheimer’s Research Foundation.

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Authors and Affiliations

  1. Centre for Education and Research on Ageing and ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia

    David G. Le Couteur & Sarah Kilmer

  2. Department of Pathology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand

    Robin Fraser

  3. Department of Pharmacology, University of Sydney, Sydney, New South Wales, Australia

    Laurent P. Rivory

  4. National Ageing Research Institute, and Department of Medicine, Royal Melbourne Hospital, University of Melbourne and Melbourne Health, Parkville, Victoria, Australia

    Allan J. McLean

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  1. David G. Le Couteur
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  2. Robin Fraser
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  5. Allan J. McLean
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Correspondence to David G. Le Couteur.

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Le Couteur, D.G., Fraser, R., Kilmer, S. et al. The Hepatic Sinusoid in Aging and Cirrhosis. Clin Pharmacokinet 44, 187–200 (2005). https://doi.org/10.2165/00003088-200544020-00004

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