Liver Disease in the Elderly

The aging process affects the liver, but to a lesser degree than other organs.

Hepatic size decreases by 20% to 40% in the elderly, and hepatic blood flow decreases by one third with advancing age; these changes may reflect alterations in cellular function and biochemical pathways in the liver.

These age-related alterations are of considerable importance, given the aging of our population and the fact that older adults use approximately one third of all prescribed medications, many of which are metabolized by the liver.

Senescence of liver cells is characterized primarily by decreased production of hepatic proteins; some abnormal proteins accumulate in aging liver cells ( Box 26.1 ).

Histopathologic changes seen in aging livers include increases in cell size, the number of abnormal nuclei, and the frequency of chromosomal abnormalities. Often, the number and size of lysosomes also increase. Mitochondria increase in volume but decrease in number, and, together with decreased hepatic blood flow, these changes may contribute to reduced metabolism of certain drugs. The observed decrease in telomeric length of hepatic stellate cells (HSCs) in the aged liver may lead to an increased tendency to fibrogenesis.

The thickness of hepatic sinusoidal cells and their number and the size of their fenestrae are reduced in aging, thereby causing disturbance of the exchange of molecules between hepatocytes and plasma that flows within the sinusoids.

Lipofuscin, the “wear-and-tear” pigment, is a common finding on liver biopsy specimens from elderly persons. Lipofuscin has been thought to represent extensive nonenzymatic glycosylation and cross-linking of heterogeneous cellular components, including nucleic acids, proteins, and lipids. Evidence suggests that lipofuscin may represent, at least in part, accumulation of retinyl palmitate. Lipofuscin was previously thought to be biologically inert, but there is increasing evidence that lipofuscin interferes with hepatocyte gene transcription processes, thereby diminishing cell survival.

As individuals age, hepatocytes become less sensitive to insulin and corticosteroids. Protein breakdown and both transcriptional and translational processes decrease. The altered breakdown of cellular protein may have important consequences for the cell life cycle and may be a major feature of the aging process.

Serum levels of routine liver biochemical tests, such as albumin, aminotransferases, and bilirubin, do not change significantly as persons age.

Age-related changes include decreases in liver weight, hepatic blood flow, metabolism of drugs, responsiveness to hormonal and growth factors, and delayed regeneration.

The systemic clearance of many drugs that are metabolized by the hepatic cytochrome P-450 (CYP) system (e.g., midazolam, phenytoin, propranolol, acetaminophen) is decreased in older adults. However, the enzymatic activities of CYP3A and CYP2E1 do not change with aging; this finding suggests that older persons may be just as susceptible as younger persons to DILI, caused by agents such as acetaminophen and ethanol.

Other mechanisms must be present to explain the reduced hepatic clearance of the previously mentioned drugs. A 40% decrease in hepatic volume and a 50% reduction in liver blood flow in older persons account for the reduction in systemic clearance of drugs, such as propranolol, that have a high first-pass hepatic uptake. The decrease in liver volume is most likely responsible for impaired clearance of medications that do not undergo significant first-pass hepatic uptake.

The volume of distribution of water-soluble drugs is generally reduced in older adults because of an increase in the ratio of body fat to body water. Although the metabolism of ethanol is essentially unaltered by aging, elevated blood ethanol levels can be observed in elderly subjects after the acute intake of ethanol as a result of a reduction in the volume of distribution.

The age-related reduction in hepatic blood results mostly from a decrease in portal blood flow. Sensitive Doppler techniques have shown that portal blood flow decreases from 740 ± 150 mL/min in persons <40 years of age to 595 ± 106 mL/min in healthy persons who are >71 years of age. The reduction in portal vein blood flow may relate to atherosclerosis, with a resulting decrease in mesenteric arterial blood flow.