Chapter 24 Liver disease in the elderly
1 The clinical presentation, prognosis, and management of several liver disorders can be different in older patients than in younger persons.
2 Hepatic blood flow, liver size, and hepatic regenerative capacity decrease with age; these changes result in decreased metabolism of certain medications and a reduced ability of the liver to recover promptly from diseases such as acute viral hepatitis.
3 Certain disorders, such as acute liver failure and drug-induced hepatitis, are more severe and have a worse prognosis in elderly patients than in younger patients.
4 The development of hepatocellular carcinoma (HCC) is directly related to the duration of cirrhosis; therefore, elderly patients with cirrhosis should be screened regularly for HCC.
5 Advanced age is not a contraindication to liver transplantation, which should be considered in selected elderly patients with irreversible end-stage liver disease. Conversely, livers can be accepted from elderly donors, albeit with some risk of poor graft function and more rapid and severe recurrence of hepatitis C virus infection in the allograft.
Cellular and Biochemical Aspects
Overview
2. Hepatic size decreases by 6.5% in men and 14.3% in women, and hepatic blood flow diminishes with advancing age; these changes may result in alterations in cellular function and biochemical pathways in the liver.
Cellular and biochemical changes in the aging liver
1. Aging of liver cells is characterized primarily by decreased production of hepatic proteins; some abnormal proteins accumulate in aging liver cells (Table 24.1).
2. 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, may contribute to reduced metabolism of certain drugs.
3. 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. Although lipofuscin is thought to be biologically inert, it may interfere with intracellular biochemical reactions.
4. 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.
TABLE 24.1 Proteins that accumulate in aging livers
| Glucose-6-phosphate dehydrogenase |
| Phosphoglycerate kinase |
| NADP cytochrome c reductase |
| Cathepsin D |
| Superoxide dismutase |
| Aminoacyl-tRNA synthetases |
NAPD, nicotinamide adenine dinucleotide phosphate.
Adapted from Dice JF. Aging and the uncertain role of sirtuins. In: Arias IM, Wolkoff A, Boyer J, et al, eds. The Liver: Biology and Pathobiology. Singapore: Wiley-Blackwell; 2009:955–960.
Pathophysiology of the Aging Liver
Overview
1. Serum levels of routine liver biochemical tests, such as albumin, aminotransferases, and bilirubin, do not change significantly as persons age.
Changes in drug metabolism
1. 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 the elderly. However, the enzymatic activities of CYP3A and CYP2E1 do not change with aging; this finding suggests that elderly persons may be just as susceptible as younger persons to the hepatotoxic effects of drugs such as acetaminophen and ethanol.
2. 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 elderly 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.
3. The volume of distribution of water-soluble drugs is generally reduced in elderly patients 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 acute intake of ethanol as a result of a reduction in the volume of distribution.
4. The age-related reduction in hepatic blood mostly results from a decrease in portal blood flow. Sensitive Doppler techniques have shown that portal blood flow decreases from 740 ± 150 mL/minute in persons less than 40 years of age to 595 ± 106 mL/minute in healthy persons who are more than 71 years old. The reduction in portal vein blood flow may relate to atherosclerosis, with a resulting decrease in mesenteric arterial blood flow.
Alterations in cholesterol metabolism
1. The cholesterol content of bile increases with advancing age, as does the lithogenic index, because of the combination of increased hepatic secretion of cholesterol and decreased bile acid production. The elderly gallbladder also may be less responsive to endogenous cholecystokinin (CCK), with a resulting decrease in postprandial contraction of the gallbladder. Supersaturated bile is four times as frequent in elderly women as in younger women.
Hepatic Diseases in the Elderly
Acute viral hepatitis (see Chapter 3)
1. Hepatitis A
Hepatitis A is relatively uncommon in the elderly because of a high rate of preexisting immunity. However, increasing proportions of elderly persons in Western countries are not immune to hepatitis A (30% in the US population who are more than 50 years of age).
Hepatitis A is relatively uncommon in the elderly because of a high rate of preexisting immunity. However, increasing proportions of elderly persons in Western countries are not immune to hepatitis A (30% in the US population who are more than 50 years of age).
2. Hepatitis B
The presentation is generally more cholestatic in the elderly, with less hepatocellular necrosis. However, patients are frequently symptomatic, sicker, and have a longer recovery interval.
The presentation is generally more cholestatic in the elderly, with less hepatocellular necrosis. However, patients are frequently symptomatic, sicker, and have a longer recovery interval.
3. Hepatitis C
The incidence of hepatitis C is reported to be similar in the young and old. As with acute hepatitis A and B, cholestasis may be a prominent feature.
The incidence of hepatitis C is reported to be similar in the young and old. As with acute hepatitis A and B, cholestasis may be a prominent feature.
4. Other causes of hepatitis
In immunosuppressed and debilitated patients with hepatitis, the possibilities of herpes virus or cytomegalovirus infection should be considered and appropriately investigated.
In the elderly patient who presents with apparent acute viral hepatitis, the differential diagnosis should include ischemic hepatitis, sepsis, hepatic metastases, drug-induced hepatitis, and obstructive jaundice (see Chapter 1).
In immunosuppressed and debilitated patients with hepatitis, the possibilities of herpes virus or cytomegalovirus infection should be considered and appropriately investigated. In the elderly patient who presents with apparent acute viral hepatitis, the differential diagnosis should include ischemic hepatitis, sepsis, hepatic metastases, drug-induced hepatitis, and obstructive jaundice (see Chapter 1).
Chronic viral hepatitis (see Chapter 4)
1. Chronic hepatitis B
The clinical presentation of chronic hepatitis B in the elderly is generally similar to that of younger patients. However, many elderly patients with chronic hepatitis B are hepatitis B e antigen (HBeAg) negative and have low levels of serum HBV DNA, findings indicating a lesser degree of viral replication and infectivity. This serologic profile generally indicates a long duration of the disease and is termed the inactive carrier state.
The clinical presentation of chronic hepatitis B in the elderly is generally similar to that of younger patients. However, many elderly patients with chronic hepatitis B are hepatitis B e antigen (HBeAg) negative and have low levels of serum HBV DNA, findings indicating a lesser degree of viral replication and infectivity. This serologic profile generally indicates a long duration of the disease and is termed the inactive carrier state.
