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Liver disease in the elderly
Chapter 24
Liver disease in the elderly Santiago J. Muñoz, Ajit Challa, MD Andrzej Marzec, MD
MD
Key Points 1 The clinical presentation, prognosis, and management of several liver disorders can be different in patients with advanced age than in younger persons. 2 Hepatic blood flow, liver size, and hepatic regenerative capacity decrease with age; the result may be a decrease in the metabolism of certain medications and a decrease in the ability of the liver to recover promptly from diseases such as acute viral hepatitis. 3 Certain disorders, such as fulminant hepatic 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 is directly related to the duration of cirrhosis; therefore, elderly patients with cirrhosis should be screened routinely for the presence of hepatocellular carcinoma. 5 Advanced age is no longer a contraindication to orthotopic 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.
Cellular and Biochemical Aspects of the Aging Liver Overview 1 The aging process affects the liver, but to a lesser degree than the rest of the body 2 Both hepatic size and blood flow diminish with advancing age; these changes may result in altered cellular function and biochemical pathways in the liver 3 These age-related alterations are of considerable importance, given the aging of our population and the fact the elderly use approximately one-third of all prescribed medications, many of which are metabolized by 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 there is also an increase in the number and size of lysosomes 305
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Pathophysiology of the aging human liver
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 Modified with permission from Dice JF, Goff SA. Aging and the liver. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology. New York: Raven Press; 1988:1245–1258.
3 Lipofuscin, the ‘wear-and-tear’ pigment, is a common finding on liver biopsies performed on elderly patients. Pongor et al. (1984) described lipofuscin as representing extensive nonenzymatic glycosylation and cross-linking of heterogeneous cellular components, including nucleic acids, proteins, and lipids. Recent evidence suggests that lipofuscin may represent, at least in part, accumulation of retinyl palmitate. While lipofuscin is thought to be biologically inert, it may interfere with intracellular biochemical reactions 4 As individuals age, hepatocytes are less sensitive to insulin and corticosteroids. There is a decrease in protein breakdown and in both transcriptional and translational processes. The altered breakdown of cellular protein may have important consequences for the cell lifecycle and may be a major feature of the aging process
Pathophysiology of the Aging Human Liver Overview 1 Routine liver biochemical tests, such as serum albumin, aminotransferases, and bilirubin, do not change significantly as individuals grow old 2 Age-related changes include decreases in liver weight, hepatic blood flow, metabolism of drugs, and responsiveness to hormonal and growth factors and delayed regeneration
Changes in drug metabolism 1 The systemic clearance of many drugs that are metabolized by the hepatic cytochrome P450 system (e.g., midazolam, phenytoin, propranolol, and acetaminophen) is decreased in the elderly. However, the enzymatic activities of cytochrome P-4503A and P-4502E1, do not change with aging; this suggests that elderly individuals may be just as susceptible as younger subjects 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 above-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 that have a high first-pass hepatic uptake, such as propranolol. 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, due to 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 due to reduction in the volume of distribution
Liver disease in the elderly
4 The age-related reduction in hepatic blood is due mostly to a decrease in portal blood flow. Using sensitive Doppler techniques, portal blood flow was shown to decrease from 740±150 mL/min in individuals less than 40 years of age to 595±106 mL/min in healthy individuals over the age of 71. The reason for the decrease in portal vein blood flow is unknown but may relate to atherosclerosis, with a resultant 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, due to 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), resulting in a decreased postprandial contraction of the gallbladder. Valdivieso et al. (1978) demonstrated that supersaturated bile is four times as frequent in elderly women as in younger women 2 The frequency of gallstones increases with age. Approximately 40–60% of individuals in their eighth decade will have gallstones. Complications of gallstone disease are more severe in the elderly (see also Ch. 32)
Hepatic Diseases in the Elderly Acute viral hepatitis (see also Ch. 3) 1 In elderly patients, the course of acute viral hepatitis may be more prolonged, severe, and indolent than in younger patients. This is probably due to an aged-related decline in immune function 2 Hepatitis A • hepatitis A is relatively uncommon in the elderly due to a high rate of pre-existing immunity. However, an increasing proportion of the elderly in Western countries is not immune to hepatitis A • the mortality of acute hepatitis A increases with advancing age. The mortality rate is 0.4% in patients between ages 15 and 39 years but 1.1% in those age 40 years and older (Fig. 24.1). In patients over 65, the mortality rate is 4% • Monovalent and bivalent vaccines against hepatitis A are now available for clinical use (e.g., Havrix™; Vacqta™; Twinrix™). Elderly individuals who plan to travel to areas
Fig. 24.1 Age-dependent case fatality rates for hepatitis A. Reproduced with permission from the AGA Clinical Teaching Project, Unit 3, Viral Hepatitis, 2nd edn., 1994.
Case 1.2 fatality rate 1.0 (%) 0.8 0.6 0.4 0.2 0.0 <1–14
15–39 40+ Age (years)
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where hepatitis A is endemic should be tested for antibody to hepatitis A virus and vaccinated if necessary • Other indications for hepatitis A vaccination, as recommended by the Advisory Committee on Immunizations Practices, apply to elderly patients as well, including preexisting liver disease 3 Hepatitis B and D • hepatitis B and D are uncommon forms in elderly persons because such individuals are generally not in high-risk groups (e.g., men who have sex with men, injection drug users) • the presentation is generally more cholestatic in the elderly, and patients are frequently symptomatic and have a long recovery interval • while the clearance of hepatitis B surface antigen (HBsAg) takes somewhat longer in the elderly than the young, the overall prognosis is similar in the two groups. However, the elderly are more likely to progress to chronic hepatitis • unfortunately, the elderly do not respond as well as younger persons to hepatitis B vaccination, probably because of a decrease in the number of antibody-producing B cells. Higher doses or booster immunization may be necessary for successful hepatitis B vaccination of older persons 4 Hepatitis C • one study in Italy by Floreani et al. (1992) has suggested that the incidence of hepatitis C is similar in both the young and old. As with hepatitis A and B, cholestasis may be a prominent feature 5 Other causes of hepatitis • in immunosuppressed and debilitated patients with hepatitis, the possibilities of herpesvirus and 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 (shock liver, resulting from anoxic injury to the liver in the setting of congestive heart failure, cardiac arrhythmia, myocardial infarction, or sepsis, see Ch. 20), hepatic metastases, drug-induced hepatitis, and obstructive jaundice. Conversely, older patients with jaundice and elevated liver enzymes presumed to be due to extrahepatic biliary obstruction also require evaluation for acute viral hepatitis
Chronic viral hepatitis (see also Ch. 4) 1 The clinical presentation of chronic hepatitis B and C 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/or have low levels of serum HBV DNA, indicating a lesser degree of viral replication and infectivity and a decreased need for antiviral therapy 2 Peginterferon and ribavirin are currently approved for the treatment of chronic hepatitis C. The tolerability of this combination therapy is often reduced in the elderly, who have difficulties tolerating interferon side-effects and anemia induced by ribavirin 3 Interferon alpha, lamivudine and adefovir dipivoxil are approved antiviral agents for the treatment of chronic hepatitis B. Prolonged therapy with lamivudine is often complicated by the development of hepatitis B mutants that are resistant to the nucleoside analog. The dose of adefovir must be reduced for creatinine clearance below 50 mL/min, which is frequently found in the elderly 4 An important complication of chronic hepatitis B and C is the development of hepatocellular carcinoma (HCC). Because the development of HCC correlates with the
Liver disease in the elderly
duration of chronic hepatitis, elderly patients with cirrhosis due to chronic hepatitis B or C should be screened twice yearly with ultrasound of the liver and serum alpha fetoprotein testing
Drug-induced hepatotoxicity (see also Ch. 8) 1 The risk of drug-induced hepatotoxicity has been shown to increase with advancing age, most notably for isoniazid. Eastwood (1971) found that approximately 20% of cases of jaundice in the elderly were secondary to medications, compared with approximately 2–5% of patients of all ages who required hospitalization for jaundice 2 Benoxaprofen is a nonsteroidal anti-inflammatory agent for which a clear association between age and hepatotoxicity was demonstrated. Nine patients taking the medication developed fulminant hepatic failure and died; all were over age 70. The drug was taken off the market and is no longer available 3 Elderly patients are more likely to be on multiple medications. Williamson and Chopin (1980) found that the frequency of adverse drug reactions was three times higher in patients taking six medications compared with those taking a single agent. Such ‘polypharmacy’ increases the chance that cytochrome P-450 activity will increase or decrease, thereby leading to drug-drug interactions 4 Drug-induced hepatotoxicity should be a major diagnostic consideration in all elderly patients who present with elevated liver enzymes and/or jaundice. All unnecessary medications should be discontinued, and necessary agents should be switched to a different class. Table 24.2 lists some drugs for which hepatotoxicity increases with age
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis – NAFLD and NASH NAFLD (and NASH) is an increasingly recognized syndrome characterized by macrovesicular steatosis in persons who are not excessive drinkers. NAFLD may be present in as much as 20% of the general population. NASH is about one-tenth as frequent but may progress to cirrhosis, liver failure and liver cancer. • the metabolic syndrome of insulin resistance, obesity, diabetes mellitus, hypertriglyceridemia, and hypertension is often present in patients with NAFLD • simple fatty liver and NASH can only be distinguished at present by liver biopsy findings • NASH may be a common initial cause of cirrhosis previously considered cryptogenic • older age is an independent predictor of severe liver fibrosis in patients with NASH
Table 24.2: Some medications for which hepatotoxicity increases with age Benoxaprofen Dantrolene Floxacillin Halothane Isoniazid Methyldopa Sulindac
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Autoimmune liver disease 1 Primary biliary cirrhosis (see also Ch. 14) • studies by Dickson et al. from the Mayo Clinic (1989) have identified advancing age as a poor prognostic indicator in patients with primary biliary cirrhosis. In contrast, a previous study by Lehmann, 1985 found that individuals presenting with primary biliary cirrhosis after age 65 were less likely to have advanced disease 2 Autoimmune hepatitis (see also Ch. 5) • typically occurs in middle-age females, but can be present in older individuals. Management in the elderly can be difficult, due to the adverse effects of long-term corticosteroid use in postmenopausal females already at high risk for osteoporosis, glaucoma, arterial hypertension, and obesity 3 Primary sclerosing cholangitis (see also Ch. 15) • usually occurs in the third or fourth decade; it is, therefore, unusual to make this diagnosis in an elderly patient
Alcoholic liver disease (see also Ch. 6) 1 The perception has been that most alcoholics who develop alcoholic liver disease will do so in middle age. However, recent studies from Europe and the USA have demonstrated that a significant proportion of patients with alcoholic liver disease present in the fifth and sixth decades 2 Older patients are more likely than younger patients to exhibit the classic signs of hepatic decompensation – ascites, jaundice, and lower extremity edema. Overall mortality due to alcoholic liver disease is higher in patients over age 60: 34% at 1 year, compared with 5% in younger patients. In patients over age 70, the 1-year mortality rate increases dramatically to 75%
Metabolic liver diseases 1 Hereditary hemochromatosis (see also Ch. 16) • while most patients with hemochromatosis present by middle age, some patients first seek medical attention at an advanced age for HCC or another complication of endstage liver disease • female patients typically become symptomatic approximately a decade after their male counterparts, due to the iron-depleting effects of regular menses and childbirth • common symptoms include fatigue, diabetes, impotence and arthritis, all of which are common in the elderly anyway • the diagnosis of hemochromatosis is suggested by a fasting transferrin saturation (serum iron/total iron binding capacity × 100) greater than 45% in males and females and an elevated serum ferritin. Early diagnosis is crucial because complications can be prevented by phlebotomy, and family members can be screened • genetic testing in peripheral blood looking for the common hemochromatosis mutations (C282Y, H63D) is now available and eliminates the need for liver tissue iron determination in many patients • a major cause of death in patients with cirrhosis due to hemochromatosis is HCC; screening with serum alpha fetoprotein testing and ultrasonography should be done every 6 months 2 Alpha-1 antitrypsin deficiency (see also Ch. 18) • patients with homozygous alpha-1 antitrypsin deficiency (α-1ATD) usually present before age 65 • heterozygous α-1ATD has been thought to be a cause of cirrhosis in approximately 5% of patients over age 65 years with cirrhosis. However, heterozygous α-1ATD is frequent
Liver disease in the elderly
in the overall population, and no evidence exists that intracellular α-1ATD globular inclusions are hepatotoxic in heterozygotes • although no effective treatment of α-1ATD related liver disease exists, diagnosis is important so that heterozygous or affected family members can be advised to avoid behavior such as alcohol, smoking, and intravenous drug use, that may jeopardize their hepatic and pulmonary function 3 Wilson disease (see also Ch. 17) • de novo diagnosis of this entity is extremely rare in elderly patients. Most patients have clinical disease well before the fifth decade
Cryptogenic cirrhosis (see also Chs 9 and 10) 1 A substantial number of elderly patients with cirrhosis have cryptogenic cirrhosis (cause unknown). Many of these cases may result from NASH that has progressed to cirrhosis 2 In a postmortem study, Ludwig and Baggenstoss (1970) described 77 patients over age 70 with cryptogenic cirrhosis, in whom the diagnosis was unsuspected when they were alive. This finding raises the possibility of a specific form of cryptogenic cirrhosis in the elderly, but further research is needed before the existence of such an entity can be established
Liver abscess (see also Ch. 28) 1 The majority of patients with pyogenic liver abscesses in the northern hemisphere are over age 60 2 The diagnosis is more difficult to make than in younger patients, since the typical presentation of fever, jaundice, and right-upper-quadrant pain is frequently absent. Elderly patients are more likely to have nonspecific symptoms, such as epigastric pain, weakness, fatigue, and shortness of breath 3 While approximately one-half of infections originate from the biliary tree (most often as a result of ascending cholangitis), other intra-abdominal and gastrointestinal sources should be investigated. These include: • penetrating gastric or duodenal ulcers • pancreatitis • perihepatic abscess • portal vein thrombosis • peritonitis (of any cause) • inflammatory bowel disease • colon cancer • diverticulitis and/or diverticular abscess • cryptogenic (in some cases due to poor dentition) 4 A retrospective study of Sridharan et al. (1990) demonstrated that almost one-third of elderly patients with hepatic abscesses at autopsy were misdiagnosed in life as having a hepatic malignancy. Confirmation of tumor by needle biopsy should be obtained, especially if a primary site of malignancy is not present 5 Pyogenic abscesses can be successfully treated by percutaneous aspiration and drainage in conjunction with systemic intravenous antibiotics
Gallstones (see also Ch. 32) 1 Gallstones are an age-related phenomenon. The mortality of untreated biliary tract disease also increases with age. Cancer of the gallbladder is also more likely to occur in older patients than in younger patients
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Table 24.3: Management of biliary disease in the elderly Condition
Treatment
Acute or chronic cholecystitis
Early cholecystectomy (preferably laparoscopic) and perioperative exploration of the bile duct (in acute cholecystitis)
Cholangitis with choledocholithiasis
ERCP with sphincterotomy and stone extraction
Choledocholithiasis with gallstones in the gallbladder
ERCP with sphincterotomy. If symptoms persist, then cholecystectomy or percutaneous cholecystostomy with removal of the gallstones
Asymptomatic gallstones
Observation generally preferred over prophylactic intervention
ERCP, endoscopic retrograde cholangiopancreatography.
2 The management of biliary disease with respect to age has been summarized by James (1991) as outlined in Table 24.3 • with the advent of laparoscopic cholecystectomy, early operative intervention has brought the mortality and morbidity rates for young and old closer together • endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy has been shown to have insignificant differences in morbidity and mortality rates between old and young, despite a longer duration of hospitalization in the elderly • incidental appendectomy during cholecystectomy should not be performed in elderly patients due to the risk of wound infection and the relatively low lifetime risk of acute appendicitis
Hepatic tumors 1 Hepatocellular carcinoma (HCC) (see also Ch. 27) • elderly patients with cirrhosis are at increased risk of HCC; there is a clear association between the development of HCC and duration of cirrhosis; in the Western world, 50% of patients with cirrhosis who develop HCC are over age 60, and 40% are over age 70 • screening for the detection of HCC should be performed as described previously; early detection of a small tumor may result in prolongation of survival by resection, radiofrequency ablation, ethanol injection, chemoembolization, or liver transplantation 2 Metastatic tumors • most common malignant tumor found in the liver • the incidence of hepatic metastases is greatest for those tumors arising within the drainage area of the portal vein (colon, pancreatic, and stomach cancer), but other tumors, such as lung and breast cancer, can also metastasize to the liver • while the prognosis for patients with hepatic metastases is poor (with an average survival of 6 months), identification and localization can be important. Survival is directly correlated with the extent of hepatic involvement; patients with solitary metastases have a survival time almost double that of patients with widespread hepatic metastases • therapy may prolong survival; 20% of patients who undergo surgical resection of a solitary hepatic metastasis may be alive 5 years after resection
Liver disease in the elderly
Fulminant hepatic failure (FHF) (see also Ch. 2) • regardless of the etiology, FHF has a higher mortality rate in the elderly than in the young (Table 24.4) • FHF due to hepatitis A is particularly devastating in the elderly, with a mortality rate much greater than that in individuals between ages 15 and 24 • the best treatment for FHF in the elderly is to prevent its occurrence: – vaccination against hepatitis A and B should be considered in all susceptible elderly individuals – hepatotoxic drugs, such as isoniazid, should not be used unless absolutely necessary – frequent monitoring of liver enzymes should be performed in elderly patients who require treatment with medications known to have potential hepatotoxicity
Complications of Cirrhosis in the Elderly Portal hypertension (see also Chs 9–13) 1 Surprisingly, elderly patients admitted with bleeding esophageal varices have short-term mortality rates similar to those of younger patients. However, their 1-year survival is less than that of their younger counterparts 2 Older patients are less likely to tolerate the effects of vasopressin (with or without nitroglycerin) during an acute variceal bleed. Continuous infusion of octreotide is preferable to vasopressin in the medical treatment of bleeding varices in the elderly 3 Band ligation, sclerotherapy, and beta blockers can be used to prevent recurrent bleeding, although some older patients may be unable to tolerate the adverse effects of beta blockers (e.g., fatigue, dizziness, depression) 4 Both transjugular intrahepatic portosystemic shunts (TIPS) and portacaval shunts can be used for recurrent variceal bleeding; however, their usefulness is limited by the high frequency of post-shunt hepatic encephalopathy • with TIPS, the frequency of hepatic encephalopathy is directly related to the shunt diameter and residual hepatic function • it is recommended that small-caliber stents of 7–8 mm be used in patients over age 60, in order to decrease the chances of hepatic encephalopathy • lowering the hepatic venous pressure gradient to just below 12 mmHg may also minimize the chances of post-TIPS hepatic encephalopathy in elderly cirrhotic patients 5 Elderly patients with refractory ascites and/or recurrent variceal bleeding, who are otherwise in good physiologic condition, should be considered for liver transplant evaluation (see later)
Table 24.4: Age-specific survival rates in FHF
Age group
Survival (%) Hepatitis B Non-A, non-B hepatitis
15–24
40
20
25–44
35
5
45+
15
0
Modified from the American Gastroenterological Association Teaching File (1988).
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Complications of cirrhosis in the elderly
Hepatocellular carcinoma See earlier and Ch. 27.
Orthotopic liver transplantation (OLT) (see also Ch. 31) 1 Advanced age is not a contraindication to OLT. Recent studies have shown that in patients older than age 60–65, survival after OLT is comparable to that of younger patients. The decision to proceed with liver transplantation should be based on the overall health of the patient, not chronological age 2 It has also been shown that donor livers from individuals over age 50 can be used safely. Previously, there had been concern over the theoretical loss of liver function with advancing age, and many older donor livers went unused based solely on age. Questions had also been raised as to whether older livers are less resistant to ischemia, preservation, and reperfusion injuries. The increasing demand for donor livers has led to the increasing use of livers from elderly donors • several groups have reported that patient and graft outcomes are identical regardless of the age of the donor livers, even though older livers have significantly increased steatosis and are more likely to be used in patients requiring urgent liver transplantation • the function of an older liver may be slightly worse in the early postoperative period, as evidenced by higher peak serum alanine aminotransferase and bilirubin levels, and slightly lower bile outputs 3 Yersiz et al. (1995) demonstrated a significant increase in delayed function of livers from donors over age 50 compared with donors below age 30. Recipients experiencing delayed function were three times as likely to require retransplantation. However, early recognition of delayed function and subsequent retransplantation led to similar 1-year patient survival rates in both groups 4 Currently, livers from donors older than age 65 are used preferentially in patients who have HCC, have a high Model for End-stage Liver Disease (MELD) score, or require urgent liver transplantation (e.g., for hepatorenal syndrome or FHF). Ischemic time should be kept to a minimum when an older donor liver is used, to lessen preservation injury and postoperative hepatic graft dysfunction 5 That livers from older donors are able to withstand the often extreme physiologic conditions imposed by liver transplantation (harvesting, implantation, reperfusion, rejection, toxic effects of drugs, infection, etc.) and ultimately provide excellent function is a clear demonstration that the human liver is highly resilient to the aging process
Further Reading American Gastroenterological Association. Technical review on non-alcoholic fatty liver. Gastroenterology 2002; 123:1705–1725. Angulo P, Keach J, Batts K, Lindor K. Independent predictors of fibrosis in patients with non-alcoholic steatohepatitis. Hepatology 1999; 30:1356–1362. Bugianesi E, Leoni N, Vanni E, et al. Expanding the natural history of non alcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123:134–140. Centers for Disease Control and Prevention. Hepatitis A. In: Atkinson W, Wolfe C, eds. Epidemiology and Prevention of Vaccine Preventable Diseases, 7th edn. Washington DC: Department of Health and Human Services; 2002:191–206. Dice JF, Goff SA. Aging and the liver. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology. New York: Raven Press; 1988:1245–1258. Dickson ER, Grambsch P, Fleming TR. Prognosis in primary biliary cirrhosis. Model for decision making. Hepatology 1989; 10:1–7. Eastwood HOH. Causes of jaundice in the elderly: a survey of diagnosis and investigation. Gerontol Clin 1971; 13:69–81. Floreani A, Bertin T, Soffiati G, et al. Anti-hepatitis C virus in the elderly: a sero-epidemiological study in a home for the aged. Gerontology 1992; 38:214–216.
Liver disease in the elderly James OFW. Liver disease in the elderly. In: McIntyre N, Benhamou JP, Bircher J, Rizzetto M, Rodes J, eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press; 1991:1305–1309. Lehmann AB, Bassendine MF, James OFW. Is primary biliary cirrhosis a different disease in the elderly? Gerontology 1985; 31:186–194. Ludwig J, Baggenstoss AH. Cirrhosis of the aged and senile cirrhosis: are there two conditions? J Gerontol 1970; 25:244–248. MacMahon M, James OFW. Liver disease in the elderly. J Clin Gastroenterol 1994; 18:330–334. Munoz SJ, Friedman LS. The liver and aging. In: Rustgi VK, Van Thiel OH, eds. The Liver in Systemic Disease. New York: Raven Press; 1993:251–266. Pongor S, Ulrich P, Bencsath A, Cerami A. Aging of proteins: isolation and identification of a fluorescent chromophore from the reaction of peptides with glucose. Proc Natl Acad Sci USA 1984; 81:2684–2688. Sridharan GV, Wilkinson SP, Primrose WR. Pyogenic liver abscess in the elderly. Age Ageing 1990; 19:199–203. Valdivieso V, Palma R, Wunkhaus R, et al. Effect of aging on biliary lipid composition and bile acid metabolism in normal Chilean women. Gastroenterology 1978; 74:871–874. Van Thiel DH, Stauber R, Gavaler J, Francavilla A. Hepatic regeneration effects of age, sex hormone status, protein and cyclosporine. Dig Dis Sci 1991; 36:1309–1312. Williamson J, Chopin JM. Adverse reactions to prescribed drugs in the elderly: a multicentre investigation. Age Ageing 1980; 9:73–80. Wynne HA, Cope LH, Mutch E, et al. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989; 9:297–301. Yersiz H, Shaked A, Olthoff K, et al. Correlation between donor age and the pattern of liver graft recovery after transplantation. Transplantation 1995; 60:790–794. Zoli M, Iervese T, Abbati S, et al. Portal flow velocity and flow in aging man. Gerontology 1989; 35:661–665.
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Liver disease in the elderly Santiago J. Muñoz, Ajit Challa, MD Andrzej Marzec, MD
MD
Key Points 1 The clinical presentation, prognosis, and management of several liver disorders can be different in patients with advanced age than in younger persons. 2 Hepatic blood flow, liver size, and hepatic regenerative capacity decrease with age; the result may be a decrease in the metabolism of certain medications and a decrease in the ability of the liver to recover promptly from diseases such as acute viral hepatitis. 3 Certain disorders, such as fulminant hepatic 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 is directly related to the duration of cirrhosis; therefore, elderly patients with cirrhosis should be screened routinely for the presence of hepatocellular carcinoma. 5 Advanced age is no longer a contraindication to orthotopic 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.
Cellular and Biochemical Aspects of the Aging Liver Overview 1 The aging process affects the liver, but to a lesser degree than the rest of the body 2 Both hepatic size and blood flow diminish with advancing age; these changes may result in altered cellular function and biochemical pathways in the liver 3 These age-related alterations are of considerable importance, given the aging of our population and the fact the elderly use approximately one-third of all prescribed medications, many of which are metabolized by 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 there is also an increase in the number and size of lysosomes 305
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Pathophysiology of the aging human liver
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 Modified with permission from Dice JF, Goff SA. Aging and the liver. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology. New York: Raven Press; 1988:1245–1258.
3 Lipofuscin, the ‘wear-and-tear’ pigment, is a common finding on liver biopsies performed on elderly patients. Pongor et al. (1984) described lipofuscin as representing extensive nonenzymatic glycosylation and cross-linking of heterogeneous cellular components, including nucleic acids, proteins, and lipids. Recent evidence suggests that lipofuscin may represent, at least in part, accumulation of retinyl palmitate. While lipofuscin is thought to be biologically inert, it may interfere with intracellular biochemical reactions 4 As individuals age, hepatocytes are less sensitive to insulin and corticosteroids. There is a decrease in protein breakdown and in both transcriptional and translational processes. The altered breakdown of cellular protein may have important consequences for the cell lifecycle and may be a major feature of the aging process
Pathophysiology of the Aging Human Liver Overview 1 Routine liver biochemical tests, such as serum albumin, aminotransferases, and bilirubin, do not change significantly as individuals grow old 2 Age-related changes include decreases in liver weight, hepatic blood flow, metabolism of drugs, and responsiveness to hormonal and growth factors and delayed regeneration
Changes in drug metabolism 1 The systemic clearance of many drugs that are metabolized by the hepatic cytochrome P450 system (e.g., midazolam, phenytoin, propranolol, and acetaminophen) is decreased in the elderly. However, the enzymatic activities of cytochrome P-4503A and P-4502E1, do not change with aging; this suggests that elderly individuals may be just as susceptible as younger subjects 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 above-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 that have a high first-pass hepatic uptake, such as propranolol. 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, due to 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 due to reduction in the volume of distribution
Liver disease in the elderly
4 The age-related reduction in hepatic blood is due mostly to a decrease in portal blood flow. Using sensitive Doppler techniques, portal blood flow was shown to decrease from 740±150 mL/min in individuals less than 40 years of age to 595±106 mL/min in healthy individuals over the age of 71. The reason for the decrease in portal vein blood flow is unknown but may relate to atherosclerosis, with a resultant 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, due to 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), resulting in a decreased postprandial contraction of the gallbladder. Valdivieso et al. (1978) demonstrated that supersaturated bile is four times as frequent in elderly women as in younger women 2 The frequency of gallstones increases with age. Approximately 40–60% of individuals in their eighth decade will have gallstones. Complications of gallstone disease are more severe in the elderly (see also Ch. 32)
Hepatic Diseases in the Elderly Acute viral hepatitis (see also Ch. 3) 1 In elderly patients, the course of acute viral hepatitis may be more prolonged, severe, and indolent than in younger patients. This is probably due to an aged-related decline in immune function 2 Hepatitis A • hepatitis A is relatively uncommon in the elderly due to a high rate of pre-existing immunity. However, an increasing proportion of the elderly in Western countries is not immune to hepatitis A • the mortality of acute hepatitis A increases with advancing age. The mortality rate is 0.4% in patients between ages 15 and 39 years but 1.1% in those age 40 years and older (Fig. 24.1). In patients over 65, the mortality rate is 4% • Monovalent and bivalent vaccines against hepatitis A are now available for clinical use (e.g., Havrix™; Vacqta™; Twinrix™). Elderly individuals who plan to travel to areas
Fig. 24.1 Age-dependent case fatality rates for hepatitis A. Reproduced with permission from the AGA Clinical Teaching Project, Unit 3, Viral Hepatitis, 2nd edn., 1994.
Case 1.2 fatality rate 1.0 (%) 0.8 0.6 0.4 0.2 0.0 <1–14
15–39 40+ Age (years)
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where hepatitis A is endemic should be tested for antibody to hepatitis A virus and vaccinated if necessary • Other indications for hepatitis A vaccination, as recommended by the Advisory Committee on Immunizations Practices, apply to elderly patients as well, including preexisting liver disease 3 Hepatitis B and D • hepatitis B and D are uncommon forms in elderly persons because such individuals are generally not in high-risk groups (e.g., men who have sex with men, injection drug users) • the presentation is generally more cholestatic in the elderly, and patients are frequently symptomatic and have a long recovery interval • while the clearance of hepatitis B surface antigen (HBsAg) takes somewhat longer in the elderly than the young, the overall prognosis is similar in the two groups. However, the elderly are more likely to progress to chronic hepatitis • unfortunately, the elderly do not respond as well as younger persons to hepatitis B vaccination, probably because of a decrease in the number of antibody-producing B cells. Higher doses or booster immunization may be necessary for successful hepatitis B vaccination of older persons 4 Hepatitis C • one study in Italy by Floreani et al. (1992) has suggested that the incidence of hepatitis C is similar in both the young and old. As with hepatitis A and B, cholestasis may be a prominent feature 5 Other causes of hepatitis • in immunosuppressed and debilitated patients with hepatitis, the possibilities of herpesvirus and 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 (shock liver, resulting from anoxic injury to the liver in the setting of congestive heart failure, cardiac arrhythmia, myocardial infarction, or sepsis, see Ch. 20), hepatic metastases, drug-induced hepatitis, and obstructive jaundice. Conversely, older patients with jaundice and elevated liver enzymes presumed to be due to extrahepatic biliary obstruction also require evaluation for acute viral hepatitis
Chronic viral hepatitis (see also Ch. 4) 1 The clinical presentation of chronic hepatitis B and C 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/or have low levels of serum HBV DNA, indicating a lesser degree of viral replication and infectivity and a decreased need for antiviral therapy 2 Peginterferon and ribavirin are currently approved for the treatment of chronic hepatitis C. The tolerability of this combination therapy is often reduced in the elderly, who have difficulties tolerating interferon side-effects and anemia induced by ribavirin 3 Interferon alpha, lamivudine and adefovir dipivoxil are approved antiviral agents for the treatment of chronic hepatitis B. Prolonged therapy with lamivudine is often complicated by the development of hepatitis B mutants that are resistant to the nucleoside analog. The dose of adefovir must be reduced for creatinine clearance below 50 mL/min, which is frequently found in the elderly 4 An important complication of chronic hepatitis B and C is the development of hepatocellular carcinoma (HCC). Because the development of HCC correlates with the
Liver disease in the elderly
duration of chronic hepatitis, elderly patients with cirrhosis due to chronic hepatitis B or C should be screened twice yearly with ultrasound of the liver and serum alpha fetoprotein testing
Drug-induced hepatotoxicity (see also Ch. 8) 1 The risk of drug-induced hepatotoxicity has been shown to increase with advancing age, most notably for isoniazid. Eastwood (1971) found that approximately 20% of cases of jaundice in the elderly were secondary to medications, compared with approximately 2–5% of patients of all ages who required hospitalization for jaundice 2 Benoxaprofen is a nonsteroidal anti-inflammatory agent for which a clear association between age and hepatotoxicity was demonstrated. Nine patients taking the medication developed fulminant hepatic failure and died; all were over age 70. The drug was taken off the market and is no longer available 3 Elderly patients are more likely to be on multiple medications. Williamson and Chopin (1980) found that the frequency of adverse drug reactions was three times higher in patients taking six medications compared with those taking a single agent. Such ‘polypharmacy’ increases the chance that cytochrome P-450 activity will increase or decrease, thereby leading to drug-drug interactions 4 Drug-induced hepatotoxicity should be a major diagnostic consideration in all elderly patients who present with elevated liver enzymes and/or jaundice. All unnecessary medications should be discontinued, and necessary agents should be switched to a different class. Table 24.2 lists some drugs for which hepatotoxicity increases with age
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis – NAFLD and NASH NAFLD (and NASH) is an increasingly recognized syndrome characterized by macrovesicular steatosis in persons who are not excessive drinkers. NAFLD may be present in as much as 20% of the general population. NASH is about one-tenth as frequent but may progress to cirrhosis, liver failure and liver cancer. • the metabolic syndrome of insulin resistance, obesity, diabetes mellitus, hypertriglyceridemia, and hypertension is often present in patients with NAFLD • simple fatty liver and NASH can only be distinguished at present by liver biopsy findings • NASH may be a common initial cause of cirrhosis previously considered cryptogenic • older age is an independent predictor of severe liver fibrosis in patients with NASH
Table 24.2: Some medications for which hepatotoxicity increases with age Benoxaprofen Dantrolene Floxacillin Halothane Isoniazid Methyldopa Sulindac
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Autoimmune liver disease 1 Primary biliary cirrhosis (see also Ch. 14) • studies by Dickson et al. from the Mayo Clinic (1989) have identified advancing age as a poor prognostic indicator in patients with primary biliary cirrhosis. In contrast, a previous study by Lehmann, 1985 found that individuals presenting with primary biliary cirrhosis after age 65 were less likely to have advanced disease 2 Autoimmune hepatitis (see also Ch. 5) • typically occurs in middle-age females, but can be present in older individuals. Management in the elderly can be difficult, due to the adverse effects of long-term corticosteroid use in postmenopausal females already at high risk for osteoporosis, glaucoma, arterial hypertension, and obesity 3 Primary sclerosing cholangitis (see also Ch. 15) • usually occurs in the third or fourth decade; it is, therefore, unusual to make this diagnosis in an elderly patient
Alcoholic liver disease (see also Ch. 6) 1 The perception has been that most alcoholics who develop alcoholic liver disease will do so in middle age. However, recent studies from Europe and the USA have demonstrated that a significant proportion of patients with alcoholic liver disease present in the fifth and sixth decades 2 Older patients are more likely than younger patients to exhibit the classic signs of hepatic decompensation – ascites, jaundice, and lower extremity edema. Overall mortality due to alcoholic liver disease is higher in patients over age 60: 34% at 1 year, compared with 5% in younger patients. In patients over age 70, the 1-year mortality rate increases dramatically to 75%
Metabolic liver diseases 1 Hereditary hemochromatosis (see also Ch. 16) • while most patients with hemochromatosis present by middle age, some patients first seek medical attention at an advanced age for HCC or another complication of endstage liver disease • female patients typically become symptomatic approximately a decade after their male counterparts, due to the iron-depleting effects of regular menses and childbirth • common symptoms include fatigue, diabetes, impotence and arthritis, all of which are common in the elderly anyway • the diagnosis of hemochromatosis is suggested by a fasting transferrin saturation (serum iron/total iron binding capacity × 100) greater than 45% in males and females and an elevated serum ferritin. Early diagnosis is crucial because complications can be prevented by phlebotomy, and family members can be screened • genetic testing in peripheral blood looking for the common hemochromatosis mutations (C282Y, H63D) is now available and eliminates the need for liver tissue iron determination in many patients • a major cause of death in patients with cirrhosis due to hemochromatosis is HCC; screening with serum alpha fetoprotein testing and ultrasonography should be done every 6 months 2 Alpha-1 antitrypsin deficiency (see also Ch. 18) • patients with homozygous alpha-1 antitrypsin deficiency (α-1ATD) usually present before age 65 • heterozygous α-1ATD has been thought to be a cause of cirrhosis in approximately 5% of patients over age 65 years with cirrhosis. However, heterozygous α-1ATD is frequent
Liver disease in the elderly
in the overall population, and no evidence exists that intracellular α-1ATD globular inclusions are hepatotoxic in heterozygotes • although no effective treatment of α-1ATD related liver disease exists, diagnosis is important so that heterozygous or affected family members can be advised to avoid behavior such as alcohol, smoking, and intravenous drug use, that may jeopardize their hepatic and pulmonary function 3 Wilson disease (see also Ch. 17) • de novo diagnosis of this entity is extremely rare in elderly patients. Most patients have clinical disease well before the fifth decade
Cryptogenic cirrhosis (see also Chs 9 and 10) 1 A substantial number of elderly patients with cirrhosis have cryptogenic cirrhosis (cause unknown). Many of these cases may result from NASH that has progressed to cirrhosis 2 In a postmortem study, Ludwig and Baggenstoss (1970) described 77 patients over age 70 with cryptogenic cirrhosis, in whom the diagnosis was unsuspected when they were alive. This finding raises the possibility of a specific form of cryptogenic cirrhosis in the elderly, but further research is needed before the existence of such an entity can be established
Liver abscess (see also Ch. 28) 1 The majority of patients with pyogenic liver abscesses in the northern hemisphere are over age 60 2 The diagnosis is more difficult to make than in younger patients, since the typical presentation of fever, jaundice, and right-upper-quadrant pain is frequently absent. Elderly patients are more likely to have nonspecific symptoms, such as epigastric pain, weakness, fatigue, and shortness of breath 3 While approximately one-half of infections originate from the biliary tree (most often as a result of ascending cholangitis), other intra-abdominal and gastrointestinal sources should be investigated. These include: • penetrating gastric or duodenal ulcers • pancreatitis • perihepatic abscess • portal vein thrombosis • peritonitis (of any cause) • inflammatory bowel disease • colon cancer • diverticulitis and/or diverticular abscess • cryptogenic (in some cases due to poor dentition) 4 A retrospective study of Sridharan et al. (1990) demonstrated that almost one-third of elderly patients with hepatic abscesses at autopsy were misdiagnosed in life as having a hepatic malignancy. Confirmation of tumor by needle biopsy should be obtained, especially if a primary site of malignancy is not present 5 Pyogenic abscesses can be successfully treated by percutaneous aspiration and drainage in conjunction with systemic intravenous antibiotics
Gallstones (see also Ch. 32) 1 Gallstones are an age-related phenomenon. The mortality of untreated biliary tract disease also increases with age. Cancer of the gallbladder is also more likely to occur in older patients than in younger patients
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Table 24.3: Management of biliary disease in the elderly Condition
Treatment
Acute or chronic cholecystitis
Early cholecystectomy (preferably laparoscopic) and perioperative exploration of the bile duct (in acute cholecystitis)
Cholangitis with choledocholithiasis
ERCP with sphincterotomy and stone extraction
Choledocholithiasis with gallstones in the gallbladder
ERCP with sphincterotomy. If symptoms persist, then cholecystectomy or percutaneous cholecystostomy with removal of the gallstones
Asymptomatic gallstones
Observation generally preferred over prophylactic intervention
ERCP, endoscopic retrograde cholangiopancreatography.
2 The management of biliary disease with respect to age has been summarized by James (1991) as outlined in Table 24.3 • with the advent of laparoscopic cholecystectomy, early operative intervention has brought the mortality and morbidity rates for young and old closer together • endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy has been shown to have insignificant differences in morbidity and mortality rates between old and young, despite a longer duration of hospitalization in the elderly • incidental appendectomy during cholecystectomy should not be performed in elderly patients due to the risk of wound infection and the relatively low lifetime risk of acute appendicitis
Hepatic tumors 1 Hepatocellular carcinoma (HCC) (see also Ch. 27) • elderly patients with cirrhosis are at increased risk of HCC; there is a clear association between the development of HCC and duration of cirrhosis; in the Western world, 50% of patients with cirrhosis who develop HCC are over age 60, and 40% are over age 70 • screening for the detection of HCC should be performed as described previously; early detection of a small tumor may result in prolongation of survival by resection, radiofrequency ablation, ethanol injection, chemoembolization, or liver transplantation 2 Metastatic tumors • most common malignant tumor found in the liver • the incidence of hepatic metastases is greatest for those tumors arising within the drainage area of the portal vein (colon, pancreatic, and stomach cancer), but other tumors, such as lung and breast cancer, can also metastasize to the liver • while the prognosis for patients with hepatic metastases is poor (with an average survival of 6 months), identification and localization can be important. Survival is directly correlated with the extent of hepatic involvement; patients with solitary metastases have a survival time almost double that of patients with widespread hepatic metastases • therapy may prolong survival; 20% of patients who undergo surgical resection of a solitary hepatic metastasis may be alive 5 years after resection
Liver disease in the elderly
Fulminant hepatic failure (FHF) (see also Ch. 2) • regardless of the etiology, FHF has a higher mortality rate in the elderly than in the young (Table 24.4) • FHF due to hepatitis A is particularly devastating in the elderly, with a mortality rate much greater than that in individuals between ages 15 and 24 • the best treatment for FHF in the elderly is to prevent its occurrence: – vaccination against hepatitis A and B should be considered in all susceptible elderly individuals – hepatotoxic drugs, such as isoniazid, should not be used unless absolutely necessary – frequent monitoring of liver enzymes should be performed in elderly patients who require treatment with medications known to have potential hepatotoxicity
Complications of Cirrhosis in the Elderly Portal hypertension (see also Chs 9–13) 1 Surprisingly, elderly patients admitted with bleeding esophageal varices have short-term mortality rates similar to those of younger patients. However, their 1-year survival is less than that of their younger counterparts 2 Older patients are less likely to tolerate the effects of vasopressin (with or without nitroglycerin) during an acute variceal bleed. Continuous infusion of octreotide is preferable to vasopressin in the medical treatment of bleeding varices in the elderly 3 Band ligation, sclerotherapy, and beta blockers can be used to prevent recurrent bleeding, although some older patients may be unable to tolerate the adverse effects of beta blockers (e.g., fatigue, dizziness, depression) 4 Both transjugular intrahepatic portosystemic shunts (TIPS) and portacaval shunts can be used for recurrent variceal bleeding; however, their usefulness is limited by the high frequency of post-shunt hepatic encephalopathy • with TIPS, the frequency of hepatic encephalopathy is directly related to the shunt diameter and residual hepatic function • it is recommended that small-caliber stents of 7–8 mm be used in patients over age 60, in order to decrease the chances of hepatic encephalopathy • lowering the hepatic venous pressure gradient to just below 12 mmHg may also minimize the chances of post-TIPS hepatic encephalopathy in elderly cirrhotic patients 5 Elderly patients with refractory ascites and/or recurrent variceal bleeding, who are otherwise in good physiologic condition, should be considered for liver transplant evaluation (see later)
Table 24.4: Age-specific survival rates in FHF
Age group
Survival (%) Hepatitis B Non-A, non-B hepatitis
15–24
40
20
25–44
35
5
45+
15
0
Modified from the American Gastroenterological Association Teaching File (1988).
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Hepatocellular carcinoma See earlier and Ch. 27.
Orthotopic liver transplantation (OLT) (see also Ch. 31) 1 Advanced age is not a contraindication to OLT. Recent studies have shown that in patients older than age 60–65, survival after OLT is comparable to that of younger patients. The decision to proceed with liver transplantation should be based on the overall health of the patient, not chronological age 2 It has also been shown that donor livers from individuals over age 50 can be used safely. Previously, there had been concern over the theoretical loss of liver function with advancing age, and many older donor livers went unused based solely on age. Questions had also been raised as to whether older livers are less resistant to ischemia, preservation, and reperfusion injuries. The increasing demand for donor livers has led to the increasing use of livers from elderly donors • several groups have reported that patient and graft outcomes are identical regardless of the age of the donor livers, even though older livers have significantly increased steatosis and are more likely to be used in patients requiring urgent liver transplantation • the function of an older liver may be slightly worse in the early postoperative period, as evidenced by higher peak serum alanine aminotransferase and bilirubin levels, and slightly lower bile outputs 3 Yersiz et al. (1995) demonstrated a significant increase in delayed function of livers from donors over age 50 compared with donors below age 30. Recipients experiencing delayed function were three times as likely to require retransplantation. However, early recognition of delayed function and subsequent retransplantation led to similar 1-year patient survival rates in both groups 4 Currently, livers from donors older than age 65 are used preferentially in patients who have HCC, have a high Model for End-stage Liver Disease (MELD) score, or require urgent liver transplantation (e.g., for hepatorenal syndrome or FHF). Ischemic time should be kept to a minimum when an older donor liver is used, to lessen preservation injury and postoperative hepatic graft dysfunction 5 That livers from older donors are able to withstand the often extreme physiologic conditions imposed by liver transplantation (harvesting, implantation, reperfusion, rejection, toxic effects of drugs, infection, etc.) and ultimately provide excellent function is a clear demonstration that the human liver is highly resilient to the aging process
Further Reading American Gastroenterological Association. Technical review on non-alcoholic fatty liver. Gastroenterology 2002; 123:1705–1725. Angulo P, Keach J, Batts K, Lindor K. Independent predictors of fibrosis in patients with non-alcoholic steatohepatitis. Hepatology 1999; 30:1356–1362. Bugianesi E, Leoni N, Vanni E, et al. Expanding the natural history of non alcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123:134–140. Centers for Disease Control and Prevention. Hepatitis A. In: Atkinson W, Wolfe C, eds. Epidemiology and Prevention of Vaccine Preventable Diseases, 7th edn. Washington DC: Department of Health and Human Services; 2002:191–206. Dice JF, Goff SA. Aging and the liver. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology. New York: Raven Press; 1988:1245–1258. Dickson ER, Grambsch P, Fleming TR. Prognosis in primary biliary cirrhosis. Model for decision making. Hepatology 1989; 10:1–7. Eastwood HOH. Causes of jaundice in the elderly: a survey of diagnosis and investigation. Gerontol Clin 1971; 13:69–81. Floreani A, Bertin T, Soffiati G, et al. Anti-hepatitis C virus in the elderly: a sero-epidemiological study in a home for the aged. Gerontology 1992; 38:214–216.
Liver disease in the elderly James OFW. Liver disease in the elderly. In: McIntyre N, Benhamou JP, Bircher J, Rizzetto M, Rodes J, eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press; 1991:1305–1309. Lehmann AB, Bassendine MF, James OFW. Is primary biliary cirrhosis a different disease in the elderly? Gerontology 1985; 31:186–194. Ludwig J, Baggenstoss AH. Cirrhosis of the aged and senile cirrhosis: are there two conditions? J Gerontol 1970; 25:244–248. MacMahon M, James OFW. Liver disease in the elderly. J Clin Gastroenterol 1994; 18:330–334. Munoz SJ, Friedman LS. The liver and aging. In: Rustgi VK, Van Thiel OH, eds. The Liver in Systemic Disease. New York: Raven Press; 1993:251–266. Pongor S, Ulrich P, Bencsath A, Cerami A. Aging of proteins: isolation and identification of a fluorescent chromophore from the reaction of peptides with glucose. Proc Natl Acad Sci USA 1984; 81:2684–2688. Sridharan GV, Wilkinson SP, Primrose WR. Pyogenic liver abscess in the elderly. Age Ageing 1990; 19:199–203. Valdivieso V, Palma R, Wunkhaus R, et al. Effect of aging on biliary lipid composition and bile acid metabolism in normal Chilean women. Gastroenterology 1978; 74:871–874. Van Thiel DH, Stauber R, Gavaler J, Francavilla A. Hepatic regeneration effects of age, sex hormone status, protein and cyclosporine. Dig Dis Sci 1991; 36:1309–1312. Williamson J, Chopin JM. Adverse reactions to prescribed drugs in the elderly: a multicentre investigation. Age Ageing 1980; 9:73–80. Wynne HA, Cope LH, Mutch E, et al. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989; 9:297–301. Yersiz H, Shaked A, Olthoff K, et al. Correlation between donor age and the pattern of liver graft recovery after transplantation. Transplantation 1995; 60:790–794. Zoli M, Iervese T, Abbati S, et al. Portal flow velocity and flow in aging man. Gerontology 1989; 35:661–665.
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