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Liver disorders in the elderly
Best Practice & Research Clinical Gastroenterology 23 (2009) 909–917
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Best Practice & Research Clinical Gastroenterology
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Liver disorders in the elderly Annarosa Floreani, Associate professor of Gastroenterology * Dept. of Surgical and Gastroenterological Sciences, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy
a b s t r a c t Keywords: Liver diseases Elderly Chronic hepatitis Ageing
Although there are no specific age-related liver diseases, it is increasingly recognized that the percentage and the actual number of elderly will increase substantially over the next twenty years. Moreover, the developments of new emerging conditions (e.g. non-alcoholic steatohepatitis) and novel therapeutic approaches have provoked increasing enthusiasm among hepatologists. Some liver diseases are particularly frequent in the elderly, e.g. chronic hepatitis C and hepatocellular carcinoma. The clinical course and management of liver disease in the elderly may differ in several aspects from those of younger adults. The problem of whether to offer antiviral treatment to a wide range of patients with chronic hepatitis C has arisen over the last eight to ten years, since the reduction in the risk of hepatocellular carcinoma was analyzed. Selected patients aged 65 and older have a chance of treatment with pegylated interferon plus ribavirin, despite a higher likelihood of side effects. The diagnosis of autoimmune hepatitis should be suspected in a patient over 65 years of age in case of ‘acute’ presentation with 10-fold increase in transaminases, jaundice and hyper-gammaglobulinemia, to avoid any delay in starting immunosuppressive therapy. The age of an end stage liver disease will increase over the next years, thus we will expects an increasing number of decompensated liver disease and hepatocellular carcinomas. Ó 2009 Elsevier Ltd. All rights reserved.
* Tel.: þ39 049 8212894; fax: þ39 049 8760820. E-mail address: annarosa.fl[email protected] 1521-6918/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.10.005
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Introduction The elderly populations of many countries are growing rapidly and they present increasing need of medical problems. The elderly are predisposed to a variety of liver diseases, which contribute to a marked increase in morbidity in this population. In particular, chronic hepatitis is an important cause of death and hospitalization in the elderly. During the 1970s, a number of studies examined morphological and functional changes in the elderly liver, and several age-related changes have been documented. However, the consequences of these age-related changes do not substantially affect the susceptibility to liver disease, with some exceptions, mainly the metabolic function decline, and the regenerative capacity [1]. In this chapter we describe a few aspects of parenchymal liver disease that have recently been revisited in the elderly. Hepatitis B virus infection In Northern Europe actually the rate of HBsAg is below 1%. This is only partially due to vaccination campaign, which are generally aimed at children or high-risk groups. However, the influx of immigrants from Eastern Europe and other underdeveloped countries poses the threat of increasing incidence of chronic HBV infection in Western countries [2]. In our experience, the decline in HBV infection in old people’s homes, as in other closed communities, is due to improvements in hygienic standard and medical care [3]. Infected elderly people often develop a subclinical or oligosymptomatic hepatitis with a low rate of HBV clearance, possibly due to their impaired immunological status. This can produce highly infective chronic hepatitis B surface antigen carriers who are substantially healthy. Chronic hepatitis and/or cirrhosis (due to infection acquired earlier in life) are generally inactive and progress slowly (maybe because patients with more severe disease do not reach old age)[4]. Hepatitis delta virus infection Hepatitis Delta Virus (HDV) is a defective virus which requires HBV particles for its transmission. No special infection has been described in the elderly. HDV infection is also declining in high-prevalence countries. Hepatitis C virus infection This is the most important clinical form of chronic hepatitis in the elderly. From the epidemiological point of view, the prevalence of antibodies against HCV increases with advancing age. In studies carried out in the general population before the 2000, the proportion of infected subjects over 65 years of age ranged from 5.2 to 42.1% (Table 1, Refs. [5–13]). This behaviour reflects a cohort effect of subjects whose infection was acquired many years before, particularly an epidemic spread of HCV infection during the Second War and in the early post-war years. The epidemiological factors included blood transfusions,
Table 1 Anti-HCV seroprevalence in the general population including elderly subjects. Author and reference
Study period
N
Age
Overall anti-HCV prevalence (%)
Anti-HCV prevalence in elderly subjects (%)
Stroffolini,1995 [5] Guadagnino, 1997 [6] Coppola, 2000 [7] Raffaele, 2001 [8] Maio, 2000 [9] Ansaldi, 2005 [10] Di Stefano, 2002 [11] Pendino, 2005 [12] Fabris, 2008 [13]
1994 1996 1994–1995 1997 1997 1996–1997 1999–2000 2002–2003 2002
681 1352 3549 250 448 3577 721 1645 965
6–70 7–91 12–90 >16 6–87 0–90 10–90 12–95 0–90
8.4 12.6 2.7 22.4 16.2 2.7 10.4 6.5 2.6
18.4 33.1 9.4 (61–70) 38.7 42.1 5.2 34 16.7 12
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but the main culprits were non-disposable syringes [14]; females were more infected than males [15]. Thus in Japan, China, and Italy, the prevalence of HCV antibodies steadily increased with age and people over 65 years old account for the majority of infected cases [16]. A recent epidemiological survey carried out in the general population of Northern Italy shows a reduction of HCV infection in the elderly, possibly due to age-related mortality [13]. The changing epidemiological features affect also the genotypes. In fact, in Italy and France Nousbaum et al [17] observed that the 1b genotype represented 30.8% of HCV-infected subjects under 40 years old, while this proportion increased with advancing age up to 82.3% in subjects over 60. Similarly, in a population of 610 patients with chronic hepatitis, Simmonds et al [18] observed that genotype 3 was more frequent in young adults, whereas genotypes 1 and 2 increased with advancing age. The clinical spectrum of case with active replication in the elderly ranges from no biochemical or clinical signs of liver disease right up to decompensated cirrhosis, sometimes with superimposed HCC [19]. At the onset of infection or the diagnosis of chronic hepatitis, old age is associated with more severe histological damage and the presence of cirrhosis.[20]. Moreover, most studies demonstrated that old age is a risk factor for progression to cirrhosis [21]. In the model of post-transfusion hepatitis the time necessary to have a 50% probability of developing cirrhosis in patients aged 21–30, 31–40 and more than 40 years was 33, 23 and 16 years respectively [22]. Hepatic damage cofactors, like alcohol, drugs or metabolic alteration, considerably affect the severity of liver disease in elderly subjects [23]. In a multicentre Italian cross-sectional study a total of 1544 patients were enrolled [24]. Chronic hepatitis was observed in 69% of patients, cirrhosis in 25%, and HCC in 5%. The remaining 1% had a diagnosis of previous infection. Among patients with liver disease 41% had normal ALT levels. Treatment strategies for hepatitis C Asymptomatic carriers of HCV with normal transaminases levels have mild histological changes and rarely develop advanced disease [25,26]. In young and adult people asymptomatic carriers with normal transaminases have indeed a good chance to obtain a sustained virological response (SVR)[27]. And there is a general opinion in favour of treating these patients. The AISF (Italian Association for the Study of Liver Disease) guidelines recommend that treatment is indicated in elderly patients (subjects aged 65 or more) who have increased risk of developing severe liver disease (2009 Annual Meeting, unpublished data). Table 2 shows the SVR rate observed in elderly patients with different genotypes in published studies [28–34]. In general, the SVR rates are lower than in adult patients, as demonstrated by a casecontrol study 45% vs. 69.7%, (p < 0.02)[33]. However, when considering the efficacy and safety of combined pegylated interferon (PEG-IFN) plus ribavirin treatment in elderly patients, the overall rate of SVR is 45% [32,33]. This rate should be considered as acceptable, unless lower than that reached in young patients. Table 2 Studies including elderly patients. Author
Study design
Antiviral treatment
Total N. of patients
N. of elderly pts
SVR rate in elderly
Effect of age on SVR
Bacosi, 2002 [28]
RCT
119
All
16% vs. 23% vs. 29%
N.A.
Alessi, 2003 [29] Kumada, 2006 [30] Iwasaki, 2006 [31] Thabut, 2006 [32]
Retrospective Observational Prospective Retrospective
Amantadine (N.42) IFN (N.39) IFNþamantadine (N.38) IFN IFN þ RBV
154 288 208 166
50 47
18% vs. 20% 25.2
n.s. n.s.
All
18.8
n.s.
Floreani, 2006 [33] Antonucci, 2007 [34]
Case-control Retrospective
99 153
33 30
45.5% vs. 69.7% 70
0.02 n.s.
N.A. ¼ not available.
IFN;IFN þ RBV;PEG-IFN; PEG-IFN þ RBN; other PEG-IFN þ RBV PEG-IFN þ RBV
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Older patients may be at risk of neurological side effects of IFN, e.g. confusion, lethargy, cognitive changes and depression, especially if they have a history of neurological and/or psychiatric disorders [35]. However, multiple side effects are common, and occasionally severe. Table 3 shows the frequency of adverse events among elderly patients treated with antiviral therapy. In general, adverse reactions to IFN seem to be more frequent in older than in younger patients. The incidence of ribavirin-induced haemolytic anaemia increases with age [36,37] and reductions or discontinuation are more frequent in patients aged >55 years [30–32]. Alcoholic liver disease Alcohol consumption is common in old age. Recent epidemiological studies showed an increasing alcohol consumption among subjects above 65 years of age [38]. It has been estimated that 5–15% of elderly people (over 65 years old) have alcohol related problems. About two thirds of these subjects already had an alcohol abuse when younger (early drinkers), whereas one third develop alcohol related problems in the elderly, often as consequence of changing lifestyles (late drinkers) [39]. Alcohol is more toxic in the aging organism because of changes in its metabolism, particularly because alcohol and acetaldehyde dehydrogenase and cytochrome P-4502E1 diminish with age [40]. Moreover, the water distribution volume decreases with advancing age [41], leading to increased blood concentrations of ethanol. Signs and symptoms of alcoholic liver disease in old people are no different from the situation in younger subjects [42], and are related to cirrhosis and its complications. However, the prognosis is worse in the elderly. In a British study the 1-year mortality risk was 75% in cirrhotics over 70 years; moreover, among the oldest patients more than 50% developed HCC [43]. Risk factors influencing the progression of liver damage include sex, genetic factors, nutritional status, HVB and HCV infections [42]. The highest mortality is due to an alcoholic hepatitis in a patient with underlying alcoholic cirrhosis. Several prognostic scores have been proposed to predict survival in these patients. The Glasgow score for alcoholic hepatitis considers the age >50 as a significant factor for a worse prognosis [44]. Alcohol abuse has been mentioned in many studies as contributing to the progression of HCVrelated liver disease. In a study including 800 patients with HCV infection heavy drinking (>50 g of ethanol a day) was associated with an increase in mean fibrosis [45]. Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological spectrum of liver abnormalities ranging from steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is mainly related to metabolic
Table 3 Histological changes in drug-induced liver damage. Histological changes
Drugs
Mechanism
Hepatic necrosis
Ticlopidine, methyldopa, thienilic acid, iproniazid, isoniazid, nitrofurantoin, valproic acid Chlorpromazine, amoxicillin-clavulanic acid, nimesulide, ajmaline, arsenicals, rifampicin, flucloxacillin Sex hormones, amiodarone, tetracyclines, perhexiline, tamoxifen Methotrexate
Immunoallergic
Chronic cholestasis
Microvesicular steatosis and steatohepatitis Hepatic fibrosis
Unknown
Inhibition of b-oxidation
Metabolite-mediated toxicity
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disorders including obesity, insulin-resistance, hyperlipidemia, nutritional disorders, inherited lipoprotein metabolism disorders, drug use and toxic ingestion. The prevalence of steatosis in the general population evaluated with ultrasound is approximately 20–30% [46]. Its prevalence is increasing with advancing age ranging a peak of 62.8% in females and 59.5% in males between 46 and 75 years in a general population from Central Italy [47]. Over 75 years the prevalence of fatty liver tends to decrease probably for the effect of mortality due to the metabolic syndrome. While prospective studies on the natural history of NASH are still lacking, approximately 10–15% of patients will progress to advanced fibrosis and cirrhosis, and even HCC [48]. A population-based cohort study carried out in the Olmsted county in Minnesota (US) demonstrated that patients with NAFLD had a significantly higher mortality than expected over a 7.6 year mean follow-up period and that mortality was independently associated with age, diabetes and cirrhosis [49]. Uncorrected dietary habits including a higher intake of soft drinks and meat, and a high fat/high calories diet are associated with an increased risk for NAFLD [47,50]. Thus therapeutic efforts for NAFLD treatment should be regarded as prevention rather than cure of this condition. In other words, preventative efforts should be addressed to children in primary school. However, gradual weight loss should be recommended also to elderly subjects who suffer from this condition. Besides a reduction of total energy intake, programs of regular exercise should be recommended in order to prevent progression to fibrosis. Drug-related liver damage The reported incidence for drug-related hepatotoxicity is between 1 in 10,000 and 1 in 100,000 patients, but the true incidence is difficult to be determined [51]. In particular, the incidence of drugrelated liver damage is very high in elderly subjects who are very high consumers of medication. Drug toxicity is multifactorial and includes: depression of the enzyme system, especially P450 cytochrome and metabolite conjugation; liver changes in the elderly; competition with enzyme systems; renal failure, and a consequent increase in the median life and bioavailability of drugs [52]. The diagnosis of drug-induced hepatic injury usually is based on circumstantial evidence (medical history positive for drug assumption) and is usually a diagnosis of exclusion. An acute presentation falls into three injury patterns: hepatocellular (cytotoxic), cholestatic (bile duct injury), or mixed. A recent paper from the Spanish registry of drug-induced liver injury, reported a total of 461 incidental cases over a 10-year period [53]. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%) and was inversely correlated with age, and had the worst common. The cholestatic pattern was more frequent in subjects >70 years of age. Presentation of drug-induced liver disease, however, is usually non-specific. Mild serum aminotransferase or alkaline phosphatase elevation are mostly commonly seen, which may be incidentally noted and typically do not cause symptoms [54]. Hepatocellular jaundice has a high but variable mortality rate, depending on the drug involved. The AST and bilirubin levels are the most important predictors of death or liver transplantation [55]. Drug-related liver toxicity sometimes evolves to chronic damage, despite the withdrawal of the medication, e.g. with amiodarone and perhexiline, whose metabolites persist in the liver tissue for several months after suspending the treatment. Table 3 summarizes the most important histological lesions in drug-induced liver damage. As far as the group characterized by hepatic necrosis is concerned, a genetic susceptibility associated with some HLA alleles has been hypothesized for some drugs. Thienilic acid is associated with the development of anti-liver/kidney microsomal type 2 antibodies directed against the P450 isoenzyme which converts thienilic acid into active metabolite. Non-organ-specific autoantibodies can develop in chronic hepatitis due to methyldopa; in addition, iproniazid liver damage can be associated with the development of antimitochondrial antibodies of the M6 subtype. Chronic cholestatic lesions (due to nimesulide) may evolve in vanishing bile duct syndrome. The main lesions involve ductules or ducts and the main clinical manifestations are pruritus and jaundice. Cholestasis is occasionally prolonged, resulting in progressive ductopenia. Drugs responsible for microvesicular steatosis and steatohepatitis can inhibit b-oxidation by sequestering coenzyme A, and thus inhibiting mitochondrial b-oxidation enzymes, or impairing mitochondrial structure and function. Fatty acids, which are poorly oxidized by mitochondria, are
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mainly esterified into tryglicerides, which accumulate in small vesicles. Other factors, such as obesity, may contribute to liver damage, as in the case of NASH induced by tamoxifen [56]. Autoimmune chronic liver disease Autoimmune hepatitis Although it has been thought to be largely a disease of young adults, 17-56% of all patients with autoimmune hepatitis (AIH) are over 65 years old at presentation [57-60]. Elderly patients with AIH most commonly present with sign of ‘acute’ presentation defined by the presence of recent onset (>30 days) symptoms (jaundice and/or fatigue and/or drowsiness) in conjunction with serum alanine transferase levels higher than 10-fold the upper normal limit [60]. An acute, even fulminant, onset may reflect de novo disease or a spontaneous exacerbation of a pre-existing chronic process [61]. The histological picture often shows more severe necroinflammatory and fibrotic changes in elderly than in younger patients, but the prognosis is excellent. Very few elderly patients with AIH have clinically aggressive disease (overt jaundice, ascites, and encephopathy). A recent paper included 205 white North American patients with type I AIH evaluated between 1975 and 2005 at Mayo Clinic [62]. Roughly, 50% of them have a follow-up of at least 5 years. The overall rate of remission during immunosuppression ranged from 50% in younger to 61% in elderly patients. In general, AIH is probably under-diagnosed in the elderly, but should be considered in the older patient, to avoid any delay in starting immunosuppressive therapy. Primary biliary cirrhosis Primary biliary cirrhosis (PBC) is a chronic cholestatic liver damage that mostly affects middle-aged women. The age at presentation in the last years is around 60 years, but many patients are over 65 at onset of the disease [63]. Several prognostic models for PBC have confirmed that increasing age does have an independent and adverse effect on prognosis [64], implying that the natural history in elderly subjects may be worse. However, some studies have demonstrate that the clinical picture at presentation is less severe that in younger adults and the percentage of asymptomatic patients is higher among the elderly [65-67]. Among the Newcastle PBC data base including 1023 patients, 397 (39%) were over 65 years old at presentation [68]. In this series there was no difference in presenting clinical features between the older and younger groups, and liver disease deaths were significantly commoner in the older groups (18% vs. 13%, p < 0.05). Hypercholesterolemia is a common finding in patients with PBC, but the incidence for cardiovascular events is not increased in those patients [69]. The risk of both hepatic and extra-hepatic malignancy in PBC patients increases with advancing age [70]. However, the main risk factors associated with HCC in PBC are the male gender, the advanced histological stage, and alcohol intake [71]. In a recent study carried out in two series of patients with PBC from two European centres (389 of Barcelona and 327 of Padova), 24 patients developed HCC; the baseline advanced histological stage was the only risk factor associated to the development of HCC [72]. Hepatocellular carcinoma HCC is the most common complication of liver cirrhosis affecting elderly people. According to the Surveillance, Epidemiology, and End Results (SEER) registries in the United States, age-adjusted HCC incidence rates tripled between 1975 and 2005 from 1.3 to 4.1 cases/100,000 inhabitants [73]. An examination of age-specific HCC incidence rates in 2000–2002 and 2003 to 2005 revealed marked increases in incidence rates among men 50–59 years of age and 75–84 years of age with slight increases in incidence rates among women in these age groups [73]. In Europe South–North and East– West decreasing gradients for HCC risk were observed; HBV, HCV, alcohol and, mainly HCV are independent risk factors that could explain this geographical pattern [74]. A recent prospective study carried out on an homogeneous cohort of 312 patients with initially compensated cirrhosis of viral etiology in the last 15 years has identified HCC as the most frequent and life-threatening complication,
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particularly in HCV-positive cases [75]. HCC often preceded the appearance of ascites and was the cause of death in 70.7% of the patients [75]. In cirrhotic patients with HBV infection, the 5 year cumulative risk of developing HCC is 17% in East Asia and 10% in Western Europe and in the Unites States [76]. HCV and HBV coinfection is a condition particularly prone to malignant transformation [77]. Another emerging condition that contributes to the development of HCC in old age is NAFLD. Although prospective studies on this condition are still lacking, several reports have identified cryptogenic cirrhosis as the end stage of liver disease due to metabolic factors underlying NAFLD-related cirrhosis. Compared with HCV patients, HCC in cryptogenic cirrhosis is diagnosed in an advanced stage, probably owing to lack of surveillance; this leads to limited treatment options and shorter survival times [78]. Moreover, HCCs developing in cryptogenic cirrhosis have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver [79]. These observations have prompted the increasing interest in surveillance programs for cirrhotic patients, aiming to detect any HCC development as early as possible. The treatment of HCC in elderly patients deserved some considerations. Hepatic resection can be safely done in cirrhotic HCC patients >70 years of age, and the prognosis for these patients is comparable to that of younger patients [80]. Radiofrequency ablation (RF), transarterial embolization/ chemoembolization (TAE/TACE) and percutaneous ethanol injection (PEI) represent valid non-surgical treatment options currently used in elderly patients. Liver transplantation is an exceptional measure for elderly patients, due to many current data concerning the management of HCC; moreover, the problem of the increasingly long waiting lists obviously restricts the life expectancy for patients with malignancies. The outcomes of a large cohort of patients with HCC who underwent to different modalities of treatment have been recently examined [81]. The study group included 2963 patients with a mean age at diagnosis of 74 years, 91% of whom were older than 65 years. Transplantation led to 3 year survival in 40.7% of patients, followed by resection (30.9%), ablation (9.8%) and TACE (6.1%). Finally, the recent demonstration, in randomized clinical trials, of survival benefit for patients with advanced HCC treated with molecular target therapy, is an encouraging progress [82]. Conflict of interest statement None. References [1] Schmucker DL. Age-related changes in liver structure and function: implications for the disease? Exp Gerontol 2005;40: 650–9. [2] Lavanchy D. Chronic viral hepatitis as a public health issue in the world. Best Pract res Clin Gastroenterol 2008;22: 991–1008. [3] Floreani A, Bertin T, Soffiati G, et al. Are homes for the elderly still a risk area for HBV infection? Eur J Epidemiol 1992;8: 808–11. [4] Chiaramente M, Floreani A, Naccarato R. Hepatitis B virus (HBV) in the elderly: an underestimated problem? Biomed Pharmacother 1987;41:121–3. [5] Stroffolini T, Menchinelli M, Taliani G, et al. High prevalence of hepatitis C virus infection in a small central Italian town: lack of evidence of parenteral exposure. Ital J Gastroenterol 1995;27:235–8. [6] Guadagnino V, Stroffolini T, Rapicetta M, et al. Prevalence, risk factors, and genotype distribution of hepatitis C virus infection in the general population: a community-based survey in Southern Italy. Hepatology 1997;26:1006–11. [7] Coppola RC, Masia G, Pradat P, et al. Impact of hepatitis C virus infection on healthy subjects in an Italian island. J Viral Hepat 2000;7:130–7. [8] Raffaele A, Valenti M, Iovenitti M, et al. High prevalence of HCV infection among the general population in a rural area of central Italy. Eur J Epidemiol 2001;17:41–6. [9] Maio G, d’Argenio P, Stroffolini T, et al. Hepatitis C virus infection and alanine transaminase levels in the general population: a survey in a Southern Italian town. J Hepatol 2000;33:116–20. [10] Ansaldi F, Buzzone B, Salmaso S, et al. Different seroprevalence and molecular epidemiology patterns of hepatitis C virus infection in Italy. J Med Virol 2005;76:327–32. [11] Di Stefano R, Stroffolini T, Ferraro D, et al. Endemic hepatitis C virus infection in a Sicilian town: further evidence for iatrogenic transmission. J Med Virol 2002;67:339–44. [12] Pendino GM, Mariano A, Surace P, et al. Prevalence and aetiology of altered liver tests: a population-based survey in a Mediterranean town. Hepatology 2005;41:1151–9. [13] Fabris P, Baldo V, Baldovin T, et al. Changing epidemiology of HCV and HBV in northern Italy: a survey in the general population. J Clin Gastroenterol 2008.
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[55] Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005;42:481–9. [56] Bruno S, Maisonneuve P, Castellana P, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. Br Med J 2005;330:932. [57] Newton JL, Burt AD, Park JB, et al. Autoimmune hepatitis in older patients. Age Ageing 1997;26:441–4. [58] Parker DR, Kingham JGC. Type I autoimmune hepatitis is primarily a disease of later life. QJM 1997;90:289–96. [59] Schramm C, Kanzler S, zum Buschenfelde KH, et al. Autoimmune hepatitis in the elderly. Am J Gastroenterol 2001;96: 1587–91. [60] Floreani A, Niro G, Rosa Rizzotto E, et al. Autoimmune hepatitis: clinical course and outcome in an Italian multicentre study. Aliment Pharmacol Ther 2006;24:1051–7. [61] Czaja AJ. Clinical features, differential diagnosis and treatment of autoimmune hepatitis in the elderly. Drugs Aging 2008; 25:219–39. [62] Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology 2006;43:532–8. [63] Siegel SM, Selmi C, Dottorini L, et al. Late-onset autoimmunity: the paradigm of primary biliary cirrhosis – a mini-review. Gerontology 2008;54:193–201. [64] Weisner RH, Porayko MK, Dickson ER, et al. Selection and timing of transplantation in primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 1992;16:1290–9. [65] Hislop WS, Hopwood D, Bouchier IAD. Primary biliary cirrhosis in elderly females. Age Ageing 1982;11:153–9. [66] Lehmann AB, Bassendine MF, James OFW. Is primary biliary cirrhosis a different disease in the elderly? Gerontology 1995; 31:186–94. [67] Floreani A, Chiaramonte M, Fabris P, et al. Primary biliary cirrhosis in the elderly. Rec Progr Med 1991;82:259–61. [68] Newton JL, Jones DE, Metcalf JV, et al. Presentation and mortality of primary biliary cirrhosis in older patients. Age Ageing 2000;29:305–9. [69] Allocca M, Crosignani A, Gritti A, et al. Hypercholesterolaemia is not associated with early atherosclerotic lesions in primary biliary cirrhosis. Gut 2006;55:1795–800. [70] Floreani A, Baragiotta A, Baldo V, et al. Hepatic and extrahepatic malignancies in primary biliary cirrhosis. Hepatology 1999;29:1425–8. [71] Jones DE, Metcalf JV, Collier JD, et al. Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes. Hepatology 1997;26:1138–42. [72] Cavazza A, Floreani A, Caballeria L, et al. Incidence and risk factors for hepatocellular carcinoma in primary biliary cirrhosis. Comparative analysis from two European referral centers. J Hepatol 2009;50(Suppl. 1):S26 (Abs). [73] Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485–91. [74] Ribes J, Cleries R, Esteban L, et al. The influence of alcohol consumption and hepatitis B and C infections on the risk of liver cancer in Europe. J Hepatol 2008:233–42. [75] Benvegnu` L, Gios M, Alberti A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 2004;53:744–9. [76] Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008;48:335–52. [77] Chiaramonte M, Stroffolini T, Vian A, et al. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 1999;85:2132–7. [78] Giannini EG, Marabotto E, Savarino V, et al. Hepatocellular carcinoma in cryptogenic cirrhosis. Clin Gastroenterol Hepatol 2009;7:580–5. [79] Paradis V, Zalinski S, Chelbi E, et al. Hepatocellular carcinoma in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009;49:851–9. [80] Yeh CN, Lee WC, Jeng LB, et al. Hepatic resection for hepatocellular carcinoma in elderly patients. Hepatogastroenterology 2004;57:219–23. [81] El-Serag HB, Siegel AB, Davila A, et al. Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol 2006;44:158–66. [82] Thomas M. Molecular targeted therapy for hepatocellular carcinoma. J Gastroenterol 2009;44(Suppl. 19):136–41.
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Best Practice & Research Clinical Gastroenterology
10
Liver disorders in the elderly Annarosa Floreani, Associate professor of Gastroenterology * Dept. of Surgical and Gastroenterological Sciences, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy
a b s t r a c t Keywords: Liver diseases Elderly Chronic hepatitis Ageing
Although there are no specific age-related liver diseases, it is increasingly recognized that the percentage and the actual number of elderly will increase substantially over the next twenty years. Moreover, the developments of new emerging conditions (e.g. non-alcoholic steatohepatitis) and novel therapeutic approaches have provoked increasing enthusiasm among hepatologists. Some liver diseases are particularly frequent in the elderly, e.g. chronic hepatitis C and hepatocellular carcinoma. The clinical course and management of liver disease in the elderly may differ in several aspects from those of younger adults. The problem of whether to offer antiviral treatment to a wide range of patients with chronic hepatitis C has arisen over the last eight to ten years, since the reduction in the risk of hepatocellular carcinoma was analyzed. Selected patients aged 65 and older have a chance of treatment with pegylated interferon plus ribavirin, despite a higher likelihood of side effects. The diagnosis of autoimmune hepatitis should be suspected in a patient over 65 years of age in case of ‘acute’ presentation with 10-fold increase in transaminases, jaundice and hyper-gammaglobulinemia, to avoid any delay in starting immunosuppressive therapy. The age of an end stage liver disease will increase over the next years, thus we will expects an increasing number of decompensated liver disease and hepatocellular carcinomas. Ó 2009 Elsevier Ltd. All rights reserved.
* Tel.: þ39 049 8212894; fax: þ39 049 8760820. E-mail address: annarosa.fl[email protected] 1521-6918/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.10.005
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Introduction The elderly populations of many countries are growing rapidly and they present increasing need of medical problems. The elderly are predisposed to a variety of liver diseases, which contribute to a marked increase in morbidity in this population. In particular, chronic hepatitis is an important cause of death and hospitalization in the elderly. During the 1970s, a number of studies examined morphological and functional changes in the elderly liver, and several age-related changes have been documented. However, the consequences of these age-related changes do not substantially affect the susceptibility to liver disease, with some exceptions, mainly the metabolic function decline, and the regenerative capacity [1]. In this chapter we describe a few aspects of parenchymal liver disease that have recently been revisited in the elderly. Hepatitis B virus infection In Northern Europe actually the rate of HBsAg is below 1%. This is only partially due to vaccination campaign, which are generally aimed at children or high-risk groups. However, the influx of immigrants from Eastern Europe and other underdeveloped countries poses the threat of increasing incidence of chronic HBV infection in Western countries [2]. In our experience, the decline in HBV infection in old people’s homes, as in other closed communities, is due to improvements in hygienic standard and medical care [3]. Infected elderly people often develop a subclinical or oligosymptomatic hepatitis with a low rate of HBV clearance, possibly due to their impaired immunological status. This can produce highly infective chronic hepatitis B surface antigen carriers who are substantially healthy. Chronic hepatitis and/or cirrhosis (due to infection acquired earlier in life) are generally inactive and progress slowly (maybe because patients with more severe disease do not reach old age)[4]. Hepatitis delta virus infection Hepatitis Delta Virus (HDV) is a defective virus which requires HBV particles for its transmission. No special infection has been described in the elderly. HDV infection is also declining in high-prevalence countries. Hepatitis C virus infection This is the most important clinical form of chronic hepatitis in the elderly. From the epidemiological point of view, the prevalence of antibodies against HCV increases with advancing age. In studies carried out in the general population before the 2000, the proportion of infected subjects over 65 years of age ranged from 5.2 to 42.1% (Table 1, Refs. [5–13]). This behaviour reflects a cohort effect of subjects whose infection was acquired many years before, particularly an epidemic spread of HCV infection during the Second War and in the early post-war years. The epidemiological factors included blood transfusions,
Table 1 Anti-HCV seroprevalence in the general population including elderly subjects. Author and reference
Study period
N
Age
Overall anti-HCV prevalence (%)
Anti-HCV prevalence in elderly subjects (%)
Stroffolini,1995 [5] Guadagnino, 1997 [6] Coppola, 2000 [7] Raffaele, 2001 [8] Maio, 2000 [9] Ansaldi, 2005 [10] Di Stefano, 2002 [11] Pendino, 2005 [12] Fabris, 2008 [13]
1994 1996 1994–1995 1997 1997 1996–1997 1999–2000 2002–2003 2002
681 1352 3549 250 448 3577 721 1645 965
6–70 7–91 12–90 >16 6–87 0–90 10–90 12–95 0–90
8.4 12.6 2.7 22.4 16.2 2.7 10.4 6.5 2.6
18.4 33.1 9.4 (61–70) 38.7 42.1 5.2 34 16.7 12
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but the main culprits were non-disposable syringes [14]; females were more infected than males [15]. Thus in Japan, China, and Italy, the prevalence of HCV antibodies steadily increased with age and people over 65 years old account for the majority of infected cases [16]. A recent epidemiological survey carried out in the general population of Northern Italy shows a reduction of HCV infection in the elderly, possibly due to age-related mortality [13]. The changing epidemiological features affect also the genotypes. In fact, in Italy and France Nousbaum et al [17] observed that the 1b genotype represented 30.8% of HCV-infected subjects under 40 years old, while this proportion increased with advancing age up to 82.3% in subjects over 60. Similarly, in a population of 610 patients with chronic hepatitis, Simmonds et al [18] observed that genotype 3 was more frequent in young adults, whereas genotypes 1 and 2 increased with advancing age. The clinical spectrum of case with active replication in the elderly ranges from no biochemical or clinical signs of liver disease right up to decompensated cirrhosis, sometimes with superimposed HCC [19]. At the onset of infection or the diagnosis of chronic hepatitis, old age is associated with more severe histological damage and the presence of cirrhosis.[20]. Moreover, most studies demonstrated that old age is a risk factor for progression to cirrhosis [21]. In the model of post-transfusion hepatitis the time necessary to have a 50% probability of developing cirrhosis in patients aged 21–30, 31–40 and more than 40 years was 33, 23 and 16 years respectively [22]. Hepatic damage cofactors, like alcohol, drugs or metabolic alteration, considerably affect the severity of liver disease in elderly subjects [23]. In a multicentre Italian cross-sectional study a total of 1544 patients were enrolled [24]. Chronic hepatitis was observed in 69% of patients, cirrhosis in 25%, and HCC in 5%. The remaining 1% had a diagnosis of previous infection. Among patients with liver disease 41% had normal ALT levels. Treatment strategies for hepatitis C Asymptomatic carriers of HCV with normal transaminases levels have mild histological changes and rarely develop advanced disease [25,26]. In young and adult people asymptomatic carriers with normal transaminases have indeed a good chance to obtain a sustained virological response (SVR)[27]. And there is a general opinion in favour of treating these patients. The AISF (Italian Association for the Study of Liver Disease) guidelines recommend that treatment is indicated in elderly patients (subjects aged 65 or more) who have increased risk of developing severe liver disease (2009 Annual Meeting, unpublished data). Table 2 shows the SVR rate observed in elderly patients with different genotypes in published studies [28–34]. In general, the SVR rates are lower than in adult patients, as demonstrated by a casecontrol study 45% vs. 69.7%, (p < 0.02)[33]. However, when considering the efficacy and safety of combined pegylated interferon (PEG-IFN) plus ribavirin treatment in elderly patients, the overall rate of SVR is 45% [32,33]. This rate should be considered as acceptable, unless lower than that reached in young patients. Table 2 Studies including elderly patients. Author
Study design
Antiviral treatment
Total N. of patients
N. of elderly pts
SVR rate in elderly
Effect of age on SVR
Bacosi, 2002 [28]
RCT
119
All
16% vs. 23% vs. 29%
N.A.
Alessi, 2003 [29] Kumada, 2006 [30] Iwasaki, 2006 [31] Thabut, 2006 [32]
Retrospective Observational Prospective Retrospective
Amantadine (N.42) IFN (N.39) IFNþamantadine (N.38) IFN IFN þ RBV
154 288 208 166
50 47
18% vs. 20% 25.2
n.s. n.s.
All
18.8
n.s.
Floreani, 2006 [33] Antonucci, 2007 [34]
Case-control Retrospective
99 153
33 30
45.5% vs. 69.7% 70
0.02 n.s.
N.A. ¼ not available.
IFN;IFN þ RBV;PEG-IFN; PEG-IFN þ RBN; other PEG-IFN þ RBV PEG-IFN þ RBV
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Older patients may be at risk of neurological side effects of IFN, e.g. confusion, lethargy, cognitive changes and depression, especially if they have a history of neurological and/or psychiatric disorders [35]. However, multiple side effects are common, and occasionally severe. Table 3 shows the frequency of adverse events among elderly patients treated with antiviral therapy. In general, adverse reactions to IFN seem to be more frequent in older than in younger patients. The incidence of ribavirin-induced haemolytic anaemia increases with age [36,37] and reductions or discontinuation are more frequent in patients aged >55 years [30–32]. Alcoholic liver disease Alcohol consumption is common in old age. Recent epidemiological studies showed an increasing alcohol consumption among subjects above 65 years of age [38]. It has been estimated that 5–15% of elderly people (over 65 years old) have alcohol related problems. About two thirds of these subjects already had an alcohol abuse when younger (early drinkers), whereas one third develop alcohol related problems in the elderly, often as consequence of changing lifestyles (late drinkers) [39]. Alcohol is more toxic in the aging organism because of changes in its metabolism, particularly because alcohol and acetaldehyde dehydrogenase and cytochrome P-4502E1 diminish with age [40]. Moreover, the water distribution volume decreases with advancing age [41], leading to increased blood concentrations of ethanol. Signs and symptoms of alcoholic liver disease in old people are no different from the situation in younger subjects [42], and are related to cirrhosis and its complications. However, the prognosis is worse in the elderly. In a British study the 1-year mortality risk was 75% in cirrhotics over 70 years; moreover, among the oldest patients more than 50% developed HCC [43]. Risk factors influencing the progression of liver damage include sex, genetic factors, nutritional status, HVB and HCV infections [42]. The highest mortality is due to an alcoholic hepatitis in a patient with underlying alcoholic cirrhosis. Several prognostic scores have been proposed to predict survival in these patients. The Glasgow score for alcoholic hepatitis considers the age >50 as a significant factor for a worse prognosis [44]. Alcohol abuse has been mentioned in many studies as contributing to the progression of HCVrelated liver disease. In a study including 800 patients with HCV infection heavy drinking (>50 g of ethanol a day) was associated with an increase in mean fibrosis [45]. Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological spectrum of liver abnormalities ranging from steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is mainly related to metabolic
Table 3 Histological changes in drug-induced liver damage. Histological changes
Drugs
Mechanism
Hepatic necrosis
Ticlopidine, methyldopa, thienilic acid, iproniazid, isoniazid, nitrofurantoin, valproic acid Chlorpromazine, amoxicillin-clavulanic acid, nimesulide, ajmaline, arsenicals, rifampicin, flucloxacillin Sex hormones, amiodarone, tetracyclines, perhexiline, tamoxifen Methotrexate
Immunoallergic
Chronic cholestasis
Microvesicular steatosis and steatohepatitis Hepatic fibrosis
Unknown
Inhibition of b-oxidation
Metabolite-mediated toxicity
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disorders including obesity, insulin-resistance, hyperlipidemia, nutritional disorders, inherited lipoprotein metabolism disorders, drug use and toxic ingestion. The prevalence of steatosis in the general population evaluated with ultrasound is approximately 20–30% [46]. Its prevalence is increasing with advancing age ranging a peak of 62.8% in females and 59.5% in males between 46 and 75 years in a general population from Central Italy [47]. Over 75 years the prevalence of fatty liver tends to decrease probably for the effect of mortality due to the metabolic syndrome. While prospective studies on the natural history of NASH are still lacking, approximately 10–15% of patients will progress to advanced fibrosis and cirrhosis, and even HCC [48]. A population-based cohort study carried out in the Olmsted county in Minnesota (US) demonstrated that patients with NAFLD had a significantly higher mortality than expected over a 7.6 year mean follow-up period and that mortality was independently associated with age, diabetes and cirrhosis [49]. Uncorrected dietary habits including a higher intake of soft drinks and meat, and a high fat/high calories diet are associated with an increased risk for NAFLD [47,50]. Thus therapeutic efforts for NAFLD treatment should be regarded as prevention rather than cure of this condition. In other words, preventative efforts should be addressed to children in primary school. However, gradual weight loss should be recommended also to elderly subjects who suffer from this condition. Besides a reduction of total energy intake, programs of regular exercise should be recommended in order to prevent progression to fibrosis. Drug-related liver damage The reported incidence for drug-related hepatotoxicity is between 1 in 10,000 and 1 in 100,000 patients, but the true incidence is difficult to be determined [51]. In particular, the incidence of drugrelated liver damage is very high in elderly subjects who are very high consumers of medication. Drug toxicity is multifactorial and includes: depression of the enzyme system, especially P450 cytochrome and metabolite conjugation; liver changes in the elderly; competition with enzyme systems; renal failure, and a consequent increase in the median life and bioavailability of drugs [52]. The diagnosis of drug-induced hepatic injury usually is based on circumstantial evidence (medical history positive for drug assumption) and is usually a diagnosis of exclusion. An acute presentation falls into three injury patterns: hepatocellular (cytotoxic), cholestatic (bile duct injury), or mixed. A recent paper from the Spanish registry of drug-induced liver injury, reported a total of 461 incidental cases over a 10-year period [53]. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%) and was inversely correlated with age, and had the worst common. The cholestatic pattern was more frequent in subjects >70 years of age. Presentation of drug-induced liver disease, however, is usually non-specific. Mild serum aminotransferase or alkaline phosphatase elevation are mostly commonly seen, which may be incidentally noted and typically do not cause symptoms [54]. Hepatocellular jaundice has a high but variable mortality rate, depending on the drug involved. The AST and bilirubin levels are the most important predictors of death or liver transplantation [55]. Drug-related liver toxicity sometimes evolves to chronic damage, despite the withdrawal of the medication, e.g. with amiodarone and perhexiline, whose metabolites persist in the liver tissue for several months after suspending the treatment. Table 3 summarizes the most important histological lesions in drug-induced liver damage. As far as the group characterized by hepatic necrosis is concerned, a genetic susceptibility associated with some HLA alleles has been hypothesized for some drugs. Thienilic acid is associated with the development of anti-liver/kidney microsomal type 2 antibodies directed against the P450 isoenzyme which converts thienilic acid into active metabolite. Non-organ-specific autoantibodies can develop in chronic hepatitis due to methyldopa; in addition, iproniazid liver damage can be associated with the development of antimitochondrial antibodies of the M6 subtype. Chronic cholestatic lesions (due to nimesulide) may evolve in vanishing bile duct syndrome. The main lesions involve ductules or ducts and the main clinical manifestations are pruritus and jaundice. Cholestasis is occasionally prolonged, resulting in progressive ductopenia. Drugs responsible for microvesicular steatosis and steatohepatitis can inhibit b-oxidation by sequestering coenzyme A, and thus inhibiting mitochondrial b-oxidation enzymes, or impairing mitochondrial structure and function. Fatty acids, which are poorly oxidized by mitochondria, are
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mainly esterified into tryglicerides, which accumulate in small vesicles. Other factors, such as obesity, may contribute to liver damage, as in the case of NASH induced by tamoxifen [56]. Autoimmune chronic liver disease Autoimmune hepatitis Although it has been thought to be largely a disease of young adults, 17-56% of all patients with autoimmune hepatitis (AIH) are over 65 years old at presentation [57-60]. Elderly patients with AIH most commonly present with sign of ‘acute’ presentation defined by the presence of recent onset (>30 days) symptoms (jaundice and/or fatigue and/or drowsiness) in conjunction with serum alanine transferase levels higher than 10-fold the upper normal limit [60]. An acute, even fulminant, onset may reflect de novo disease or a spontaneous exacerbation of a pre-existing chronic process [61]. The histological picture often shows more severe necroinflammatory and fibrotic changes in elderly than in younger patients, but the prognosis is excellent. Very few elderly patients with AIH have clinically aggressive disease (overt jaundice, ascites, and encephopathy). A recent paper included 205 white North American patients with type I AIH evaluated between 1975 and 2005 at Mayo Clinic [62]. Roughly, 50% of them have a follow-up of at least 5 years. The overall rate of remission during immunosuppression ranged from 50% in younger to 61% in elderly patients. In general, AIH is probably under-diagnosed in the elderly, but should be considered in the older patient, to avoid any delay in starting immunosuppressive therapy. Primary biliary cirrhosis Primary biliary cirrhosis (PBC) is a chronic cholestatic liver damage that mostly affects middle-aged women. The age at presentation in the last years is around 60 years, but many patients are over 65 at onset of the disease [63]. Several prognostic models for PBC have confirmed that increasing age does have an independent and adverse effect on prognosis [64], implying that the natural history in elderly subjects may be worse. However, some studies have demonstrate that the clinical picture at presentation is less severe that in younger adults and the percentage of asymptomatic patients is higher among the elderly [65-67]. Among the Newcastle PBC data base including 1023 patients, 397 (39%) were over 65 years old at presentation [68]. In this series there was no difference in presenting clinical features between the older and younger groups, and liver disease deaths were significantly commoner in the older groups (18% vs. 13%, p < 0.05). Hypercholesterolemia is a common finding in patients with PBC, but the incidence for cardiovascular events is not increased in those patients [69]. The risk of both hepatic and extra-hepatic malignancy in PBC patients increases with advancing age [70]. However, the main risk factors associated with HCC in PBC are the male gender, the advanced histological stage, and alcohol intake [71]. In a recent study carried out in two series of patients with PBC from two European centres (389 of Barcelona and 327 of Padova), 24 patients developed HCC; the baseline advanced histological stage was the only risk factor associated to the development of HCC [72]. Hepatocellular carcinoma HCC is the most common complication of liver cirrhosis affecting elderly people. According to the Surveillance, Epidemiology, and End Results (SEER) registries in the United States, age-adjusted HCC incidence rates tripled between 1975 and 2005 from 1.3 to 4.1 cases/100,000 inhabitants [73]. An examination of age-specific HCC incidence rates in 2000–2002 and 2003 to 2005 revealed marked increases in incidence rates among men 50–59 years of age and 75–84 years of age with slight increases in incidence rates among women in these age groups [73]. In Europe South–North and East– West decreasing gradients for HCC risk were observed; HBV, HCV, alcohol and, mainly HCV are independent risk factors that could explain this geographical pattern [74]. A recent prospective study carried out on an homogeneous cohort of 312 patients with initially compensated cirrhosis of viral etiology in the last 15 years has identified HCC as the most frequent and life-threatening complication,
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particularly in HCV-positive cases [75]. HCC often preceded the appearance of ascites and was the cause of death in 70.7% of the patients [75]. In cirrhotic patients with HBV infection, the 5 year cumulative risk of developing HCC is 17% in East Asia and 10% in Western Europe and in the Unites States [76]. HCV and HBV coinfection is a condition particularly prone to malignant transformation [77]. Another emerging condition that contributes to the development of HCC in old age is NAFLD. Although prospective studies on this condition are still lacking, several reports have identified cryptogenic cirrhosis as the end stage of liver disease due to metabolic factors underlying NAFLD-related cirrhosis. Compared with HCV patients, HCC in cryptogenic cirrhosis is diagnosed in an advanced stage, probably owing to lack of surveillance; this leads to limited treatment options and shorter survival times [78]. Moreover, HCCs developing in cryptogenic cirrhosis have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver [79]. These observations have prompted the increasing interest in surveillance programs for cirrhotic patients, aiming to detect any HCC development as early as possible. The treatment of HCC in elderly patients deserved some considerations. Hepatic resection can be safely done in cirrhotic HCC patients >70 years of age, and the prognosis for these patients is comparable to that of younger patients [80]. Radiofrequency ablation (RF), transarterial embolization/ chemoembolization (TAE/TACE) and percutaneous ethanol injection (PEI) represent valid non-surgical treatment options currently used in elderly patients. Liver transplantation is an exceptional measure for elderly patients, due to many current data concerning the management of HCC; moreover, the problem of the increasingly long waiting lists obviously restricts the life expectancy for patients with malignancies. The outcomes of a large cohort of patients with HCC who underwent to different modalities of treatment have been recently examined [81]. The study group included 2963 patients with a mean age at diagnosis of 74 years, 91% of whom were older than 65 years. Transplantation led to 3 year survival in 40.7% of patients, followed by resection (30.9%), ablation (9.8%) and TACE (6.1%). Finally, the recent demonstration, in randomized clinical trials, of survival benefit for patients with advanced HCC treated with molecular target therapy, is an encouraging progress [82]. Conflict of interest statement None. References [1] Schmucker DL. Age-related changes in liver structure and function: implications for the disease? Exp Gerontol 2005;40: 650–9. [2] Lavanchy D. Chronic viral hepatitis as a public health issue in the world. Best Pract res Clin Gastroenterol 2008;22: 991–1008. [3] Floreani A, Bertin T, Soffiati G, et al. Are homes for the elderly still a risk area for HBV infection? Eur J Epidemiol 1992;8: 808–11. [4] Chiaramente M, Floreani A, Naccarato R. Hepatitis B virus (HBV) in the elderly: an underestimated problem? Biomed Pharmacother 1987;41:121–3. [5] Stroffolini T, Menchinelli M, Taliani G, et al. High prevalence of hepatitis C virus infection in a small central Italian town: lack of evidence of parenteral exposure. Ital J Gastroenterol 1995;27:235–8. [6] Guadagnino V, Stroffolini T, Rapicetta M, et al. Prevalence, risk factors, and genotype distribution of hepatitis C virus infection in the general population: a community-based survey in Southern Italy. Hepatology 1997;26:1006–11. [7] Coppola RC, Masia G, Pradat P, et al. Impact of hepatitis C virus infection on healthy subjects in an Italian island. J Viral Hepat 2000;7:130–7. [8] Raffaele A, Valenti M, Iovenitti M, et al. High prevalence of HCV infection among the general population in a rural area of central Italy. Eur J Epidemiol 2001;17:41–6. [9] Maio G, d’Argenio P, Stroffolini T, et al. Hepatitis C virus infection and alanine transaminase levels in the general population: a survey in a Southern Italian town. J Hepatol 2000;33:116–20. [10] Ansaldi F, Buzzone B, Salmaso S, et al. Different seroprevalence and molecular epidemiology patterns of hepatitis C virus infection in Italy. J Med Virol 2005;76:327–32. [11] Di Stefano R, Stroffolini T, Ferraro D, et al. Endemic hepatitis C virus infection in a Sicilian town: further evidence for iatrogenic transmission. J Med Virol 2002;67:339–44. [12] Pendino GM, Mariano A, Surace P, et al. Prevalence and aetiology of altered liver tests: a population-based survey in a Mediterranean town. Hepatology 2005;41:1151–9. [13] Fabris P, Baldo V, Baldovin T, et al. Changing epidemiology of HCV and HBV in northern Italy: a survey in the general population. J Clin Gastroenterol 2008.
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