Liver Diseases in the Elderly

Chapter 26

Liver Diseases in the Elderly K. Tajiri1 and Y. Shimizu2 1

Toyama University Hospital, Toyama, Japan; 2Nanto Municipal Hospital, Toyama, Japan

CHANGES FOUND IN THE AGED LIVER Anatomical and Physiological Changes Liver volume is reduced by 20e40% in the elderly, and the alteration is more marked in women (up to 44% decline) than in men (Schmucker, 2005). Liver blood flow is also estimated to be reduced by 35e50% in the elderly, and this may be responsible for age-related reduction of liver volume (Wynne, 1989). The aged liver has elevated numbers of hepatocytes with decreased numbers of mitochondria but increased volume of individual mitochondria. Aged hepatocytes also contain increased secondary lysosomes and lipofuscin compared to those of younger subjects (Schmucker and Sachs, 2002). Accumulation of lipofuscin is thought to be due to chronic oxidative stress and failure to degrade damaged and denatured proteins (Jung, 2007). The senescence of hepatocytes with aging results in morphological changes in the liver. Senescent hepatocytes expressing p21 or gH2AX show an increased frequency of vacuolated nuclei (Aravinthan, 2012). The nuclear size of hepatocytes is associated with telomere shortening and p21 upregulation in nonalcoholic fatty liver disease (NAFLD) (Nakajima, 2010), suggesting that it is a marker of hepatocyte senescence. Cellular senescence is associated with aberrant activation of oncogenes and the secretion of cytokines and chemokines through interaction with the environment, resulting in immune-mediated clearance of these cells. If such immune surveillance is impaired, hepatocellular carcinoma (HCC) tends to develop (Kang, 2011), accounting for the preferential development of HCC in aged patients with chronic liver disease (Nakajima, 2011).

Liver Function Tests Liver functions are relatively well preserved in the elderly. Hepatic enzymes are well maintained, while bilirubin levels

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may decline with age due to reduced muscle mass and hemoglobin concentrations (Tietz, 1992). In another study, modest decreases in albumin and g-glutamyl transpeptidase levels and an increase in bilirubin level in the serum were observed with increasing age after adjustment for sex, alcohol use, and metabolic syndrome traits (Dong, 2010). Alanine aminotransferase (ALT) levels were reported to decrease with age in both men and women independent of metabolic syndrome components, suggesting the need to set an optimal cut-off point for normal ALT in the elderly (Dong, 2010).

Drug Metabolism A previous report suggested that drug metabolism is reduced by up to 30% after 70 years of age, possibly due to reduced liver volume and hepatic blood flow and a reduction in liver cytochrome P450. Sotaniemi et al. (1997) reported a 32% decrease in cytochrome P450 activity in subjects over 70 years old compared with a group 20e 29 years of age. Furthermore, age-related decreases in hepatic transporters, such as multidrug resistance protein 1a, multidrug resistanceeassociated protein 2, breast cancer resistance protein, and organic anionetransporting polypeptide were also reported (Kawase, 2015). Thus, drug metabolism is reduced with aging, resulting in increased susceptibility to drug-induced liver injury (DILI) in the elderly.

Liver Regeneration Liver regeneration capacity was reported to decline with age (Ono, 2011; Schmucker and Sanchez, 2011). The mechanisms underlying the reduced regeneration capability are complex. One of the mechanisms involves a decrease in concentration of circulating epidermal growth factor (EGF)

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in the elderly, and the response of hepatocytes to EGF is also reduced due to age-associated loss of EGF receptors or deficits in signaling after binding of EGF to its receptor (Sawada, 1989). Another mechanism of reduced hepatocyte proliferation capacity may be the inhibition of cyclindependent kinases by interaction with the chromatin remodeling protein Bim, which is expressed in aged hepatocytes (Iakova, 2003). In association with impaired regenerative capacity, telomere length in the aged liver, especially with liver disease, was reported to be reduced (Takubo, 2000). Decreased cell-cycle rate and increased autophagy and apoptosis were found in the liver after hepatectomy in aged mice (Enkhbold, 2015). Cellautonomous declines in replicative capacity and regenerative response after hepatectomy were found in hepatocytes of the aged liver (Serra, 2015). These mechanisms are responsible for decreased recovery after liver injury or hepatectomy in the elderly.

Immune Functions Most of the immune cells involved in innate immunity, such as monocytes/macrophages and natural killer (NK) cells, show decreased function with aging (Fulop, 2011). Although the percentage and number of CD56bright NK cells gradually decrease with age, CD56dim NK cells progressively increase (Borrego, 1999). In addition, dendritic cells (DCs), which are the most potent antigen-presenting cells, show significant functional changes with aging (Iwasaki and Medzhitov, 2010). Immature DCs promote tolerance through induction of regulatory T cells (Treg), whereas mature DCs stimulate effector T cells. DCs in the elderly show inappropriate maturation induced by infections or tissue injury, which may lead to alterations in the balance between tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases (Agrawal, 2012). T cell number and repertoire diversity are decreased and T cell expansion, differentiation, and signaling intensity are impaired with aging. The numbers of CD4þ T cells are decreased, while those of CD8þ T cells are increased. There is a decrease in expression of the costimulatory molecule CD28 on T cells, which results in impaired ability of T cells to proliferate and secrete interleukin-2 (Kaltoft, 1998). Treg function is decreased after the age of 50, which may be associated with increases in autoimmunity (Tsaknaridis, 2003). In addition, the numbers of B cell precursors in the bone marrow (preB cells), as well as peripheral B cells, decrease with age (Frasca, 2011). On the other hand, immunoglobulin levels may increase (Frasca, 2008), but the quantities of specific antibodies and the diversity of the B cell repertoire decrease (Gibson, 2009).

The level of b2-microglobulin, a component of major histocompatibility complex class 1 molecules, was reported to be elevated in the blood, promoting age-related cognitive dysfunction and impairing neurogenesis (Smith, 2015). In summary, immune responses against antigens, including malignant cells, seem to be impaired with age because of the reductions in number and function of most immunocompetent cells. On the other hand, the decrease in Tregs and impairment of DC maturation may result in a predisposition to autoimmunity.

LIVER DISEASES IN THE ELDERLY The prevalence rates of some liver diseases increase with aging, and advanced liver disease is seen more frequently in older than younger patients. The rate of liver-related mortality increases among patients with chronic liver diseases and cirrhosis, representing the fourth leading cause of death in persons aged between 45 and 54 years and the seventh leading cause of death in those aged between 55 and 64 years (Asrani, 2013). Thus, aging appears to be associated with increasing burden of liver disease. Moreover, various physiological changes with aging may affect the pathogenesis of liver diseases (Fig. 26.1), and the decreased reserve capacity of most organs should be taken into consideration in the management of liver diseases in the elderly.

Viral Hepatitis Hepatitis A Acute hepatitis A virus (HAV) infection is usually selflimiting. However, elderly patients with acute HAV infection seem to show hepatocellular dysfunction with frequent jaundice and coagulopathy, as well as an increased incidence of complications, such as prolonged cholestasis, pancreatitis, and ascites (Brown and Persley, 2002). Higher hospitalization and mortality rates have been reported in elderly patients with HAV; 42% of patients aged 70 years or older required hospitalization compared with 3e20% of adults aged 40e49 years during an outbreak of HAV infection in the United States (Willner, 1998). Age-related differences in outcomes were also reported: 0.004% deaths in individuals 5e14 years old and 2.7% in those older than 49 years of age (Brown and Persley, 2002). Data from the Centers for Disease Control and Prevention (CDC, 2009 Surveillance) also indicate that mortality rate due to HAV increases with age with no fatalities reported in patients younger than 34 years of age. The mortality rates are estimated to be 0.05 per 100,000 patients aged between 45 and 54 years, and 0.11 per 100,000 patients older than 75 years of age. Vaccination for hepatitis A should, therefore, be considered for people, especially the elderly, planning to travel to endemic areas (Mahon and James, 1994).

Liver Diseases in the Elderly Chapter | 26

333

Liver

Volume↓ Drug-induced liver injury

Blood↓

Reduced treatment tolerance

Drug metabolism↓ Alteration of immune function

DC maturation↓ Treg function↓

Autoimmune liver disease

Regeneration↓ T cell & B cell impairment↓

Liver tumor

Systemic organs

Reserve capacity↓ FIGURE 26.1 Physiological changes in elderly subjects associated with the development or pathophysiological modification of liver diseases. Decreases in volume, blood flow, drug metabolism, and regenerative capacity of the liver, and alteration of immune functions occur with age. These changes with decreased reserve functions of various organs could affect the clinical characteristics and management of liver diseases in the elderly. Treg, regulatory T cell; DC, dendritic cell.

Hepatitis B Acute hepatitis B virus (HBV) infection is uncommon in the elderly because the opportunities for HBV infection are estimated to be low in this population. However, HBV infections have been reported in aged residents of nursing homes (Kondo, 1993; Sugauchi, 2000), and the risk factors include sharing bath brushes, nondisposable syringes, shaving blades, and sexual contact. Clinical manifestations of acute HBV infection are similar to those in younger adults. During an outbreak of acute HBV in elderly nursing home residents, most infected patients were asymptomatic, and no fatalities or patients requiring hospitalization were reported during the outbreak (Kondo, 1993). However, the rate of progression to chronic hepatitis B is higher in elderly than younger patients. A report from an outbreak of acute HBV infection in a nursing home showed that 59% of patients older than 65 years of age developed chronic infection (Kondo, 1993). This may be due to decreased immune response preventing evasion of pathogens. The prevalence rates of HBeAg and HBsAg are inversely related to the patient’s age in the natural course of chronic HBV infection. The prevalence rates of HBsAg in Taiwanese men and of HBeAg among HBsAg-positive men older than 60 years of age were reported to be 12.5% and 5.5%, respectively, while respective values of 23.8% and 23.3% were reported in patients aged 30e39 years (Yang, 2002). There were some differences in serum HBV-DNA levels among reports according to

country, and these were associated with the status of HBeAg or HBV genotype (Chen, 2009). Older age and male sex in addition to serum HBV-DNA levels are regarded as risk factors not only for progression to cirrhosis (Iloeje, 2006), but also development of HCC (Chen, 2006). The incidence of HCC increases with age in hepatitis B (Hamada, 2002) With regard to treatment of HBV infection, the efficacy of nucleos(t)ide analogs has been established, with similar efficacy in the elderly and in younger patients (Kawaoka, 2007). Although interferon-based therapy may also be effective for the treatment of chronic HBV infection, its therapeutic effects are inferior in elderly patients (Song, 2004). Aging has also been reported to be an important determinant of humoral and T cell responses to HB vaccination, possibly due to the decreased expression of CD62 L on naïve and central memory T cells with aging (Rosenberg, 2013).

Hepatitis C The prevalence of hepatitis c virus (HCV) infection is different between populations according to age because HCV infection is induced by blood contact, such as blood transfusion (especially before 1992), military service, intravenous drug use, tattoos, hemodialysis, and health care work. In the United States, the prevalence of HCV infection is highest in patients aged 40e49 years (4.3%), with lower prevalence rates of 0.9% and 1% in elderly patients aged

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60e69 years and 70 years or older, respectively (Armstrong, 2006; Mindikoglu and Miller, 2009). A European study showed that the prevalence of HCV with genotype 1 among cases of HCV infection increases with age: 57% in patients aged <65 years, 72% in those 65e80 years of age, and 84% in patients 80 years of age (Thabut, 2006). Older age at the time of infection, but not duration of infection, is an important factor associated with fibrotic progression (Thabut, 2006) and hepatocarcinogenesis (Hamada, 2002). Elderly patients with HCV infection are more likely to show normal ALT levels than younger patients (46% vs. 10.6%, respectively) (Monica, 2006). However, older patients often show more fibrosis regardless of serum ALT level (Thabut, 2006). In addition to aging, menopause has been shown to be associated with advanced fibrosis (Di Martino, 2004; Codes, 2007). Postmenopausal women given hormone therapy showed decreased rates of fibrosis progression, suggesting a protective effect of estrogen against progression of liver fibrosis (Di Martino, 2004). Moreover, the incidence of HCC also increases with aging in cases of hepatitis C (Beasley, 1988). Therefore, progression of fibrosis and development of HCC should be considered especially in elderly patients with chronic viral hepatitis. With regard to treatment for HCV infection, interferonbased therapies, including pegylated interferon and ribavirin, were applied in these two decades. However, adverse effects were observed more often in older patients (Honda, 2007). The rate of sustained viral response (SVR) is lower in elderly patients than younger patients (46% vs. 69.7%, respectively), which may be because the proportions of elderly patients stopping antiviral therapy due to side effects is double that among younger patients (Floreani, 2006). Furthermore, a large cohort study showed that elderly patients exhibit not only lower SVR rate (<64 years, 65.3%; 65e74 years, 49.6%; 75 years, 46.5%; P < .001) and higher rates of withdrawal from treatment (<64 years, 15.0%; 65e74 years, 21.5%; 75 years, 32.4%; P < .001) among patients receiving interferon therapy (Sato, 2015). Menopause has also been shown to have a negative effect in treatment of HCV infection. Menopause was shown to be associated with severe necroinflammation, steatosis, and fibrosis, leading to a negative influence on the response to HCV treatment with pegylated interferon and ribavirin (Villa, 2011). Recently, interferon-free regimens with directacting antiviral agents, such as proteinase inhibitors, NS5A inhibitors, or NS5B inhibitors, were introduced for the treatment of chronic hepatitis or compensated liver cirrhosis induced by HCV infection (Vespasiani-Gentilucci, 2015). Aged patients can tolerate these treatments and the efficacy in this population has been shown to be same as in younger patients (Vespasiani-Gentilucci, 2015).

Hepatitis E The prevalence of hepatitis E virus (HEV) infection is quite different between endemic and nonendemic areas. However, recent reports suggested that exposure to HEV occurs frequently in Western countries. In the United States, 16% of blood donors younger than 60 years of age were positive for anti-HEV IgG, while 25.5% of those older than 60 years were positive (Dalton, 2008). Furthermore, 3% of patients with acute liver injury suspected to be DILI were also seropositive for anti-HEV IgM. The majority of patients with serology consistent with acute HEV infection were older than 60 years of age (Davern, 2011). Recent studies in Asia also showed a higher incidence of HEV infection with aging (>50 years vs. <50 years: 6.6% vs. 2.7%), respectively; in Japan, a less endemic country; 61e70 years vs. 18e30 years: 14.3% vs. 71.4%, respectively; in South-west Iran, a high endemic country (Farshadpour, 2015; Takahashi, 2010). The possibility of HEV infection should always be considered in patients with liver injury of unknown etiology, especially in endemic areas.

Autoimmune Liver Disease The prevalence rates of autoimmune liver disease, such as autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), are relatively high in older patients, whereas primary sclerosing cholangitis is more common in those in the third or fourth decade of life (Wiesner, 1989; Talwalkar and Lindor, 2003; Al-Chalabi, 2006). However, there are no significant differences in results of laboratory tests associated with these autoimmune liver diseases with advanced age, and treatment strategies are usually identical in older and younger patients.

Autoimmune Hepatitis Almost 20% of patients develop AIH after 60 years of age, and the disease is frequently progressive and unexpected because ascites and cirrhosis are common manifestations at presentation with few other symptoms (Al-Chalabi, 2006; Czaja and Carpenter, 2006; Czaja, 2008). Elderly patients usually respond well to corticosteroid therapy (Czaja and Carpenter, 2006). Treatment failure occurs less frequently in older than in younger patients (5% vs. 24%, respectively), and elderly patients have lower rates of fatality from liver failure or need for liver transplantation (5% vs. 21%, respectively) (Czaja and Carpenter, 2006; Czaja, 2008). Notably, elderly patients are at risk of treatment-related complications, especially osteopenia and compression fractures (Czaja, 2009). Furthermore, they may have other comorbidities and medication requirements that complicate their management.

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Primary Biliary Cirrhosis Advancing age has been identified as a poor prognostic factor in patients with PBC, and elderly patients diagnosed with PBC at a young age are likely to show poor prognosis (Dickson, 1989). On the other hand, patients with PBC diagnosed after 65 years of age are less likely to have progressive or advanced disease (Lehmann, 1985). Recently, two types of phenotypic expression of PBC were reported; the first is the classical asymptomatic onset in middle to late age with mild biochemical activity, and the other is symptomatic onset at a young age with high biochemical activity (Muratori, 2008). Administration of ursodeoxycholic acid, which is the only recommended therapy for PBC, appears to be safe and has few side effects. However, the risk of osteoporosis should be taken into consideration, especially in elderly patients.

Alcoholic Liver Disease Alcohol consumption is common in the elderly. In a study of individuals ranging from 60 to 92 years of age in the United Kingdom, 62% of the subjects were drinkers, and heavy drinking was reported in 13% of men and 2% of women (Mirand and Welte, 1996). In a report on alcoholic liver disease (ALD), elderly people presenting with ALD had more advanced disease than young patients (Potter and James, 1987). Half of the elderly patients that develop cirrhosis die within 1 year of diagnosis (Adams and Cox, 1995). In patients with HCV infection, alcohol drinking was associated with accelerated disease progression (Monto, 2004). Adverse effects of benzodiazepines as treatment for withdrawal symptoms, such as drowsiness, fatigue, confusion, ataxia, falls, and incontinence, are more common with increasing age (Kruse, 1990).

Nonalcoholic Fatty Liver Disease NAFLD is a disease predominantly seen in middle-aged to older people. It has been reported that a significant proportion of cryptogenic cirrhosis could be due to the endstage of NAFLD, and age is a risk factor for liver fibrosis and higher mortality rate in NAFLD (Angulo, 1999). Older patients have significantly more risk factors for NAFLD in association with hypertension, obesity, diabetes, or hyperlipidemia (Frith et al., 2009a). In 351 patients in the United Kingdom, albumin, ALT, ALT/AST ratio, and platelet counts were reported to be significantly reduced with advancing age (Frith et al., 2009a). Furthermore, menopause is also associated with progression of NAFLD, as well as HCV infection. Postmenopausal women were shown to have an increased risk of metabolic disease due to decreased energy expenditure with development of increased visceral fat, increased weight gain, and increases

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in triglycerides and cholesterol (Polotsky and Polotsky, 2010). Recent data indicated that progression of hepatic fibrosis occurs even in nonobese postmenopausal women (Yang, 2014; Yoneda, 2014). Thus, aged patients with NAFLD are considered to have advanced liver disease. Recently, sirtuin 1, a negative regulator of aging, was reported to play a key role in the regulation of lipid and glucose homeostasis (Colak, 2011); these observations suggest a close relation between aging and the development of NAFLD, and also indicate the possibility of activating sirtuin 1 as a novel therapeutic strategy for NAFLD. Hepatocyte senescence, including telomere shortening and increased expression of p21, has been reported in NAFLD, and the increased expression of p21 has been shown to be associated with fibrosis progression in patients with NAFLD (Aravinthan, 2013). Recent studies in murine models showed increased levels of tumor necrosis factoralpha and monocyte chemoattractant protein 1 in aged mice given high-fat diets, and significant steatohepatitis was found only in these older mice (Fontana, 2013). Increased accumulation of fat is observed in many nonadipose tissues, including the liver (Slawik and Vidal-Puig, 2006). The effect of aging on metabolic syndrome is complex and wide-ranging, and further investigations are required.

Drug-Induced Liver Injury Old age is a risk factor of DILI because the elderly are susceptible to adverse drug reactions (Danan and Benichou, 1993). It has been suggested that older age is associated with cholestatic type liver injury, but is not a predisposing factor for DILI (Lucena, 2009). A study in Japan also showed that elderly patients were more likely to have cholestatic liver injury (46% in patients over 65 years vs. 31.6% in patients less than 65 years). Patients over 75 years old required significantly longer hospitalization for DILI (Onji, 2009). IIn elderly patients, many types of drugs may be administered for treatment of comorbid conditions. A Japanese study of DILI showed that elderly patients over 75 years of age were taking significantly more concomitant drugs at the time of liver injury (Onji, 2009). Other reports from Western countries also suggested greater drug usage among elderly patients. In Germany, 466 patients over 70 years of age were receiving an average of 3.7 prescribed medicines in addition to 1.4 over-the-counter medications daily (Junius-Walker, 2007). In a prospective study in the Netherlands, 94.2% of elderly patients with a mean age of 82.3 years were taking more than one drug, and 73.3% were prescribed four or more drugs (Tulner, 2009). Several pharmacokinetic and pharmacodynamic mechanisms that may predispose a patient on multiple medications to increased risk of DILI have been proposed (Herrlinger and

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TABLE 26.1 Characteristics of Liver Diseases in Elderly Patients Etiology

Findings

Points of Note in Treatment

Hepatitis A

Mortality[

Symptomatic therapy

Hepatitis B

FrequencyY, HCC[, Mortality[

Antiviral treatmenta

Hepatitis C

HCC[, treatment tolerabilityY

Antiviral treatmentb

Hepatitis E

Frequency[

Symptomatic therapy

Autoimmune

Frequency[

Corticosteroidc

Alcoholic

Disease severity[

Stop drinking, symptomatic therapy

NAFLD

Disease progression, cardiovascular disorders[

Symptomatic therapy, correct metabolic disorders

Drug-induced

Frequency[ (especially cholestatic)

Cessation of causative drug

Liver tumor

Frequency[

Systemic weakness

HCC, hepatocellular carcinoma, NAFLD, nonalcoholic fatty liver disease. a Antiviral treatment using nucleos(t)ide analogs is effective and safe. b Direct antiviral drugs are now available. c Prophylaxis for osteoporosis is important.

Klotz, 2001). Adverse effects of both the drugs themselves and synergistic interactions of several drugs should be taken into consideration in elderly patients.

Liver Tumor HCC is more common in elderly patients with liver cirrhosis (Altekruse, 2009). Elderly patients were reported to develop HCC even without fibrosis (Honda, 2011), suggesting that aging itself may be a predisposing factor for hepatocarcinogenesis. The impact of viral eradication on HCC prevention was found to be less significant in older patients than in younger patients with chronic HCV infection, especially at advanced stages of liver disease (Asahina, 2010). Based on these observations, long-term follow-up is recommended in elderly patients with chronic HCV infection even after virus eradication, especially in male patients with liver cirrhosis. With regard to treatment for HCC, hepatic resection can be performed safely and effectively in elderly patients (Yeh, 2004; Huang, 2009). Regional therapy, such as radiofrequency ablation or transarterial chemoembolization, may also be considered for elderly patients with HCC, as well as for younger patients, if liver function and tumor stage are acceptable (Bove, 2011). However, a report suggested that advanced age and sarcopenia are poor prognostic factors after hepatectomy (Higashi et al., 2016).

Liver Transplantation The proportion of adult liver transplantation recipients older than 60 years increased from 10% in 1990 to more than 20% by 1999 in the United States (Garcia, 2001). Some problems remain to be addressed with regard to liver

transplantation for elderly patients. Some studies indicated that advancing age is associated with a poorer survival rate (Azoulay, 2002; Ghabril, 2008), whereas others suggested that advanced age alone should not be a contraindication for liver transplantation (Pfitzmann, 2007; Schmitt et al., 2009). Schmitt et al. reported that more than 10% of transplant recipients over 60 years of age underwent retransplantation among a total of 2141 retransplantation cases. However, this report indicated that age over 60 years was not independently associated with an increase in mortality when adjusted for factors that were found to influence survival (Schmitt et al., 2009). It should be noted that elderly patients have multiple risk factors, such as coronary artery disease or malignancy, and face ageassociated quality of life impairments, such as instability, incontinence, immobility, dementia, and polypharmacy (Frith et al., 2009b). Moreover, aged recipients show significantly lower quality of life, such as physical functioning, bodily pain, general health, vitality, social functioning, emotional, and physical component score (Werkgartner, 2013). Therefore, careful consideration is required for liver transplantation in elderly patients.

SUMMARY Aged patients show various changes in the liver that could affect the clinical characteristics of liver diseases in these patients (Table 26.1). The decreases in function of the liver and other organs as well as alterations in immune functions should be taken into consideration in the management of liver diseases. Recent advances in the treatment of liver diseases, such as antiviral therapy or resection, enable the relatively safe management of elderly patients.

Liver Diseases in the Elderly Chapter | 26

ACKNOWLEDGMENT Part of this chapter has been previously published in World J. Gastroenterol. 2013 Dec 14; 19(46):8459e67. http://dx.doi.org/10.3748/ wjg.v19.i46.8459.

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