Introduction

Aging causes time-dependent, inevitable physiologic organ dysfunction that alters normal homeostasis and is a major risk factor for cancer development [1]. In the United States, as of 2009, there are 39.6 million people older than the age of 65, equating to 13% of the country’s total population. This number is expected to increase to 72 million or 19% of the total US population by 2030 [2-4]. Aging has shown increase vulnerability to acute liver injury as well as progression to liver fibrosis. This is associated with associated with poor prognosis of various liver diseases including Nonalcoholic Fatty Liver Disease (NAFLD), Alcoholic Liver Disease (ALD), Hepatitis C (HCV), Hepatocellular Carcinoma (HCC) and Liver Transplantation (LT). Studies have compared changes in the liver due to liver diseases with the process of aging [5]. Approximately, 8 million Americans suffer from chronic hepatic diseases, of which, more than half a million people have cirrhosis and nearly, 31 thousand Americans die each year from cirrhosis [6-8]. Old age seems to favor NAFLD, NASH, and ultimately HCC, in agreement with the inflammatory aging theory, according to which aging accrues inflammation [5]. The higher vulnerability to environmental factors (Especially oxidative stress), the reduction in the rate of hepatic blood flow, the reduced mitochondrial capacity and the impaired immunity are all mechanisms possibly involved in a faster progression of liver damage [9].

Aging and Liver Volume, Blood Flow, And Function

Both liver volume and blood flow decrease significantly with age. Hepatic blood flow is estimated to be decreased by 35%-50% in the elderly and may be responsible for age-related reductions in liver volume [10]. The neural fat and cholesterol volumes in the liver gradually expand as one gets older, and therefore causes an increase in total serum cholesterol and high-density lipoprotein cholesterol. Meanwhile, the metabolism of the low-density lipoprotein cholesterol decreases by 35%. The serum γ-glutamyltransferase and alkaline phosphatase levels increase with aging, while Alanine Aminotransferase (ALT) concentrations and serum bilirubin are gradually reduced with age, independent of components of the metabolic syndrome, the serum aminotransferase maintains normal level and albumin remains within normal limits or is slightly decreased due to aging [11]. Humans show a slight decrease in the serum albumin concentration or maintain the normal level in the natural aging process [11].

Alanine Aminotransferase (ALT) concentrations have been reported to decrease with age, independent of components of the metabolic syndrome. These findings suggest the need to identify an optimal cut-off point for normal ALT in Geriatric patients [12]. Hepatic Encephalopathy (HE) also can occur because of portal hypertension. Resistance to blood flow leads to shunting of blood around the liver, allowing blood from the gut containing ammonia and other byproducts of bacterial metabolism to bypass the liver and reach the systemic circulation [7]. Exposing the brain to these chemicals can result interfere with the normal synaptic transmission of electrical and chemical signaling. As a result, cognition and memory are affected, leading to memory loss, impaired thinking, and an inability to perform fine motor tasks [13,14].

Aging-Related Changes in Liver Cells

Aging-related changes in liver cells include volume changes, polyploidy, accumulation of dense bodies (Lipofuscin) inside liver cells, a decreased area of the smooth endoplasmic reticulum, and a declining number and dysfunction of mitochondria [15]. Compared with the studies on liver cells, relatively little is known about what kind of effect aging has on liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells [16]. The functionality of Kupffer cells is to remove antigen–antibody complexes or nanoparticles such as senescent cell fragments in the liver sinusoidal vascular system and is important to point out that aging increases the number and activation level of Kupffer cells [17]. A study by Sotaniemi, et al [18], suggested that drug metabolism is reduced by up to 30% after 70 years of age, and that a reduction in liver cytochrome P450 may also contribute to decreased drug metabolism. Cytochrome P450 activity was shown to be 32% lower in subjects > 70 years than in subjects aged 20-29 years [18].

First-pass hepatic uptake (Phase I) of drugs has been reported to be decreased in the elderly, possibly due to reduced liver volume and hepatic blood flow, leading to a decline in hepatic drug metabolism [19]. Metabolism of drugs with low phase I hepatic metabolism is likely to be impaired mainly by liver volume reduction [19]. Volume and blood flow changes coupled with decreased cytochrome P450 activity can affect drug metabolism, increasing susceptibility to drug-induced liver injury [20]. Immune responses against pathogens or neoplastic cells are decreased in the elderly, although individuals may also be predisposed to autoimmunity through impairment of dendritic cell maturation and reduction of regulatory T cells [21]. Such changes in immune functions could alter the pathogenesis of viral hepatitis and autoimmune liver diseases and development of hepatocellular carcinoma [22,23]. Geriatric patients have significantly decreased reserve functions of various other organs as well, reducing their tolerability to treatments for liver diseases [24].

Hepatic Diseases of Elderly

NAFLD

Non-alcoholic fatty liver disease is a clinical syndrome predicted to be the next global epidemic affecting millions of people worldwide, especially the geriatric population [25,26]. The natural course of this disease including its subtype, Non-Alcoholic Steatohepatitis (NASH), is not clearly defined especially in the elderly segment of the US population [26]. NAFLD affects mainly the middle-aged and the elderly and previously was reported be benign, however more recent studies suggest an increased mortality in the patients older than 60-year [27]. With advancing age come more risk factors for its development. Aging increases risk factors which predispose progression to NAFLD. Older patients have more severe biochemical, hematological, and histological changes [28]. The pivotal role of inflammation in the pathogenesis of liver steatosis has been emphasized in the literature; the link between insulin resistance and inflammation and the possible role of C‐Jun N‐Terminal Kinases (JNKs) in the progression of this condition has been clearly defined, along with the involvement of endoplasmic reticulum stress and of the unfolded protein response [29]. Aging-related alterations of the pro-inflammatory vs anti-inflammatory balance, described as the inflammatory aging theory may represent the biological background of these findings [30]. Current guidelines for treatments for NAFLD are to control body weight and treatment of metabolic disorders by changing lifestyle and improve insulin resistance [31,32].

Metformin and thiazolidinedione’s are insulin sensitizers, which metformin is known to be effective in reducing body weight and improving insulin resistance [33], but its histological effect of improving necrotic inflammation in the NASH has not been proven [34,35]. In very rare cases, it can cause lactic acidosis in the elderly [36,37]. Another treatment option would be bariatric surgery, but is important to note that bariatric surgery causes an upsurge in the morbidity rate among geriatric patients compared with younger patients, and is no significant difference in the mortality rate except for those with patients with cardiovascular diseases [38,39]. Liver transplantation can be an option for patients with decompensated liver cirrhosis due to NASH and, it is also worthy to not that, in the geriatric patients, careful consideration should be paid in consideration of common age-related comorbidities, which has a significant influence on their survival and hospitalization period after liver transplantation, due to cardiovascular complications which they will have [40,41]. More accurate understanding of the molecular pathways, gut microbiome analysis, and precise investigation of the mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual geriatric patients [42-46]. With aging, the liver undergoes substantial changes in structure and function that are associated with significant impairment of detoxification activities and many hepatic metabolic dysfunctions [47-49].

Acute Liver Failure

Acute Liver Failure (ALF), is an uncommon condition with potentially devastating consequences, including an increased rate of short-term morbidity and mortality [50-52]. Common causes for ALF in elderly is excessive alcohol consumption and in some rare cases which physicians should pay close attention for is overly excessive use of acetaminophen [53,54]. The primary treatment for alcoholic liver disease is abstinence from drinking and provide sufficient nutrients and vitamins, but in geriatric patients, this is a major problem due to prolonged use of alcohol and late diagnosis of ALF [55]. Half of the elderly patients who develop cirrhosis die within 1 year of diagnosis [56]. Glucocorticoid treatment can be helpful for some patients with mild to moderate alcohol hepatitis whose Maddrey’s discriminant function scores are higher than 32 [57]. However current research has described glucocorticoids-induced hyperglycemia elderly patients and physicians should be aware of this complication [58]. For patients who have a contraindication for steroids, pentoxifylline, a TNF-α Inhibitor (TNFI), can be considered as an alternative treatment which the retention rate of TNFI in the elderly is comparable with that in younger patients [59]. It is imperative to identify geriatric patients with ALF as soon as possible to transfer them to a liver transplant center for an evaluation and life style modification. Emergent liver transplant in the geriatric patient with ALF may place the patient at risk for severe complications in the postoperative period [60], but in the long run, may help to prevent mortality.

Hepatitis A

Although Acute Hepatitis A (HAV) infection is usually self-limiting in general population. However, elderly patients with acute HAV infection can experience hepatocellular dysfunction with frequent jaundice and coagulopathy, as well as an increased incidence of complications, such as prolonged pancreatitis, cholestasis, and ascites [61]. During 1994 and 1995, Memphis and Shelby County, Tennessee, experienced an epidemic of HAV, which 42% of patients aged 70 years or older required hospitalization compared with 3%-20% of adults aged 40-49 years [62]. Vaccination for HAV should be offered for those who plan to travel to endemic areas, especially patients living in nursing homes.

Hepatitis B

Acute Hepatitis B Virus (HBV) infection is very uncommon in the geriatric patients because the opportunities for acquiring HBV infection are estimated to be low in this population. However, HBV infections have been reported in residents of nursing homes [63]. The rate of progression to chronic hepatitis B is higher in the elderly vs younger patients [64]. A report of an outbreak in a nursing home showed that 59% of patients older than 65 years of age developed chronic HBV infection [64]. Regarding the lab results of elderly patients with HBV infection, older age and male, in addition to serum HBV DNA levels, are regarded as risk factors not only for progression to cirrhosis [65], but the development of HCC [66]. Nucleoside analogs are effective in treating HBV infected patients, with similar efficacy in the elderly as in younger patients [67]. Interferon-based therapy may also be effective for the treatment of chronic HBV infection, however, its therapeutic effects are inferior in elderly patients [68]. Vaccinations should be considered if patients have not been vaccinated.

Hepatitis C

The population infected with HCV is aging as most in the US acquired the infection during World War II [69]. A total of 320,000 deaths, 157,000 cases of HCC, and 203,000 cases of cirrhosis are predicted in the US for the upcoming 35 years, despite the highly effective and readily available treatment regimens [70]. An increased number of Americans with advanced liver diseases in part can be attributed to the 3.3% prevalence of HCV in the geriatric population [71]. According to a research by Poynard, et al. [9], age itself is more important than duration of infection for predicting the occurrence of cirrhosis. This will create a tremendous burden on the healthcare system, including skilled nursing and long-term care facilities [72-75]. In the US, most patients with HCV infection were born between 1945 and 1965, who acquired the infection during the 1970s and 1980s from exposure to blood or blood products [76-78]. Evidence shows that treatment of HCV can prevent the progression of end-stage liver disease in geriatric patients [79]. Since the first introduction of the interferon-alone treatment, the antiviral treatments for chronic hepatitis C have developed dramatically through the combination therapy of peg-interferon-α and ribavirin to direct-acting antiviral agents such as protease inhibitors and polymerase inhibitors.

When the elderly people aged more than 65 years are treated with a combination therapy of peg-interferon-α and ribavirin, their Sustained Virological Response (SVR) is lower than those under 65 years old (Genotype 1: 22.9 vs. 47.3%; genotype 2: 65.6 vs. 82.9%), whereas their treatment termination rate is higher due to side-effects (genotype 1: 42.9 vs. 24.1%; genotype 2: 24.4 vs. 10.8%) [80-82]. The combination of three agents such as peg-interferon-α., telaprevir, and ribavirin is given to genotype 1 patients showed no significant difference in their SVR between the young and elderly [83]. Also, this treatment regime was discontinued due to complications such as severe malaise [84-86]. According to a research by Pawlotsky [87], it is important to state that, all-oral, interferon-free combinations of drugs are expected to cure more than 90% of infections, but this has not been tested in elderly patients [87]. Current research supports that the supplementation of vitamin D and vitamin B12 increases the SVR, and as elderly people have a lack of these vitamins, they should be taking these supplements [88-92].

SVR has been shown to improve biochemical characteristics and portal hypertension in some patients diagnosed with HCV, it is unclear in which specific patients may benefit from treatment with a history of decompensated liver disease [93]. It is thoroughly documented that HCV infection has a negative impact on the quality of life of elderly patients, until this date, the complexity of treatment and the lack of supportive data in elderly patients have significantly limited the treatment options [84]. Now that the era of baby boomers and populations is rapidly changing, and that new IFN-free treatment options are becoming widely available, the limited but available evidence concerning the benefit of viral eradication in the elderly population should be carefully considered [69]. The faster the health care system changes their policy with respect to an a priori obstacle for anti-HCV treatment in the elderly, the sooner we will begin to help many geriatric patients diagnosed with HCV [69]. HCV infection is the most common indication for Orthotopic Liver Transplantation (OLT) in the United States [94]. Recent studies from selected centers have suggested that older donor age is associated with worse outcomes after transplantation for HCV [95].

According to a research by Dultz, et al. [96] both older donor age and older recipient age plus markers of severity of disease, including requirement for mechanical ventilation and renal insufficiency, are negatively associated with survival after liver transplantation [94]. According to a research by Pyrsopoulos, et al. [97] the combination of LED/SOF with RBV for 12 weeks or ledipasvir/sofosbuvir for 24 weeks is very effective and safe in treating OLT recipients with recurrent HCV [97]. These factors should be considered when assessing OLT recipient and donor candidacy in patients with HCV. Concerted efforts are necessary to increase diagnosis and treatment rates, optimize care of patients with cirrhosis and HCC and provide care to liver transplant recipients to reduce the overall HCV-related disease burden in the United States [96].

Cholestatic Liver Disease

Primary Sclerosing Cholangitis (PSC) and Primary Biliary Cirrhosis (PBC) are chronic diseases which can manifest in adult patients [98]. In a recent study by Tanaka, et al. [98] they reported that conclude that PSC in the young resembles those in Europe and the USA in terms of the onset age and prevalence of IBD, while PSC in the elderly is really unique in Japan. Presenting complications of elderly patients with PSC is no different than those of the younger patients [99], but there is certain degree of cholangiocarcinoma presentation in older patients [100-102]. Eventually all patients with PSC will require LT, and is better for the elderly patient to receive the LT before the age of 60 [99]. According to a research by Newton, et al. [103] they reported that 35% of patients out of 1000 examined had PBC. Symptoms of clinical presentation was no different for young patients versus the elderly [103]. Although there has been reported that a 92 year-old men with PBC after under undergoing Computed Tomography (CT) and ultrasound scans of his abdomen revealed a large hepatic tumor, which was confirmed on liver biopsy to be HCC [104]. Furthermore, biomarkers reflecting disease activity and prognosis in Primary Sclerosing Cholangitis (PSC) have not been firmly established and due to complex interplay which exists between IBD, PSC, and LT which requires explanation with further research.

Hepatocellular Carcinoma

With age the risk of HCC increases significantly, and this is independent of prolonged HCV infection as a shorter interval between acquiring HCV infection and the diagnosis of HCC has been demonstrated in elderly patients [105]. Many elderly HCC patients with intermediate to terminal stage at their initial diagnosis will have more compromised liver regeneration and comorbidities compared with those of younger age [106]. Elderly patients require long-term follow-up even after viral eradication and especially male patients with liver cirrhosis since research has shown that they are prone to developing HCC [107]. Hepatic resection for HCC can be performed safely and effectively in elderly patients [108-110]. A recent report by Borzio, et al. [111] showed that age did not predict short-mid-term survival within 24 months, while it was a significant independent predictor of long-term survival. Also age had a substantial long-term survival effect mainly on early HCC stages (Barcelona Clinic for Liver Cancer [BCLC] 0-A), its influence on BCLC B stage was shown to be lower, while it was negligible for advanced terminal stages Age should not impact on short-mid-term prognosis of elderly patients with HCC and should not represent a restriction to the management [112]. The pool of elderly patients with the history of HCC receiving a liver transplantation is increasing [113]. This can be attributed to the improvement of HCC surveillance approaches and diagnostic techniques leading to earlier diagnoses of HCC in the elderly population.

Geriatric Liver Transplant

Liver Transplant (LT) is a standard treatment for End-Stage Liver Disease (ESLD). At present, 1-year survival rate is approximately 90% and 10-year survival rate may exceed 70% in many indications [114,115]. Patients with ESLD will require liver transplantation to prevent morbidity and mortality associated with end-stage-liver disease [116]. The proportion of adult liver transplantation recipients in the United States older than 60 years of age increased from 10% in 1990 to more than 20% by 1999 [117]. The era when an ideal liver donor was younger than the age of 40 years seems to have be gone out of current practice management [118]. Many transplant programs have expanded eligibility to include patients previously ineligible because of advanced age [119]. Several studies showed that outcomes after LT with livers of patients older than 70-years are comparable, and sometimes even better compared to younger donors, with 1-year and 3-year patient and graft survival ranging 66-95% and 58-91%, respectively [120].

According to a research by Adani, et al. [121], clinical outcomes after liver transplantation in the elderly are nearly similar to young people, considering if individual surgery risks are equivalent [121]. United Network for Organ Sharing Database conducted a study which revealed prognostic factors: they found that diabetes mellitus, the ventilator status, history of HCV, creatinine at least 1.6 mg/dl, and combined donor age and the recipient age are the most prevailing prognostic indicators among the recipients of LT older than 60-years old [122]. If the numbers of positive indicators among them are 0, 1, and 2, their 5-year survival rates are recorded at 75, 69, and 58%, respectively. If the number of positive indicators is more than three, the elderly patients 5-year survival rate was below 50% [123].

Although it is important to note that geriatric patients may have multiple risk factors, including artery disease or malignancy, coronary disease and face age-related quality of life impairments, such as incontinence, gate instability, immobility, dementia, and many are on regimen of polypharmacy [124]. It is important for the healthcare team to also take in account these parameters when considering the patient for LT. A successful LT depends on the liver’s structure and hepatic function, but as research indicate these parameters decline with the process of aging [125]. Considering that there is a rise in elderly patients the aging population is increasingly suffering from cerebrovascular disease [126-131], the use of chronologically old, but biologically young liver donors would expand the donor pool and, hopefully, reduce waitlist mortality. Advanced age alone should not be considered a contraindication for LT due to potentially poor quality of life outcomes [132]. Further research is necessary to confirm whether and which geriatric-like measures can be used to select livers of older donors for LT.

Conclusion

Geriatric patients show various changes in the liver, which play a role in the clinical characteristics of liver diseases in these patients. Decreases in the functioning of the liver and other organs, as well as, alterations in immune functions should be taken into consideration in the management of the liver diseases. Aging has been shown to not only enhance vulnerability to acute liver injury but also increase the susceptibility of the fibrotic response. Aging has a significant impact on the risk and poor prognosis of various liver diseases including NAFLD, ALD, HCV, and liver transplantation. The diagnosis of advanced liver disease is important to make in the elderly population since many of the condition’s features are treatable and can lead to improved quality of life and, most importantly, decrease the likelihood of acute care hospitalization, which carries a high risk of nosocomial infections and therapeutic mishaps in the aged population. Geriatric patients with risk factors for hepatitis should be screened for liver disease, along with those that have a family history of liver diseases, or a history of long-term or heavy alcohol consumption. Age cannot be a single exclusion criterion from the liver transplantation, and an individualization strategy, which takes into consideration all risk factors of a recipient, needs to be considered. We suggest geriatric patients should be a candidate for liver transplant, and the healthcare team treating our elderly generation to collaborate for these patients for them to have a smoother transition both in pre-transplant phase and post-transplant phase.

Disclosure

None.

Funding

None.

References

1. Aunan JR, Cho WC, Soreide K (2017) The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks. Aging Dis 8: 628-642.
2. Kim IH, Kisseleva T, Brenner DA (2015) Aging and liver disease. Curr Opin Gastroenterol 31: 184-191.
3. (2014) United States faces crisis in cancer care because of aging population, rising costs, complexity of care, says new report; shift needed toward patient-centered, evidence-based care. Home Healthc Nurse 32: 12-13.
4. McGinnis SL, Moore J (2006) The impact of the aging population on the health workforce in the United States--summary of key findings. Cah Sociol Demogr Med 46: 193-220.
5. Sheedfar F, Di Biase S, Koonen D, Vinciguerra M (2013) Liver diseases and aging: friends or foes? Aging Cell 12: 950-954.
6. Ye Y, Kerr WC (2011) Alcohol and liver cirrhosis mortality in the United States: comparison of methods for the analyses of time-series panel data models. Alcohol Clin Exp Res 35: 108-115.
7. Pievsky D, Rustgi N, Pyrsopoulos NT (2018) Classification and Epidemiologic Aspects of Acute Liver Failure. Clin Liver Dis 22: 229-241.
8. Centers for Disease Control and Prevention (2001) Update: Fatal and severe liver injuries associated with Rifampin and Pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations--United States, 2001. JAMA 286: 1445-1446.
9. Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, et al. (2001) Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. J. Hepatol 34: 730-739.
10. Li CH, Ge XL, Pan K, Wang PF, Su YN, et al. (2017) Laser speckle contrast imaging and Oxygen to See for assessing microcirculatory liver blood flow changes following different volumes of hepatectomy. Microvasc Res 110: 14-23.
11. Tietz NW, Shuey DF, Wekstein DR (1992) Laboratory values in fit aging individuals--sexagenarians through centenarians. Clin Chem 38: 1167-1185.
12. Dong MH, Bettencourt R, Barrett-Connor E, Loomba R (2010) Alanine aminotransferase decreases with age: The Rancho Bernardo Study. PLoS One 5: e14254.
13. Akhtar AJ, Alamy ME, Yoshikawa TT (2002) Extrahepatic conditions and hepatic encephalopathy in elderly patients. Am J Med Sci 324: 1-4.
14. Edula RG, Pyrsopoulos NT (2015) New Methods of Testing and Brain Imaging in Hepatic Encephalopathy: A Review. Clin Liver Dis 19: 449-459.
15. Schmucker DL (2005) Age-related changes in liver structure and function: Implications for disease? Exp Gerontol 40: 650-659.
16. Le Couteur DG, Warren A, Cogger VC, Smedsrod B, Sorensen KK, et al. (2008) Old age and the hepatic sinusoid. Anat Rec (Hoboken) 291: 672-683.
17. Hilmer SN, Cogger VC, Le Couteur DG (2007) Basal activity of Kupffer cells increases with old age. J Gerontol a Biol Sci Med Sci 62: 973-978.
18. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M (1997) Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 61: 331-339.
19. Klotz U (2009) Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 41: 67-76.
20. Wauthier V, Verbeeck RK, Calderon PB (2007) The effect of ageing on cytochrome p450 enzymes: consequences for drug biotransformation in the elderly. Curr Med Chem 14: 745-757.
21. Fuentes E, Fuentes M, Alarcon M, Palomo I (2017) Immune System Dysfunction in the Elderly. An Acad Bras Cienc 89: 285-299.
22. Raouf S, Weston C, Yucel N (2015) Registered report: senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Elife 26: 4.
23. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, et al. (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479: 547-551.
24. Nakajima T, Nakashima T, Yamaoka J, Shibuya A, Konishi E, et al. (2011) Greater age and hepatocellular aging are independent risk factors for hepatocellular carcinoma arising from non-B Non-C non-alcoholic chronic liver disease. Pathol Int 61: 572-576.
25. Bertolotti M, Lonardo A, Mussi C, Baldelli E, Pellegrini E, et al. (2014) Nonalcoholic fatty liver disease and aging: epidemiology to management. World J Gastroenterol 20: 14185-14204.
26. Sherif ZA, Saeed A, Ghavimi S, Nouraie SM, Laiyemo AO, et al. (2016) Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations. Dig Dis Sci 61: 1214-1225.
27. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, et al. (2005) The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129: 113-121.
28. Frith J, Day CP, Henderson E, Burt AD, Newton JL (2009) Non-alcoholic fatty liver disease in older people. Gerontology 55: 607-613.
29. Tarantino G, Caputi A (2011) JNKs, insulin resistance and inflammation: A possible link between NAFLD and coronary artery disease. World J Gastroenterol 17: 3785-3794.
30. Salvioli S, Monti D, Lanzarini C, Conte M, Pirazzini C, et al. (2013) Immune system, cell senescence, aging and longevity--inflamm-aging reappraised. Curr Pharm Des 19: 1675-1679.
31. Reeves HL, Zaki MY, Day CP (2016) Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD. Dig Dis Sci 61: 1234-1245.
32. Musso G, Cassader M, Rosina F, Gambino R (2012) Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 55: 885-904.
33. Xu C, Zhao J, Zhou X, Zhang R, Xie T, et al. (2018) Thiazolidinediones versus metformin on improving abnormal liver enzymes in patients with type 2 diabetes mellitus: a meta-analysis. Oncotarget 9: 12389-12399.
34. Tan S, Vollmar N, Benson S, Sowa JP, Bechmann LP, et al. (2015) Liver Injury Indicating Fatty Liver but Not Serologic NASH Marker Improves under Metformin Treatment in Polycystic Ovary Syndrome. Int J Endocrinol 2015: 254169.
35. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ (2009) The Effect of Metformin and Standard Therapy versus Standard Therapy alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial. Therap Adv Gastroenterol 2: 157-163.
36. Angioi A, Cabiddu G, Conti M, Pili G, Atzeni A, et al. (2018) Metformin associated lactic acidosis: a case series of 28 patients treated with sustained low-efficiency dialysis (SLED) and long-term follow-up. BMC Nephrol 19: 77.
37. Hess C, Unger M, Madea B, Stratmann B, Tschoepe D (2018) Range of therapeutic metformin concentrations in clinical blood samples and comparison to a forensic case with death due to lactic acidosis. Forensic Sci Int 286: 106-112.
38. Dorman RB, Abraham AA, Al-Refaie WB, Parsons HM, Ikramuddin S, et al. (2012) Bariatric surgery outcomes in the elderly: an ACS NSQIP study. J Gastrointest Surg 16: 35-44.
39. Varela JE, Wilson SE, Nguyen NT (2006) Outcomes of bariatric surgery in the elderly. Am Surg 72: 865-869.
40. Mikolasevic I, Racki S, Zaputovic L, Lukenda V, Sladoje-Martinovic B, et al. (2014) Nonalcoholic fatty liver disease (NAFLD) and cardiovascular risk in renal transplant recipients. Kidney Blood Press Res 39: 308-314.
41. Dureja P, Mellinger J, Agni R, Chang F, Avey G, et al. (2011) NAFLD recurrence in liver transplant recipients. Transplantation 91: 684-689.
42. Leung C, Rivera L, Furness JB, Angus PW (2016) The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 13: 412-425.
43. Gangarapu V, Yildiz K, Ince T, Baysal B (2014) Role of gut microbiota: obesity and NAFLD. Turk J Gastroenterol 25: 133-140.
44. Martins MJ, Ascensao A, Magalhaes J, Collado MC, Portincasa P (2015) Molecular Mechanisms of NAFLD in Metabolic Syndrome. Biomed Res Int 2015: 621080.
45. Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L (2009) Molecular mechanisms involved in NAFLD progression. J Mol Med (Berl) 87: 679-695.
46. Shen TD, Pyrsopoulos N, Rustgi VK (2018) Microbiota and the liver. Liver Transpl 24: 539-550.
47. Mallikarjuna K, Shanmugam KR, Nishanth K, Wu MC, Hou CW, et al. (2010) Alcohol-induced deterioration in primary antioxidant and glutathione family enzymes reversed by exercise training in the liver of old rats. Alcohol 44: 523-529.
48. Zhang C, Cuervo AM (2008) Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 14: 959-965.
49. Fung P, Pyrsopoulos N (2017) Emerging concepts in alcoholic hepatitis. World J Hepatol 9: 567-585.
50. Pyrsopoulos NT (2018) Acute Liver Failure. Clin Liver Dis 22: xiii-xiv.
51. Patel P, Okoronkwo N, Pyrsopoulos NT (2018) Future Approaches and Therapeutic Modalities for Acute Liver Failure. Clin Liver Dis 22: 419-427.
52. Krawitz S, Lingiah V, Pyrsopoulos NT (2018) Acute Liver Failure: Mechanisms of Disease and Multisystemic Involvement. Clin Liver Dis 22: 243-256.
53. Corral Gudino L, Cruz Sanchez MA, Argenta Fernandez S, Belhassen Garcia M (2017) Elderly woman with acute liver failure. Rev Clin Esp 217: 370-376.
54. Schiodt FV, Chung RT, Schilsky ML, Hay JE, Christensen E, et al. (2009) Outcome of acute liver failure in the elderly. Liver Transpl 15: 1481-1487.
55. Meier P, Seitz HK (2008) Age, alcohol metabolism and liver disease. Curr Opin Clin Nutr Metab Care 11: 21-26.
56. Adams WL, Cox NS (1995) Epidemiology of problem drinking among elderly people. Int J Addict 30:1693-1716.
57. Clarkson E, Raj Bhatia S (2006) Perioperative management of the patient with liver disease and management of the chronic alcoholic. Oral Maxillofac Surg Clin North Am 18: 213-225.
58. Zhou Y, Zhao Y, Yuan T, Jiang N, Dong Y, et al. (2018) High-Dose Glucocorticoid Treatment Does Not Induce Severe Hyperglycemia in Young Patients with Autoimmune Diseases by Cgms. Endocr Pract 24: 60-68.
59. Cho SK, Sung YK, Kim D, Won S, Choi CB, et al. (2016) Drug retention and safety of TNF inhibitors in elderly patients with rheumatoid arthritis. BMC Musculoskelet Disord 17: 333.
60. Olivo R, Guarrera JV, Pyrsopoulos NT (2018) Liver Transplantation for Acute Liver Failure. Clin Liver Dis 22: 409-417.
61. Brown GR, Persley K (2002) Hepatitis A epidemic in the elderly. South Med J 95: 826-833.
62. Willner IR, Uhl MD, Howard SC, Williams EQ, Riely CA, et al. (1998) Serious hepatitis A: an analysis of patients hospitalized during an urban epidemic in the United States. Ann Intern Med 128: 111-114.
63. Sugauchi F, Mizokami M, Orito E, Ohno T, Kato H, et al. (2000) Hepatitis B virus infection among residents of a nursing home for the elderly: seroepidemiological study and molecular evolutionary analysis. J Med Virol 62: 456-462.
64. Kondo Y, Tsukada K, Takeuchi T, Mitsui T, Iwano K, et al. (1993) High carrier rate after hepatitis B virus infection in the elderly. Hepatology 18: 768-774.
65. Iloeje UH, Yang HI, Su J, Jen CL, You SL, et al. (2006) Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 130: 678-686.
66. Chen CJ, Yang HI, Su J, Jen CL, You SL, et al. (2006) Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295: 65-73.
67. Kawaoka T, Suzuki F, Akuta N, Suzuki Y, Arase Y, et al. (2007) Efficacy of lamivudine therapy in elderly patients with chronic hepatitis B infection. J Gastroenterol 42: 395-401.
68. Song BC, Suh DJ, Lee HC, Chung YH, Lee YS (2004) Which patients with chronic hepatitis B are more likely to relapse after interferon alpha-induced hepatitis B e antigen loss in Korea? J Clin Gastroenterol 38: 124-129.
69. Vespasiani-Gentilucci U, Galati G, Gallo P, De Vincentis A, Riva E, et al. (2015) Hepatitis C treatment in the elderly: New possibilities and controversies towards interferon-free regimens. World J Gastroenterol 21: 7412-7426.
70. Chhatwal J, Wang X, Ayer T, Kabiri M, Chung RT, et al. (2016) Hepatitis C Disease Burden in the United States in the era of oral direct-acting antivirals. Hepatology 64: 1442-1450.
71. Castrejon M, Chew KW, Javanbakht M, Humphries R, Saab S, et al. (2017) Implementation of a Large System-Wide Hepatitis C Virus Screening and Linkage to Care Program for Baby Boomers. Open Forum Infect Dis 4: ofx109.
72. Solid CA, Peter SA, Natwick T, Guo H, Collins AJ, et al. (2017) Impact of Renal Disease on Patients with Hepatitis C: A Retrospective Analysis of Disease Burden, Clinical Outcomes, and Health Care Utilization and Cost. Nephron 136: 54-61.
73. Xie L, Kariburyo MF, Wang Y, Baser O (2014) Evaluating the Economic Burden and Health Care Utilizations of U. S. Veteran Patients Diagnosed with Chronic Hepatitis C. Value Health 17: A671.
74. Chen G, Block JM, Evans AA, Huang P, Cohen C (2014) Gateway to Care campaign: a public health initiative to reduce the burden of hepatitis B in Haimen City, China. BMC Public Health 14: 754.
75. Norton BL, Park L, McGrath LJ, Proeschold Bell RJ, Muir AJ, et al. (2012) Health care utilization in HIV-infected patients: assessing the burden of hepatitis C virus coinfection. AIDS Patient Care STDS 26: 541-545.
76. Harris M, Bonnington O, Harrison G, Hickman M, Irving W (2018) Understanding hepatitis C Intervention Success-Qualitative findings from the HepCATT study. J Viral Hepat 25: 762-770.
77. Aisyah DN, Shallcross L, Hully AJ, O'Brien A, Hayward A (2018) Assessing hepatitis C spontaneous clearance and understanding associated factors-A systematic review and meta-analysis. J Viral Hepat 25: 680-698.
78. Falade-Nwulia O, Sulkowski MS, Merkow A, Latkin C, Mehta SH (2018) Understanding and addressing hepatitis C reinfection in the oral direct-acting antiviral era. J Viral Hepat 25: 220-227.
79. Arase Y, Ikeda K, Suzuki F, Suzuki Y, Kobayashi M, et al. (2007) Interferon-induced prolonged biochemical response reduces hepatocarcinogenesis in hepatitis C virus infection. J Med Virol 79:1485-1490.
80. Iwasaki Y, Okamoto R, Ishii Y, Araki Y, Hashimoto N, et al. (2015) Randomized trial of low-dose peginterferon alpha-2b plus low and escalating doses of ribavirin in older patients with chronic hepatitis C with high viral load genotype 1. J Med Virol 87: 2082-2089.
81. Kainuma M, Furusyo N, Kajiwara E, Takahashi K, Nomura H, et al. (2010) Pegylated interferon alpha-2b plus ribavirin for older patients with chronic hepatitis C. World J Gastroenterol 16: 4400-4409.
82. Antonucci G, Longo MA, Angeletti C, Vairo F, Oliva A, et al. (2007) The effect of age on response to therapy with peginterferon alpha plus ribavirin in a cohort of patients with chronic HCV hepatitis including subjects older than 65 yr. Am J Gastroenterol 102: 1383-1391.
83. Lens S, Fernandez I, Rodriguez-Tajes S, Hontangas V, Vergara M, et al. (2017) Interferon-Free Therapy in Elderly Patients with Advanced Liver Disease. Am J Gastroenterol 112: 1400-1409.
84. Akutagawa M, Ide K, Kawasaki Y, Yamanaka M, Iketani R, et al. (2017) Safety Profile of Telaprevir-Based Triple Therapy in Elderly Patients: A Real-World Retrospective Cohort Study. Biol Pharm Bull 40: 1525-1529.
85. Takita M, Hagiwara S, Kudo M, Kouno M, Chishina H, et al. (2014) Efficacy and safety of telaprevir-based antiviral treatment for elderly patients with hepatitis C virus. Oncology 87: 110-117.
86. Hara T, Akuta N, Suzuki F, Sezaki H, Suzuki Y, et al. (2013) A pilot study of triple therapy with telaprevir, peginterferon and ribavirin for elderly patients with genotype 1 chronic hepatitis C. J Med Virol 85: 1746-1753.
87. Pawlotsky JM (2014) New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology 146: 1176-1192.
88. Kalantari H, Karimzadeh H, Kalantari S, Talebi M, Yaran M, et al. (2018) Correlation between Vitamin D3 level and extrahepatic manifestation in chronic hepatitis Type-C virus patients. J Res Med Sci 23: 22.
89. Jin CN, Chen JD, Sheng JF (2018) Vitamin D deficiency in hepatitis C virus infection: what is old? what is new? Eur J Gastroenterol Hepatol 30: 741-746.
90. Abdel-Mohsen MA, El-Braky AA, Ghazal AAE, Shamseya MM (2018) Autophagy, apoptosis, vitamin D, and vitamin D receptor in hepatocellular carcinoma associated with hepatitis C virus. Medicine (Baltimore) 97: e0172.
91. Mechie NC, Goralzcyk AD, Reinhardt L, Mihm S, Amanzada A (2015) Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study. BMC Res Notes 8: 260.
92. Rocco A, Compare D, Coccoli P, Esposito C, Di Spirito A, et al. (2013) Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus. Gut 62: 766-773.
93. Roche B, Samuel D (2012) Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int 32: 120-128.
94. Condron SL, Heneghan MA, Patel K, Dev A, McHutchison JG, et al. (2005) Effect of donor age on survival of liver transplant recipients with hepatitis C virus infection. Transplantation 80: 145-148.
95. Lue A, Solanas E, Baptista P, Lorente S, Araiz JJ, et al. (2016) How important is donor age in liver transplantation? World J Gastroenterol 22: 4966-4976.
96. Dultz G, Graubard BI, Martin P, Welker MW, Vermehren J, et al. (2017) Liver transplantation for chronic hepatitis C virus infection in the United States 2002-2014: An analysis of the UNOS/OPTN registry. PLoS One 12: e0186898.
97. Pyrsopoulos N, Trilianos P, Lingiah VA, Fung P, Punnoose M (2018) The safety and efficacy of ledipasvir/sofosbuvir with or without ribavirin in the treatment of orthotopic liver transplant recipients with recurrent hepatitis C: real-world data. Eur J Gastroenterol Hepatol 30: 761-765.
98. Tanaka A, Tazuma S, Okazaki K, Tsubouchi H, Inui K, et al. (2015) Clinical profiles of patients with primary sclerosing cholangitis in the elderly. J Hepatobiliary Pancreat Sci 22: 230-236.
99. Jansen PL (2002) Liver disease in the elderly. Best Pract Res Clin Gastroenterol 16: 149-158.
100. Tao CY, Liu WR, Jin L, Tang Z, Tian MX, et al. (2018) Surgical Treatment of Combined Hepatocellular-Cholangiocarcinoma is as Effective in Elderly Patients as it is in Younger Patients: A Propensity Score Matching Analysis. J Cancer 9: 1106-1112.
101. Vitale A, Spolverato G, Bagante F, Gani F, Popescu I, et al. (2016) A multi-institutional analysis of elderly patients undergoing a liver resection for intrahepatic cholangiocarcinoma. J Surg Oncol 113: 420-426.
102. Sawada T, Kita J, Rokkaku K, Kato M, Shimoda M, et al. (2008) Outcome of surgical resection for hilar cholangiocarcinoma in elderly patients. Hepatogastroenterology 55: 1971-1974.
103. Newton JL, Jones DE, Metcalf JV, Park JB, Burt AD, et al. (2000) Presentation and mortality of primary biliary cirrhosis in older patients. Age Ageing 29: 305-309.
104. Tanaka Y, Naitoh M, Yoshiura K, Ookubo K, Uegaki S, et al. (2000) Hepatocellular carcinoma arising in an elderly male with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 12: 239-241.
105. Ohishi W, Kitamoto M, Aikata H, Kamada K, Kawakami Y, et al. (2003) Impact of aging on the development of hepatocellular carcinoma in patients with hepatitis C virus infection in Japan. Scand J Gastroenterol 38: 894-900.
106. Kinoshita A, Koike K, Nishino H (2017) Clinical features and prognosis of elderly patients with hepatocellular carcinoma not indicated for surgical resection. Geriatr Gerontol Int 17: 189-201.
107. Asahina Y, Tsuchiya K, Tamaki N, Hirayama I, Tanaka T, et al. (2010) Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology 52: 518-527.
108. Nozawa A, Kubo S, Takemura S, Sakata C, Urata Y, et al. (2015) Hepatic resection for hepatocellular carcinoma in super-elderly patients aged 80 years and older in the first decade of the 21st century. Surg Today 45: 851-857.
109. Peng ZW, Liu FR, Ye S, Xu L, Zhang YJ, et al. (2013) Radiofrequency ablation versus open hepatic resection for elderly patients (> 65 years) with very early or early hepatocellular carcinoma. Cancer 119: 3812-3820.
110. Lee CR, Lim JH, Kim SH, Ahn SH, Park YN, et al. (2012) A comparative analysis of hepatocellular carcinoma after hepatic resection in young versus elderly patients. J Gastrointest Surg 16: 1736-1743.
111. Borzio M, Dionigi E, Vitale A, Rossini A, Marignani M, et al. (2017) Management and prognosis of hepatocellular carcinoma in the elderly: Results of an in-field multicenter cohort study. Liver Int 37: 1184-1192.
112. Guo H, Wu T, Lu Q, Dong J, Ren YF, et al. (2017) Hepatocellular carcinoma in elderly: Clinical characteristics, treatments and outcomes compared with younger adults. PLoS One 12: e0184160.
113. Akdur A, Fidan C, Ayvazoglu Soy E, Kirnap M, Yarbug Karakayali F, et al. (2015) Results of liver transplant in elderly patients: a single center experience. Exp Clin Transplant 13: 124-126.
114. Sanchez Cabus S, Estalella L, Pavel M, Calatayud D, Molina V, et al. (2017) Analysis of the long-term results of living donor liver transplantation in adults. Cir Esp 95: 313-320.
115. Mohamadnejad M, Vosough M, Moossavi S, Nikfam S, Mardpour S, et al. (2016) Intraportal Infusion of Bone Marrow Mononuclear or CD133+ Cells in Patients with Decompensated Cirrhosis: A Double-Blind Randomized Controlled Trial. Stem Cells Transl Med 5: 87-94.
116. Pezzati D, Hassan A, Buccini L, Liu Q, Diago Uso T, et al. (2017) Liver transplantation with geriatric liver allograft in the US: a matter of epidemiology or outcome requirements? Transpl Int 30: 1190-1191.
117. Garcia CE, Garcia RF, Mayer AD, Neuberger J (2001) Liver transplantation in patients over sixty years of age. Transplantation 72: 679-684.
118. Montenovo MI, Hansen RN, Dick AAS, Reyes J (2017) Donor Age Still Matters in Liver Transplant: Results from the United Network for Organ Sharing-Scientific Registry of Transplant Recipients Database. Exp Clin Transplant 15: 536-541.
119. De Boer JD, Koopman JJ, Metselaar HJ, Braat AE, Blok JJ (2017) Liver transplantation with geriatric liver allografts: the current situation in Eurotransplant. Transpl Int 30: 432-433.
120. Jimenez-Romero C, Caso Maestro O, Cambra Molero F, Justo Alonso I, Alegre Torrado C, et al. (2014) Using old liver grafts for liver transplantation: where are the limits? World J Gastroenterol 20: 10691-10702.
121. Adani GL, Baccarani U, Lorenzin D, Rossetto A, Nicolini D, et al. (2009) Elderly versus young liver transplant recipients: patient and graft survival. Transplant Proc 41: 1293-1294.
122. Trieu JA, Bilal M, Hmoud B (2018) Factors associated with waiting time on the liver transplant list: an analysis of the United Network for Organ Sharing (UNOS) database. Ann Gastroenterol 31: 84-89.
123. Aloia TA, Knight R, Gaber AO, Ghobrial RM, Goss JA (2010) Analysis of liver transplant outcomes for United Network for Organ Sharing recipients 60 years old or older identifies multiple model for end-stage liver disease-independent prognostic factors. Liver Transpl 16: 950-959.
124. Frith J, Newton J (2009) Liver transplantation in more elderly age. Transpl Int 22: 599-600.
125. Saito Y, Morine Y, Shimada M (2017) Mechanism of impairment on liver regeneration in elderly patients: Role of hepatic stellate cell function. Hepatol Res 47: 505-513.
126. Nakanishi K, Jin Z, Homma S, Elkind MSV, Rundek T, et al. (2018) Association Between Heart Rate and Subclinical Cerebrovascular Disease in the Elderly. Stroke 49: 319-324.
127. Kim YH, Her AY, Kim BK, Shin DH, Kim JS, et al. (2017) Previous cerebrovascular disease is an important predictor of clinical outcomes in elderly patients with percutaneous coronary interventions: The Nobori-Biolimus eluting stent prospective multicenter 1-year observational registry in South Korea. Anatol J Cardiol 18: 128-135.
128. Fountoulakis KN, Siamouli M, Magiria S, Kaprinis G (2008) Late-life depression, religiosity, cerebrovascular disease, cognitive impairment and attitudes towards death in the elderly: interpreting the data. Med Hypotheses 70: 493-496.
129. Panza F, Solfrizzi V, Colacicco AM, D'Introno A, Capurso C, et al. (2006) Cerebrovascular disease in the elderly: lipoprotein metabolism and cognitive decline. Aging Clin Exp Res 18: 144-148.
130. Matsumoto M (2006) [Cerebrovascular disease in the elderly people]. Nihon Ronen Igakkai Zasshi 43: 152-154.
131. Shimada K (2005) [Cerebrovascular disease in the elderly]. Nihon Ronen Igakkai Zasshi 42: 532-534.
132. Krenzien F, Krezdorn N, Morgul MH, Wiltberger G, Atanasov G, et al. (2017) The elderly liver transplant recipients: anxiety, depression, fatigue and life satisfaction. Z Gastroenterol 55: 557-563.