Nonalcoholic fatty liver disease and aging: Epidemiology to management

Table 1 Anatomical and physiological changes associated with aging liver

Increased fibrosis with reduced percentage of fat on liver biopsy[3,4]; decreased size mirroring decreased hepatic blood flow[5]

Loss of regenerative capacity, i.e. “replicative senescence” involving cross talks of growth hormone, glycogen synthase kinase 3β and cyclin D3 and shortening of telomeric ends of chromosomes[5,6]

Increased inflammatory changes, hence the definition of “inflamm-aging” which, in its turn, has a detrimental effect on the regenerative response[7]

Defective autophagy[8,9]

Decrease in hepatic free radical scavenging system leads to increased oxidative stress resulting mainly from non-enzymatic processes in the liver[5] and is exacerbated by ethanol drinking[10]

Table 2 Influences of age and gender on non alcoholic fatty liver disease prevalence: Evidence from population-based and large cohort studies from three continents[17,18,21-46]

Asia
Nomura et al[21], 1988	Cross sectional study on 2574 Japanese healthy residents (1271 males), age 0-70+ yr , FL in 14%	Prevalence of FL in persons under 19 yr old was only 1.2%, and increased with age to a maximum (25.6%) in persons 40-49 yr of age and then decreased
Kojima et al[22], 2003	Cross-sectional and prospective study on 39151 Japanese first-time examinees, 61% males, 12-yr survey period	The prevalence of FL was uniformly high in males and declined in those in the 6th and 7th decades. The prevalence in females tended to rise gradually with age and declined in those in their 7th decade of life
Shen et al[23], 2003	4009 administrative officers non-drinkers, aged 20-81 yr, 64% males, FL in 12.9%	At multivariate analysis the prevalence of FL was positively correlated to several risk factors, including male gender and age > 50 yr
Fan et al[24], 2005	This cross-sectional study with randomized multistage stratified cluster sampling included 3175 subjects (1218 men) with a mean age of 52 yr. FL was found in 661 (20.82%) subjects	Age-adjusted prevalence of FL was significantly higher in men than women, and LRA showed that male gender was closely related to FL. The prevalence of FL increased with age in both sexes, peaking in women 60-69 yr of age, and in men 40-49 yr of age. Interestingly, the prevalence was higher in males than females under the age of 50, but was lower in males than females among people older than 50 yr
Chen et al[25], 2006	The cross-sectional community study examined 3245 adults in a rural village of Taiwan.The prevalence of NAFLD was 11.5% (372/3245)	Male sex was an independent risk factors for NAFLD in the general population. Age ≥ or 65 yr was inversely related to NAFLD
Park et al[26], 2006	Cross-sectional study was performed with data obtained from 6648 subjects, all of whom were older than 20 yr of age (3530 men and 3118 women). The unadjusted and age-adjusted prevalences of NAFLD were 18.7% (23% in men, 13.7% in women) and 16.1% (21.6% in men, 11.2% in women), respectively	NAFLD prevalence was higher in men than in women. Age was an independent predictor of NAFLD in women only. Menopause status was an independent predictor of NAFLD
Zelber-Sagi et al[27], 2006	A cross-sectional study of a subsample of the Israeli national health survey (n = 352). Three hundred and twenty-six subjects (53.4% male, mean age 50.5 ± 10.3) met the inclusion criteria. The prevalence of primary NAFLD was 30% (25%-35% 95%CI)	Male gender was found to be an independent risk factor for NAFLD which remained significant even after adjustment for obesity and abdominal obesity
Zhou et al[28], 2007	A cross-sectional survey of a random sample of 3543 over 7-yr-old inhabitants in 6 urban and rural areas in China. Among the 3543 subjects, 609 (17.2%) were diagnosed having FLD (18.0% males, 16.7% females, P > 0.05). Among them, the prevalence of confirmed alcoholic liver disease (ALD), suspected ALD and nonalcoholic fatty liver disease (NAFLD) were 0.4%, 1.8%, and 15.0%, respectively. The prevalence rate (23.0%) was significantly higher in urban areas than (12.9%) in rural areas	The prevalence rate was significantly higher in men than in women under the age of 50 yr. However, the opposite phenomenon was found over the age of 50 yr Multivariate and logistic regression analysis indicated that male gender was among the independent risk factors for FLD
Eguchi et al[34], 2012	A cross-sectional study was conducted among 8352 subjects who received health checkups from 2009 to 2010 in three health centers in Japan The overall prevalence of NAFLD was 29.7%	The prevalence of NAFLD is higher in males than that in females at all ages, it is “inverted U-Shaped” in males (peaking at 40-49 yr); it gradually increases in all age groups in women but declines in those ladies in their seventies
Al-hamoudi et al[35], 2012	Prospective study among 1312 patients referred for ultrasonography in Saudi Arabia The prevalence of NAFLD was 16.6% (218/1312)	In a multivariate analysis, younger age and being male were significant predictors of high ALT levels
Wang et al[18], 2013	Chinese case-control study based on all 4226 adults above 60 yr of age from a previously cohort investigated compared to 3145 randomly selected younger controls (< 60 yr) from the same cohort. NAFDL was higher in the elderly (26.7%) than in the non-elderly (22.8%) and similar in the elderly between men and women (26.6% vs 27.0%, P > 0.05)	The prevalence of FLD is higher in the elderly, and is broadly related to the same metabolic risk factors as in the non-elderly. However, female-sex is no longer protective with increasing age, and the prevalence of steatohepatitis with advanced fibrosis is estimated to be considerably higher in the elderly FLD patients than in the younger FLD controls
Foster et al[36], 2013	3056 participants of the Multi Ethnic Study of Atherosclerosis were included in this study. NAFLD was defined as LS ratio < 1, the prevalence of NAFLD was and 11 % in African Americans	Younger age was among the independent correlates of NAFLD in this population
Xu et al[37], 2013	Cross-sectional study on 6905 nonobese (BMI < 25). Risk factors for the development of NAFLD were assessed in a subsequent prospective study in NAFLD-free individuals at baseline, 494 of whom had developed NAFLD during the 5-yr follow-up. Prevalence of NAFLD was 7.27%	Older age and male gender are associated with both the prevalence and the incidence of novel NAFLD cases in a non obese Chinese population
Yan et al[38], 2013	Random sampling of 3762 adults Chinese residents. Ultrasonography revealed fatty liver in 1486 residents with a prevalence of 39.5%	At univariate analysis, NAFLD cases were statistically younger and more often males
Europe
Lonardo et al[39], 2006	Hospital cohort study of 449 individuals undergoing both liver and carotid US evaluation for clinical indications	U-shaped curve with NAFLD peak prevalence in the 30-39 and 40-49 age groups. The phenomenon may either reflect a decrease of risk factor for NAFLD, (e.g., obesity) or selectively increased mortality among those with FL. At logistic regression analysis FL is more common in younger male individuals
Bedogni et al[40], 2007	A follow-up study on 144 subjects without and 336 with fatty liver followed for a median 8.5 yr time	Male sex is a predictor of incidence of fatty liver; male sex and age are predictors of death in those with fatty liver
Caballeria et al[41], 2010	multicentre, cross-sectional, populational study recruiting 766 Individuals between 15 and 85 yr of age randomly selected from 25 primary healthcare centres in Spain	On multivariate analysis, male sex, age and other factors were associated with NAFLD
Koehler et al[17], 2012	2811 participants in the population-based Rotterdam Study. Mean age of participants was 76.4 yr (range 65.3-98.7 yr)	NAFLD is common in the elderly. However, the prevalence of NAFLD decreased with advancing age suggesting a positive selection of the elderly without NAFLD
Soresi et al[42], 2013	Study on the prevalence of NAFLD in metabolic syndrome	Men and women with steatosis were younger than those without steatosis. At multivariate analyses, was associated with higher ALT
United States of America
Browning et al[43], 2004	An observational study on 2287 subjects from a multiethnic, population-based sample (of white, Black, and Hispanic)	In whites, but not in Hispanics or blacks, the frequency of hepatic steatosis was approximately 2-fold higher in men than in women related to ethanol intake, not to differences in the frequency of obesity or insulin resistance
Younossi et al[44], 2012	A retrospective study on 11613 participants included in the National Health and Nutrition Examination Survey III (NHANES III); 2185 had NAFLD; and, of these, 307 had NASH	NAFLD was independently associated with younger age and female sex; and NASH was independently associated with having a younger age in those United States lean individuals with NAFLD
Bambha et al[45], 2012	628 adults enrolled either in the observational Database or the PIVENS trial between 2004 and 2008 and thus submitted to liver biopsy	Advancing age and female gender were among the independent predictors of advanced fibrosis at LRA
North et al[46], 2012	A total of 1242 (1064 EA, 178 AA) and 1477 (1150 EA, 327 AA) men and women, respectively, underwent CT examination from which LA and abdominal adipose volume were measured	Mean LA varied significantly by sex, [(men) 57.76 ± 10.03 HU and (women) 60.03 ± 10.91 HU, P = 0.0002], but not by race. Higher LA was associated with older age
Foster et al[36], 2013	3056 participants of the Multi Ethnic Study of Atherosclerosis were included in this study. NAFLD was defined as LS ratio < 1	Younger age was among the independent correlates of NAFLD in this population

AA: African Americans; ALD: Alcoholic liver disease; FL: Fatty liver; FLD: Fatty liver disease; NAFLD: Non alcoholic fatty liver disease; NASH: Non alcoholic steatohepatitis.

Table 3 Selected cohort studies of geriatric patients[3,50,51]

Kagansky et al[50], 2004	In this prospective study, 91 octogenarians who were admitted to the rehabilitation departments of a geriatric hospital were compared to 46 NAFLD young patients	NAFLD is a common and benign finding in the elderly population, in whom it is not associated with the metabolic syndrome
Frith et al[3], 2009	In this retrospective, cohort study set in a tertiary liver clinic in United Kingdom. Three hundred and fifty one consecutive biopsy-proven NAFLD patients were divided into an older (≥ 60), a middle-aged (≥ 50 to < 60) and a younger (< 50) group	NAFLD affects mainly the middle-aged and the elderly. Older patients show more risk factors and more severe laboratori alterations and histological changes, with cirrhotics having a significantly more advanced age than those with milder disease
Noureddin et al[51], 2013	A cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥ 65 yr) and 735 nonelderly (18-64 yr) participants	The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% vs 72%, P = 0.02), and advanced fibrosis (25% vs 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% vs 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each)

NAFLD: Non alcoholic fatty liver disease; NASH: Non alcoholic steatohepatitis.