Introduction
Compliance with Ethics Guidelines
Epidemiology of NAFLD
Risk of NAFLD
Incidence
Study | Method | Findings | Conclusion | ||
---|---|---|---|---|---|
Study population | Diagnosis of FL | Incidence (longitudinal studies) | Independent predictors | ||
Kojima et al. [33] | 35,519 Japanese subjects (health check-up), 65.2% M, mean age 45.8 years, F-up 12 years | US | 14.3% | M sex (OR 1.7), metabolic factors (BMI OR 6.3) | M sex and metabolic factors are independent risk factors for the incidence of NAFLD |
Hamaguchi et al. [34] | 3147 healthy Japanese (1694 M), aged 21–80 years, mean F-up 414 days | US | 10%; in M (14%) > F (5%) | Age (only in F), weight gain, and MetS | NAFLD is more incident in men than in women |
Suzuki et al. [35] | 1537 Japanese subjects (1352 M), mean age 35 years, mean F-up 60 months | AST, ALT | 31/1000 person-years | M sex overall and in subjects <40 years (HR 4.6); metabolic factors | M sex and metabolic factors are independent risk factors for the incidence of NAFLD |
Tsuneto et al. [36] | 1635 Nagasaki atomic bomb survivors (606 M), mean age 63 years, F-up 11.6 years | US | 19.9/1000 person-years (22.3 in M > 18.6 in F); M (38%) > F (25%) before 50 years | Obesity, hypertension, and high-TG (gender NS) | Gender is not an independent risk factor for incident NAFLD |
Hamaguchi et al. [37] | 1603 Japanese women, aged 21–80 years, mean F-up 414 days | US | 5% in F; in postmenopausal (6.1–7.5%) and under HRT (5.3%) > premenopausal (3.5%) | Age (only in premenopausal), weight gain, and MetS | There is a gradient in the incidence of NAFLD in women: postmenopausal > HRT > premenopausal |
Zhou et al. [38] | 507 Chinese NAFLD-free participants, median F-up 4 years | US | 9.1%; in M 7.3% > F 9.7% | Age, metabolic factors (gender NS) | Gender is not an independent risk factor for incident NAFLD |
Zelber-Sagi et al. [39] | 147 Israeli subjects, mean age 51.2 years, F-up 7 years | US | 19.0% (2.7%/year) | Weight gain and HOMA (gender NS) | Gender is not an independent risk factor for incident NAFLD |
Sung et al. [40] | 2589 Korean subjects, mean F-up 4.37 years | US | 34.7/1000 person-years; in M (23.4%) > F (9.7%) | MetS traits (gender NS) | Gender was not an independent risk factor for incident NAFLD |
Xu et al. [41] | 5562 non-obese Chinese subjects, mean age 43 years, F-up 5 years | US | 8.9% | M sex, younger age, and metabolic factors | M sex is a risk factor for the incidence of NAFLD at multivariate analysis |
Wong et al. [42] | 565 Hong Kong subjects, mean age 48 years, median F-up 47 months |
1H NMR | 3.4%/year | MetS (M sex predictor only at univariate analysis) | M sex is a risk factor for the incidence of NAFLD at univariate analysis |
Yun et al. [43] | 37,130 Korean subjects, mean age (M 39.4, F 38.6 years), 46% M, F-up 2 years | US | M (44.5/1000 person-years) > F (20.4/1000 person-years) | WC gain in both sexes | Visceral obesity strongly predicts NAFLD in either gender |
Study population | Diagnosis of FL | Prevalence (cross-sectional studies) | Independent predictors | ||
---|---|---|---|---|---|
Kojima et al. [33] | 39,151 Japanese subjects (health check-up), mean age 45.8 years, 61% M | US | M (26%) > F (12.7%) | NA | NAFLD is more prevalent in M gender |
Shen et al. [46] | 4009 Chinese administrative officers non-drinkers, aged 20–81 years, 64% M | US | M (13.3%) > F (2.7%) before 50 years; similar after 50 years | M sex, age >50 years, and metabolic traits | M sex and metabolic factors are independent risk factors for the prevalence of NAFLD |
Fan et al. [47] | 3175 Chinese subjects from Shanghai, mean age 52years, 38.4% M | US | M (19.2%) > F (11.3%) before 50 years; F > M after 50 years | M sex (OR 2.7) and metabolic factors | M sex and metabolic factors are independent risk factors for the prevalence of NAFLD |
Chen et al. [48] | 3245 adults in a Taiwan rural village, aged ≥18 years, 45.3% M | US | M (19.7%) > F (10.7%) | M sex and metabolic factors; age ≥65 years negative predictor | M sex and metabolic factors are independent risk factors for the prevalence of NAFLD |
Park et al. [49] | 6648 Korean subjects, aged ≥20 years, 53% M | US | M (22.6%) > F (6.8%) before 50 years; similar after 50 years | Menopause status and increasing age in F | Menopause is a strong risk factor for prevalent NAFLD |
Zelber-Sagi et al. [50] | 352 Israeli subjects, mean age 51 years, 53.4% M | US | M (38%) > F (21%) | M sex (after adjustment for obesity) | M sex and metabolic factors are independent risk factors for prevalent NAFLD |
Zhou et al. [51] | 3543 inhabitants of 6 urban and rural areas in China, aged >7 years, 37% M | US | M (13.8%) > F (7.1%) before 50 years; the opposite after 50 years | M sex and metabolic factors | M sex and metabolic factors are independent risk factors for prevalent NAFLD |
Li et al. [52] | 9094 Chinese subjects (medical check-up), aged >18 years, 52% M | US | M (18.9%) > F (5.7%); increased with age in both sexes <50 years | M sex, increasing age, BMI, and other MetS features | M sex and metabolic factors are independent risk factors for prevalent NAFLD |
Caballeria et al. [53] | 766 Spanish individuals, aged 17–83 years, 33.4% M | US | M (42.2%) > F (20.3%) | M sex, increasing age, and metabolic factors | M sex and metabolic factors are independent risk factors for prevalent NAFLD |
Hu et al. [54] | 7152 employees of Shanghai work-units, aged 18–65 years, 60.5% M | US | M > F in the same age group, peaking at 50–65 years; in F > 50 years doubled | High TG level was the strongest predictor in M while obesity the strongest one in F | Risk factors for prevalent NAFLD are gender-specific |
Wong et al. [55] | 922 individuals from Hong Kong population, aged 19–72 years, 58% F |
1H MRS | M (36.8%) > F (22.7%); in M peaking at 40 years; in F increasing after menopause | Metabolic factors (M sex and older age NS) | Gender is not an independent risk factor for prevalent NAFLD |
Hamaguchi et al. [37] | 4401 Japanese subjects (health check-up), aged 21-80 years, 51.6% men | US | M (24%) and postmenopausal F (15%) >remenopausal F (6%); increased with age in F only | Postmenopause and HRT NS (age and MetS adjusted); aging in premenopausal F only (weight gain and MetS adjusted) | Menopause and HRT are not independent risk factors for prevalent NAFLD |
Eguchi et al. [56] | 8352 Japanese subjects (health check-ups), aged 21–86 years, 51.8% M | US | M > F at all ages | Metabolic factors (age >50 years in F only) | Gender is not an independent risk factor for prevalent NAFLD |
Younossi et al. [57] | 11,613 American participants (from NHANES III) | US | 19% | F sex and younger age for lean NAFLD; the opposite for NAFLD with BMI ≥25 | F sex is a risk factor for lean NAFLD |
Lazo et al. [58] | 12,454 American subjects (from NHANES III), aged 20–74 years | US | M (20.2%) > F (15.8%) | Prevalence in M (20.2%) > F (15.8%) (adjusted for age, race, BMI, T2D) | M gender is associated with an increased NAFLD prevalence |
Wang et al. [59] | 4226 Chinese subjects >60 years vs 3145 controls <60 years from the same cohort | US | M (32%) > F (9%) before 60 years; similar after 60 years | M sex (only in those <60 years) and metabolic factors | M sex and metabolic factors are independent risk factors for prevalent NAFLD |
Xu et al. [41] | 6905 non-obese (BMI < 25) Chinese subjects, 63% M | US | 7.3% | M sex, younger age, and metabolic factors | M sex and metabolic factors are independent risk factors for prevalent NAFLD |
Yan et al. [60] | 3762 Chinese residents, aged 20–92 years, 61.9% M | US | M (45%) > F (30%); higher before 50 years but similar after | Metabolic factors (M sex predicted only at univariate analysis) | M sex is a risk factor for prevalent NAFLD at univariate analysis only |
Chiloiro et al. [61] | 2974 South Italian subjects, aged 30–89 years, 56.5% M | US | M (37%) > F (26%) | MetS and its features, BMI, visceral, and subcutaneous fat in both M and F | Risk factors for prevalent NAFLD are not gender-specific |
Foster et al. [62] | 3056 American multiethnic subjects, mean age 63 years, 55% F | CT | NA | F sex protective in all and AAs; not in Caucasians and Hispanics. Younger age in all, Caucasians and Hispanics; not in AAs | F sex is spared from prevalent NAFLD |
Yang et al. [63] | 2256 Chinese subjects (health check-up), mean age 62.04 years, 87.9% M | US | M (28.4%) > F (20.3%) | Younger age, RDW and metabolic factors (gender NS) | Gender is not an independent risk factor for prevalent NAFLD |
Saida et al. [64] | 3110 Japanese subjects (health check-up), aged ≥30 years, 59.5% M | US | M (45%) > F (23%) | Weight gain ≥10 kg since the age of 20 years regardless of sex | Gender is not an independent risk factor for prevalent NAFLD |
Wang et al. [65] | 25,032 Chinese subjects (health check-up), aged 18–94 years, 62% M | US | M (32%) > F (13%); similar in both sexes >60 years | Metabolic parameters in both sexes; increasing age (≥60 years) only in F | Risk factors for prevalent NAFLD are not gender-specific |
Schneider et al. [66] | 4037 non-Hispanic white, 2746 non-Hispanic black, and 2892 Mexican–American adults in the NHANES III | US | M (15%) > F (10%) among non-Hispanic whites only (age-adjusted) | Gender difference still significant after adjustment for BMI and WC | M gender is associated with an increased NAFLD prevalence independent of visceral obesity |
Xiao et al. [67] | 18,676 Chinese subjects, mean age 40.6 years, 55.4% M | US | M (33%) > F (8%) | M sex and metabolic factors | M sex is an independent risk factor for prevalent NAFLD |
Martínez-Alvarado et al. [68] | 846 Mexican subjects, mean age 53 years, 49.3% M | CT | M (36.5%) > F (28.4%) | Metabolic factors (MetS in F only) | Gender is not an independent risk factor for prevalent NAFLD |
Liu et al. [69] | 11,200 Chinese gallstone-free subjects, 46.7% M | US | M (31%) > F (13%) | NA | NAFLD is more prevalent in M gender |
Amirkalali et al. [70] | 5023 Iranian participants, mean age 45.35 years, 56.7% M | US | F (46%) > M (42%); peaking in M 40–60 years, in F >60 years | Age, MetS, and its factors (higher ORs in F) | Gender is not an independent risk factor for prevalent NAFLD |
Nishioji et al. [71] | 3271 Japanese subjects (health check-up), 44.2% M | US | M > F for all ages, except in obese ≥70 years | Metabolic factors in M and F | Risk factors for prevalent NAFLD are not gender-specific |
Huang et al. [72] | 8626 Chinese subjects ≥40 years | US | M (28.7%) ~ F (28.1%) | NA | No gender specific difference in prevalent NAFLD |
Fattahi et al. [73] | 2980 Iranian subjects, aged ≥18 years, 31.3% M | US | M (32.9%) > F (27.4%) | NA | NAFLD is more prevalent in M gender |
Motamed et al. [74] | 5052 Iranian subjects, aged ≥18 years, 56.6% M | US | F (44.2%) > M (40.1%) | Age, metabolic factors; F sex protective | F sex is spared from prevalent NAFLD |
Prevalence
Risk of NASH and Fibrosis Progression
Study | Method Cross-sectional studies | Findings | Conclusion | ||
---|---|---|---|---|---|
Study population | Diagnosis of NASH | Prevalence | Independent predictors | ||
Singh et al. [90] | 71 consecutive Asian-Indian NASH patients, aged 9–57 years, 76.1% M | Biopsy | NA | F sex for fibrosis stage | F sex is an independent risk factor for fibrosis |
Hossain et al. [91] | 432 American NAFLD patients, mean age 43.6 years, 22.9% M | Biopsy | 26.8% NASH and 17.4% moderate-to severe fibrosis | M sex for NASH and moderate-to-severe fibrosis in addition to ethnicity, ALT, AST, metabolic factors | M gender is a strong independent risk factor for both NASH and fibrosis |
Al-hamoudi et al. [92] | 1312 Saudi Arabian inpatients, mean age 44.7 years, 51.0% M | US | 16.6% NASH (by ALT >60 U/L) | M sex, young age and low total CH predicted high ALT in NAFLD | M gender is a strong independent risk factor for hypertransaminasemic NAFLD |
Bambha et al. [93] | 1026 adults (NASH CRN Database), mean age 48.8 years, 37% M | Biopsy | 61% NASH and 29% advanced fibrosis | F sex for NASH and advanced fibrosis; increasing age for advanced fibrosis; plus metabolic factors | F sex is an independent risk factor for NASH and fibrosis |
Younossi et al. [57] | 11,613 American participants (from NHANES III) | US | 12% NASH (by grade 2–3 US-FL + high ALT, AST, and/or T2D/IR) | Younger age and metabolic factors (gender NS) | Gender is not an independent risk factor for NASH |
Tapper et al. [94] | 358 NAFLD patients, 62.9% M | Biopsy | NASH and advanced fibrosis > in F vs M (45% vs 30%; 23% vs 14%) | F sex, BMI, and ALT for NASH; age, AST, and APRI for advanced fibrosis | F sex is an independent risk factor for NASH and fibrosis |
Wang et al. [65] | 25,032 Chinese subjects (health check-up), aged 18–94 years, 62% M | US | NASH with advanced fibrosis (by BAAT score, AST/ALT) > F vs M | NA | Prevalence of NASH with advanced fibrosis is higher in F sex |
Yang et al. [95] | 541 American patients with NASH, mean age 48 years, 35.1% M | Biopsy | 100% NASH; 22% advanced fibrosis | M sex, postmenopausal F status (premenopausal F reference; borderline P), pre-T2D/T2D for fibrosis | M sex and postmenopausal status are independent risk factors for fibrosing NASH |
Turola et al. [29] | 244 females and 244 age-matched males with NAFLD | Biopsy | F2–F4 fibrosis | Menopause, metabolic factors, and NASH for F2–F4 fibrosis in F with NAFLD | Menopause is strongly associated with fibrosing NASH |
Klair et al. [96] | 488 postmenopausal NAFLD subjects | Biopsy | Advanced fibrosis 38.4% in premature menopause F vs 32.7% in other F | Premature menopause and time from menopause for advanced fibrosis (adjusted for age, race, metabolic factors) | The longer the duration of postmenopausal status the higher the risk of NASH |
Yang et al. [97] | 1112 American NAFLD patients (160 premenopausal and 489 postmenopausal F; 463 M) | Biopsy | NASH > in pre/postmenopausal F (62%) vs M (50%) | Lobular inflammation risk increased in (1) premenopausal F > M and postmenopausal F, (2) oral contraceptives and HRT users (adjusted for covariates of liver metabolic stress) | Fertile age and estrogen use may predispose to more necroinflammatory NASH variants |
Risk of Hepatocellular Carcinoma
NAFLD and CVD
Gender-Specific Risk of CVD in Studies on NAFLD and CVD
Gender Differences in the Association Between NAFLD and CVD
Role of Gender, Reproductive Status, and Age in the Heterogeneity of NAFLD Pathobiology
Factors Associated with NAFLD are Different in Men and in Women
NAFLD Epidemiology and Physiopathology are Modulated by Age at Menarche and Postmenopausal Status
Men | Women | Both sexes | Obesity/type 2 diabetes | |
---|---|---|---|---|
Estradiol | Estradiol in men is essential for modulating libido, erectile function, and spermatogenesis [140] A study conducted in healthy men suggests that estradiol protects from NAFLD [141] | Endogenous estrogens are master regulators of lipid metabolism and inhibit inflammation, vascular cell growth, and plaque progression in premenopausal women [142] The loss of estrogens which occurs postmenopausally is associated with a modest increase in LDL cholesterol with either no change or a small decrease in HDL cholesterol. Estrogen administration decreases LDL cholesterol and Lp(a) levels while increasing triglycerides and HDL cholesterol levels, but these effects are dependent on the dose and route of administration [143] | Estrogens improve inflammation related to metabolic dysfunction (“metaflammation”). Further to a direct downregulation of inflammatory pathways, this effect is also mediated by metabolic amelioration [144] | Obesity is associated with hyperestrogenism which, in turn, increases the risk of breast cancer in men [145] |
Progesterone | Progesterone has important effects in regulating male fertility by affecting the energetic homeostasis of sperm [146] | Progesterone has a major role in the ovarian and menstrual cycle; moreover it exerts an immuno regulatory function; regulates the contraction of human intestinal smooth muscle cells and the motility of various human cell types [147] Progesterone is an independent predictor of insulin resistance in girls [148] | Progesterone has been potentially implicated as a therapeutic adjunct in many clinical conditions such as traumatic brain injury, Alzheimer’s disease, and diabetic neuropathy [147] | Increasing levels of progesterone have been associated with the development of systemic insulin resistance [149] Little is known regarding the role, if any, of serum progesterone in NAFLD |
Androgens | The synthesis of testosterone is key to male fertility. A negative feedback finely regulates the secretion of hormones at the levels of hypothalamic-pituitary–gonadal axis. Congenital or acquired disturbances of this axis will lead to hypogonadism and thus impair male fertility [150]. Testosterone has no significant correlation with NAFLD in a study from China [141]. However, it is an independent predictor of insulin resistance in boys [148] | Androgens have important biological roles in young women, influencing bone and muscle mass, vascular health, cognition, mood, well-being, and libido [151] | Sarcopenia, namely the decline in muscle mass and strength which occurs with ageing, has been associated with a deficiency in both 17β-estradiol and testosterone, two sex hormones which act on satellite cells. These remain quiescent throughout life and are activated in response to stressful events, enabling them to guide repair and regeneration of the skeletal muscle [154] | Obese men tend to be hypogonadic as a result of the functional suppression of the hypothalamic–pituitary–testicular axis [155]. However, weight loss obtained with either a low-calorie diet or bariatric surgery is associated with the normalization of sex hormone levels exhibiting a significant increase in bound and unbound testosterone and gonadotropin levels and a decrease in estradiol [156]. A study from Japan reported that testosterone levels were inversely associated with diabetes among men but not among women [157] |