Abstract
Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common chronic liver disease worldwide, along with the concurrent epidemics of metabolic syndrome and obesity. Patients with NAFLD have increased risks of end-stage liver disease, hepatocellular carcinoma, and liver-related mortality. However, the largest cause of death among patients with NAFLD is cardiovascular disease followed by extrahepatic malignancies, whereas liver-related mortality is only the third cause of death. Extrahepatic complications of NAFLD include chronic kidney disease, extrahepatic malignancies (such as colorectal cancer), psychological dysfunction, gastroesophageal reflux disease, obstructive sleep apnea syndrome, periodontitis, hypothyroidism, growth hormone deficiency, and polycystic ovarian syndrome. The objective of this narrative review was to summarize recent evidences about extrahepatic complications of NAFLD, with focus on the prevalent/incident risk of such diseases in patients with NAFLD. To date, an appropriate screening method for extrahepatic complications has not yet been determined. Collaborative care with respective experts seems to be necessary for patient management because extrahepatic complications can occur across multiple organs. Further studies are needed to reveal risk profiles at baseline and to determine an appropriate screening method for extrahepatic diseases.
Keywords: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, extrahepatic complications, chronic kidney disease, colorectal cancer, major depressive disorder, gastroesophageal reflux disease, obstructive sleep apnea syndrome, periodontitis, hypothyroidism
1. Introduction
Over the last few decades, the incidences of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been increasing worldwide, along with the concurrent epidemics of metabolic syndrome and obesity. A recent meta-analysis estimated that the overall global prevalence of NAFLD is very high at 25.2% [1]. In this analysis, the regional prevalence of NAFLD was reported to be highest in the Middle East (31.7%) and South Africa (30.4%). Thus, NAFLD has been recognized as the most common chronic liver disease worldwide. Compared with matched, controlled populations without NAFLD, patients with NAFLD have increased risks of end-stage liver disease, hepatocellular carcinoma (HCC) [2], and liver-related mortality [1]. Therefore, both hepatologists and patients must recognize hepatic conditions, especially those characterized by liver fibrosis [3,4]. However, hepatic involvement is just one component of the multiorgan manifestation of NAFLD. In fact, a recent multicenter cohort study revealed that the largest cause of death among patients with NAFLD is cardiovascular disease (CVD) followed by extrahepatic malignancies, whereas liver-related mortality is only the third cause of death [3]. NAFLD represents a liver component of metabolic syndrome and is associated with risk factors for metabolic syndrome, including obesity [5], diabetes mellitus [6], and dyslipidemia [7]. Recently, a growing body of evidence has been collected that supports the notion that NAFLD should be treated as an early mediator of systemic diseases and metabolic syndrome, as well as liver-specific diseases [8,9]. The objective of this narrative review was to summarize recent evidences about extrahepatic complications of NAFLD, with focus on the prevalent/incident risk of such diseases in patients with NAFLD. The association between NAFLD and CVD is not mentioned in this article because it is discussed in great detail in another article in this special issue.
2. Chronic Kidney Disease
Chronic kidney disease (CKD) is a worldwide public health problem, with possible adverse outcomes that include end-stage renal disease (ESRD), CVD, and premature death. CKD is defined by a sustained reduction in the glomerular filtration rate or evidence of structural or functional abnormalities of the kidneys on urinalysis, biopsy, or imaging [10]. The two major risk factors of CKD are hypertension and diabetes mellitus, which are also major risk factors for NAFLD. A recent meta-analysis demonstrated that patients with NAFLD had a significantly higher risk of incident CKD than those without NAFLD (random-effects hazard ratio (HR), 1.37; 95% confidence interval (CI), 1.20-1.53) [11]. In other studies, patients with NAFLD were similarly reported to have a higher prevalence of CKD than patients without NAFLD (Table 1) [12,13,14,15,16,17,18,19]. Importantly, the majority of these studies demonstrated that NAFLD was independently associated with CKD even after adjustments for risk factors including age, sex, body mass index (BMI), hypertension, diabetes mellitus, smoking, and hyperlipidemia. The possible pathogeneses linking NAFLD and CKD include the upregulation of the renin–angiotensin system and the impairment of antioxidant defense. An excess dietary fructose may also contribute to NAFLD and CKD. Moreover, CKD may mutually aggravate NAFLD and associated metabolic disturbances through altered intestinal barrier function and microbiota composition, alterations in glucocorticoid metabolism, and the accumulation of uremic toxic metabolites [20].
Table 1.
Author, Year of Publication |
Study Population | Country | Diagnosis of NAFLD | Results |
---|---|---|---|---|
Retrospective studies | ||||
Yun et al., 2009 [12] | 37,085 healthy subjects who underwent health examinations | Korea | Serum ALT > 40 IU/L (patients with hepatitis B or C, or alcoholic liver disease were excluded) |
ALT > 40 IU/L group had a significantly higher creatinine level than ALT < 40 IU/L group (0.9 mg/dL vs. 0.8 mg/dL). |
Targher et al., 2010 [13] | 80 patients with biopy-proven NASH and 80 control subjects matched for age, sex, and BMI | Italy | Histological | NASH was independently associated with an increased prevalence of CKD (25% vs. 3.7%). Adjusted OR, 6.14 (95% CI, 1.60–12.8). |
Yasui et al., 2011 [14] | 174 patients with biopsy-proven NAFLD | Japan | Histological | Prevalence of CKD was significantly higher among NASH group (21%) than among simple steatosis group (6%). Adjusted OR, 2.46 (p = 0.11; not significant because of dependency on hypertension) |
Sirota et al., 2012 [15] | 11,469 volunteers who participated in the National Health and Nutrition Examination Survey (NHANES 1988–1994) | United States | Ultrasonography (other chronic liver disease were excluded) | NAFLD was not associated with the prevalence of CKD after adjustment for components of metabolic syndrome. |
Sinn et al., 2017 [16] | 41,430 adult men and women without CKD at baseline who underwent repeated health check-up examinations | Korea | Ultrasonography | NAFLD was associated with an increased risk of CKD development. Adjusted HR, 1.22 (95% CI, 1.04–1.43). The risk of CKD increased progressively with increases in the NAFLD fibrosis score. |
Park et al., 2019 [17] | 262,619 newly diagnosed patients with NAFLD and 769,878 propensity score (1:3)-matched non-NAFLD patients from the Truven Health MarketScan Database (2006–2015) | United States | Ultrasonography | Patients with NAFLD had a 41% increased risk of developing advanced (stages 3–5) CKD compared with non-NAFLD patients. Adjusted HR, 1.41 (95% CI, 1.36–1.46). |
Prospective studies | ||||
Chang et al., 2008 [18] | 8329 healthy male volunteers with normal baseline kidney functions (Follow-up duration: 3.2 years) |
Korea | Ultrasonography | NAFLD was independently associated with the development of CKD. Adjusted relative risk, 1.55. |
Targher et al., 2008 [19] | 2103 patiens with type 2 diabetes mellitus | Italy | Ultrasonography | NAFLD was associated with increased risk of CKD (OR, 1.87) independently of age, sex, BMI, hypertension, diabetes duration, HbA1c, or LDL-cholesterol. |
ALT: Alanine aminotransferase, NAFLD: Non-alcoholic fatty liver disease, NASH: Non-alcoholic steatohepatitis, BMI: Body mass index, CKD: chronic kidney disease, OR: Odds ratio, CI: Confidence interval, HR: Hazard ratio, HbA1c: Hemoglobin A1c, LDL: Low-density lipoprotein.
3. Extrahepatic Malignancies
3.1. Colorectal Cancer
Colorectal cancer is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in the world, accounting for about 1.4 million new cases and almost 700,000 deaths in 2012 [21]. A recent meta-analysis of observational studies suggested that NAFLD was independently associated with a moderately increased prevalence and incidence of colorectal adenomas and cancer (Odds ratio (OR), 1.28 for prevalent adenomas and 1.56 for prevalent cancer; HR, 1.42 for incident adenomas and 3.08 for cancer) [22]. In addition, several studies have reported the prevalent risk of colorectal cancer in patients with NAFLD (Table 2) [23,24,25,26,27,28,29]. However, these retrospective studies were mainly reported from Asia. Therefore, future studies are needed to confirm the true risks of colorectal cancer among various NAFLD populations.
Table 2.
Author, Year of Publication |
Study Population | Country | Diagnosis of NAFLD | Results |
---|---|---|---|---|
Wong et al., 2011 [23] | 199 patients with NAFLD and 181 healthy controls | China | Magnetic resonance spectroscopy (n = 64) and liver biopsy (n = 135) | NASH was independently associated with colorectal adenomas (adjusted OR, 4.89; 95% CI, 2.04–11.70) and advanced colorectal neoplasms (adjusted OR, 5.34; 95% CI, 1.92–14.84). |
Stadlmayr et al., 2011 [24] | 1211 subjects who underwent screening colonoscopy | Austria | Ultrasonography (other chronic liver diseases were excluded) | The prevalence of colorectal lesions was 34% in the NAFLD group and 21.7% in the control group (p < 0.001). NASH was independently associated with colorectal adenomas (adjusted OR, 1.47; 95% CI, 1.08–2.00). |
Touzin et al., 2011 [25] | 94 patients with biopsy-proven NAFLD and 139 patients without NAFLD | United States | Histological | No significant difference in the prevalence of colonic adenomas (24.4% in NAFLD patients compared with 25.1% in non-NAFLD patients) was seen. NAFLD patients had significantly greater numbers of colonic adenomas than non-NAFLD patients (p = 0.016). |
Lee et al., 2012 [26] | 5517 women (831 patients with NAFLD) who underwent health check-up | Korea | Ultrasonography | NAFLD was independently associated with colorectal adenomatous polyps (adjusted OR, 1.94; 95% CI, 1.11–3.40) and colorectal cancer (adjusted OR, 3.08; 95% CI, 1.02–9.34). |
Huang et al., 2013 [27] | 1522 health-check individuals who underwent two consecutive colonoscopies (no adenomas were detected at first colonoscopy) | Taiwan | Ultrasonography | NAFLD was an independent risk factor (OR, 1.45; 95% CI, 1.07–1.98) for adenoma formation after a negative baseline colonoscopy. |
Ahn et al., 2017 [28] | 26,540 subjects who underwent a first-time colonoscopy as part of a health check-up program | Korea | Ultrasonography | NAFLD was independently associated with colorectal neoplasia (adjusted OR, 1.10; 95% CI, 1.03–1.17) and advanced colorectal neoplasia (adjusted OR, 1.21; 95% CI, 0.99–1.47). |
Blackett et al., 2020 [29] | 123 patients with biopsy-proven NAFLD and controls without liver disease matched by age, sex, and endoscopist | United States | Histological | Patients with biopsy-proven NAFLD had a significantly higher colorectal adenoma prevalence independently of hyperlipidemia, diabetes, and obesity (OR, 1.74; 95% CI, 1.05–2.88). |
NAFLD: Non-alcoholic fatty liver disease, NASH: Non-alcoholic steatohepatitis, OR: Odds ratio, CI: Confidence interval.
The presence of metabolic syndrome, especially diabetes mellitus and obesity, is a well-known risk factor for colorectal cancer [30,31]. However, whether NAFLD is associated with an increased risk of colorectal cancer simply as a consequence of the shared metabolic risk factors, or whether NAFLD itself may contribute to the development of colorectal cancer, is uncertain [22]. Regarding the former possibility, hyperinsulinemia induced by insulin resistance promotes carcinogenesis by stimulating the proliferation pathway through its effect on insulin receptors on cancer cells. In addition, hyperinsulinemia increases the expression of insulin-like growth factor (IGF)-1, which has mitogenic and anti-apoptotic activities that are more potent than those of insulin and can act as a stimulus for the growth of preneoplastic and neoplastic cells [30]. Regarding the latter possibility, patients with NAFLD reportedly have reduced serum levels of adiponectin, which has anti-carcinogenic effects. This mechanism is due to the ability of adiponectin to stop the growth of colon cancer cells through AMPc-activated protein kinase (AMPK) and to induce a caspase-dependent pathway resulting in endothelial cell apoptosis [32].
3.2. Other Malignancies
Although the association with colorectal cancer and NAFLD is most frequently reported, several studies have reported an increased risk of extrahepatic malignancies in other organs in patients with NAFLD. A recent study from Korea reported that female patients with NAFLD had an increased risk of developing breast cancer (HR, 1.92; 95% CI, 1.15–3.20) [33]. Furthermore, a few studies have suggested increased risks of developing gastric cancer [34,35], pancreatic cancer [35,36], prostate cancer [37], and esophageal cancer [33,35] in patients with NAFLD.
4. Psychological Dysfunction
Major depressive disorder (MDD) is an important public health problem. Among those affected, 28% experience a moderate degree of functional impairment, whereas 59% experience severe reductions in their normal functional ability [38]. MDD is often comorbid with other chronic diseases, such as cardiovascular disease, arthritis, asthma, and diabetes mellitus, and the presence of MDD reportedly worsens the health outcomes of these associated conditions [39]. Similarly, an association between chronic liver disease and MDD has also been demonstrated. Patients with NAFLD reportedly have a prevalence of MDD of 27.2%, which is higher than that of the general population [40]. Our previous study showed that NAFLD patients with comorbid MDD have severe histological steatosis and a higher NAFLD activity score, as well as significantly higher levels of serum aminotransferase, γ-glutamyl transpeptidase, and ferritin than age- and sex-matched NAFLD patients without MDD. They also demonstrated that NAFLD patients with MDD had a poor response to the standard care for NAFLD, consisting mainly of lifestyle modifications [41]. The pathogenesis linking NAFLD and MDD remains uncertain. However, a recent study investigated possible changes in brain tissue volumes in patients with NAFLD. They reported that the brain volumes of white and gray matter were significantly reduced in patients with NAFLD, compared with control subjects. Accordingly, this reduction in brain volume might be related to a higher risk of depression in patients with NAFLD [42]. In addition, NAFLD reportedly correlated with other types of psychological dysfunction, such as cognitive impairment and Alzheimer’s disease. Cerebrovascular alterations, neuroinflammation, and brain insulin resistance are thought to be key factors in the pathogenesis of these diseases [43].
5. Gastroesophageal Reflux Disease
Gastroesophageal reflux disease (GERD) and NAFLD are commonly associated with metabolic syndrome, especially visceral obesity. Visceral obesity increases the intragastric pressure because of the accumulation of adipose tissue in the whole abdominal cavity, which may induce an abnormal gastroesophageal reflux leading to GERD symptoms [44]. Patients with NAFLD reportedly have a high prevalence of symptoms of GERD [45,46]. Several studies have shown that GERD is associated with sleep problems [47]. Symptoms of GERD (such as heartburn or regurgitation) during the night are thought to cause multiple short periods of awakening, leading to sleep fragmentation. Taketani et al. reported that nearly 30% of Japanese patients with biopsy-proven NAFLD had insomnia, which was independently associated with GERD symptoms. They also demonstrated that treatment with a proton pump inhibitor could relieve both insomnia and the GERD symptoms [48]. Changes in the secretion of hormones (such as cortisol, leptin, and ghrelin) and increased insulin resistance because of a short sleep duration are thought to increase the risks of obesity and diabetes [49,50]. Therefore, GERD and insomnia may lead to the progression and worsening of NAFLD.
6. Obstructive Sleep Apnea Syndrome
Patients with obstructive sleep apnea syndrome (OSAS) have repetitive episodes of shallow or paused breathing during sleep that cause a reduction in blood oxygen saturation. This chronic intermittent hypoxia (CIH) induces increased oxidative stress, the generation of reactive oxygen species (ROS), and the release of inflammatory cytokines, resulting in systemic inflammation that drives the exacerbation of NAFLD and the progression to liver fibrosis [51,52]. Musso et al. conducted a meta-analysis of eighteen cross-sectional studies and reported that OSAS is associated with an increased risk (independent of age, sex, and BMI) of NAFLD (OR, 2.99), NASH (OR, 2.37), and advanced fibrosis (OR, 2.30) [53]. Some non-randomized observational studies have reported a beneficial effect of continuous positive airway pressure (CPAP) on surrogate markers of NAFLD [53,54]. However, the currently available evidence from randomized controlled trials [55,56] does not suggest that the treatment of OSAS with CPAP can reverse the exacerbation of NAFLD.
7. Periodontitis
Individuals with chronic periodontitis reportedly have a significantly increased risk of developing CVD, including atherosclerosis, myocardial infarction, and stroke [57]. Furthermore, a two-way relationship exists between diabetes and periodontitis—diabetes increases the risk of periodontitis, while periodontal inflammation negatively affects glycemic control [58]. Similarly, an association between periodontitis and NAFLD has also been reported in various studies [59]. Yoneda et al. investigated the detection frequency of Porphyromonas gingivalis, which is well known as a major causative agent of periodontitis, in 150 biopsy-proven NAFLD patients and 60 healthy controls [60]. They found that the frequencies of P. gingivalis detection in patients with biopsy-proven NAFLD (46.7%) and NASH (52.0%) were significantly higher than that in non-NAFLD control subjects (21.7%). Moreover, they also demonstrated that non-surgical periodontal treatments in NAFLD patients ameliorated the serum levels of Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT). Although further large-scale clinical trials are needed, periodontal treatments may be useful supportive measures in the management of patients with NAFLD.
8. Endocrinopathies
8.1. Hypothyroidism
Pagadala et al. reported that the prevalence of hypothyroidism was significantly higher among patients with biopsy-proven NAFLD than among age-, sex-, race-, and BMI-matched control subjects (21% vs. 9.5%) [61]. Moreover, they found that NASH was associated with hypothyroidism, in a manner that was independent of diabetes mellitus, dyslipidemia, hypertension, and age. In addition, Chung et al. investigated the prevalence of NAFLD in 2324 cases with hypothyroidism, compared with age- and sex-matched controls [62]. They found that the prevalence of NAFLD was significantly higher not only in patients with overt hypothyroidism, but also in patients with subclinical hypothyroidism (even in the upper normal range of thyroid-stimulating hormone (TSH) levels), than in subjects with euthyroidism, independent of known metabolic risk factors [62].
8.2. Adult Growth Hormone Deficiency
Growth hormone (GH) profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Moreover, GH directly reduces lipogenesis in hepatocytes [63]. Adult growth hormone deficiency (AGHD) is characterized by metabolic abnormalities associated with visceral obesity, impaired quality of life, and increased mortality. Nishizawa et al. reported that the prevalence of NAFLD in patients with AGHD was significantly higher than in age-, sex-, and BMI-matched healthy controls (77% vs. 12%, p < 0.001) [64]. They also demonstrated the effectiveness of GH replacement therapy for NAFLD, although the sample size was too small to assess the true effectiveness.
8.3. Polycystic Ovarian Syndrome
Polycystic ovarian syndrome (PCOS), also known as hyperandrogenic anovulation, is one of the most common endocrine disorders in women of reproductive age. Several studies have demonstrated that the prevalence of NAFLD was significantly higher among patients with PCOS, and that hyperandrogenism was an independent risk factor for NAFLD [65,66]. Although PCOS and NAFLD share similar metabolic comorbidities such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome, androgen excess itself is thought to increase insulin resistance [67]. The prevalence of PCOS in patients with NAFLD is still unclear. However, a cross-sectional study from Australia reported that the prevalence of PCOS was very high at 71% (10/14) among female NAFLD patients of reproductive age (20–45 years) [68].
9. Discussion
Although considerable evidence and suggestions have been collected to reveal associations between NAFLD and extrahepatic complications, most of these reports were based on cross-sectional or observational studies with short follow-up periods. An appropriate screening method for extrahepatic complications has not yet been clearly described in any guidelines or guidances, such as the European guidelines from the European Association for the Study of the Liver (EASL) [69], guidance from the American Association for the Study of Liver Disease (AASLD) [70], or guidelines from the Japanese Society of Gastroenterology (JSG) [71]. However, intensive surveillance and early intervention for these extrahepatic complications might benefit the patients with NAFLD. For extrahepatic malignancies, the NAFLD patients who have never undergone colonoscopy should undergo total colonoscopy at least once. Further studies are needed to reveal the risk profiles at baseline and to determine appropriate screening methods for extrahepatic diseases. There are some limitations in this narrative review. First, we did not conduct a statistical analysis about bias risk in our selection of referenced literatures. Second, the association between NAFLD and CVD was not mentioned in this article because it was discussed in great detail in another article in this special issue. Recently, clinical trials examining new therapeutic drugs for NAFLD/NASH that act via various mechanisms are being performed in several countries [72]. The influence of these drugs on the risks and outcomes of extrahepatic complications should be considered in these clinical trials. To date, the influence of life style modifications to extrahepatic complications are unclear, therefore it might be the candidate for future studies. Since extrahepatic complications occur across multiple organ systems, collaborative care with respective experts is needed for the management of patients with NAFLD. In conclusion, compared to healthy controls, patients with NAFLD have higher prevalence/incidence risk of extrahepatic complications in multiple organs. Not only hepatologists, but also patients with NAFLD, should be aware of these increased risks for extrahepatic diseases.
Abbreviations
AASLD | American Association for the Study of Liver Disease |
AGFD | Adult growth hormone deficiency |
ALT | Alanine aminotransferase |
AMPK | AMPc-activated protein kinase |
AST | Aspartate aminotransferase |
BMI | Body mass index |
CI | Confidence interval |
CPAP | Continuous positive airway pressure |
CVD | Cardiovascular disease |
EASL | European Association for the Study of the Liver |
ESRD | End-stage renal disease |
GERD | Gastroesophageal reflux disease |
GH | Growth hormone |
HbA1c | Hemoglobin A1c |
HCC | Hepatocellular carcinoma |
HR | Hazard ratio |
JSG | Japanese Society of Gastroenterology |
LDL-C | Low-density lipoprotein-cholesterol |
MDD | Major depressive disorder |
NAFLD | Non-alcoholic fatty liver disease |
NASH | Non-alcoholic steatohepatitis |
OR | Odds ratio |
OSAS | Obstructive sleep apnea syndrome |
PCOS | Polycystic ovarian syndrome |
TSH | Thyroid-stimulating hormone |
Author Contributions
Conceptualization, W.T. and K.I.; writing—original draft preparation, W.T., T.T. (Takuya Takayanagi), Y.E., K.S., T.T. (Tsuneyuki Takimoto), K.H., T.K. (Takashi Kobayashi), A.N. (Asako Nogami), T.K. (Takayuki Kato), Y.H., T.K. (Takaomi Kessoku), and Y.O.; writing—review and editing, K.I., H.K., Y.S., and M.Y.; supervision, Y.S., M.Y., S.S., and A.N (Atsushi Nakajima). All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Footnotes
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Younossi Z.M., Koenig A.B., Abdelatif D., Fazel Y., Henry L., Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. doi: 10.1002/hep.28431. [DOI] [PubMed] [Google Scholar]
- 2.CME Exam 3: Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease. Gastroenterology. 2018;155:e18. doi: 10.1053/j.gastro.2018.11.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Angulo P., Kleiner D.E., Dam-Larsen S., Adams L.A., Bjornsson E.S., Charatcharoenwitthaya P., Mills P.R., Keach J.C., Lafferty H.D., Stahler A., et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149:389–397.e10. doi: 10.1053/j.gastro.2015.04.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ekstedt M., Hagström H., Nasr P., Fredrikson M., Stål P., Kechagias S., Hultcrantz R. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–1554. doi: 10.1002/hep.27368. [DOI] [PubMed] [Google Scholar]
- 5.Sasaki A., Nitta H., Otsuka K., Umemura A., Baba S., Obuchi T., Wakabayashi G. Bariatric Surgery and Non-Alcoholic Fatty Liver Disease: Current and Potential Future Treatments. Front. Endocrinol. 2014;5:164. doi: 10.3389/fendo.2014.00164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Leite N.C., Salles G.F., Araujo A.L., Villela-Nogueira C.A., Cardoso C.R. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with tpe-2 diabetes mellitus. Liver Int. 2009;29:113–119. doi: 10.1111/j.1478-3231.2008.01718.x. [DOI] [PubMed] [Google Scholar]
- 7.Assy N., Kaita K., Mymin D., Levy C., Rosser B., Minuk G. Fatty Infiltration of Liver in Hyperlipidemic Patients. Dig. Dis. Sci. 2000;45:1929–1934. doi: 10.1023/A:1005661516165. [DOI] [PubMed] [Google Scholar]
- 8.Armstrong M.J., Adams L.A., Canbay A., Syn W.-K. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014;59:1174–1197. doi: 10.1002/hep.26717. [DOI] [PubMed] [Google Scholar]
- 9.Adams L.A., Anstee Q.M., Tilg H., Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138–1153. doi: 10.1136/gutjnl-2017-313884. [DOI] [PubMed] [Google Scholar]
- 10.Levey A.S., Eckardt K.-U., Tsukamoto Y., Levin A., Coresh J., Rossert J., Zeeuw D.D., Hostetter T.H., Lameire N., Eknoyan G. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO) Kidney Int. 2005;67:2089–2100. doi: 10.1111/j.1523-1755.2005.00365.x. [DOI] [PubMed] [Google Scholar]
- 11.Mantovani A., Zaza G., Byrne C.D., Lonardo A., Zoppini G., Bonora E., Targher G. Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: A systematic review and meta-analysis. Metabolism. 2018;79:64–76. doi: 10.1016/j.metabol.2017.11.003. [DOI] [PubMed] [Google Scholar]
- 12.Yun K.E., Shin C.Y., Yoon Y.S., Park H.S. Elevetad alanine aminotransferase levels predict mortality fron cardiovascular disease and diabetes in Koreans. Atherosclerosis. 2009;205:533–537. doi: 10.1016/j.atherosclerosis.2008.12.012. [DOI] [PubMed] [Google Scholar]
- 13.Targher G., Bertolini L., Rodella S., Lippi G., Zoppini G., Chonchol M. Relationship between Kidney Function and Liver Histology in Subjects with Nonalcoholic Steatohepatitis. Clin. J. Am. Soc. Nephrol. 2010;5:2166–2171. doi: 10.2215/CJN.05050610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Yasui K., Sumida Y., Mori Y., Mitsuyoshi H., Minami M., Itoh Y., Kanemasa K., Matsubara H., Okanoue T., Yoshikawa T. Nonalcoholic steatohepatitis and increased risk of chronic kidney disease. Metabolism. 2011;60:735–739. doi: 10.1016/j.metabol.2010.07.022. [DOI] [PubMed] [Google Scholar]
- 15.Sirota J.C., McFann K., Targher G., Chonchol M., Jalal D.I. Association between Nonalcoholic Liver Disease and Chronic Kidney Disease: An Ultrasound Analysis from NHANES 1988–1994. Am. J. Nephrol. 2012;36:466–471. doi: 10.1159/000343885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Sinn D.H., Kang D., Jang H.R., Gu S., Cho S.-J., Paik S.W., Ryu S., Chang Y., Lazo M., Guallar E., et al. Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: A cohort study. J. Hepatol. 2017;67:1274–1280. doi: 10.1016/j.jhep.2017.08.024. [DOI] [PubMed] [Google Scholar]
- 17.Park H., Dawwas G.K., Liu X., Nguyen M.H. Nonalcoholic fatty liver disease increases risk of incident advanced chronic kidney disaease: A propensity-matched cohort study. J. Intern. Med. 2019;286:711–722. doi: 10.1111/joim.12964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Chang Y., Ryu S., Sung E., Woo H.-Y., Oh E., Cha K., Jung E., Kim W.S. Nonalcoholic fatty liver disease predicts chronic kidney disease in nonhypertensive and nondiabetic Korean men. Metabolism. 2008;57:569–576. doi: 10.1016/j.metabol.2007.11.022. [DOI] [PubMed] [Google Scholar]
- 19.Targher G., Bertolini L., Rodella S., Zoppini G., Lippi G., Day C., Muggeo M. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia. 2007;51:444–450. doi: 10.1007/s00125-007-0897-4. [DOI] [PubMed] [Google Scholar]
- 20.Musso G., Cassader M., Cohney S., Pinach S., Saba F., Gambino R. Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease. Trends Mol. Med. 2015;21:645–662. doi: 10.1016/j.molmed.2015.08.005. [DOI] [PubMed] [Google Scholar]
- 21.Arnold M., Sierra M.S., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2016;66:683–691. doi: 10.1136/gutjnl-2015-310912. [DOI] [PubMed] [Google Scholar]
- 22.Mantovani A., Dauriz M., Byrne C.D., Lonardo A., Zoppini G., Bonora E., Targher G. Assoiation between nonalcoholic fatty liver disease and colorectal tumors in asymptomatic adults undergoing screening colonoscopy: A systematic review and meta-analysis. Metabolism. 2018;87:1–12. doi: 10.1016/j.metabol.2018.06.004. [DOI] [PubMed] [Google Scholar]
- 23.Wong V.W.-S., Wong G.L.-H., Tsang S.W.-C., Fan T., Chu W.C.-W., Woo J., Chan A.W.-H., Choi P.C.-L., Chim A.M.-L., Lau J.Y.-W., et al. High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut. 2011;60:829–836. doi: 10.1136/gut.2011.237974. [DOI] [PubMed] [Google Scholar]
- 24.Stadlmayr A., Aigner E., Steger B., Scharinger L., Lederer D., Mayr A., Strasser M., Brunner E., Heuberger A., Hohla F., et al. Nonalcoholic fatty liver disease: An independent risk factor for colorectal neoplasia. J. Intern. Med. 2011;270:41–49. doi: 10.1111/j.1365-2796.2011.02377.x. [DOI] [PubMed] [Google Scholar]
- 25.Touzin N.T., Bush K.N., Williams C.D., Harrison S.A. Prevalence of colonic adenomas in patients with nonalcoholic fatty liver disease. Ther. Adv. Gastroenterol. 2011;4:169–176. doi: 10.1177/1756283X11402118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Lee Y.I., Lim Y.-S., Park H.S. Colorectal neoplasms in relation to non-alcoholic fatty liver disease in Korean women: A retrospective cohort study. J. Gastroenterol. Hepatol. 2011;27:91–95. doi: 10.1111/j.1440-1746.2011.06816.x. [DOI] [PubMed] [Google Scholar]
- 27.Huang K.-W., Leu H.-B., Wang Y.-J., Luo J.-C., Lin H.-C., Lee F.-Y., Chan W.-L., Lin J.-K., Chang F.-Y. Patients with nonalcoholic fatty liver disease have higher risk of colorectal adenoma after negative baseline colonoscopy. Colorectal Dis. 2013;15:830–835. doi: 10.1111/codi.12172. [DOI] [PubMed] [Google Scholar]
- 28.Ahn J.S., Sinn D.H., Min Y.W., Hong S.N., Kim H.S., Jung S.-H., Gu S., Rhee P.-L., Paik S.W., Son H.J., et al. Non-alcoholic fatty liver diseases and risk of colorectal neoplasia. Aliment. Pharmacol. Ther. 2016;45:345–353. doi: 10.1111/apt.13866. [DOI] [PubMed] [Google Scholar]
- 29.Blackett J.W., Verna E.C., Lebwohl B. Increased Prevalence of Colorectal Adenomas in Patients with Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study. Dig. Dis. 2019;38:222–230. doi: 10.1159/000502684. [DOI] [PubMed] [Google Scholar]
- 30.Sasazuki S., Charvat H., Hara A., Wakai K., Nagata C., Nakamura K., Tsuji I., Sugawara Y., Tamakoshi A., Matsuo K., et al. Diabetes mellitus and cancer risk: Pooled analysis of eight cohort studies in Japan. Cancer Sci. 2013;104:1499–1507. doi: 10.1111/cas.12241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Moghaddam A.A., Woodward M., Huxley R. Obesity and Risk of Colorectal Cancer: A Meta-analysis of 31 Studies with 70,000 Events. Cancer Epidemiol. Biomark. Prev. 2007;16:2533–2547. doi: 10.1158/1055-9965.EPI-07-0708. [DOI] [PubMed] [Google Scholar]
- 32.Sanna C., Rosso C., Marietti M., Bugianesi E. Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers. Int. J. Mol. Sci. 2016;17:717. doi: 10.3390/ijms17050717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Kim G.-A., Lee H.C., Choe J., Kim M.-J., Lee M.J., Chang H.-S., Bae I.Y., Kim H.-K., An J., Shim J.H., et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J. Hepatol. 2018;68:140–146. doi: 10.1016/j.jhep.2017.09.012. [DOI] [PubMed] [Google Scholar]
- 34.Hamaguchi M., Hashimoto Y., Obora A., Kojima T., Fukui M. Non-alcoholic fatty liver disease with obesity as an independent predictor for incident gastric and colorectal cancer: A population-based longitudinal study. BMJ Open Gastroenterol. 2019;6:e000295. doi: 10.1136/bmjgast-2019-000295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Allen A.M., Hicks S.B., Mara K.C., Larson J.J., Therneau T.M. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity – A longitudinal cohort study. J. Hepatol. 2019;71:1229–1236. doi: 10.1016/j.jhep.2019.08.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Chang C.-F., Tseng Y.-C., Huang H.-H., Shih Y.-L., Hsieh T.-Y., Lin H.-H. Exploring the relationship between nonalcoholic fatty liver disease and pancreatic cancer by computed tomographic survey. Intern. Emerg. Med. 2017;13:191–197. doi: 10.1007/s11739-017-1774-x. [DOI] [PubMed] [Google Scholar]
- 37.Liu S.-S., Ma X.-F., Zhao J., Du S.-X., Zhang J., Dong M.-Z., Xin Y.-N. Association between nonalcoholic fatty liver disease and extrahepatic cancers: A systematic review and meta-analysis. Lipids Health Dis. 2020;19:1–10. doi: 10.1186/s12944-020-01288-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Wang P.S., Simon G., Kessler R.C. The economic burden of depression and the cost-effectiveness of treatment. Int. J. Methods Psychiatr. Res. 2003;12:22–33. doi: 10.1002/mpr.139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Moussavi S., Chatterji S., Verdes E., Tandon A., Patel V., Ustun B. Depression, chronic diseases, and decrements in health: Results from the World Health Surveys. Lancet. 2007;370:851–858. doi: 10.1016/S0140-6736(07)61415-9. [DOI] [PubMed] [Google Scholar]
- 40.Weinstein A.A., Price J.K., Stepanova M., Poms L.W., Fang Y., Moon J., Nader F., Younossi Z.M. Depression in Patients with Nonalcoholic Fatty Liver Disease and Chronic Viral Hepatitis B and C. J. Psychosom. Res. 2011;52:127–132. doi: 10.1016/j.psym.2010.12.019. [DOI] [PubMed] [Google Scholar]
- 41.Tomeno W., Kawashima K., Yoneda M., Saito S., Ogawa Y., Honda Y., Kessoku T., Imajo K., Mawatari H., Fujita K., et al. Non-alcoholic fatty liver disease comorbid with major depressive disorder: The pathological features and poor therapeutic efficacy. J. Gastroenterol. Hepatol. 2015;30:1009–1014. doi: 10.1111/jgh.12897. [DOI] [PubMed] [Google Scholar]
- 42.Filipović B., Marković O., Đurić V., Filipović B. Cognitive Changes and Brain Volume Reduction in Patients with Nonalcoholic Fatty Liver Disease. Can. J. Gastroenterol. Hepatol. 2018;2018:1–6. doi: 10.1155/2018/9638797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Colognesi M., Gabbia D., De Martin S. Depression and Cognitive Impairment—Extrahepatic Manifestations of NAFLD and NASH. Biomedcine. 2020;8:229. doi: 10.3390/biomedicines8070229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.El-Serag H.B., Tran T., Richardson P., Ergun G. Anthropometric correlates of intragastric pressure. Scand. J. Gastroenterol. 2006;41:887–891. doi: 10.1080/00365520500535402. [DOI] [PubMed] [Google Scholar]
- 45.Fujikawa Y., Tominaga K., Fujii H., Machida H., Okazaki H., Yamagami H., Tanigawa T., Watanabe K., Watanabe T., Fujiwara Y., et al. High prevelance of gastroesophageal reflux symptoms in patients with non-alcoholic fatty liver disease associated with serum levels of triglyceride and cholesterol but not simple visceral obesity. Digestion. 2012;86:228–237. doi: 10.1159/000341418. [DOI] [PubMed] [Google Scholar]
- 46.Miele L., Cammarota G., Vero V., Racco S., Cefalo C., Marrone G., Pompili M., Rapaccini G., Biano A., Landolfi R., et al. Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux sumptoms. Dig. Liver Dis. 2012;44:1032–1036. doi: 10.1016/j.dld.2012.08.005. [DOI] [PubMed] [Google Scholar]
- 47.Jansson C., Nordenstedt H., Wallander M., Johansson S., Johnsen R., Hveem K., Lagergren J. A Population-Based Study Showing an Association Between Gastroesophageal Reflux Disease and Sleep Problems. Clin. Gastroenterol. Hepatol. 2009;7:960–965. doi: 10.1016/j.cgh.2009.03.007. [DOI] [PubMed] [Google Scholar]
- 48.Taketani H., Japan Study Group of NAFLD (JSG-NAFLD) Sumida Y., Tanaka S., Imajo K., Yoneda M., Hyogo H., Ono M., Fujii H., Eguchi Y., et al. The association of insomnia with gastroesophageal reflux symptoms in biopsy-proven nonalcoholic fatty liver disease. J. Gastroenterol. 2013;49:1163–1174. doi: 10.1007/s00535-013-0871-5. [DOI] [PubMed] [Google Scholar]
- 49.Spiegel K., Leproult R., L’Hermite-Balériaux M., Copinschi G., Penev P.D., Van Cauter E. Leptin Levels Are Dependent on Sleep Duration: Relationships with Sympathovagal Balance, Carbohydrate Regulation, Cortisol, and Thyrotropin. J. Clin. Endocrinol. Metab. 2004;89:5762–5771. doi: 10.1210/jc.2004-1003. [DOI] [PubMed] [Google Scholar]
- 50.Donga E., Van Dijk M., Van Dijk J.G., Biermasz N.R., Lammers G.-J., Van Kralingen K.W., Corssmit E.P.M., Romijn J.A. A Single Night of Partial Sleep Deprivation Induces Insulin Resistance in Multiple Metabolic Pathways in Healthy Subjects. J. Clin. Endocrinol. Metab. 2010;95:2963–2968. doi: 10.1210/jc.2009-2430. [DOI] [PubMed] [Google Scholar]
- 51.Aron-Wisnewsky J., Clement K., Pépin J.-L. Nonalcoholic fatty liver disease and obstructive sleep apnea. Metabolism. 2016;65:1124–1135. doi: 10.1016/j.metabol.2016.05.004. [DOI] [PubMed] [Google Scholar]
- 52.Parikh M.P., Gupta N.M., McCullough A.J. Obstructive Sleep Apnea and the Liver. Clin. Liver Dis. 2019;23:363–382. doi: 10.1016/j.cld.2019.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Musso G., Cassader M., Olivetti C., Rosina F., Carbone G., Gambino R. Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obes. Rev. 2013;14:417–431. doi: 10.1111/obr.12020. [DOI] [PubMed] [Google Scholar]
- 54.Chin K., Nakamura T., Takahashi K., Sumi K., Ogawa Y., Masuzaki H., Muro S., Hattori N., Matsumoto H., Niimi A., et al. Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients. Am. J. Med. 2003;114:370–376. doi: 10.1016/S0002-9343(02)01570-X. [DOI] [PubMed] [Google Scholar]
- 55.Kohler M., Pepperell J.C., Davies R.J., Stradling J.R. Continuous Positive Airway Pressure and Liver Enzymes in Obstructive Sleep Apnoea: Data from a Randomized Controlled Trial. Respiration. 2009;78:141–146. doi: 10.1159/000170785. [DOI] [PubMed] [Google Scholar]
- 56.Jullian-Desayes I., Tamisier R., Zarski J.-P., Aron-Wisnewsky J., Launois-Rollinat S.H., Trocme C., Levy P., Joyeux-Faure M., Pépin J.-L. Impact of effective versus sham continuous positive airway pressure on liver injury in obstructive sleep apnoea: Data from randomized trials. Respirology. 2015;21:378–385. doi: 10.1111/resp.12672. [DOI] [PubMed] [Google Scholar]
- 57.Seymour G., Ford P., Cullinan M., Leishman S., Yamazaki K. Relationship between periodontal infections and systemic disease. Clin. Microbiol. Infect. 2007;13:3–10. doi: 10.1111/j.1469-0691.2007.01798.x. [DOI] [PubMed] [Google Scholar]
- 58.Preshaw P.M., Alba A.L., Herrera D., Jepsen S., Konstantinidis A., Makrilakis K., Taylor R. Periodontitis and diabetes: A two-way relationship. Diabetologia. 2012;55:21–31. doi: 10.1007/s00125-011-2342-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Alakhali M.S., Al-Maweri S.A., Al-Shamiri H.M., Al-Haddad K., Halboub E. The potential association between periodontitis and non-alcoholic fatty liver disease: A systematic review. Clin. Oral Investig. 2018;22:2965–2974. doi: 10.1007/s00784-018-2726-1. [DOI] [PubMed] [Google Scholar]
- 60.Yoneda M., Naka S., Nakano K., Wada K., Endo H., Mawatari H., Imajo K., Nomura R., Hokamura K., Ono M., et al. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterol. 2012;12:16. doi: 10.1186/1471-230X-12-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Pagadala M.R., Zein C.O., Dasarathy S., Yerian L.M., Lopez R., McCullough A.J. Prevalence of Hypothyroidism in Nonalcoholic Fatty Liver Disease. Dig. Dis. Sci. 2012;57:528–534. doi: 10.1007/s10620-011-2006-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Chung G.E., Kim D., Kim W., Yim J.Y., Park M.J., Kim Y.J., Yoon J.-H., Lee H.-S. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J. Hepatol. 2012;57:150–156. doi: 10.1016/j.jhep.2012.02.027. [DOI] [PubMed] [Google Scholar]
- 63.Takahashi Y. The Role of Growth Hormone and Insulin-Like Growth Factor-I in the Liver. Int. J. Mol. Sci. 2017;18:1447. doi: 10.3390/ijms18071447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Nishizawa H., Iguchi G., Murawaki A., Fukuoka H., Hayashi Y., Kaji H., Yamamoto M., Suda K., Takahashi M., Seo Y., et al. Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. Eur. J. Endocrinol. 2012;167:67–74. doi: 10.1530/EJE-12-0252. [DOI] [PubMed] [Google Scholar]
- 65.Kim J.J., Kim D., Yim J.Y., Kang J.H., Han K.H., Kim S.M., Hwang K.R., Ku S.Y., Suh C.S., Kim S.H., et al. Polycystic ovary sundrome with hyperandrogenism as a risk factor for non-obese non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 2017;45:1403–1412. doi: 10.1111/apt.14058. [DOI] [PubMed] [Google Scholar]
- 66.Wu J., Yao X.-Y., Shi R.-X., Liu S.-F., Wang X.-Y. A potential link between polycystic ovary syndrome and non-alcoholic fatty liver disease: An update meta-analysis. Reprod. Health. 2018;15:1–9. doi: 10.1186/s12978-018-0519-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Asfari M.M., Sarmini M.T., Baidoun F., Al-Khadra Y., Ezzaizi Y., Dasarathy S., McCullough A. Association of non-alcoholic fatty liver disease and polycystic ovarian syndrome. BMJ Open Gastroenterol. 2020;7:e000352. doi: 10.1136/bmjgast-2019-000352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Brzozowska M.M., Ostapowicz G., Weltman M.D. An association between non-alcoholic fatty liver disease and polycystic ovarian syndrome. J. Gastroenterol. Hepatol. 2009;24:243–247. doi: 10.1111/j.1440-1746.2008.05740.x. [DOI] [PubMed] [Google Scholar]
- 69.Sberna A.L., Bouillet B., Rouland A., Brindisi M.-C., Nguyen A., Mouillot T., Duvillard L., Denimal D., Loffroy R., Vergès B., et al. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) clinical practice recommendations for the management of non-alcoholic fatty liver diseas. Diabet. Med. 2018;35:368–375. doi: 10.1111/dme.13565. [DOI] [PubMed] [Google Scholar]
- 70.Chalasani N., Younossi Z., LaVine J.E., Charlton M., Cusi K., Rinella M., Harrison S.A., Brunt E.M., Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–357. doi: 10.1002/hep.29367. [DOI] [PubMed] [Google Scholar]
- 71.Watanabe S., Hashimoto E., Ikejima K., Uto H., Ono M., Sumida Y., Seike M., Takei Y., Takehara T., Tokushige K., et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J. Gastroenterol. 2015;50:364–377. doi: 10.1007/s00535-015-1050-7. [DOI] [PubMed] [Google Scholar]
- 72.Tomeno W., Yoneda M., Imajo K., Ogawa Y., Kessoku T., Saito S., Eguchi Y., Nakajima A. Emerging drugs for non-alcoholic steatohepatitis. Expert Opin. Emerg. Drugs. 2013;18:279–290. doi: 10.1517/14728214.2013.811232. [DOI] [PubMed] [Google Scholar]