The impact of Metabolic Syndrome on the outcome of NASH: Cirrhosis,
Hepatocellular Carcinoma and Mortality
Ramy Younes
1; Elisabetta Bugianesi
1 Affiliations:1Department of Medical Sciences, Division of Gastroenterology
University of Turin, Turin, Italy Corresponding Author:
Prof. Elisabetta Bugianesi, MD PhD Department of Medical Sciences University of Torino
AOU Città della Salute e della Scienza Corso Dogliotti 14
10126 Torino, Italy
elisabetta.bugianesi@unito.it
Keywords: non-alcoholic fatty liver disease, insulin resistance, obesity, diabetes, cirrhosis, hepatocellular carcinoma, mortality
Word count: 3438 Number of tables: 2
Conflict of interest: no conflict of interest by authors for this study
Human and Animal Rights: this article does not contain any studies with human or animal subjects performed by any of the authors.
Abstract (max 150 words)
Purpose of review: In this review, we describe the interaction between the Metabolic Syndrome (MS) and Non-alcoholic fatty liver disease (NAFLD) and examine the impact of the features of MS on the most worrisome outcomes of Nonalcoholic steatohepatitis (NASH), (cirrhosis, hepatocellular carcinoma), overall mortality and mortality from liver and cardiovascular events.
Recent findings: Insulin resistance pathophysiology, as well as obesity and dyslipidaemia pro-inflammatory environment, have a causal role in hepatic fibrogenesis and oncogenesis in NAFLD patients. Studies repeatedly reported the conditions linked to MS as independent predictors of overall-, cardiovascular- and liver-related mortality.
Summary: MS significantly contribute to NAFLD patient death for liver-related events. Dysmetabolic factors stemming from insulin resistance play a key role in liver damage progression. Obesity, Type 2 Diabetes (T2DM), dyslipidaemia and arterial hypertension are independent predictors of liver fibrosis and cirrhosis; furthermore, obesity and T2DM play a key role in the development of hepatocellular carcinoma both in cirrhotic and non-cirrhotic NASH patients.
Introduction
NAFLD is a very common liver disease, with an overall prevalence up to 25% in the general population and peaks in South America and particularly in the Middle East, where the prevalence of fatty liver exceeds 30% [1]. Nonetheless the rate of patients who progress to Non-Alcoholic Steatohepatitis (NASH), as well as the proportion of those who progress to fibrosis and cirrhosis, are proportionally low [2]. Factors responsible for the development of end-stage live disease in NAFLD are not fully understood and are the focus of research in recent years, but the Metabolic Syndrome (MS) and its individual components are certainly involved both in the onset of NAFLD and in its progression to end-stage liver disease.
The borders of the syndrome, previously known as the insulin-resistance syndrome, have long been unsettled. In 2001, the Third Report of the National Cholesterol Education Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATPIII]) provided a working definition of the MS, based on a combination of 5 categorical and discrete risk factors (central obesity, hypertension, hypertriglyceridemia, low levels of high-density lipoprotein [HDL]-cholesterol, and hyperglycemia), derived from the guidelines of the International Societies [3]. The underlying metabolic defect among patients presenting this syndrome is the presence of insulin resistance, intended as an impairment in cell sensitivity to insulin action in the target tissues (liver, muscle and adipose tissue) [3].
Physiopathological considerations, clinical associations, and laboratory investigations support a central role for insulin resistance in the pathogenesis of NAFLD. Insulin resistance may occur both in NAFLD patients who present features of the MS and in those who are not obese and with normal glycaemia [4], and it can be found even in NAFLD subjects with normal
liver enzymes and apparently no signs of liver damage [5]. It is now clear that MS and NAFLD could be considered as parts of a spectrum of a metabolic disorder, with constant and bidirectional interactions that impact on the final clinical outcome of patients.
In this review we summarize how the Metabolic Syndrome and its individual features impacts on the most worrisome outcomes of NASH, namely cirrhosis and hepatocellular carcinoma (HCC), as well as on overall mortality from liver-related and cardiovascular events.
The Metabolic Syndrome and the progression to Cirrhosis in NAFLD
A seminal study dating back to 2003 first highlighted that the simultaneous presence of multiple components of MS can significantly increase the risk of more severe stages of liver disease [6]. This association was maintained also in patients without overt diabetes, where the very high prevalence of the MS might blur the relationship.
The finding of a tight link between MS features and NASH, with more severe necroinflammatory activity and fibrosis, is particularly relevant in epidemiologic terms as it underlines the existence of an exceedingly large population at risk of forthcoming liver failure in the next decades, provided they survive the burden of cardiovascular disease mortality. Each component of the syndrome may have a different impact on the final clinical outcome in a subject with NAFLD (table 1) .
Obesity, intended as increased fat in subcutaneous and/or visceral depots, could be seen as a global inflammatory condition leading to multiple systemic and liver-related outcomes. The dysfunctional adipose tissue associated with obesity leads to a dysregulation of several homeostatic pathways, a higher expression of pro-inflammatory cytokines, e.g. IL-6 and TNF-α, and the abnormal activation of macrophages both in the adipose tissue and in the liver [7, 8]. The latter mechanism was recently highlighted by Kazankov et al. by the soluble macrophage activation marker CD163, confirming the role of macrophages as mediators of liver injury in NAFLD patients [9].
In 2008, an Australian study analysed the impact of visceral fat on the progression of fatty liver disease and the occurrence of advanced fibrosis [10]. They reported an odds ratio for increasing liver inflammation and fibrosis of 2.4 for each 1% increase in visceral fat. Furthermore, visceral fat was able to independently predict NASH and fibrosis, even after adjustment for common confounders like insulin resistance. A previous study had already suggested that macrophage infiltration in the white adipose tissue of 55 obese patients, who underwent omental and subcutaneous fat biopsies during gastric surgery, was associated with a fibro-inflammatory progression of NAFLD [11]. Comparing liver fat of obese NAFLD patients with patients homozygous for the PNPLA3 rs738409[G] variant (any BMI), adipose tissue inflammation as well as the incidence of insulin resistance were seen only in the obese NAFLD group, showing that the role of adipose tissue should not be isolated from a dysfunctional metabolic context, where obesity has a leading role [12].
Insulin Resistance and Type 2 Diabetes Mellitus
A main component of the metabolic syndrome, Type 2 Diabetes (T2DM) is also considered one of the most important negative prognostic factors for NAFLD progression to NASH and
fibrosis. Insulin resistance and the associated compensatory hyperinsulinaemia can impair both gluconeogenesis in the liver and insulin clearance by the muscle, finally leading to hyperglycaemia [13]. In addition, this mechanism also contributes to an impaired lipid turnover and delivery of fat to the liver, increased de novo lipogenesis and synthesis of more lipotoxic intrahepatic lipids, local production of pro-inflammatory cytokines and other mediators involved in the development and maintenance of liver fibrosis.
In the UK, McPherson et al. analysed data of 108 NAFLD patients who underwent repeat liver biopsies with a median interval of 6.6 years [14]. In their study, 80% of patients who experienced fibrosis progression were diabetic, while the prevalence of diabetes among patients who did not progress was 25%, reinforcing the concept that T2DM itself is one of the strongest independent predictor of adverse liver-related outcome. A Swedish study by Nasr et al. confirmed their finding [15]. They enrolled 129 NAFLD patients who were initially assessed between 1988 and 1993 and then recalled for a first follow up between 2003 and 2005 (n=88) and a second one between 2013 and 2015 (n=59). The prevalence of T2DM among patients who developed end-stage liver disease was 33% vs 8.5% in non-progressors; of note, a higher rate of diabetic patients was reported among subjects with simple steatosis at baseline who developed biopsy-proven advanced fibrosis. In 2017, Petta et al. investigated the impact of the metabolic syndrome on the progression of NAFLD in a cohort of 863 patients with biopsy-proven fatty liver disease [16]. They stratified patients according to their age, dividing them in three age-groups (<41 years, 41-54 years, > 54 years respectively) and evaluated the prognostic value of MS components. Interestingly, while the impact of visceral adiposity and dyslipidaemia varied across the age spectrum, only T2DM confirmed its role as predictor of advanced fibrosis and cirrhosis in all patient categories. Similarly, an Italian group demonstrated that T2DM in NAFLD is independently correlated with a “fast” histological worsening toward advanced fibrosis and that the use of inhibitors of the
renin-angiotensin-aldosterone (RAA) axis, which have beneficial effects on multiple aspects of the MS, could slower the T2DM-driven progression of the disease [17].
Arterial Hypertension
The relationship between NAFLD and arterial hypertension (HTN) is bidirectional, being hypertension associated with the incidence and progression of NAFLD and the latter playing an important role in the development of hypertension [18]. Pathophysiological mechanisms underlying this dual interaction include a combination of genetic background and RAA-system influence, in the context of insulin-resistance. In fact, Miyaaki et al. showed that alterations in the RAA-axis represent a key point in the development of liver fibrosis and Ono et al. demonstrated that NASH patients have a higher prevalence of angiotensinogen mutations, which lead to higher diastolic blood pressure and NASH progression [19, 20]. Interestingly, in an experimental study on animal models, liver fibrosis progression was attenuated by blocking aldosterone activity, which in turn inhibited the activation of hepatic stellate cells and neovascularization [21]. Conversely, insulin resistance promote HTN by enhancing the expression of the NF-Κb downstream cytokine production and causing peripheral vasoconstriction, principally involving kidney vessels [22, 23].
Clinically, data from longitudinal studies confirmed arterial hypertension as a predictor of cirrhosis or advanced fibrosis in patients with NAFLD. Sorrentino et al. collected data from a cohort of 149 patients with dual biopsies, performed after a median time of 6.4 years. In their study, HTN resulted as an independent predictor of worsening of fibrosis, with an odds ratio of 4.8 [24]. Finally, a meta-analysis carried out in 11 studies including 411 NAFLD patients with paired-biopsies, confirmed the negative prognostic value of HTN, which was independently and significantly associated with fibrosis progression [25].
Dyslipidaemia
Dyslipidaemia is both a cause and a consequence of the dysfunctional environment generated by the metabolic syndrome. In fact, most NAFLD patients present a dyslipidaemic profile consisting of high triglyceride (TG) and low-density lipoprotein (LDL) as well as low high-density lipoprotein (HDL) plasma levels [26, 27]. In addition, patients with NAFLD have a qualitative dysfunction of HDL particles, characterised by a lower concentration of the more anti-atherogenic sub-fractions [28], and a higher prevalence of the more atherogenic small dense LDL (sdLDL). These dysfunctions, along with a significant higher postprandial lipemia and an increased activity of the lipoprotein lipase (LPL) and hepatic lipase, contribute to create a fertile ground for the progression from NAFLD to advanced fibrosis and for the occurrence of cardiovascular events [29-32].
Clinical trials that evaluated the effect of statins on liver histology in patients with NAFLD indirectly demonstrated how dyslipidaemia, in the context of the MS, could be a predictor of advanced fibrosis and cirrhosis. In 2010 Kimura et al. recruited 43 patients with biopsy-proven NASH and dyslipidaemia for a 12-month treatment with atorvastatin 10 mg daily. After 1 year, 22 patients underwent a follow up liver biopsy which demonstrated an improvement in both steatosis and non-alcoholic fatty liver disease activity score (NAS) [33]. Another trial recruiting 20 biopsy-proven NASH patients demonstrated the resolution of NASH in 19 subjects at the follow up liver biopsy, after being treated with rosuvastatin 10 mg/daily for 12 months [34]. A wider multicentric European study demonstrated how targeting dyslipidaemia protects patients from steatosis, steatohepatitis, advanced fibrosis and cirrhosis, indirectly revealing the impact of dyslipidaemia on liver damage and liver-related outcomes [35].
The Metabolic Syndrome and Hepatocellular Carcinoma in NAFLD
In 2002, a high prevalence of MS features among patients affected by liver cancer was revealed in a cohort of patients with hepatocellular carcinoma (HCC) and cryptogenic cirrhosis, suggesting that these HCCs occurred on a NASH background [36]. Today, the link between HCC, MS and NASH is consolidated and an adequate surveillance program in subjects with metabolic risk factors for HCC is becoming a mandatory issue [37]. Here we analyse how MS components promote this complication in NAFLD patients.
Obesity
Most of the mechanisms underlying the progression to advanced fibrosis and cirrhosis also favour carcinogenesis both in cirrhotic and non-cirrhotic livers of patients with NASH. These factors include the pro-inflammatory role of a dysfunctional adipose tissue, where the M1 macrophage-subtypes produce cytokines promoting cancer development [38, 39], and some adipokines resulting from the adipose tissue endocrine activity [40]. In this regard, leptin can promotes oncogenesis via its interaction with multiple cell proliferative pathways, endothelial cell activity and angiogenesis [41-44]. On the other hand, adiponectin has a leptin-antagonist role, protecting the liver from damage and carcinogenesis, but its concentration is inversely related to the grade of obesity [45-47]. Recently, an impaired autophagy was also linked to the progression of NAFLD to fibrosis and to liver cancer. Autophagy is intended as the ability of the cell to prevent the accumulation of damaged particles, and it is also involved in lipid metabolism and insulin sensitivity [48, 49]. The blockage of this mechanism induces hepatosteatosis, promoting inflammation and oxidative stress [50].
In the clinical setting, a wide prospective cohort study involving more than 900.000 U.S. adults demonstrated that obesity is related to an increased cancer incidence and a consequent higher cancer-related mortality. Particularly, considering HCC, the relative risk of death in male patients increased from 1.90 for a BMI between 30 and 34.9 to 4.52 when the BMI is > 35 [51]. Other studies then confirmed this finding. Of note, obesity at a younger age (mid-20s to mid-40s) has been related to an increased HCC incidence later in life and to a 3.89-month decrease in age at HCC diagnosis per each unit increase in BMI in early adulthood [52]. Similarly, a longitudinal study [53] including Danish schoolchildren aged 7-13 years showed that each unit increase in BMI z-score will rise by 20–30% the risk of liver cancer 30 years later. Past obesity has also been associated with the development of HCC later in life in a French study that recruited 905 HBV/HCV-negative patients [54]. Finally, a meta-analysis which evaluated literature findings from 1966 to 2007, confirm that the overall relative risk for HCC in obese patients is almost doubled compared to the lean counterpart [55].
Visceral fat accumulation is likely to play an important role, particularly in the non-obese population. In the EPIC (European Prospective Investigation into Cancer) cohort, the waist-to-hip ratio, a rough estimate of abdominal fat, predicted better than BMI the incidence of HCC over an 8.6-year follow-up and conferred a three-fold HCC risk to subjects in the upper tertile [56].
Insulin Resistance and Type 2 Diabetes Mellitus
The first causal connection between diabetes and cancer incidence was observed by A. Marble in 1934 [57]. Later in 1986, Lawson et al. found a 4-fold prevalence of diabetic patients among HCC cases with no association with other known aetiologies of liver cancer [58]. In the last 30 years many case-control and cohort studies confirmed these findings. A
Chinese epidemiological study recruited 63,257 patients in the period 1993-1998. After a follow up of 14 years, 499 patients developed HCC and tumour onset was linked to history of diabetes with a hazard ratio (HR) of 2.14 . [59]. Similar results were reported in another cohort study carried in Japan, where 7,473 patients, over a population of 97,771 subjects, developed HCC in a period of 9 years. In this study diabetes was related to the incidence of HCC with a HR of 2.24 for men and 1.92 for women [60]. More recently, in a US retrospective cohort study, diabetes and hypertension were both linked to HCC occurrence even in the absence of cirrhosis. In the same study, the anti-diabetic drug metformin seemed to have a protective role against the incidence of liver cancer, together with cholesterol treatment, including statins [61].
Pathophysiological mechanisms underpinning the increased HCC incidence in patients with T2DM are likely connected with insulin resistance. In fact, hyperinsulinemia itself is recognized to have an oncogenic role, as high levels of insulin could activate the PI3K-anti-apoptotic pathway, leading to uncontrolled cell proliferation [62, 40]. Hyperinsulinemia also increases circulating levels of insulin-like growth factor-1 (IGF-1), which is involved in anti-apoptosis, angiogenesis and cell migration, and it can lead to increase cytokine signals involved in HCC development by stimulating the insulin-receptor-substrate-1 (IRS-1) [40]. Finally, recent studies highlighted the possible role of the so-called “gut dysbiosis” in the setting of NAFLD and MS, which is able to maintain and enhance the pro-inflammatory status, thus boosting fibrosis progression and HCC development [63].
Usually, subjects present more than one feature of MS, with a likely reciprocal interaction at the pathophysiological level so that the risk of developing HCC is globally increased. While the role of obesity and T2DM as predictors of liver cancer is well established, the role of hypertension and dyslipidaemia is still controversial. Nonetheless, as mentioned above, these two factors contribute to the progression to advanced fibrosis, which is per se the most
important predictor of HCC. Finally, drugs like metformin or statins, which ameliorate the MS, seem also to prevent HCC occurrence, underlying an important connection between the two conditions.
The Metabolic Syndrome and the impact on Mortality in NAFLD
Since the definition was introduced, many studies have highlighted a significant link between the metabolic syndrome and the increased risk of mortality in the general population (table 2) [64-66]. The San Antonio Heart Study, which included 2815 patients with a median follow up of 12.7 years, found a HR for all-cause mortality and cardiovascular mortality of 1.27 and 2.01 respectively, in patients who met the NCEP criteria [64]. In addition, Ford et al. analysed the follow up data from the National Health and Nutrition Examination Survey II (NHANES II) and found that the metabolic syndrome was related to a HR of 1.37 for cardiovascular mortality, 1.29 for mortality from coronary heart disease, 1.68 for mortality from stroke and 1.15 for all-cause mortality, with a linear association between MS and cardiovascular mortality [65]. A review which summarized the prospective studies evaluating the longitudinal clinical impact of MS, found a strict relationship between MS and overall mortality, with a significant relative risk of 1.65 [66].
In patients with NAFLD, fibrosis is the main histologic feature significantly associated with mortality [67]. As discussed above, there is a direct correlation between MS and fibrosis progression in NAFLD patients and this explains how the syndrome could also indirectly influence the mortality outcome in these patients. In 2015, Angulo et al. reported that in biopsy-proven NAFLD patients, followed up for a median period of more than 12 years, mortality was associated with all stages of fibrosis and not with any other histological parameter. Interestingly, mortality was also associated with type 2 diabetes mellitus [67].
A recent study by Golabi et al. carried a survival analysis on 3613 patients of the American NHANES III cohort [68]. All patients had an ultrasound-diagnosis of NAFLD and the follow up period was over 19 years. Among the 1039 deaths, the rate of all-cause mortality was 34 times higher in NAFLD patients with at least one component of MS. Diabetes and arterial hypertension were independent predictors of cardiovascular mortality, while diabetes alone was an independent predictor of all-cause mortality.
Another study followed up 289 biopsy-proven NASH patients for a median period of 150 months [69]. Again, diabetes was recognized as an independent predictor of overall mortality. In addition, T2DM increased the risk of liver related mortality, with a significant adjusted hazard ratio of 2.19. The correlation between the metabolic syndrome and liver-related mortality in patients with NAFLD was also reported by Rafiq et al. in a longitudinal study including 173 biopsy-proven NAFLD patients. Among the 78 deaths, liver-related mortality was significantly higher in diabetic patients, and a hazard ratio of 6.7 for liver-related mortality was found when NAFLD patients with diabetes were compared to the non-diabetic NAFLD group [70].
Finally, when compared to the general population, patients with NASH have an increased risk of death for cardiovascular and liver events, in addition to an increased overall mortality risk. Looking into mortality predictors among the features of the MS, diabetes is the most important risk factor for patient death due to all cause, cardiovascular- or liver-related events [68, 71].
Conclusions
Non-alcoholic fatty liver disease has an intertwined relationship with the metabolic syndrome and both share the pathophysiological mechanisms underpinning their main clinical
outcomes. While obesity, diabetes, arterial hypertension and dyslipidaemia can be easily diagnosed in clinical practice, the diagnosis of NASH still relies on liver biopsy due to the lack of a non-invasive validated biomarker [72], hence liver involvement and distress is often under-estimated in patients with the metabolic syndrome.
The parallel rising of obesity, diabetes and NAFLD in the general population highlights that metabolic syndrome and NAFLD are part of a single pathological condition with reciprocal influences [73]. A further confirmation is given by the recent and encouraging results of bariatric surgery, where a net and considerable weight loss corresponds to a simultaneous regression of the conditions related to MS and, as recently reported, also of NASH [74]. As summarized in this review, the impact of the metabolic syndrome on the progression of NAFLD is crucial. It affects not only the progression to cirrhosis, but it also contributes to the development of hepatocellular carcinoma and drastically reduces patient survival, by increasing all-cause, cardiovascular and liver-related mortality.
It is therefore essential a screening for hepatic involvement in all patients with conditions of the metabolic syndrome, as suggested by the joint EASL-EASD-EASO clinical guidelines [75]; just as it is crucial to treat metabolic co-morbidities in patients with NAFLD. This holistic and multidisciplinary approach represents the future of NAFLD therapy, together with a comprehensive effort to optimize a non-invasive diagnosis and to realize personalized surveillance programs for the prevention of liver related complications, among which HCC is the most worrisome although the most overlooked.
Supported by grant from the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413.
Table 1 Metabolic Syndrome and NAFLD Progression to Fibrosis and HCC
MS and Progression to Cirrhosis and HCC
ObesityVan den Poorten et al., 2008 [10]
Visceral fat is directly associated with liver inflammation and fibrosis (OR 2.4 for liver inflammation; OR 3.5 for fibrosis)
Cancello R. et al., 2006 [11] Macrophages in white adipose tissue induce hepatic fibroinflammatory lesions
Angulo et al., 2006 [8] Different fat components promote and enhance liver fibro-inflammation
Calle et al., 2003 [51] Prospective cohort study involving more than 900.000 U.S. adults. RR of death in patients with HCC increased from 1.90 for a BMI between 30 and 34.9 to 4.52 when the BMI is > 35
Berentzen et al., 2014 [53] Longitudinal study including Danish schoolchildren. Each unit increase in BMI z-score rises by 20–30% the risk of liver cancer 30 years later. Larsson et al., 2007 [55] Meta-analysis of 11 cohort studies. The summary RR of liver cancer was
1.89 for those who were obese, compared with persons of normal weight Type 2 Diabetes
McPherson et al., 2015 [14] In NASH patients with repeat biopsies, 80% of those having fibrosis progression were diabetic compared with 25% of non-progressors Nasr et al., 2018 [15] Among 129 patients with serial liver biopsies for NASH , diabetes was
common in patients who developed end-stage liver disease.
Petta et al., 2017 [16] 863 patients with biopsy-proven NAFLD. T2DM was a predictor of advanced fibrosis and cirrhosis in all patient categories (stratified by age).
Koh et al., 2013 [59] Chinese epidemiological study, 63,257 patients recruited. HCC onset was linked to history of diabetes with a HR of 2.14
Inoue et al., 2006 [60] Japanese cohort study, including 97,771 subjects. Diabetes was related to the incidence of HCC with a HR of 2.24 for men and 1.92 for women
Dyslipidaemia
Kimura et al, 2010 [33] 43 patients with biopsy-proven NAFLD, treated with atorvastatin 10 mg/daily. Improvement of both steatosis and NAS score at the follow up biopsy.
Kargiotis et al., 2015 [34] NASH resolution in patients treated with rosuvastatin
Arterial Hypertension
Sorrentino et al., 2010 [24] 149 patients with dual biopsies for NASH. Arterial hypertension was an independent predictor of worsening of fibrosis (OR 4.8)
Singh et al., 2015 [25] Meta-analysis of 11 studies, including 411 NAFLD patients with paired-biopsies. Hypertension was independently associated with fibrosis progression.
OR: Odds Ratio, RR: relative risk, BMI: Body Mass Index, NAFLD: Non Alcoholic Fatty Liver Disease, NASH: Non Alcoholic Steato-Hepatitis, HCC: Hepatocellular Carcinoma, T2DM: Type 2 Diabetes Mellitus
Table 2. MS and the risk of mortality in patients with NAFLD.
Metabolic Syndrome and Morality
Study Description Risk
Hunt et al., 2004 [64] San Antonio Heart Study: 2815 patients with a median follow up of 12.7 years
HR for all-cause mortality and cardiovascular mortality was 1.27 and 2.01 in patients with MS
Ford, 2003 [65] Population of the U.S. NHANES II survey
MS was related to a HR of: 1.37 for cardiovascular mortality 1.29 for mortality from coronary heart disease
1.68 for mortality from stroke 1.15 for all-cause mortality Ford, 2005 [66] Review on the longitudinal clinical
impact of MS
Relationship between MS and overall mortality, with a RR of 1.65 Golabi et al., 2018 [68] Survival analysis on 3613 NAFLD
patients of the US NHANES III cohort
The rate of all-cause mortality was 34 times higher in NAFLD patients with at least one component of MS. Stepanova et al., 2013
[69]
289 biopsy-proven NASH patients followed up for a median period of 150 months
T2DM is an independent predictor of overall mortality.
T2DM increased the risk of liver related mortality, with a HR of 2.19. Rafiq et al., 2009 [70] Longitudinal study including 173
biopsy-proven NAFLD patients
HR of 6.7 for liver-related mortality for diabetic NAFLD patients when compared to non-diabetic
HR: Hazard Risk, RR: Relative Risk, MS: Metabolic Syndrome, NAFLD: Non Alcoholic Fatty Liver Disease, NASH: Non Alcoholic Steato-Hepatitis, NHANES: National Health and Nutrition Examination Survey
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