Elsevier

Metabolism

Volume 111, Supplement, October 2020, 154183
Metabolism

Established and emerging factors affecting the progression of nonalcoholic fatty liver disease

https://doi.org/10.1016/j.metabol.2020.154183Get rights and content

Highlights

  • NAFLD affects approximately 25% of the population globally.

  • 5–10% of NAFLD patients develop cirrhosis-related complications with risk of death.

  • Hepatic fibrosis is the most important predictor of future complications.

  • Components of the metabolic syndrome and genetic factors are associated with risk for progression.

  • Lifestyle factors may also influence the risk of developing complications.

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease affecting approximately 25% of the global population. Although a majority of NAFLD patients will never experience liver-related symptoms it is estimated that 5–10% will develop cirrhosis-related complications with risk of death or need for liver transplantation. NAFLD is closely associated with cardiovascular disease and components of the metabolic syndrome. However, NAFLD is not uncommon in lean individuals and may in these subjects represent a different entity with separate pathophysiological mechanisms involved implying a higher risk for development of end-stage liver disease. There is considerable fluctuation in the histopathological course of NAFLD that may partly be attributed to lifestyle factors and dietary composition. Nutrients such as fructose, monounsaturated fatty acids, and trans-fatty acids may aggravate NAFLD. Presence of type 2 diabetes mellitus seems to be the most important clinical predictor of liver-related morbidity and mortality in NAFLD. Apart from severity of the metabolic syndrome, genetic polymorphisms and environmental factors, such as moderate alcohol consumption, may explain the variation in histopathological and clinical outcome among NAFLD patients.

Introduction

Accumulation of lipids (steatosis) is the most common histopathologic hepatic alteration/finding globally. Hepatic triglyceride content can be accurately measured non-invasively with magnetic resonance imaging (MRI) [1,2]. Using a cut-off of 5.56% the prevalence of fatty liver among 2287 individuals included in the Dallas Heart Study was 31% [3] and the global prevalence has been estimated to 25% [4]. However, recently it was shown that more subjects with biopsy-proven steatosis could be diagnosed with MRI using a cut-off of 3% [5] which implies that the prevalence of fatty liver has probably been underestimated in previous studies.

In most individuals with hepatic steatosis the underlying cause is alcohol overconsumption or nonalcoholic fatty liver disease (NAFLD) [6]. NAFLD is considered the hepatic manifestation of the metabolic syndrome [7]. Initially NAFLD was considered a benign disease but these days the progressive potential of NAFLD is indisputable with 5–10% of subjects progressing to cirrhosis, end-stage liver disease, or hepatocellular carcinoma (HCC) [8]. Although the vast majority of NAFLD patients will never experience liver-related complications the high prevalence of NAFLD entails a significant public health issue with a high disease and economic burden and an increased need of liver transplantation [4].

NAFLD entails a spectrum of histopathological features that ranges from simple steatosis via establishment of inflammation and hepatocellular injury, i.e. nonalcoholic steatohepatitis (NASH), with or without fibrosis to cirrhosis with risk for development of end-stage liver disease or HCC [9,10]. An overview of the putative mechanisms involved in progression of NAFLD is shown in Fig. 1.

NAFLD is independently associated with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [[11], [12], [13], [14]]. Moreover, there is a collinearity between the severity of NAFLD and the components of the metabolic syndrome [[15], [16], [17]]. There is considerable fluctuation (i.e. progression and regression) of inflammation and fibrosis in NAFLD [18,19]. Particularly inflammation is highly dynamic, partly attributed to lifestyle factors that are difficult to completely account and control for in clinical trials. These include weight change, dietary composition and alcohol consumption. Although inflammation and hepatocellular injury, i.e. NASH, is considered a progressive form of NAFLD, follow-up studies have shown that hepatic fibrosis is the only independent predictor of clinical disease progression. There are 14 studies with paired biopsies in NAFLD [[20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]], including in total 996 patients with a median follow-up time ranging from 1.8 to 13.8 years (Table 1). Whether NASH precedes fibrosis in NAFLD is disputed. NASH correlates with presence of fibrosis, but this does not mean that NASH equals the prediction of fibrosis progression. To date, there is no objective evidence that presence of NASH at baseline, correlates with progression of fibrosis.

NAFLD patients with advanced fibrosis, as defined by stage 3–4 fibrosis, are at the highest risk of developing cirrhosis-related complications which may lead to liver transplantation or death [[34], [35], [36]]. The presence of advanced fibrosis, particularly cirrhosis, alters clinical management, including the possible initiation of surveillance for gastroesophageal varices and HCC, and consideration for treatment, including in the context of clinical trials. The burden of advanced fibrosis caused by NAFLD is projected to further increase in coming decades because of the rising prevalence of obesity [37]. Thus, this review will primarily focus on factors that have been shown to be associated with advanced fibrosis and/or affect fibrosis progression and the development of cirrhosis, end-stage liver disease, liver-related, and all-cause mortality in NAFLD (Fig. 2).

Section snippets

Obesity

Overweight and obesity increase the risk of incident NAFLD substantially. The prevalence of NAFLD increases exponentially with higher BMI and reaches 57% in men and 44% in women with BMI >35 kg/m2 when ultrasonography is used as diagnostic tool [38]. However, the sensitivity of ultrasonography is poor in low grade steatosis and thus the prevalence of NAFLD is probably even higher among obese subjects. Weight gain during young adulthood has been linked to future development of NAFLD [39].

Physical activity

In a cross-sectional Korean study, 139,056 middle-aged subjects underwent a health examination. Ultrasonography was used to diagnose NAFLD. Physical activity and sitting time were assessed with questionnaires. It was shown that prolonged sitting time and decreased physical activity level were positively associated with presence of NAFLD [60].

Increasing physical activity reduces intrahepatic triglyceride content and markers of hepatocellular injury in NAFLD patients independently of weight loss.

Type 2 diabetes and NAFLD

Since 1980 the age-standardized prevalence of T2DM in adults has increased substantially [66]. Among the components of the metabolic syndrome, T2DM seems to be the most important risk factor for having NAFLD (including NASH) and the most important clinical predictor of liver-related morbidity and mortality [[67], [68], [69], [70], [71]]. NAFLD is highly intertwined with T2DM, showing a bidirectional interaction [17,[72], [73], [74], [75]] but whether NAFLD precedes or succeeds T2DM has not been

Hypertension

In a meta-analysis [93] of 11 cohort studies (411 patients) assessing paired liver biopsy specimens to estimate the rates of fibrosis progression in NAFLD patients it was found that the presence of hypertension (odds ratio, 1.94; 95% CI, 1.00–3.74) at the time of baseline biopsy was associated with the development of progressive fibrosis.

Dyslipidemia

Hypertriglyceridemia is common in NAFLD patients [94]. Increased non-HDL cholesterol levels are associated with NASH, which correlates with presence of fibrosis and is likely to impact on risk of developing future end-stage liver disease [95,96]. However, when cirrhosis develops due to NAFLD the severity of the initial hyperlipidemia is often blunted because of hepatic biosynthetic failure [[97], [98], [99]], which parallels the disappearance of hepatic steatosis in NASH cirrhosis [100].

Sarcopenia

The strongest evidence to prove an independent association of NAFLD with sarcopenia, i.e., the loss of muscle mass and/or strength, was given in a study from Korea [101], in which this association was investigated in a large cohort of both obese and non-obese subjects (n = 15,132). A strong inverse relationship of the skeletal muscle index, a measure for muscle mass, with NAFLD was found. Accordingly, the prevalence of NAFLD in sarcopenic subjects was higher compared to non-sarcopenic subjects,

Age

Cross-sectional studies have demonstrated increasing age to be associated with more severe fibrosis in NAFLD. However, this may reflect the cumulative sum of metabolic exposures and longer duration of the disease in these populations [68,107,108]. In contrast, longitudinal studies have not consistently demonstrated age to impact the rate of fibrosis progression [93].

Alcohol

Alcohol overconsumption is the leading cause of end-stage liver disease in the Western world [109]. A putative crucial factor for the course of NAFLD is the impact of the quantity, pattern, and duration of alcohol consumption. Weekly alcohol consumption in excess of 210 g for men and 140 g for women is not compatible with diagnosis of NAFLD and excludes subjects from NAFLD research studies [110]. However, these arbitrary thresholds are based on levels above which the risk of cirrhosis is higher

Genome-wide association studies

Genome-wide association studies (GWAS) have identified numerous gene loci associated with NAFLD. The two most extensively studied polymorphisms are the patatin-like phospholipase domain-containing 3 (PNPLA3) and the transmembrane 6 superfamily 2 (TM6SF2). PNPLA3 codes for adiponutrin, a protein involved in lipid remodeling, and the gene product of TM6SF2 is involved in VLDL secretion from hepatocytes. Both genes have in several studies been associated with hepatic steatosis, NASH and advanced

Nutrients

In subjects with the metabolic syndrome excessive dietary carbohydrate and fat intake have been associated with the occurrence of insulin resistance as well as NAFLD [[166], [167], [168]]. Carbohydrates are important stimuli of hepatic de novo lipogenesis and are more likely to directly contribute to NAFLD than dietary fat [169]. Especially fructose has been linked as a major substrate for de novo hepatic lipogenesis and fibrosis [170]. Sugar-sweetened beverages increased liver and visceral fat

Conclusions

NAFLD is present in approximately 25% of the population globally. The natural history and impact on patient morbidity and mortality is widely divergent. Presence of high age, metabolic factors, such as T2DM, obesity, and hypertension, influence the severity of underlying liver histology and, thus, are likely to impact on risk of developing cirrhosis and HCC. Recent studies have emphasized the importance of fibrosis stage in determining future mortality risk. NAFLD patients with the

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interests

The authors have no competing interests to declare.

Acknowledgments

This article is published as part of a supplement sponsored by Gilead Sciences, Inc.

References (176)

  • V. Ratziu et al.

    Liver fibrosis in overweight patients

    Gastroenterology

    (2000)
  • S.A. Harrison et al.

    The natural history of nonalcoholic fatty liver disease: a clinical histopathological study

    Am J Gastroenterol

    (2003)
  • L.A. Adams et al.

    The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies

    J Hepatol

    (2005)
  • R. Pais et al.

    A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver

    J Hepatol

    (2013)
  • S. McPherson et al.

    Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management

    J Hepatol

    (2015)
  • H. Hagström et al.

    Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD

    J Hepatol

    (2017)
  • S. Zelber-Sagi et al.

    Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up

    J Hepatol

    (2012)
  • P. Mathurin et al.

    The evolution of severe steatosis after bariatric surgery is related to insulin resistance

    Gastroenterology

    (2006)
  • P. Mathurin et al.

    Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease

    Gastroenterology

    (2009)
  • H. Hagström et al.

    Overweight in late adolescence predicts development of severe liver disease later in life: a 39 years follow-up study

    J Hepatol

    (2016)
  • G.N. Ioannou et al.

    Is obesity a risk factor for cirrhosis-related death or hospitalization? A population-based cohort study

    Gastroenterology

    (2003)
  • S. Ryu et al.

    Relationship of sitting time and physical activity with non-alcoholic fatty liver disease

    J Hepatol

    (2015)
  • L.A. Orci et al.

    Exercise-based interventions for nonalcoholic fatty liver disease: a meta-analysis and meta-regression

    Clin Gastroenterol Hepatol

    (2016)
  • C.N. Katsagoni et al.

    Effects of lifestyle interventions on clinical characteristics of patients with non-alcoholic fatty liver disease: a meta-analysis

    Metabolism

    (2017)
  • C. Thoma et al.

    Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review

    J Hepatol

    (2012)
  • S.E. Keating et al.

    Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis

    J Hepatol

    (2012)
  • Z.M. Younossi et al.

    Nonalcoholic fatty liver disease in patients with type 2 diabetes

    Clin Gastroenterol Hepatol

    (2004)
  • P. Mofrad et al.

    Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values

    Hepatology

    (2003)
  • C.D. Williams et al.

    Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study

    Gastroenterology

    (2011)
  • K. Björkström et al.

    Histologic scores for fat and fibrosis associate with development of type 2 diabetes in patients with nonalcoholic fatty liver disease

    Clin Gastroenterol Hepatol

    (2017)
  • J. Ma et al.

    Bi-directional analysis between fatty liver and cardiovascular disease risk factors

    J Hepatol

    (2017)
  • Z.M. Younossi et al.

    The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis

    J Hepatol

    (2019)
  • J.M. Hazlehurst et al.

    Non-alcoholic fatty liver disease and diabetes

    Metabolism

    (2016)
  • M. Kingston et al.

    Diabetes mellitus in chronic active hepatitis and cirrhosis

    Gastroenterology

    (1984)
  • H.B. El-Serag et al.

    Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma

    Gastroenterology

    (2004)
  • J. Dyson et al.

    Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team

    J Hepatol

    (2014)
  • V.T. Männistö et al.

    Lipoprotein subclass metabolism in nonalcoholic steatohepatitis

    J Lipid Res

    (2014)
  • K.E. Corey et al.

    Non-high-density lipoprotein cholesterol as a biomarker for nonalcoholic steatohepatitis

    Clin Gastroenterol Hepatol

    (2012)
  • P. Loria et al.

    Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology

    Atherosclerosis

    (2014)
  • S.B. Reeder et al.

    Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy

    J Magn Reson Imaging

    (2011)
  • J.D. Browning et al.

    Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity

    Hepatology

    (2004)
  • Z.M. Younossi et al.

    Global epidemiology of nonalcoholic fatty liver disease - meta-analytic assessment of prevalence, incidence, and outcomes

    Hepatology

    (2016)
  • P. Nasr et al.

    Using a 3% proton density fat fraction as a cut-off value increases sensitivity of detection of hepatic steatosis, based on results from histopathology analysis

    Gastroenterology

    (2017)
  • Z.M. Younossi et al.

    Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008

    Clin Gastroenterol Hepatol

    (2011)
  • G. Marchesini et al.

    Nonalcoholic fatty liver disease: a feature of the metabolic syndrome

    Diabetes

    (2001)
  • P. Nasr et al.

    Natural history of nonalcoholic fatty liver disease: a prospective follow-up study with serial biopsies

    Hepatol Commun

    (2017)
  • S. Wu et al.

    Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: a systematic review and meta-analysis

    Sci Rep

    (2016)
  • G. Targher et al.

    Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease

    N Engl J Med

    (2010)
  • C.D. Byrne et al.

    Metabolic disturbances in non-alcoholic fatty liver disease

    Clin Sci (Lond)

    (2009)
  • S.L. Friedman et al.

    A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

    Hepatology

    (2018)
  • Cited by (46)

    • Polycystic ovary syndrome and nonalcoholic fatty liver disease

      2022, Polycystic Ovary Syndrome: Challenging Issues in the Modern Era of Individualized Medicine
    View all citing articles on Scopus
    View full text