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Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical outcomes. T2DM is also one of the strongest risk factors for the faster progression of NAFLD to nonalcoholic steatohepatitis, advanced fibrosis or cirrhosis. However, the link between NAFLD and T2DM is more complex than previously believed. Strong evidence indicates that NAFLD is associated with an approximate twofold higher risk of developing T2DM, irrespective of obesity and other common metabolic risk factors. This risk parallels the severity of NAFLD, such that patients with more advanced stages of liver fibrosis are at increased risk of incident T2DM. In addition, the improvement or resolution of NAFLD (on ultrasonography) is associated with a reduction of T2DM risk, adding weight to causality and suggesting that liver-focused treatments might reduce the risk of developing T2DM. This Review describes the evidence of an association and causal link between NAFLD and T2DM, discusses the putative pathophysiological mechanisms linking NAFLD to T2DM and summarizes the current pharmacological treatments for NAFLD or T2DM that might benefit or adversely affect the risk of T2DM or NAFLD progression. This Review describes the evidence of an association and causal link between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), discusses their pathophysiological mechanisms and summarizes the pharmacological treatments that might benefit or adversely affect the risk of T2DM or NAFLD progression. Key points An updated meta-analysis of 33 observational studies showed that nonalcoholic fatty liver disease (NAFLD) is associated with an approximate doubled risk of type 2 diabetes mellitus (T2DM), irrespective of obesity and other metabolic risk factors. Patients with more advanced stages of liver fibrosis are at increased risk of T2DM; some observational studies have shown that improvement or resolution of NAFLD on ultrasonography is closely associated with a reduction of diabetes risk. NAFLD exacerbates hepatic and peripheral insulin resistance, predisposes to atherogenic dyslipidaemia and causes the systemic release of pro-inflammatory cytokines and hepatokines that can promote the development of T2DM. Treatment of NAFLD and T2DM is based on lifestyle modifications aiming at substantial weight loss in individuals with overweight or obesity. Although no pharmacotherapy is currently approved for NAFLD, some antihyperglycaemic drugs, such as pioglitazone, glucagon-like peptide 1 analogues and sodium–glucose cotransporter 2 inhibitors, have some efficacy. Multiple investigational compounds for NAFLD treatment, including modulators of bile acid and lipid metabolism, are in phase II and phase III randomized controlled trials.

Non-alcoholic fatty liver disease (NAFLD) is a public health problem, affecting up to a third of the world’s adult population. Several cohort studies have consistently documented that NAFLD (especially in its more advanced forms) is associated with a higher risk of all-cause mortality and that the leading causes of death among patients with NAFLD are cardiovascular diseases (CVDs), followed by extrahepatic malignancies and liver-related complications. A growing body of evidence also indicates that NAFLD is strongly associated with an increased risk of major CVD events and other cardiac complications (ie, cardiomyopathy, cardiac valvular calcification and cardiac arrhythmias), independently of traditional cardiovascular risk factors. This narrative review provides an overview of the literature on: (1) the evidence for an association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications, (2) the putative pathophysiological mechanisms linking NAFLD to CVD and other cardiac complications and (3) the current pharmacological treatments for NAFLD that might also benefit or adversely affect risk of CVD.

Nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus are common diseases that often coexist and might act synergistically to increase the risk of hepatic and extra-hepatic clinical outcomes. NAFLD affects up to 70-80% of patients with type 2 diabetes mellitus and up to 30-40% of adults with type 1 diabetes mellitus. The coexistence of NAFLD and diabetes mellitus increases the risk of developing not only the more severe forms of NAFLD but also chronic vascular complications of diabetes mellitus. Indeed, substantial evidence links NAFLD with an increased risk of developing cardiovascular disease and other cardiac and arrhythmic complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus. NAFLD is also associated with an increased risk of developing microvascular diabetic complications, especially chronic kidney disease. This Review focuses on the strong association between NAFLD and the risk of chronic vascular complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus, thereby promoting an increased awareness of the extra-hepatic implications of this increasingly prevalent and burdensome liver disease. We also discuss the putative underlying mechanisms by which NAFLD contributes to vascular diseases, as well as the emerging role of changes in the gut microbiota (dysbiosis) in the pathogenesis of NAFLD and associated vascular diseases.

Key Points Accumulating evidence indicates that the presence and severity of non-alcoholic fatty liver disease (NAFLD) is strongly associated with an increased prevalence of chronic kidney disease (CKD) The presence and severity of NAFLD predicts the development of incident CKD, independent of traditional cardiorenal risk factors Evidence suggests that NAFLD exacerbates insulin resistance, predisposes to atherogenic dyslipidaemia, and causes the release of proinflammatory, procoagulant, pro-oxidant and profibrogenic mediators that are important in the pathophysiology of CKD Despite the growing evidence linking NAFLD to CKD, whether a causal association exists has not been definitively established These findings call for a more active and systematic search for NAFLD in patients with CKD with a view to potential earlier treatment Non-alcoholic fatty liver disease (NAFLD) not only affects the liver, but can also increase the risk of developing extra-hepatic diseases, including type 2 diabetes mellitus, cardiovascular disease and chronic kidney disease (CKD). Here, Targher and Byrne discuss the epidemiologic and mechanistic evidence of a pathogenic link between NAFLD and CKD. Non-alcoholic fatty liver disease (NAFLD) is caused by an accumulation of fat in the liver; the condition can progress over time to increase the risk of developing cirrhosis, end-stage liver disease and hepatocellular carcinoma. The prevalence of NAFLD is increasing rapidly owing to the global epidemics of obesity and type 2 diabetes mellitus (T2DM), and NAFLD has been predicted to become the most important indication for liver transplantation over the next decade. It is now increasingly clear that NAFLD not only affects the liver but can also increase the risk of developing extra-hepatic diseases, including T2DM, cardiovascular disease and chronic kidney disease (CKD), which have a considerable impact on health-care resources. Accumulating evidence indicates that NAFLD exacerbates insulin resistance, predisposes to atherogenic dyslipidaemia and releases a variety of proinflammatory factors, prothrombotic factors and profibrogenic molecules that can promote vascular and renal damage. Furthermore, communication or 'crosstalk' between affected organs or tissues in these diseases has the potential to further harm function and worsen patient outcomes, and increasing amounts of evidence point to a strong association between NAFLD and CKD. Whether a causal relationship between NAFLD and CKD exists remains to be definitively established.

ObjectiveFollow-up studies have shown that non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of incident diabetes, but currently, it is uncertain whether this risk changes with increasing severity of NAFLD. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident diabetes.DesignWe systematically searched PubMed, Scopus and Web of Science databases from January 2000 to June 2020 using predefined keywords to identify observational studies with a follow-up duration of at least 1 year, in which NAFLD was diagnosed by imaging techniques or biopsy. Meta-analysis was performed using random-effects modelling.Results33 studies with 501 022 individuals (30.8% with NAFLD) and 27 953 cases of incident diabetes over a median of 5 years (IQR: 4.0–19 years) were included. Patients with NAFLD had a higher risk of incident diabetes than those without NAFLD (n=26 studies; random-effects HR 2.19, 95% CI 1.93 to 2.48; I 2 =91.2%). Patients with more ‘severe’ NAFLD were also more likely to develop incident diabetes (n=9 studies; random-effects HR 2.69, 95% CI 2.08 to 3.49; I 2 =69%). This risk markedly increased across the severity of liver fibrosis (n=5 studies; random-effects HR 3.42, 95% CI 2.29 to 5.11; I 2=44.6%). All risks were independent of age, sex, adiposity measures and other common metabolic risk factors. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias.ConclusionThis updated meta-analysis shows that NAFLD is associated with a ~2.2-fold increased risk of incident diabetes. This risk parallels the underlying severity of NAFLD.

Advances have been made in the field of nonalcoholic fatty liver disease in 2019. One paper highlights the role of gut microbiota in hepatocellular carcinoma (HCC) pathogenesis, another presents a noninvasive algorithm for detecting advanced liver fibrosis and another suggests a potential novel approach to treating nonalcoholic steatohepatitis and suppressing HCC development.Key advancesThe altered gut microbiota profile is associated with systemic inflammation in patients with nonalcoholic fatty liver disease (NAFLD)-related cirrhosis who have hepatocellular carcinoma2Measuring blood markers related to type III collagen might be useful for staging liver fibrosis in both adults and children with NAFLD5,6Platelet count, activation and aggregation are increased in nonalcoholic steatohepatitis (NASH) and antiplatelet therapies should be tested10

ObjectiveWe performed a meta-analysis of observational studies to quantify the magnitude of the association between non-alcoholic fatty liver disease (NAFLD) and risk of extrahepatic cancers.DesignWe systematically searched PubMed, Scopus and Web of Science databases from the inception date to 30 December 2020 using predefined keywords to identify observational cohort studies conducted in individuals, in which NAFLD was diagnosed by imaging techniques or International Classification of Diseases codes. No studies with biopsy-proven NAFLD were available for the analysis. Meta-analysis was performed using random-effects modelling.ResultsWe included 10 cohort studies with 182 202 middle-aged individuals (24.8% with NAFLD) and 8485 incident cases of extrahepatic cancers at different sites over a median follow-up of 5.8 years. NAFLD was significantly associated with a nearly 1.5-fold to twofold increased risk of developing GI cancers (oesophagus, stomach, pancreas or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2-fold to 1.5-fold increased risk of developing lung, breast, gynaecological or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias.ConclusionThis large meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). Further research is required to decipher the complex link between NAFLD and cancer development.

ObjectiveStudies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD.DesignWe systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling.Results13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2, with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; I 2 =60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias.ConclusionThis large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.

NAFLD is becoming much more common, and will soon be the major underlying aetiology for liver transplantation. This article discusses the evidence that NAFLD is a multisystem disease and outlines the factors that determine interindividual variation in the development and progression of NAFLD. NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease). Key Points NAFLD is a spectrum of progressive liver disease that includes steatosis, NASH, fibrosis, cirrhosis and hepatocellular carcinoma NAFLD is a common and underdiagnosed condition that is strongly associated with features of the metabolic syndrome, particularly abdominal obesity and type 2 diabetes mellitus NAFLD, and especially NASH, are associated with an increased risk of morbidity and mortality related to the liver and cardiovascular system NAFLD is also associated with an increased risk of developing type 2 diabetes mellitus Considerable interindividual variation exists in the severity of NAFLD and the risk of morbidity and mortality that might be influenced by a combination of genetic and environmental factors

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in children, paralleling the increasing prevalence of obesity worldwide. The pathogenesis of paediatric NAFLD is not fully understood, but it is known that obesity, nutrition, lifestyle variables, genetic and epigenetic factors may be causally involved in the development of this common metabolic liver disease. In particular, obesity and nutrition are among the strongest risk factors for paediatric NAFLD, which may exert their adverse hepatic effects already before birth. Excess energy intake induces hypertrophy and hyperplasia of adipose tissue with subsequent development of systemic insulin resistance, which is another important risk factor for NAFLD. Diet composition and in particular simple carbohydrate intake (especially high fructose intake) may promote the development of NAFLD, whereas non-digestible carbohydrates (dietary fiber), by affecting gut microbiota, may favour the integrity of gut wall and reduce inflammation, opposing this process. Saturated fat intake may also promote NAFLD development, whereas unsaturated fat intake has some beneficial effects. Protein intake does not seem to affect the development of NAFLD, but further investigation is needed. In conclusion, lifestyle modifications to induce weight loss, through diet and physical activity, remain the mainstay of treatment for paediatric NAFLD. The use of dietary supplements, such as omega-3 fatty acids and probiotics, needs further study before recommendation.