Extrahepatic complications of nonalcoholic fatty liver... : Hepatology (original) (raw)
Abbreviations ALT; alanine transaminase; AST; aspartate transaminase; ATP III; adult treatment panel III; BMD; bone mass density; BMI; body mass index; BP; blood pressure; CI; confidence interval; CHD; coronary heart disease; CKD; chronic kidney disease; CLD; chronic liver disease; CRP; C-reactive protein; CVD; cardiovascular disease; EDTA; ethylenediamine tetraacetic acid; eGFR; estimated glomerular filtration rate; FGF-21; fibroblast growth factor 21; FRS; Framingham Risk Score; GGT; gamma glutamyltransferase; HbA1c; glycosylated hemoglobin 1c; HCC; hepatocellular carcinoma; HDL; high density lipoprotein; HOMA-IR; homeostatic model assessment-insulin resistance; HR; hazard ratio; IGF-1; insulin growth factor 1; IGT; impaired glucose tolerance; IL-6; interleukin 6; LDL; low density lipoprotein; MDRD; Modification of Diet in Renal Disease; MRS; magnetic resonance spectroscopy; NAFLD; nonalcoholic fatty liver disease; NASH; nonalcoholic steatohepatitis; NEFA; nonesterified fatty acid; NHANES; National Health and Nutrition Survey; OGTT; oral glucose tolerance test; OR; odds ratio; OPN; osteopontin; OSAS; Obstructive Sleep Apnea Syndrome; PAI-1; plasminogen activator inhibitor 1; PCOS; polycystic ovarian syndrome; RBP-4; retinol binding protein 4; RR; relative risk; T2DM; type 2 diabetes mellitus; TG; triglycerides; TNFα; tumour necrosis factor alpha; TSH; thyroid stimulating hormone; ULN; upper limit of normal; USS; ultrasound; VEGF; vascular endothelial growth factor; VLDL; very low density lipoprotein; vWF; von willebrand factor; WC. waist circumference.
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological entity that encompasses simple hepatic steatosis, necroinflammation with varying stages of fibrosis known as nonalcoholic steatohepatitis (NASH), and cirrhosis. It is strongly associated with the metabolic syndrome and may be the leading cause of chronic liver disease worldwide, reaching epidemic proportions in many high-income countries.1,2 Compared with the general population of similar age and gender, NAFLD increases the risk of endstage liver disease, hepatocellular carcinoma (HCC),3 as well as liver-related and all-cause mortality.4-7 There is general consensus, however, that the majority of deaths among individuals with NAFLD are attributed to cardiovascular disease and malignancy.2,6,8 Unsurprisingly, these observations have fuelled concern that NAFLD, either independently or in combination with other metabolic risk factors, could pose an important risk factor or driver of extrahepatic diseases.
To date, most studies have sought to evaluate associations between NAFLD and cardiovascular disease (CVD), type 2 diabetes (T2DM), chronic kidney disease (CKD), and colorectal cancer. It is important that both physicians and patients are aware of these potential extrahepatic associations, as many of the tools used for screening are readily available in clinical practice (i.e., glycosylated hemoglobin 1c [HbA1c], urinalysis), and if disease is identified early, be appropriately managed with standard medical therapies. Herein we review the extrahepatic diseases most strongly associated with NAFLD, highlighting recent key studies. We focus on the incident risk of extrahepatic diseases and the extent that the risk is independent of features of the metabolic syndrome and patient characteristics that commonly coexist in adult patients with NAFLD. Finally, we propose future studies necessary to strengthen our understanding of these risks, and present a possible screening strategy.
Cardiovascular Disease
CVD is the commonest cause of death globally, with greater than 75% of events being attributed to coronary heart disease (CHD) and stroke. The risks of CVD can be mitigated by addressing recognized risk factors, such as smoking cessation, having a healthy diet, increasing physical activity, and aggressive management of comorbidities including T2DM, dyslipidemia, and hypertension.
CVD and NAFLD share common risk factors, including insulin resistance (peripheral and hepatic), central adiposity, and the risk factors listed above.9,10 Cumulative studies using subclinical markers of CVD show that patients with biopsy-proven NAFLD, and in particular NASH, exhibit endothelial dysfunction,11 impaired left ventricular diastolic dysfunction/energy metabolism,12-14 increased carotid intima-media thickness,15,16 and show a higher prevalence of carotid atherosclerotic plaques compared with patients without NAFLD.17 Three large cross-sectional studies (total >20,000 participants) from East Asia reported that ultrasound (USS)-defined NAFLD is independently associated (after adjustment of other CHD risk factors) with the presence of coronary artery disease.18-20 In both Korean studies18,19 computer tomography was used to calculate coronary artery calcium scores (subclinical marker of atherosclerosis) as part of routine health checks, while Wong et al.20 from China performed coronary angiography in over 600 patients attending hospital. Collectively, investigators found that individuals with NAFLD are at greater risk of having concomitant CVD than those without NAFLD. These observations were supported by baseline data from the Valpolicella Heart Diabetes Study of 2,392 Italian participants, which highlighted a higher prevalence of CVD (CHD, stroke, and peripheral vascular disease) in patients with coexisting T2DM and NAFLD (age-/sex-adjusted prevalence ˜50%) compared to those without NAFLD (prevalence ˜35%).21 Importantly, significant association between NAFLD and CVD remained, even after adjustment for classical CVD risk factors, medications, glycemic control, and the metabolic syndrome (odds ratio [OR] ˜1.6).21 Similar findings were reported in larger, population-based studies in the U.S. (National Health and Nutrition Survey; NHANES III-1998 to 1994)22 and China.23
A large number of retrospective4,5,7,24-26 and prospective20,22,27-33 studies using hard endpoints of CVD (i.e., myocardial infarction, ischemic stroke, cerebral hemorrhage) have assessed the risk of incident CVD and/or CVD-related mortality in patients with USS- and/or biopsy-proven NAFLD (Table 1).34
Prospective and Retrospective Studies of the Risk of CVD Morbidity and Mortality in Patients With NAFLD (Defined by Imaging or Biopsy)
Continued
Retrospective Studies
Over 6 to 18 years of follow-up, several hospital-based studies have reported that patients with biopsy-proven NAFLD (or USS-proven in one study) have a significantly higher all-cause and CVD-related mortality than the general population.5,7,25,26 Significant differences in overall mortality rates were only detected when patients with NASH, rather than those with simple steatosis, were compared with the general population.5,7,26,35 It should be noted, however, that only all-cause mortality was significantly powered in these studies (i.e., retrospective design and small cohort size), and adjustment for potential confounding metabolic factors was not performed.
Prospective Studies
Prospective studies (Table 1) to date have utilized USS (±liver enzymes) to define NAFLD, as the invasiveness and expense of liver biopsy markedly limit its use in nonselected populations. Importantly, the majority of these studies have statistically adjusted for potential confounding cardiovascular risk factors, thus allowing for the determination of the true independent association between NAFLD and CVD endpoints.
Using age and sex matched controls from a diabetes outpatient department, Targher et al.28 reported that USS-defined NAFLD is independently associated with a risk of incident nonfatal CVD events (hazard ratio [HR] 1.87) and CVD mortality over 6.5 years follow-up. Large community-based studies with similar periods of follow-up, from Japan,29 Germany,30 and, more recently, China,32 have reported comparable findings. In contrast, a recent analysis of the U.S. NHANES III database of over 11,000 U.S. participants found that NAFLD is not associated with an increased risk of all-cause and CVD mortality over 14 years.22,31 This study, however, was limited by the inclusion of individuals with mild hepatic steatosis within the control arm and sole reliance on USS to exclude hepatic steatosis. USS lacks sensitivity in the morbidly obese (24% of cohort) and when the degree of liver fat infiltration is less than 33% of hepatic content.36 Furthermore, a loss of hepatic fat occurs during disease progression to advanced fibrosis.37 In combination, these factors could have accounted for the apparent absence of a demonstrable mortality risk in the NHANES study.31
Interestingly, the latest analysis of the same NHANES cohort found that patients with NAFLD and advanced fibrosis, as defined by noninvasive scoring systems (i.e., NAFLD Fibrosis Score, the aspartate aminotransferase to platelet ratio index, Fib-4), are indeed at increased risk of CVD death (HR range 2.5-3.5, depending on the score used) after adjustment for other common risk factors.2
Take-Home Message
The aggregate evidence provides strong evidence that individuals with NAFLD are at increased “independent” risk of developing CVD. The risk of CVD mortality may be greater in subgroups of subjects with NASH and advanced fibrosis, compared to those with simple steatosis
Future Studies
Additional long-term prospective studies in well-defined NAFLD, and in particular NASH ± fibrosis, are necessary to assess the independent risks of premature CVD and related death. Understanding how modification of the underlying liver disease progression may affect CVD outcome is important.
Type 2 Diabetes (T2DM)
By 2030, the estimated prevalence of diabetes worldwide is expected to exceed 500 million people, of which 90% will be attributed to T2DM due to the aging population and rapidly rising numbers of obesity. Of concern, T2DM is associated with a 2-fold risk of chronic liver disease secondary to NAFLD, cirrhosis, and HCC.3 The relationship between NAFLD and T2DM, however, is complex. A diagnosis of NAFLD (mainly on imaging) in patients with established T2DM is strongly associated poor glycemic control,21 proliferative retinopathy,38 increased prevalence of cardiac/kidney disease,21 and a 2.2-fold increase in all-cause mortality compared to patients without NAFLD.39
Studies Using Liver Enzymes
Over the last 10 years, several large population-based cohort studies have shown that elevated serum alanine aminotransferase (ALT) and/or γ-glutamyltransferase (GGT) are independently associated with an increased incidence of T2DM after adjustment for age, body mass index (BMI), smoking, and other key risk factors of T2DM.40-46 In 2009, Fraser et al.47 pooled data from 18 prospective population-based studies investigating the association of ALT (three studies; 8,650 participants), GGT (four studies; 36,115 participants), or both ALT and GGT (11 studies; 28,076 participants) with incident T2DM. Mild to moderately elevated ALT and GGT predicted incident T2DM, with the risk of developing T2DM increasing by 85% and 92%, respectively, for a 1.0 IU/L increase in Log ALT and Log GGT.47 Despite uniform adjustments for the common risk factors of T2DM, including age, sex, BMI, alcohol intake, and smoking in all studies included in the meta-analysis, the strengths of their findings were limited by the inconsistent adjustment for homeostatic model assessment-insulin resistance (HOMA-IR) and fasting plasma glucose. Despite NAFLD being the commonest cause of liver enzyme abnormalities,1 the lack of USS / detailed liver screen and the low specificity of liver enzymes (particularly GGT) limits the translation of many of these studies to the NAFLD population. In addition, patients with coexisting NAFLD and T2DM can have normal liver enzymes.
Studies Using USS to Diagnose NAFLD
Musso et al.6 reported similar findings in their meta-analysis, in which they included three studies that used USS to define NAFLD. They described an adjusted OR 3.5 for the risk of new-onset T2DM. In concordance with these findings, seven large Asian community-based studies with USS at baseline found that NAFLD is independently associated with incident T2DM (adjusted OR 2.05-4.6048-51; HR 1.33-5.50).52-54 The reported frequencies of incident T2DM ranged from 2.5% to 20.3% in NAFLD subjects and 0.5% to 5.2% in non-NAFLD subjects, over a minimum follow-up period of 4 years48-54 (Table 2). The majority of these studies (2007-present) defined T2DM by fasting glucose ≥7.0 mmol/L, clinical history or diabetes drug therapy, but were inconsistent in excluding impaired glucose tolerance at baseline and in adjusting for potential confounders such as family history of T2DM and measures of central adiposity. In general, the magnitude of risk of incident DM with NAFLD is attenuated after adjusting for potential metabolic confounding variables. Surprisingly, Okamoto et al.55 found no association between NAFLD and incident hyperglycemia (fasting plasma glucose ≥6.1 mmol/L, HbA1c ≥6.5%), even after adjusting for age, BMI, family history, alcohol consumption, and glycemic control. This could be potentially explained by a selection bias, as all study subjects had received medical consultation and advice, which could have led to changes in behavior (positive lifestyle modifications) and, hence, an underestimation of the natural progression to T2DM. In support, a recent Korean study by Sung et al.56 highlighted that resolution of fatty liver by USS resets the risk of incident T2DM to that of a non-NAFLD population (OR 0.95).
Prospective and Retrospective Studies of the Risk of Incident Type 2 Diabetes in Patients With NAFLD (Defined by Imaging or Biopsy Only)
Continued
Continued
Liver Biopsy-Proven NAFLD (or Staged)
Currently there is a lack of study investigating histological-defined NAFLD as a predictor of incident T2DM. Although several studies on long-term mortality included patients with biopsy-proven NAFLD,5,7,26 only Ekstedt et al.'s5 retrospective study of 129 Swedish patients reported rates of new-onset T2DM. Over a 14-year follow-up, 78% of biopsy-proven NAFLD patients with abnormal liver enzymes (at baseline) were noted to have developed impaired glucose tolerance (IGT) (20%) or T2DM (58%).5 Unfortunately, fasting plasma glucose or HbA1c were not sampled at baseline; therefore, the progression rate towards T2DM may have been overestimated.
Take-Home Message
USS-defined NAFLD is associated with a 2- to 5-fold risk of developing T2DM after adjustment of several lifestyle and metabolic confounders.
Future Studies
Validation of the risk of NAFLD for incident T2DM in non-Asian populations is required. Future studies should assess whether the presence of NASH ± fibrosis is associated with greater risk of incident T2DM than simple steatosis. It is essential that these studies robustly rule out IGT and T2DM at study entry (i.e., HbA1c <6.0% or 42 mmols/mol) and adjust for family history of T2DM and baseline levels of insulin resistance.
Kidney Disease
CKD is a leading public health concern, with hypertension and diabetes being two major risk factors.57,58 The prevalence of CKD now stands at 4.3%-13% in the general population,59,60 but is expected to increase by 7% annually.61 The high morbidity, mortality, and healthcare costs associated with CKD have led to investigators attempting to identify new modifiable risk factors. This is evident by an increasing number of studies evaluating the hypothesis that NAFLD may be an independent risk factor for CKD (Table 3).38,46,62-77
Prospective and Retrospective/Cross-Sectional Studies of the Risk of Developing Chronic Kidney Disease in Patients With NAFLD (Including Elevated Liver Enzymes, USS- and/or Biopsy-Defined)
Continued
Continued
Continued
Retrospective Studies
In several large cross-sectional population-based46,62-72 and hospital-based studies64-70 the prevalence of CKD (defined as estimated glomerular filtration rate [eGFR] ≤60 ml/min/1.73 m2 or overt proteinuria) and/or microalbuminuria (urinary albumin/creatinine ≥30 mg/g) were significantly higher among patients with NAFLD compared to those without disease. The prevalence of CKD in NAFLD patients ranged from 21% to 54% compared to 3.7%-24.2% in non-NAFLD patients,65,66,68,70 with the highest rates being noted by Targher et al.68 in an outpatient-based study of 343 type 1 diabetics. Importantly, the majority of these studies reported that NAFLD was independently associated with CKD even after adjusting for traditional risk factors including age, sex, BMI, hypertension, diabetes (and duration), smoking, and hyperlipidemia.46,64-69 Although all studies used comparable criteria for diagnosing CKD, and made similar final conclusions, there was marked heterogeneity in terms of study population (outpatient; community setting), diabetes status (type 1; type 2; or nondiabetic), and how NAFLD was diagnosed (liver enzymes; ultrasonography; liver biopsy).
The marked differences in the outcomes of cross-sectional studies are exemplified by the recent findings from the U.S.-NHANES.46,71 After adjusting for alcohol consumption, viral hepatitis status, and other metabolic confounders, Targher et al.46 (NHANES 2001-2006 of 13,188 participants) reported that mildly elevated GGT is associated with increased prevalence of CKD, while Sirota et al.71 (NHANES 1988-1994 of 11,469 participants) found that USS-defined NAFLD was not associated with CKD after adjusting for components of the metabolic syndrome (adjusted OR 1.05). Community-based studies from Asia, on the other hand, reported a strong independent relationship between liver enzyme or USS-diagnosed NAFLD and CKD.62,72 Even though it is uniformly agreed that it would be unethical to perform liver biopsies in large epidemiological studies, the variance in these reports may be the result of the lack of histological confirmation (i.e., reliance on USS to exclude NAFLD), differences in disease staging, or genetic variance between populations.
To date, three hospital-based studies of adult CKD prevalence have used liver biopsies to diagnose NAFLD.64,65,70 The study by Targher et al.65 was one with a control arm, where 80 NASH patients were matched for age, sex, and BMI. NASH was found to be independently associated with a higher prevalence of CKD (25% versus 3.7%) after adjustment for CVD risk factors and insulin resistance. In another study, Yilmaz at al.64 described worsening eGFR and microalbuminuria in association with fibrosis stage. In summary, hospital-based studies with selected well-characterized NAFLD patients support the association between NAFLD and CKD; however, two large population-based studies are conflicting. The cross-sectional designs of the above studies preclude an assessment of causality.
Prospective Studies
Five large prospective studies evaluating the relationship between NAFLD and the development of CKD have been published (Table 3).73-77 Three studies defined NAFLD according to elevated GGT, and thus these need to be interpreted with caution due to the relative lack of diagnostic accuracy. In addition, there was marked heterogeneity in the duration of follow-up (range 3.2-19 years). With this in mind, four of the five studies suggest that NAFLD is independently associated with an increased risk of CKD and/or microalbuminuria (HR 1.49-4.38).73,75-77 All four studies excluded the presence of CKD at baseline (with normal eGFR and urine analysis) and, therefore, provide compelling support for NAFLD being an independent risk factor for incident CKD. The fifth study (data from 3,451 participants in the Framingham Offspring Heart Study), by comparison, did not find any significant association between GGT and CKD.74 This could be explained by the use of serum creatinine to define kidney function (rather than eGFR), and a cross-sectional analysis for CKD association (primary outcome measures were CVD endpoints).
Take-Home Message
NAFLD (in particular, biopsy-proven NASH) is associated with a greater prevalence of CKD (20% to 50% of patients). USS-defined NAFLD carries a 1.5- to 2-fold adjusted risk of incident CKD.
Future Studies
Further prospective population-based studies (including studies among different ethnic populations) are required to clarify the association between NAFLD and incident CKD. Prospective studies will also be needed to address whether NASH ± fibrosis (i.e., disease severity) is associated with an additional risk of progression from CKD stage 3 (eGFR 30-59 ml/min/1.73 m) to stage 5 (eGFR<15 or dialysis-dependent). The use of direct measurements of GFR (i.e., exogenous filtration markers, EDTA) should be encouraged, as the Modification of Diet in Renal Disease (MDRD) GFR equation may underestimate renal function in the morbidly obese.
Other Putative Extrahepatic Complications
Colorectal Cancer
Colorectal cancer is the third commonest cancer worldwide, with an estimated 1.2 million new cases diagnosed each year.78 The large geographical variation in incidence across the world is attributed to differences in diet, excess alcohol, smoking, limited physical activity, and rates of obesity and/or the metabolic syndrome.79,80 Recent studies from East Asia have attempted to address the question if patients with NAFLD (or NASH) are at risk of developing colorectal cancer, and whether this risk is independent of established risk factors for carcinogenesis (Table 4).
Retrospective/Cross-Sectional Studies of the Risk of Colorectal Adenomas and Cancer in Patients With NAFLD
Continued
In a retrospective cohort study of 5,517 Korean women, Lee et al.81 observed an adjusted 2-fold increase in the occurrence of adenomatous polyps and a 3-fold increase in colorectal cancer in patients with NAFLD (n = 833) compared with healthy individuals. Importantly, NAFLD did not influence prognosis of colorectal cancer or disease recurrence after treatment,81 consistent with findings from obesity studies.82 In the largest European study to date, Stadlmayr et al.83 reported an independent association of NAFLD with colorectal adenomas (OR 1.47) among Caucasians (n = 1,211), with men exhibiting increased risk of malignancy (1.6%). In contrast, a smaller U.S. study did not detect any significant difference in the prevalence of colorectal adenomas between biopsy-proven NAFLD (simple steatosis, n = 65; NASH, n = 29) and non-NAFLD controls.84 These discrepancies may be attributed to smaller sample size (94 versus >500 patients in previous studies81,83,85 and younger age of cohort (i.e., 55 versus 65 years in previous studies.83
Wong et al.86 were the first to use proton magnetic resonance spectroscopy (H-MRS) and liver biopsy to define NAFLD and NASH, respectively (Table 4). Consistent with findings from USS-based studies, individuals with NAFLD had a significantly higher prevalence of colorectal adenomas (34.7% versus 21.5%) and (pre-) cancerous lesions (18.6% versus 5.5%) than healthy individuals. Intriguingly, this association was most strongly observed in NASH patients and absent in those with simple steatosis. Even after adjusting for confounding demographic and metabolic risk factors, NASH patients were found to harbor a much higher risk of both benign (adjusted OR 4.89) and advanced colorectal lesions (adjusted OR 5.34).86 Importantly, the authors observed that a significant proportion of lesions had developed in the proximal colon and at a much younger age (i.e., below the age that is currently recommended for bowel screening). The cross-sectional design of previous studies, however, precludes any assessment of causality. Recently, Huang et al.87 reported on 1,522 asymptomatic individuals who had undergone (routine) metabolic phenotyping and had received paired colonoscopies (all index colonoscopies were negative). NAFLD on USS was found to be an independent risk factor for new adenoma development (adjusted OR 1.45) after adjustment for metabolic confounders, including smoking. The limited interval of only 2.4 years between colonoscopies likely explains the low number of advanced adenomas (6.7% >1 cm, villous or high-grade dysplasia) detected in their study, as most benign adenomas take 10 years to progress to malignancy (i.e., adenoma-carcinoma sequence).
Due to a paucity of well-designed, prospective studies (with a minimum of 10 years follow-up) a true causal relationship between NASH and colorectal cancer cannot be confirmed. Future studies will be needed to confirm risks of colorectal cancer (or advanced adenomas) among various NAFLD populations, and to evaluate the utility of earlier large bowel screening (i.e., younger age) within this high-risk group of individuals.
Endocrinopathies
Several endocrinopathies have been associated with NAFLD, including growth hormone deficiency, hypogonadism, hypopitiutarism, polycystic ovarian syndrome, hypercortisolemia, and hypothyroidism.88 However, data in this field remain limited. Outside case series/retrospective cohort studies,89-99 no prospective study has evaluated the temporal relationship between NAFLD and these conditions, and the majority of studies have simply evaluated the prevalence and/or severity of NAFLD as a consequence of endocrinopathies.93,95,97
Hypothyroidism
Pagadala et al.89 found that biopsy-proven NAFLD is associated with a higher prevalence of hypothyroidism (21% versus 9.5%) compared with controls matched for age, sex, ethnicity, and BMI. Furthermore, they found a significant association of NASH and hypothyroidism, independent of T2DM, dyslipidemia, hypertension, and age. This was confirmed in a larger study of over 2,000 patients with hypothyroidism.90 Here the authors reported that overt and subclinical hypothyroidism (even in the range of normal thyroid stimulating hormone [TSH] levels) are both associated with NAFLD, independent of known metabolic risk factors.
Polycycstic Ovarian Syndrome (PCOS)
Studies suggest that patients with PCOS are at risk of NAFLD, independent of BMI.91 It is unclear, however, if the converse is true. Nevertheless, a cross-sectional study from Australia reported that 71% (10/14) of patients with USS- and/or biopsy-proven NAFLD (age 20-45 years) had PCOS,92 which is significantly higher than the average prevalence (6%-10%) of a matched American female population.
Obstructive Sleep Apnea Syndrome (OSAS)
A recent meta-analysis by Musso et al.100 of 18 cross-sectional studies (>2,000 participants) found 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). Although no studies to date have specifically examined the association between NAFLD and incident OSAS, symptoms of fatigue,101 daytime somnolence, and decreased quality of life often complicate NAFLD. OSAS is effectively managed by continuous positive airway pressure (CPAP). As such, Musso et al.100 recommended a two-stage approach in screening individuals with NAFLD for OSAS; namely, an Epworth Sleepiness Scale questionnaire followed by nocturnal monitoring in those who have high-risk scores. It should be noted, however, that screening questionnaires for OSAS have relatively poor sensitivity/specificity and have not been validated for use in patients with NAFLD.
Osteoporosis
Accumulating data supports an inverse relationship between obesity (and NAFLD) and low bone-mass density (BMD)/osteoporotic fracture. In a cross-sectional study of 481 postmenopausal Korean women, Moon et al.102 found that individuals with USS-defined NAFLD had an increased independent risk of lower BMD (using dual-energy x-ray absorptiometry). The significance remained after adjustment for BMI, smoking, age, alcohol, and the metabolic syndrome. This risk does not appear to be sex-specific, as a large Chinese questionnaire-based study (n > 7,000) recently reported that male patients with USS-defined NAFLD were 2.5 times more likely to have osteoporotic fractures than those without NAFLD.103 Of concern, these risks are not restricted to adults. Pardee et al.104 highlighted that children with biopsy-proven NAFLD (n = 36) (even as young as 10 years old) have a higher incidence of low BMD than age- and weight-matched controls (45% versus 0%). Furthermore, children with NASH had lower BMD than those with simple steatosis.
Proposed Mechanisms for the Development of Extrahepatic Complications
A detailed description of the mechanisms involved in the development of NAFLD-associated extrahepatic disease105-109 is beyond the scope of the current review. Overall, a clear understanding of the biological and genetic pathways involved remains lacking because of the close relationships between NAFLD and central obesity, dyslipidemia, and insulin resistance.
In brief, NAFLD is a proinflammatory condition characterized by a milieu of proinflammatory mediators, oxidative stress, insulin resistance, and lipotoxicity, which are intricately associated with the development of atheroma, hyperglycemia, and cancer. There is a growing interest in the role of (pathogenic) crosstalk between the liver and the adipose tissue105 (Fig. 1). The initial process in NAFLD development is postulated to be the result of the expansion of adipose tissue, secondary to putative environmental/dietary factors and underlying genetic susceptibility. The resultant adipose tissue (peripheral) insulin resistance and localized inflammation results in the release of lipotoxic metabolites into the systemic circulation. “Lipotoxicity,” in turn, activates a cascade of inflammatory changes (activation of macrophages/immune cells), cellular dysfunction, and necro-apoptosis in the liver and other organs (including the pancreas, muscle, and vascular beds). A cycle of hepatic and adipose tissue dysfunction occurs, and leads to development of a pathogenic milieu containing excessive levels of insulin, glucose, lipids (NEFA, LDL, VLDL), carcinogenic growth factors (IGF-1, VEGF), procoagulants (fibrinogen, PAI-1) and proinflammatory cytokines (e.g., CRP, IL-6, TNFα, osteopontin). The accumulation of hepatic steatosis and development of liver injury in NASH play a key role in increasing systemic levels of these pathogenic mediators. These pathogenic mediators may be directly secreted by hepatocytes or hepatic immune cells in response to lipotoxic insults or may indirectly increase mediators, for example, by increasing hepatic insulin resistance and, thus, resulting in systemic hyperinsulinemia. It is likely that these factors act in concert to promote the systemic abnormalities often seen in NAFLD-associated extrahepatic disease (CVD, T2DM, CKD, and malignancy) (Fig. 1).
(A-D) A schematic of the putative mechanisms for the development of extrahepatic disease in patients with NAFLD. The pathogenic crosstalk between the liver and the adipose tissue is thought to be the key factor that promotes the systemic abnormalities that occur with the development of common extrahepatic disease in NAFLD (A). The main mediators of such crosstalk include hormonal/cytokine signals from the liver (fetuin-A, FGF-21, RBP-4), and adipose tissue (adiponectin, leptin, TNF-α, IL-6). Dysregulation of this network promotes the development of atherosclerosis (B), T2DM (C), and malignancy (D). CRP, C-reactive protein; CKD, chronic kidney disease; CVD, cardiovascular disease; FGF-21, fibroblast growth factor 21; HDL, high density lipoprotein; IGF-1, insulin growth factor 1; IL-6, interleukin 6; LDL, low density lipoprotein; OPN, osteopontin; PAI-1, plasminogen activator inhibitor 1; RBP-4, retinol binding protein 4; T2DM, type 2 diabetes mellitus; TNFα, tumour necrosis factor; VEGF, vascular endothelial growth factor; VLDL, very low density lipoprotein; vWF, von Willebrand factor. The content of the figure is evidence summarized in detail elsewhere by Muhidin et al.,106 Cusi et al.,105 and Targher et al.107,108
Potential Screening for Extrahepatic Complications
Despite the cumulative evidence that NAFLD (specifically NASH and fibrosis) is an important risk factor for extrahepatic morbidity and death, current guidelines have yet to include any recommendations for screening these complications.110 As discussed above, adequately powered and prospective studies that use comparable inclusion criteria (i.e., NAFLD diagnosis) will be needed to confirm the incident risk of specific extrahepatic disease among different NAFLD populations. Future studies will also be necessary to evaluate the cost-effectiveness and risk:benefit balance of screening.
A proposed screening and clinical awareness strategy is described in Fig. 2 (views of authors only). Screening for T2DM in patients with NAFLD could be easily performed in routine clinics. The 2-hour oral glucose tolerance test (OGTT) has been shown to be more sensitive at detecting T2DM and impaired glucose tolerance than fasting blood glucose,111 but may be limited in some clinics due to time constraints. Due to recent changes in the World Health Organization (2011) recommendation, HbA1c measurements (greater than 6.5% or 48 mmols/mol) may be a more practical approach, but this awaits validation in NAFLD. Quantifying the short-term and lifetime risk of CVD in patients with NAFLD remains a challenge. Traditional CHD-risk calculators (i.e., Framingham Risk Score [FRS], Reynolds Risk Score) were originally designed to estimate the 10-year risk of CHD in individuals from the general population.112,113 The most frequently studied scoring system, the FRS, consists of age, gender, total cholesterol, HDL cholesterol, smoking status, and blood pressure. The failure of such scoring systems to incorporate important features of the metabolic syndrome (such as insulin resistance, obesity, and serum triglyceride levels), which are typical features of NAFLD and known risk factors for CVD, raises questions of their validity in NAFLD. Indeed, the FRS has been shown to underestimate the risk of CV disease in patients with the metabolic syndrome.114 In a most recent longitudinal study, the FRS was reported to demonstrate good predictive accuracy among NAFLD individuals.33 Nevertheless, the absence of a non-NAFLD control arm in this study, and the lack of any other prospective controlled study, limits the routine use of current CHD-risk scoring systems in NAFLD.
A schematic of potential screening modalities for extrahepatic diseases in patients with NAFLD. Patients with NAFLD should be screened for T2DM, CKD, and CVD. There is insufficient data at present to recommend routine screening for colorectal cancer (i.e., earlier screening), endocrinopathies (such as PCOS and hypothyroidism), sleep apnea, and osteoporosis (with the exception of individuals undergoing liver transplant assessment).115 Nevertheless, an increased awareness of the symptoms and/or early warning signs associated with NAFLD-associated extrahepatic conditions is warranted. BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HCC, hepatocellular carcinoma; T2DM, type 2 diabetes mellitus; USS, ultrasound. *Central adiposity measured by bio-impedance, waist circumference, or BMI (least representative).
Conclusions
Over the last decade it has become apparent that the clinical burden of NAFLD is not restricted to liver-related morbidity, but is in fact related to its independent associations with CVD, hyperglycemia, and malignancy. Despite the current evidence being restricted to observational and case-control studies, physicians and patients with NAFLD (in particular NASH ± fibrosis) should be aware of these increased risks. Greater emphasis should be placed on specific lifestyle modifications (i.e., smoking cessation, weight loss, physical activity) and aggressive pharmaceutical modification (i.e., lipid-lowering, insulin sensitizers) which would not only reduce the risk of progressive liver disease, but could also significantly impact extrahepatic and overall prognosis. Future studies should collect detailed risk profiles at baseline and extend the duration of follow-up beyond 10 years. Community-based studies, where liver biopsy is limited, should aim to use novel noninvasive modalities (e.g., transient elastography and serum biomarkers) to stage NAFLD. The impact of any NAFLD treatment on the risks and outcomes of extrahepatic disease should be assessed.
Acknowledgment
M.J.A. and W.K.S. are the guarantors and take full responsibility for the integrity of the data from inception to the published article. M.J.A. and W.K.S. performed the literature search and wrote the first draft of the article. All authors edited the article and approved the final version. M.J.A. is in receipt of a Wellcome Trust Clinical Research Fellowship.
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