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Abstract

  1. Top of page
  2. Abstract
  3. NAFLD and T2DM: Clear Evidence of an Association
  4. NAFLD and CVD Events: Evidence of an Association?
  5. Conclusions
  6. References

In recent years, a strong link has been established between nonalcoholic fatty liver disease (NAFLD) and the pathogenesis of type 2 diabetes mellitus. The potential role of NAFLD in cardiovascular disease (CVD) has also attracted interest. Published studies have tended to use biochemical and imaging surrogate markers of NAFLD, such as elevated gamma glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) and fatty liver on ultrasound, when investigating associations with incident CVD events. Positive associations between both baseline GGT and temporal change in GGT, as well as cardiovascular events and cardiovascular mortality independent of alcohol intake, have been reported in several prospective studies. However, adjustment for confounders is often incomplete, and there is scant evidence of improvement in cardiovascular risk prediction beyond established risk scores when incorporating such data. There also appears to be a strong and underrecognized age interaction, with associations between GGT and incident coronary heart disease (CHD) being strong in young individuals but relatively weak in the elderly. By contrast, ALT appears to be only weakly associated with incident CHD and may exhibit a U-shaped association with total mortality. Finally, although some studies have linked imaging-defined and biopsy-confirmed NAFLD with CVD risk, the evidence is inconsistent, with few incident events and/or insufficient potential confounders. Conclusion: A diagnosis of NAFLD is insufficient to consider patients as being at high risk for CVD. The presence of NAFLD should be a clear indication for diabetes screening, but cardiovascular risk screening should be performed with the use of existing risk calculators and should be guided by established cardiovascular risk factors. (HEPATOLOGY 2010;)

In recent years, there has been increased evidence of the role of nonalcoholic fatty liver disease (NAFLD) in the pathogenesis of type 2 diabetes mellitus (T2DM) and the potential role of liver enzymes and liver imaging in diabetes risk prediction.1, 2 The potential link between NAFLD and cardiovascular disease (CVD) is also attracting interest.3

If unfavorable changes in liver enzymes and liver fat content are associated with T2DM and hypertension,4 both of which are established risk factors for CVD,5-7 one might expect that elevations in liver enzymes and liver fat may signal increased CVD risk. However, the evidence has been inconsistent in this regard.

In this review, we examine data from recent prospective studies and meta-analyses investigating associations between both surrogate markers of NAFLD, namely the liver enzymes alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT) plus imaging-diagnosed NAFLD, and histologically diagnosed NAFLD with T2DM and cardiovascular disease.

NAFLD and T2DM: Clear Evidence of an Association

  1. Top of page
  2. Abstract
  3. NAFLD and T2DM: Clear Evidence of an Association
  4. NAFLD and CVD Events: Evidence of an Association?
  5. Conclusions
  6. References

There are plentiful data linking the liver enzymes ALT and GGT, both of which correlate with liver fat,8, 9 with incident diabetes. A recent meta-analysis showed that 1 U/L higher ALT (on a log scale) was associated with a hazard ratio (HR) of 3.05 (95% confidence interval [CI] 2.59-3.59, I2 = 26%) and 1 logged U/L higher GGT was associated with an HR of 2.56 (CI 2.31-2.84, I2 = 32%) in univariate age-adjusted analyses for the development of diabetes.1 In the model adjusted for major risk factors for diabetes, 1 logged U/L higher ALT yielded an HR of 1.85 (1.57-2.18, I2 = 19%, 14 comparisons) and 1 logged U/L higher GGT yielded an HR of 1.92 (CI 1.66-2.21, I2 = 55%, 18 comparisons). However, whereas there was adjustment for common risk factors for all studies (age, sex, body mass index/waist circumference, smoking, alcohol intake) included in the meta-analysis, other variables including physical activity, family history of diabetes, cholesterol, insulin sensitivity, and fasting plasma glucose were not consistently adjusted for. In the same meta-analysis, data on ultrasound-diagnosed nonalcoholic fatty liver disease (NAFLD) as a determinant of incident T2DM were examined from three Asian studies. The pooled relative risk comparing mild (defined as a slight diffuse increase in the fine echoes in the hepatic parenchyma with normal visualization of the diaphragm and intrahepatic vessel borders) versus no NAFLD for incident T2DM was 2.52 (95% CI 1.07-5.96), but there was evidence of considerable heterogeneity between studies (I2 = 90%).

There is, therefore, a relatively large and broadly consistent body of evidence establishing liver enzymes as predictors of diabetes, as well as other evidence to support correlations of ALT and GGT with liver fat content.10 Furthermore, mechanisms underpinning these associations are being determined as recently reviewed.11 The authors of this review suggested that excessive intrahepatic triglyceride represents an imbalance between complex interactions of metabolic events. However, there is uncertainty as to whether NAFLD causes metabolic dysfunction or whether metabolic dysfunction is responsible for intrahepatic triglyceride accumulation, or possibly both. Regardless, this work has helped establish fatty liver as a major player in the pathogenesis of T2DM.12 There is preliminary evidence that liver enzymes can improve prediction of diabetes beyond established predictors, albeit modestly so.13 These observations clearly suggest that patients with NAFLD or raised enzymes indicative of NAFLD without known diabetes should be screened for diabetes and given appropriate lifestyle advice, including increased physical activity and fiber intake, two strategies known to lower diabetes risk, liver fat levels, and related surrogate markers.14-16

NAFLD and CVD Events: Evidence of an Association?

  1. Top of page
  2. Abstract
  3. NAFLD and T2DM: Clear Evidence of an Association
  4. NAFLD and CVD Events: Evidence of an Association?
  5. Conclusions
  6. References

Published data linking NAFLD with incident CVD events are sparse, particularly in relation to milder and asymptomatic forms of NAFLD (such as simple or bland steatosis). Although a recent review concluded that NAFLD is independently associated with increased CVD risk based on prospective data from 13 studies,3 the strength of the evidence is modest.

Associations Between Liver Enzymes and CVD

GGT and CVD.

Associations between GGT and the incidence of cardiovascular events independent of alcohol intake have been described in several prospective studies, as summarized in a recent meta-analysis17 (Table 1). In the entire meta-analysis cohort, with data pooled from 10 studies (albeit variably adjusted), 1 U/L higher GGT (on a log scale) was associated with a 20% increase in the risk of coronary heart disease (CHD), a 54% increase in the risk of stroke, and a 34% increase in the risk of CHD and stroke combined. Importantly, the adjusted HR was similar in the subgroup of nondrinkers. There was, however, marked heterogeneity in all of the analyses. Exclusion of the three studies from Asia partially attenuated the associations, but all remained significant.

Table 1. Fully Adjusted HRs for Incident CVD Outcomes for Combined and Nondrinkers of Alcohol Based on Data from 2007 Meta-analysis17
GGT and OutcomeNumber of Comparisons*Fully Adjusted HR (95% CI) of Incident CVD by ExposureHeterogeneity Between Studies, I2P Value
  • *

    The number of comparisons may not necessarily represent the number of studies, because some studies have been subdivided for analysis purposes.

1 U/L higher GGT, on log scale (outcome = CHD)101.20 (1.02-1.40)76%<0.001
1 U/L higher GGT, on log scale (outcome = stroke) only in nondrinkers81.33 (1.00-1.71)72%<0.001
1 U/L higher GGT, on log scale (outcome = stroke)91.54 (1.20-2.00)82%<0.001
1 U/L higher GGT, on log scale (outcome = stroke) only in nondrinkers41.76 (0.98-3.16)58%
1 U/L higher GGT, on log scale (outcome = any CVD)141.34 (1.22-1.48)73%<0.001
1 U/L higher GGT, on log scale (outcome = any CVD) only in nondrinkers41.45 (0.97-2.17)67%

Several other prospective studies examining the association between GGT and CVD events have since been published, and the results have been broadly comparable.18-20 Wannamethee et al.18 prospectively followed 6,997 males with no prior history of T2DM and CVD at baseline for 24 years. Baseline GGT was positively associated with increased risk of fatal (but not nonfatal) CHD events, major stroke events, and total CVD mortality after adjustment for established CVD risk factors. The adjusted relative risks comparing the highest GGT quartile to the lowest were 1.43 (95% CI 1.09-1.84) for fatal CHD events, 1.56 (95% CI 1.20-2.04) for stroke events, and 1.40 (95% CI 1.16-1.70) for CVD mortality. Strengths of this study included the large study sample, >99% completeness of follow-up, and exclusion of baseline diabetes.

Beyond associations with baseline measures, Strasak et al.19 followed 76,113 Austrian men for a median of 10.2 years and reported an association between longitudinal increases in GGT (from normal levels at baseline) and incident CVD mortality. Compared with men who had no or minimal change in GGT (−0.7-1.3 U/L) over 7 years, men in whom GGT increased beyond 9.2 U/L had an HR of 1.40 (95% CI 1.09-1.81) for total CVD mortality.

Evidence of Age Interaction

When the relationship between baseline GGT and incident CVD deaths is studied in more detail, it becomes apparent that age is relevant to observed associations. Figure 1 is derived from a recent nested case-control study by Lee et al.20 and shows clearly that higher GGT values within the normal range have a stronger association with incident CVD death in younger versus older subjects. In addition, this study also showed that the association of GGT with incident CVD death was significant only in the younger group. A similar interaction with age was described by Wannamethee et al.18 in their analyses of the British Regional Heart Study the HR for CVD death for the highest versus lowest quartile of GGT was 1.62 in men <50 years of age, 1.57 in men 50-55 years of age, and 1.18 in men >55 years of age at baseline (P = 0.01 for interaction). Similar age interactions were noted by Strasak et al.19 in their longitudinal analyses report.

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Figure 1. GGT and incident CVD deaths by age over and under 70 years. (Adapted from data in Lee et al., Eur J Cardiovasc Prev Rehabil 2009;16:16-20.) [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Can GGT Improve Prediction of CVD Events?

Despite the data linking GGT to incident CVD events, only one study has examined the question of prediction. Wannamethee et al.18 reported that whereas GGT improved prediction for CHD and CVD mortality, the area under the curve for CVD death showed only a slight increase from 0.725 (model with age) to 0.729 (model with age, Framingham risk score, and GGT) (P = 0.01). The same observation held true for prediction of fatal CHD.

ALT and CVD.

Although ALT appears at least as strongly linked to diabetes risk as GGT,1 its association with CVD event risk appears somewhat weaker. A liver enzyme–CVD meta-analysis by Fraser et al.17 found that whereas GGT was clearly associated with CVD risk, ALT was not. Three other recent studies have likewise failed to show a strong association. Data from the Framingham Offspring Study showed that 1 SD higher log ALT at baseline was associated with an increased risk of CVD in age/sex-adjusted models after 20 years of follow-up (HR 1.23, 95% CI 1.12-1.34), but this was attenuated in multivariable adjusted models (HR 1.05, 95% CI 0.96-1.16).21 Another study followed up 980 subjects with suspected NAFLD (based on unexplained ALT elevation) and 6,594 subjects without suspected NAFLD for a mean of 8.7 years. Cardiovascular mortality overall was not significantly increased in the suspected NAFLD group (HR 1.17, 95% CI 0.69-1.98). However, a subgroup analysis demonstrated that CVD mortality was increased in the 45- to 54-year age group (HR 8.15, 95% CI 2.00-33.20) after adjusting for age, sex, race, systolic and diastolic blood pressure, waist circumference, total cholesterol, high-density lipoprotein cholesterol, triglyceride, smoking, c-reactive protein, total daily alcohol, physical activity, diabetes, and statin use.22 The final study followed up apparently healthy Koreans with unexplained elevated ALT levels for a median of 5 years for CVD or diabetes-related mortality.23 The multivariate relative risk (including adjustment for presence of T2DM at baseline) for CVD or diabetes-related death in subjects with ALT >40 IU/L was 2.26 (95% CI 1.22-4.19). However, no subanalysis was performed on the nondiabetic group for CVD-related death only; therefore, these results are not as pure as the other two studies.

It appears that any proposed linear relationship between ALT and incident CVD is debatable, as others have recently shown that ALT may in fact exhibit a U-shaped association with total mortality24, 25 and unpublished data from our group (Ford et al.) suggests that ALT's associations with CVD events may be similarly shaped with increased risk also apparent at low ALT concentrations. Thus, current evidence goes against a linear association of ALT with CVD events.

Why GGT may be more strongly linked than ALT to vascular outcomes is not entirely clear. GGT levels may capture processes relevant to atherogenesis, but such observations are currently speculative and further studies are needed.

Associations Between Ultrasound-Diagnosed NAFLD and CVD

Liver imaging is inevitably a more reliable method for diagnosing NAFLD than elevated liver enzymes; for example, the use of routine ultrasound has been reported to have a sensitivity of 89% and specificity of 93% for the identification of fatty liver.26 However, linkages of liver enzymes with incident events have been more carefully considered in recent meta-analyses as discussed above.

Data from five studies with imaging-diagnosed NAFLD are summarized in Table 2. The individual study end points are not uniform, and have been specified in the table. Two reports related to subjects with T2DM,27, 28 and both are based on the same cohort (the Valpolicella Heart Diabetes Study). The first report was a nested case-control study for incident CVD events over 5 years and reported an increased risk of events (odds ratio [OR] 1.53, 95% CI 1.1-1.7) after controlling for several risk factors, including the metabolic syndrome.27 The second report used the full cohort data, and the results were broadly similar.28

Table 2. Image-Diagnosed NAFLD and CVD Outcomes
StudyCasesControl GroupDuration of Follow-upMeasured OutcomeAdjustments ConsideredRisk for CVD Events or CVD Mortality with or Without Fatty Liver (95% CI)
  • *

    Results for male subjects with GGT levels in 5th quintile.

Valpolicella Heart Diabetes Study (nested case-control)27T2DM with NAFLD, all free from CVD at baselineT2DM without NAFLD, all free from CVD at baseline5 yearsNonfatal CVD eventsAge, sex, smoking history, T2DM duration, HbA1c, low-density lipoprotein cholesterol, GGT, use of medication, and metabolic syndromeRR 1.53 (1.1-1.7)
Valpolicella Heart Diabetes Study (full cohort analysis)28T2DM with NAFLD, all free from CVD at baselineT2DM without NAFLD, all free from CVD at baseline6.5 yearsAs aboveAge, sex, smoking history, T2DM duration, HbA1c, low-density lipoprotein cholesterol, use of medication, and metabolic syndromeHR 1.87 (1.2-2.6)
Jepsen et al. (registry-based cohort study)29Hospital diagnosis of fatty liverGeneral population mortality data taken from national mortality ratesUp to 16 yearsDeath due to CVDExclusion of known alcohol-related liver diseaseSMR 2.1 (1.8-2.5)
Hamaguchi et al. (cohort study)30Subjects with NAFLD without CVDSubjects without NAFLD without CVD7 yearsIncident CHD (unstable angina, acute MI and silent MI, ischemic stroke and cerebral hemorrhage)Age, smoking (Brinkman index), systolic blood pressure, low-density lipoprotein cholesterol, and metabolic syndromeOR 4.12 (1.58-10.75)
Haring et al. (cohort study)31Male subjects with NAFLDMale subjects without NAFLD7.2 yearsDeath due to CVDAge, waist circumference, alcohol consumption, physical activity, education level, civil status, equalized income, functional comorbidity index, and multiplicative interaction term of continuous GGT with liver ultrasoundHR 6.22 (1.22-31.62)*

Of the three remaining imaging studies,29-31 only one had outcomes based on incident CVD events, including both fatal and nonfatal events for a population with NAFLD graded as simple steatosis.30 Among 1,221 participants, 231 had simple steatosis; the incidence of CVD was higher in these 231 subjects (11 CVD events) than in subjects without NAFLD (10 events). Multivariate analyses indicated that NAFLD was a predictor of CVD independent of conventional risk factors (OR 4.12, 95% CI 1.58-10.75, P = 0.004); however, with such small numbers, the CI was inevitably very broad. The last study prospectively followed up 7,372 patients discharged with a diagnosis of fatty liver, using the Danish Death Registry to obtain information on mortality data.29 Comparative general population data were based on national CVD mortality rates for each sex in 5-year age groups and calendar periods under observation. The standardized mortality ratio (SMR) for CVD in those with fatty liver was 2.1 (95% CI 1.8-2.5). The latter study was limited in its ability to consider the extent to which such excess risk was accounted for by established risk factors.

Another study investigated the association of GGT with mortality, assessing whether accompanying ultrasound-determined liver steatosis strengthened the observed associations.31 The study followed subjects (including those with baseline CVD) for a mean of 7.2 years. The association of GGT levels alone with CVD mortality only became significant when comparing subjects with GGT levels in the highest quintile with those in the lowest quintile (HR 1.86, 95% CI 1.10-3.14), adjusted for age, waist circumference, alcohol consumption, physical activity, education level, civil status, equalized income, and functional comorbidity index. When further stratified by ultrasound pattern, the results only remained significant in men with raised GGT who also had a hyperechogenic ultrasound pattern (multiple-adjusted HR 6.22, 95% CI 1.2-31.62), although the CIs were very broad. Once again, clinical interpretation of the above study was limited by lack of adjustment for established CVD risk factors.

Associations Between Biopsy-Diagnosed NAFLD and CVD

A small number of prospective studies have been based on gold standard liver biopsy–diagnosed NAFLD,32-36 with two showing no increased mortality with simple steatosis.32, 33 Of the remaining studies, one followed only 132 subjects for a mean of 104 months (12.7 years), 45 of whom died.34 Nine of these 45 deaths were CVD-related (joint second with cirrhosis-related death, the most common cause being neoplasia [n = 11]), but there was no consideration of other CVD risk factors and no control group to enable risk calculations. The next study included 420 subjects with NAFLD (varying severity) for a mean of 7.6 ± 4.0 years (range, 0.1-23.5 years).35 This study included subjects with CVD at baseline. The results showed that there was an increase in overall mortality in subjects with NAFLD compared with the general population (CVD prevalence not specified); the SMR was 1.34 (95% CI 1.00-1.76), with 13 of the 53 deaths due to ischemic heart disease, the second highest cause after neoplasia (28%). The authors also noted that overall mortality for subjects with simple steatosis at baseline was less than that in subjects with more severe forms of NAFLD (20% versus 35%), but that this difference was not statistically significant. Clearly, the modest sample sizes limit firm conclusions.

Another study from Sweden prospectively followed 256 subjects who underwent liver biopsy between 1980 and 1984 for up to 28 years and, similar to the study by Jepsen et al.,29 used the national death registry to obtain information on mortality data.36 The SMR for all cause mortality compared with the adjusted total Swedish population was 1.69 (95% CI 1.24-2.25) for subjects with NAFLD (bland steatosis and nonalcoholic steatohepatitis combined); 1.55 (95% CI 0.98-2.32) for subjects with bland (simple) steatosis, and 1.86 (95% CI 1.19-2.76) for nonalcoholic steatohepatitis. The most common cause of death in NAFLD subjects was CVD (30% [n = 14]), closely followed by extrahepatic malignancy (28% [n = 13]). In subjects with bland steatosis, seven of the 23 deaths were due to CVD, and five were due to extrahepatic malignancy. This study had the strength of including asymptomatic subjects with a definitive diagnosis of NAFLD or nonalcoholic steatohepatitis, but again was limited by small sample size and its ability to consider the extent to which such excess risk was accounted for by established risk factors.

Conclusions

  1. Top of page
  2. Abstract
  3. NAFLD and T2DM: Clear Evidence of an Association
  4. NAFLD and CVD Events: Evidence of an Association?
  5. Conclusions
  6. References

There is a robust association between higher GGT levels even within the normal range and incident CVD events, but this association is influenced by age, with the association being much stronger in younger adults. However, evidence to suggest that GGT can add additional information in CVD risk prediction is limited. By contrast, current data suggest that ALT levels are not significantly associated with CVD risk. With regard to image-reported NAFLD, the current evidence base is inconsistent and, due to study design, often unable to fully consider confounding or mediation by established cardiovascular risk factors. Even where adjustments have been made, they have often included weak variables such as the metabolic syndrome, rather than the full range of continuous established CVD risk factors used in clinical practice. We conclude that a diagnosis of NAFLD (or increases in liver enzymes) is insufficient to warrant labeling patients as being at high risk for CVD. By contrast, the presence of NAFLD should be a clear indication for screening for diabetes. The evidence base for cardiovascular risk screening based on the presence of NAFLD is weaker, and we recommend that risk assessment is estimated according to measurement of established risk factors and through the use of existing risk charts.

References

  1. Top of page
  2. Abstract
  3. NAFLD and T2DM: Clear Evidence of an Association
  4. NAFLD and CVD Events: Evidence of an Association?
  5. Conclusions
  6. References
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