Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease in the United States, affecting approximately 1 out of every 4 Americans. NAFLD is a spectrum of disorders including simple steatosis, characterized by the presence of hepatic steatosis with minimal inflammation, and nonalcoholic steatohepatitis (NASH), characterized by the presence of hepatic steatosis with lobular inflammation, ballooning with or without peri-sinusoidal fibrosis. NASH may lead to progressive fibrosis, and therefore, Individuals with NASH and, in particular, hepatic fibrosis are at increased risk for both liver- and cardiovascular-related outcomes compared to those with steatosis alone. New treatments for NASH and hepatic fibrosis are emerging, so now, more than ever, it is important to identify individuals with more advanced disease who may be candidates for therapy. Noninvasive methods to accurately diagnosis, risk stratify, and monitor both NASH and fibrosis are critically needed. Moreover, since clinically relevant outcomes, such as developing end stage liver disease or liver cancer, take many years to develop, reliable surrogate markers of outcome measures are needed to identify and evaluate potential therapies. In this review, we discuss methods to noninvasively diagnosis and monitor both NASH and fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease in the United States, affecting approximately 1 out of every 4 Americans. NAFLD is a spectrum of disorders including simple steatosis, characterized by the presence of hepatic steatosis with minimal inflammation, and nonalcoholic steatohepatitis (NASH), characterized by the presence of hepatic steatosis with lobular inflammation, ballooning with or without peri-sinusoidal fibrosis. NASH may lead to progressive fibrosis, and therefore, Individuals with NASH and, in particular, hepatic fibrosis are at increased risk for both liver- and cardiovascular-related outcomes compared to those with steatosis alone. New treatments for NASH and hepatic fibrosis are emerging, so now, more than ever, it is important to identify individuals with more advanced disease who may be candidates for therapy. Noninvasive methods to accurately diagnosis, risk stratify, and monitor both NASH and fibrosis are critically needed. Moreover, since clinically relevant outcomes, such as developing end stage liver disease or liver cancer, take many years to develop, reliable surrogate markers of outcome measures are needed to identify and evaluate potential therapies. In this review, we discuss methods to noninvasively diagnosis and monitor both NASH and fibrosis.

Background

Adiposity amplifies the genetic risk of non-alcoholic fatty liver disease (NAFLD).

Aim

We evaluated the association between overweight-years, a cumulative exposure based on the product of the duration and severity of excess body weight (body mass index (BMI) ≥ 25 kg/m² ), and genetic risk on liver fat and fibrosis.

Methods

This is a longitudinal analysis derived from a prospective cohort of adults in the Framingham Heart Study who underwent genotyping and vibration-controlled-transient-elastography with controlled attenuation parameter. Univariable and multivariable linear and logistic regression analyses were used to assess the association between overweight-years and liver fat and fibrosis. The association between genetic variants of liver fat (PNPLA3, TM6SF2, GCKR) and fibrosis (PNPLA3, TM6SF2, HSD17B13) was also assessed using a polygenic risk score.

Results

Our sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m² , respectively. The mean follow-up was 14(±0.9) years, and each participant underwent three study visits. The prevalence of NAFLD was 28.3% (n = 700), and 207 (8.4%) had clinically significant fibrosis. In age-, sex- and diabetes-adjusted multivariable analyses, overweight-years (per SD) had a strong association with NAFLD (aOR 3.53 [95% CI: 3.10-4.02], p < 0.001), clinically significant fibrosis (aOR 1.60 [95% CI: 1.40-1.84], p < 0.001) and cirrhosis (aOR 1.81 [95% CI: 1.38-2.37], p < 0.001). High-polygenic risk was significantly associated with liver fat and clinically significant fibrosis (p < 0.05).

Conclusion

Overweight-years is strongly associated with NAFLD and clinically significant fibrosis and combined with polygenic risk may assist in defining the trajectory of NAFLD.

Background and aims

The factors associated with incident hepatic steatosis are not definitively known. We sought to determine factors associated with incident hepatic steatosis, as measured on computed tomography, in the community.

Methods

We studied Framingham Heart Study participants without heavy alcohol use or baseline hepatic steatosis who underwent computed tomography scans between 2002-2005 (baseline) and 2008-2011 (follow-up). We performed a stepwise logistic regression procedure to determine the predictors associated with incident hepatic steatosis.

Results

We included 685 participants (mean age: 45.0 ± 6.2 years, 46.8% women). The incidence of hepatic steatosis in our sample was 17.1% over a mean 6.3 years of follow-up. Participants who developed hepatic steatosis had more adverse cardiometabolic profiles at baseline compared to those free of hepatic steatosis at follow-up. Multivariable stepwise regression analysis showed that a simple clinical model including age, sex, body mass index, alcohol consumption and triglycerides was predictive of incident hepatic steatosis (C statistic = 0.791, 95% CI: 0.748-0.834). A complex clinical model, which included visceral adipose tissue volume and liver phantom ratio added to the simple clinical model, and had improved discrimination for predicting incident hepatic steatosis (C statistic = 0.826, 95% CI: 0.786-0.866, P < .0001).

Conclusions

The combination of demographic, clinical and imaging characteristics at baseline was predictive of incident hepatic steatosis. The use of our predictive model may help identify those at increased risk for developing hepatic steatosis who may benefit from risk factor modification although further investigation is warranted.

Background and aims

NAFLD is increasing in prevalence and will soon be the most common chronic liver disease. Liver stiffness, as assessed by vibration-controlled transient elastography (VCTE), correlates with hepatic fibrosis, an important predictor of liver-related and all-cause mortality. Although liver fat is associated with cardiovascular risk factors, the association between hepatic fibrosis and cardiovascular risk factors is less clear.

Approach and results

We performed VCTE, assessing controlled attenuation parameter (CAP; measure of steatosis) and liver stiffness measurement (LSM) in 3,276 Framingham Heart Study adult participants (53.9% women, mean age 54.3 ± 9.1 years) presenting for a routine study visit. We performed multivariable-adjusted logistic regression models to determine the association between LSM and obesity-related, vascular-related, glucose-related, and cholesterol-related cardiovascular risk factors. The prevalence of hepatic steatosis (CAP ≥ 290 dB/m) was 28.8%, and 8.8% had hepatic fibrosis (LSM ≥ 8.2 kPa). Hepatic fibrosis was associated with multiple cardiovascular risk factors, including increased odds of obesity (OR, 1.82; 95% CI, 1.35-2.47), metabolic syndrome (OR, 1.49; 95% CI 1.10-2.01), diabetes (OR, 2.67; 95% CI, 1.21-3.75), hypertension (OR, 1.52; 95% CI, 1.15-1.99), and low high-density lipoprotein cholesterol (OR, 1.47; 95% CI, 1.09-1.98), after adjustment for age, sex, smoking status, alcohol drinks/week, physical activity index, aminotransferases, and CAP.

Conclusions

In our community-based cohort, VCTE-defined hepatic fibrosis was associated with multiple cardiovascular risk factors, including obesity, metabolic syndrome, diabetes, hypertension, and high-density lipoprotein cholesterol, even after accounting for covariates and CAP. Additional longitudinal studies are needed to determine if hepatic fibrosis contributes to incident cardiovascular disease risk factors or events.

Background & aims

Little is known regarding the risk of hepatic steatosis (HS) among adult children of affected parents. We examined the association between parental and offspring HS in the multigenerational Framingham Heart Study, which characterized HS using computed tomography.

Methods

We performed multivariable logistic regression models adjusted for age, sex, alcohol use, and body mass index to generate the odds of HS according to parental HS. We determined the proportion of participants with HS according to parental HS and the presence or absence of hypertension, diabetes, or obesity (BMI ≥30 kg/m² ). After excluding heavy alcohol use (n = 126) and missing covariates (n = 1), 785 offspring with at least one parent were included.

Results

Approximately 23% (183/785) had at least one parent with HS and 1.1% had two affected parents (9/785). In adjusted models, participants with at least one parent with HS had a nearly two-fold increased odds of HS compared to participants without a parental history of HS (OR 1.86, 95% confidence interval 1.15-3.03). Among participants without hypertension, diabetes, or obesity, a higher proportion had HS if they had a parental history of HS compared to those without (16.1% vs 5.2%, P < 0.001). However, for participants with cardiometabolic risk factors, we did not observe a difference in HS among those with and without parental HS (30.3% vs 28.5%, P = 0.78).

Conclusions

Individuals with a parental history of HS are at increased risk for HS. Specifically, a parental history of HS may be an important factor among those that are otherwise metabolically healthy.

Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging-proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m² , respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging-proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716-1, P < 0.0001).

Conclusions

Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547-1558).

Background and aims

Electronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

Approach and results

Researchers with an interest in EHR-based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR-based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research.

Conclusions

This expert panel consensus statement can help harmonize and improve generalizability of EHR-based NAFLD research.

BACKGROUND: Liver fibrosis, is independently associated with incident heart failure (HF). Investigating the association between liver fibrosis and type of HF, specifically HF with reduced ejection fraction (EF; HFrEF) or HF with preserved ejection fraction (HFpEF), may provide mechanistic insight into this association. We sought to determine the association between liver fibrosis score (FIB-4) and type of HF, and to assess whether HIV or hepatitis C status modified this association. METHODS: We included patients alive on or after 4/1/2003 from the Veterans Aging Cohort Study. We followed patients without prevalent cardiovascular disease until their first HF event, death, last clinic visit, or 9/30/2015. We defined liver fibrosis as: likely advanced fibrosis (FIB-4 > 3.25), indeterminate (FIB-4 range 1.45-3.25), unlikely advanced fibrosis (FIB-4 < 1.45). Primary outcomes were HFrEF and HFpEF (defined using ICD-9 diagnoses for HF, and EF extracted from electronic medical records using natural language processing). Cox proportional hazards models were adjusted for potential confounders and used to estimate hazard ratios (HR). RESULTS: Among 108,708 predominantly male (96%) participants mean age was 49 years. Likely advanced fibrosis was present in 4% at baseline and was associated with an increased risk of HFpEF [HR (95% confidence interval)] [1.70 (1.3-2.3)]; and non-significantly with HFrEF [1.20 (0.9-1.7)]. These associations were not modified by HIV or hepatitis C status. CONCLUSION: Likely advanced fibrosis was independently associated with incident HFpEF but not HFrEF. This suggests that risk factors and/or mechanisms for liver fibrosis may have greater overlap with those for HFpEF than HFrEF.

Background

Liver fibrosis, is independently associated with incident heart failure (HF). Investigating the association between liver fibrosis and type of HF, specifically HF with reduced ejection fraction (EF; HFrEF) or HF with preserved ejection fraction (HFpEF), may provide mechanistic insight into this association. We sought to determine the association between liver fibrosis score (FIB-4) and type of HF, and to assess whether HIV or hepatitis C status modified this association.

Methods

We included patients alive on or after 4/1/2003 from the Veterans Aging Cohort Study. We followed patients without prevalent cardiovascular disease until their first HF event, death, last clinic visit, or 9/30/2015. We defined liver fibrosis as: likely advanced fibrosis (FIB-4 > 3.25), indeterminate (FIB-4 range 1.45-3.25), unlikely advanced fibrosis (FIB-4 < 1.45). Primary outcomes were HFrEF and HFpEF (defined using ICD-9 diagnoses for HF, and EF extracted from electronic medical records using natural language processing). Cox proportional hazards models were adjusted for potential confounders and used to estimate hazard ratios (HR).

Results

Among 108,708 predominantly male (96%) participants mean age was 49 years. Likely advanced fibrosis was present in 4% at baseline and was associated with an increased risk of HFpEF [HR (95% confidence interval)] [1.70 (1.3-2.3)]; and non-significantly with HFrEF [1.20 (0.9-1.7)]. These associations were not modified by HIV or hepatitis C status.

Conclusion

Likely advanced fibrosis was independently associated with incident HFpEF but not HFrEF. This suggests that risk factors and/or mechanisms for liver fibrosis may have greater overlap with those for HFpEF than HFrEF.