Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.

Purpose of review

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are strongly associated. Both also associate with an increased risk of cardiovascular disease (CVD).

Recent findings

Several studies have provided evidence that NAFLD could be an independent CVD risk factor. Given the strong association between NAFLD and T2DM, assessing the independent CV effect of these two conditions remains challenging. However, patients with T2DM and NAFLD exhibit higher risk of CVD compared with T2DM without NAFLD suggesting a potential synergistic increase of CV risk in patients with both T2DM and NAFLD supported by several shared pathophysiological pathways. Several anti-diabetic therapies have shown beneficial effect on both NAFLD and CVD. Patients with T2DM and NAFLD should be considered at high risk of CVD and could benefit from more intensive CV prevention. Additional long-term follow-up is needed to demonstrate that the treatment of NAFLD effectively reduces the risk of CVD.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in developed countries.¹ Patients with nonalcoholic steatohepatitis (NASH) are considered to be at a higher risk of fibrosis progression and development to cirrhosis and hepatocellular carcinoma.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and the progressive form of this condition, nonalcoholic steatohepatitis (NASH), has become one of the leading indications for liver transplantation. Despite intensive investigations, there are currently no United States Food and Drug Administration-approved therapies for treating NASH. A major barrier for drug development in NASH is that treatment response assessment continues to require liver biopsy, which is invasive and interpreted subjectively. Therefore, there is a major unmet need for developing noninvasive, objective, and quantitative biomarkers for diagnosis and assessment of treatment response. Emerging data support the use of magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) as a noninvasive, quantitative, and accurate measure of liver fat content to assess treatment response in early-phase NASH trials. In this review, we discuss the role and utility, including potential sample size reduction, of MRI-PDFF as a quantitative and noninvasive imaging-based biomarker in early-phase NASH trials. Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide.⁽⁾ NAFLD can be broadly classified into two categories: nonalcoholic fatty liver, which has a minimal risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), the more progressive form of NAFLD, which has a significantly increased risk of progression to cirrhosis.⁽⁾ Over the past two decades, NASH-related cirrhosis has become the second leading indication for liver transplantation in the United States.⁽⁾ For these reasons, pharmacological therapy for NASH is needed urgently. Despite intensive investigations, there are currently no therapies for treating NASH that have been approved by the United States Food and Drug Administration.⁽⁾.

Background & aims

Controlled attenuation parameter (CAP) measurements using M probe have been reported to be lower than those of the XL-probe in detection of hepatic steatosis. However, there has been no direct comparison of CAP with the M vs the XL probe in patients with nonalcoholic fatty liver disease (NAFLD). We compared CAP with the M vs the XL probe for quantification of hepatic fat content, using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the standard.

Methods

We performed a prospective study of 100 adults (mean body mass index [BMI], 30.6 ± 4.7 kg/m2) with and without NAFLD, assessed by CAP with the M probe and XL probe on the same day, at a single research center, from November 2017 through November 2018. We then measured the MRI-PDFF as the reference standard. Outcomes were presence of hepatic steatosis, defined as MRI-PDFF ≥ 5%, and detection of hepatic fat content ≥ 10%, defined as MRI-PDFF ≥ 10%. We performed area under the receiver operating characteristic curve (AUROC) analyses to assess the diagnostic accuracy of CAP for each probe in detection of hepatic steatosis (MRI-PDFF ≥ 5%) and of hepatic fat content ≥ 10%.

Results

Of the study participants, 68% had an MRI-PDFF of 5% or more and 48% had an MRI-PDFF of 10% or more. The mean CAP measured by the M probe (310 ± 62 db/m) was significantly lower than by the X probe (317 ± 63 db/m) (P = .007). When M probe was used in participants with BMIs <30 kg/m² and XL probe in participants with BMIs ≥30 kg/m², the CAP measured by the M probe (312 ± 51.4 db/m) remained significantly lower than that of the XL probe (345 ± 47.6 db/m) (P = .0035.), when the MRI-PDFF was above 5%. The optimal threshold of CAP for the detection of MRI-PDFF≥5%, was 294 db/m with the M probe and 307 db/m with the XL probe. The optimal threshold of CAP for the detection of MRI-PDFF ≥ 10%, was 311 db/m with the M probe and 322 db/m with the XL probe. For only the XL probe, CAP measurements with an interquartile range below 30 dB/m detected an MRI-PDFF≥5% with a lower AUROC (0.97; 95% CI, 0.80-1.00) than CAP measurements with an interquartile range above 30 dB/m (AUROC, 0.82; 95% CI, 0.71-0.90) (P = .0129).

Conclusions

In an analysis of the same patients using CAP with the M probe and XL probe, with MRI-PDFF as the standard, we found that the M probe under-quantifies CAP values compared with the XL probe, independent of BMI. The type of probe should be considered when interpreting CAP data from patients with NAFLD.

Background

Eicosanoid and related docosanoid polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives have been proposed as noninvasive lipidomic biomarkers of nonalcoholic steatohepatitis (NASH). Therefore, we investigated associations between plasma eicosanoids and liver fibrosis to evaluate their utility in diagnosing and monitoring NASH-related fibrosis.

Methods

Our analysis used baseline eicosanoid data from 427 patients with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), and longitudinal measurements along with liver fibrosis staging from 63 patients with NASH and stage 2/3 fibrosis followed for 24 weeks in a phase II trial.

Results

At baseline, four eicosanoids were significantly associated with liver fibrosis stage: 11,12-DIHETE, tetranor 12-HETE, adrenic acid, and 14, 15-DIHETE. Over 24 weeks of follow up, a combination of changes in seven eicosanoids [5-HETE, 7,17-DHDPA, adrenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), 16-HDOHE, and 9-HODE) had good diagnostic accuracy for the prediction of ⩾1 stage improvement in fibrosis (AUROC: 0.74; 95% CI: 0.62-0.87), and a combination of four eicosanoids (7,17-DHDPA, 14,15-DIHETRE, 9-HOTRE, and free adrenic acid) accurately predicted improvement in hepatic collagen content (AUROC: 0.72; 95% CI: 0.50-0.77).

Conclusion

This study provides preliminary evidence that plasma eicosanoids may serve as noninvasive biomarkers of liver fibrosis and may predict liver fibrosis improvement in NASH.

Background & aims

Controlled attenuation parameter (CAP) measurements using M probe have been reported to be lower than those of the XL-probe in detection of hepatic steatosis. However, there has been no direct comparison of CAP with the M vs the XL probe in patients with nonalcoholic fatty liver disease (NAFLD). We compared CAP with the M vs the XL probe for quantification of hepatic fat content, using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the standard.

Methods

We performed a prospective study of 100 adults (mean body mass index [BMI], 30.6 ± 4.7 kg/m2) with and without NAFLD, assessed by CAP with the M probe and XL probe on the same day, at a single research center, from November 2017 through November 2018. We then measured the MRI-PDFF as the reference standard. Outcomes were presence of hepatic steatosis, defined as MRI-PDFF ≥ 5%, and detection of hepatic fat content ≥ 10%, defined as MRI-PDFF ≥ 10%. We performed area under the receiver operating characteristic curve (AUROC) analyses to assess the diagnostic accuracy of CAP for each probe in detection of hepatic steatosis (MRI-PDFF ≥ 5%) and of hepatic fat content ≥ 10%.

Results

Of the study participants, 68% had an MRI-PDFF of 5% or more and 48% had an MRI-PDFF of 10% or more. The mean CAP measured by the M probe (310 ± 62 db/m) was significantly lower than by the X probe (317 ± 63 db/m) (P = .007). When M probe was used in participants with BMIs <30 kg/m² and XL probe in participants with BMIs ≥30 kg/m², the CAP measured by the M probe (312 ± 51.4 db/m) remained significantly lower than that of the XL probe (345 ± 47.6 db/m) (P = .0035.), when the MRI-PDFF was above 5%. The optimal threshold of CAP for the detection of MRI-PDFF≥5%, was 294 db/m with the M probe and 307 db/m with the XL probe. The optimal threshold of CAP for the detection of MRI-PDFF ≥ 10%, was 311 db/m with the M probe and 322 db/m with the XL probe. For only the XL probe, CAP measurements with an interquartile range below 30 dB/m detected an MRI-PDFF≥5% with a lower AUROC (0.97; 95% CI, 0.80-1.00) than CAP measurements with an interquartile range above 30 dB/m (AUROC, 0.82; 95% CI, 0.71-0.90) (P = .0129).

Conclusions

In an analysis of the same patients using CAP with the M probe and XL probe, with MRI-PDFF as the standard, we found that the M probe under-quantifies CAP values compared with the XL probe, independent of BMI. The type of probe should be considered when interpreting CAP data from patients with NAFLD.

Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (DM2).¹ Accurately assessing CVD risk in NAFLD patients is critical to improving clinical outcomes.¹ Use of liver stiffness measurements to noninvasively assess for liver fibrosis is broadening, and magnetic resonance elastography (MRE) is the most accurate modality in NAFLD.² However, the association between fibrosis severity on MRE and the degree of CVD risk is unknown. The aim of this study was to determine whether MRE-assessed liver fibrosis stage is associated with CVD risk determined by Framingham risk score (FRS) and coronary artery calcium (CAC).

Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (DM2).¹ Accurately assessing CVD risk in NAFLD patients is critical to improving clinical outcomes.¹ Use of liver stiffness measurements to noninvasively assess for liver fibrosis is broadening, and magnetic resonance elastography (MRE) is the most accurate modality in NAFLD.² However, the association between fibrosis severity on MRE and the degree of CVD risk is unknown. The aim of this study was to determine whether MRE-assessed liver fibrosis stage is associated with CVD risk determined by Framingham risk score (FRS) and coronary artery calcium (CAC).