Allen, Alina M.

Disease monitoring in nonalcoholic steatohepatitis (NASH) is limited by absence of noninvasive biomarkers of disease regression or progression. We aimed to examine the role of multiparametric three‐dimensional magnetic resonance elastography (3D‐MRE) and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH regression after interventions. This is a single‐center prospective clinical trial of 40 patients who underwent bariatric surgery. Imaging and liver biopsies were obtained at baseline and 1 year after surgery. The imaging protocol consisted of multifrequency 3D‐MRE to determine the shear stiffness at 60 Hz and damping ratio at 40 Hz, and MRI‐PDFF to measure the fat fraction. A logistic regression model including these three parameters was previously found to correlate with NASH. We assessed the model performance in the detection of NASH resolution after surgery by comparing the image‐predicted change in NAFLD activity score (delta NAS) to the histologic changes. A total of 38 patients (median age 43, 87% female, 30 of 38 with NAS ≥ 1, and 13 of 38 with NASH) had complete data at 1 year. The NAS decreased in all subjects with NAS ≥ 1 at index biopsy, and NASH resolved in all 13. There was a strong correlation between the predicted delta NAS by imaging and the delta NAS by histology (r = 0.73, P < 0.001). The strength of correlation between histology and the predicted delta NAS using single conventional parameters, such as the fat fraction by MRI‐PDFF or shear stiffness at 60 Hz by MRE, was r = 0.69 (P < 0.001) and r = 0.43 (P = 0.009), respectively. Conclusion: Multiparametric 3D‐MRE and MRI‐PDFF can detect histologic changes of NASH resolution after bariatric surgery. Studies in a nonbariatric setting are needed to confirm the performance as a composite noninvasive biomarker for longitudinal NASH monitoring.

OBJECTIVES: Cardiovascular (CV) disease is the top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). Female sex is protective against CV disease. We aimed to determine whether female sex remains a protective factor against CV disease (myocardial infarction, angina, and stroke) in NAFLD. METHODS: We identified all adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1997 and 2014 and selected an age- and sex-matched (1:4) referent cohort from the general population. NAFLD was ascertained using a code-based algorithm with high validity tested by medical record review. The impact of female sex on incident CV events was examined using Cox proportional hazards regression analysis stratified by standard clinical risk factors. RESULTS: A total of 3,869 NAFLD and 15,209 age- and sex-matched referent subjects were identified. After a median follow-up time of 7 (range 1–20) years, 3,851 CV events were recorded. Female sex was protective for ischemic CV events in the general population (hazard ratio = 0.71, 95% confidence interval 0.62–0.80, P < 0.001), but the impact was significantly diminished among those with NAFLD (hazard ratio = 0.90, 95% confidence interval 0.74–1.08, P = 0.25), even after stratification by time-dependent CV risk factors and control for diagnostic testing (liver enzymes and ultrasound) during routine medical evaluations, as a surrogate of access to care. Among those with NAFLD, excess events were higher in women than in men: CV disease (18% vs 9%) and mortality (9% vs 6%). DISCUSSION: Women with NAFLD lose the CV protection conferred by the female sex, and their risk is underestimated by current estimating methods in clinical practice.

Diabetes increases the risk of liver disease progression and cirrhosis development in patients with nonalcoholic steatohepatitis (NASH). The association between diabetes and the risk of hepatocellular carcinoma (HCC) in NASH patients with cirrhosis is not well quantified. All patients with the diagnosis of NASH cirrhosis seen at Mayo Clinic Rochester between January 2006 and December 2015 were identified. All adult liver transplant registrants with NASH between 2004 and 2017 were identified using the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation registry for external validation. Cox proportional hazard analysis was performed to investigate the association between diabetes and HCC risk. Among 354 Mayo Clinic patients with NASH cirrhosis, 253 (71%) had diabetes and 145 (41%) were male. Mean age at cirrhosis evaluation was 62. During a median follow‐up of 47 months, 30 patients developed HCC. Diabetes was associated with an increased risk of developing HCC in univariate (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 1.1‐11.9; P = 0.04) and multivariable analysis (HR = 4.2; 95% CI = 1.2‐14.2; P = 0.02). In addition, age (per decade, HR = 1.8; 95% CI = 1.2‐2.6; P < 0.01) and low serum albumin (HR = 2.1; 95% CI = 1.5‐2.9; P < 0.01) were significantly associated with an increased risk of developing HCC in multivariable analysis. Other metabolic risk factors, including body mass index, hyperlipidemia, and hypertension, were not associated with HCC risk. Among UNOS NASH registrants (N = 6,630), 58% had diabetes. Diabetes was associated with an increased risk of developing HCC in univariate (HR = 1.4; 95% CI = 1.1‐1.8; P < 0.01) and multivariable (HR = 1.3; 95% CI = 1.0‐1.7; P = 0.03) analysis. Conclusion: Diabetes is associated with an increased risk of HCC in patients with NASH cirrhosis.

The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of three‐dimensional magnetic resonance elastography (3D‐MRE), with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015 and 2017 (prospective cohort, n = 88) and 2010 and 2013 (retrospective cohort, n = 87). The imaging protocol consisted of multifrequency 3D‐MRE (mf3D‐MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH, and MRI‐PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D‐MRE technical parameters for NASH detection. The two cohorts were then combined to derive predictive models of NASH and disease activity by nonalcoholic fatty liver disease activity score (NAS) using the three imaging parameters that correlated with NASH. A total of 175 patients (median age 45, 81% women, and 81 [46%] with histologic NASH) were used for model derivation. From the complex shear modulus output generated by mf3D‐MRE, the damping ratio at 40 Hz and shear stiffness at 60 Hz best correlated with NASH. The fat fraction obtained from MRI‐PDFF correlated with steatosis ( P < 0.05 for all). These three parameters were fit into a logistic regression model that predicted NASH with cross‐validated area under the receiver operating characteristic curve (AUROC) = 0.73, sensitivity = 0.67, specificity = 0.80, positive predictive value = 0.73 and negative predictive value = 0.74, and disease activity by NAS with cross‐validated AUROC = 0.82. Conclusion: The mf3D‐MRE allows identification of imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in nonbariatric cohorts.

Background Hepatic steatosis is strongly associated with cardiovascular disease in the general population. Whether recurrent or de novo, it can occur in the allograft, but the impact on survival and long-term clinical outcomes remains unclear. In this study, we aim to determine both the frequency and impact of allograft steatosis on long-term posttransplant outcomes. Methods A retrospective review of 588 adult liver transplant (LT) recipients (1999-2006) was performed. Cox regression analysis (time-dependent) was used to evaluate differences in time to steatosis post-LT, patient survival, and cardiovascular outcomes. Results Mean age 51.9 ± 10.6 years, 64.6% males, underlying nonalcoholic steatohepatitis (NASH) (9.4%), previous tobacco (52%), pre-LT diabetes mellitus (30.3%), pre-LT hypertension (23.2%), and known cardiovascular disease (9.7%). Overall, 254 recipients developed allograft steatosis (at 10 years: 77.6% NASH recipients, 44.7% Non-NASH recipients). Risk factors for allograft steatosis were female sex (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.09-2.00; P = 0.014), hepatitis C virus diagnosis (HR, 2.49; 95% CI, 1.77-3.94; P < 0.001), and time-dependent BMI (per unit: HR, 1.08; 95% CI, 1.05-1.10; P < 0.001). Allograft steatosis was not associated with post-LT survival (P = 0.25) nor cardiovascular events (HR, 1.08; 95% CI, 0.73-1.59; P = 0.70). Underlying NASH associated with cardiovascular events (HR, 2.04; 95% CI, 1.37-3.04; P < 0.001). Conclusions Allograft steatosis is common but not associated with survival or cardiovascular events in this study. Larger prospective studies are needed to better define the natural history of allograft steatosis.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. The health care burden resulting from the multidisciplinary management of this complex disease is unknown. We assessed the total health care cost and resource utilization associated with a new NAFLD diagnosis, compared with controls with similar comorbidities. We used OptumLabs Data Warehouse, a large national administrative claims database with longitudinal health data of over 100 million individuals enrolled in private and Medicare Advantage health plans. We identified 152,064 adults with a first claim for NAFLD between 2010 and 2014, of which 108,420 were matched 1:1 by age, sex, metabolic comorbidities, length of follow‐up, year of diagnosis, race, geographic region, and insurance type to non‐NAFLD contemporary controls from the OptumLabs Data Warehouse database. Median follow‐up time was 2.6 (range 1‐6.5) years. The final study cohort consisted of 216,840 people with median age 55 (range 18‐86) years, 53% female, 78% white. The total annual cost of care per NAFLD patient with private insurance was $7,804 (interquartile range [IQR] $3,068‐$18,688) for a new diagnosis and $3,789 (IQR $1,176‐$10,539) for long‐term management. These costs are significantly higher than the total annual costs of $2,298 (IQR $681‐$6,580) per matched control with similar metabolic comorbidities but without NAFLD. The largest increases in health care utilization that may account for the increased costs in NAFLD compared with controls are represented by liver biopsies (relative risk [RR] = 55.00, 95% confidence interval [CI] 24.48‐123.59), imaging (RR = 3.95, 95% CI 3.77‐4.15), and hospitalizations (RR = 1.87, 95% CI 1.73‐2.02). Conclusion: The costs associated with the care for NAFLD independent of its metabolic comorbidities are very high, especially at first diagnosis. Research efforts shouldfocus on identification of underlying determinants of use, sources of excess cost, and development of cost‐effective diagnostic tests.

Background Sex-based disparities in liver transplantation (LT) are incompletely understood. We assessed the role of height, Model for End-Stage Liver Disease (MELD), MELD-Na, and exception points in the disparate access to LT. Methods Adults waitlisted for LT at Organ Procurement and Transplantation Network between 2002 and 2013 were included. Covariates associated with likelihood of LT were analyzed by Cox proportional model. In a separate cohort of waitlisted adults with glomerular filtration rate measurement by iothalamate clearance (n = 611), we determined the number of creatinine-derived MELD points in men versus women, across all ranges of glomerular filtration rate. The impact of correcting the MELD score deficit in women on LT was modeled. Results Among 90 720 Organ Procurement and Transplantation Network registrants, women had higher mortality than men (4 years after listing: 22% vs 18%, P < 0.0001), and lower likelihood of LT (49% vs 58%, P < 0.0001); women were 20% less likely to be transplanted (hazard ratio, 0.80; 95% confidence interval, 0.78-0.81). Differences in height and MELD exception scores accounted for most of the LT deficit in women (hazard ratio, 0.91; 95% confidence interval, 0.89-0.94). Women received between 1 and 2.4 fewer creatinine-derived MELD points than men with similar renal dysfunction. MELD-Na worsened the gender disparity. Addition of 1 or 2 MELD points to women significantly impacted LT access. Conclusions Differences in height and MELD exception points explained most of the sex-based disparity in LT. Additionally, MELD score underestimated disease severity in women by up to 2.4 points and MELD Na exacerbated this disparity. The degree of underestimation based on MELD had significant impact on allocation.

Recent population‐based data on nonalcoholic fatty liver disease (NAFLD) epidemiology in general, and incidence in particular, are lacking. We examined trends in NAFLD incidence in a U.S. community and the impact of NAFLD on incident metabolic comorbidities (MCs), cardiovascular (CV) events, and mortality. A community cohort of all adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1997 and 2014 was constructed using the Rochester Epidemiology Project database. The yearly incidence rate were calculated. The impact of NAFLD on incident MCs, CV events, and mortality was studied using a multistate model, with a 4:1 age‐ and sex‐matched general population as a reference. We identified 3,869 NAFLD subjects (median age, 53; 52% women) and 15,209 controls; median follow‐up was 7 (1‐20) years. NAFLD incidence increased 5‐fold, from 62 to 329 in 100,000 person‐years. The increase was highest (7‐fold) in young adults, aged 18‐39 years. The 10‐year mortality was higher in NAFLD subjects (10.2%) than controls (7.6%; P < 0.0001). NAFLD was an independent risk factor for incident MCs and death. Mortality risk decreased as the number of incident MCs increased: relative risk (RR) = 2.16 (95% confidence [CI], 1.41‐3.31), 1.99 (95% CI, 1.48‐2.66), 1.75 (95% CI, 1.42‐2.14), and 1.08 (95% CI, 0.89‐1.30) when 0, 1, 2, or 3 MCs were present, respectively. The NAFLD impact on CV events was significant only in subjects without MCs (RR = 1.96; 95% CI = 1.35‐2.86). NAFLD reduced life expectancy by 4 years, with more time spent in high metabolic burden. Conclusion: Incidence of NAFLD diagnosis in the community has increased 5‐fold, particularly in young adults. NAFLD is a consequence, but also a precursor of MC. Incident MC attenuates the impact of NAFLD on death and annuls its impact on CV disease. (H epatology 2018;67:1726‐1736).

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Up to one third of individuals with NAFLD will develop nonalcoholic steatohepatitis (NASH), which is associated with progression to cirrhosis and is rapidly becoming the leading indication for liver transplantation. Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. It is observed in up to 60% of patients with end‐stage liver disease and portends a poor prognosis. Recent studies have shown that sarcopenia is a novel risk factor for developing NAFLD. Pathophysiological mechanisms relating sarcopenia and NASH may include insulin resistance (IR) and increased inflammation. IR leads to accumulation of triglycerides in both muscle tissue and the liver. It also exacerbates proteolysis and leads to muscle depletion. Chronic inflammation leads to liver injury and progression of fibrosis. The inflammatory milieu also stimulates protein catabolism. Viewing skeletal muscle as an endocrine organ that secretes various salutary myokines may help us understand its role in the development of steatosis. A better understanding of the pathophysiology will aid in developing physical and pharmacological therapeutic interventions. In this review, we will explore the complex inter‐relationships between sarcopenia and NASH. We will discuss the impact of sarcopenia in patients with NASH and therapeutic options for the management of sarcopenia. (Hepatology 2017;66:2055–2065)