Head-to-head comparison of magnetic resonance elastography-based liver stiffness, fat fraction, and T1 relaxation time in identifying at-risk NASH.

BACKGROUND AND AIMS: The presence of at-risk NASH is associated with an increased risk of cirrhosis and complications. Therefore, noninvasive identification of at-risk NASH with an accurate biomarker is a critical need for pharmacologic therapy. We aim to explore the performance of several magnetic resonance (MR)-based imaging parameters in diagnosing at-risk NASH. APPROACH AND RESULTS: This prospective clinical trial (NCT02565446) includes 104 paired MR examinations and liver biopsies performed in patients with suspected or diagnosed NAFLD. Magnetic resonance elastography-assessed liver stiffness (LS), 6-point Dixon-derived proton density fat fraction (PDFF), and single-point saturation-recovery acquisition-calculated T1 relaxation time were explored. Among all predictors, LS showed the significantly highest accuracy in diagnosing at-risk NASH [AUC LS : 0.89 (0.82, 0.95), AUC PDFF : 0.70 (0.58, 0.81), AUC T1 : 0.72 (0.61, 0.82), z -score test z >1.96 for LS vs any of others]. The optimal cutoff value of LS to identify at-risk NASH patients was 3.3 kPa (sensitivity: 79%, specificity: 82%, negative predictive value: 91%), whereas the optimal cutoff value of T1 was 850 ms (sensitivity: 75%, specificity: 63%, and negative predictive value: 87%). PDFF had the highest performance in diagnosing NASH with any fibrosis stage [AUC PDFF : 0.82 (0.72, 0.91), AUC LS : 0.73 (0.63, 0.84), AUC T1 : 0.72 (0.61, 0.83), |z| <1.96 for all]. CONCLUSION: Magnetic resonance elastography-assessed LS alone outperformed PDFF, and T1 in identifying patients with at-risk NASH for therapeutic trials.

CS-iCCA, A New Clinically Based Staging System for Intrahepatic Cholangiocarcinoma: Establishment and External Validation.

INTRODUCTION: Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with poor prognosis. Current prognostic methods are most accurate for patients with surgically resectable disease. However, a significant proportion of patients with iCCA are not surgical candidates. We aimed to develop a generalizable staging system based on clinical variables to determine prognosis of all patients with iCCA. METHODS: The derivation cohort included 436 patients with iCCA seen between 2000 and 2011. For external validation, 249 patients with iCCA seen from 2000 to 2014 were enrolled. Survival analysis was performed to identify prognostic predictors. All-cause mortality was the primary end point. RESULTS: Eastern Cooperative Oncology Group status, tumor number, tumor size, metastasis, albumin, and carbohydrate antigen 19-9 were incorporated into a 4-stage algorithm. Kaplan-Meier estimates for 1-year survival were 87.1% (95% confidence interval [CI] 76.1-99.7), 72.7% (95% CI 63.4-83.4), 48.0% (95% CI 41.2-56.0), and 16% (95% CI 11-23.5), respectively, for stages I, II, III, and IV. Univariate analysis yielded significant differences in risk of death for stages II (hazard ratio [HR] 1.71; 95% CI 1.0-2.8), III (HR 3.32; 95% CI 2.07-5.31), and IV (HR 7.44; 95% CI 4.61-12.01) compared with stage I (reference). Concordance indices showed the new staging system was superior to the TNM staging for predicting mortality in the derivation cohort, P < 0.0001. In the validation cohort, however, the difference between the 2 staging systems was not significant. DISCUSSION: The proposed independently validated staging system uses nonhistopathologic data to successfully stratify patients into 4 stages. This staging system has better prognostic accuracy compared with the TNM staging and can assist physicians and patients in treatment of iCCA.

Performance of American Gastroenterological Association Clinical Care Pathway for the risk stratification of patients with nonalcoholic fatty liver disease in the US population.

BACKGROUND AND AIMS: The American Gastroenterological Association (AGA) recently launched the Clinical Care Pathway for the Risk Stratification and Management of Patients with NAFLD to identify adults with significant fibrosis. We aimed to examine this pathway's performance in the US population. APPROACH AND RESULTS: Using the 2017-2018 National Health and Nutrition Examination Survey data, we identified participants aged ≥18 with available Fibrosis-4 (FIB-4) score and liver stiffness measurement (LSM) in the absence of other liver diseases. Based on the AGA clinical pathway, FIB-4 < 1.3 and LSM < 8 kilopascals (kPa) by vibration-controlled transient elastography (VCTE) are associated with low risk of significant fibrosis. Using these cutoffs, we examined the pathway performance using negative predictive value (NPV) and positive predictive value (PPV) and explored alternative risk-stratification strategies. There were 2322 participants with available data (projected to 94.2 million US adults). The NPV of LSM ≥ 8 kPa among those with FIB-4 < 1.3 was 90%, whereas the PPV among those with FIB-4 1.3-2.67 was 13%. As diabetes was a strong predictor of fibrosis, we propose a simple, alternative strategy to eliminate the indeterminate FIB-4 range and perform VCTE in those with FIB-4 ≥ 1.3 and diabetes. This strategy would decrease the number of VCTEs from 14.5 to 4.9 million and increase PPV from 13% to 33% without compromising the NPV among those who did not undergo VCTE. CONCLUSION: The implementation of the current AGA clinical pathway would lead to overutilization of VCTE. An alternative strategy using FIB-4 ≥ 1.3 and diabetes to select adults undergoing second-line testing will improve this pathway's performance and minimize unnecessary VCTEs.

Prognostic utility of systemic inflammatory markers and chronic hepatitis C virus infection status in hepatocellular carcinoma patients treated with local ablation.

BACKGROUND: Hepatocellular carcinoma (HCC) has high incidence and mortality worldwide. Local ablation using radiofrequency ablation (RFA) or microwave ablation (MWA) is potentially curative for early-stage HCC with outcomes comparable to surgical resection. We explored the influence of demographic, clinical, and laboratory factors on outcomes of HCC patients receiving ablation. METHODS: This retrospective cohort study included 221 HCC patients receiving local ablation at Mayo Clinic between January 2000 and October 2018, comprising 140 RFA and 81 MWA. Prognostic factors determining overall survival (OS) and disease-free survival (DFS) were identified using multivariate analysis. RESULTS: There was no clinically significant difference in OS or DFS between RFA and MWA. In multivariate analysis of OS, pre-ablation lymphocyte-monocyte ratio [Hazard ratio (HR) 0.7, 95% confidence interval (CI) 0.58-0.84, P = 0.0001], MELD score [HR 1.12, 95%CI 1.068-1.17, P <  0.0001], tumor number [HR 1.23, 95%CI 1.041-1.46, P = 0.015] and tumor size [HR 1.18, 95%CI 1.015-1.37, P = 0.031] were clinically-significant prognostic factors. Among HCC patients with chronic hepatitis C (HCV) infection, positive HCV PCR at HCC diagnosis was associated with 1.4-fold higher hazard of death, with 5-year survival of 32.8% vs 53.6% in HCV PCR-negative patients. Regarding DFS, pre-ablation lymphocyte-monocyte ratio [HR 0.77, 95%CI 0.66-0.9, P = 0.001], MELD score [HR 1.06, 95%CI 1.022-1.11, P = 0.002], Log2 AFP [HR 1.11, 95%CI 1.033-1.2, P = 0.005], tumor number [HR 1.29, 95%CI 1.078-1.53, P = 0.005] and tumor size [HR 1.25, 95%CI 1.043-1.51 P = 0.016] were independently prognostic. CONCLUSIONS: Pre-ablation systemic inflammation represented by lymphocyte-monocyte ratio is significantly associated with OS and DFS in HCC patients treated with local ablation. HCV viremia is associated with poor OS. Tumor biology represented by tumor number and size are strongly prognostic for OS and DFS while AFP is significantly associated with DFS only.

Aspirin, Statins, Non-aspirin NSAIDs, Metformin, and the Risk of Biliary Cancer: A Swedish Population-Based Cohort Study.

BACKGROUND: Chemoprevention for biliary tract cancers (BTC), which comprise intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer, is controversial. We examined associations between low-dose aspirin, statins, NSAIDs, and metformin with BTC risk. METHODS: We used a population-based cohort of 5.7 million persons over age 18 without personal history of cancer (except nonmelanoma skin cancer), receiving at least one commonly prescribed drug between July 1, 2005, and December 31, 2012, from the Swedish Prescribed Drug Registry. Hazard ratios (HR) were calculated using age-scaled multivariable-adjusted Cox models. RESULTS: 2,160 individuals developed BTC. Low-dose aspirin was not associated with BTC risk [HR, 0.93; 95% confidence interval (CI), 0.81-1.07], iCCA (HR, 1.21; 95% CI, 0.93-1.57), eCCA (HR, 0.80; 95% CI, 0.60-1.07), or gallbladder cancer (HR, 0.87; 95% CI, 0.71-1.06). Statins were associated with lower risk of BTC (HR, 0.66; 95% CI, 0.56-0.78), iCCA (HR, 0.69; 95% CI, 0.50-0.95), eCCA (HR 0.54; 95% CI, 0.38-0.76), and gallbladder cancer (HR, 0.72; 95% CI, 0.57-0.91). For all BTC subtypes, combined low-dose aspirin and statins were not associated with lower risk than statins alone. NSAIDs were associated with higher risk of BTC and its subtypes. Metformin was not associated with BTC risk (HR, 0.98; 95% CI, 0.82-1.18), iCCA (HR, 1.06; 95% CI, 0.77-1.48), eCCA (HR, 1.15; 95% CI, 0.82-1.61), or gallbladder cancer (HR, 0.84; 95% CI, 0.63-1.11). CONCLUSIONS: Statins were associated with a decreased risk of BTC and its subtypes. Low-dose aspirin alone was not associated with a decreased risk, and use of both was not associated with further decrease in risk beyond statins alone. IMPACT: Statins were most consistently associated with a decreased risk of BTC and its subtypes.

Natural History of Nonalcoholic Fatty Liver Disease With Normal Body Mass Index: A Population-Based Study.

BACKGROUND & AIMS: The natural history of lean nonalcoholic fatty liver disease (NAFLD) is not well-understood. Consequently, patient counseling and disease management are limited. We aimed to compare the natural history of lean, overweight, and obese NAFLD in a U.S. population with long-term follow-up. METHODS: All adults diagnosed with NAFLD in Olmsted County, MN between 1996 and 2016 were identified, and all subsequent medical events were ascertained using a medical record linkage system. Subjects were divided on the basis of body mass index (BMI) at NAFLD diagnosis into 3 groups: normal, overweight, and obese. The probability to develop cirrhosis, decompensation, malignancies, cardiovascular events, or death among the 3 groups was estimated by using the Aalen-Johansen method, treating death as a competing risk. The impact of BMI categories on these outcomes was explored by using Cox proportional hazards regression analysis. RESULTS: A total of 4834 NAFLD individuals were identified: 414 normal BMI, 1189 overweight, and 3231 obese. Normal BMI NAFLD individuals were characterized by a higher proportion of women (66% vs 47%) and lower prevalence of metabolic comorbidities than the other 2 groups. In reference to obese, those with normal BMI NAFLD had a nonsignificant trend toward lower risk of cirrhosis (hazard ratio [HR], 0.33, 95% confidence interval [CI], 0.1-1.05). There were no significant differences in the risk of decompensation (HR, 0.79; 95% CI, 0.11-5.79), cardiovascular events (HR, 1.05; 95% CI, 0.73-1.51), or malignancy (HR, 0.87; 95% CI, 0.51-1.48). Compared with obese, normal BMI NAFLD had higher risk of all-cause mortality (HR, 1.96; 95% CI, 1.52-2.51). CONCLUSIONS: NAFLD with normal BMI is associated with a healthier metabolic profile and possibly a lower risk of liver disease progression but similar risk of cardiovascular disease and malignancy than obese NAFLD.

Liver stiffness measurement by magnetic resonance elastography is not affected by hepatic steatosis.

OBJECTIVES: To evaluate the relationship between biopsy-assessed hepatic steatosis, magnetic resonance imaging (MRI)-assessed proton density fat fraction (PDFF), and magnetic resonance elastography (MRE)-assessed liver stiffness measurement (LSM), in patients with or at risk for nonalcoholic fatty liver disease (NAFLD). METHODS: A retrospective study was performed, encompassing 256 patients who had a liver biopsy and MRI/MRE examination performed within 1 year. Clinical and laboratory data were retrieved from the electronic medical record. Hepatic steatosis and fibrosis were assessed by histopathological grading/staging. First, we analyzed the diagnostic performance of PDFF for distinguishing hepatic steatosis with the receiver operating characteristic analyses. Second, variables influencing LSM were screened with univariant analyses, then identified with multivariable linear regression. Finally, the potential relationship between PDFF and LSM was assessed with linear regression after adjustment for other influencing factors, in patients with diagnosed steatosis (PDFF ≥ 5%). RESULTS: The diagnostic accuracy of PDFF in distinguishing steatosis grades (S0-3) was above 0.82. No significant difference in LSM was found between patients with S1, S2, and S3 steatosis and between all steatosis grades after patients were grouped according to fibrosis stage. No statistically significant relationship was found between the LSM and PDFF (estimate = - 0.02, p = 0.065) after adjustment for fibrosis stage and age in patients with diagnosed steatosis (PDFF ≥ 5%). CONCLUSIONS: In patients with NAFLD, the severity of hepatic steatosis has no significant influence on the liver stiffness measurement with magnetic resonance elastography. KEY POINTS: • The MRI-based proton density fat fraction provides a quantitative assessment of hepatic steatosis with high accuracy. • No significant effect of hepatic steatosis on MRE-based liver stiffness measurement was found in patients with S1, S2, and S3 steatosis and between all steatosis grades after patients were grouped according to fibrosis stage. • After adjusting for fibrosis stage and age, there was no statistically significant relationship between liver stiffness and proton density fat fraction in patients with hepatic steatosis (p = 0.065).

Automated Analysis of Multiparametric Magnetic Resonance Imaging/Magnetic Resonance Elastography Exams for Prediction of Nonalcoholic Steatohepatitis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) affects 25% of the global population. The standard of diagnosis, biopsy, is invasive and affected by sampling error and inter-reader variability. We hypothesized that widely available rapid MRI techniques could be used to predict nonalcoholic steatohepatitis (NASH) noninvasively by measuring liver stiffness, with magnetic resonance elastography (MRE), and liver fat, with chemical shift-encoded (CSE) MRI. Besides, we validate an automated image analysis technique to maximize the utility of these methods. PURPOSE: To implement and test an automated system for analyzing CSE-MRI and MRE data coupled with model-based prediction of NASH. STUDY TYPE: Prospective. SUBJECTS: Eighty-three patients with suspected NAFLD. FIELD STRENGTH/SEQUENCE: A 1.5 T using a flow-compensated motion-encoded gradient echo MRE sequence and a multiecho CSE-MRI sequence. ASSESSMENTS: The MRE and CSE-MRI data were analyzed by two readers (5+ and 1 years of experience) and an automated algorithm. A logistic regression model to predict pathology-diagnosed NASH was trained based on stiffness and proton density fat fraction, and the area under the receiver operating characteristic curve (AUROC) was calculated using 10-fold cross validation for models based on both automated and manual measurements. A separate model was trained to predict the NASH severity score (NAS). STATISTICAL TESTS: Pearson's correlation, Bland-Altman, AUROC, C-statistic. RESULTS: The agreement between automated measurements and the more experienced reader (R2  = 0.87 for stiffness and R2  = 0.99 for proton density fat fraction [PDFF]) was slightly better than the agreement between readers (R2  = 0.85 and 0.98). The model for predicting biopsy-diagnosed NASH had an AUROC of 0.87. The NAS-prediction model had a C-statistic of 0.85. DATA CONCLUSION: We demonstrated a workflow that used a limited MRI acquisition protocol and fully automated analysis to predict NASH with high accuracy. These methods show promise to provide a reliable noninvasive alternative to biopsy for NASH-screening in populations with NAFLD. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

BALAD and BALAD-2 predict survival of hepatocellular carcinoma patients: a North American cohort study.

BACKGROUND: The BALAD score and BALAD-2 class derived from bilirubin, albumin, AFP, AFP-L3, and des-gamma-carboxyprothrombin (DCP) are effective in predicting mortality in HCC, but have not been validated in North America. METHODS: 148 HCC patients from 2000 to 2015 who had all five biomarkers tested at diagnosis were included. Hazard ratios (HR) were calculated. RESULTS: 75 patients died during a median follow-up of 21.9 months. 1-and 3-year survival rates were 70.8% and 47.6%. 114 (77%) had cirrhosis. The HR (95%CI) for death were 1.24 (0.42-3.67), 1.79 (0.61-5.26), 2.83 (0.95-8.38), and 7.19 (2.26-22.91) for BALAD scores 1, 2, 3, and 4 vs. BALAD 0. The HR (95%CI) for death were 1.25 (0.65-2.40), 1.75 (0.94-3.23), and 6.20 (3.29-11.68) for BALAD-2 classes 2, 3, and 4 vs. BALAD-2 class 1. A multivariate model incorporating maximal tumor diameter, tumor number, neutrophil-lymphocyte ratio, and BALAD had HR of 1.43 (1.14-1.81) per increase of 1 BALAD score. A similar model with BALAD-2 had HR of 1.50 (1.18-1.90) per increase of 1 BALAD-2 class. CONCLUSION: BALAD models at diagnosis can predict the survival of HCC patients in North America. AFP, AFP-L3, and DCP reflect tumor progression and metastasis of HCC and distinguish the BALAD model from other predictive models.

Predicting future rates of tau accumulation on PET.

Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer's clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer's disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.

Lymphocyte to monocyte ratio-based nomogram for predicting outcomes of hepatocellular carcinoma treated with sorafenib.

BACKGROUND: The ability of the pretreatment lymphocyte to monocyte ratio (LMR) to predict outcomes of patients with hepatocellular carcinoma (HCC) receiving sorafenib is not conclusively determined. METHODS: We retrospectively studied patients treated with sorafenib for HCC in two tertiary referral centres in Asia and North America. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Predictive factors for the outcomes were determined by Cox proportional hazards models. A risk assessment tool was developed. RESULTS: Compared to the North America cohort, the Asia cohort was more heavily pretreated (72.1% vs. 35.2%; p < 0.001), had higher hepatitis B virus infection (87.6% vs. 5.6%; p < 0.001), and more distant metastases (83.2% vs. 25.4%; p < 0.001). Lower monocyte count in the Asia cohort (median 462.7 vs. 600.0/µL; p = 0.023) resulted in a higher LMR (median 2.6 vs. 1.8; p < 0.001). High LMR was associated with a significantly higher OS [hazard ratio (HR) 0.88; 95% confidence interval (CI) 0.81‒0.97; p = 0.007]. This was confirmed in a sensitivity analysis including patients treated in Asia only (HR 0.89; 95% CI 0.81‒0.97; p = 0.010). An OS nomogram was constructed with the following variables selected in the multivariate Cox model: LMR, treatment location, previous treatment, performance status, alpha-fetoprotein, lymph node metastasis, and Child‒Pugh score. The concordance score was 0.71 (95% CI, 0.67‒0.75). LMR did not predict PFS. CONCLUSION: LMR measured before sorafenib administration predicts OS in advanced HCC patients. Our OS nomogram, incorporating LMR, can be offered to clinicians to improve their ability to assess prognosis, strengthen the prognosis-based decision-making, and inform patients in the clinic.

Effect of Statins on the Risk of Extrahepatic Cholangiocarcinoma.

BACKGROUND AND AIMS: Statins have been proven to be cytotoxic to human cholangiocarcinoma cells by inhibiting cell division and inducing apoptosis. We aimed to determine the effect of statin use on the risk of cancer development and survival in patients with extrahepatic cholangiocarcinoma (ECC), including perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). APPROACH AND RESULTS: A total of 394 patients with ECC and hyperlipidemia who received care at Mayo Clinic Rochester between 2005 and 2015 were matched by age, sex, race, ethnicity, and residency to 788 controls with hyperlipidemia. Clinical and outcome data were abstracted. The odds ratios (ORs) for risk and hazard ratios for outcomes were calculated. The mean age and standard deviation (SD) for cases and controls was 65.6 years (13.8). The number of statin users in cases and controls was 73 (19%) and 403 (51%), respectively. Hepatitis C virus infection (OR, 15.84; 95% confidence interval [CI], 4.06-61.87; P < 0.001) was the most significant risk factor for pCCA followed by inflammatory bowel disease and cirrhosis, whereas other liver disease, including biliary stone disease (OR, 4.06; CI, 2.24-7.36; P < 0.001), was the only significant risk factor for dCCA. Statin use was associated with significantly reduced risk for all ECC (OR, 0.22; CI, 0.16-0.29) as well as for the subtypes pCCA (OR, 0.3; CI, 0.21-0.41) and dCCA (OR, 0.06; CI, 0.03-0.14), all P < 0.0001. Moderate-intensity dosage was found to decrease the risk of ECC (OR, 0.48; CI, 0.34-0.67; P < 0.001). Comparing statin ever users to nonusers, patients with dCCA who used statins had significantly overall better survival (hazard ratio = 0.53; CI, 0.29-0.97; P = 0.04). CONCLUSIONS: This case-control study suggests that statins decrease the risk of ECC and may improve survival in patients with dCCA. Additional validation studies are warranted.

Multiparametric Magnetic Resonance Elastography Improves the Detection of NASH Regression Following Bariatric Surgery.

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.

The Role of Three-Dimensional Magnetic Resonance Elastography in the Diagnosis of Nonalcoholic Steatohepatitis in Obese Patients Undergoing Bariatric Surgery.

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.

The bivariate distribution of amyloid-ß and tau: relationship with established neurocognitive clinical syndromes.

Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-ß and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A+T-), or high amyloid and high tau (A+T+). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A+T- (28%), and A+T+ (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A+T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A+T+ quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes.

The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - A longitudinal cohort study.

BACKGROUND & AIMS: Cancer is a major cause of death in patients with non-alcoholic fatty liver disease (NAFLD). Obesity is a risk factor for cancers; however, the role of NAFLD in this association is unknown. We investigated the effect of NAFLD versus obesity on incident cancers. METHODS: We identified all incident cases of NAFLD in a US population between 1997-2016. Individuals with NAFLD were matched by age and sex to referent individuals from the same population (1:3) on the index diagnosis date. We ascertained the incidence of cancer after index date until death, loss to follow-up or study end. NAFLD and cancer were defined using a code-based algorithm with high validity and tested by medical record review. The association between NAFLD or obesity and cancer risk was examined using Poisson regression. RESULTS: A total of 4,722 individuals with NAFLD (median age 54, 46% male) and 14,441 age- and sex-matched referent individuals were followed for a median of 8 (range 1-21) years, during which 2,224 incident cancers occurred. NAFLD was associated with 90% higher risk of malignancy: incidence rate ratio (IRR) = 1.9 (95% CI 1.3-2.7). The highest risk increase was noted in liver cancer, IRR = 2.8 (95% CI 1.6-5.1), followed by uterine IRR = 2.3 (95% CI 1.4-4.1), stomach IRR = 2.3 (95% CI 1.3-4.1), pancreas IRR = 2.0 (95% CI 1.2-3.3) and colon cancer IRR = 1.8 (95% CI 1.1-2.8). In reference to non-obese controls, NAFLD was associated with a higher risk of incident cancers (IRR = 2.0, 95% CI 1.5-2.9), while obesity alone was not (IRR = 1.0, 95% CI 0.8-1.4). CONCLUSIONS: NAFLD was associated with increased cancer risk, particularity of gastrointestinal types. In the absence of NAFLD, the association between obesity and cancer risk is small, suggesting that NAFLD may be a mediator of the obesity-cancer association. LAY SUMMARY: We studied the incidence of malignancies in a community cohort of adults with non-alcoholic fatty liver disease (NAFLD) in reference to age- and sex-matched adults without NAFLD. After 21 years of longitudinal follow-up, NAFLD was associated with a nearly 2-fold increase in the risk of developing cancers, predominantly of the liver, gastrointestinal tract and uterus. The association with increased cancer risk was stronger in NAFLD than obesity.

Polyclonal serum free light chain elevation is associated with increased risk of monoclonal gammopathies.

Monoclonal gammopathies (MG) constitute a spectrum of disorders starting from a monoclonal gammopathy of undetermined significance (MGUS) to active disease requiring therapy such as multiple myeloma. MG are characterized by proliferation of clonal plasma cells (PC) secreting a monoclonal protein either as intact immunoglobulin or free kappa or lambda free light chains (FLC). We hypothesized that a polyclonal elevation of serum FLC may indicate an inflammatory state that precedes development of MG. We studied 15,630 individuals from Olmsted county, who did not have MGUS based on baseline screening studies. At a median follow-up of 18.1 years, 264 patients had developed a clonal PC disorder; 252 with MGUS, 1 with SMM, 8 with MM, and 3 with amyloidosis, translating to an annual incidence of development of a MG of 0.1%. We examined the baseline polyclonal ΣFLC (kappa + lambda FLC) from the initial screening and grouped them into deciles. The highest decile group had a 2.6-fold (95% CI; 1.8, 3.7) increase in the risk of developing a MG, P < 0.001. We demonstrate for the first time, the increased risk of developing MG in patients with elevated serum FLC, suggesting that an underlying inflammatory state may play an etiologic role.

Prediction of nonalcoholic fatty liver disease (NAFLD) activity score (NAS) with multiparametric hepatic magnetic resonance imaging and elastography.

OBJECTIVES: To investigate the use of MR elastography (MRE)-derived mechanical properties (shear stiffness (|G*|) and loss modulus (G″)) and MRI-derived fat fraction (FF) to predict the nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in a NAFLD mouse model. METHODS: Eighty-nine male mice were studied, including 64 training and 25 independent testing animals. An MRI/MRE exam and histologic evaluation were performed. Pairwise, nonparametric comparisons and multivariate analyses were used to evaluate the relationships between the three imaging parameters (FF, |G*|, and G″) and histologic features. A virtual NAS score (vNAS) was generated by combining three imaging parameters with an ordinal logistic model (OLM) and a generalized linear model (GLM). The prediction accuracy was evaluated by ROC analyses. RESULTS: The combination of FF, |G*|, and G″ predicted NAS > 1 with excellent accuracy in both training and testing sets (AUROC > 0.84). OLM and GLM predictive models misclassified 3/54 and 6/54 mice in the training, and 1/25 and 1/25 in the testing cohort respectively, in distinguishing between "not-NASH" and "definite-NASH." "Borderline-NASH" prediction was poorer in the training set, and no borderline-NASH mice were available in the testing set. CONCLUSION: This preliminary study shows that multiparametric MRI/MRE can be used to accurately predict the NAS score in a NAFLD animal model, representing a promising alternative to liver biopsy for assessing NASH severity and treatment response. KEY POINTS: • MRE-derived liver stiffness and loss modulus and MRI-assessed fat fraction can be used to predict NAFLD activity score (NAS) in our preclinical mouse model (AUROC > 0.84 for all NAS levels greater than 1). • The overall agreement between the histological-determined NASH diagnosis and the imaging-predicted NASH diagnosis is 80-92%. • The multiparametric hepatic MRI/MRE has great potential for noninvasively assessing liver disease severity and treatment efficacy.

Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015.

OBJECTIVE: To determine the incidence of immunoglobulin light chain amyloidosis (AL amyloidosis) in a strictly defined geographic area from 1990 through 2015. PATIENTS AND METHODS: We searched a computerized database for the records of all Olmsted County, Minnesota, residents with a diagnosis of AL amyloidosis from January 1, 1990, through December 31, 2015. In addition, records of all residents with a mention of amyloidosis were obtained from the Rochester Epidemiology Project, which contains the medical records of Mayo Clinic and Olmsted Medical Group. The diagnosis of AL amyloidosis was determined by mass spectrometry, immunohistochemical analysis, or positive Congo red staining. RESULTS: Thirty-five patients were identified as having AL amyloidosis. The median age at diagnosis was 76 years (range, 38-90 years), with men accounting for 54%. The incidence rate of AL amyloidosis from 1990 through 2015 adjusted for age and sex was 1.2 per 100,000 person-years (95% CI, 0.8-1.6 per 100,000 person-years). Rates were similar across the decades 1990-1999, 2000-2009, and 2010-2015 at 1.1, 0.9, and 1.6 per 100,000 person-years, respectively, with no suggestion of an increasing rate during the 26 years. There was a trend toward an increasing incidence over time from 1950 through 2015 in Olmsted County, but it was not significant (P=.15). Applying the rate of 1.2 per 100,000 person-years to the US population of 321 million in 2015, one would expect 3852 new cases of AL amyloidosis in the United States each year. CONCLUSION: The incidence of AL amyloidosis in Olmsted County has not changed significantly in the past 66 years.