Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Limited access to liver transplantation and TIPS despite high mortality, healthcare resource use and costs of cirrhosis in Germany.

BACKGROUND AND AIMS: Data on number of patients with cirrhosis in Germany are limited. We therefore aimed to estimate prevalence, comorbidities, mortality, utilization of healthcare resources and costs of patients with cirrhosis and incidence of decompensation of cirrhosis in Germany. METHODS: This longitudinal observational study was based on an anonymized representative claims database including 4.9 million persons insured by a statutory health insurance (SHI) between 2015-2020. Patients with decompensated and compensated cirrhosis were selected via diagnostic ICD codes and followed for 2 years. RESULTS: Prevalence of cirrhosis in 2015 was 250/100 000, resulting in 201 747 (95% CI: 197 540-206 040) patients extrapolated to the German population. Out of all patients with compensated cirrhosis in 2015 who did not deceased, 16.0% developed a decompensation within 3 years. Overall, 978 patients (Ø-age: 68 years; 60% male) were included in the decompensated, and 5135 patients (Ø-age: 66 years; 59% male) in the compensated cirrhosis cohort. Patients with decompensated cirrhosis had a higher burden of comorbidities (Charlson Comorbidity Index 7.3 vs. 4.4) and 3 times higher costs per quarter (7172 € vs. 2213 €) than patients with compensated cirrhosis. 1-year mortality after decompensation was 51% compared to 8% in compensated cirrhosis. Of note, only few patients with decompensated cirrhosis received a liver transplantation or transjugular intrahepatic portosystemic shunts (TIPS) (1% and 5%). CONCLUSION: Patients with cirrhosis have a high healthcare burden in especially decompensated stage. Accordingly, 1-year mortality of decompensated cirrhosis in Germany is high. Despite high health resource utilization, only few patients have access to liver transplantation or TIPS.

The Cost of Diagnosing and Managing Non-alcoholic Steatohepatitis in Europe and the United States.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is acknowledged as a severe disease that is associated with a significant burden on patients, payers, and society. However, limited evidence exists on the cost associated with NASH across different countries. This analysis aims to describe the cost associated with the routine care of patients with NASH in France, Germany, and the United States. METHODS: Data was sourced from the Gesellschaft für Konsumforschung (now Ipsos) Disease Atlas Real- World Evidence program collected from July through November 2017 in France, Germany, and the United States. Country-level unit cost was estimated from national databases for diagnostic tests and procedures, prescription drugs, hospital stays, and outpatient visits in respective local currency based on 2017 values. These were combined to provide an estimate of the cost of management of confirmed NASH in this specific patient population and are presented as mean cost per patient per year for each country in local currency and as USD adjusted for purchasing power parity for comparison. RESULTS: Annual mean ± standard deviation cost of non-alcoholic steatohepatitis ranged from purchasing power parity USD 1,049±2,461 in Germany to USD 1,723±2,988 in the United States. In all markets, the predominant contributor to cost is healthcare resource use represented by hospitalisation and outpatient visits. CONCLUSIONS: This study reveals that costs associated with NASH treatment and management vary across the three countries studied, in part due to differences in healthcare systems but also due to different approaches in managing this disease. Our analysis represents the costs for a specific cohort of patients and further studies are warranted to better understand the progressive impact of NASH on healthcare systems and society.

Noncommunicable diseases, climate change and iniquities: What COVID-19 has taught us about syndemic.

BACKGROUND: COVID-19 is generating clinical challenges, lifestyle changes, economic consequences. The pandemic imposes to familiarize with concepts as prevention, vulnerability and resilience. METHODS: We analysed and reviewed the most relevant papers in the MEDLINE database on syndemic, noncommunicable diseases, pandemic, climate changes, pollution, resilience, vulnerability, health costs, COVID-19. RESULTS: We discuss that comprehensive strategies must face multifactorial consequences since the pandemic becomes syndemic due to interactions with noncommunicable diseases, climate changes and iniquities. The lockdown experience, on the other hand, demonstrates that it is rapidly possible to reverse epidemiologic trends and to reduce pollution. The worst outcome is evident in eight highly industrialized nations, where 12% of the world population experienced about one-third of all COVID-19-deaths worldwide. Thus, a great economic power has not been fully protective, and a change of policy is obviously needed to avoid irreversible consequences. CONCLUSIONS: We are accumulating unhealthy populations living in unhealthy environments and generating unhealthy offspring. The winning policy should tackle structural inequities through a syndemic approach, to protect vulnerable populations from present and future harms.

Assessing physician preferences on future therapeutic options and diagnostic practices in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: There is currently no data on physician preferences regarding future therapies for non-alcoholic steatohepatitis (NASH); this study explores these preferences and characteristics that are relevant to physician decision-making when choosing a potential therapy for a patient with NASH. The results were compared with those from a similar patient preference survey which was conducted in parallel. METHOD: Initial exploratory 30-minute telephone interviews were conducted to inform the design of a 15-minute quantitative online specialist physicians survey, containing direct questions and a preference survey. This was based on a best-worst scaling (BWS) experiment to assess the relative importance of different treatment characteristics (attributes), followed by several paired comparison questions to understand the preference for 5 hypothetical product profiles. RESULTS: The answers come from 121 physicians from Canada (n = 31), Germany (n = 30), the UK (n = 30) and the USA (n = 30). The primary driving element in NASH treatment decision-making was efficacy (49.23%), defined as "[hypothetical product] impact on liver status" and "[slowing of] progression to cirrhosis". Physicians reported the common use of non-invasive NASH diagnostic tests and 81% reported performing liver biopsy. In 57% of cases, physicians reported that "concerns related to the available diagnostic methods" limit the number of patients with biopsy-confirmed NASH. CONCLUSIONS: This first physician preference study reveals that efficacy will be the main driver for physicians in selecting future NASH drugs. The findings also confirm the widespread use of non-invasive diagnostic tests and the reluctance to perform confirmatory liver biopsy despite guideline recommendations, mainly due to limited therapeutic options and patient refusal. LAY SUMMARY: This study explores physician preferences in relation to future therapies for non-alcoholic steatohepatitis (NASH) and characteristics that are relevant to physician decision-making when choosing a potential therapy for a patient with NASH. The results of a short online survey completed by 121 specialist physicians determined that the primary factor that influences treatment decision-making is efficacy, and that a wide range of non-invasive techniques are used to diagnose NASH, while confirmatory liver biopsy is not performed by all physicians despite guideline recommendations.

Neuro-musculoskeletal flexible multibody simulation yields a framework for efficient bone failure risk assessment.

Fragility fractures are a major socioeconomic problem. A non-invasive, computationally-efficient method for the identification of fracture risk scenarios under the representation of neuro-musculoskeletal dynamics does not exist. We introduce a computational workflow that integrates modally-reduced, quantitative CT-based finite-element models into neuro-musculoskeletal flexible multibody simulation (NfMBS) for early bone fracture risk assessment. Our workflow quantifies the bone strength via the osteogenic stresses and strains that arise due to the physiological-like loading of the bone under the representation of patient-specific neuro-musculoskeletal dynamics. This allows for non-invasive, computationally-efficient dynamic analysis over the enormous parameter space of fracture risk scenarios, while requiring only sparse clinical data. Experimental validation on a fresh human femur specimen together with femur strength computations that were consistent with literature findings provide confidence in the workflow: The simulation of an entire squat took only 38 s CPU-time. Owing to the loss (16% cortical, 33% trabecular) of bone mineral density (BMD), the strain measure that is associated with bone fracture increased by 31.4%; and yielded an elevated risk of a femoral hip fracture. Our novel workflow could offer clinicians with decision-making guidance by enabling the first combined in-silico analysis tool using NfMBS and BMD measurements for optimized bone fracture risk assessment.

Non-invasive assessment of NAFLD as systemic disease-A machine learning perspective.

BACKGROUND & AIMS: Current non-invasive scores for the assessment of severity of non-alcoholic fatty liver disease (NAFLD) and identification of patients with non-alcoholic steatohepatitis (NASH) have insufficient performance to be included in clinical routine. In the current study, we developed a novel machine learning approach to overcome the caveats of existing approaches. METHODS: Non-invasive parameters were selected by an ensemble feature selection (EFS) from a retrospectively collected training cohort of 164 obese individuals (age: 43.5±10.3y; BMI: 54.1±10.1kg/m2) to develop a model able to predict the histological assessed NAFLD activity score (NAS). The model was evaluated in an independent validation cohort (122 patients, age: 45.2±11.75y, BMI: 50.8±8.61kg/m2). RESULTS: EFS identified age, γGT, HbA1c, adiponectin, and M30 as being highly associated with NAFLD. The model reached a Spearman correlation coefficient with the NAS of 0.46 in the training cohort and was able to differentiate between NAFL (NAS≤4) and NASH (NAS>4) with an AUC of 0.73. In the independent validation cohort, an AUC of 0.7 was achieved for this separation. We further analyzed the potential of the new model for disease monitoring in an obese cohort of 38 patients under lifestyle intervention for one year. While all patients lost weight under intervention, increasing scores were observed in 15 patients. Increasing scores were associated with significantly lower absolute weight loss, lower reduction of waist circumference and basal metabolic rate. CONCLUSIONS: A newly developed model (http://CHek.heiderlab.de) can predict presence or absence of NASH with reasonable performance. The new score could be used to detect NASH and monitor disease progression or therapy response to weight loss interventions.

Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. METHODS: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. RESULTS: If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population. CONCLUSIONS: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. LAY SUMMARY: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.

Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the model for end-stage liver disease era.

OBJECTIVES: To design a new score on risk assessment for orthotopic liver transplantation (OLT) based on both donor and recipient parameters. BACKGROUND: The balance of waiting list mortality and posttransplant outcome remains a difficult task in the era of the model for end-stage liver disease (MELD). METHODS: Using the United Network for Organ Sharing database, a risk analysis was performed in adult recipients of OLT in the United States of America between 2002 and 2010 (n = 37,255). Living donor-, partial-, or combined-, and donation after cardiac death liver transplants were excluded. Next, a risk score was calculated (balance of risk score, BAR score) on the basis of logistic regression factors, and validated using our own OLT database (n = 233). Finally, the new score was compared with other prediction systems including donor risk index, survival outcome following liver transplantation, donor-age combined with MELD, and MELD score alone. RESULTS: Six strongest predictors of posttransplant survival were identified: recipient MELD score, cold ischemia time, recipient age, donor age, previous OLT, and life support dependence prior to transplant. The new balance of risk score stratified recipients best in terms of patient survival in the United Network for Organ Sharing data, as in our European population. CONCLUSIONS: The BAR system provides a new, simple and reliable tool to detect unfavorable combinations of donor and recipient factors, and is readily available before decision making of accepting or not an organ for a specific recipient. This score may offer great potential for better justice and utility, as it revealed to be superior to recent developed other prediction scores.

The model for end-stage liver disease allocation system for liver transplantation saves lives, but increases morbidity and cost: a prospective outcome analysis.

We analyzed the first 100 patients who underwent liver transplantation by Model for End-Stage Liver Disease (MELD) allocation, and compared the outcome of patients on the waiting list and after orthotopic liver transplantation with the last 100 patients who underwent transplantation prior to the introduction of the MELD system in July 2007. MELD allocation resulted in decreased waiting list mortality (386 versus 242 deaths per 1000 patient-years, P < 0.0001) and the transplantation of sicker recipients (uncorrected median MELD score 13.5 versus 20, P = 0.003). Recipient posttransplant morbidity was significantly higher, mainly caused by increased percentage of renal failure requiring renal replacement therapy (13 versus 46%, P < 0.0001). However, kidney function recovered in most cases within 6 months after OLT. Hospital mortality remained similar in both groups (6% versus 9%). Patient 1-year survival was 91% versus 83% (pre-MELD versus MELD era, P = 0.2154), graft 1-year survival was 88% versus 78% (P = 0.1013), respectively. Costs accumulated were significantly higher after introduction of the MELD policy (US $81,967 versus US $127,453, a 55% increase, P = 0.02) with a strong correlation with the individual MELD score (P < 0.0001). The MELD system addresses the goal of fairness well. However, the postoperative course appears more difficult in the MELD era with increased financial burden, but reasonable patient and graft survival. This is the inevitable price to balance justice and utility in liver graft allocation.